Brain and Heart Crosstalk [1st ed.] 9789811524967, 9789811524974

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Physiology in Clinical Neurosciences Brain and Spinal Cord Crosstalks Hemanshu Prabhakar Series Editor

Hemanshu Prabhakar Indu Kapoor Editors

Brain and Heart Crosstalk

Physiology in Clinical Neurosciences – Brain and Spinal Cord Crosstalks Series Editor Hemanshu Prabhakar Department of Neuroanesthesiology and Critical Care All India Institute of Medical Sciences New Delhi, India

Central nervous system that includes brain and spinal cord has high metabolic demand. The physiology of the brain is such that it is easily affected by any altered physiology of other systems which in turn may compromise cerebral blood flow and oxygenation. Together the brain and spinal cord control our body systems to function automatically. While other systems of body controls individual functions, central nervous system at the same time does many different functions, especially, controlling the function of other systems. However, only little is known that central nervous system itself affects almost all the other systems of the body for example, cardiovascular, respiratory, renal, genitourinary, gastrointestinal, hematological etc. This interaction of brain and spinal cord with other systems makes it important for us to understand how any kind of injury to the central nervous system may at times, produce complications in remote organs or systems of the body. It is these lesser known crosstalks between acutely or chronically affected brain and spinal cord and other systems of the body that is discussed in this book series. Each system would be considered in a separate book. More information about this series at http://www.springer.com/series/16228

Hemanshu Prabhakar  •  Indu Kapoor Editors

Brain and Heart Crosstalk

Editors Hemanshu Prabhakar Neuroanaesthesiology and Critical Care All India Institute of Medical Sciences New Delhi, India

Indu Kapoor Neuroanaesthesiology and Critical Care All India Institute of Medical Sciences New Delhi, India

ISSN 2524-8294     ISSN 2524-8308 (electronic) Physiology in Clinical Neurosciences – Brain and Spinal Cord Crosstalks ISBN 978-981-15-2496-7    ISBN 978-981-15-2497-4 (eBook) https://doi.org/10.1007/978-981-15-2497-4 © Springer Nature Singapore Pte Ltd. 2020 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Singapore Pte Ltd. The registered company address is: 152 Beach Road, #21-01/04 Gateway East, Singapore 189721, Singapore

To our parents and our families, with whom lies our “heart,” and without whom our “brains” fail to function! Hemanshu Prabhakar Indu Kapoor

Preface

Central nervous system that includes the brain and spinal cord has high metabolic demand. The physiology of the brain is such that it is easily affected by any altered physiology of other systems which in turn may compromise cerebral blood flow and oxygenation. Together the brain and spinal cord control our body systems to function automatically. While other systems of body controls individual functions, central nervous system at the same time does many different functions, especially, controlling the function of other systems. This interaction of the brain with other systems makes it important for us to understand how any kind of injury to the brain may at times produce complications in remote organs or systems of the body such as the heart. The nervous system is integrator of afferent information and modulates the efferent (neuro-humoral) mechanisms of homeostasis. The cardiovascular system performs a vegetative function and is central to homeostasis. It is teleological as well as natural for cardiovascular responses to be in consonance with ongoing function of other organ systems of the body, for example, feeding, thermoregulation, reproduction, and muscle activity. It is therefore logical that neural control of cardiovascular system must interact with neural control of other organ systems like motor activity, reproduction, gastro-intestinal tract, thermoregulation, and so and so forth. It is these lesser known cross talks between acutely or chronically affected the brain and the heart that is discussed in this book. We are ever grateful to the contributors who believed in the proposed format of the work. We are sure the readers would be benefited by the insights of the renowned experts. The purpose of this volume will be truly accomplished if we are able to improve the clinical conditions of our patients by providing better care. New Delhi, India  Hemanshu Prabhakar New Delhi, India   Indu Kapoor

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Acknowledgement

We wish to acknowledge the support of the administration of the All India Institute of Medical Sciences (AIIMS), New Delhi, in allowing us to conduct this academic task. We thank our team for their unconditional support and tireless efforts in helping us fulfill our dreams—Charu Mahajan, Vasudha Singhal, and Nidhi Gupta. We thank the faculty and staff of the Department of Neuroanaesthesiology and Critical Care, AIIMS, New Delhi, for their support. Special thanks are due to the team of Springer—Naren Aggarwal, Gaurav Singh, Jagjeet Kaur, and Suraj Kumar. Hemanshu Prabhakar Indu Kapoor

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Contents

1 Neurophysiology of Heart ������������������������������������������������������������������������    1 Ashok Kumar Jaryal, Akanksha Singh, and Kishore Kumar Deepak 2 Physiology of Cardiovascular System������������������������������������������������������   35 Ashok Kumar Jaryal, Akanksha Singh, and Kishore Kumar Deepak 3 The Brain–Heart Crosstalk����������������������������������������������������������������������  103 Anna Teresa Mazzeo, Valentina Tardivo, Simone Cappio Borlino, and Diego Garbossa

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About the Editors

Hemanshu Prabhakar, MBBS, MD, PhD  is currently working as a Professor in the Department of Neuroanaesthesiology and Critical Care at All India Institute of Medical Sciences, New Delhi. He has research experience spanning over 20 years and is a member of numerous national and international societies. His extensive research in the field of neuroanesthesia and critical care has been published in various national and international journals. Dr. Prabhakar is an eminent author and written several books. He received the AIIMS Excellence Award 2012 for his contributions to academia. He was featured in the Limca Book of Records 2019. Indu Kapoor  holds an MBBS from the Lady Hardinge Medical College and an MD in Anesthesiology from University College of Medical Sciences, Delhi, and is currently an Associate Professor in the Department of Neuroanaesthesiology and Critical Care. She has published more than 75 research papers in national and international journals and contributed numerous book chapters. She also received the prestigious Dr. TN. JHA Memorial award from the Indian Society of Anaesthesiologists and the Smt. Chandra and Sh. Narayan Wadhwani memorial award. She has edited three books related to neuroanesthesia, neurotrauma, and geriatric neuroanesthesia. She is also a reviewer for national as well as international journals.

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Chapter 1

Neurophysiology of Heart Ashok Kumar Jaryal, Akanksha Singh, and Kishore Kumar Deepak

Contents 1.1  B  asic Architecture of Cardiac Control 1.2  Neural Substrate for Control of Heart 1.2.1  C1 Neurons of Ventrolateral Medulla (VLM) 1.2.2  Nucleus Ambiguus (NA) 1.2.3  Nucleus Tractus Solitarius (NTS) 1.3  Innervation of the Human Heart 1.3.1  Afferents from the Heart 1.3.2  Efferents to the Heart 1.3.3  Cardiac Plexus 1.3.4  Intrinsic Cardiac Nervous System 1.4  Effect of Sympathetic and Parasympathetic Drive on Heart 1.4.1  Laterality in the Autonomic Control of the Heart 1.4.2  Reciprocal Antagonism 1.4.3  Synergistic Co-activation 1.4.4  Sequential Activation 1.4.5  Context Specific Co-activation 1.5  Neural Organization for Cardiovascular Control References

   3    4    5    8    9    11    13    15    16    17    18    19    19    20    21    21    21    25

Heart begins to beat before we are born and occupies a central position both physiologically and philosophically in emotional travails of our lives. This chapter focuses on the neural substrate and the mechanisms that control functioning of the heart at rest and modulate it with changing physiological demands and behaviour states. Maintenance of continuous and adequate blood supply to each and every cell is prerequisite for survival of a multicellular organism. The success of multicellularity is dependent upon existence of such a mechanism for transport of the nutrients and other solutes from one part of the body to the other. On an evolutionary timescale, the circulatory system evolved along with the digestive system and early neural structures in invertebrates and as such predates the evolution of respiratory and excretory system. The cardiovascular system and A. K. Jaryal (*) · A. Singh · K. K. Deepak Department of Physiology, All India Institute of Medical Sciences, New Delhi, India e-mail: [email protected] © Springer Nature Singapore Pte Ltd. 2020 H. Prabhakar, I. Kapoor (eds.), Brain and Heart Crosstalk, Physiology in Clinical Neurosciences – Brain and Spinal Cord Crosstalks, https://doi.org/10.1007/978-981-15-2497-4_1

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neuro-humoral mechanisms integrate independent functioning organ systems into one whole organism. While the nervous and hormonal systems directly control the functioning of independent units, the cardiovascular system provides a means of transport of nutrients, hormones and other solutes to nervous system and in the process also gets controlled by the nervous and hormonal systems. The mammalian cardiovascular system consists of a low-volume high-pressure systemic circulation in series with a low-pressure pulmonary circulation (Fig. 1.1a). The left ventricle of the heart provides the kinetic and potential energy for the movement of blood through the systemic vasculature. Blood is dispersed to all the parts of the body through the branches of aorta. The large arteries provide the elastic recoil to maintain a central head pressure during diastole. These large arteries branch into smaller muscular arteries that provide resistance to the flow resulting in fall of the intravascular pressure to lower values before the blood reaches capillary network of tissues where the exchange occurs. The arterial network converts the intermittent a Pulmonary Circulation Systemic Circulation Left Chambers Right Chambers

b Lung Heart Resistance arteries

Venules Splanchnic circulation

Capacitance veins

Elastic Conduit Arteries

neural circulation

Renal circulation

Cutaneous circulation Musculo-skeletal circulation

Fig. 1.1 (a) Systemic and pulmonary circulation in series. (b) Architecture of cardiovascular system

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p­ ulsatile aortic flow into a continuous flow at the level of capillaries. The blood returns to the heart through low-pressure high-compliance venous system to right atrium and is further pumped into the pulmonary system for exchange of gases (Fig. 1.1b). From hydrodynamic perspective, the circulatory beds of all organ systems are arranged parallel to each other, and the driving force (central blood pressure in large conduit arteries) for circulation is provided by the heart. Such an organization has inherent vulnerability based on Ohm’s law that any change in the dimensions of vasculature (i.e. resistance and thereby flow) in any of organ system will affect the central blood pressure, thereby affecting the flow of blood to the other organ-­ systems. Similarly, a change in central blood pressure will affect the flow to all organ systems. The neural control of cardiovascular system provides mechanism to minimize the effect of changes in the circulatory bed of one organ system onto flow characteristic of the other while also maintaining the head pressure in central large arteries. Each organ system has independent local mechanisms (metabolic and myogenic) to modulate regional blood flow according to its metabolic needs. The neural control provides a mechanism to modulate the vasculature of the organ-system in context of the whole organism. The neural control of cardiovascular system is also intimately intertwined to all other neural regulatory mechanisms because each neural action leads to changes in metabolism in the target organ systems, thereby necessitating changes in blood supply to organ systems. The cardiovascular control systems modulate the function of heart and vasculature in response to afferent information from peripheral receptors and feed-forward signals from higher centres. This chapter focuses on the neural substrates, their connectivity as well as afferent and efferent pathways that modulate the functioning of the heart. The regulation of vascular bed is beyond the scope of this chapter. Reference to it will be incidental and for the sake of completion of the present discussion.

1.1  Basic Architecture of Cardiac Control Figure 1.2 shows the basic architecture of cardiac  control. The core regulatory nuclei are located in the medulla, viz. ventrolateral medulla (VLM) and nucleus ambiguus (NA) and nucleus tractus solitarius (NTS). The efferent cardiac control is mediated by VLM and NA motor outputs. The VLM provides the efferent sympathetic drive not only to the heart, but also to vasculature, renal system, adrenal glands and other sympathetically innervated structures. VLM consists of an excitatory pressor region and an inhibitory depressor region. The VLM projects to the preganglionic sympathetic neurons in the intermediolateral (IML) horn of thoracic spinal cord. The preganglionic sympathetic fibres arise from the neurons of the IML and synapse in ganglia of sympathetic chains. The post-ganglionic fibres from the ganglia then innervate heart and vasculature. The preganglionic and post-ganglionic sympathetic fibres to adrenal medulla provide additional humoral mechanism to control the heart and vasculature. NA provides the efferent parasympathetic drive to the heart. NA itself contains the

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A. K. Jaryal et al. Supra-bulbar Nuclei

Ponto-medullary nuclei

NTS

VLM

Medullary NA Core Nuclei vagus

V, VII, IX, X

Heart, Vasculature, Lungs, Nasopharynx

Muscle afferents

Heart

Sympathetic nerves

Vestibular apparatus

Vasculature

Fig. 1.2  Basic architecture of cardiac control

preganglionic parasympathetic fibres which reach the heart via the vagal branches to synapse in ganglia located in the heart. The post-ganglionic parasympathetic fibres then innervate the heart. The NTS receives sensory inputs from the heart, vasculature and respiratory system via the glossopharyngeal and vagus nerves. The sensory afferents from nasal tract (trigeminal), pain pathways, muscles and vestibular apparatus also reach the core cardiovascular nuclei in the medulla. The sympathetic and parasympathetic fibres in the cardiac nerves of the sympathetic chain and vagus, respectively, form a plexus at the base of heart around aorta and pulmonary artery. Over last few decades, a distinct organized intrinsic cardiac nervous system (ICNS) in the heart has been identified in many species including humans. ICNS has been shown to play an important role in the integration of afferent information from the heart with sympathetic and parasympathetic efferent signals from the core medullary network for beat-to-beat regulation of the heart [1]. The medullary cardiovascular  nuclei are under direct or indirect modulatory influence of multiple nuclei of the brainstem and the neural centres in cortical and sub-cortical regions of brain. These connections serve to integrate the cardiovascular neural network with other neural networks. Each of the components of the neural substrate for control of the heart will be elaborated in detail in the following sections.

1.2  Neural Substrate for Control of Heart The core neural substrate for cardiac control  consists of ventrolateral medulla (VLM), nucleus ambiguus (NA) and nucleus tractus solitarius (NTS) in the medulla. The VLM and NA provide efferent projections for sympathetic and parasympathetic control of cardiovascular system, respectively. The NTS receives afferent projections from heart and vasculature and provides a mechanism of integration of these

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with afferent projections from respiratory and gastrointestinal system. These nuclei are located in close proximity of the medullary respiratory core group of neurons. Figure  1.3a, b shows the location of these nuclei in the brainstem. The VLM is located anterior while the NA is located posterior to the medullary respiratory column.

1.2.1  C1 Neurons of Ventrolateral Medulla (VLM) Traditionally two regions are identified rostro-caudally in VLM that take part in cardiac control, viz. the excitatory rostral ventrolateral medulla (RVLM) and inhibitory caudal ventrolateral medulla (CVLM) [2–4] (Fig.  1.4). These regions were labelled as pressor and depressor regions in the early literature. The neurons of VLM that are involved in the cardiovascular control  are identified by presence of enzymes for synthesis of epinephrine and are called C1 neurons [5]. Based on neural properties, three separate regions have been identified in VLM zone, namely rostral ventrolateral medulla (RVLM), intermediate ventrolateral medulla (IVLM) and caudal ventrolateral medulla (CVLM) [6]. The neurons of the RVLM and IVLM are C1 type (synthesizing epinephrine) while that of CVLM are A1 type (synthesizing norepinephrine). The IVLM contains interneurons projecting to RVLM and is functionally similar to CVLM mentioned in the earlier literature. Keeping in line with this  nomenclature, the term IVLM will be used instead of CVLM to refer to the vasodepressor region of the VLM referred in the earlier literature. The neurons of the IVLM sends excitatory as well as inhibitory projections to RVLM [7, 8]. The C1 neurons of VLM have a diffuse viscerotopic organization with distinct output to cardiovascular system, renal system, adrenal glands and other targets of sympathetic response [9, 10]. The C1 neurons are critical to varied aspect of autonomic and endocrine responses to hypoxia, hypotension, nociception, hypoglycaemia, hypothermia and hyperthermia [6]. Given the scope of this chapter, only the aspects related to the control of heart will be further elaborated upon in this section. The neurons of RVLM are intrinsically active [11–14]. The level of tonic activity of the RVLM determines the central sympathetic drive to the preganglionic sympathetic fibre and the sympathetic tone is a sum-total of the modulatory influences on the intrinsic pacemaker property of the RVLM neurons [15]. C1 neurons of the IVLM are either activated or inhibited by the baroreflex input from NTS. The NTS-activated neurons of IVLM inhibit the neurons in the RVLM to decrease the sympathetic drive to preganglionic sympathetic fibres of the thoracic spinal cord. The NTS-inhibited neurons of IVLM project to paraventricular nucleus (PVN) of the hypothalamus. Connections of VLM: The neural activity of RVLM determines the final sympathetic drive, and therefore, the RVLM integrates  inputs from a large number of regions of the brain (Fig. 1.4). The RVLM receives cardiorespiratory afferent information from the NTS mainly through the IVLM [5, 16–19]. IVLM is driven by both baroreceptor-dependent and -independent inputs. Additional direct pathways from

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a NTS DMV NA

VLM

b

PB

Pons

V

VII

DMV NTS

NA

VRC

VLM

NRA

Medulla

PICO

RTN

Rostral Ventral Fig. 1.3 (a) Location of core medullary cardiovascular nuclei in cross-section. (b) Location of core medullary cardiovascular nuclei in sagittal section. Abbreviations: NTS nucleus tractus solitarius, DMV dorsal nucleus of vagus, NA nucleus ambiguus, VLM ventrolateral medulla, PB parabrachial nucleus, RTN retrotrapezoid nucleus, VRC ventral respiratory column, NRA nucleus retroambigualis, PICO post-inhibitory complex, VII facial nerve nucleus 

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Th

mPFC

Amyg

HypTh

LC pMn

PPt Rp

Vn

Spinal Cord Spinal Cord Fig. 1.4  Connections of rostral (RVLM) and caudal (CVLM) ventrolateral medulla. Abbreviations: NTS nucleus tractus solitarius, DMV dorsal nucleus of vagus, NA nucleus ambiguus, VLM ventrolateral medulla, PB parabrachial nucleus, RTN retrotrapezoid nucleus, VRC ventral respiratory column, NRA nucleus retroambigualis, PICO post-inhibitory complex, VII facial nerve nucleus

NTS to RVLM also exist [5, 6, 15, 20, 21]. The RVLM is also reciprocally and antagonistically connected with NA.  The somatic, renal and visceral inputs also reach RVLM [22, 23]. The RVLM also receives direct glutamatergic as well as GABAergic inputs from the vestibular nuclear complex and indirect inputs via NTS for feed-forward changes in the cardiovascular system during postural changes [24, 25]. Excitatory acetylcholinergic projections comes from pediculopontine tegmentum [26] and lateral parabrachial nucleus [27–29] for the modulation of heart and vasculature during locomotion and arousal. The inputs from raphe to RVLM are serotonergic and inhibitory [30]. The pontine reticular formation provides tonic excitatory input to RVLM [31–33] along with excitatory input from cuneiform nuclei [34–36]. The neurons of the RVLM receives projections from the various nuclei of the ventral respiratory column (including Botzinger, pre-Botzinger, post-inspiratory complex) for the modulation of heart rate with respiration [12, 37]. The RVLM also

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receives projections from multiple nuclei of hypothalamus such as posterior hypothalamus [38], paraventicular nucleus [39–42], lateral hypothalamus and perifornical hypothalamus [43]. The dorsomedial hypothalamus activates RVLM directly and indirectly through the PVN [44–46]. The RVLM also receives projections from amygdala [47, 48] and ventrolateral periaqeductal grey region [49, 50]. A direct inhibitory input also comes from medial prefrontal cortex to RVLM [34, 51]. The efferent projections from RVLM and IVLM are both myelinated and unmyelinated. It is proposed that myelinated projections set the baseline sympathetic tone while the unmyelinated projections modulate vascular bed-specific responses [52]. The C1 neurons of RVLM mainly project to the preganglionic sympathetic fibres in the thoracic spinal cord through monosynaptic and disynaptic pathways [53–59]. Even though the main projections to spinal cord are excitatory glutamatergic, inhibitory GABAergic projections have also been demonstrated [60]. The projection to PVN of hypothalamus mainly comes from IVLM with minor contribution from RVLM [61]. The PVN controls endocrine expression of vasopressin, CRH/ACTH/ corticosterone response to hypotension and dehydration [6, 62, 63]. The RVLM also projects to locus ceruleus, A1 and A2 noradrenergic group of neurons [64, 65], basal forebrain and respiratory neurons [66]. The RVLM of the two sides also communicate with each other [67]. These bulbar and suprabulbar connections of RVLM modulate the sympathetic tone as part of an integrated response to stress, hypoglycaemia, hypovolemia, pain and emotions, temperature, osmolarity and during motivated behaviour such as locomotion, flight or fight response and exercise.

1.2.2  Nucleus Ambiguus (NA) The nucleus ambiguus is an elongated region in the ventrolateral medulla located dorsal to ventral respiratory group of neurons (Fig. 1.3). The cardiovascular system-related neurons are located in the ventral and caudal part of the nucleus ambiguus [68]. The cardiac vagal motor neurons arising in the NA are first directed dorsomedially towards the dorsal motor nucleus of vagus (DMV) and then accompany the DMV fibres to traverse in the vagus. The preganglionic parasympathetic vagal fibres to heart mainly originate in the nucleus ambiguus with minor contributions from the dorsal nucleus of vagus and an intermediate zone between the two [69–73]. It has been suggested that NA provides myelinated fibres while DMV provides non-myelinated efferent fibres of the vagus [74]. The cardiac vagal fibres of NA show respiratory modulation while that of the intermediate zone and the DMV do not [74, 75]. The NA projections show more divergence as compared to the DMV fibres to the heart and both synapse on distinct cells in cardiac ganglia. Data across species suggest that with evolution, the role of DMV neurons in control of heart has diminished. A diffuse segregation of neurons having predominant chronotropic or dromotropic effects on heart has also been demonstrated in the NA [76, 77]. The neurons of the NA are more active during the

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post-inspiratory phase of respiration, similar to the activity of post-inspiratory complex (PICO) of core respiratory network. Unlike the neurons of RVLM, the neurons of nucleus ambiguus do not show inherent pacemaker properties [78]. The baseline firing of NA neurons is the sum-­ total of excitatory and inhibitory projections from brainstem nuclei as well as suprabulbar regions of the brain. The major drivers of the vagal tone are projections from the NTS and modulatory projections from pre-Botzinger, RVLM, IVLM, and central projections from the hypothalamic paraventricular and arcuate nuclei. Connections of NA: The main excitatory inputs to NA comes specifically from the medial subnucleus of the NTS [69, 79–82] (Fig. 1.5). The inhibitory GABAergic projections to NA come from NTS, pre-Botzinger, RVLM, IVLM, paraventricular nucleus, arcuate nucleus and parabrachial complex [80, 83–89]. The inhibitory GABAergic and glycinergic inputs to NA are modulated by adrenergic, dopaminergic, serotoninergic and acetlycholinergic inputs [45, 90–97]. The acetylcholinergic projections from the nucleus of superior laryngeal nerve are facilitatory to GABAergic inputs [98, 99]. The activity of the NA is increased by local acidosis, bradykinin, ATP, αMSH and serotonin to decrease the heart rate [92, 100–103]. The catecholaminergic inputs either increase (via α2, D2, β1 receptors) or decrease (via α1) the heart rate by differential modulation of the inhibitory GABAergic or glycinergic inputs over the NA [93–96]. NA also sends reciprocal projections to RVLM and IVLM [83] as well as to the contralateral NA. Effects of anaesthetics over NA: General anaesthetics including isoflurane and propofol facilitate the GABAergic inhibition of the NA leading to vagal withdrawal resulting in increase in heart rate [104, 105]. Fentanyl on the other hand inhibits the GABAergic inputs leading to a decrease in heart rate [104]. The opioids (morphine) inhibit the glycinergic inputs leading to a decrease in heart rate [106]. Ketamine blocks respiratory sinus arrhythmia by interfering with respiratory inputs on the NA [107].

1.2.3  Nucleus Tractus Solitarius (NTS) Nucleus tractus solitarius is a large collection of sensory neurons on the dorsal aspect of the medulla. This region receives afferent fibres carrying sensory information from the cardiovascular, respiratory and gastrointestinal organs through vagus, glossopharyngeal and trigeminal nerves [108, 109]. The vagal and glossopharyngeal cardiovascular afferents terminate ipsilaterally in the caudal 2/3rd and rostral 2/3rd of the NTS, respectively, with the middle 1/3rd having terminals from both. The NTS also receives collaterals from the ascending muscle afferents and trigeminal nerve [110, 111]. NTS of the two sides communicate with each other through the commissural part. The NTS integrates chemoreceptor inputs with baroreceptor [112, 113]. Connections of NTS: The NTS receives projections from many brainstem nuclei such as vestibular nucleus, Kolliker-Fuse nucleus and periaqueductal grey for ­modulation of afferent signals (Fig. 1.6). NTS also receives direct input from the posterior part of lateral hypothalamus that causes depressor effects and a region medial to

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Fig. 1.5  Connections of nucleus ambiguus. Abbreviations: HypTh hypothalamus, V motor nucleus of trigeminal nerve, PB parabrachial nucleus, VII nucleus of facial nerve, PICO post-inhibitory complex, RTN retrotrapezoid nucleus, LC locus ceruleus, pMn paramedian nucleus, VLM ventrolateral medulla, VRC ventral respiratory column, NA nucleus ambiguus, NRA nucleus retroambigualis, DMV dorsal nucleus of vagus, NTS nucleus tractus solitarius

the lateral hypothalamus that results in pressor effects. These hypothalamic regions also project to directly sympathetic preganglionic neurons of intermediolateral horn of thoracic cord. The NTS sends efferent projections to various nuclei of the brainstem including a prominent projection to ipsilateral nucleus ambiguus, IVLM, nuclei of the core respiratory group (pre-Botzinger, retrotrapezoid, lateral parafacial respiratory group), parabrachial nucleus, medial accessory olive, Kolliker-Fuse nucleus, lateral periaqueducal grey, lateral cuneate nucleus and paramedian reticular formation [79, 114]. The NTS sends efferent projections to ventral posteromedial nucleus of the thalamus [115]. The projections from NTS also reach various nuclei of hypothalamus (arcuate, paraventricular), regions of basal forebrain, amygdala, prefrontal cortex, orbitofrontal cortex and sensory cortex. The descending efferent projections are mainly to phrenic nucleus for inspiration and to intermediolateral horn of the spinal cord for cardiovascular control [114].

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Fig. 1.6  Connections of nucleus tractus solitarius. Abbreviations: mPFC medial prefrontal cortex, OrF orbitofrontal cortex, Amyg amygdala, PAG periaqueductal grey, PB parabrachial nucleus, VLM ventrolateral medulla, NTS nucleus tractus solitarius

1.3  Innervation of the Human Heart There is renewed interest in the detailed neuroanatomical innervation of the heart due to recent advancements in surgical approaches to treat arrhythmias by selective lesioning of the neural pathways to heart. It is important to note that the gross anatomical features of the cardiac sympathetic and parasympathetic nerves in humans is considerably different from mammals, and even from higher primates. In recent decades, two systematic descriptions of the cardiac nerves and plexuses have been reported [116, 117]. The following description is based on these two reports. Note that cardiac nerves have been named differently in the two reports. Figure 1.7 nomenclature is based on a report by Kawashima and Table 1.1 gives corresponding names used by Janes et al. The sympathetic nerves for human heart originate mainly from middle cervical and stellate ganglia. The nerves originating from the superior cervical ganglion have

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A. K. Jaryal et al. Lt Vagus

Cervical Chain

Rt Vagus

Rt Stellate Ganglia

MCN VCN

MCN

RcL

VCN

ICN

ICN

Thoracic Chain

SCB ICB TCB

Fig. 1.7  Sympathetic and vagal innervation of the heart. Abbreviations: VCN vertebral cardiac nerve, MCN middle cardiac nerve, ICN inferior cardiac nerve, SCB superior cardiac branch, ICB inferior cardiac branch, TCB thoracic cardiac branch, RcL recurrent laryngeal Table 1.1  Human cardiac innervation (corresponding nomenclature from two reports) Kawashima [117] Sympathetic cardiac nerves 1. Superior cardiac nerve 2. Middle cardiac nerve 3. Vertebral cardiac nerve 4. Inferior cardiac nerve 5. Thoracic nerves Vagal branches 1. Superior cardiac branch 2. Inferior cardiac branch 3. Thoracic cardiac branches

Janes et al. [116] 1. – 2. Dorsal lateral cardiopulmonary nerve 3. Dorsal medal cardiopulmonary nerve 4. Stellate cardiopulmonary nerve 5. – 1. – 2. Recurrent cardiopulmonary branch 3. Craniovagal cardiopulmonary branch Caudovagal cardiopulmonary branches

also been postulated to reach the heart [117]. The middle cervical ganglia represents a series of swellings on the lower half of the cervical sympathetic chain. The ­lower-­most ganglion (also referred to as the vertebral ganglion) of the middle cervical group communicates with stellate ganglion via the ansa subclavius. The stellate ganglion is located at the level of seventh cervical vertebra and the head of first and second thoracic rib with considerable inter-individual variations. The stellate ganglion represents the upper most part of the thoracic sympathetic chain. The middle cervical and the stellate ganglion have many communicating branches with the spinal nerves  with wide inter-individual variability. Middle cervical ganglion may communicate with C3 to C7 spinal nerves, similarly stellate may communicate with C5 to T3 spinal nerves.

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The middle cervical ganglia give rise to two nerves on each side, namely middle cardiac nerve (dorsal medial cardiopulmonary nerve, Table 1.1) and vertebral cardiac nerve (dorsal lateral cardiopulmonary nerve). On the left side an additional nerve named left ventral cardiopulmonary nerve has been reported by Janes et al. but not by Kawashima, and this nerve descends anterior to the aortic arch unlike other nerves that descend behind the aortic arch. Stellate ganglion gives rise to inferior cardiac nerve (stellate cardiopulmonary nerve). Macroscopically, even though nerves from the thoracic sympathetic chain do not appear to be innervating the heart, it has been reported that neural fibres of right thoracic nerves may reach heart after ascending around the thoracic aorta while the left thoracic nerve reaches directly [117]. Vagus gives multiple cardiac branches at different levels for innervation of heart, and these have been named as superior cardiac, inferior cardiac (recurrent cardiopulmonary nerve) and thoracic cardiac branches (craniovagal and caudovagal). Ten percent of fibres in cervical vagus are cardiac of which  20%  are efferent and 80%  are afferent [118].

1.3.1  Afferents from the Heart The receptors in the heart sense mechanical distortion and chemical milieu of the myocardium. These receptors are sensory endings of the nerve fibres that are located all over the heart but with greater density in the sino-atrial zone, dorsal aspect of both the atria, endocardium of the ventricular outflow tract and the papillary muscles. Many of the receptors show spontaneous firing during normal cardiac contraction while many remain silent. The silent receptors are activated by larger mechanical changes perhaps due to higher thresholds for activation [119]. Three classes of receptors are identified in heart, namely mechanoreceptors, chemoreceptors and multimodal receptors [1]. The mechanoreceptors primarily respond to mechanical distortion, the chemoreceptors are activated primarily by changes in the chemical milieu, and multi-modal receptors respond to both the mechanical and chemical stimulation [120]. Most of the afferent neurites tends to be multimodal [120, 121]. The differentiation between the mechanoreceptor and chemoreceptor is also based on the phasic nature of the firing in the mechanoreceptor afferents and the tonic nature of the firing in chemoreceptor afferents. Both mechanoreceptor and chemoreceptors can be activated by alternative stimulus but with higher threshold. Mechanoreceptors: The mechanoreceptors are mainly located in the superior vena cava, sino-atrial nodal region, upper right atrium, dorsal left atrium and ventricles [122–129]. The receptors in the ascending aorta as well in the arch of aorta are considered as part of the network and are included in the following description. These receptors respond to mechanical distortion in their receptive fields. Their activity is phase locked to different phases of the cardiac cycle which is dependent upon the location of receptor in different chambers of the heart. Table 1.2 provides

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Table 1.2  Properties of the mechanoreceptors in atria, ventricle and aorta Property Receptive field Phase locking

Fibre type Fibre class Fibre diameter Duration of action potential Maximum firing frequency Conduction velocity Location

Ventricle receptor 0.5–2.5 mm

Aortic receptors 1 mm

Atrial receptor Right: 0.5–1 mm Left: 3–5 mm Type A: ‘a’ and ‘c’ wave of venous pulse Type B: ‘v’ wave of venous pulse Myelinated Type A/Class III

Systole (isovolumetric contraction phase) Systole and diastole

Systole

Myelinated Type C

1.2–2.9 μm 0.65–1.1 ms

0.4–0.55 μm 0.25–0.55 ms

Myelinated Type A/Class III 0.9–1.3 μm 0.7–1.3 ms

260 Hz

200 Hz

200 Hz

12–27 m/s 8–29 m/s Adventitia

8–19 m/s

26–43 m/s

Endocardium, myocardium and epicardium

Adventitia

comparative properties of mechanoreceptors of atria, ventricle and aorta based on various reports. Chemoreceptors: The chemoreceptors are activated by changes in the chemical milieu, and their firing patterns do not show phase locking with cardiac cycle. They are mainly located in the epicardium of the ventricles [120, 130]. The chemoreceptors respond by an increase or decrease in the firing rates. They respond to adenosine, angiotensin II, bradykinin, CGRP, histamine, acid solution, H2O2, substance P, norepinephrine, VIP amongst other compounds [120]. Chemoreceptors are also located in the ascending aorta and aortic arch. Receptors in atria: Two types of atrial receptors, type A and type B, are identified on the basis of their firing pattern in relation to the cardiac cycle. Both type A and B are distributed in both the atria. Type A receptors are activated with atrial contraction [123, 129] while type B receptors are generally silent during the atrial systole but increase their firing with increased filling of atria [125, 131]. Type B atrial mechanoreceptors show phase locking with respiration, and these effects are produced due to the effect of respiration on venous return and consequent filling of atria. Type B atrial receptors show a linear relationship of firing rate with atrial distention and are slow adapting in nature with a time constant of about 2 s. The receptive fields of receptors of right atria are more punctate than that of left atria. Type B receptor senses the atrial volume while type A senses the atrial tension (pressure). The afferent fibres are carried in both sympathetic and vagus nerves [129]. Type B receptors are insensitive to anoxia and ischemia but respond to a variety of chemicals [131].

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Receptors in ventricles: The receptors in both left and right ventricles are located mainly in the endocardium, around the anterior papillary muscles, epicardium with sparse distribution in mid-myocardium. The myocardial and endocardial receptors are primarily mechanoreceptors and sense the ventricular pressure while those in epicardium are primarily chemoreceptors. However, a large number of these r­eceptors are multimodal. The ventricular septal receptors are activated by changes in either ventricle. Afferent pathways: The afferent activity from the atria and ventricles is carried in sympathetic and parasympathetic afferents [119, 129, 132–137]. Left ventricle is more densely innervated as compared to the right. Cell bodies of afferent neurons are located in the ICNS [138, 139], intrathoracic extracardiac neural pool, sympathetic chain ganglia [135, 136, 140], nodose ganglia and dorsal root ganglia of C6– T6 [121, 141–143], where they synapse with second-order neurons for central transmission or initiation of the short, medium and long loop reflexes [1]. The nodose ganglia carry the parasympathetic afferents while the dorsal root ganglia carry the sympathetic afferents. The dorsal root ganglia mainly receive the multimodal afferents and show a faster firing rate (10 Hz). The nodose ganglia receive more afferents from the mechanoreceptors (90%) as compared to chemoreceptors, from the atria as well as ventricles [142] and have very slow firing rate (0.1 Hz). Posterior-inferior ventricular pericardium and posterior septal ventricular endocardium send afferents to nodose, while the anterior-superior part of the heart sends afferents via sympathetic nerves to dorsal root ganglia [144]. The posterior atrial wall, parietal pericardium, atrioventricular valve and aortic valve send afferents via sympathetic nerves to dorsal root ganglia [145, 146]. In the spinal cord, the afferent sympathetic fibres terminate in the lamina I, V, VII and X of the spinal cord [143, 146]. This afferent information is then relaye to the nucleus tractus solitarius for integration with other afferent information from vascular, respiratory and gastrointestinal system. The afferent information also converges with spinothalamic tract and ascends to ventroposterolateral nucleus of thalamus and then to somatosensory cortex [143, 147, 148].

1.3.2  Efferents to the Heart The cell bodies of the preganglionic sympathetic fibres to the heart are present in zona intermedia of the spinal cord from T1 to T6. The main contribution comes from T1 to T3 with maximum from T3 [149–152]. The sympathetic preganglionic neuronal bodies are organized in distinct groups in each spinal segment as shown Fig. 1.8 [143, 149, 153]. The preganglionic neurons are located in zone 1 (nucleus intermediolateral thoracolumbaris pars principalis), zone 3 (nucleus intercalatus spinalis) and zone 4 (nucleus interacalatus spinalis pars paraependymatus) in the spinal cord. The supraspinal fibres from the RVLM and other nuclei mainly end in the zone 2 (nucleus intermediolateral thoracolumbaris pars funicularis), while the visceral and somatosensory afferents end in zone 5 (intermediomedial) and other zones. Even though there is some evidence that within the thoracic spinal cord, the

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4

3 1 2 5

Fig. 1.8  Organization of preganglionic sympathetic neurons in the spinal cord. Zone 1, nucleus intermediolateral thoracolumbaris pars principalis; Zone 2, nucleus intermediolateral thoracolumbaris pars funicularis; Zone 3, nucleus intercalatus spinalis; Zone 4, nucleus intercalatus spinalis pars paraependymatis; Zone 5, nucleus intermediomedial

preganglionic fibres are arranged in target organ-specific columns, there is large overlap in their distribution [153]. Similarly, conclusive evidence regarding strict topographical innervation of the heart by different spinal segments is still elusive and unlikely to be the case. The preganglionic sympathetic efferent fibres leave the spinal cord in the ventral root at each level via the white rami communicantes. The fibres originating in the T1 directly reach the stellate ganglion (cervicothoracic ganglia), while those from T2 to T6 ascend in the sympathetic chain to reach the stellate and middle cervical ganglia. The postganglionic cardiac fibres originate primarily in stellate [154] and partially from middle cervical [155] and vertebral ganglion. There is no apparent topographical arrangement of sympathetic neurons in the ganglia [156]. The preganglionic parasympathetic fibres originate in the nucleus ambiguus, course in the vagus and reach the heart in the cardiac branches of vagus (see Sect. 1.2.2 for details). The postganglionic parasympathetic cell bodies are located in the intracardiac ganglia.

1.3.3  Cardiac Plexus The nerves from sympathetic chain and the branches of the vagus course towards the heart and mix with each other before reaching the hilum of the heart. Unlike dogs and other mammals, in humans vagus does not make direct connections with the stellate or middle cervical ganglion before reaching the heart [117, 157]. The right-sided vagal and sympathetic nerves course around the brachiocephalic artery to form right cardiac plexus while the left-sided vagal and sympathetic nerves course around arch of aorta to form left cardiac plexus. The right and left plexuses join to form dorsal and ventral plexuses in the mediastinum. The dorsal plexus is located dorsal to arch of aorta and pulmonary artery just anterior to trachea before its bifurca-

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tion. The ventral plexus is located anterior to aorta and pulmonary artery and is connected to the dorsal plexuses via connecting branches around the pulmonary artery. The dorsal plexus gives rise to many branches of which two are prominent: (1) left coronary cardiac nerve (mainly sympathetic) that courses around the coronaries and (2) left lateral cardiac nerve (mainly vagal) that courses anterior to left atrial appendage and left atrial vein to finally innervate left lateral ventricle. The ventral plexus gives rise to right coronary cardiac nerve that courses along the right coronary artery.

1.3.4  Intrinsic Cardiac Nervous System The intrinsic cardiac nervous system (ICNS) consists of a well-organized ganglionated network of neurons that are located in the heart. The ganglionated plexuses of ICNS are found in atria, atrioventricular groove, roots of great vessels, ventricles and interventricular sulci [158–160]. The ICNS has independent sensory and motor components to coordinate the activties of the different regions of the heart and is the final integratort of the local information with the systemic information from the higher level. The soma and nerve fibres are located in sub-epicardium as well as sub-endocardium in different mammals [161] including human neonates [162]. Initially these neurons were considered to be efferent sympathetic and parasympathetic fibres even though there were speculations regarding the possible sensory role of these fibres. These intracardiac neurons are organized within specific ganglionated plexuses that show considerable interconnections. Their intricate connectivity led to the speculation that ICNS may function similar to intrinsic neural networks of the intestine and that the final control of the pattern of cardiac rhythm may lie within the ICNS [163–165]. By late 1980s and early 1990s through physiological recordings in animals after chronic decentralization of ICNS, the sensory nature of these neurons was established [139, 166, 167]. Morphology of ICNS: The morphology of ICNS has been described in large number of species including dog [168], pig [169], sheep [170], rat [171], mouse [172], rabbit [173], guinea pig [174] and human [159, 175, 176]. In humans, about 14,000 neurons are estimated to be present in the ICNS. The neuron bodies are located primarily in the epicardium. The neurons are organized into ganglia in atria as well as ventricles that are interconnected with nerves forming loose plexuses. Different reports have grouped the  neurons of the ICNS into six [177, 178], ten [159] and seven plexuses [176]. The description by Worobiew and Pauza et al. is very similar and the following description is based on the report by Pauza et al. The epicardial ICNS is made up of seven ganglionated sub-plexuses. Each of them have a distinct ganglionated fields in the atria and ventricles. These are 1 . Left coronary subplexus 2. Right coronary subplexus 3. Ventral right atrial subplexus 4. Ventral left atrial subplexus 5. Left dorsal subplexus 6. Dorsal right atrial subplexus 7. Middle dorsal subplexus

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The left and the right coronary subplexuses are located in the roots of the aorta and the pulmonary trunk. The two subplexuses supply different region of the ventricles with the right coronary subplexus supplying the right ventricle while the left coronary subplexus supplying the left ventricle. The left ventricle receives additional innervation from the left dorsal subplexus. The right atrium, including the zone containing sino-atrial node, is innervated by two subplexuses, i.e. ventral right atrial and dorsal right atrial. The left atrium is innervated by three subplexuses, i.e. ventral left atrial, middle dorsal and left dorsal subplexuses. The functional importance of the ICNS is discussed in Sect. 1.5.

1.4  E  ffect of Sympathetic and Parasympathetic Drive on Heart Stimulation of the autonomic nerves affects heart rate, cardiac contractility, rate of conduction of cardiac impulse, excitability of the heart, coronary blood flow and release of atrial natriuretic peptide. In an experimental setup, the autonomic stimulation may produce all or few of the effects depending upon the location of stimulation, specific autonomic nerve that is stimulated, strength and pattern of stimulation amongst other aspects including species-specific differences. Therefore, considerable attention needs to be paid to the experimental design of the study before extrapolating the same to human subjects or making generalized conclusions. The earliest reports have mainly commented upon the effects of sympathetic and parasympathetic stimulation on heart rate  and strength of contraction [179, 180]. Later the effects on other aspects of myocardial functions were reported. In resting state in human, the vagal activity dominates such that heart rate is under vagal restraint and can be increased by vagal withdrawal. The resting efferent vagal activity occurs in-between the phrenic activity, i.e. during expiratory phase while the sympathetic activity coincides with phrenic activity [181]. Sympathetic stimulation: The stimulation of sympathetic efferents leads to an increase in heart rate (positive chronotropy), contractility (positive ionotropy), rate of conduction (positive dromotropy) and excitability (positive bathmotropy) as well as faster and better relaxation of cardiac muscle during diastole (positive lusitropy). On stimulation of the sympathetic nerves, the increase in heart rate (decrease in RR interval) begins to manifest in 2.5–8 s and reaches maximum in 7–12 s. On stoppage of stimulation, the heart rate returns to baseline value in about 15–63 s [182, 183]. The sympathetic efferents affect atria as well as ventricles. Parasympathetic stimulation: The stimulation of the parasympathetic efferents leads to a decrease in heart rate (negative chronotropy), contractility (negative ionotropy), rate of conduction (negative dromotropy) and excitability (negative bathmotropy) of the heart [184, 185]. The innervation and direct effects of vagal stimulation is restricted to atria in human [158, 186, 187]. The observed effects of decrease in ventricular contraction due to vagal stimulation are attributable to Bowditch effect, i.e. decrease in heart rate per se can decrease the contractility of the

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ventricles [188]. The increase in vagal activity or stimulation decreases the heart rate (increase in the RR interval) within the next beat, i.e. next beat is delayed. On stoppage of vagal stimulation, the heart rate returns to baseline value in 1–3 s [182]. Simultaneous sympathetic and parasympathetic stimulation: When sympathetic and parasympathetic efferents are stimulated simultaneously, a decrease in heart rate is observed, i.e. a vagal predominance is seen. However, when sympathetic stimulation is done before the vagal stimulation, then the effect of vagal stimulation is diminished. This is due to release of NPY by the sympathetic terminal that affects the release of acetylcholine by postganglionic fibres [189]. A prior vagal stimulation however does not affect the sympathetic responses. Even as vagal stimulation directly decreases heart rate by its direct action on the sino-atrial node, it also inhibits the ongoing sympathetic stimulation at presynaptic as well as postsynaptic levels [190]. The vagal inhibition of the sympathetic effects is quantitative. With large doses of adrenaline, vagal stimulation becomes ineffective [191].

1.4.1  Laterality in the Autonomic Control of the Heart While interpreting the results of experiments on the laterality of stimulation of autonomic nerves, caution must be paid to the species-specific differences in innervation, specific location at which the stimulation was done, the strength of the stimulation and individual variations even within the same species. In dogs, strong stimulation of the right vagus leads to immediate arrest of heart (0.4 s), and the heart rarely escapes from the inhibition at both the atrial and ventricular levels. The stimulation of the left vagus leads to a range of effects from decrease in heart rate along with delay in conduction as well as actual atrio-­ ventricular conduction blocks [192]. The sino-atrial node is under the control of right vagus while the atrio-ventricular node is under the control of both vagi with the left being more effective. The difference between right and left stellate ganglia stimulation seems to be quantitative rather than qualitative [183]. The left stellate ganglion stimulation leads to predominantly ionotropic effects (T1–T2) while the right stellate ganglion stimulation has predominantly chronotropic effects (T2–T3) [150]. The preganglionic fibres from the spinal cord innervates both sides of the heart [156]. More peripheral stimulation tends to have more discrete and qualitatively different effects [156].

1.4.2  Reciprocal Antagonism On the basis of opposite effects of sympathetic and parasympathetic stimulation as mentioned above, a simplistic description of them being reciprocally antagonistic took shape in the early twentieth century. However, later experimental studies

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also pointed to co-activation of both sympathetic and parasympathetic pathways in certain specific contexts [181]. Despite large amount of evidence of co-activation, reciprocal antagonism tends to be the prevailing notions amongst physiologists and physicians alike. The coordinated reciprocal antagonism, i.e. sympathetic in activation and parasympathetic activation, is observed during baroreflex activation. The increase in blood pressure is associated with simultaneous vagal activation and withdrawal of the sympathetic activity [181]. Similarly, non-hypotensive hypovolemia leads to an increase in heart rate by vagal withdrawal as well as sympathetic stimulation [193]. During the response to non-hypotensive hypovolemia, vagal withdrawal leads to an immediate but small increase in heart rate, while the sympathetic stimulation takes few seconds to become effective to bring out larger increase in the heart rate. Thus, the two mechanisms operate in a temporal manner wherein an early increase in heart rate is brought about by vagal withdrawal and later increase in magnitude of increase in the heart rate is done via sympathetic stimulation as also observed at the start of muscular exercise.

1.4.3  Synergistic Co-activation Many other reflexes and responses have been observed during which both the sympathetic and parasympathetic system are activated simultaneously. While it appears counter-intuitive on superficial analysis, the data suggests that simultaneous co-­ activation is indeed synergistic [181, 194]. The synergism becomes apparent when the details of differential intensities and time course of activation is taken into consideration. The sum effect on heart rate and its time course during co-activation is dependent upon relative intensities and sequence of activation of sympathetic and parasympathetic component. Co-activation leading to bradycardia: Diving and diving-like reflexes such as facial or nasopharyngeal reflexes lead to bradycardia and are associated with the co-activation of sympathetic and parasympathetic efferents [195]. Co-activation has also been observed in the activation of oculo-cardiac reflex reported during ophthalmic surgeries. Experimentally it can be induced in animals by corneal pressure or traction of extraocular muscles. The bradycardia in these reflexes leads to indirect decrease in the ventricular contractility (Bowditch phenomenon). A precipitous decrease in ventricular contraction is prevented by simultaneous sympathetic activation. This increase in sympathetic activity also leads to ventricular ectopics sometimes seen during diving reflex. Co-activation leading to tachycardia: Painful stimulus leads to co-activation of sympathetic and parasympathetic nerves manifesting as tachycardia [196]. Tachycardia is also produced with intense stimulation of peripheral chemoreflex. Thus, while sympathetic activation is necessary for increasing the cardiac function (cardiac output) by increase in heart rate, contractility and rate of conduction, the

1  Neurophysiology of Heart

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simultaneous parasympathetic activation may protect against excessive increase in heart rate which would otherwise compromise the ventricular filling time.

1.4.4  Sequential Activation The startle response is associated with initial vagally mediated bradycardia followed by sympathetically mediated tachycardia [197]. The initial bradycardia represents the alerting response wherein the animal gets oriented to startle stimulation. This may be associated with breath-holding. The later tachycardia response represents the anxiety, fight or flight response. The tachycardia response followed by bradycardia is also seen in the activation of peripheral chemoreflex (mild hypercapnia or mild hypoxia).

1.4.5  Context Specific Co-activation Defence response usually involves activation of the sympathetic system associated with an increase in heart rate. However, in certain contextual conditions, the animals show freezing response, wherein a co-activation of the vagal pathways leads to bradycardia on a background of heightened sympathetic drive [198, 199]. This freeze response or playing dead response may have survival advantage as many predators avoid a dead prey or may not be able to detect the presence of prey. A role of mesencephalic cuneiform nuclei in pain and freezing response related rise in blood pressure with decrease in heart rate has been proposed [36].

1.5  Neural Organization for Cardiovascular Control The concept of vasomotor area in the medulla was postulated in late nineteenth century. The first experimental data from a lesioning study led to the development of the model of two half-centres in medulla [2]. A vasomotor region on the ventral aspect of medulla was later  identified [200]. The interconnections between the afferent inputs from the spinal cord to NTS and from there to NA was suggested in late 1960s [79]. The current model of the cardiovascular regulation at the level of medulla is majorly based on research work done in 1970s and 1980s using anatomical, physiological and pharmacological methods [11, 18]. The connections between RVLM and spinal cord preganglionic sympathetic fibres were shown anatomically as well electrophysiologically [53, 55, 56]. The vagal preganglionic fibres were localized to NA [70, 201]. Connections between NTS and RVLM, NTS and NA were established [5]. NTS was established as the receiver of afferent information from the

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Fig. 1.9  Classic model and modified model of operation of core cardiovascular nuclei in medulla. Abbreviations: RVLM rostroventrolateral medulla, NTS nucleus tractus solitarius, IVLM intermediolateral medulla, NA nucleus ambiguus

Zs>D

Ͳ

/s>D

E

н

,ĞĂƌƚ

Ed^

н н

Ͳ

cardiovascular and respiratory system [202]. In last three decades, the tools of molecular biology and imaging have further advanced our knowledge [14, 37, 150]. The classical model is shown in Fig. 1.9. According to this model, the RVLM is intrinsically active and provides the tonic drive to sympathetic preganglionic ­neurons of the spinal cord to increase the heart rate and blood pressure. The increase in the blood pressure is sensed by the baroreceptors and afferents are sent to the NTS. The NTS activates the IVLM/CVLM which in turn inhibits the RVLM so that its tonic drive to sympathetic preganglionic neurons is kept under check. The NTS also sends an excitatory input to the NA to increase the vagal drive to heart. The NA itself does not have intrinsic activity and is dependent upon the synaptic projections from NTS. Recently, a modification of the classical circuit has been proposed on the basis of diffusion tensor imaging (dashed lines in Fig. 1.9), but it remains to be seen whether it stands the test of time [203]. Over the last three decades, accumulating data has expanded the classical model of cardiovascular control to include intrinsic cardiac nervous system (Sect. 1.3.4) and extracardiac intrathoracic ganglionic pool as additional sites for integration and control. The model in Fig. 1.10 describes the three-level hierarchical control of the cardiac function [1], from neural centres to heart. 1 . Level 1: Central medullary and spinal neurons 2. Level 2: Extracardiac intrathoracic neuronal pool 3. Level 3: Intrinsic cardiac nervous system (ICNS) The ICNS has independent integration abilities and continues to provide short loop reflexes even after the plexuses are surgically disconnected from central connections to spinal cord or medulla [139]. Even though each subplexus has distinct regional distribution, because of interconnectivity amongst them, activity in any of the subplexus can affect activity in regions of the heart that are not directly innervated by it [168, 204]. For example, even though the SA node is innervated by the ventral right atrial subplexus, the heart rate can be decreased by the stimulation of any of the plexuses [204]. The ICNS neurons respond to local mechanical distortion and changes in the chemical milieu and are additionally modulated by efferent stimulation of the stel-

1  Neurophysiology of Heart

23

Limbic system

Pre-Frontal Cortex

Motor Cortex

Sensory Cortex

Medullary-Pontine-Midbrain Nuclei

Level 1 Respiratory Renal Musculoskeletal Splanchnic

Level 2

Level 3

Cardiovascular Homeostatic Regulation (Negative Feedback) Cardiovascular Regulation with Motivated Behaviour (Feed Forward)

Fig. 1.10  Multi-level hierarchical control of the cardiovascular system in negative feedback and feed forward mode

late ganglia and cervical vagus nerves [166, 205]. The local circuit neurons are present in the ICNS as well as extracardiac intrathoracic ganglionic neural pool. These neurons do not transduce afferent information from the heart and also do not have any direct motor connections to the heart. Various populations of local circuit neurons have been recognized, namely afferent-related, efferent-related and integrative local circuit neurons [205]. Each level has independent ability to integrate afferent information and provide efferent output. While each level has independent operation, it can be modified with input from the other levels. The mechanosensitive and chemosensitive afferent information from the heart is relayed to each of the three level for processing and integration. These interactions lead to reflexes with short latency (at the level of ICNS), medium latency (at the level of the intrathoracic extracardiac neural pool) and long latency (at the level of medulla and spinal cord). The efferent component of the reflexes is relayed to the heart through sympathetic and parasympathetic pathways. The short latency (short loop) reflexes (20–40 ms) within ICNS provide within beat coordination of the activities of the different parts of the heart. Medium latency reflexes provide coordination over few beats and integrate inputs from the lungs and vessels being carried by afferent vagal and sympathetic fibres. The long latency

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reflexes coordinate the cardiac activity with the inputs from the baroreceptors, chemoreceptors and metaboreceptors for matching the cardiovascular function with the systemic parameters. The central control, i.e. medulla and spinal cord, receives inputs from the higher centres to match the overall functioning of the cardiovascular system with the behavioural state of the animal such as emotional responses, sleep– wake cycle and fight–flight response. A neural control mechanism is able to seamlessly manage the homeostatic needs with the motivated behaviours. The neural control of the cardiovascular system is federal in operation with relative independence to regional circulation and a centralized regulation of the blood pressure with veto-powers over regional circulation. The cerebral and renal circulation are given prioritized treatment under this arrangement. Thus, the control of cardiovascular system operates under two independent but interrelated modes, namely 1. Negative feedback mechanism: As a homeostatic process to maintain blood pressure irrespective of cause of the change. Baroreflex is an example of such a mode of operation. 2. Feedforward mechanism: As an adaptive process to make changes in cardiovascular control in consonance with ongoing interactions of the animal with the environment. Changes in blood pressure during emotions, motivated behaviour or exercise are examples of such modes of operation. At a very basic homeostatic level, the neural cardiovascular regulatory mechanisms maintain adequate blood pressure. Blood pressure is the regulated variable which acts as a surrogate for cardiac output. The blood pressure is regulated by modulation of the controlled variables, namely heart rate, contractility, vascular tone and diameter. Motivated behaviours such as fight or flight require an increase in blood pressure for maximizing flow to skeletal muscles and thus necessitating a mechanism to override homeostatic range. In these scenarios, the operating point of the baroreflex shifts to a higher level so that heart rate and blood can simultaneously increase without the activation of the baroreflex. The core medullary nuclei for the control of cardiovascular system are interconnected with each other, get continuous inputs from the peripheral afferents as well as descending signals from the cortical and sub-cortical centres for seamless operation in negative feedback and feedforward mode. Acknowledgements  The concepts and information presented in this chapter have been drawn from the research reports of hundreds of scientists from countless laboratories over last century, only a few of whom have been referred directly. We have made efforts to compile diverse and detailed data into simple unifying notions, to be able to visualize forest without losing sight of the trees.

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118. Agostoni E, Chinnok JE, De daly MB, Murray JG (1957) Functional and histological studies of the vagus nerve and its branches to the heart, lungs and abdominal viscera in the cat. J Physiol 135(1):182–205 119. Uchida Y, Murao S (1974) Excitation of afferent cardiac sympathetic nerve fibers during coronary occlusion. Am J Physiol 226(5):1094–1099 120. Thompson GW, Horackova M, Armour JA (2000) Chemotransduction properties of nodose ganglion cardiac afferent neurons in guinea pigs. Am J Physiol Regul Integr Comp Physiol 279(2):R433–R439 121. Huang MH, Horackova M, Negoescu RM, Wolf S, Armour JA (1996) Polysensory response characteristics of dorsal root ganglion neurones that may serve sensory functions during myocardial ischaemia. Cardiovasc Res 32(3):503–515 122. Whitteridge D (1948) Afferent nerve fibres from the heart and lungs in the cervical vagus. J Physiol 107(4):496–512 123. Neil E, Zotterman Y (1950) Cardiac vagal afferent fibers in the cat and the frog. Acta Physiol Scand 20(2–3):160–165 124. Dickinson CJ (1950) Afferent nerves from the heart region. J Physiol 111(3–4):399–407 125. Paintal AS (1953) Another atrial receptor. J Physiol 119(1):10P–11P 126. Coleridge JC, Hemingway A, Holmes RL, Linden RJ (1956) Atrial receptors in the dog. J Physiol 132(3):68–9P 127. Coleridge JC, Hemingway A, Holmes RL, Linden RJ (1957) The location of atrial receptors in the dog: a physiological and histological study. J Physiol 136(1):174–197 128. Coleridge HM, Coleridge JC (1980) Cardiovascular afferents involved in regulation of peripheral vessels. Annu Rev Physiol 42:413–427 129. Armour J (1973) Physiological behavior of thoracic cardiovascular receptors. Am J Physiol Content [Internet] 2251(1):177–185. Available from: http://www.physiology.org/ doi/10.1152/ajplegacy.1973.225.1.177 130. Coleridge HM, Coleridge JCG, Kidd C (1964) Cardiac receptors in the dog, with particular reference to two types of afferent ending in the ventricular wall. J Physiol [Internet] 174(3):323–339. Available from: http://doi.wiley.com/10.1113/jphysiol.1964.sp007490 131. Paintal AS (1973) Vagal sensory receptors and their reflex effects. Physiol Rev [Internet] 53(1):159–227. Available from: http://www.ncbi.nlm.nih.gov/pubmed/4568412 132. Malliani A, Parks M, Tuckett RP, Brown AM (1973) Reflex increases in heart rate elicited by stimulation of afferent cardiac sympathetic nerve fibers in the cat. Circ Res 32(1):9–14 133. Casati R, Lombardi F, Malliani A (1979) Afferent sympathetic unmyelinated fibres with left ventricular endings in cats. J Physiol 292:135–148 134. Barber MJ, Mueller TM, Davies BG, Zipes DP (1984) Phenol topically applied to canine left ventricular epicardium interrupts sympathetic but not vagal afferents. Circ Res 55(4):532–544 135. Armour JA (1986) Neuronal activity recorded extracellularly in chronically decentralized in situ canine middle cervical ganglia. Can J Physiol Pharmacol 64(7):1038–1046 136. Bosnjak ZJ, Kampine JP (1989) Cardiac sympathetic afferent cell bodies are located in the peripheral nervous system of the cat. Circ Res 64(3):554–562 137. Wang H-J, Rozanski GJ, Zucker IH (2017) Cardiac sympathetic afferent reflex control of cardiac function in normal and chronic heart failure states. J Physiol 595(8):2519–2534 138. Cheng Z, Powley TL, Schwaber JS, Doyle FJ III (1997) Vagal afferent innervation of the atria of the rat heart reconstructed with confocal microscopy. J Comp Neurol 381(1):1–17 139. Ardell JL, Butler CK, Smith FM, Hopkins DA, Armour JA (1991) Activity of in vivo atrial and ventricular neurons in chronically decentralized canine hearts. Am J Physiol [Internet] 260(3 Pt 2):H713–H721. Available from: http://www.ncbi.nlm.nih.gov/pubmed/2000967 140. Armour JA (1983) Synaptic transmission in the chronically decentralized middle cervical and stellate ganglia of the dog. Can J Physiol Pharmacol 61(10):1149–1155 141. Hopkins DA, Armour JA (1989) Ganglionic distribution of afferent neurons innervating the canine heart and cardiopulmonary nerves. J Auton Nerv Syst 26(3):213–222

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163. Irisawa H (1978) Comparative physiology of the cardiac pacemaker mechanism. Physiol Rev 58(2):461–498 164. Moravec M, Courtalon A, Moravec J (1986) Intrinsic neurosecretory neurons of the rat heart atrioventricular junction: possibility of local neuromuscular feed back loops. J Mol Cell Cardiol 18(4):357–367 165. Moravec M, Moravec J (1984) Intrinsic innervation of the atrioventricular junction of the rat heart. Am J Anat [Internet] 171(3):307–319. Available from: http://doi.wiley.com/10.1002/ aja.1001710307 166. Gagliardi M, Randall WC, Bieger D, Wurster RD, Hopkins DA, Armour JA (1988) Activity of in vivo canine cardiac plexus neurons. Am J Physiol 255(4 Pt 2):H789–H800 167. Armour JA, Hopkins DA (1990) Activity of in vivo canine ventricular neurons. Am J Physiol Circ Physiol [Internet] 258(2):H326–H336. Available from: http://www.physiology.org/ doi/10.1152/ajpheart.1990.258.2.H326 168. Yuan BX, Ardell JL, Hopkins DA, Losier AM, Armour JA (1994) Gross and microscopic anatomy of the canine intrinsic cardiac nervous system. Anat Rec 239(1):75–87 169. Arora RC, Waldmann M, Hopkins DA, Armour JA (2003) Porcine intrinsic cardiac ganglia. Anat Rec A Discov Mol Cell Evol Biol 271(1):249–258 170. Saburkina I, Rysevaite K, Pauziene N, Mischke K, Schauerte P, Jalife J et al (2010) Epicardial neural ganglionated plexus of ovine heart: anatomic basis for experimental cardiac electrophysiology and nerve protective cardiac surgery. Hear Rhythm 7(7):942–950 171. de Souza RR, Gama EF, de Carvalho CA, Liberti EA (1996) Quantitative study and architecture of nerves and ganglia of the rat heart. Acta Anat (Basel) 156(1):53–60 172. Rysevaite K, Saburkina I, Pauziene N, Noujaim SF, Jalife J, Pauza DH (2011) Morphologic pattern of the intrinsic ganglionated nerve plexus in mouse heart. Hear Rhythm 8(3):448–454 173. Pauziene N, Alaburda P, Rysevaite-Kyguoliene K, Pauza AG, Inokaitis H, Masaityte A et al (2016) Innervation of the rabbit cardiac ventricles. J Anat 228(1):26–46 174. Leger J, Croll RP, Smith FM (1999) Regional distribution and extrinsic innervation of intrinsic cardiac neurons in the guinea pig. J Comp Neurol 407(3):303–317 175. Armour JA (2008) Potential clinical relevance of the “little brain” on the mammalian heart. Exp Physiol 93(2):165–176 176. Pauza DH, Skripka V, Pauziene N, Stropus R (2000) Morphology, distribution, and variability of the epicardiac neural ganglionated subplexuses in the human heart. Anat Rec 259(4):353–382 177. Worobiew W (1925) Die Nerven des menschlichen und tierischen Herzens. Dtsch Med Wochenschr 36:1509–1535 178. Worobiew W (1928) Plica nervina atrii sinistri. Z Anat Entwicklungs 26:509–516 179. Roy CS, Adami JG (1892) Contributions to the physiology and pathology of the mammalian heart. BMJ [Internet] 1(1626):428–430. Available from: http://www.bmj.com/cgi/ doi/10.1136/bmj.1.1626.428 180. Bayliss WM, Starling EH (1892) On some points in the innervation of the mammalian heart. J Physiol [Internet] 13(5):407–418. Available from: http://doi.wiley.com/10.1113/ jphysiol.1892.sp000416 181. Kollai M, Koizumi K (1979) Reciprocal and non-reciprocal action of the vagal and sympathetic nerves innervating the heart. J Auton Nerv Syst 1(1):33–52 182. Samaan A (1935) The antagonistic cardiac nerves and heart rate. J Physiol [Internet] 83(3):332–340. Available from: http://www.ncbi.nlm.nih.gov/pubmed/16994634 183. Anzola J, Rushmer RF (1956) Cardiac responses to sympathetic stimulation. Circ Res 4(3):302–307 184. Hoffman BF, Siebens AA, Brooks CM (1952) Effect of vagal stimulation on cardiac excitability. Am J Physiol 169(2):377–383 185. Reeves TJ, Hefner LL (1961) The effect of vagal stimulation on ventricular contractility. Trans Assoc Am Phys 74:260–270

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Chapter 2

Physiology of Cardiovascular System Ashok Kumar Jaryal, Akanksha Singh, and Kishore Kumar Deepak

Contents 2.1  H  aemodynamics of Cardiovascular System 2.1.1  Evolutionary Origins of Design of Cardiovascular System 2.1.2  Pressures and Volumes of Heart and Vasculature 2.1.3  Heart as a Pump 2.1.4  Vasculature 2.1.5  Cardiac Output 2.1.6  Assessment of Pump Function of Heart 2.2  Cardiac Reflexes 2.2.1  Afferent and Efferent Pathways for Cardiac Reflexes 2.2.2  Reflexes Originating from the Baroreceptors 2.2.3  Reflexes from Atria 2.2.4  Reflexes from the Left Ventricle 2.2.5  Cardiac Sympathetic Afferent Reflex 2.2.6  Vestibulosympathetic Reflex 2.2.7  Somatosympathetic Reflex 2.2.8  Cardiorespiratory Coupling 2.2.9  Regulation of Circulatory Blood Volume References

                                                     

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2.1  Haemodynamics of Cardiovascular System The primary purpose of the cardiovascular system is to transport the available blood through pulmonary and systemic circulation fast enough to allow transfer of oxygen from the lungs to the tissues at a rate that is commensurate with the oxygen demand of the body. At the lungs levels, the thinner the alveolar capillaries membrane, the better is the loading of the oxygen onto the erythrocytes. At the cardiovascular level, movement of blood with optimal oxygen carrying capacity is required to carry the oxygen from the lungs to the tissues. At the tissue level, the transfer of the oxygen from blood in the capillaries to the cells occurs by diffusion and therefore smaller A. K. Jaryal (*) · A. Singh · K. K. Deepak Department of Physiology, All India Institute of Medical Sciences, New Delhi, India e-mail: [email protected] © Springer Nature Singapore Pte Ltd. 2020 H. Prabhakar, I. Kapoor (eds.), Brain and Heart Crosstalk, Physiology in Clinical Neurosciences – Brain and Spinal Cord Crosstalks, https://doi.org/10.1007/978-981-15-2497-4_2

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the distance between capillaries and cells, better will be the transfer of the oxygen from the erythrocytes to the cell. From physiological perspective, the highest oxygen demand occurs at the time of physical activity when skeletal muscles are used for fight or flight responses, i.e., to catch a prey or to escape from a predator. Having an efficient system for transfer of oxygen from the lungs to the skeletal muscle offers survival advantage and thus has evolutionary selection pressure. The basic design of the cardiovascular system has remained same throughout the course of vertebrate evolution. The heart occupies the central position in the system and receives the blood through veins and pumps it into pulmonary circulation and systemic circulation.  This chapter focusses on the role of heart and vasculature in the haemodynamics and various reflexes that modulate the function of the heart to modulate these haemodynamics.

2.1.1  E  volutionary Origins of Design of Cardiovascular System Theoretically, the flow of blood will occur in the systemic vasculature as long as there is a pressure difference between the aorta and right atria. A combination of the pressure difference and resistance determines the flow rate of blood (Ohm’s law). A higher flow rate can be achieved either by decreasing the resistance or by increasing the pressure gradient. The decrease in the resistance can be achieved by increase in the diameter of the vasculature and the increase in pressure gradient by a stronger pumping heart. The analysis of observations regarding the capillary density, erythrocyte size, number of chambers of the heart, and pressures in the systemic and pulmonary circulation over the course of evolution suggest that high pressure rather than low resistance has been the evolutionary solution for having a higher cardiac output. During the course of the evolution following changes have occurred from amphibians to reptiles to birds and mammals that have impacted the evolution of the cardiovascular system: 1. Ectothermy to endothermy : Cold blooded animals (fish, amphibians, reptiles) to warm blood animals (mammals and birds) 2. Increase in capillary density in the muscles 3. Decrease in the size of the erythrocytes with increase in mean corpuscular haemoglobin concentration and haemoglobin content of the blood 4. Two-chambered heart in fish to four-chambered heart in mammals 5. Separation of pulmonary circulation and systemic circulation 6. Trabecular myocardium to compact myocardium with development of coronary circulation 7. Increase in the pressure in the systemic circulation

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The amphibians and reptiles are cold blooded while the birds and mammals are warm blooded. The metabolic rate of the birds and mammals is about 5–10 times per unit mass higher than the amphibians and reptiles [1]. The capillary density in muscles is the highest in the mammals with the mean distance between capillary and a cell of about 20 μm as compared to 35 μm in amphibians. The size of the erythrocytes has reduced from about 50 μm in amphibians to about 7 μm in mammals. The mean corpuscular haemoglobin concentration has increased from 21% to 32% along with an increase in the haemoglobin concentration of the blood from 8g% to 14 g%. The chambers of the heart have increased from two chambers in fish to three chambered in amphibians to partial septation of the ventricles in reptiles and four chambered heart in the mammals and birds. The myocardium in fish and amphibians is predominantly trabecular with random arrangement. The mammalian and avian heart is primarily compact in nature without any trabecular fibres and is designed for generation for higher pressures. The pressures in the systemic and pulmonary circulation show evolutionary trends [2, 3]. In three-chambered heart with single ventricles (fish and amphibians), the pressure in the pulmonary and systemic circulation is low (40/20  mmHg, systolic/diastolic). In reptiles, with incomplete division of the ventricles, the mean pressure in the systemic circulation is slightly higher (60–80  mmHg) while the pulmonary pressure is still low (15–20 mmHg). In mammals, with complete division of the ventricles and complete separation of the pulmonary circulation and systemic circulation, the average blood pressure in the systemic circulation is 120/60  mmHg (systolic/diastolic) and the blood pressure in the pulmonary circulation is 25/15 mmHg. The birds have higher systemic blood pressures of 150–170/70  mmHg and but similar  pulmonary blood pressures of 25/15 mmHg. It is interesting to note despite huge variation in size and shape, almost all mammals have similar blood pressure and the ratio of heart size to body mass is 0.6% for a shrew with total body weight of 2–5 g and also for 600 kg blue whale and 70 kg man. 2.1.1.1  Teleology The fact that all mammals, irrespective of their size, tend to have blood pressure in the similar range perhaps indicates some underlying unifying mechanism that must have provided some survival advantage. The following is the teleological explanation for the development of mammalian cardiovascular system. The development of endothermy requires a high metabolic rate in mammals and birds even at rest. In survival terms, it means higher food requirements, and consequent exposure to danger along with partitioning of resources required for reproductive success. But the fact that endothermy was an evolutionary success suggests that the benefits of endothermy must have outweighed the costs. A high metabolic rate allows animals to sustain longer duration and wider range of locomotor activities leading to expansion of the behavioural repertoire. The high rate of aerobic metabolism can be sustained only with high amount of oxygen supply to the tissues. Thus, evolutionary changes in the lungs, cardiovascular system, and oxygen c­ arrying

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capacity of the blood must have occurred simultaneously with the evolution of endothermy. The oxygen transport at the tissues got enhanced with increase in the capillary density. The increase in capillary density was achieved with a decrease in the diameter of capillary and erythrocytes that could pass through these smaller capillaries. However, the decrease in diameter resulted in an increase in the peripheral resistance and that would have slowed the flow rate of the blood if the rise of pressure gradient in systemic circulation had not occurred. Maintenance of high blood flow with high oxygen carrying capacity necessitated a separation of the systemic circulation from pulmonary circulation with formation of the four-chambered heart, such that higher pressures can be sustained in the systemic circulation without affecting the low pressures in the pulmonary circulation.A thin respiratory membrane is required for efficient exchange of gases in lung and capillaries of the pulmonary circulation cannot sustain a higher pulmonary pressure. All the energy required to move the blood comes from the heart and the work of the heart could be lessened if the vasculature was highly distensible but then this would have led to inability to raise the cardiac output in emergency survival situations. Thus, a high pressure, low volume, high flow systemic circulation with a low pressure, low volume, high flow pulmonary circulation design of the cardiovascular system appears to have arisen to sustain a high metabolic rates of the birds and mammals.

2.1.2  Pressures and Volumes of Heart and Vasculature The cardiovascular system of human like all vertebrates consists of closed system of arteries, capillaries, and veins with the pulsatile heart at the centre providing the necessary force to circulate the blood through them. The amount of blood pumped is matched to total oxygen demand of the body and indeed the human data shows a linear increase in the cardiac output with increase in the oxygen demand  during exercise [4–8] and interestingly the slope of relationship is same in dogs, humans, and horses. The oxygen demands of the organ systems keep varying with changing metabolism as per physiological needs. This necessitates a mechanism to alter the blood flow to each organ system as per its physiological needs and also a mechanism to ensure that the change in blood supply to one organ system should not affect the blood supply to other organ systems. The control of cardiovascular system is designed to ensure seamless management of local needs with global deeds. The heart is a hollow viscoelastic compressive organ that pumps the blood that it receives. The blood is pushed intermittently by the left ventricle during the systole into the aorta that distributes the blood to various organ systems through large elastic arteries (Fig. 1.2, Chap. 1). The large arteries further divide into muscular arteries that carry the blood into specific organ systems. The circulation in the organ systems is arranged in parallel to each other. Within the organ systems, the arteries further divide to form arterioles and capillaries where the exchange of fluids and gases takes between the blood and cells. The capillaries coalesce to form venules

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and large veins that bring the blood back to the right atrium. The blood in the right atrium is then pushed into the right ventricle that pushes the blood intermittently into the low pressure pulmonary circulation for oxygenation and later the blood return to the left atrium and left ventricle to complete a cycle of circulation. 2.1.2.1  Mean Circulatory Filling Pressure Vasculature is a closed system of hollow tubes viz arteries, capillaires and veins with differential diameters and wall properties. The vasculature is filled with blood and like any space lined by distensible walls, it has some pressure. The amount of the pressure developed in vasculature is due to the presence of the blood and its value depends upon the amount of the blood in the vasculature, capacity of the vasculature, the combined compliance of the whole vasculature, and active contraction (tone) of the vasculature. However, such filling pressure of the vasculature is masked by rhythmic contractile activity of the heart and the ‘fullness’ of the vasculature cannot be assessed unless it is measured immediately after death when the heart has stopped [9]. The fullness of the vasculature in live animal is measured by temporary fibrillating the heart and allowing a few seconds to elapse so  that the pressure equates in all the compartments of the vasculature and measuring it before the autonomic reflex are activated. This pressure is called as mean circulatory filling pressure when the whole of circulation is taken into consideration or mean systemic filling pressure when only the systemic circulation is taken into consideration [10, 11]. Since systemic circulation forms the major part of the total circulatory vasculature, the two tend to be equal and mean circulatory filling pressure has been estimated to be about 7–10 mmHg in resting human. Mean circulatory filling pressure is slightly higher than the mean systemic filling pressure because of lesser compliance of the pulmonary circulation. 2.1.2.2  Stressed and Unstressed Blood Volume That the mean circulatory filling pressure is positive (7–10 mmHg) indicates that 5 L volume of blood is larger than the un-stretched capacity of vasculature. Based on the concept of the mean systemic filling pressure, the total blood volume in the vasculature is divided into stressed volume and unstressed volume. Decrease in blood volume leads to decrease in the mean circulatory filling pressure. The stressed volume refers to the amount of the blood which when removed will lead to decrease in the mean systemic filling pressure to zero. The volume of the blood remaining in the vasculature at which the mean circulatory filling pressure is zero is called the unstressed volume. Thus the stressed volume is the one that stretches the walls of vasculature leading to generation of the mean circulatory filling pressure. The unstressed volume is haemodynamically ‘inert’ meaning that it just fills the vasculature and does not provide the pressure gradient and ‘is not available’ for circulation. The stressed volume on the other hand provides the necessary pressure gradient

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that is thus haemodynamically ‘available’. It must, however, be remembered the partitioning of blood volume into stressed and unstressed volume is a conceptual physiological partitioning and should not be taken to mean a physical separation of blood volume into compartments. The whole volume of blood is always in circulation and the stressed volume represents its driving force. The increase in the tone and decrease in diameter of the vasculature leads to decrease in the unstressed volume and its conversion to stressed volume. This is also associated with increase in mean circulatory filling pressure and the pressure gradient for venous return. The unstressed volume of the vasculature is estimated to be about 60  mL/kg, 3.5 L [12–14] The vascular compliance is estimated to be about 2.72 mL/kg body weight per 1 mmHg change in the transmural pressure therefore with a mean circulatory filling pressure of 7 mmHg, the stressed volume is 20 (2.72 × 7) mL/kg. The intense sympathetic stimulation decreases the capacitance by about 15% and changes 8.7 mL/kg of unstressed volume to stressed volume [15–17]. 2.1.2.3  Factors Affecting Mean Circulatory Filling Pressure Figure 2.1a shows the schematic representation of different compartments of the vasculature. The pulmonary circulation is not depicted for the sake of simplicity. The mean circulatory filling pressure will increase if there is decrease in the capacity of the vasculature either by decrease in the diameter of the venous or the arterial compartment (Fig. 2.1b). The venous contraction has larger effect on mean circulatory filling pressure due to its large capacity as compared to the arterial compartment. The mean circulatory filling pressure will also increase with increase in the volume of the blood (Fig. 2.1c). The condition shown in the Fig. 2.1b can also be produced by a decrease in the blood volume, but in this situation the mean c­ irculatory filling pressure will decrease. It must however be noted, that the above description does not take into consideration any reflexive adjustments in the homeostatic machinery that will occurs in an intact animal. Sympathetic stimulation per se decreases the unstressed volume of the vasculature and increases the stressed volume of the vasculature resulting in increase in the mean circulatory filling pressure.

A Heart

C

B

2

4 3

1

1

1

2

4 3

4

2 3

Fig. 2.1  Factors affecting mean circulatory filling pressure. (1) elastic large arteries, (2) muscular conduit arteries, (3) local circulation, (4) venous compartment

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Fig. 2.2  Effect of stroke volume on pressure in aorta

2.1.2.4  Effect of Pulsatile Activity of Heart The heart is an intermittently acting compression pump. Assuming that the heart has been quiescent for a while and therefore the pressure in all parts of the vasculature has equalized to mean circulatory filling pressure. Now if heart contracts just one time, then a small volume of the blood is pumped by the left ventricle into the aorta. This push of small amount of blood leads to a temporary rise of pressure in the aorta. The amount of increase in pressure in aorta and its temporal profile depends upon the amount of blood pushed in one contraction (stroke volume), duration of the ejection, rate of ejection, compliance of the aorta, and outflow resistance  to blood in aorta. Figure 2.2 depicts effect of compliance of aorta and outflow resistance on the pressure profile with other factors remaining constant. The curve S in Fig. 2.2a represents temporal prolife of pressure in aorta due to a single contraction of left ventricle with normal aortic compliance and normal outflow resistance. The baseline represents the mean circulatory filling pressure (Psf). As shown, the contraction of the heart results in ejection of the stroke volume into the aorta. In the early part of ejection period, the rate of the inflow of the blood in the aorta is faster than the outflow and the kinetic energy of the blood flow gets converted into potential energy (pressure). The peak pressure in aorta will be higher with larger stroke volume, faster ejection of the same stroke volume and decrease in the compliance of the aorta (curve 1 in Fig. 2.2a). The pressure will rise as long as the inflow (ejection) of the blood into the aorta is faster than the outflow (early part of the ejection phase) and the pressure will begin to decrease when the inflow is slower than the outflow (later part of the ejection). The pressure will continue to fall after the completion of the ejection phase as the blood runs out of the aorta into the large arteries. The slope of decrease in the pressure in aorta during late ejection phase and after systole is dependent upon the outflow resistance. When the resistance is less, the fall

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in the pressure will be faster and vice versa. Eventually, if there no second contraction, the pressure will fall back to the mean circulatory filling pressure. If the outflow obstruction is zero, then all the work of the heart will be converted into kinetic energy and there will no rise of the pressure. With increase in the outflow resistance, more and more the kinetic energy will be converted to potential energy of the pressure that will dissipate as the blood flows out of the aorta (curve 2 in Fig. 2.2b). When the outflow is completely blocked, then the pressure rise in the aorta will be maximum and will depend upon the compliance of the aorta, contractility of the heart and the end-diastolic volume in the heart. For a given end-diastolic volume the maximum pressure developed by the heart can be plotted in such conditions of complete block of ejection from the heart by clamping the aorta. The slope of the maximum pressure  developed in the ventricles against the end-diastolic volume is a measure of the contractility of the ventricle (Fig. 2.3). Rhythmic beating of the heart results in intermittent stroke volume inflows into the aorta. Figure 2.4 shows the effect of rhythmic contraction and intermittent push of stroke volumes into the aorta. The first beat leads to rise of the pressure in the aorta as described earlier. The pressure begins to fall during late ejection phase and during the diastole. If the second heart contraction occurs before the falling pressure has reach the mean circulatory filling pressure, then summation of the pressure begins to take place with each successive beat and the peak pressure in aorta beings to rise with each beat (systolic pressure) along with lowest pressure during the diastole (diastolic pressure) provided the venous return is not a limiting factor. The rising pressure also increases the pressure gradient for outflow of blood for the unchanged outflow resistance. A steady state is soon reached wherein for a given stroke volume, heart rate, outflow resistance, contractility of the heart, and aortic compliance, a steady state systolic pressure and diastolic pressure is established.

Peak LV Isovolumteric Pressure

Fig. 2.3  Effect of end-diastolic volume on peak isovolumetric pressure in ventricle

End-diastolic volume

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Pressure

Systolic Pressure

S

Diastolic pressure

Psf

Time Fig. 2.4  Effect of rhythmic stroke volumes on the pressure in aorta

The systolic pressure is a composite manifestation of cardiac output (end-diastolic volume, stroke volume, and heart rate), compliance of the aorta, and outflow resistance. The diastolic pressure is a composite manifestation of outflow resistance, stroke volume, and heart rate. The higher the resistance, the higher the diastolic pressure. The higher the heart rate, the higher will be diastolic pressure as the time for fall in the blood pressure decreases with increase in the heart rate provided the venous return is not a limiting factor. On the similar lines, the generation of the pressures in the pulmonary system can be described. The pressure in the pulmonary circulation is lower than systemic despite having same cardiac output. This is primarily because of the lower resistance offered by the pulmonary circulation.

2.1.3  Heart as a Pump Heart is a simple and efficient mechanical pump [18, 19]. Earlier the atria were not considered as force pump because of absence of valves between atria and veins but later it was shown that atrial contraction does contribute to the pump function with a wave like contraction that pushes the blood into ventricles [20, 21]. Based on the initial descriptions by Frank and Starling, the heart was considered to be active during the systole and generated force that pushed the blood into the aorta. The diastole is passive period which during filling of ventricles occurs due to pressure gradient of blood from the vein and atria into the ventricles (a non-sucking pump). However, based on the observations that right atrial pressure is generally very low, the heart moves substantially during the systole and diastole in the mediastinum and that at end of the systole the ventricles have a natural tendency to expand led to the proposal and observations that the ventricles itself sucks the blood from the atria and veins during intial part of diastole and behaves like a sucking pump in the intial part of the diastole [19, 22, 23].

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For heart to function as a pump, both anatomical and physiological integrity is required. Thus, heart may not be able to function as a pump despite having a physiologically active myocardium because of the valve defects. Similarly, even with the anatomy intact, the heart will not work as an effective pump if the spread of the impulse gets disturbed as in arrhythmias. The fundamental properties of the heart were established in late 1800s and early 1900s [24–27]. It was established that heart follows all or none law and the magnitude of the ‘All’ is determined by the heart’s inherent properties. The heart has intrinsic ability to adjust its pump function to changing venous return and this intrinsic ability of the heart to adjust itself was termed as autoregulation and was observed to be of two types [28]. 2.1.3.1  Heterometric Autoregulation (Frank–Starling’s Law of Heart) The changing venous return affects the pre-systolic volumes and pressures in the ventricle and these were found to be important determinants of the magnitude of the contraction produced by the heart. The strength of the contraction of the heart was directly proportional to the initial length of the fibres. Thus, end-diastolic volume (initial length of the ventricular fibres) was considered to an important factor in determining the strength of the contraction of the heart. When the heart rate and blood pressure are kept constant, increase in venous return increases the cardiac output till the maximal distension ability of the heart is reached. When the venous return and arterial resistance is kept constant, increasing the heart rate from 60 to 200 does not change the cardiac output [25]. This led to propositions that the venous return is the primary determinant of the cardiac output and that the heart has intrinsic ability to match its function to the changing venous on beat-to-beat basis by changes in the initial length of the fibre. 2.1.3.2  Homeometric Autoregulation Over and above the heterometric autoregulation it was observed that even when the end-diastolic volumes are kept constant, the intrinsic contractility of the heart changed with changes in the aortic pressures as well as heart rate per se. These homeometric autoregulation takes a few beats to manifest as opposed to the heterometric autoregulation that manifest in the same heartbeat. 2.1.3.2.1  Anrep Effect (Effect of Sudden Changes in the Aortic Pressure) The change in the contractility of the heart in response to changes in the aortic pressure is called Anrep effect. A sudden increase in the aortic pressure initially leads to early closure of the aortic valves and less emptying the ventricles (decrease in stroke volume) and increase in the left ventricular end-diastolic volume. The increase in the end-diastolic volumes leads to increase in force of contraction such that stroke

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volume is maintained (heterometric regulation). However, within few beats, the left ventricular end-diastolic volumes  begins to fall even though the aortic pressure remains raised and a new contractile state is achieved in which the heart is able to generate a higher force with the same initial lengths. Thus, the initial heterometric (length–tension) response is replaced over few beats by an increase in the contractility when the aortic pressure is suddenly increased. 2.1.3.2.2  Bowditch Effect (Effect of Sudden Change in the Heart Rate) Bowditch effect refers to increase in the contractility of the heart due to increase in heart rate per se. A sudden increase in the heart rate is associated with increase in the left-ventricular end-diastolic volume/pressure due to initial few weaker beats. Then the left ventricular end-diastolic volume decreases with increase in contractility. The aortic pressures and pulse pressures decrease due to high rate and smaller stroke volumes. When the heart rate becomes very high, the systolic time required for ejecting a given volume of the blood decreases. 2.1.3.3  Importance of Heterometric and Homeometric Autoregulation For many years, the Frank–Starling’s law of the heart was thought to be the primary mechanism responsible for changes in the cardiac output. However, later with the advent of the cine-radiography it was realized that in intact animals, the primary mechanism of increase in cardiac output was increase in heart rate and most observations showed that end-diastolic volumes were not raised during increased venous return and that heart did not empty completely after systole. Therefore, it became apparent that the heterometric autoregulation may play a role in beat-to-beat variation of the stroke volume with changing end-diastolic volumes but other mechanisms must play role a larger role in intact animals for raising the cardiac output. The homeometric autoregulation (Anrep effect) allows the heart to eject same volume of blood in case of changing aortic pressure (after load) without having to change the intial length. The increase in the heart rates affects the duration of the diastole and thereby the ventricular filling. The increase in the contractility with increase in heart rate (Bowditch effect), decrease the duration of the systole so that adequate time is available for ventricular filling. 2.1.3.4  Effect of Neural Stimulation on Heart Sympathetic stimulation: The stimulation of sympathetic efferents leads to increase in heart rate (positive chronotropy), contractility (positive ionotropy), rate of conduction (positive dromotropy), and excitability (positive bathmotropy) and faster and better relaxation of cardiac muscle during diastole (positive lusitropy). When sympathetic stimulation is done at the level of stellate ganglia, the effect occurs with

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a latency of 2–4 s and reaches maximum by about 7–10 s. The sympathetic efferents affect atria as well as ventricles. Even when the heart rate, end-diastolic volume, and aortic pressure are kept constant, sympathetic stimulation leads to an increase in stroke volume, aortic pressure (systolic as well as diastolic), fall in mean atrial pressure along with lowering of ventricular end-diastolic pressure, more rapid rate of tension development, shorter duration of the ejection, and more rapid relaxation [29]. Parasympathetic stimulation: The stimulation of the parasympathetic efferents leads to decrease in heart rate (negative chronotropy), contractility (negative ionotropy), rate of conduction (negative dromotropy), and excitability (negative bathmotropy) [30, 31]. The innervation and direct effects of vagal stimulation is restricted to atria in human. The observed effects of decrease in ventricular contraction due to vagal stimulation are attributable to Bowditch effect, i.e. decrease in heart rate per se can decrease the contractility of the ventricles. Vagal stimulation leads to decrease in refractory period of the atria without any changes in the ventricles. 2.1.3.5  Cardiac Cycle In early 1900s, the cardiac cycle was divided into a period of systole (contraction) and a period of diastole (relaxation). However, with simultaneous recording of the pressure changes in the left atria, left ventricle, and aorta further details of the cardiac cycle were established in animals and later corroborated in humans [32, 33]. This division of the cardiac cycle into eight components is part and parcel of every basic text book of medical physiology and is  often referred as Wiggers diagram after Carl Wiggers who first suggested these divisions for left ventricular activity. The following are the phases of cardiac cycle of left ventricle. 2.1.3.5.1  Left Ventricular Systole 1. Isometric/isovolumetric contraction: This phase starts with the rise in the tension in the ventricles/first heart sound/rise of C-wave of atrial pressure and ends with rise of the aortic pressure. During this phase, the A–V valves as well as semilunar valves are closed and the ventricle contract as closed chamber leading to initial slow and later rapid rise of the intra-ventricular pressure. Even though the volume of the ventricle remains same during this phase, the geometry of the ventricles undergoes torsional movement making it more spheroidal with decrease in the apex-base length and increase in the circumference of left ventricle [34, 35] 2. Rapid ejection phase: This phase starts from the rise of the pressure in the aorta and ends at the peak of the aortic pressure. During this phase the blood is ejected rapidly from the ventricles into the aorta. The pressure in aorta rises because the outflow from ventricles into the aorta is faster than the outflow from the aorta. 3. Slow ejection phase: This phase starts from peak of pressure in aorta and ends with beginning of the incisura in the aortic pressure waveform. During this phase

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the blood is ejected slowly from the ventricles into the aorta. The pressure drops in the aorta despite ongoing ejection because in later part of ejection the outflow from the ventricles into the aorta is slower than the outflow of the blood from the aorta into the large arteries. 2.1.3.5.2  Left Ventricular Diastole 1. Proto-diastole: This period represents the period during which the semilunar valves of the aorta are moving from open position to closed position. This phase begins with start of the incisura and ends at the bottom of the incisura of the pressure wave of the aorta. 2. Isometric/isovolumetric relaxation: This phase starts from the bottom of the incisura and ends with fall in the atrial pressures. During this phase the ventricles are relaxing as closed chamber because both the semilunar as well as the A–V valves are closed and is associated with rapid drop of the intra-ventricluar pressures. 3. Rapid inflow phase: This phase starts with the fall in the pressure in the atria and ends with start of the rise of pressure in the atria. During this phase the blood that was pooled in the atria (during the ventricle systole) rapidly moves into the ventricle after opening of the A–V valves. The movement of blood into ventricles during this phase was considered to be passive but recent data suggests that some amount of suction pressure created by relaxing ventricle plays a role in inflow of the blood from atria to ventricles. 4. Diastasis: This phase starts with rise of pressure in atria and ends with start of the atria contraction. During this phase the blood coming from the pulmonary veins moves into ventricles with atria acting as passive conduit  and is best observed at slower heart rates. 5. Atrial systole: This phase begins with the rise of the pressure in the atria and ends with rise of the pressure in the ventricles marking the beginning of next cycle. During this phase additional amount of the blood is pushed by atria into the ventricle (atrial kick). 2.1.3.6  Ventricular Function Curve Ventricular function curves are the graphic representation of the relationship between stroke work of the ventricles with the end-diastolic volumes/pressure [28, 36]. These curves are similar to the Starling’s curves that depicted stroke volume changes with end-diastolic volumes. For ventricular function curves, the ventricular end-diastolic volumes/end-diastolic pressure/left atrial end-diastolic pressure is plotted as independent variable on the x-axis and its effect on the ventricular stroke work (i.e. stroke volume x [mean arterial pressure—mean atrial pressure]) on y-axis. Figure 2.5 shows the changes in the stroke work with the changes in the end-­ diastolic pressure. With increase in the end-diastolic pressure the amount of the stroke work increases. In the initial parts, the rise is much steeper than the later

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Sympathetic stimulation Positive ionotropy

Left Ventricular Stroke Work

Fig. 2.5 Relationship between stroke work and end-diastolic pressure

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Control Failing heart

Left Ventricle end-diastolic pressure parts. This is because of the nature of the relationship between the end-diastolic volume and end-diastolic pressure. The slope of the  relationship  between stroke work and end-diastolic pressure  reflects the contractile state of the heart and as shown in Fig. 2.5, in failing heart, the rise the of the stroke work is lesser (right and downward shift) and when the heart is sympathetically stimulated then the curves shifts to left and upwards with larger stroke work for the same end-diastolic pressure. 2.1.3.7  Pressure–Volume Curves of Ventricles The pressure–volume curves of the ventricles during the cardiac cycle are used to depict the work done by heart as a compression pump [18]. Figure 2.6 shows the changes in the volume and pressure in the left ventricles during systole and diastole during a cardiac cycle. The diastolic pressure–volume relationship represents the diastolic tone and reflects the compliance of the ventricles. The systolic pressure– volume relationship represents the systolic tone and reflects the contractility of the ventricle. The change in the pressure and volume at different phases of the cardiac cycle is as follows: Point A represents the end-diastolic volume and pressure at the beginning of the ventricular systole. The end-diastolic volumes and pressure is determined by the volume of the blood left in the ventricles after the end of systole of the previous ventricular contraction (end-systolic volume), the gradient of filling (i.e. pressure difference driving the blood from the veins into the ventricles), time available for filling (duration of the diastole dependent upon heart rate), the compliance of the ventricles (diastolic tone) [32, 37], and suction force generated due to preceding ventricular systole [19]. The segment A–B represents the isovolumetric phase of the ventricular systole which is associated with rapid rise of the pressure in the ventricles. The pressure rise in the ventricles is dependent upon the pressure in the aorta because this isovolumet-

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Fig. 2.6 Pressure–volume curve of ventricles

Systolic Tone

B

Pressure

D

C

Diastolic Tone

A

E Volume

ric phase continues till the pressure in the ventricles becomes higher than the aortic pressure leading to opening of the semilunar valves. It must be noted that ventricles can generate more pressure than that is usually needed. The strength of the contraction of the ventricles is dependent upon the end-diastolic volume (Starling’s law of the heart), the heart rate (Bowditch effect), aortic pressures (Anrep effect), and the contractility of the heart (ionic and neurohormonal influences). Point B marks the start of the ejection period of the ventricular systole and its value is dependent upon the aortic pressures. The segment B–C–D represents the ejection period during which the volume of the ventricles decreases and the pressure in ventricles mirrors the pressure in the aorta. In the initial part (segment B–C, rapid ejection phase), the pressure in ventricles mirrors the pressure in the aorta and it rises due to ejection of the blood into aorta faster than the outflow of the blood from the aorta. In the later part (segment C–D, slow ejection phase), the pressure in the ventricles begins to fall due to ejection of blood into aorta at a rate slower than outflow of blood from aorta and when the pressure in the ventricles becomes lower than that in the aorta, the closure of the semilunar vales beings to occur. The stroke volume is a function of end-diastolic volume and all the factors that affect contractility of the heart with some effects of the outflow resistance of the aorta. In intact animals, the heart rate is an important factor that determines the stroke volume as changes in the heart rate affects the time duration of the diastoldic filling of ventricles and thereby the end-diastolic volume. In addition, the heart rate has direct effect on the contractility (Bowditch effect). During the ejection phase the ventricles are contracting against the pressure in the aorta (afterload). The increase in loading leads to adjustment in the heart in acute and chronic manner. The acute changes include dilatation (heterometric autoregulation), tachycardia and increased in contractility (homeometric autoregulation,

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reflexes, neurohormonal). The chronic changes include concentric hypertrophy of the heart. Point D represents the protodiastolic period between the end of the ejection phase and start of the isovolumetric relaxation phase. The segment D–E represents the isovolumetric relaxation phase, wherein the A–V valves and semilunar valves are closed and the pressure in the ventricles rapidly drops. The volume at point D/E is the end-systolic volume. The end-systolic volume is dependent upon the contractility of the ventricle and the aortic pressure (dependent upon the peripheral resistance). This residual volume in the ventricle plays an important role in beat-to-beat adjustments of the cardiac output above or below the venous return. Thus the cardiac output is matched to the venous return over few beats but not for each beat to beat. Similarly, each stroke volume of the left and right ventricles is not matched beat to beat but over few beats. 2.1.3.8  Cardiac Energetics The effort of heart is to propel the blood (kinetic energy) and maintain a pressure (potential energy). Any increase in kinetic energy (cardiac output) or potential energy (aortic pressure) requires additional work to be done and increases the myocardial oxygen demand. The oxygen reserve of the heart is very low, and it cannot tolerate oxygen debt, therefore any change in the oxygen requirement is met with change in the coronary blood flow such that the ratio coronary blood flow/cardiac oxygen consumption remains constant. Hypercapnia, acidemia, and high catecholamines increases the slope of coronary blood flow/cardiac oxygen relationship, i.e. more oxygen is available to the heart. The other way by which more oxygen can be supplied to heart is increase in the arterial-venous oxygen difference (A-VO2, oxygen extraction). The primary mechanism by which increase in the oxygen supply to heart can be achieved in face of increasing work–load on the heart is the increase in coronary blood flow. Oxygen consumption is directly proportional to tension developed and it can be derived from the area under the curve of pressure–volume loop. The stroke work for each beat increases with increase in end-diastolic volume (pre-load) and arterial pressure (after-load). However, the relationship between stroke work and after-load is much more linear than with pre-load. The cardiac work is also  directly proportion to the heart rate (number of contraction of the heart). Because of this proportionality, rate x pressure product has been used as an index of oxygen demand/consumption by the heart. The mechanical efficiency is about 25–35% [38].

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2.1.4  Vasculature Peripheral circulation is a commonly used but ironically ill-defined terminology as was observed by Burton in 1953 ’No one seems able to define’ peripheral circulation. ’Does it include the circulation of the viscera, the brain, the lungs? Some even have replied that it included everything outside the heart itself and were not sure that even the coronary circulation should not be included. After all, the term’ peripheral ‘must mean something in the phrase’. Hence, instead of delving into semantics, the term vasculature is used here to refer to all the components of the circulation that is not heart. As mentioned in Section 2.1.1 on  evolutionary perspective, selection pressure led to the development of the high pressure, low volume systemic circulation. At the level of capillaries, a high pressure would be counter-productive as it would lead to exudation of the intra-vascular fluid into the interstitial fluid and also at the level of capillaries a continuous flow of the blood would be preferable to pulsatile flow for efficient exchange of gases, electrolytes, and nutrients. A combination of distensible vessels (large arteries) and resistance vessels (arterioles) upstream of the capillaries converts the pulsatile high-pressure blood flow to low-pressure streamlined blood flow. The different components of the vasculature have different anatomical and physiological properties suited to their functional needs. The aorta and large arteries are distensible and provide a mechanism to hold the energy of the stroke volume as potential energy and then dissipate it during the diastole such that a head pressure is maintained throughout the diastole and flow through the vasculature is maintained. The muscular arteries and arterioles are main site of resistance in the systemic circulation and high resistance leads to rapid drop of pressure along arteries  to reach optimal levels in the capillaries. The pre-capillary sphincters are part of the resistance vessels and acts as gate keepers to control microcirculation to the local needs. The capillaries are the site of exchange of gases, nutrients, etc. The venules and small veins and large veins are thin walled, highly compliant and have a large capacitance. The total volume of blood is distributed in different compartments of the vasculature. The systemic arterial compartment has low volume (9%) and low compliance while the systemic venous compartment has high volume (60–70%) and high compliance. The systemic capillaries have low capacity with near low compliance. The chambers of the heart hold about 7% of total blood volume with pulmonary system accounting for another 9%. Compliance of pulmonary system is one-seventh of the systemic circulation.

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2.1.4.1  Effect of Resistance on Pressure Gradient in Vasculature The pressure in the aorta is built up due to intermittent inflow of the blood into the aorta with each stroke volume (cardiac output) and presence of an outflow resistance. If the cardiac output remains same, a decrease in the outflow resistance will result in decrease in the pressure in the aorta. If the outflow resistance remains, then any increase in the cardiac output will cause increase in the pressure in the aorta. The pressure in the aorta drives the blood through the conduit arteries into the capillaries, through the venules, vein into the right atria. Assuming that the pressure in the right atrium is zero, the pressure gradient from the aorta to the right atrium is the  mean blood pressure in the aorta. This pressure drops along the vasculature and  is influenced by the resistance offered to the blood flow along its  course. Figure 2.7 demonstrates the effect of the change in the resistance at a point R in vasculature [39]. Assume that the pressure gradient of P1 − P2 is maintained is from Point A to Point B along the course of the vasculature and diameter of the vasculature is same throughout, then the pressure drop will be uniform and linear along the length of the vasculature as shown in the Fig. 2.7 (black line). Now if diameter of the vasculature decreases at Point R, the pressure distribution across the vasculature changes. Due to decrease in the diameter, the resistance at R increases leading to rise of the pressure (but P2) in the regions downstream of region R.  This raised pressure, just upstream of the point R,  pushes the blood across R at higher velocities due to increase in pressure gradient across the region of Point R. Here it is assumed that the driving force upstream of this segment of the vasculature is adaptable and large enough to maintain the forward flow of blood at the same flow rate despite increase in the resistance. Such a scenario occurs during arterial vasoconstriction that leads to increase of pressure in the aorta (upstream) and decrease of pressure in the

R

Fig. 2.7  Effect of resistance on pressure gradient in vasculature

B

A P1 upstream

downstream

Pressure

P1

P2

P2 Points on the vasculature between A and B

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c­ apillaries (downstream) but the cardiac output does not decrease because the heart is able to push the same stroke volume despite the increase in the aortic pressure. The flow of blood through any local circulation is determined by the pressure gradient between its arterial and the venous ends and the resistance offered by its vasculature. If the pressure gradient remains same then the any increase in diameter (vaso-relaxation) will lead to increase in the flow. Similarly, if the pressure gradient increases then the flow will increase if the resistance remains the same. The changes in resistance of local circulation occur in response to changes in the metabolism of the tissue (metabolic control), shear stress (endothelium dependent), mechanical factors, or central drive (neuro-hormonal control) [40–43]. In addition, the local circulation shows phenomenon of myogenic autoregulation, where in the changes in pressure gradient results in the opposing changes in the resistance such that flow rate does not change [44]. For each local circulation, the relative dominance of the metabolic control, myogenic autoregulation, and central control is varied [45]. For example, skin circulation has dominant central controls, while the coronary, muscular, and cerebral circulation show a dominant metabolic control while the renal circulation shows a dominant myogenic autoregulation. The different regions of the vasculature have differential relative responsiveness to  above mentioned factors [8]. 2.1.4.2  Distribution of Cardiac Output The cardiac output of 5 L is distributed to various organ systems in proportion to their physiological functions [cerebral circulation (14%), heart (5%), liver and gastrointestinal tract (23%), kidneys (22%), skin (4%), muscles (18%), and rest to other tissues such as bones, fat, etc.]. The pressure head that drives the flow into these vascular beds is same and therefore the amount of flow into any of the beds is dependent upon the resistance offered by the vascular bed. Similarly, an increase in head pressure will tend to the push the blood through all the vascular beds. A combination of local metabolic control of resistance, myogenic properties of the arteries, and central modulation of the vasculature achieves a near perfect equilibrium between local and global needs. The increase in resistance upstream of a vascular bed results in decrease in the flow into the vascular bed along with decrease in the pressure in the vascular bed. The decrease in the distending pressure decreases the dimension of the vascular bed resulting in decrease capacity of that vascular bed [46]. These passive effects of changes in resistance can lead to up to 65% decrease in the amount of the blood in a vascular bed and redistribution of the blood from this vascular bed to other vascular beds. Sympathetic stimulation can differentially affect the arterial resistance of different vascular beds. The vascular  beds where the resistance is increased by larger value will lead to diversion of the blood from these  vascular beds to vascular beds with lesser rise of the resistance. However, if the region where the blood volume was diverted has larger compliance, then the outflow rates from that region will

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become slower impacting the venous return. Therefore, simultaneous decrease in the compliance is also important to prevent damming of the blood. At rest, the vascular system has a basal sympathetic tone and this can be gauged by the fact the sympathetic blockade leads to decrease in the mean circulatory filling pressure by about 1.5 mmHg. The sympathetic reserve is large and on intense stimulation, the mean circulatory filling pressure can rise by 16  mmHg leading to shift of about 18 mL/kg of blood from unstressed volume to stressed volume [11, 47].

2.1.5  Cardiac Output The function of the heart is to pump the blood and its operational functionality is best quantified by the amount of blood pumped over unit time, i.e. cardiac output in L/min. For cardiac output to occur two primary conditions need to be satisfied, i.e. there should be blood entering the heart (venous return) and there must exist a heart that can contract and relax adequately and rhythmically to pump the blood entering it. Over and above these two factors, two other additional factors come into play to determine  the cardiac output, i.e. heart rate and the pressure in the aorta against which the blood has to be pumped. These four factors are the primary determinants of the cardiac output. All other known physiological and pathological variables modulate/affect cardiac output by changing these four fundamental determinants of the cardiac output. Presence of adequate amount blood is a given. Since the amount of blood is 5 L, any increase in the cardiac output simply means that the blood is being moved faster through the closed circuit of the circulation. The increase in the flow in such a scenario can occur only with higher conductance through arterial vasculature as well as venous vasculature. Based on the Frank–Starling’s law of the heart, in early 1900s it was a general consensus that the heart has intrinsic ability to adjust its function to ensure that it could pump all the venous return that came to it and therefore the rate limiting step in the determining the cardiac output was the venous return [25, 46]. However, with the development of imaging techniques later, it became apparent that increase in stroke volume during exercise was associated with better emptying of the ventricles rather than increase in the end-diastolic volumes and role of other factors were amalgamated with law of the heart for application in intact animals. In an intact animal, a change in any one of above mentioned four factors affects the other factors over a period of time and as part of numerous reflexes. Therefore, caution is advisable while extrapolating the experimental data where the factors are controlled deliberately and artificially, to clinical conditions or intact animals where the factors are free to influence each other. When the afterload is increased experimentally with a constant end-diastolic pressure, the stroke volume decreases. But in intact animal, increase in the after load leads to changes in the end-diastolic volume such that stroke volume maintained at higher cost of cardiac work despite rise of the systemic arterial pressure [48, 49].

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2.1.5.1  Effect of Change in Resistance on Cardiac Output For any discussion on factors affecting cardiac output one should constantly be aware that circulation is a closed circuit and cardiac output is determined both by the ability of the heart to pump and ability of the vascular system to send the blood back to the heart. Therefore, a change in the resistance in any part of the circulation will affect the flow of the blood back to heart and thus likely to affect the venous return and thus cardiac output [50]. Had the vascular system been made of rigid tubes, the changes in resistance in any part of the vasculature would have had same effects on the cardiac output irrespective of the location of the site of the resistance. But vasculature is made up of variably distensible regions with differential capacities. Also sudden changes in the resistance in part of the vascular (change in diameter leading to  change in the capacity) is not accompanied by change in the total  blood volume; therefore a shift of blood volume from one compartment to another will occur. Changes of resistance in the venous compartment affects cardiac output quantitatively much more than changes in the resistance in arterial compartment. This is because, when the resistance to venous outflow increases,it begins to expand due to its high compliance and capacity. Since the total  blood volume is not going to change suddenly and dramatically, the blood gets shifted from the arterial compartment to the venous compartment. Additionally, as the blood is shifted from arterial to venous compartment, the arterial pressure drops and the pressure gradient driving the blood through veins also drops. The combination results in pooling of the blood in the venous compartment and decrease of blood in the arterial compartment. However, if the arterial resistance increases then only a small amount of the blood will pool in the arterial compartment because its poor distensibility and the pressure rise is large. Since only a small amount of blood pools in the arterial compartment, then only a small shift will occur from venous compartment. Additionally, due to high capacitance and low pressure of the venous compartment only a small drop in pressure will occur  in venous compartment due to shift of blood volume. The increase in the pressure in the arterial compartment is easily overcome by the contractile normal heart (this may be an issue when the heart is failing or weak). Over longer term, pressure changes at the capillary level, the fluid movement occurs between the intra-vascular and interstitial fluid and the changes in the blood volume begins to occur. The cardiovascular system is extremely sensitive to physiological and psychological conditions, therefore it has been extremely difficult to quantify resting or basal values of cardiac output in humans. Careful and detailed studies on human revealed that resting cardiac output is about 5 L with standard deviation of about 30% [51, 52]. The cardiac output decreases by 1% every year after age of 20 and this is attributed to a decrease in stroke volume along with decrease in body mass.

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2.1.5.2  Matching Cardiac Output with Oxygen Demand At this juncture it is pertinent to explicitly clarify crucial but often ignored concepts about the controlled variables and regulated variables in the scheme of the homeostasis. A ‘variable’ is any measurable physiological feature like blood pressure, temperature, heart rate, venous return, membrane potential, body weight, etc. A ‘regulated variable’ is the variable that is being maintained within a ‘set’ range of physiological limits. A ‘controlled variable’ is the variable that is being actively modulated as part of the reflex machinery to maintain the ‘regulated variable’ with in the physiological range. From physiological point of view, for any variable to be a regulated variable, there must exist receptors in the body that can sense the changes in the variable and these receptors must be linked to afferent components of the given reflex. And for any variable to act as controlled variable, it must be linked to efferent components of the reflex. Depending upon the context the same variable can be a regulated variable or a controlled variable contingent upon its position in the reflex arc. Thus, in the context of the classical baroreflex operation in negative feedback mode, blood pressure is the regulated variable, while the heart rate is the controlled variable. However, in context of regulation of glomerular filtration rate in the kidney, blood pressure becomes the controlled variable, while the rate of the glomerular filtration (sensed by load of NaCl at macula densa) becomes the regulated variable. Internal variables are all the variables that are part of the given reflex. External variables are variables that are not the part of the given reflex. For example, in context of baroreflex, blood pressure and heart rate are internal variables but glomerular filtration rate and blood volume are external variables for baroreflex. Set-­ point is that value of the regulated variable at which it is maintained by the feedback mechanisms. Error is any change in the regulated variable beyond the set-point that can be detected by the receptors linked to the afferent component of the feedback mechanism. Coming back to the fact that  cardiac output changes in near perfect concordance with the changing oxygen demands of the body, it may appear that a reflex mechanism may exist that directly links oxygen demand to cardiac output. Unfortunately, there is no mechanism in the body to ‘sense’ either the total oxygen demand or the cardiac output. In relation to cardiovascular system, the ‘sensors’ exist for sensing the blood pressure in the aortic arch and the carotid sinus (baroreceptors), sensing the oxygen and carbon dioxide partial pressure in the blood in the aortic and carotid bodies (chemoreceptors) and sensing the blood volume in the great veins and atria (low pressure volume receptors). Thus, the regulated variables in the respect of cardiovascular system are blood pressure, blood volume, and partial pressure of the oxygen  and carbon dioxide in the blood and other measured variables including contractility, heart rate, tone of arteries, veins, resistances, etc. are controlled variables. Variables such as cardiac output and venous return are manifestation of interplay of the regulated and controlled variables. What then leads to matching of cardiac output with total oxygen demand in a near perfect manner? It appears that cardiac output at any given time is an un-­ intended equilibrium point that is an emergent property of interlinked mechanistic

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and reflexive processes having stochastic and deterministic components driven by tissue level changes in the oxygen demand. To comprehend this proposal, a detailed elaboration of the structural design and properties of different components of the cardiovascular system is essential and is presented below in a step-wise manner. The local circulation of each organ system is finely tuned to its metabolic demand. The circulation of the organ system is arranged in parallel as shown in Fig. 2.8. Let us assume that metabolism in one of the local circulation (X) increases. The increase in metabolites cause immediate relaxation of the arterioles in  local circulation X leading to sudden drop in the resistance offered by this local circulation. Since, the regional circulations are arranged in parallel, a decrease in the resistance of the local circulation X leads to drop in the pressure in this region as well in the combined resistance offered by all the local circulations. The vasodilation in the local circulation X leads to increase in the blood flow to local circulation X and since the cardiac output is still the same, it leads to decrease in the aortic blood pressure and compromise of other local circulations. The decrease of blood flow in other local circulation leads to a mismatch between their metabolism and blood flow such that these local circulations may also respond by vasodilation and a direct relaxation of the conduit arteries though myogenic mechanism for autoregulation of the blood flow (i.e. maintenance of blood flow to an organ system despite changes in the blood pressure). Thus, a drop in central blood pressure is an immediate and unavoidable consequence of increase in metabolism in any local circulation. The drop in blood pressure leads to activation of baroreflex that causes the generalized vasoconstriction (venous as well as arterial) and increases the contractility of heart and its rate. These measures lead to increase in the systemic filling pressures that increase the venous return to heart. It must be noted that unless the venous return to heart increases, no amount of increase in contractility and increase in heart rate will be useful because even if the heart has the capacity to pump, it can only pump what comes to it. The increase in venous return manifests as the increase in the cardiac output such that inflow into aorta now matches the increased outflow caused by the vasodilation of the local circulation X and blood pressure is restored.

Fig. 2.8  Venous return curve

Sympathetic stimulation Increase in blood volume

Venous Return

Control Sympathetic blockade Decrease in blood volume

2 1

Right Atrial Pressure

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Thus, in homeostatic conditions, the changes in the metabolism of any organ tissue is exactly matched with the changes in the cardiac output such that blood flow demands of that organ system are taken care of without affecting the blood flow to other organ systems. Even though there are no sensors for total oxygen demand and no sensors for the cardiac output, the matching between the two occurs due to haemodynamic consequences and operation of the baroreflex. A note of caution is warranted here that in motivated behaviour such as exercise and emotions, additional feed-forward mechanism play a dominant role in the producing changes in the cardiac output with resetting of baroreflex at higher operation point. The role of baroreflex in such situations perhaps is to fine tune rather than being a linker between the oxygen demand and the cardiac output. During exercise, the blood pressure and pulse rate changes immediately upon the onset of exercise far before the increase in the metabolism of the muscle [4, 46]. 2.1.5.3  Cardiac Output as Point of Circulatory Equilibrium As mentioned in the preceding section, the cardiac output is niether a regulated variable nor a controlled variable. There are no sensors in the body to quantify cardiac output and what cannot be sensed cannot be regulated. However, it is also a fact that cardiac output is finely matched with total oxygen demand of the body. Thus despite having no homeostatic machinery to regulate cardiac output and match it to oxygen demand, the matching is near perfect. The equilibrium point concept was demonstrated and elaborated by Guyton as a point of cross-over between the cardiac-response curve and the venous-return curve with experiments conducted in the 1950s [53]. Effects of any haemodynamic change on the cardiac output cannot be determined unless one takes into account the effect of that haemodynamic change on the functioning of the heart as well as on the venous return, for heart can only pump the blood that it receives. 2.1.5.3.1  Venous Return Curve Venous return curve is a plot of the pressure in the right atrium as independent variable on the x-axis and venous return as dependent variable on the y-axis as per the experimental design [54] (Fig.  2.8). The venous return into the heart follows the Ohm’s law and is driven by the pressure gradient between the average pressure in the venous vasculature and the right atrium. The average pressure in the venous vasculature is taken to be equal to the mean circulatory filling pressure. When the pressure in the right  atrium is raised from a normal of 2–3  mmHg, the pressure gradient decreases and therefore the venous return begins to fall till it becomes zero when the right atrial pressure becomes equal to means circulatory filling pressure (Segment 1, Fig. 2.8). A decrease in right atrial pressure results in the increase in venous return; however, when the right atrial pressure becomes negative, venous return does not increase further because of collapse of the great veins and ­consequent

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rise in the resistance and thereby nullifying the effect of increased pressure gradient (Segment 2, Fig. 2.8). The mean circulatory filling pressure is caused by presence of stressed blood volume and therefore any change in the volume of the blood directly affects the means systemic filling pressure and thereby the pressure gradient for venous return. The changes in the capacitance of the venous compartment caused by sympathetic vasoconstriction have similar effects because vasoconstriction decreases the unstressed volume and increases the stressed volume. 2.1.5.3.2  Cardiac Response Curve The cardiac response curve represents the effect of the right atrial pressure on the cardiac output and is similar to Starling and co-workers’ plots for demonstrating the law of the heart and to ventricular function curves of Sarnoff [28] (Fig. 2.9). The right atrial pressure is plotted on the x-axis as independent variable while the cardiac output is plotted on the y-axis as dependent variable as per the experimental design. The blood flows into ventricles due to a pressure gradient between the right atria and the ventricle. The pressure in the ventricles at the end of the isovolumetric relaxation is zero (recent data however suggests that a negative suction pressure is created during the relaxation of ventricle). Thus, the pressure in right atrium provides the necessary driving force for  filling up of the ventricles during diastole. Increase in the right atrial pressure increases the filling of the ventricles (increase in the end-diastolic volume) leading to increase in force of contraction and increase in stroke volume and cardiac output (Segment 1, Fig. 2.9) (Frank–Starling’s law of the heart). With further increases in the right atrial pressure, the rise of end-diastolic volume becomes less steeper as the physical limits of the stretching of ventricles is reached till the end-diastolic volumes cannot increase further and cardiac response plateau is reached (Segment 2, Fig. 2.9). The slope of relationship between cardiac output and atrial pressure reflects the intrinsic contractility of the heart. The change in contractility of the heart changes the quantitative relationship between the cardiac Fig. 2.9  Cardiac response curve

Sympathetic stimulation Increase in blood volume

Cardiac Output

Control

2

Sympathetic blockade Decrease in blood volume

1

Right Atrial Pressure

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output and right atrial pressure. The sympathetic stimulation leads to shift of curve upwards and to the left, i.e. higher cardiac output is achieved with same right atrial pressure and this happens because of the decrease in the end-systolic volume such that more blood enters heart during diastole for the same right atrial pressure. 2.1.5.3.3  Circulatory Equilibrium All discussions about the circulation and cardiac output should begin with acceptance of certain fundamentals and these are 1. The circulation is closed circuit and therefore eventually venous return will affect cardiac and cardiac output will affect venous return. Therefore, there is no dependent or independent variables in physiologically intact animal in contrast with experimental conditions wherein the variables are artificially controlled and effect of one variable over other can be studied. All variables of the circulatory system are interdependent [1]. 2. In intact animal, the blood volume is limited and therefore changes in cardiac output can occur only by circulating the same amount of blood at different rates. 3. Over few beats, the cardiac output and venous return will be exactly same because heart can pump only what it gets and gets what it pumps. On the basis the above, the venous return curve (dashed lines) and cardiac response curve (regular lines) can be superimposed on each as shown in Fig. 2.10. The right atrial pressure curves are plotted on the x-axis while the venous return/ cardiac output is plotted on the y-axis. The green lines represent the plots at resting state. R represents the point at which the resting venous return curve and resting cardiac response curves cross over and at this point the venous return and cardiac output are same. Now if some amount of blood is suddenly removed from the circulation the venous return will be shifted to dashed red line (see venous return curves) and now the cross-over point will be ‘H’ where the cardiac output is reduced with lowered right atrial pressure. A low blood volume initiates reflex sympathetic Fig. 2.10  Cardiac output as circulatory equilibrium

Sympathetic stimulation

Cardiac Output

Control

Decrease in blood volume

R

C

H

Right Atrial Pressure

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s­timulation which shifts the venous return curve as well as the cardiac response curve to new setting (blue lines). Point C represents the new cross-over point and cardiac output is restored to the resting level due to activation of the sympathetic system after loss of blood. Accordingly, similar curves can be plotted for any factor that affects venous return curves and cardiac output response curves and the cardiac output then is  point of cross-over of the two curves. Readers are encouraged to determine the cardiac output by the point of the cross-over (circulatory equilibrium) if the sympathetic stimulation was applied only to vasculature or the heart. In the original descriptions, the properties of the pulmonary circulation that lies between the right atria pressure and left ventricular cardiac output were not taken into consideration. These have now been taken into consideration and the Guyton’s 2D plots of cardiac output/venous return with right atrial pressure has been extended to include left atrial pressure in a 3D plot and have been shown to accurately predict the experimental data [14, 55, 56].

2.1.6  Assessment of Pump Function of Heart Assessment of pump function of heart is clinically useful for assessment of the severity of cardiac dysfunction. Since the primary function of the heart is to pump blood, one of the best ways to assess the function of the heart is measuring the cardiac output during rest and during exercise to determine its reserve. The cardiac output was initially measured using Fick’s principle, dye dilution principle and later the technique of thermodilution became common. With the improvement in the imaging techniques and advanced computation processing, the cardiac output can be determined non-invasively. However, measurement of the cardiac output alone is not sufficient to assess the contractile state of the heart because the pump function is affected by factors beyond the contractile function of the heart. In addition, the preload, afterload, and heart rate per se affect the contractility of the heart; therefore these factors need to factored-in while assessing the contractility of the heart. Stroke volume is measurable by invasive (thermodilution) as well as non-invasive techniques (transthoracic echocardiography) for clinical purposes [57, 58]. Preload can be estimated invasively by directly measuring the left atrial pressure/ pulmonary venous pressures/left ventricle end-diastolic volume and pressures. 3D Imaging techniques are now used for the measurement of the end-diastolic volumes. The afterload is estimated by the blood pressure. The cardiac contractility is estimated by ejection fraction, left ventricular fractional shortening, and velocity of circumferential shortening. The normal ejection fraction is about 65–75% in human. The interpretation of the ejection fraction, as a measure of cardiac contractility, should be done with caution because it is affected by all the factors that affect stroke volume over and above intrinsic contractility of the heart. When the preload and afterload are kept constant, the stroke volume, stroke work, stroke power, peak left ventricular pressure rise (dP/dt), and ejection velocity vary as a direct function of the contractile state of the myocardium. Therefore, a

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number of methods have been employed wherein these parameters are obtained with different pre-loading and after-loading conditions and indices of the left ventricle contractility can be determined. The gold standard technique for assessment of cardiac contractility still remains the plotting of pressure–volume relationship with varying load conditions and computing the ratio of maximum end-systolic pressure and volume. Maximal rate of rise of ventricular pressure (Max dP/dt) during isovolumetric contraction phase is not usable in patients because of wide range of values.

2.2  Cardiac Reflexes The cardiovascular system has multiple reflex mechanisms that allows it to adapt to the changes in metabolic demand consequent to challenges introduced in internal or external environmental. The cardiovascular system operates either in negative feedback mode for maintenance of blood pressure during changes in physiological states, change of posture, and low blood volume or in feed-forward mode for modulating the blood pressure and heart rate during sleep, glucoprivation, emotions such as fear, pain, and motivated behaviours such as exercise, fight, or flight. These reflex mechanisms are activated for maintenance of blood pressure and to provide adequate perfusion to the all tissues of the body, despite regional, systemic, or external perturbations. Though, it is customary to separately describe the cardiovascular reflexes and pulmonary reflexes, one must not lose the sight of the fact that both the cardiovascular and pulmonary systems operate in tandem for the transfer to gases between environment and tissues. Therefore, many reflexes that originate and have effects on cardiovascular system have additional respiratory effects and similarly many reflexes that originate and have effects on the respiratory system have additional cardiovascular effects and thus are described  as cardiopulmonary reflexes. The afferent information for these reflexes originates from receptors located in the great veins, heart, aorta, carotid  arteries, lung parenchyma, and airways. All afferent information reaches the nucleus tractus solitarius for further processing in the medulla. The reflex response is activation or inhibition of the cardiovascular and respiratory centres. Based on the pattern of the central effects, the cardiopulmonary reflexes are classified into many types as mentioned in Table 2.1. In this chapter, only the reflexes that either originate in heart or affect the heart will be discussed.

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Table 2.1  Classification of the cardiopulmonary reflexes (adapted from [59]) Type Type 1

Type 2 Type 2a Type 2b Type 2c Type 2d Type 3 Type 4

Effect on cardiovascular and respiratory centres Reflexes that result in perfect inhibition

Reflexes that result in imperfect inhibition Reflexes that do not have respiratory components Reflexes that do not have cardiac inhibition Reflexes that have primarily cardiac inhibition Reflexes with respiratory inhibition only Reflexes that cause activation Reflexes that produce activation or inhibition

Reflexes originating from baroreceptors in aortic arch and carotid sinus Reflexes originating from pulmonary conus Reflexes originating from left ventricle Reflexes from baroreceptors and stretch receptors Reflexes from the right atrium Reflexes from the pulmonary veins Reflexes from left atrium Reflexes from lung parenchyma Reflexes from chemoreceptors of carotid and aortic bodies Reflexes from great veins and right atrium, lung parenchyma, lower and upper respiratory tract, and limb muscles during exercise

2.2.1  Afferent and Efferent Pathways for Cardiac Reflexes The mechanosensitive and chemosensitive information from the heart is carried in afferent fibres of the vagus and sympathetic nerves. The afferent information is integrated with other inputs from the higher centres for triggering an appropriate output from the cardiovascular nuclei in the medulla. The resting efferent firing in the cervical vagus occurs during post-inspiratory phase while the sympathetic resting firing synchronizes with inspiratory phase of the respiration. The efferent discharge in the pre-ganglionic sympathetic fibres is tonic in nature with a frequency of less than 10–15 Hz. The sympathetic discharges show multiple rhythms of 2–6, 10, 0.05, 5–20 Hz. These rhythms synchronize with respiration and pulse [60, 61]. The efferent firing in nerves can be entrained with stimulated afferent firing [62]. The effect of increase in vagal activity or stimulation manifests within next beat, i.e. next beat is delayed resulting in increase in R–R interval and slowing of the heart rate. On stoppage of stimulus of vagus, the heart rate returns to baseline value in 1–3 s [63]. The effect of sympathetic stimulation occurs on slower time scale as compared to the vagus. On stimulation of the sympathetic nerves, the increase in heart rate (decrease in R–R interval) begins to manifest in 2.5–8 s and reaches maximum in 7–12 s. On stoppage of stimulation the heart rate returns to baseline value in about 15–63 s [62, 63].

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2.2.2  Reflexes Originating from the Baroreceptors The baroreflex is a rapid homeostatic negative feedback mechanism that maintains the blood pressure within the normal range. In natural circumstances, the most likely threat to stable blood pressure is decrease in blood volume due to haemorrhage during fight or after accidental trauma. In bipeds including humans, additional circumstances that leads to sudden decrease in the blood pressure is change of posture from recumbent to standing. Prevention of decrease in blood pressure is critical to avoid loss of consciousness and eventual death. The increase in blood pressure in natural circumstances is usually associated with preparatory stage as well active stage of defence response (fight/flight) and other emotive behaviours. In such circumstances, the baroreflex does not oppose the increase of blood pressure and instead is reset to higher operating levels at the desired blood pressure. The activation of the baroreflex in response to decrease in arterial blood pressure leads to activation of multiple neuro-hormonal mechanisms that act on different components of cardiovascular system to restore the blood pressure and these are: 1. Arterial constriction (increase in peripheral resistance leading to increase in diastolic pressure) 2. Venous constriction (decrease in venous capacitance leading increase in systemic filling pressure) 3. Increase in heart rate and cardiac contractility (increase in cardiac output and systolic pressure) In addition, mechanisms to maintain and restore the blood volume are also activated as part of baroreflex. These mechanisms occur in concurrence with other mechanisms initiated by low blood volume and changes in the osmolality of plasma and include: 1 . Increase in the renal sympathetic nerve activity (retention of salt and water) [64] 2. Release of vasopressin from supra-optic nucleus and paraventricular nucleus of hypothalamus [65] 3. Stimulation of the adrenal glands to release epinephrine and aldosterone 4. Release of adrenocorticotropic hormone via release of corticotropin releasing hormone from paraventricular nucleus of the hypothalamus 5. Activation of thirst and salt appetite Even though changes in the heart rate are quick to occur, it cannot become effective without the arterial and venous vasoconstriction. The restoration of the volume occurs over a longer time scale through activation of the renal sympathetic nerve activity and release of anti-diuretic hormone and adrenocorticotropic hormone and activation of thirst and salt appetite.

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2.2.2.1  Neural Mechanism of Baroreflex The afferent and efferent pathways of the baroreflex are mediated by vagal and sympathetic nerves. For regulation of the blood pressure, the vagal pathways affect the heart rate while the sympathetic pathways affect the all properties of vascular tone and heart. The pressure of the blood in aorta and carotid artery is continuously transduced by the mechanoreceptors located in adventitia of these vessels. The afferent fibres from arch of aorta ascend in the vagus nerve, while the afferent fibres from the carotid sinus ascend in the glossopharyngeal [66]. The circumferential stretching of the elastic vasculature by pulsatile pressure leads to increase in the rate of impulses in the afferent fibres. The properties of aortic receptors are detailed in Chap. 1. The afferent firing is phasic and occurs during systole and early diastole. The rate of firing is proportional to steady state pressure as well as to the rate of change of pressure during the systolic pulse. The dynamic and steady state features of the blood pressure fluctuations are coded by Type I (Type A) and Type II (Type C) baroreceptors, respectively [67, 68]. The varied thresholds for activation of baroreceptors have been reported in the literature and the differences are  due to the nature of stimulus used during the experiments, i.e. steady state pressure or the pulsatile pressure. With the steady state pressure, the threshold for firing of aortic receptor has been determined to be about 80 mmHg, while with the pulsatile pressure, lower values have been reported. The maximal firing rate in afferent  fibres occurs at the blood pressure of 250  mmHg. The rate of firing is considered to be more effective than total number of impulses per cardiac cycle in determination of the quantitative baroreflex response [69]. The aortic receptors and afferents transduce the systemic pressure while the carotid receptors and afferents transduce the pressure in the cerebral circulation. The cerebral circulation is only regional circulation that has separate baroreceptors underlining the criticality of maintenance of blood flow to brain. The aortic as well as carotid baroreflex can independently maintain the blood pressure [70]. In a mismatch between the firing rates from two afferents, the aortic afferent information is preferred for maintenance of blood pressure [69]. The afferents from the aorta have more effects on the heart rate mainly through modulation of the vagal efferent activity rather than sympathetic activity [71]. The neural substrate for integration of afferent information  and activation of efferent sympathetic and parasympathetic outflow is located in the medulla and has been described in detail in Chap. 1. Figure 2.11 shows the schematic of neural circuitry for baroreflex. Briefly, decrease in blood pressure leads to decrease in the firing in the afferent fibres in the vagus and glossopharyngeal. This leads to decrease in the firing of the second-order barosensitive neurons in the NTS. The decrease in the firing of the NTS decreases its excitatory effects on NA resulting in withdrawal of vagal drive with consequent increase in the heart rate. The decrease in firing of the NTS also disinhibits RVLM through decrease in activity of IVLM [72–75]. The increased firing in RVLM leads to increase in sympathetic outflow to the pre-­ ganglion sympathetic fibres in the intermediolateral horn of the spinal cord resulting in vascular as well as cardiac effects.

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Intermediolateral horn of spinal cord

Sympathetic Stimulation

Vagal afferents from the carotid sinus and aortic arch baroreceptors sense low blood pressure

Vagal withdrawal

Fig. 2.11  Neural mechanism of sympathetic activation and vagal withdrawal after fall in blood pressure. RVLM rostral ventrolateral medulla, IVLM intermediate ventrolateral medulla, NA nucleus ambiguus, NTS nucleus tractus solitarius

The modulation of parasympathetic as well as sympathetic efferent affects the heart rate at different time scales. The quick changes in the heart rate occur by the vagal modulation and the sustained changes occur in concurrence with sympathetic activation [62, 63]. The increase in heart rate with change of posture occurs primarily via the modulation of the vagal activity [76, 77]. Species specific differences are also observed. In dogs, the baroreflex during haemorrhage operates mainly via the carotid rather than aortic baroreceptors while in rabbits, the aortic baroreceptors play a primary role [78]. 2.2.2.2  Quantification of Baroreflex Sensitivity Though the inverse relationship between the blood pressure and heart rate was observed in mid-nineteenth century [79], the method for quantification of baroreflex sensitivity in human was established in 1969 [80]. In human, it is done by the raising the blood pressure by injecting a vasopressor (phenylephrine or angiotensin-­II) and noting the changes in R–R intervals. The ratio of change in R–R interval (ms) and change in blood pressure (mmHg) is taken as a measure of baroreflex sensitivity (ms/mmHg). The use of heart rate instead of R–R may be tempting but should not be done because of hyperbolic relationship between the R–R interval and heart rate and data is more consistent when R–R interval is used instead of heart rate for computation of the baroreflex sensitivity. Over years, additional techniques based on the variable pressure neck suction [81] and quantification of spontaneous fluc-

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tuations in the blood pressure and heart rate have been developed [25, 82]. With the development of beat-to-beat non-invasive methods of measurement of blood pressure quantification of baroreflex sensitivity can be easily done in laboratory settings. Even though baroreflex has multiple effects, the heart rate response is used to compute baroreflex (cardiac baroreflex because the quantification is done only for response in heart rate and not the other components of the baroreflex). It must, however, be noted that the changes in the heart rate may not necessarily mimic the vascular or other effects, both in temporal and in amplitude terms. Even though quantification of baroreflex by spontaneous method is attractive, the data shows inherent limitation of this method as a measure of  baroreflex sensitivity. Our lab has reported that in early stage of haemorrhage, the computed spontaneous BRS actually decreases which is counter intuitive as one would expect raised values of baroreflex sensitivity during hemorrhage [83]. We propose that this apparent discrepancy is due to the stiffening of elastic vasculature caused by sympathetic drive initiated via the low pressure receptors in atria and large veins triggered by decreasing central venous pressure during early haemorrhage [84–86]. Similar decrease in baroreflex sensitivity has been reported when lower body negative pressure is used to decrease the central venous pressure [87] or during hypovolemia induced by furosemide [88]. However, when baroreflex sensitivity is computed by neck suction method in these conditions, it is found to be either unchanged or even enhanced. 2.2.2.3  Normal Values of Baroreflex Sensitivity The baroreflex sensitivity in healthy subject is 10–12 ms/mmHg [83, 89, 90]. The latency of the baroreflex mediated changes in firing of vagal efferent and sympathetic efferent is 80 ms and 180–400 ms, respectively [62, 91]. The vagal stimulation has immediate within beat effect, i.e. the next beat is delayed and withdrawal of vagal tone manifests in 1–3 s. On the other hand, the effect sympathetic stimulation on the heart rate is slower to manifest in 2.5–8 s and reaches maximum in 7–12 s. The effect of sympathetic stimulation lasts for about 15–63 s after withdrawal of sympathetic drive. On change of posture increase in the heart rate occurs within next beat and reaches its peak by about 10 s and the blood pressure begins to return to normal values by about 6 s and the restoration of the blood pressure is complete by 12 s [92]. 2.2.2.4  Factors Affecting Baroreflex Sensitivity Physiological changes such as age, standing, and exercise are associated with decrease in baroreflex sensitivity (BRS) [93–95]. Baroreflex is inhibited during inspiration [96, 97]. Sleep is associated with increase in BRS [80]. Anxiety and alertness may lead to depression of baroreflex. As such hypoxia or hypercapnia does not affect BRS [90] but activation of chemoreceptors enhances the sympathetic component of carotid baroreflex during hypoxia [98].

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2.2.2.5  Baroreflex Sensitivity in Diseases Low BRS has been reported in many clinical conditions [99] including renal failure [100–103], cardiovascular disorders [104], diabetes [105], non-alcoholic fatty liver disease [106], and spinocerebellar ataxia [107]. The decrease in BRS can occur due to deficits in the neural pathways or vascular stiffness or both [108]. 2.2.2.6  R  ole of Baroreflex in Short-Term and Long-Term Regulation of the Blood Pressure The role of baroreflex in short- and long-term regulation of blood pressure has fluctuating historical consensus. Initially it was a consensus that baroreflex plays a role both in short- and long-term regulation of the blood pressure. In 1970s, based on the data from the animal experimental, the role of the baroreflex was restricted to short-­ term regulation. The standard understanding is that the baroreflex plays a role only during the short-term regulation of the blood pressure and that resetting of the baroreflex to a higher value leads to the hypertension. However, in obesity induced hypertension as well in experimental hypertension induced by Angiotensin-II, the baroreflex is chronically activated without resetting indicating a role for baroreflex in long term regulation of blood pressure [109]. In hypertension caused by angiotensin-­II, chronic activation of the baroreflex leads to decrease in renal sympatethic nerve activity [64].

2.2.3  Reflexes from Atria The atria are the low pressure chambers of the heart. Due to high compliance, the diastolic volume in the atria is dependent upon the central venous pressure which itself reflects the circulating blood volume (systemic filing pressure). Thus, in contrast to baroreceptors that code for the arterial pressure, the atrial receptors codes for the volume rather than the pressure in atria. The usual circumstances for decrease in the circulating blood volume is haemorrhage or other conditions that leads to decrease in total body water such as diarrhoea or burns. The restoration of blood volume after decrease in circulatory blood volume is primarily a function of reflexes originating in the atria along with osmoreceptors in the brain. The reflexes originating in atria operate in parallel with baroreflex and are not masked by it [110]. The baroreflex on the other hand primarily maintains the blood pressure and does not contribute substantially to the restoration of the blood volume. The reflex responses originating in atria include: 1. Cardiovascular changes to maintain haemodynamics (a) Arterial vasoconstriction

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(b) Increase in systemic filling pressure by vasoconstriction especially in renal and splanchnic beds 2. Conservation of water and electrolyte (a) Increase in secretion of anti-diuretic hormone (b) Decrease in renal sympathetic nerve activity (c) Decrease in secretion of atrial natriuretic peptide 3. Behavioural drinking of water to restore body water. Additionally, sudden changes in venous return due to postural changes also requires quick changes in heart rate and cardiac contractility for beat-to-beat control of stroke volume. These changes are also mediated by the receptors located in the atria. From evolutionary perspective, the reflexes originating in atria are oriented to counter and reverse the effects of the decrease in blood volume. However, most of the experimental data has been obtained by noting the effects of the atrial stretching rather than decrease in stretch that occurs during haemorrhage, because of easier quantification of atrial stretch by balloon or volume expansion. The earliest known effect of volume expansion was increase in the heart rate. The responses to stretching of right and left atria are qualitatively and quantitatively varied [111–113] and also depend on the method of stimulation used, i.e. balloon stretching or increase in perfusing volume. The volume expansion as a method of stimulation of the atria is better than balloon stretching because it is more physiological due to associated haemodynamic effects. The stretching by balloons on the other hand is more useful in characterization of neural pathways. The stretch of atria results in 1. Increase in heart rate (Bainbridge reflex): Even though earlier reports suggested that effect of atrial stretching on heart rate (increase or decrease) depends upon the baseline heart rates,  this  observations has not been found to be consistent [110, 111]. The stretching of left and right atria increases the heart rate. The effect of stretch on heart rate is primarily due to neural mechanism with a minor contribution from the myogenic acceleration. The left atrial stretching shows a biphasic response with initial slowing for few seconds followed by increase in heart rate [110, 112]. 2. Decrease in renal sympathetic nerve activity [114, 115] and renin activity [116]. 3. Increase in the urine outflow [117] with decrease in urine osmolality [112]. These effects are consistently observed with stretching of the left atrium. 4. Decrease in secretion of anti-diuretic hormone [118]. 5. Increase in release of atrial natriuretic peptide [119, 120]. 6. Inhibition of intestinal fluid resorption [121]. 7. Decrease in water intake [122]. 8. Decrease in aldosterone secretion [123]. 9. Change in blood pressure (increase as well as decrease) has been variably reported [54, 124].

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2.2.3.1  Neural Mechanism of Atria Reflexes The wall of the atria has stretch sensitive mechanoreceptors that response to changes in the atrial dimension. Based on the firing patterns and their relation to the cardiac cycle, two types of receptors are identified in the atria (see Sect. 1.3, Chap. 1 for details). Type A atrial receptors are activated during systole of the atria while Type B atrial receptors are activated progressively during the atrial diastole [111]. Type A atrial receptors code for the tension in the atrial wall during contraction, while the Type B receptors code for the diastolic volume in the atria. Though Type B receptors play dominant role in all the responses, Type A may also play a minor role by release of atrial natriuretic peptide [120, 125]. The afferents from the atrial receptors are carried in the vagus and are critical for all components of the responses to atrial stretch [126, 127] and synapse in the NTS (Fig. 2.12). The second order neurons in the NTS carrying atrial sensation project primarily to the nucleus ambiguus, A1 neurons in ventrolateral medulla and C1 neurons of intermediate ventrolateral medulla [115, 128, 129]. These neurons then

SON/PVN.MDH

HypTh

Amygdala

OVLT

Intermediolateral horn of spinal cord

Vagal afferents from Atria

Vagal efferents Cardiac efferents

Renal sympathetic nerve activity

Fig. 2.12  Neural circuitry for reflexes from atria. SON supraoptic nucleus, PVN paraventricular nucleus, MDH medial dorsal hypothalamus, OVLT organum vasculosum of lamina terminalis, RVLM rostral ventrolateral medulla, IVLM intermediate ventrolateral medulla, NA nucleus ambiguus, NTS nucleus tractus solitarius

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project to neurons in the supra-optic nucleus, paraventricular nucleus and neurons of the organum vasculosum of lamina terminalis (OVLT) where the atrial volume information converges with osmolar information for an integrated response for modulation of vasopressin release [113, 118, 130, 131]. The projections also reach lateral hypothalamus for modulation of thirst and to medial dorsal hypothalamus for further projection to modulate of release of adrenocorticotropic hormone [130]. The atrial mechanosensitive projections from commissural sub-nucleus of  NTS also reach lateral parabrachial nucleus for upstream projection to centres modulating water intake [132, 133]. The hypothalamic projections are necessary even for cardiovascular responses. The descending pathways from the hypothalamic nucleus (PVN) to RVLM are important for activation of cardiac sympathetic nerves on stretching of the atria. The stretching of atria leads to increase in the activity of both vagus and cardiac sympathetic efferent nerves. The stretching of right atrium shows increase in sympathetic activity (peak at 20 s) and vagal activity (peak at 40–60 s). The stretching of left atrium leads to an increase in vagal firing along with a biphasic response with initial inhibition of cardiac sympathetic activity followed by the increase in the sympathetic activity. The changes in sympathetic activity dominate therefore the heart rate increases [110]. Even though atrial stretching leads to activation of cardiac sympathetic efferent, the renal sympathetic nerve discharges decrease on atrial stretching [114, 115]

2.2.4  Reflexes from the Left Ventricle The Bezold–Jarisch reflex refers to a triad of bradycardia, hypotension, and apnea on intravenous injection of the veratrum alkaloids. These effects were observed by von Bezold in 1867 and the role of receptors located in ventricles for cardiovascular effects was established in 1939 by Jarisch [59]. The Bezold–Jarisch reflex is elicited by a large number of chemicals present in plant alkaloids, venoms of snake, insects, and marine animals, components of tissues such as potassium, chloride, histamine, and serotonin. The primary effects is severe bradycardia resulting in hypotension. The receptors for the Bezold–Jarisch reflex are widely distributed in the left ventricle [134]. The afferent fibres exit the heart along the course of coronary artery [135]. The afferent information is carried in vagal fibres to NTS for strong activation of the vagus efferent, and inhibition of sympathetic efferents that may be ­preceded by transient sympathoexcitation [136, 137]. Even more complex non-uniformities in Bezold–Jarish reflex have been reported [138]. Neural Mechanism: The afferents from the left ventricle are carried in vagus as well as sympathetic nerves and reach the commissural part of NTS [139, 140]. The central connectivity for sympathetic inhibition and vagal stimulation is similar to that of baroreflex [137]. The bradycardia component of the Bezold–Jarisch reflex can be inhibited by stimulation of periaqueductal grey [141].

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2.2.4.1  Physiological and Clinical Implications of Bezold–Jarisch Reflex Prima facie, Bezold–Jarisch reflex does not seem to serve any physiological purpose. However, following physiological purposes for Bezold–Jarisch reflex, its clinical implication have been proposed: 1. The receptors for Bezold–Jarisch reflex are polymodal even though they were identified in context of chemically mediated excitation of the Bezold–Jarisch reflex. The mechanical activation of the polymodal Bezold–Jarisch reflex receptors can occur with high or very low ventricular pressure (especially with cardiogenic hypotension) and it has been suggested that in such scenario Bezold–Jarisch reflex may be take part in regulation of the blood pressure [142]. Bezold–Jarisch reflex has been shown to blunt arterial baroreflex [143]. 2. It has been also been proposed that apnea and bradycardia of Bezold–Jarisch reflex is part of defense response in presence of toxic chemicals in the environmental air. Apnea prevents further inhalation of these chemical and further loading of the same into the blood while the bradycardia slows the distribution of the inhaled and absorbed chemicals. 3. Bezold–Jarisch reflex may just represent the effects of the venom from snake, bees, scorpions, and marine for quick death of the prey. 4. It has also been proposed that activation of Bezold–Jarisch reflex and slowing of heart during ischemia especially of inferoposterior myocardium may be protective [144]. 5. Bezold–Jarish reflex can also be activated due to severe distortion of the left ventricle that may occur in situations with low end-diastolic volumes (poor venous return), high heart rate, and high myocardial contractility. Such activations have been implicated in vaso-vagal syncope that occurs in the context of exercise, postural challenges, etc. [145–147]. 6. Large (>30%) and rapid decrease in the blood volume leads to bradycardia [143]. For many years, reverse Bainbridge was considered to cause of bradycardia in face of severe hypotension or blood loss. However, it now appears that non-­ myelinated afferent are activated by severe mechanical distortion of the ventricles due to a very low end-diastolic volume and the Bezold–Jarish reflex play dominant role in this phenomenon [148, 149]. 7. Bezold–Jarisch reflex is also thought to underlie the often observed reflex bradycardia and hypotension during coronary arteriography [145].

2.2.5  Cardiac Sympathetic Afferent Reflex Historically, the afferent activity from the heart has largely been reported to be carried in the vagal fibres perhaps due to easier accessibility of vagal afferents for recording during the animal experiments. Experimental data obtained in the late 1960s and 1970s pointed towards physiologically relevant afferent activity in the sympathetic fibres and presence of reflexes responses to the afferent activity in these

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fibres [150–153]. The sympathetic afferent fibres fire at a very low rate (one impulse every cardiac cycle) in comparison to the vagal afferents, and therefore were missed out in the earlier experiments and were thought to be activated only in pathophysiological states such as ischemia [154]. The afferent sympathetic fibres carry mechanosensitive and chemosensitive information from the atria, ventricles, coronaries, large thoracic vessels including aorta, pulmonary artery, and veins [155]. These fibres show tonic activity albeit at a low rate of firing and firing rate increases with ischemia or after application of bradykinin and are responsible for painful sensation of ischemia. The pain of myocardial ischemia is abolished if the sympathetic afferents are removed [156–158]. Release of bradykinin, histamine, and adenosine during ischemia along with increase in K+ and H+ leads to activation of the multimodal sympathetic afferents and contributes to the pain sensation of myocardial ischemia. The cardiac sympathetic afferent reflex is a positive feedback mechanism that enhances the sympathetic drive to the heart. Stimulation of the sympathetic afferents from ventricles, aorta and coronaries lead to widespread increase in the sympathetic efferent activity including the cardiac, renal, and splanchnic nerves [159]. An increase in diameter of aorta results in the pressor reflex (increase in heart and blood pressure) and blunting of the baroreflex [160, 161]. This reflex has also been referred to as cardio–cardiac reflex, viscero-cardiac reflex in early literature [162, 163]. 2.2.5.1  Neural Mechanism of Cardiac Sympathetic Afferent Reflex The sensory afferent information primarily from the ventricles is carried in the sympathetic afferents, myelinated as well as unmyelinated fibres, to the spinal cord. The sensory information is then relayed to the nucleus tractus solitarius (Fig. 2.13). At the NTS, the afferent signals of the cardiac sympathetic afferent reflex converge onto to the afferent signals of the baroreceptors neurons on the NTS for its inhibition [164, 165]. The central cardiovascular neural regions, specifically RVLM and PVN are part of the neural circuitry of the cardiac sympathetic afferent reflex [166, 167]. The early components of the cardiac sympathetic afferent reflex are integrated at the level of the spinal cord, while the late components of the cardiac sympathetic afferent reflex involve the supra-spinal neural elements [162, 168]. The paraventricular nucleus of hypothalamus is critical part of complete circuitry of the cardiac sympathetic afferent reflex [169]. The supra-spinal neural elements provide a tonic inhibitory drive to the spinal components of the cardiac sympathetic afferent reflex [162, 170]. 2.2.5.2  Clinical Importance The heart failure is associated with features of enhanced sympathetic tone such as increase in plasma norepinephrine, vasopressin, renin, angiotensin-II, and aldosterone along with suppressed vagal tone. The elevated sympathetic activity in heart

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PVN Amygdala OVLT

Intermediolateral horn of spinal cord

Baroreceptor afferent

Sympathetic efferents

Sympathetic afferents from Left ventricles, coronary etc

Fig. 2.13  Neural circuitry for cardiac sympathetic afferent reflex. PVN paraventricular nucleus, OVLT organum vasculosum of lamina terminalis, RVLM rostral ventrolateral medulla, IVLM intermediate ventrolateral medulla, NA nucleus ambiguus, NTS nucleus tractus solitarius

failure is associated with enhanced cardiac sympathetic afferent reflex [171, 172]. A positive feedback mechanism through cardiac sympathetic afferent reflex rather than inhibition of the baroreflex and other cardiopulmonary reflexes is responsible for elevated sympathetic tone in the congestive heart failure [165, 172, 173]. The high sympathetic drive to heart predisposes it to lethal arrhythmias. The increase in the gain of cardiac sympathetic afferent reflex occurs  at the central level and is caused by increased angiotensin-II and reduced NO in the medullary regions. The RVLM, PVN have implicated in the increase in the cardiac sympathetic afferent reflex in cardiac failure. An enhancement of the cardiac sympathetic afferent reflex has also been reported in early diabetes [174]. Given the central role of sympathetic over-drive in progression of the heart failure and associated attenuation of the baroreflex and cardiopulmonary reflexes, a number of novel strategies are being attempted for modulation of sympathetic overdrive. These include baroreceptor stimulation, vagal stimulation, renal denervation, and stellate ganalion blockade [175].

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2.2.6  Vestibulosympathetic Reflex The postural changes and bodily adjustment for balance during movement is controlled by vestibular system with its cerebellar connections. Given the fact that a change of body posture from lying to standing causes a sudden decrease in blood pressure, a role for vestibular system cue for feedforward maintenance of blood pressure during postural changes is intuitive. Stoppage of blood flow to brain even for few seconds can lead to syncope, therefore a feedforward mechanism that would detect the changes in the posture and initiate mechanism to raise the blood pressure even before it has started falling after change of posture appeared reasonable and the same was shown to be operational in cats [176]. Despite significant literature on the role of vestibular system in regulation of blood pressure during nose-up tilts in last few decades, the baroreflex is still considered to be main mechanism for maintenance of blood pressure during orthostatic challenge. The baroreflex operates as a negative feedback mechanism to detect, minimize, and restore the postural decreases in the blood pressure. The vestibulo-­ sympathetic reflex on the other hand is initiated with change of posture from lying to supine and leads to a feedforward stimulation of sympathetic systems to raise the blood pressure even before it begins to fall [177–179]. 2.2.6.1  Neural Mechanism for Vestibulosympathetic Reflex The change in posture is detected by the otolith receptors in the vestibular apparatus. The afferents originating in pitch sensitive otolith receptors relay in the medial and inferior vestibular nucleus (Fig. 2.14). The neurons in these nuclei project to RVLM, directly as well indirectly through the brain stem nuclei [180]. The vestibular nuclear complex sends projections to NTS, lateral tegmentum, parabarachial complex and paramedian reticulospinal nucleus [181–184]. The paramedian nucleus directly sends projections to pre-ganglionic sympathetic fibres of the intermediolateral horn of the spinal cord. The paramedian reticulospinal nucleus also receives inputs from the pressor region of the fastigial nucleus of the cerebellum [185]. A part of vestibulosympathetic reflex is mediated via cerebellum [186]. The postural information is also sent to paraventricular nucleus for modulation of vasopressin release [187, 188]. The pathways to RVLM result in short latency component of the vestibulosympathetic reflex, while the pathways to paraventricular nucleus results in long latency component of the vestibulosympathetic reflex [189]. 2.2.6.2  P  hysiological and Clinical Implication of the Vestibulosympathetic Reflex The vestibulosympathetic reflex is important to maintain blood pressure during movement especially that involves nose-up tilts and climbing. The changes in the renal sympathetic nerve activity caused by change of posture occur even before the

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Fastigial nucleus

Vestibular nuclei

Afferents from Otolith

pMn

Intermediolateral horn of spinal cord

Sympathetic efferents Fig. 2.14  Neural circuitry for the vestibulosympathetic reflex. pMN paramedian nucleus, RVLM rostral ventrolateral medulla, IVLM intermediate ventrolateral medulla, NA nucleus ambiguus, NTS nucleus tractus solitarius

change of the blood pressure and activation of the baroreflex [190, 191]. Even though it is termed as vestibulosympathetic reflex, the changes in heart rate occur within beat and therefore a role of vagal withdrawal cannot be discounted [179]. The cerebellum may play role in learning of feed-forward responses to maintain blood pressure during complex and high speed learnt movements such as gymnastics. Impairments in vestibular nuclei have been associated with large fall in blood pressure on orthostatic stress [192]. Long term exposure of microgravity results in alterations in vestibulosympathetic reflex in astronauts [193, 194]. Similarly prolonged bed rest also results in attenuation of the vestibulosympathetic reflex [195]. Delay in activation and inability to restore the blood pressure after postural change leads to medical conditions termed as initial orthostatic hypotension and orthostatic hypotension, respectively. Dizziness, light headedness, and even syncope are associated with these conditions due to decrease in cerebral circulation on account of decreasing in blood pressure [196]. A role of impaired vestibulosympathetic reflex in these conditions espeically in context of neurodegenerative disorders should not be discounted.

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2.2.7  Somatosympathetic Reflex The somato-sensory nerves carry the sensory information from varied sensory receptors to the spinal cord. The different sensations are carried in myelinated and unmyelinated fibres, grouped as Group I to IV [197]. The stimulation of these afferent sensory fibres produce differential effects on the efferent sympathetic activity ranging from excitation to depression and no effect [198–201]. Stimulation of Group I fibres (muscle and tendon organ) does not cause any change in the sympathetic activity. Stimulation of Group II and III (myelinated, mechanosensitive from muscles and joints) results in initial activation followed by depression of sympathetic activity. Stimulation of Group IV (unmyelinated, chemosensitive receptors in muscles) leads to the activation of the sympathetic efferent pathways affecting blood pressure and heart rate. The somatosympathetic reflexes are of short latency and long latency operating at the spinal or supraspinal level, respectively. Stimulation of Group II afferents results long latency supra-spinal sympathetic reflex while that of Group III results in short latency spinal sympathetic reflex. Stimulation of Group IV (unmyelinated) results in short as well as long latency sympathetic responses [201]. 2.2.7.1  Neural Mechanism of Somatosympathetic Reflex The somatic afferents relay in the dorsal column pathway and synapse in the laminar regions nears the intermediolateral horn of the spinal cord (Fig. 2.15). The short latency component of somatosympathetic reflex is integrated at this level. The

Intermediolateral horn of spinal cord

Dorsal column

Somatic Afferents

Sympathetic efferents

Fig. 2.15  Neural circuitry of the somatosympathetic reflex. RVLM rostral ventrolateral medulla, IVLM intermediate ventrolateral medulla, NA nucleus ambiguus, NTS nucleus tractus solitarius

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ascending somatic information project to the medullary centre to finally reach rostral ventrolateral medulla [202, 203]. The rostral ventrolateral medulla then relays the long latency component of the somatosensory reflex. The spinal component is under tonic inhibition from the RVLM [204]. 2.2.7.2  Physiological Implications of Somatosympathetic Reflex The sensory information from the exercising muscles is carried in Group III and Group IV somatic afferents. The Group III carries the mechanosensitive information from the exercising muscle, while Group IV carries the information regarding  metabolic state of the exercising muscles [205, 206]. The activation of these afferents leads to increase in the blood pressure and heart and this phenomenon is termed as exercise pressor reflex [207, 208]. The increase in blood pressure and heart rate during exercise is driven by feedforward mechanism from the higher centres and feedback signal from the exercising muscles. Group III and IV afferents from muscle start firing immediately upon the start of muscle activity [209]. In heart failure, the somatosympathetic reflex gets activated at a lower workload.

2.2.8  Cardiorespiratory Coupling Cardiovascular system and respiratory system operate in sequence for transport of oxygen and carbon dioxide between the external environment and the cells of the body. The respiratory system provides a means of external convection for movement of air between the external environment and alveolar exchange zone (respiratory membrane) where diffusion of oxygen and carbon dioxide occurs between air and blood. The cardiovascular system provides a means for internal convection for movement of the blood with dissolved gases between the alveolar exchange zone and the cells of the body. Ventilation (achieved by respiratory system) and perfusion (achieved by cardiovascular system) is synchronized at all levels of operation for efficient transport of gases. The coupling of cardiovascular system and respiratory systems is an operational necessity. Cardiorespiratory coupling refers to various phenomena that show synchronization between cardiovascular variables and respiratory variables observable in ­animals including humans. These couplings result in shared input, common rhythms, and complementary functions of the cardiovascular and respiratory system. The couplings can be grouped into: 1 . Respiratory system driven couplings 2. Cardiovascular system driven couplings The earliest observed couplings were the cyclical fluctuations in blood pressure and heart rate with respiration (respiratory sinus arrhythmia). The heart rate

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increases with inspiration and decreases with expiration. With experimental observations, advancement in technology and computation tools many other couplings have been recognized. These will now be discussed individually. 2.2.8.1  Respiratory System Driven Couplings 1 . Respiratory modulation of the heart rate and blood pressure 2. Respiratory modulation of sympathetic activity and modulation by baroreflex 3. Effect of phase of respiration on baroreflex 2.2.8.1.1  Respiratory Modulation of Heart Rate and Blood Pressure The earliest observation that demonstrated coupling between the respiration and cardiovascular system was the cyclical fluctuations of the heart rate (respiratory sinus arrhythmia) and blood pressure (Traube–Hering waves) with respiration. The cyclical fluctuations of heart rate are easily entrained by the frequency of respiration [210]. The heart rate increases with inspiration and decreases with expiration. The respiratory sinus arrhythmia is primarily due to the modulation of the vagal efferent activity but respiratory rhythmicity is also observed in cervical sympathetic nerves [211, 212]. The respiration driven increase in sympathetic nerve activity is maximal in late inspiration and early expiration [213]. On the other hand, the activity of vagal fibres shows increased respiratory firing during the post-inspiratory phase and decreased firing during inspiration and late expiration. The respiration affects blood pressure  mechanistically. The negative intrathoracic pressure during inspiration leads to increase in venous return to the right atrium and increase in right ventricular stroke volume [214]. This increased right ventricular output passes through the lungs and reaches the left atrium after a delay of few beats. In addition, the expansion of the lungs during the inspiration increases vascular capacity of the pulmonary circulation such that the increase in venous return to right atrium manifests as increase in the left ventricular stroke volume after a delay. When the respiratory frequency is set to once every 10 s (5 s inspiration and 5 s expiration), the inspiration is associated with fall in the blood pressure while the expiration is associated with rise in the blood pressure as a result of combination of time lag and cyclic nature of the respiration (Fig. 2.16). Mechanism of RSA The mechanism of respiratory sinus arrhythmia (RSA) was initially elucidated in animal experiments and was later deciphered in the human subject who had undergone cardiac or lung transplants. The RSA is sum total of following mechanisms/ components [215, 216]:

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Fig. 2.16  Fluctuation of blood pressure and heart rate with respiration

1 . Central component driven by the cardio-respiratory centres in the medulla 2. Peripheral pulmonary component driven by the afferents from the lungs 3. Peripheral cardiac component driven by atrial receptors and mechanisms intrisinc to heart 1. Central Component of the Respiratory–Cardiovascular Coupling The respiratory neurons of the ventral respiratory column directly project to the RVLM [217, 218]. The neurons of the RVLM show multiple types of respiration related characteristics such as increasing or decreasing activity with different phases of respiration [219]. The neurons from the pre-Bötzinger projects facilitate GABAergic inhibition of the NA, thereby leading to vagal withdrawal during inspiration. The central component of respiratory modulation of heart rate, sympathetic nerve activity and blood pressure requires input from Pons [213] and the Kolliker–Fuse [220]. 2. Peripheral Components of the Respiratory–Cardiovascular Coupling The neurons of the NTS receive converging inputs from the baroreceptors and inflation specific receptors from the lungs. These neurons of NTS show inhibition that coincides with inspiration [221]. The baroreceptive neurons of the NTS send a stimulatory projection to the NA. The inhibition of these neurons during inspiration decreases the vagal output leading to increase in the heart rate. 3. Peripheral Cardiac Component Driven by Atrial Receptors and Mechanisms Intrinsic to Heart The inspiration results in increase in venous return due to decrease in intrathoracic pressure. The stretching of the heart by balloon or increase blood volume results in increase in the heart rate. The increase in the heart rate can occur via a neural mechanism as described in Section 2.2.2.3 or due intrinsic property of the right atrium or due to short latency reflexes of ICNS (Chap. 1). The heart rate changes primarily occur by modulation of the vagal activity rather than sympathetic efferent activity, given the time frame in which the respiratory sinus arrhythmia occurs [222, 223]. Thus, either the vagal output decreases during

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the inspiration to quicken the heart or vagal output increases during the expiration to slow down the heart or both. The data suggests the during inspiration the activity of the NA is inhibited by central pre-Bötzinger neurons and a loss of drive from barosensitive NTS neurons and during the expiration the activity of NA increases by stimulation of the post-inhibitory neurons of respiratory neural network. The magnitude of the contribution of each component in RSA is different in animals and human. In animals, the RSA is majorly driven by the central and peripheral pulmonary components [216]. The central and peripheral pulmonary components operate independently and can compensate for the absence of the other. Studies on humans who had undergone heart or lung transplants have shown that about 50% of RSA is due to peripheral pulmonary component, 35% is due to central component and 15% is from the non-neural peripheral cardiac components [224, 225]. Additionally, it has been proposed that in humans, the heart rate fluctuations at respiratory frequency, are simply a manifestation of baroreflex fluctuating at respiratory frequencies [226]. Physiological Role of RSA RSA is universally observed in all vertebrates. In fish, heart rate fluctuates rhythmically with the movement of gills [227, 228]. Evolutionary persistence of such a relationship is considered either to be of functional important or just an epiphenomenon without any physiological consequence. Based on experimental data, it was proposed that increase in the heart rate during inspiration, ensures that the stroke volume does not increase with increase in venous return during  inspiration. This assumes importance in the context of quantitative information that the capillary volume of pulmonary circulation is almost equal to stroke volume. Thus, the volume of blood that can exchange gases in the alveoli is approximately equal to the stroke volume and is replaced with every beat. It is also pertinent to note that the capillary flow in the pulmonary circulation is pulsatile, the pulmonary arterial system does not show autoregulation and does not have pre-capillary sphincters. Therefore, any increase in stroke volume above the capillary volume will be similar to physiological shunting and any decrease in stroke volume below the capillary volume will be similar to physiological dead space. The changes in heart rate with phase of respiration is presumed to ensure matching of the stroke volume with pulmonary capillary volume to minimize the physiological shunting and physiological dead space to increase the efficiency of the oxygen transport [229–231]. However, the role of RSA in humans in increasing the efficiency of oxygen transport has been guardedly supported on the basis of obtained data [232–234]. Based on limited data, a role of RSA in stabilization of the blood pressure has also been proposed [235, 236].

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Clinical Value of RSA The magnitude of RSA is computed as a ratio of longest R–R interval during expiration and smallest R–R interval during inspiration. A value above 1.21 is considered normal for human beings. Even though the dependence of the RSA on intact vagus [237] and back ground vagal tone was established in 1930s [63, 215], the quantification of RSA in human and its clinical potential was explored from 1980s onwards. This was perhaps due to technology challenges in automation of processing that was required for routine clinical use. A number of reports were published regarding the possible utility of the RSA as measure of vagal tone in diabetes [238], sick sinus syndrome [239], athletes, elderly [240], hypercapnia [241, 242], psychological states [243], and depth of anesthesia [244]. Given the fact that the RSA can be driven by central as well as peripheral components, RSA alone should not be taken as a measure of autonomic neuropathy [245]. With accumulating data, the consensus is that the RSA as a measure of vagal tone is of limited use (r = 0.6) in human [237]. 2.2.8.1.2  R  espiratory Modulation of Sympathetic Activity and Modulation by Baroreflex The activity in the efferent sympathetic nerve fibres show respiratory modulation with maximum discharge coinciding with the inspiration [211]. The respiratory fluctuations are observed not only in the cardiovascular sympathetic efferent fibres but also in sympathetic efferent supply to other organ systems such as renal, adrenal, and muscles. Neural Mechanisms for Respiratory Modulation of Sympathetic Activity The ventral respiratory column in the medulla is the site of generation of the inspiratory and expiratory rhythms. The RVLM, located next  to VRC, sends the spinal projections to activate the sympathetic pre-ganglionic fibres in the intermediolateral horn of the spinal cord (Chap. 1). The ongoing inspiratory  activity in the pre-­ Bötzinger /rostral ventral respiratory group is transmitted to RVLM. Even though both these respiratory and cardiovascular regions are located next to each other in the ventral part of the medulla, the data suggests that their connectivity is looped via the neuron groups in Pons [213]. Clinical Implications of Respiratory Modulation of Sympathetic Activity Hypercapnia has been shown to enhance the inspiration associated rise in sympathetic nerve activity and appearance of sympathetic activity during the expiration. Chronic intermittent hypoxia and hypercapnia associated with obstructive sleep apnea results in sustained activation of the sympathetic efferent during inspiration as well expiration. This is thought to be responsible higher neurogenic hypertension in patients with obstructive sleep apnea [246].

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2.2.8.1.3  Effect of phase of respiration on baroreflex Vagal as well as sympathetic components of baroreflex as well as chemoreflex are inhibited during inspiration and facilitated during postinspiration and expiration in animals as well as human [96, 97, 247, 248]. These effects are mediated through central as well as pulmonary afferents [249, 250]. The baroreflex is more effective during expiration as compared to inspiration [251]. 2.2.8.2  Cardiovascular System Driven Couplings 2.2.8.2.1  Effect of Baroreflex on Respiration The effect of baroreflex on respiration were observed during animal experimental when it was notice that sudden changes in the blood pressure led to changes in the duration of the inspiratory and expiratory phase of the respiration along with changes in the tidal volumes. Increase in pressure lead to prolongation of the inspiratory and expiratory phase and decrease in pressure had opposite effect. However, in both the situations, the tidal volume decreased [252, 253]. In whole animal experiment, stimulation of baroreceptors during inspiration leads to prolongation of inspiration and stimulation during expiration leads to prolongation of expiration. But in whole brainstem model, the effect of baro-stimulation occurs only during the expiration phase with prolongation of expiration [254]. Neural Mechanism: The afferent fibres from the baroreceptor in the carotid sinus and arch of aorta carried in glossopharyngeal and vagus relay in the NTS.  The second-­order barosensitive NTS neurons project to post-inspiratory neurons, aug E neurons and other neurons in the ventral respiratory column including the regions of the pre-Bötzinger complex, Bötzinger complex, and the ventral respiratory group. The post-inspiratory complex gets dense projections from pontine nuclei and these are critical for effect of barostimulation effects on respiration. The Kolliker–Fuse nuclei of the pons is the most likely neuronal group as it also participates in the respiratory sinus arrhythmia. The respiratory neurons in medulla show baroreceptor input modulation and barostimulation activates post I neurons and depresses the augE neurons. 2.2.8.3  Cardiorespiratory Synchronization and Coordination The advancement in computation  has revealed much deeper levels of relatioship between heart rate and respiratory cycle which were otherwise invisible. Two terminologies are used to describe these relationships namely, synchrogram and coordigram. The synchrogram are plots of occurrence of heart beats with the phase of the respiration (phase domain) while the coordigram are plots of the timing of the heart beats from the start of inspiration (time domain). It was observed heart beats tended to cluster at specific phase of the respiration. The synchronization between heart

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beat and respiration is higher in athletes. The synchronizations are impaired in patients with sleep apnoea. Cardiorespiratory coordination is observed in patients under anesthesia, during rest, and sleep [255, 256]. With the development of wearable physiological monitoring devices and use of advanced methods of data processing, it is likely that many more hidden relationships are likely to emerge. Whether these have biological value or are just epiphenomenon can only be revealed with time.

2.2.9  Regulation of Circulatory Blood Volume The terrestrial animals have evolved robust mechanisms for homeostasis of the body fluids and its osmolality, sodium being the major cation. Under natural circumstances, decrease in body fluids occurs due to unavailability of drinking water and salt, loss of body fluids due to vomiting and diarrhoea, and loss of blood during fight, flight, or accidental trauma. Out of the total volume of the body water (~42 L for average 60 kg man), ~66% (~27 L) is intracellular, ~24% (~10 L) is in interstitial compartment and ~8% (~3.3 L) is in the intravascular compartment. Out of the three compartments in which the body fluid is distributed, the intravascular compartment is the most vulnerable and critical for body fluid homeostasis. Presence of adequate amount of the blood volume is prerequisite for normal haemodynamic functioning of the cardiovascular system and evolutionary selection pressure have resulted in development of robust mechanism to defend it. The neural regulatory mechanisms use the volume and osmolarity of the intravascular fluid as representative of the status of total body fluid and this strategy works because all three compartments are in continuous equilibrium with each other. 2.2.9.1  Haemodynamic Response to Haemorrhage The recordings of atrial pressures and cardiac output during experimental haemorrhage in volunteers during World War II provided data upon which the detailed understanding of the haemodynamic response to haemorrhage has been built. Two distinct phases of response were identified in these studies. In the initial phase, the compensatory mechanisms maintain adequate pressure and cardiac output. The intensity of compensatory mechanism is proportional to progressively increasing blood loss. Later, with loss of about 30% of total blood volume, the compensated phase suddenly shifts to a decompensated phase with dramatic fall in blood pressure and cardiac output. The shift from compensated phase to decompensated phase is associated with reduction of heart rate and happens too quickly to be relegated as a passive process due to failure of compensatory mechanisms and it was later identified to an active mechanism.

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2.2.9.1.1  Phase 1: Compensated Phase (Sympathoexcitation) The neuro-hormonal response to haemorrhage is directed towards maintenance of haemodynamic stability and restoration of blood volume. The intensity and effectiveness of the homeostatic response to haemorrhage is primarily dependent upon the amount and rate of the blood loss. The other factors such as age, gender, constitutional differences, general health (nutrition, fluid balance), season, environmental temperature also affect the magnitude of cardiovascular response [257]. This phase is associated with sympathetic activation [258] resulting in increase in heart rate, increase in cardiac contractility, and vasoconstriction in the venous compartment and selected arterial compartments. The vasoconstriction occurs predominantly in the splanchnic and musculocutaneous vascular beds with sparing of the ‘vital’ cerebral and coronary vascular beds [257, 259, 260]. The vasoconstriction begins to occur early in the progressive haemorrhage and significant rise of heart occurs only after loss of about 10% of blood volume [261]. Release of catecholamines due to sympathetic stimulation also leads to decrease in clotting time, rise in blood glucose, dilation of pupils, and sweating in man. A blood loss of less than 25–35% of total blood volume  can be compensated by neuro-hormonal responses. Passive elastic recoil of vasculature leading to redistribution of the blood and transcapillary movement of fluid from the interstitial compartment to the intravascular compartment also play a role during the compensated phase. Importance of Reflex Constriction of the Capacitance Vessel Vasoconstriction is an important component of response [262] and intact sympathetic nervous system is critical for vasoconstriction [47]. The total available blood volume in the body is notionally divided into the stressed (1.5 L) and unstressed volume (3.5 L). The unstressed volume is considered haemodynamically inert and it just fills the vasculature. In absence of any compensatory mechanism, loss of 1.5 L of blood volume would result in drop of mean circulatory filling pressure to zero. Zero mean circulatory filling pressure means no venous return and hence total cessation of cardiac output. However, due to venoconstriction about ½ of the 3.0 L unstressed blood volume is converted to adequate stressed blood volume to maintain adequate mean circulatory filling pressures, venous return, and cardiac output despite loss of about 20–30% of blood volume. 2.2.9.1.2  Neural Mechanism for Phase I (Compensated Phase) In humans, the cardiopulmonary mechanoreceptors in the great veins and atria play an important role in detection of mild haemorrhage [259, 263]. Even a mild decrease in central blood volume results in the decrease in central venous pressure and is detected by these low pressure volume receptors. The baroreceptors are brought into play only when blood volume loss is large enough to cause decrease in blood pressure [264]. It is also proposed that decrease in pulse pressure or stiffening of the

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aorta and carotid due artery to sympathetic stimulation initiated by cardiopulmonary receptors may lead to decrease in neural firing in baroreceptors afferents (neuromechanical dissociation) leading to activation of baroreflex even though the mean arterial pressure is apparently normal. The sympathetic activation initiated through the cardiopulmonary afferents from low pressure volume receptors leads to selective activation of renal sympathetic nerves and later when the baroreflex is activated, a generalized vasoconstriction occurs in all the beds with relative sparing of the cerebral and coronary vascular beds [148]. The afferent information from the cardiopulmonary afferents and baroreceptors is carried via vagus and hypoglossal nerve to the nucleus tractus solitarius. Through the medullary and supra-medullary cardiovascular network, reflex mechanisms are activated for: 1. Cardiovascular changes to maintain haemodynamics: (a) Arterial vasoconstriction (b) Venous vasoconstriction (c) Increase in cardiac contractility (d) Increase in heart rate 2. Conservation of water and electrolyte (a) Increase in secretion of vasopressin (b) Increase in renal sympathetic nerve activity (c) Decrease in secretion of atrial natriuretic peptide 3. Behavioural drinking of water to restore the volume. The cardiovascular response is quick and it maintains adequate cardiac output and perfusion to tissues. However, it does not correct the primary error which is the loss of blood volume. The restoration of the blood volume occurs by shift of body fluid from the interstitial fluid to intravascular fluid (mechanical), reflex decrease in further loss of sodium and water from the kidneys and most importantly activation of the thirst mechanism for water intake. Without water intake the lost blood volume cannot be restored. The naturally available water is hypotonic and therefore salt appetite is activated along with thirst so that decrease in osmolality on drinking of natural hypotonic water is prevented. The increase in renal sympathetic nerve activity is an important part of this response because it leads to activation of renin–angiotensin mechanism. The angiotensin-­II directly stimulates the neurons of the lamina terminalis for initiation of secondary mechanism for restoration of the blood volume by activation of  thirst mechanism, salt appetite, and secretion of vasopressin. Vasopressin may not rise till large fall in blood pressure occurs and it may play a role perhaps in long-term regulation for restoration of the blood volume. The neural substrate for the Phase I response is shown in Fig. 2.17. Briefly, the afferents from the cardiopulmonary receptors, baroreceptors synapse in the nucleus tractus solitarius. The medullary network leads to inhibition of the nucleus a­ mbiguus (vagal withdrawal) and activation of the rostral ventrolateral medulla (sympathetic

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SFO

Osmolarity

MnPO OVLT

PVTh Thirst, Salt appetite PVN/SON Vasopressin PB

Intermediolateral horn of spinal cord Baroreceptor afferent Ang II

Renal Sympathetic nerve efferent

Cardiopulmonary afferent

Fig. 2.17  Neural substrate for compensated phase of response to hemorrhage. SFO sub-fornical organ, MnPO median preoptic nucleus, PVTh paraventricular nucleus of thalamus, OVLT organum vasculosum of lamina terminalis, PVN paraventricular nucleus of hypothalamus, SON supraoptic nucleus, PB parabrachial nucleus, RVLM rostral ventrolateral medulla, IVLM intermediate ventrolateral medulla, NA nucleus ambiguus, NTS nucleus tractus solitarius

activation). The increase in angiotensin-II due to activation of the renin–angiotensin system is detected by the sub-fornical organ while the changes in osmolarity are detected by the organum vasculosum of the lamina terminalis [265–267]. Aldosterone also stimulates neurons in the nucleus tractus solitarius and sub-­ fornical organ. The sub-fornical organ and organum vasculosum of lamina terminalis are located outside the blood–brain barrier and project to the median pre-optic nucleus which is now considered to be integral to the body fluid homeostasis [268]. The projections of median pre-optic nucleus to paraventricular nucleus and lateral hypothalamus modulate the sympathetic activity through its connections with cardiovascular neural network in medulla. The projection to paraventricular nucleus of thalamus modulates the thirst and salt appetite through its connection to cingulate and insular cortex. The projections to supra-optic and paraventricular nucleus also modulate the endocrine and autonomic responses. The projection from sub-fornical organ and nucleus tractus solitarius also reach bed nucleus of stria terminalis perhaps for memory of aversive sensations or situations that may have led to the loss of blood or body fluids [269]. The lateral parabrachial nucleus and dorsal raphe nucleus

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have also been implicated in the regulation of body fluid volume and osmolarity [270, 271]. 2.2.9.1.3  Phase 2: Decompensated Phase (Sympathoinhibition) With progressive loss of blood volume, it is observed that compensated phase suddenly shifts into a decompensated phase with sudden drop in blood pressure and heart rate with vasodilation and paradoxical rise of right atrial pressure. Data obtained using lower body negative pressure have shown that based on the time and quantum of hypovolemia at which the decompensation occurs, people can be grouped into those with high tolerance and those with low tolerance [272]. Individuals with high tolerance are able to maintain cerebral perfusion better, have greater reserve of increase in heart rate, smaller stroke volume, and higher increase in peripheral vascular resistance. The high tolerance individuals also demonstrate better vagal withdrawal, higher rise of sympathetic tone, and better neuro-endocrine vasopressor response, and a  decrease in spontaneous baroreflex (a measure of increased vascular stiffness) [83]. It has also been observed that oscillations in sympathetic response (assessed by oscillations in blood pressure) are associated with good tolerance, and this may be of use in early detection of those with poor tolerance. Decompensation is sudden with sympathetic withdrawal and vagal stimulation due to (1) local vasodilation caused by accumulation of metabolites during tissue hypoxia (2) activation of the Bezold–Jarish reflex especially in rapid haemorrhage with high heart rate and low stroke volume and (3) activation of ischemic nociceptive afferents in tissue because of tissue hypoxia due to intense arterial vasoconstriction [148, 259, 273]. Neural Mechanism of Decompensation The sharpness and suddenness with which an individual shifts from the compensated state to the decompensated state along with sympathoinhibition suggested active involvement of the neural centres in the brain. Figure 2.18 shows the neural substrate for decompensated phase. The ventrolateral periaqueductal grey is central to the decompensated phase [274]. The ventrolateral periaqueductal grey receives vagal inputs from nucleus tractus solitarius and ischemic signals from peripheral tissues through polysynaptic pathways. It sends descending excitatory signals to caudal ventrolateral medulla [275, 276] and inhibitory signals to rostral ventrolateral medulla [277]. It is pertinent to mention here that the vasodepressor action of the ventrolateral periaqueductal grey is part of larger response consisting of behaviour quiescence, decrease vigilance, hyporeactivity, and opioid analgesia on severe trauma and deep pain [278]. Recent data suggests that people with low tolerance and high tolerance show quantitatively similar response to haemorrhage but the threshold of activation of the ventrolateral periaqueductal grey may be lower in people with low tolerance to haemorrhage [279].

2  Physiology of Cardiovascular System Fig. 2.18  Neural substrate for decompensated phase of response to hemorrhage. vlPAG ventrolateral periaqueductal grey, PB parabrachial nucleus, RVLM rostral ventrolateral medulla, IVLM intermediate ventrolateral medulla, NA nucleus ambiguus, NTS nucleus tractus solitarius

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Nociceptive afferents from tissues Afferents from ventricles (Bezold-Jarish) Infusion of blood or other supplements to increase the blood volume: The purpose of the volume infusion is to increase the unstressed volume reserve. In a background of sympathetic drive, infusion of fluids to increase the volume of blood will lead to reflexive withdrawal of the sympathetic tone and the unstressed volume will increase with relaxation of the vasculature. However, if the vasoconstrictive drugs have been given, then rapid infusion may actually add only to stressed volume as the vessels are not relaxing and this will lead to increase in the mean circulatory filling pressure. The increase in the mean circulatory pressure has additional consequences on capillary filtration and leads to leak of the fluid into the third space resulting in loss of inflused fluids into extravascular space. When intervention is done, the response is dependent upon rate, site of infusion, condition of the transfused blood, anaesthetic conditions, and degree of trauma or surgical bleed. Acknowledgements  The concepts and information presented in this chapter have been drawn from the research reports of hundreds of scientists from countless laboratories over last century, only a few of whom have been referred directly. We have made efforts to compile diverse and detailed data into simple unifying notions, to be able to visualize forest without losing sight of the trees.

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Chapter 3

The Brain–Heart Crosstalk Anna Teresa Mazzeo, Valentina Tardivo, Simone Cappio Borlino, and Diego Garbossa

Contents 3.1  S  tress-Related Cardiomyopathy Syndromes in Anaesthesia and Intensive Care 3.2  Pathophysiology of Neurogenic Stress Cardiomyopathy (NSC) 3.2.1  Main Pathogenetic Mechanisms of NSC 3.2.2  Cardioregulatory Centres 3.2.3  Polymorphisms of Adrenergic Receptors 3.3  Clinical Implications 3.3.1  Clinical Manifestation 3.3.2  Monitoring for NSC 3.3.3  Treatment of NSC 3.4  Conclusions References

                                

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Abbreviations ACS AIS ANS ARs

Acute coronary syndrome Acute ischemic stroke Autonomic nervous system Adrenergic receptors

A. T. Mazzeo (*) Division of Anesthesia and Intensive Care, Department of Surgical Sciences, University of Torino, Torino, Italy Azienda Ospedaliera Universitaria Policlinico G. Martino, Messina, Italy e-mail: [email protected] V. Tardivo · D. Garbossa Neurosurgery, Department of Neurosciences and Mental Health, University of Torino, Torino, Italy S. Cappio Borlino Division of Anesthesia and Intensive Care, Department of Surgical Sciences, University of Torino, Torino, Italy © Springer Nature Singapore Pte Ltd. 2020 H. Prabhakar, I. Kapoor (eds.), Brain and Heart Crosstalk, Physiology in Clinical Neurosciences – Brain and Spinal Cord Crosstalks, https://doi.org/10.1007/978-981-15-2497-4_3

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AV node Atrioventricular node CAD Coronary artery disease CBN Contraction band necrosis CI Confidence interval CM Cardiomyopathy CNS Central nervous system COMT Catechol-O-methyl-transferase ECG Electrocardiogram GRK5 G-protein-coupled receptor kinase 5 HR Hazard ratio ICH Intracranial haemorrhage LV Left ventricle LVEF Left ventricular ejection fraction NOS Nitric oxide synthase NSC Neurogenic stress cardiomyopathy NSM Neurogenic stunned myocardium RWMA Regional wall motion abnormality SA node Sinoatrial node SAH Subarachnoid haemorrhage TBI Traumatic brain injury TNF Tumour necrosis factor TTC Takotsubo cardiomyopathy

3.1  S  tress-Related Cardiomyopathy Syndromes in Anaesthesia and Intensive Care In the setting of organ crosstalk, the interaction between brain and heart emerges in a prominent way in case of acute brain damage, regardless of the nature of the injury. As a matter of fact, in these patients, the brain–heart crosstalk may be responsible for cardiac dysfunction potentially affecting their management and the prognosis. This phenomenon has been described as stress-related cardiomyopathy [1], a spectrum of myocardial disorders in which the heart muscle is structurally and functionally abnormal, in the absence of coronary artery disease (CAD), hypertension, valvular disease and congenital heart disease able to cause the observed myocardial abnormality. Ivan Pavlov was the first to postulate that dysfunction of a visceral organ can occur due to a neurological insult [1]. Later, in 1942, Dr. Cannon, published a paper entitled “‘Voodoo’ Death”: he described anecdotal experiences, largely from the anthropology literature, of death from fear, and he hypothesized that death was caused “by a lasting and intense action of the sympathoadrenal system” [2]. Haemorrhage into the subarachnoid space (SAH), traumatic brain injury (TBI) [2], stroke [3], either haemorrhagic or ischemic, infections of the central nervous

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system and epileptiform seizure activity may induce a syndrome known as neurogenic stress cardiomyopathy (NSC) [4, 5]. The stress-related cardiomyopathy syndromes include NSC and takotsubo cardiomyopathy (TTC) with its typical apical and midventricular myocardial dysfunction. Despite some authors advocate that a distinction should not be made between these two conditions—as they show the same clinical presentation, tendency to resolve in some days and, probably, a similar pathophysiology—in NSC, an organic or functional injury to the brain is always present, while TTC seems to be triggered by profound psychological or physical stresses in the absence of a structural brain damage. Both NSC and TTC mimic acute coronary syndromes (ACS) and present transient left ventricular hypokinesis. TTC, also known as broken heart syndrome, or ampullashaped cardiomyopathy, resembling the traditional Japanese octopus trap, usually presents with basal hypercontractility and apical akinesia. In NSC, different location of regional wall motion abnormalities (RWMA) have been described, from the involvement of a single segment of left ventricle (LV) to a global LV hypokinesis [6–9]. It is now currently accepted that TTC and NSC are on a continuum of the same pathophysiology, with SAH-induced cardiac dysfunction being on the more severe end of the spectrum [1, 10] and, furthermore, the most frequently described in literature. By definition, stress cardiomyopathy is characterized by an acute cardiac dysfunction that can manifest either as electrocardiographic signs, eventually associated with ventricular or supraventricular arrhythmias, or in the form of left ventricular wall motion abnormalities or with myocardial necrosis enzyme release [3, 11–13]. Stress cardiomyopathy syndromes are usually transient and reversible and, thus, requiring only supportive treatment. However, the clinical course of NCS can be severe, with hypokinesis, akinesia, or dyskinesis of the left ventricle, haemodynamic instability, arrhythmias, cardiogenic shock, pulmonary oedema and sudden cardiac death [11, 14]. Patients with severe neurological impairment may require to be sedated and intubated to be managed in the intensive care unit and may not be able to communicate presenting symptoms. Consequently, most cases of NSC are detected by ECG changes, echocardiographic abnormalities, cardiac biomarkers elevation, or clinical manifestations, such as pulmonary oedema or cardiogenic shock. Acute cardiac complications should be suspected, screened and taken into account while dealing with patients affected by acute critical brain disease, as neurocardiogenic injury is associated with an increased risk of all-cause mortality [hazard ratio (HR): 5.3; confidence interval (CI): 3.0–9.3], cardiac mortality (HR: 7.3; CI: 1.7–31.6), and heart failure (HR: 4.3; CI: 1.53–11.88) [15]. So far, treatment of stress cardiomyopathy has been largely supportive with aims to prevent further brain injury and prevent and treat associated medical complications, which may add further harmful effects to an already potentially life-­threatening neurological disease.

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3.2  P  athophysiology of Neurogenic Stress Cardiomyopathy (NSC) The interaction between heart and brain is complex and integral to the maintenance of normal cardiovascular function. The central nervous system (CNS) has an extensive influence on the cardiovascular system, and the cardiovascular system in turn has both physiologic and pathologic influences on the CNS (such as cardioembolic stroke and cerebral hypoperfusion). The autonomic nervous system (ANS) modulates heart rate and conduction velocity, as well as cardiac contractility through ascending and descending connection to the cardiovascular system. These effects are mainly mediated via parasympathetic and sympathetic nervous system innervation of the sinoatrial (SA) and atrioventricular (AV) nodes. However, these systems are also influenced by supratentorial modulatory centres like the insula [16]. Afferent connections from the cardiovascular system to the CNS play a major role in providing regulatory feedback on cardiac rate and contractility. The afferent system is composed by chemoreceptors and baroreceptors projecting to the brainstem nuclei of the solitary tract and dorsal vagal and forward to the parabrachial nucleus via the fibres of the IX and X cranial nerves [17]. The parabrachial nucleus has connection with the central nucleus of the amygdala, the hypothalamus, the infralimbic cortex (ventromedial prefrontal cortex), as well as with the ventral basal thalamus. From the infralimbic cortex and the basal thalamus (specifically, the paraventricular nucleus), the afferent pathway continues to the ipsilateral and contralateral insular cortex which has relevant descending projection involved in the cardiovascular modulation. The descending pathway continues with parasympathetic ganglia and the superior, middle and inferior cervical sympathetic cardiac nerves along with innervation from the thoracic sympathetic ganglia through the intermediolateral column of the spinal cord to the cardiac plexus. Parasympathetic control is mostly mediated by the vagus nerve. The final targets of the descending autonomic system are the cardiac plexus, the SA node and the AV node [16]. Activation of the sympathetic system leads to an increase of heart rate and contractility, while the parasympathetic branch of the ANS is responsible for slowing heart rate and antagonizing sympathetic input [18]. It has been demonstrated that parasympathetic innervation is richer in atrial myocardium and in SA and AV nodes rather than at the level of the ventricle [19]. Moreover it has been reported that the SA node is mainly innervated by the right vagus nerve, while the left one innervates preferentially the AV node [20, 21]. This anatomic asymmetry seems to explain the component of laterality in neurocardiac manifestation of CNS process reported in humans and animal studies [18]. Based on case series and animal studies, it has been postulated that damage to the CNS may cause cardiac dysfunction via impairment of regulatory centres of the autonomic nuclei [17, 22].

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3.2.1  Main Pathogenetic Mechanisms of NSC Many putative causes of neurogenic stress cardiomyopathy have been proposed over years, such as: 1 . Transient multivessel coronary artery spasm 2. Microvascular dysfunction 3. Aborted myocardial infarction with spontaneous coronary thrombus lysis [23, 24] 4. Increased level of catecholamine The first hypothesis has been a matter of debate in literature. In studies in which coronary angiogram data are available, normal coronary arteries have been documented in the setting of ongoing ST-segment elevation [25–27]. Moreover, in SAH dog models, RWMA have been correlated with angiographic absence of focal coronary spasm [28]. In his work Nguyen et al. highlights that apical-sparing pattern of LV dysfunction, suggests a neurally mediated mechanism of injury and claims against obstruction or vasospasm of the coronary arteries [3]. However, if we focus on TTC, spontaneous coronary artery spasm was observed in 7–40% of cases [29, 30]. Therefore, there is currently no common consensus about the mechanisms underlying the development of local coronary spasm in intact vessels and its potential role in NSC pathogenesis. Microvascular dysfunction theory in NSC is largely unsupported as microvascular perfusion has been demonstrated to be normal by myocardial contrast echocardiography in a SAH dog model [28]. In addition, also clinical case reports have failed to demonstrate decreased perfusion in SAH myocardium, potentially excluding also the occurrence of spontaneous coronary thrombus lysis [26]. Thus, there is little evidence for decreased perfusion or ischemia on a macro- or microvascular level. Therefore, observational studies and experimental models failed to demonstrate strong validity of the first three theories, with only few reports in recent literature. Conversely, the ‘catecholamine hypothesis’, consistent with catecholamine-­ mediated direct myocardial injury, is currently the most accepted and widely reported pathomechanism of NSC [11]. Catecholamine-mediated cardiac dysfunction may involve different mechanisms, like an imbalance between sympathetic and parasympathetic tone, increased production of catecholamines, repolarization abnormalities, premature ventricular beats and other arrhythmias, decrease in baroreceptor reactivity and alteration in sympathetic tone [31]. Catecholamine surge frequently occurs with the neurologic insult and may predispose to repolarization abnormalities, as well as premature ventricular beats and other arrhythmias that could turn into malignant ones [32]. Structural brain damage and a sudden increase in intracranial pressure lead to an autonomic storm followed by an elevation in tissue and circulating catecholamine levels. Naredi et al. reported a threefold increase in total body norepinephrine spill into the plasma within the first 48 h of SAH, and these levels can still be elevated

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after 1 week [33]. High myocardial interstitial concentrations of noradrenaline result in myocyte calcium overload causing cardiac dysfunction, free radical production and adenosine triphosphate depletion, with resulting ECG changes, failure of myocardial contraction and possible cell death [1, 34, 35]. Exaggerated sympathetic stimulation, triggering a switch in intracellular signal trafficking in ventricular cardiomyocytes, has also been proposed as a major pathogenic mechanism of myocardial stunning due to sudden emotional stress [34, 36–38]. In the case of TTC, plasma catecholamine levels at presentation were 2–3 times higher than the values measured in patients with Killip class III myocardial infarction and 7–34 times higher than normal values [36]. Echocardiography revealed that repeated intravenous infusion of epinephrine overdose in cynomolgus monkeys induced Takotsubo-like cardiomyopathy, which was characterized by progressive left ventricle dysfunction and depressed systolic function along with severe hypokinesis in apical regions and hyperkinesis in the basal region [39]. In NSC, cell death results in hypercontracted state with the formation of contraction band necrosis (CBN), early onset of calcification and myofibrillar lesions, seen within minutes of onset, in proximity to cardiac innervation [13]. Most often, the changes are best seen in the anterolateral or inferolateral leads, they are usually reversible and not limited to single epicardial vessel distribution. However, since CBN still occurred following bilateral adrenalectomy, circulating catecholamines do not appear to be the only crucial mediator of neurogenic cardiac injury, but rather suggest that also local release of norepinephrine from myocardial sympathetic nerve terminals is key in the pathogenesis of CBN [40]. According to the results of clinical studies, an excessive release of norepinephrine from myocardial sympathetic nerves in humans was associated with LV systolic dysfunction or even with the development of transient LV apical ballooning [41]. Experimental studies show not only an immediate enhancement of activity in sympathetic nerve terminals with massive release of catecholamines into the cardiac tissue [35, 40, 42] and a small leak into the systemic circulation, but also increased sensitivity to norepinephrine infusion. It is of interest that catecholamines can induce apoptosis of cardiomyocytes and endothelial cells both by direct effects on the cell membrane and by indirect effects via beta receptors. According to the literature, norepinephrine-induced apoptosis in neonatal rat cardiomyocytes through a reactive oxygen species-TNF-caspase signalling pathway and through the adrenergic pathway (via beta-1-adrenergic receptors) [43, 44]. The left ventricle contains apical-basal gradients of β-adrenergic receptors (βARs) and sympathetic innervation, with the apex characterized by highest βAR and lowest sympathetic nerve density. This pattern results in increased apical responsiveness to circulating catecholamines, as a compensatory mechanism for the sparse apical sympathetic innervation, to ensure optimal ventricular response to stress. High plasma levels of epinephrine can act as a negative inotrope through ligandmediated trafficking of the β2AR from stimulatory G protein to inhibitory G protein subcellular signalling pathways. The process of ligand- or stimulus-directed trafficking or biased agonism explains that, at higher concentrations of epinephrine, the

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β2AR switches coupling from Gs protein to inhibitory Gi. This switch happening in favourable conditions of high catecholamine stress depends on β2AR phosphorylation by both protein kinase A and G-protein receptor-coupled kinases (GRKs). Norepinephrine has a much lower affinity (20 times less) for the β2AR compared to the β1AR and weaker β2AR stimulus trafficking to the Gi pathway. Although this negative inotropy is detrimental from a mechanical perspective, the Gs to Gi switch is potentially both antiapoptotic and antidysrhythmic and may represent a cardioprotective mechanism against β1AR catecholamine cardiotoxicity [1, 11]. Despite the catecholamine theory focuses on sympathetic nervous system-­ mediated cardiomyocytes cell death, recent studies reported that also the parasympathetic nervous system may be responsible for ECG abnormalities and cardiac dysfunction in NSC. As a matter of fact, the parasympathetic nervous system modulates the myocardial inflammatory response through acetylcholine receptors [45, 46]. While acetylcholine inhibits the release of pro-inflammatory cytokines, parasympathetic dysfunction may facilitate uncontrolled inflammation, causing myocardial injury [47]. Inflammation as a mechanism in neurogenic stunned myocardium has been supported further by a few studies showing elevation of cytokines such as tumour necrosis factor-α (TNFα), interleukin (IL)-6, IL-8, IL-1β, IL-1 receptor antagonist, platelet-activating factor, and TNFα receptor 1 in cerebrospinal fluid and serum of SAH patients, contributing to neurocardiogenic damage [48–52]. In addition, if an increase in sympathetic tone may lead to supraventricular tachycardia, it is hypothesized that impaired parasympathetic tone caused by right hemispheric injury may be responsible for the excess in arrhythmias [3].

3.2.2  Cardioregulatory Centres As described earlier, brain–heart crosstalk is the result of a fine-tuned system, organized into ascending and descending pathways. Through a series of well-regulated neural mechanisms involving the ANS, the cardiovascular system can adapt its function to respond to challenging clinical conditions. In particular, the hypothalamic-­ pituitary-­adrenocortical and sympatho-adrenomedullary axes play a master role in the stress response that results in neuroendocrine changes, including an increase in epinephrine and norepinephrine levels [53]. Recently much attention has been focused on the “cardioregulatory centres”, brain areas or nuclei that seem to coordinate the brain-heart axis. Several forebrain structures (insula, cingulate cortex, hippocampus, amygdala, and hypothalamus) intimately involved in seizure networks turned out to regulate autonomic output (Fig. 3.1). The insula represents a key cortical site for the brain–heart crosstalk, and it is thought to exert major influence on the baroreflex. The insular cortex contains baroreceptive units of sympatho-excitatory and sympatho-inhibitory neurons that regulate blood pressure and heart rate. Lesions in this part of the brain have been found

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Fig. 3.1 (a) Brain MRI, coronal cut, T2-weighted image in which the main cardioregulatory centres are highlighted, [1] Cingulate gyrus, that is involved in autonomic, affective and cognitive integration; [2] Insula, responsible for autonomic somatotopic representation; [3] Hypothalamus, which plays an important role in the stress response; [4] Temporo-mesial area, where the amygdala is located, involved in the sympathetic response to fear. (b) Brain MRI, axial cut, T1-weighted image, right (R) and left (L) insula are marked. (c) Schematic representation of the lateralization of cardiovascular function in the insular cortex. Several studies support that the right insula predominantly regulates sympathetic tone, whereas parasympathetic effects are described after stimulation of the left insula [54–57]. In patients with acute ischaemic stroke, ischaemia of the right insular cortex was associated with higher arterial pressure and norepinephrine levels, and there was a relationship between right insular cortex lesions, ECG abnormalities and increased risk of mortality at 3 months [56, 58]. Left insular cortex injury can be associated with cardiac dysfunction and myocardial wall motion impairment [59]

to result in an increase in norepinephrine levels in the blood which cause ventricular dysfunction [54, 55, 59]. The type and location of the insular damage may determine the type of myocardial dysfunction as each cerebral hemisphere seems to have a different influence on cardiac function [60], with the right insula principally regulating sympathetic outflow and the left insula controlling parasympathetic action (Fig. 3.1). In the CNS, right insular stimulation in humans has been associated with tachycardia and relative hypotension, while the opposite has been associated with the stimulation of the left insula [55]. Patients affected by AIS, SAH and ICH tend to have elevated level of circulating epinephrine and norepinephrine and resting heart rate if the right insula is involved. Therefore, it has been advocated that this would partially explain the higher incidence of ECG changes and cardiac arrhythmias if the right insula is injured [61]. Barron et al. reported a reduction in heart rate variability (HRV), a measure of cardiovascular autonomic dysfunction, in patients with both left- and right-sided insular infarcts, however a greater reduction in HRV was recorded in patient with infarcts on the right [22]. Tokgozoglu et al. demonstrated that rates of autonomic dysfunction were greater in patients with right insular lesions [62], similar to what was reported by other authors [56, 63]. According to Cechetto et al. different part of the insula regulates different functions, as pressor responses occurred with rostral insular cortex stimulation, while caudal insular stimulation had depressor effects [64].

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Right insular lesions have been associated with a poor prognosis as these subjects have a mortality odds ratio greater than 6 compared to those without a right insular lesion [57, 58]. Thus, evaluation of insular involvement on the neuroimaging techniques may help stratify the relative risk of adverse outcomes when assessing a patient with acute brain injury, suggesting close cardiac monitoring [11, 65]. The insula together with the cingulate cortex and the amygdala forms the “limbic system”, a highly interconnected system, working as interfaces between emotional feeling states engendered by our external environment and social interactions and visceral responses of the body that guide our motivational behaviour. Some clinical studies and neuroimaging experiments with the positron emission tomography suggest that the anterior cingulate cortex together with the insula is particularly involved in the generation of sympathetic responses (Fig. 3.1) [66–68]. The anterior cingulate cortex seems to take part in the efferent cardiovascular response drive through dorsal anterior cingulate activation and ventral anterior cingulate deactivation [69–72]. The amygdala is a subcortical nucleus, important in detecting and learning threat even in the absence of conscious awareness. Links between amygdala function and sympathetic response have been described (Fig. 3.1) [73, 74]. However, while in some studies amygdala activation leads to heart rate acceleration, other studies show the opposite effect or failed to find a correlation with heart rate modification [68, 70, 71, 75]. It has been postulated that the amygdala, with the insula and the periacqueductal grey, forms a site of integration of afferent and efferent autonomic control, where baroreceptor feedback and individual parasympathetic tone alter efferent sympathetic responses to the cardiovascular system [72, 76, 77]. Involvement of the hypothalamus may produce ECG repolarisation changes, increasing sympathetic traffic to the heart and lowering the threshold for electrical induction of ventricular fibrillation as demonstrated in experimental studies on cats [78].

3.2.3  Polymorphisms of Adrenergic Receptors According to the catecholamine theory, stress-related cardiomyopathies are caused by the toxic effect of an exaggerated and uncontrolled release of catecholamine in cardiac tissue and blood after a stressful event, as an acute neurological damage or an intense emotional incident. However, this theory does not explain why only some patients develop cardiac dysfunction, among all those who experience raised catecholamines and plasma levels either after an acute brain injury or after an acute emotional stress. Recently, it has been proposed that specific polymorphisms in the genes of adrenergic receptors and proteins involved in catecholamine regulation may mediate an individual different sensibility to the catecholamine toxic effect on cardiac cells. In the last two decades, the genetic theory stimulated the research towards assessing the implication of many genetic variants in the susceptibility to stress

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cardiomyopathies. As of today, little accordance exists between the different authors, and for none of these polymorphisms, definite and strong evidences have been produced. The most studied polymorphisms and the putative effect on cardiovascular function in stress-related cardiomyopathy are listed in Table 3.1. β1AR is the predominant βAR expressed in myocardium, and it is activated by circulating epinephrine and local norepinephrine released from sympathetic nervous terminals. β1AR activation induces inotropic, dromotropic and chronotropic effect on myocardium [89]. The β1AR(Arg389Gly) polymorphism is a common polymorphism in population, studied in different context: the Arg389 form has a much greater ability to induce cAMP production and intracellular message transduction, increasing myocardium sensibility to catecholamines [89]. Therefore the Arg389 form has been associated with • Higher frequency of troponin I elevation (>1 μg/L) after SAH [80] • Higher risk of RWMA after SAH [80] or brain death [81] • Higher prevalence in TTC patients in relation to control group [79] Patients with Gly389 variant, indeed, demonstrated to require increased dose of dopamine to treat hypotension during organ donor management [81], because it reduces cardiomyocytes sensibility to catecholamines. Nevertheless, not all authors agree on the correlation between β1AR(Arg389Gly) polymorphism and stress-related cardiomyopathy, as multiple studies failed to observe a higher prevalence of the Arg389 variant in patients with stress cardiomyopathy (in particular TTC) [85, 86, 90]. The β1AR (Ser49Gly) polymorphism is another interesting genetic variant of β1AR, because the wild-type genotype (AA form) increases myocardium sensibility to β-agonists stimulation and therefore in patients with heart failure exhibiting high level of circulating catecholamine, it could increase the risk of death or complications [91]. However, the AA genotype alone did not demonstrate an association with higher incidence of myocardionecrosis markers elevation, LVEF reduction, RMWA or higher vasoactive amine requirement after SAH or brain death [80, 81]. β2AR is expressed in myocardium and vascular smooth muscle cells. It mediates cardiac inotropic and chronotropic effect [92], cardiomyocytes apoptosis [93] and vasodilatation [94]. Two different polymorphisms of β2AR were found to be involved in stress-related cardiomyopathy: 1. The Glu27 form of the β2AR(Gln27Glu) polymorphism increases the adrenergic receptor response to catecholamines and therefore carries a beneficial effect facilitating coronary vasodilatation [95]. Conversely, patients homozygous for Gln27 demonstrated a higher risk of coronary events after SAH [83], higher incidence of troponin I elevation after SAH [80] and a trend of association with RWMA after brain death [81]. Nevertheless not all authors agree on the protective effect of Glu27 form, as subjects homozygous for Glu27 were found to be at higher risk of TTC [79]. 2. The Arg16 form of β2AR(Gly16Arg) polymorphism enhances agonist-mediated desensitization of β2AR and probably decreases catecholamine-mediated

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Table 3.1  The most studied polymorphisms of adrenergic receptor and related proteins Gene β1AR

dBSNP ID rs1801253

DNA Variant 1165 C>G

Protein variant β1AR(Arg389Gly)

Putative clinical role in stress-CM Arg389 form associated with: • ↑ risk of stress-CM [79] • ↑ cardiac necrosis biomarkers [80] • ↑ risk of RWMA [81] rs1801252 145 A>G β1AR(Ser49Gly) AA genotype ↑ risk of stress-CM if associated with precedent polymorphism [82] β2AR rs1042714 79 C>G β2AR(Gln27Glu) Gln27 form demonstrated: • ↑ cardiac necrosis biomarkers [80] • ↑ risk of coronary events [83] • ↑ risk of RWMA [81] rs1042713 46 G>A β2AR(Gly16Arg) Gly16 increases the risk of ↓ LVEF [81] α2AR rs17098707 964del12bp α2AR(del322-325) The deletion increases the risk of ↓ LVEF [80] GRK5 rs17098707 122 A>T GRK5(Leu41Gln) Leu41 form → βAR desensitization: inconsistencies in clinical significance [84–87] COMT rs4680 472 G>A COMT(Val158Met) Few evidences on its role in stress-CM [85] eNOS rs2070744 786 T>C – 786 T>C is associated with ↑ risk of: • Myocardial infarction • Arrhythmias • Vasopressors need [88]

α2AR adrenergic receptor type α2, β1AR adrenergic receptor type β1, β2AR adrenergic receptor type β2, CM cardiomyopathy, COMT Catechol-ossi-methyl-transferase, dBSNP single nucleotide polymorphism database, eNOS endothelial nitric oxide synthase, GRK5 G-protein-coupled receptor kinase 5, rs# refSNP cluster, reference SNP ID number in the single nucleotide polymorphism database, RWMA regional wall motion abnormalities

­ yocardium injury [95]. Khush et al. found an association between the Gly16 m form and higher prevalence of LVEF C polymorphism of eNOS in stress cardiomyopathy, and further investigations are needed.

3.3  Clinical Implications 3.3.1  Clinical Manifestation As foretold, NSC is a phenomenon where acute neurological events like ischemic or haemorrhagic stroke, SAH, TBI, infections and seizures give rise to an autonomic nervous system dysregulation that may result in cardiac abnormalities, including ECG changes, arrhythmias, release of myocardial necrosis enzymes and B-type natriuretic peptide, and both systolic and diastolic dysfunction of LV. Serum markers of cardiac injury (troponin I, myoglobin, CK-MB, copeptin, among others) are increased in 20–30% of patients with the most severe grades of SAH. ECG abnormalities are more often detected in patients with intracranial haemorrhage (ICH; 60–70%) or SAH (40–70%) than those with acute ischemic stroke (AIS; 15–40%) [101]. The most common stroke-related ECG abnormality is QT prolongation, found in 45–71% of SAH patients, 64% of ICH patients and 38% of AIS patients [102–104]. In subjects with a neurovascular diagnosis, ST-segment

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depression and prolonged QTc, respectively, occur at a frequency of 7 and 10 times more often than control patients, with an incidence of T-wave inversion, premature ventricular beats and conduction abnormalities that was 2–4 times the rate of control patients [105]. Typical QT prolongation, T inversion and ST abnormalities are shown in Figs. 3.2 and 3.3. QTc prolongation has proven to be a significant risk factor for arrhythmias development that may lead to haemodynamic instability or even sudden death [106]. Reported rhythm disturbances observed in NSC include bradycardia, supraventricular tachycardia, atrial flutter, atrial fibrillation, ectopic ventricular beats, multifocal ventricular tachycardias, torsade de pointes, ventricular flutter and ventricular fibrillation [3]. Malignant ventricular tachyarrhythmias, including torsade de pointes and sudden death, are described in patients with SAH with QT prolongation [104, 107]. Patients affected by acute neurologic injury may develop RWMAs [41], which can be detected on echocardiography. In NSC, these abnormalities usually have a distinct pattern from that seen in coronary artery disease, as they do not respect the perfusion territories of coronary arteries. Basal and mid-ventricular segments of the anteroseptal and anterior walls are the most frequently affected [3, 108], although motion abnormalities may also progress to involve the entire LV, with global hypokinesis. LV dysfunction is more frequently seen in SAH patients with elevated cardiac enzymes and BNP, as well as poor neurologic grade [109, 110]. RWMA in NSC may rarely lead to cardiogenic shock that negatively impacts prognosis in brain-injured patients [11].

Fig. 3.2  Electrocardiogram recorded in a patient with subarachnoid haemorrhage. It shows a prolonged QTc of 490–500  ms (double-ended arrows) and T inversion in precordial leads V2–V6 (downward arrows)

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Fig. 3.3  Electrocardiogram recorded in a patient with subarachnoid haemorrhage. It shows a prolonged QTc of 520 ms (double-ended arrow) and T-ST abnormalities in inferior and lateral leads (circle)

In Takotsubo syndrome, instead, motion abnormalities are less variable among different patients, as it generally presents with basal hypercontractility and apical akinesia (Fig. 3.4a, b).

3.3.2  Monitoring for NSC In most cases cardiac abnormalities related to acute neurological events resolve spontaneously after few days and with neurological improvement. Nevertheless, this awareness should not divert attention from monitoring and treating cardiac involvement. An increasing body of literature, indeed, is demonstrating that neurogenic cardiac abnormalities significantly impact on short-term [111] and long-term patient outcome [112]. In a large meta-analysis, van der Bilt et al. proved that wall motion anomalies, troponin, CK-MB, BNP, Q waves, ST depression and T-wave abnormalities were associated with poor outcomes, mortality and delayed cerebral ischemia in patients after SAH [113]. These findings have been confirmed in more recent works about the impact of cardiac abnormalities on patient outcome after SAH [15, 88, 114–120] or after other acute neurological events, as acute ischemic stroke [121, 122] and traumatic brain injury [123]. In the heart–brain crosstalk, not only the brain status impacts on cardiac function, but also the reverse influence occurs: for example, neurogenic wall motion abnormalities after SAH may reduce LVEF and favour cerebrovascular spasm [18, 114, 124], leading to a secondary brain insult.

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Fig. 3.4 (a, b) Echocardiographic frames showing the typical takotsubo contraction pattern early after a stressful event (a and b) and the regression of contraction abnormalities after few days (c and d). (a) Apical two-chamber view of left atrium and ventricle during systole: apical akinesia (thin arrow) and basal hypercontractility (thick arrow). (b) Apical two-chamber view of left atrium and ventricle during diastole. Subxiphoid four-chamber view during systole (c) and diastole (d)

For this reason, tight cardiac monitoring is indicated for each patient with acute neurological injury, with two purposes: 1 . Identify patients who may develop or already exhibit NSC 2. Differentiate the occurrence of NSC from other causes of cardiac abnormalities (mainly acute coronary syndrome) in neurological patients SAH patients represent the population in which cardiac abnormalities have been more investigated and reported, nevertheless the same alterations should be investigated in any kind of acute brain injury. In order to be efficacious and efficient, the depth of cardiological investigations should be adapted to the single patient status and risk of NSC development. A baseline cardiological screening may be indicated for any patient with SAH with complete clinical history, ECG, chest X-rays and laboratory tests: cardiac enzyme profile, proBNP, electrolytes panel and lipid profile [3, 125]. Evidences indicate that there are no significant differences in cardiac morbidity between surgical and endovascular treatment of the aneurysm [3], thus these examinations should be done for every patient unrelated to treatment strategy.

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An advanced cardiac monitoring—with transthoracic echocardiography, echo-­ colour-­Doppler for coronary flow assessment, serial ECG/telemetry and repeated cardiac enzymes—should be performed for patients with: • Risk factors for developing NSC: SAH severity grading systems [110, 116, 126, 127], female gender [110], lack of hypertension [110, 120, 127], right insular cortex involvement [11, 65]. The severity of neurological injury is strongly related to the risk of cardiac injury [110]. • Alterations of cardiac baseline examinations and signs of myocardial dysfunction or haemodynamic instability [3]: troponin I elevation [109, 114, 117, 126, 128], BNP elevation [117, 129], ECG abnormalities [113, 114, 120]. In a recent study, Sugimoto et al. elaborated an ECG-based scoring system to predict NSC development in SAH patients: T-wave inversion, ST elevation and ST depression were able to predict WMA occurrence and may be an important tool to prepare in advance to possible later adverse events [120]. Finally, an invasive cardiological monitoring is indicated for patients with cardiogenic shock after SAH, with echocardiography to exclude dynamic obstruction of ventricular outflow tract, cardiac catheterization and pulmonary artery catheter placement, if clinically indicated [3]. The need of prolonged cardiac monitoring in patients with NSC during the hospital stay and long-term follow-up is still uncertain. Evidences suggest repeating echocardiography after 5–7 days of hospitalization to document the reversibility of cardiac injury [3]. Kilbourn et  al. demonstrated that RWMA persists for a long period after SAH and that it is necessary to repeat echocardiography in 4–6 months in these patients [117]. A correct differential diagnosis between neurogenic stress cardiomyopathy and acute coronary syndrome is the second relevant aim of a cardiological monitoring, as NSC can mimic ACS by showing ST-segment depression or elevation, T-wave inversion and Q waves [3]. For patients with SAH, Bulsara et al. suggested the following criteria for distinguishing NSC from ACS: 1 . No history of heart disease 2. New-onset cardiac dysfunction 3. WMA that do not correspond to ischemic ECG changes 4. Troponin C 1polymorphism in the promoter region of endothelial nitric oxide synthase (eNOS) and risk of coronary artery disease: a systematic review and meta-analysis. Gene 545:175–183 101. Cheung RTF, Hachinski V (2004) Cardiac effects of stroke. Curr Treat Options Cardiovasc Med 6:199–207 102. Sakr YL et al (2004) Relation of ECG changes to neurological outcome in patients with aneurysmal subarachnoid hemorrhage. Int J Cardiol 96:369–373 103. Di Pasquale G et al (1987) Holter detection of cardiac arrhythmias in intracranial subarachnoid hemorrhage. Am J Cardiol 59:596–600 104. Sommargren CE, Zaroff JG, Banki N, Drew BJ (2002) Electrocardiographic repolarization abnormalities in subarachnoid hemorrhage. J Electrocardiol 35:257–262 105. Dimant J, Grob D (1977) Electrocardiographic changes and myocardial damage in patients with acute cerebrovascular accidents. Stroke 8:448–455 106. Cubeddu LX (2003) QT prolongation and fatal arrhythmias: a review of clinical implications and effects of drugs. Am J Ther 10:452–457 107. Machado C et al (1997) Torsade de pointes as a complication of subarachnoid hemorrhage: a critical reappraisal. J Electrocardiol 30:31–37 108. Michael Frangiskakis J et al (2009) Ventricular arrhythmia risk after subarachnoid hemorrhage. Neurocrit Care 10:287–294 109. Parekh N et  al (2000) Cardiac troponin I predicts myocardial dysfunction in aneurysmal subarachnoid hemorrhage. J Am Coll Cardiol 36:1328–1335 110. Tung P et al (2004) Predictors of neurocardiogenic injury after subarachnoid hemorrhage. Stroke 35:548–553 111. Yarlagadda S et al (2006) Cardiovascular predictors of in-patient mortality after subarachnoid hemorrhage. Neurocrit Care Care 5:102–107 112. Coghlan LA et al (2009) Independent associations between electrocardiographic abnormalities and outcomes in patients with aneurysmal subarachnoid hemorrhage findings from the intraoperative hypothermia aneurysm surgery trial. Stroke 40:412–418 113. van Der Bilt IA et al (2015) Time course and risk factors for myocardial dysfunction after aneurysmal subarachnoid hemorrhage. Neurosurgery 76:700–706

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