Case-based Atlas of Cardiovascular Magnetic Resonance 3031325923, 9783031325922

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Andrea Barison · Santo Dellegrottaglie Gianluca Pontone · Ciro Indolfi Editors

Case-based Atlas of Cardiovascular Magnetic Resonance

Società Italiana di Cardiologia

LA SOCIETÀ DELLE TRE ANIME

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Case-based Atlas of Cardiovascular Magnetic Resonance

Andrea Barison  •  Santo Dellegrottaglie Gianluca Pontone  •  Ciro Indolfi Editors

Case-based Atlas of Cardiovascular Magnetic Resonance

Editors Andrea Barison Cardiology & Cardiovascular Medicine Division Fondazione Toscana Gabriele Monasterio Pisa, Italy

Santo Dellegrottaglie Advanced Cardiovascular Imaging Unit Ospedale Accreditato Villa dei Fiori Acerra (Naples), Italy

Gianluca Pontone Department of Perioperative Cardiology and Cardiovascular Imaging Centro Cardiologico Monzino IRCCS Milan, Milano, Italy

Ciro Indolfi Division of Cardiology, Department of medical and surgical sciences Magna Grecia University of Catanzaro Catanzaro, Italy

ISBN 978-3-031-32592-2    ISBN 978-3-031-32593-9 (eBook) https://doi.org/10.1007/978-3-031-32593-9 © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 This work is subject to copyright. All rights are solely and exclusively licensed 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 Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

This Atlas is dedicated to Dr Silvia Pica, bright colleague and beloved friend The Editors and the Authors, on behalf of the Italian Society of Cardiology

Foreword

Cardiovascular magnetic resonance (CMR) has become an essential tool for the evaluation of patients affected by cardiovascular diseases. Indeed, CMR provides an accurate, non-invasive assessment of cardiac anatomy and function, intra- and extracardiac flows, and myocardial tissue changes (including edema, fatty infiltration, and fibrosis), making this imaging technique of utmost importance for correct phenotyping and tailored treatment. This case-based atlas on CMR represents a significant and clear example of the current effectiveness of this innovative imaging technique in daily cardiology practice. Many excellent specialized texts and articles have already been published about the physical principles and the clinical applications of CMR across the entire spectrum of cardiovascular diseases. In this atlas, however, the Authors have intentionally reserved little space for the theoretical and academic issues, which might discourage the over busy clinician, while they have focused their efforts to connect clinical and pathophysiological matters to easy-to-understand cases, stimulating the readers to focus on the diagnostic potentialities of CMR. The tight link between CMR and the clinical environment across the wide spectrum of cardiovascular diseases is here presented and discussed not by imaging experts, but by cardiologists which are experts in imaging, implying a pathophysiological and clinical interpretation of the cases shown in each chapter. After an introductory chapter about the physics of magnetic resonance (Chap. 1) and an overview of CMR sequences and scanning planes (Chap. 2), each chapter presents ten clinical cases of the most common cardiovascular diseases: ischemic heart disease (Chaps. 3 and 4), cardiomyopathies (Chaps. 5, 6, 7, 8, 9, and 10), as well as adaptive changes taking place in athletes (Chap. 11). Proper emphasis has been given to inflammatory, tumoral, valvular, and aortic diseases (Chaps. 12, 13, 14, 15, and 16). The atlas is completed by two chapters in the field of congenital heart disease (Chaps. 17 and 18), which represent one of the most relevant applications of CMR, also because the contribution of advanced imaging to the diagnosis and prognosis of complex diseases is nowadays considered mandatory. Finally, this book represents a milestone in underlying the cooperative atmosphere within the Working Group on CMR of the Italian Society of Cardiology, whose scientific credibility has reached an international level. The readers will have the opportunity to appreciate the rigorous approach applied in building this text, which takes advantage of the specific clinical and scientific background of the members of the Working Group, of their remarkable capability to apply a multimodality approach for the assessment of cardiovascular disease and to establish constructive cooperation with the different specialties. Multimodality Cardiac Imaging Unit IRCCS Policlinico San Donato, Milan, Italy Division of Cardiology Magna Graecia University, Catanzaro, Italy

Massimo Lombardi

Ciro Indolfi

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Preface

Clinical, electrocardiographic, echocardiographic, and biohumoral assessment represents the cornerstone of cardiac evaluation in all cardiovascular patients, both for first-line diagnosis and regular follow-up. In many cases, however, advanced cardiac imaging (including cardiovascular magnetic resonance [CMR], nuclear medicine, and computed tomography) is necessary for definite diagnosis, etiological assessment, risk stratification, therapeutic management, and disease monitoring. The choice to refer to CMR patients with cardiovascular diseases should always be guided by clinical suspicion and by medical reasoning, and the exams should be tailored to answer specific clinical questions, also because such powerful techniques might yield misleading results when disconnected from the clinical context. CMR is the reference standard to demonstrate underlying structural and/or functional alterations across almost the entire spectrum of cardiovascular diseases, including ischemic, valvular, congenital, myocardial, pericardial, and vascular pathologies. With its inherently high spatial resolution, superior signal-to-noise ratio, and multi-parametric and tomographic nature, CMR represents an attractive imaging modality that is uniquely able to provide detailed information about cardiac morphology, function, perfusion, viability, and tissue characterization all in a single examination. In particular, CMR allows quantification of biventricular volumes, mass, wall thickness, systolic and diastolic function, and intra- and extracardiac flows. Moreover, CMR allows superior tissue characterization of the myocardium and the pericardium, which are crucial for a non-invasive etiological and histopathological assessment of most cardiovascular diseases: conventional T1-weighted, T2-weighted, and post-contrast sequences are now complemented by quantitative mapping sequences, including T1, T2, T2* mapping as well as extracellular volume quantification. Further experimental sequences are under investigation, including diffusion tensor analysis, blood oxygenation-dependent sequences, hyperpolarized contrast agents, spectroscopy, and elastography. Finally, artificial intelligence is beginning to help clinicians involved in dealing with such an extraordinary amount of information from CMR exams. This case-based atlas on CMR aims to offer pictures and videos of practical guidance for healthcare professionals interested in learning how to make adequate clinically oriented use of CMR. With its case-based approach, the book provides a detailed guide to CMR application in the most common clinical cardiovascular scenarios. In dedicated chapters, a great number of real cases are presented, including brief clinical data, clear descriptions of major information obtained from CMR, and their meaning in terms of patient management. Emphasis is placed on traditional as well as newer CMR techniques, but always keeping a practical format, focused on the hands-on knowledge required for an accurate image interpretation. The description of each case is supplemented with additional videos, providing further resources for understanding how CMR principles apply to modern clinical practice in cardiology.

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The Atlas has been conceived, edited, and produced within the CMR Working Group of the Italian Society of Cardiology. The Editors are grateful to all the Authors for their remarkable contributions to case collection, description, and discussion, and to the Italian Society of Cardiology for strongly supporting this project. Pisa, Italy Naples, Italy  Milan, Italy  Catanzaro, Italy 

Andrea Barison Santo Dellegrottaglie Gianluca Pontone Ciro Indolfi

Contents

1 Introduction  to Cardiac MRI������������������������������������������������������������������������������������   1 Andrea Barison, Nicola Martini, Santo Dellegrottaglie, and Gianluca Pontone 2 How  to Scan a Patient: Overview of Cardiac MRI Sequences and Scanning Planes���������������������������������������������������������������������������������  13 Anna Baritussio, Antonella Cecchetto, Camilla Torlasco, and Silvia Castelletti 3 Acute Coronary Syndromes�������������������������������������������������������������������������������������   31 Alessandra Scatteia, Santo Dellegrottaglie, Ciro Indolfi, and Chiara Bucciarelli Ducci 4 Chronic Coronary Syndromes�����������������������������������������������������������������������������������  51 Fabrizio Ricci, Nazario Carrabba, Amedeo Chiribiri, and Pasquale Perrone Filardi 5 Non-ischaemic Dilated Cardiomyopathy �����������������������������������������������������������������  83 Andrea Barison, Stefano Figliozzi, Pier Giorgio Masci, and Gianfranco Sinagra 6 Hypertrophic Cardiomyopathy��������������������������������������������������������������������������������� 103 Giancarlo Todiere, Giovanni Quarta, Gherardo Finocchiaro, and Roberto Pedrinelli 7 Cardiac Amyloidosis��������������������������������������������������������������������������������������������������� 119 Aldostefano Porcari, Gianfranco Sinagra, Marianna Fontana, and Silvia Pica 8 Arrhythmogenic Cardiomyopathies������������������������������������������������������������������������� 133 Alberto Cipriani, Antonio De Luca, Antonio Curcio, and Martina Perazzolo Marra 9 Crypts,  Diverticula, and Left Ventricular Noncompaction������������������������������������� 155 Daniele Andreini, Edoardo Conte, Francesca Garinei, and Andrea Cardona 10 Iron Overload Cardiomyopathies����������������������������������������������������������������������������� 173 Alessia Pepe, Paola Sormani, Antonella Meloni, and Camilla Torlasco 11 Cardiac  Remodeling Versus Cardiomyopathies in Athletes����������������������������������� 187 Viviana Maestrini, Domenico Filomena, Marta Focardi, and Gaetano Nucifora 12 Myocarditis  and Inflammatory Cardiomyopathies������������������������������������������������� 205 Giovanni Camastra, Federica Ciolina, Manuel De Lazzari, and Cristina Basso 13 Pericardial Diseases ��������������������������������������������������������������������������������������������������� 229 Gianluca Di Bella, Roberto Licordari, Fausto Pizzino, and Massimo Imazio 14 Valvular Heart Diseases��������������������������������������������������������������������������������������������� 249 Alessandra Volpe, Riccardo Maragna, Andrea Igoren Guaricci, and Gianluca Pontone

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15 Cardiac Tumors and Pseudotumors������������������������������������������������������������������������� 267 Giovanni Donato Aquaro, Chrysanthos Grigoratos, Stefano Figliozzi, and Lorenzo Monti 16 Aortic Diseases ����������������������������������������������������������������������������������������������������������� 283 Alberto Aimo, Lucia La Mura, Giuseppina Quattrocchi, and Patrizia Pedrotti 17 Simple  Congenital Heart Diseases����������������������������������������������������������������������������� 303 Francesco Bianco, Valentina Bucciarelli, Chiara Lanzillo, and Francesca Raimondi 18 Complex  Congenital Heart Diseases������������������������������������������������������������������������� 317 Pierluigi Festa, Paolo Ciancarella, Lamia Ait Ali, and Aurelio Secinaro

Contents

1

Introduction to Cardiac MRI Andrea Barison, Nicola Martini, Santo Dellegrottaglie, and Gianluca Pontone

Introduction to MRI Physics

a specific questionnaire focused on potentially unsafe implants or devices [5]; Magnetic Fields 2. The gradient magnetic fields produce a linear variation in magnetic field intensity in a certain direction in space, Magnetic resonance imaging (MRI) is a multiparametric, with the consequence that aligned proton spins show difhighly reproducible, comprehensive imaging technique, with ferent resonant frequencies depending on their spatial a wide range of clinical applications [1–3]. The key principle positions on the gradient axes (Gx, Gy, Gz). The gradient of routine clinical CMR imaging is the interaction of differmagnetic fields are rapidly switched on and off during ent “magnetic fields” with the hydrogen nuclei of biological image acquisition to enable spatial encoding along the tissues [4], each magnetic field being activated in a pre-­ three dimensions. Since they can theoretically generate specified temporal “sequence” and set with several different electric currents in any electrically conductive material, parameters according to the image we want to obtain. In parincluding biological tissues, their strength (slew rate) is ticular, three different types of magnetic fields are applied set far below the threshold of peripheral nerve stimuladuring a CMR exam (Fig. 1.1): tion. Moreover, their rapid switching causes the gradient coils to vibrate, creating a high acoustic noise: besides the 1. The static magnetic field (B0, usually 1.5  T or 3.0  T) headsets or ear plugs worn by patients during the scan, aligns the proton spins in the patient’s body and generates active noise cancellation techniques and silent sequences a net magnetization vector (M) lying parallel to B0. The are commonly used [5]; static magnetic field is always on and can only be turned 3. The radiofrequency (RF) magnetic field (B1) is centred at off with an emergency “quench” procedure. Since it the Larmor frequency (= 42.6 MHz/T × B0) of hydrogen attracts any ferromagnetic object (magneto-­mechanical nuclei to make them resonate in-phase (coherently) and effect) causing potential severe injuries, before entering flip away from their equilibrium position. When the RF the scanning room patients and staff are requested to field is switched off, the protons start to fall out of phase remove all ferromagnetic materials and patients undergo with each other and to return to their equilibrium magnetization. During this process, the protons produce a small moving magnetic field that can be picked up from the A. Barison (*) receiver coil (like an antenna would pick up radio waves) Fondazione Toscana Gabriele Monasterio, Pisa-Massa, Italy forming an MR signal. The time during which the magneScuola Superiore Sant’Anna, Pisa, Italy tization vector M returns to the equilibrium is different e-mail: [email protected] for each tissue, and this results in an MR signal with two N. Martini main imaging parameters, T1 and T2, which directly Fondazione Toscana Gabriele Monasterio, Pisa-Massa, Italy relate to the image contrast. Because the RF energy is S. Dellegrottaglie transformed into heat within tissues, its amount (expressed Clinica Villa dei Fiori Acerra, Naples, Italy by SAR, specific absorption rate, in W/kg) must be set G. Pontone below specific thresholds, to avoid unpleasant heating or Centro Cardiologico Monzino IRCCS, Universita’ degli Studi di even burns. In particular, the risk of burns is significantly Milano, Milan, Italy increased in the presence of conductive objects that cone-mail: [email protected]

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 A. Barison et al. (eds.), Case-based Atlas of Cardiovascular Magnetic Resonance, https://doi.org/10.1007/978-3-031-32593-9_1

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Fig. 1.1  Effects of the static magnetic field (B0), gradient magnetic fields (Gx, Gy, Gz), and radiofrequency magnetic field (RF or B1) on the matter. Modified with permission from Ref. [5]

centrate the RF energy (antenna effect), representing another reason why all patients are requested to remove all metal/conductive objects and to undergo a safety questionnaire before the exam [5].

 patial Localization: From K-Space to Clinical S Imaging To localize the MR signal in three dimensions, i.e. to produce an MR image, the three separate magnetic field gradients are applied in a three-step process. First, the resonance of protons is confined to a slice of tissue, by applying a gradient magnetic field during the RF excitation pulse; the RF frequency corresponds to the Larmor frequency at a chosen point along the direction of the applied gradient. This process is known as slice selection, the orientation of the slice being determined by the direction of the applied gradient (Gs). Rather than just a single frequency, the transmitted RF pulse is comprised of a small range of frequencies, known as the transmit bandwidth of the RF pulse, giving the slice a thickness: the thickness of the slice is determined by the combination of the RF pulse bandwidth and the steepness (or strength) of the gradient. Following slice selection, a second gradient (Gp) is applied before signal read-out, causing the protons to rotate at different frequencies according to their relative position along the gradient. Where the gradient increases the magnetic field, the protons acquire a higher frequency of precession, while where the gradient decreases the mag-

netic field, the protons acquire a lower frequency of precession. When the gradient is switched off, the protons will have changed their relative phase by an amount depending on their position along the gradient. This process is known as phase encoding and the direction of the applied gradient is known as the phase encoding direction. Finally, a third gradient named frequency encoding gradient (Gf) is applied during signal readout in a direction perpendicular to the phase encoding gradient and causes the protons to rotate at different frequencies according to their relative position along that direction gradient. The received MR signal is comprised of a range of frequencies (or bandwidth), corresponding to the Larmor frequencies of the protons at different locations along the gradient. The digitized MR signal is then stored in the raw data space also called k-space. The k-space is filled line by line by repeating the above three-step process (slice selection, phase encoding and frequency encoding), i.e. by applying the same slice selection and frequency encoding gradient, but different phase encoding gradient intensities. The k-space contains the spatial frequency information of an object in two dimensions. The central regions of the k-space, i.e. the low spatial frequencies, provide information on the general contrast of the image, while the peripheral regions of the k-space provide information on the anatomical details at high spatial frequencies. Once the k-space is completely filled, the final image is reconstructed using a mathematical operation called 2D inverse Fourier Transform (Fig. 1.2).

1  Introduction to Cardiac MRI

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Fig. 1.2  From MR signal to K space to image reconstruction. (a) Diagram of a gradient-echo pulse sequence: the slice selection gradient (Gs) is applied during the RF excitation pulse, then the phase encoding gradient (Gp) is applied to encode the position of the spin in the phase of the MR signal; finally, a frequency encoding gradient is used to generate the echo signal. This signal is digitized and stored in the row of the k-space matrix. This three-step process is repeated for each phase

encoding step in order to fill the k-space in line-by-line manner. Once the k-space is completely filled, the image is reconstructed using the 2D inverse Fourier Transform. (b) The central regions of the k-space are related to the low spatial frequencies and provide information on the general contrast of the image, while the peripheral regions of the k-space provide information on the anatomical details at high spatial frequencies

Pulse Sequences

180° inverting pulse and the 90°-pulse is called the inversion time (TI). The inversion pulse flips the initial longitudinal magnetization (Mz) of all tissues to its negative value, −Mz. During the TI interval, tissues return to Mz according to their T1 relaxation times. The spin-echo 90° pulse is then applied at the exact time when longitudinal magnetization reaches the null point for the tissue we want to suppress. For example, in STIR (Short Tau Inversion Recovery) sequences a short TI of typically 140 ms at 1.5 T is used to suppress the fat signal which has a short T1. In the saturation recovery (SR) sequence, multiple 90° RF pulses at relatively short repetition times (TR) are applied to suppress the signal from specific tissues immediately before the SE sequence. For example, fat saturation sequences are based on SR pulses with a fat-specific frequency to suppress fat signal. The second major family of pulse sequences is the gradient-­echo (GRE). Unlike in the SE sequences where the echo signal is generated by a refocusing RF pulse, in GRE sequences the gradient-echo is produced by the frequency-­ encoding gradient which is executed twice in succession and in opposite directions: first a negative lobe is used to enforce transverse dephasing of spinning protons and then a positive lobe acts as readout gradient (like in the SE) to re-align the dephased protons and hence to acquire the MR signal. GRE sequences allow faster acquisitions, thanks to their short TR combined with a low flip angle excitation, typically between 30° and 60°. Due to the short TR in GRE sequences, a residual transverse magnetization remains before the next excita-

MRI pulse sequences may be classified in two large families: spin-echo (SE) and gradient-echo (GRE) sequences. The basic spin-echo sequence (Fig. 1.3a) is given by a 90° RF excitation pulse followed by an 180° RF refocusing pulse at TE/2 and signal readout at TE (echo time). This series of events is repeated at each time interval TR (Repetition time) with a different phase encoding to collect a different k-space line. In multi-shot SE acquisitions like RARE (Rapid Acquisition with Relaxation Enhancement), multiple refocusing pulses are used to acquire multiple k-space lines during one TR, thus reducing the scan time. In single-shot techniques, such as HASTE (Half-Fourier Acquisition Single-shot Turbo spin Echo imaging), the number of refocusing pulses, called echo train length (ETL), is set to the total number of phase encoding steps so that the entire k-space data are acquired in a single TR. Spin-echo images may have proton density (PD), T1- or T2-weighting depending on the choice of the TE and TR parameters. In particular, PD-weighted images have a long TR and a short TE, T1-weighted images have a short TR and short TE, and T2-weighted images have long TR and long TE. Spin-echo sequences may be further modified to obtain a particular image contrast, by adding inversion recovery (IR) or saturation recovery (SR) preliminary pulses. Basically, in the IR sequence an inversion (180°) RF pulse is played before the spin-echo pulse sequence. The time between the

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Fig. 1.3  Diagram of most common CMR sequences. (a) In the spin-­ echo (SE) sequence, the MR echo signal is generated by a refocusing 180° RF pulse. (b) In gradient-echo sequences (GRE), the MR signal is produced by the frequency-encoding gradient (Gf) which is executed twice in succession and in opposite directions. (c) The pulse sequence family tree with the most common CMR acquisition techniques. The same information (for example, T2 mapping) can be achieved with different sequences. b-SSFP, balanced steady state free precession;

tion, especially in tissue with long T2 values. GRE sequences can be classified into two major types depending on how this residual transverse magnetization is managed:

CEMRA, contrast enhanced magnetic resonance angiography; DIR, double inversion recovery; HASTE, Half-Fourier Acquisition Singleshot Turbo spin Echo; LGE, late gadolinium enhancement; MOLLI, modified look-locker inversion recovery; MRA, magnetic resonance angiography; PC, phase contras; RARE, Rapid Acquisition with Relaxation Enhancement; RF, radiofrequency; SPGR, spoiled gradient echo; STIR, short-tau (or triple) inversion recovery; TE, echo time; TR; repetition time.

As in the case of the SE family, the image contrast in GRE can also be manipulated by the additional application of specific RF pulses and gradients. In post-contrast late enhancement, an inversion pulse (IR) is played before the • In spoiled/incoherent GRE sequences, the residual trans- spoiled GRE sequence with a proper TI to null the signal of verse magnetization is destroyed (“spoiled”) before the the normal myocardium. In first-pass perfusion sequences, following TR by using proper spoiling gradients or RF an SR pulse is played to suppress native tissue signal and to pulses. increase T1-contrast during gadolinium injection. In coro• In coherent GRE sequences, the residual transverse mag- nary magnetic resonance angiography (MRA), a series of netization is refocused so that after a few repetition cycles, blocks 90°–180°–90° RF pulses, also called T2-preparation, it leads to a stable level (“steady state”). An example is the are executed within a 3D GRE sequence to generate a balanced Steady-State Free Precession (SSFP) sequence T2-weighting needed to differentiate the arterial blood and which has all the gradients (slice selection, phase encod- myocardium. In phase-contrast MRI (PC-MRI), an addiing and readout) fully balanced, i.e. the gradient-induced tional gradient is inserted in a cardiac cine GRE sequence to dephasing within TR is zero. The balanced SSFP sequence encode the velocity of the spins into the phase of the is commonly used for cardiac cine imaging since its T2 recorded MR signal. The clinical use of the PC-MRI is the over T1 (T2/T1) weighting makes it ideal for the blood-­ quantification of blood flows and velocities within the heart myocardium image contrast. and great vessels.

1  Introduction to Cardiac MRI

Respiratory and Cardiac Motion in CMR In a CMR examination, the image acquisition must be synchronized with the respiratory and cardiac movements to eliminate motion artefacts. The most straightforward way to address respiratory motion is the use of fast breath-held acquisitions of about 8–12 s depending on patient cooperation. For longer scans, such as whole-heart 3D scans, motion compensation strategies are applied to free-breathing acquisitions. As an example, the respiratory navigator technique allows the detection of the movement of the diaphragm to trigger the acquisition in the end-expiration phase. Cardiac motion is addressed by synchronizing the pulse sequence to the patient’s electrocardiogram (ECG). Cardiac synchronization techniques can be classified into two main categories: ECG triggering and ECG gating. In ECG triggering, the scanner detects the R-wave and then waits a specific time (“trigger delay”) to run the sequence (SE or GRE) in a fixed phase of the cardiac cycle. Examples of ECGtriggered sequences are the static images acquired with T1-, T2- and PD-weighted FSE sequences used for the morphological characterization of the myocardium, or the post-contrast late enhancement GRE sequences. ECG gating is the standard technique for the acquisition of cardiac cine images, i.e. the collection of multiple images throughout the cardiac cycle. In particular, in retrospective gating k-space data are continuously acquired during the heartbeat and the temporal interval is also recorded. Subsequently k-space data are subdivided into N different cardiac frames before the image reconstruction of the N cardiac phases, resulting in the creation of all the single images required to generate a cine loop.

Clinical Application of CMR Sequences CMR has become the gold standard for non-invasive assessment of cardiac morphology, function and myocardial tissue changes [2, 3]. Indeed, it allows not only the quantification of biventricular volumes, mass, wall thickness, systolic- and diastolic function, intra- and extracardiac flows, but also the detection of myocardial oedema, fibrosis and the accumulation of other intra/extracellular substances (such as fat, iron and amyloid). Thus, it is capable of providing unique information for the etiological, diagnostic and prognostic definition of cardiovascular disorders. Compared to other imaging techniques, CMR presents optimal spatial, temporal and contrast resolution (Table 1.1), but should always be complemented by clinical, electrocardiographic and other cardiovascular imaging techniques for an integrated diagnostic and prognostic assessment of cardiac diseases (Table 1.2).

5 Table 1.1  Spatial, temporal and contrast resolutions of cardiovascular imaging techniques

Echocardiography CMR SPECT PET CT Catheter angiography

Spatial resolution (mm) 0.5–2 1–2 5–15 4–8 0.5 0.15

Temporal resolution (ms)  A), while a 99m-Technetium diphosphonate (Tc-DPD) scintigraphy showed weak myocardial uptake (Perugini 1), which was confirmed in tomographic SPET images, suggesting possible early stage ATTR amyloidosis (Fig.  6.3). Close clinical and imaging follow-up was recommended.

106 Fig. 6.2  Cine SSFP imaging in three-chamber (a) and short-axis view (b), LGE image in three-chamber (c), and SA view (d)

Fig. 6.3  DPD scintigraphy with mild myocardial uptake (red asterisk), as assessed by tomographic images in axial (a), coronal (b), and sagittal (c) views and by planimetric view (d)

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6  Hypertrophic Cardiomyopathy

Case 2: HCM with Apical Aneurysm A 64-year-old man with a family history of SCD (great grandmother die at 25 years, and mother at 70 years), with hyperlipidemia and arterial hypertension, was referred to cardiological evaluation because of effort angina. His ECG showed negative T waves (Fig.  6.4). Echocardiography showed severe LV hypertrophy with apical involvement without LVOT obstruction. A 24 h Holter ECG monitoring recorded brief episodes of non-sustained ventricular tachycardia (NSVT) and a CMR showed normal LV systolic function and septal hypertrophy (maximal WT 20  mm) with apical involvement and evidence of apical aneurysm.

Fig. 6.4  Resting ECG

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Myocardial fibrosis was detected, with a midwall distribution in the septum and a transmural distribution in the apical segments (Fig. 6.5). Based on symptoms and morphological abnormalities, he underwent coronary angiography that documented critical stenosis of the right coronary artery with atherosclerotic, ulcerated plaque, and percutaneous revascularization was performed. A genetic test confirmed a sarcomeric pathogenetic mutation in the MYBPC3 gene (c772 G > A), and no mutations were found in the alpha-galactosidase A gene. After 2 years, following syncopal episodes, episodes of NSVT at Holter ECG, and diffuse myocardial fibrosis with apical aneurysm, the patient underwent ICD implantation.

108 Fig. 6.5  Cine SSFP imaging in four-chamber (a), LGE imaging in four-chamber (b), LGE imaging in short-axis at basal (c), mid (d), and apical (e) level

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Case 3: HCM with Apical Involvement A 62-year-old woman with a previous familiar history of unclassified cardiomyopathy and atrial fibrillation, giant negative T waves in the inferior and lateral leads, was referred

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to CMR. The exam showed normal LV systolic function and limited apical hypertrophy (maximal wall thickness 16 mm), with normal LV systolic function (EF 66%), as well as mild nonischemic LGE localized in the apical segments (Fig. 6.6, arrow).

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Fig. 6.6  Cine SSFP imaging in four-chamber (a), LGE imaging in four-chamber (b), and apical short-axis view (c)

 ase 4: Hypertrophic Cardiomyopathy C with Brugada ECG Pattern A 26-year-old man, with family history of SCD (paternal great grandfather) and hypertrophic cardiomyopathy (paternal grandfather and father, the latter with an ICD implanted for secondary prevention) was referred to cardiological evaluation because of chest pain. His echocardiography documented a septal hypertrophy of 14 mm. A CMR scan was performed, showing asymmetric LV hypertrophy (maximal septal thickness of 15 mm, basal inferolateral wall of 9 mm) and multiple

myocardial crypts in the inferior septum, without LGE (Fig. 6.7). A 24-h Holter ECG monitoring recorded few ventricular ectopic beats without episodes of NSVT.  A genetic test detected a pathogenic mutation in the MYBPC3 gene and consequently a regular follow-up was suggested. After 3 years, when he was 30 years old, a spontaneous type 1 Brugada ECG pattern was detected. After collegial d­ iscussion, it was decided to perform an electrophysiological study which induced ventricular fibrillation and the patient underwent ICD implantation for primary prevention. After gene analysis revision, no pathogenic mutation in Na channels was detected.

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Fig. 6.7  Cine SSFP imaging in two different two-chamber views (a, b), LGE imaging in two-chamber (c)

Case 5: Obstructive HCM A 70-year-old woman with effort dyspnea was referred to echocardiography, which disclosed LV asymmetric hypertrophy (maximal wall thickness 19  mm), LVOT obstruction (peak LVOT gradient after Valsalva maneuver of 80 mmHg), an hypercontractile LV function (EF 70%), left atrial dilation (parasternal diameter of 45  mm), and calcification/calcific necrosis of the posterior mitral anulus with mild to moderate mitral regurgitation. She was referred to a CMR scan. Morphofunctional abnormalities were: normal biventricular volumes and function (LV EDV 87 mL/m2, LVEF 79%), septal hypertrophy (18 mm, increased LV mass of 81 g/m2), subaortic signal void in bSSFP images secondary to LVOT obstruction (Video 6.1, and white arrow in Fig. 6.8), mitral calcifications

and moderate mitral regurgitation (red arrow in Fig. 6.8); no significant areas of LGE were present (Fig. 6.8). Genetic analysis confirmed HCM with the presence of two sarcomeric pathogenic mutations (c2348 G > A in the MYH7 gene, and c472 G  >  A in the MYBPC3 gene). Her 24-h Holter ECG monitoring did not document significant ventricular arrhythmias. Under beta-blocker treatment, the patient experienced symptom improvement with reduction of the dynamic LVOT gradient (from 80 mmHg to 40 mmHg after Valsalva, and a resting value of 16 mmHg). After 4 years, following episodes of atrial fibrillation and drug refractory exercise dyspnea, her echocardiography showed new worsening of the LVOT dynamic gradient (rest value of 65 mmHg) and severe mitral regurgitation. She was referred to myectomy and mitral valvuloplasty, with a significant improvement of her clinical status.

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Fig. 6.8  Two-chamber cine SSFP imaging in systole (a), diastole (b); late enhancement imaging (c)

Case 6: Fabry Disease A 62-year-old woman was admitted to the emergency department complaining of severe chest pain. Rapid acute atrial fibrillation with negative T waves from V4 to V6 leads, associated to troponin increase, was documented. Echocardiography found a concentric LV hypertrophy (14 mm) with normal LV dimensions and ventricular ­function (EF 56%). Coronary angiography was normal. The patient was referred to CMR examination that confirmed concentric

LV hypertrophy (Fig.  6.9). Native T1 values were reduced (global T1 value 920 ms, lower reference range 996 ms) corresponding to the blue areas in the map, suggesting glycosphingolipid accumulation. Pseudo-normalization of native T1 values was present in the inferolateral scar (native T1 966 ms), corresponding to the green area in the map (Fig. 6.9b, black arrow) and matching with the inferolateral area of intramural LGE (Fig.  6.9c, d, white arrow). A genetic test was performed and showed a pathogenic c334C > T (pArg112Cys) mutation in the alpha-­galactosidase A gene.

112 Fig. 6.9  Cine SSFP imaging in SA view (a), native T1 mapping short-axis map (b), LGE imaging in three-­ chamber (c), and SA view (d)

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 ase 7: Hypertrophic Cardiomyopathy C with Ventricular Arrhythmias A 59-year-old man, complaining of effort angina and palpitations, with familiar history of SCD (paternal grandfather) and history of atrial fibrillation underwent an echocardiography that documented a septal hypertrophy of 20 mm with a peak dynamic LVOT gradient of 38 mmHg, which normalized after introduction of beta-blocker therapy. A CMR scan was performed, which confirmed an asymmetric septal hypertrophy (maximal wall thickness at basal anterior septum of 23 mm, with a basal inferolateral

wall of 9 mm) (Fig. 6.10). Tissue characterization showed areas of myocardial edema localized in the anterior wall and anterior septum (Fig. 6.11a), with diffuse LGE (22% of myocardial mass using 6 SD method of quantification), with a high global dispersion score (Figs. 6.10b, 6.11b–d). His 24-h Holter ECG monitoring recorded some episodes of NSVT. A genetic test detected a pathogenic MYBPC3 gene mutation (c1090 G > A). High levels of HS troponin were found (25 ng/L). His 5-year risk score for malignant ventricular arrhythmias was high, about 6.7%, so the patient underwent ICD implantation for primary prevention.

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Fig. 6.10  Cine SSFP imaging three-chamber view (a), LGE imaging two-­ chamber view (b)

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Fig. 6.11  Short-axis T2 STIR imaging for edema (a), LGE imaging for fibrosis (b), LGE quantification map (c) and LGE dispersion map (d)

 ase 8: Apical Ballooning Syndrome C Mimicking Apical HCM A 63-year-old woman developed chest pain and palpitations following an episode of intense psychological stress; her ECG showed lateral negative T waves. Markers of inflammation were negative, while high sensitivity troponin levels were mildly increased (20 ng/L) despite a normal coronary angiography. She was then referred to a CMR scan for ­suspected stress cardiomyopathy. Her CMR revealed an api-

cal hypertrophy (maximal wall thickness of 15  mm in the apical anterior wall, with a distal/basal segments wall thickness ratio > 1), hypokinesia of apical segments and normal global systolic LV function (EF 65%). T2 STIR showed areas of transmural myocardial edema in the apical segments with no LGE (Fig. 6.12). After 6 months, a CMR exam was repeated and the apical hypertrophy disappeared together with the myocardial edema (Fig. 6.13). This was a case of “Tako-­ tsubo syndrome” mimicking apical hypertrophic cardiomyopathy.

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Fig. 6.12  Two-chamber cine SSFP (a), T2 STIR (b) and LGE (c) imaging in the acute phase

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Fig. 6.13  Two-chamber cine SSFP (a), T2 STIR (b), and LGE (c) imaging after 6 months

 ase 9: Fibrosis as a Dynamic Phenomenon C in HCM A 40 year-old man, symptomatic for dyspnea and palpitations, with family history of HCM, underwent an echocardiogram and a CMR scan following a cascade genetic analysis which tested positive for the same familial mutation in MYH7 gene. Septal reverse hypertrophy was found (maximal wall thickness at mid anterior wall of 27 mm and mid inferior septum of 25 mm). Elongation of the anterior

mitral leaflet with systolic anterior movement and accessory ­papillary muscles were detected; diffuse LGE in the septum, inferior and anterior walls were found (Fig. 6.14). He was then diagnosed with obstructive HCM.  After 6 years of follow-up, a second CMR scan was performed (Fig.  6.15). Comparing the LGE extent between the two examinations (with 6 SD method), an increase in the amount of myocardial fibrosis was clearly demonstrated in the anterior and inferior walls, confirming a progression of the disease over time.

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Fig. 6.14  Two-chamber cine SSFP (a) and LGE imaging (b) at first scan

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Fig. 6.15  Two-chamber cine SSFP (a) and LGE imaging (b) at follow-up scan

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Case 10: HCM vs. Pseudotumor/Tumor An 80-year-old woman, symptomatic for chest pain, underwent an echocardiographic examination with evidence of asymmetrical hypertrophy and normal LV ejection fraction (EF 60%). Her ECG showed negative T waves in the precordial leads. The patient was referred to a CMR scan. Septal hypertrophy was confirmed (maximal wall thickness of 22  mm) with normal LV systolic function (EF 69%), but

without LVOT acceleration/turbulence (Fig.  6.16). Both in balanced SSFP and in T2 STIR images, multiple gross hypointense oval areas were detected in the septum and inferolateral wall (Fig. 6.16, arrows). After contrast administration, early and late enhancement images disclosed a hypointense core with hyperintense borders, compatible with multiple areas of calcific necrosis, mimicking hypertrophic cardiomyopathy (Fig. 6.17). A close clinical and imaging follow-up was recommended.

116 Fig. 6.16  Two-chamber cine SSFP (a) and T2-STIR imaging (b), showing two hypointense masses (arrows)

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Fig. 6.17  Postcontrast short-axis cine SSFP (a), early enhancement LAVA (b), and late enhancement (c) imaging

Pearls and Pitfalls • Hypertrophic cardiomyopathy, defined as left ventricular hypertrophy not explained by loading conditions, is often due to sarcomeric gene mutations and may overlap with other nonischemic cardiomyopathies (including metabolic, neuromuscular, and infiltrative disorders), and CMR should be integrated in the clinical context. • As a 3D technique, CMR allows an accurate measurement of every pattern of hypertrophy without the echocardiographic limitations due to acoustic windows, except for some patients with artifacts from ICD/pacemaker and those with claustrophobia. • CMR allows an accurate assessment of the geometry and thickness of each myocardial segment, including small morphological abnormalities (myocardial crypts, diverticula, papillary muscle abnormalities) and right ventricular abnormalities. • Tissue characterization, using T2-weighted sequences (STIR and T2 mapping), LGE images, native T1 and postcontrast T1 mapping are fundamental in the differential diagnosis of cardiac hypertrophy.

• In patients with contraindications to contrast agent administration, morphological and tissue data obtained from cine-sequences, T2-weighted images, and native T1 mapping may be important to exclude some hypertrophic phenocopies. • LGE and T1 mapping are robust techniques for noninvasively detection and quantification of myocardial fibrosis in HCM. • Even if accurate techniques to evaluate flow with CMR scan, such as 2D and 4D Flow, are available, echocardiography remains the gold standard for quantification of resting/dynamic LVOT gradient. • Diffusion Tensor CMR (DT-CMR) is a novel imaging technique that may detect and quantify myocardial disarray in HCM, but unfortunately this technique requires long scan times and selection of patients who are able to guarantee consistency of breath-holding during the scan. • CMR is an imaging technique without ionizing radiations which allows repeating the examination over time, for possible disease progression and potentially to test the efficacy of pharmacological treatments.

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Conclusions CMR is currently one of the cornerstones of cardiac imaging for the evaluation of patients with nonischemic heart disease. It allows an accurate and reproducible evaluation of cardiac morphology and function in 3D dimensions without any limit due to the acoustic window. The added value of CMR lies in its unique ability to combine morphological and functional assessment together with an extremely accurate in vivo myocardial tissue characterization, using sequences with and without contrast administration. CMR allows an accurate measurement of global myocardial mass and of the geometry and thickness of each segment of the left ventricle; even very small morphological abnormalities, as myocardial crypts, can be easily identified by CMR.  Tissue characterization, using different techniques, is fundamental for the differential diagnosis of cardiac hypertrophy, including infiltrative, metabolic, inflammatory cardiomyopathies, and cardiac masses. LGE is very common in HCM patients, described in up to 80% of HCM patients, usually involving the most hypertrophic myocardial segments. Besides the diagnostic information, CMR allows to obtain prognostic data with quantitative analysis. The extent of myocardial mass and LGE are related to a worse prognosis, and quantitative assessment of LGE has been reported as an important marker for clinical decision for primary prevention ICD implantation. New CMR markers, such as myocardial disarray and scar heterogeneity, may play a role as emerging risk factors for malignant ventricular arrhythmias. CMR is an imaging technique without ionizing radiations, allowing to repeat the examination over time and to detect patients at risk of disease progression, including progression of myocardial fibrosis, which might predict the occurrence of heart failure and sudden cardiac death. Finally, new specific drugs have been shown to significantly improve symptoms in patients with HCM and CMR may be fundamental to test the efficacy of these drugs.

References 1. Authors/Task Force members, Elliott PM, Anastasakis A, Borger MA, Borggrefe M, Cecchi F, Charron P, Hagege AA, Lafont A, Limongelli G, Mahrholdt H, WJ MK, Mogensen J, Nihoyannopoulos P, Nistri S, Pieper PG, Pieske B, Rapezzi C, Rutten FH, Tillmanns C, Watkins H.  ESC Guidelines on diagnosis and management of hypertrophic cardiomyopathy: the task force for the diagnosis and management of hypertrophic cardiomyopathy of the European Society of Cardiology (ESC). Eur Heart J. 2014;35(39):2733–79. https://doi.org/10.1093/eurheartj/ehu284. 2. Neubauer S, Kolm P, Ho CY, Kwong RY, Desai MY, Dolman SF, Appelbaum E, Desvigne-Nickens P, JP DM, Friedrich MG, Geller N, Harper AR, Jarolim P, Jerosch-Herold M, Kim DY, Maron MS, Schulz-Menger J, Piechnik SK, Thomson K, Zhang C, Watkins H, Weintraub WS, Kramer CM, HCMR Investigators. Distinct

117 subgroups in hypertrophic cardiomyopathy in the NHLBI HCM Registry. J Am Coll Cardiol. 2019;74(19):2333–45. https://doi. org/10.1016/j.jacc.2019.08.1057. 3. Rajappan K, Bellenger NG, Anderson L, Pennell DJ.  The role of cardiovascular magnetic resonance in heart failure. Eur J Heart Fail. 2000;2(3):241–52. https://doi.org/10.1016/ s1388-­9842(00)00096-­9. 4. Maron MS, Maron BJ, Harrigan C, Buros J, Gibson CM, Olivotto I, Biller L, Lesser JR, Udelson JE, Manning WJ, Appelbaum E.  Hypertrophic cardiomyopathy phenotype revisited after 50 years with cardiovascular magnetic resonance. J Am Coll Cardiol. 2009;54(3):220–8. https://doi.org/10.1016/j.jacc.2009.05.006. 5. Kwon DH, Smedira NG, Rodriguez ER, Tan C, Setser R, Thamilarasan M, Lytle BW, Lever HM, Desai MY. Cardiac magnetic resonance detection of myocardial scarring in hypertrophic cardiomyopathy: correlation with histopathology and prevalence of ventricular tachycardia. J Am Coll Cardiol. 2009;54(3):242–9. https://doi.org/10.1016/j.jacc.2009.04.026. 6. Maron MS.  Clinical utility of cardiovascular magnetic resonance in hypertrophic cardiomyopathy. J Cardiovasc Magn Reson. 2012;14(1):13. https://doi.org/10.1186/1532-­429X-­14-­13. 7. Messroghli DR, Moon JC, Ferreira VM, Grosse-Wortmann L, He T, Kellman P, Mascherbauer J, Nezafat R, Salerno M, Schelbert EB, Taylor AJ, Thompson R, Ugander M, van Heeswijk RB, Friedrich MG. Clinical recommendations for cardiovascular magnetic resonance mapping of T1, T2, T2* and extracellular volume: a consensus statement by the Society for Cardiovascular Magnetic Resonance (SCMR) endorsed by the European Association for Cardiovascular Imaging (EACVI). J Cardiovasc Magn Reson. 2017;19(1):75. https://doi.org/10.1186/s12968-­017-­0389-­8. 8. De Cobelli F, Esposito A, Belloni E, Pieroni M, Perseghin G, Chimenti C, Frustaci A, Del Maschio A. Delayed-enhanced cardiac MRI for differentiation of Fabry's disease from symmetric hypertrophic cardiomyopathy. AJR Am J Roentgenol. 2009;192(3):W97– 102. https://doi.org/10.2214/AJR.08.1201. 9. Grigoratos C, Todiere G, Barison A, Aquaro GD. The role of MRI in prognostic stratification of cardiomyopathies. Curr Cardiol Rep. 2020;22(8):61. https://doi.org/10.1007/s11886-­020-­01311-­3. 10. Swoboda PP, AK MD, Erhayiem B, Broadbent DA, Dobson LE, Garg P, Ferguson C, Page SP, Greenwood JP, Plein S.  Assessing myocardial extracellular volume by T1 mapping to distinguish hypertrophic cardiomyopathy From Athlete's Heart. J Am Coll Cardiol. 2016;67(18):2189–90. https://doi.org/10.1016/j. jacc.2016.02.054. 11. Quarta G, Aquaro GD, Pedrotti P, Pontone G, Dellegrottaglie S, Iacovoni A, Brambilla P, Pradella S, Todiere G, Rigo F, Bucciarelli-­ Ducci C, Limongelli G, Roghi A, Olivotto I. Cardiovascular magnetic resonance imaging in hypertrophic cardiomyopathy: the importance of clinical context. Eur Heart J Cardiovasc Imaging. 2018;19(6):601–10. https://doi.org/10.1093/ehjci/jex323. 12. Ariga R, Tunnicliffe EM, Manohar SG, Mahmod M, Raman B, Piechnik SK, Francis JM, Robson MD, Neubauer S, Watkins H.  Identification of myocardial disarray in patients with hypertrophic cardiomyopathy and ventricular arrhythmias. J Am Coll Cardiol. 2019;73(20):2493–502. https://doi.org/10.1016/j. jacc.2019.02.065. 13. Todiere G, Pisciella L, Barison A, Del Franco A, Zachara E, Piaggi P, Re F, Pingitore A, Emdin M, Lombardi M, Aquaro GD. Abnormal T2-STIR magnetic resonance in hypertrophic cardiomyopathy: a marker of advanced disease and electrical myocardial instability. PLoS One. 2014;9(10):e111366. https://doi.org/10.1371/journal. pone.0111366. eCollection 2014 14. Chan RH, Maron BJ, Olivotto I, Pencina MJ, Assenza GE, Haas T, Lesser JR, Gruner C, Crean AM, Rakowski H, Udelson JE, Rowin E, Lombardi M, Cecchi F, Tomberli B, Spirito P, Formisano F, Biagini E, Rapezzi C, De Cecco CN, Autore C, Cook EF, Hong SN,

118 Gibson CM, Manning WJ, Appelbaum E, Maron MS. Prognostic value of quantitative contrast-enhanced cardiovascular magnetic resonance for the evaluation of sudden death risk in patients with hypertrophic cardiomyopathy. Circulation. 2014;130(6):484–95. https://doi.org/10.1161/CIRCULATIONAHA.113.007094. 15. Todiere G, Nugara C, Gentile G, Negri F, Bianco F, Falletta C, Novo G, Di Bella G, De Caterina R, Zachara E, Re F, Clemenza F, Sinagra G, Emdin M, Aquaro GD. Prognostic role of late gadolinium enhancement in patients with hypertrophic cardiomyopathy and low-to-intermediate sudden cardiac death risk score. Am J Cardiol. 2019;124(8):1286–92. https://doi.org/10.1016/j.amjcard.2019.07.023. Epub 2019 Jul 29 16. Petersen SE, Jerosch-Herold M, Hudsmith LE, Robson MD, Francis JM, Doll HA, Selvanayagam JB, Neubauer S, Watkins H. Evidence for microvascular dysfunction in hypertrophic cardiomyopathy: new insights from multiparametric magnetic resonance imaging. Circulation. 2007;115:2418–25. https://doi.org/10.1161/ CIRCULATIONAHA.106.657023. 17. Aquaro GD, Grigoratos C, Bracco A, Proclemer A, Todiere G, Martini N, Habtemicael YG, Carerj S, Sinagra G, Di Bella G. Late

G. Todiere et al. gadolinium enhancement-dispersion mapping: a new magnetic resonance imaging technique to assess prognosis in patients with hypertrophic cardiomyopathy and low-intermediate 5-year risk of sudden death. Circ Cardiovasc Imaging. 2020;13(6):e010489. https://doi.org/10.1161/CIRCIMAGING.120.010489. 18. Todiere G, Aquaro GD, Piaggi P, Formisano F, Barison A, Masci PG, Strata E, Bacigalupo L, Marzilli M, Pingitore A, Lombardi M. Progression of myocardial fibrosis assessed with cardiac magnetic resonance in hypertrophic cardiomyopathy. J Am Coll Cardiol. 2012;60(10):922–9. https://doi.org/10.1016/j.jacc.2012.03.076. 19. Nordin S, Kozor R, Vijapurapu R, Augusto JB, Knott KD, Captur G, Treibel TA, Ramaswami U, Tchan M, Geberhiwot T, Steeds RP, Hughes DA, Moon JC. Myocardial storage, inflammation, and cardiac phenotype in fabry disease after one year of enzyme replacement therapy. Circ Cardiovasc Imaging. 2019;12(12):e009430. https://doi.org/10.1161/CIRCIMAGING.119.009430. 20. Mavrogeni S, Pepe A, Lombardi M. Evaluation of myocardial iron overload using cardiovascular magnetic resonance imaging. Hell J Cardiol. 2011;52(5):385–90.

7

Cardiac Amyloidosis Aldostefano Porcari, Gianfranco Sinagra, Marianna Fontana, and Silvia Pica

Introduction Cardiac amyloidosis (CA) is considered the paradigm of the restrictive cardiomyopathies. Previously thought to be a rare disease, it is now emerging as an underdiagnosed cause of heart failure [1]. More than 30 proteins can form amyloid fibrils, but almost all clinical cases of CA are from either misfolded monoclonal immunoglobulin light chains (AL amyloidosis) produced by an abnormal clonal proliferation of plasma cells in the bone marrow, or transthyretin (ATTR amyloidosis), a protein synthetized by the liver normally involved in the transportation of the hormone thyroxine and retinol-binding protein [1]. ATTR amyloidosis may in turn be either hereditary (vATTR) arising from the misfolded mutated TTR, or non-hereditary, from misfolded wild-type TTR (wtATTR). According to available data, AL amyloidosis has a prevalence of 10–16 cases in 1 million/person/year [2]. The recognition of wtATTR amyloidosis has increased exponentially over the last few years [3]. Considered until very recently rare, current reports estimate a prevalence of 10–16% in some cohorts— particularly elderly (>80-year-old) patients with either heart failure, hypertrophy, aortic stenosis, or carpal tunnel (CT) syndrome [3, 4]. Supplementary Information The online version contains supplementary material available at https://doi.org/10.1007/978-­3-­031-­32593-­9_7.

In patients with systemic amyloidosis, the presence and degree of cardiac involvement is the major determinant of survival [1]. Amyloid deposition in the heart leads to expansion of the extracellular space with associated disruption in myocardial architecture, followed by systolic and diastolic dysfunction [5]. The increase in myocardial mass determines a progressively smaller ventricular cavity size, with a fixed end-diastolic volume (i.e., pre-load). Right and left ventricular ejection fraction (LVEF) tend to be preserved until end stage although LVEF is felt to be a poor marker of systolic function in this patients’ population. Assessment of myocardial mechanics with longitudinal strain provides a more accurate evaluation of myocardial contraction, which is reduced in patients with CA, with the reduction in longitudinal strain typically involving the basal and mid myocardial segments and sparing the apex, giving the characteristic “bull’s-eye” picture on parametric longitudinal strain polar maps [6, 7]. Biatrial dilatation is invariably present although severe degrees of dilatation are uncommon, as direct infiltration of the atrial wall prevents severe dilatation. Infiltration of the atrial walls is also associated with progressive loss of atrial function and increased stiffness, which in severe cases manifest as atrial electromechanical dissociation [8]. In this setting, cardiac output becomes critically dependent on increasing the heart rate as fixed and low stroke volume are a disease hallmark [9]. Whilst cardiac ATTR amyloidosis is felt to be a disease of pure infiltration, the pathophysiology of cardiac AL amyloidosis is more complex. In the latter

A. Porcari (*) Cardiovascular Department, Center for Diagnosis and Treatment of Cardiomyopathies, Azienda Sanitaria Universitaria Giuliano-­ Isontina (ASUGI), University of Trieste, Trieste, Italy National Amyloidosis Centre, Division of Medicine, University College London, London, UK e-mail: [email protected] G. Sinagra Cardiovascular Department, Center for Diagnosis and Treatment of Cardiomyopathies, Azienda Sanitaria Universitaria Giuliano-­ Isontina (ASUGI), University of Trieste, Trieste, Italy e-mail: [email protected]

M. Fontana National Amyloidosis Centre, Division of Medicine, University College London, London, UK e-mail: [email protected] S. Pica Multimodality Cardiac Imaging Section, IRCCS Policlinico San Donato, Milan, Italy

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 A. Barison et al. (eds.), Case-based Atlas of Cardiovascular Magnetic Resonance, https://doi.org/10.1007/978-3-031-32593-9_7

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case, indeed, a double-hit process involves not only the amyloid deposition, but also the direct “toxic” effect exerted by circulating pre-amyloid proteins causing oxidative stress and mitochondrial damage and contributing independently to disease progression [10]. The assessment of the structural and functional changes by echocardiography can provide an estimate of the likelihood of cardiac amyloid infiltration versus other hypertrophic phenocopies and can assess the severity of cardiac involvement. However, echocardiography cannot provide a conclusive diagnosis. Historically, the gold standard for the diagnosis and subtyping of CA has been cardiac biopsy. However, a wide use of endomyocardial biopsy (EMB) has been limited by procedural risks, access limited to experienced centers and availability of pathologists with specific expertise to accurately interpret the histological findings [11, 12]. Major advances in imaging such as bone tracer scintigraphy and cardiac magnetic resonance (CMR) have transformed the non-invasive approach for the diagnosis of CA. A landmark study by Gillmore et al. paved the way for the clinical application of bone scintigraphy for the non-invasive diagnosis of ATTR-CA, demonstrating that the positive predictive value of a moderate-high grade of cardiac uptake in the absence of a monoclonal protein in serum and urine approaches 100% [13]. CMR offers accurate information regarding the heart’s structure and function with advantages over echocardiography. Recent CMR studies shed light on the patterns of cardiac hypertrophy in CA. Although concentric and symmetric hypertrophy was considered a typical finding in CA as opposed to asymmetric wall thickening in hypertrophic cardiomyopathy, the most common phenotype in ATTR-CA is asymmetrical hypertrophy (≈80% of cases) [14]. However, the key advantage of CMR in CA is its unique ability to give information about the tissue composition by myocardial tissue characterization [15, 16]. The administration of commonly used extracellular gadolinium-based contrast agents that accumulate in the gaps between cells allows to visualize the extracellular matrix expansion resulting from amyloid fibril deposition [15]. CA has a highly characteristic appearance on late gadolinium enhancement imaging (LGE), with diffuse subendocardial LGE in early stages, later transmural LGE coupled with abnormal gadolinium kinetics with the myocardium and blood nulling at the same time [15]. Interpretation of LGE imaging can be challenging in light of the diffuse myocardial amyloid deposition, which makes it more difficult to determine the optimal null point for the myocardium [16]. Traditional LGE imaging is a thresholding or comparison technique that requires adequate nulling of the supposedly normal myocardium by an expert operator. Phasesensitive inversion recovery (PSIR) approach overcomes this limitation because the PSIR reconstruction always determines the myocardium containing less contrast agent to appear darker emphasizing areas with contrast accumulation

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and making the technique less operator dependent [9]. However, LGE is a non-quantitative technique, limiting the role of LGE in quantifying the amyloid burden. T1 mapping, instead, offers a quantitative measure of the myocardial T1 relaxation time—either pre-contrast (native) or post-­contrast. Native myocardial T1 increases in CA and tracks markers of systolic and diastolic function, as well as the degree of cardiac amyloid infiltration [17]. Native myocardial T1 elevation is associated, in single center studies, with a high diagnostic accuracy for CA, in settings with high pre-­test probability [15, 18]. However, native T1 is a composite myocardial signal from both interstitium and myocytes and does not differentiate fully the underlying processes (fibrosis, edema, amyloid, myocyte response). Using gadolinium-­based contrast agents permits extracellular volume (ECV) measurement, which is a surrogate measure of cardiac amyloid burden [9]. ECV is an early disease marker, tracks disease severity across the spectrum of amyloid infiltration, and correlates independently with prognosis in both types of amyloidosis [19, 20]. In initial experiences, it has been shown to be able to track response to treatment in both AL and ATTR-CA [9].

Case 1: Wild-Type ATTR Cardiac Amyloidosis A 67-year-old gentleman with previous bilateral CT decompression was admitted to the Cardiology Department due to worsening HF with NYHA class III and atrial fibrillation. His NT-proBNP was 11,435 ng/L and serum troponin T was 120  ng/L.  His echocardiogram was highly suggestive of CA, and he was referred to as CMR.  Cine steady-state free precession (SSFP) images showed a severely increased biventricular wall thickness (MWT 26  mm) and overall cardiac mass (171  g/m2) with low stroke volume (32 mL/m2) and impaired longitudinal function (MAPSE 3 mm, TAPSE 10 mm). On tissue characterization (Fig. 7.1a), native myocardial T1 was significantly elevated. Biventricular diffuse transmural LGE and elevated ECV were noted. Scintigraphy with 3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-­DPD) showed grade 2 cardiac uptake (Fig. 7.1b) and no monoclonal proteins were identified. Genetic sequencing ruled out the presence of TTR variants. The patient was diagnosed with wtATTR-CA and was started on tafamidis. Learning Point

This represents a typical case of CA, where a characteristic CMR and grade 2 uptake on bone scintigraphy, in the absence of a plasma cell dyscrasia (normal free light chains, negative blood, and urine electrophoresis and immunofixation) are sufficient to confirm a diagnosis of CA without the need of an EMB.

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Fig. 7.1 (a)Top raw: late gadolinium enhancement imaging. Middle row: T1 and T2 mapping imaging. Bottom raw: ECV imaging. (b) Bone tracer scintigraphy with planar (top) and SPECT (bottom) imaging

Case 2: Hereditary ATTR Cardiac Amyloidosis A 63-year-old gentleman with a family history of familial amyloid polyneuropathy associated with TTR variant Ser77Tyr presented with a 3-month history of exertional breathlessness, pre-syncope and mild ankle edema. Previous bilateral CT decompression, lumbar canal stenosis, and IgM lambda MGUS. His echocardiogram showed features in keeping with CA and 99mTc-DPD scan showed grade 1 cardiac uptake (Fig. 7.2b), which was confirmed by SPECT/CT study. Cine SSFP images showed severely increased biventricular wall thickness (MWT 23  mm) and LV mass (244  g/m2), reduced stroke volume (LV SVi 36 mL/m2) and poor overall systolic function (LVEF 41%, TAPSE 9 mm) (Fig.7.2a, Videos 7.1 and 7.2). Borderline native T1 and transmural LGE with

RV involvement were noted. Bone marrow biopsy showed 5–10% plasma cells with no evidence of amyloid. A diagnosis of low-grade IgM lambda secreting clonal dyscrasia was confirmed. Immunochemistry on EMB was positive for amyloid of TTR type. He was diagnosed with ATTR-CA-associated S77Y TTR variant and was started on patisiran.

Learning Point

ATTR amyloidosis associated with S77Y TTR variant has been confirmed in the literature as one of the TTR variants with low or absent cardiac uptake on bone scintigraphy. CMR in these variants has a crucial role in the diagnosis of CA.

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Fig. 7.2 (a). Top raw: steady-state free precession cine imaging. Middle raw: late gadolinium enhancement imaging. Bottom raw: native myocardial T1 mapping and ECV imaging. (b) Bone tracer scintigra-

phy with planar (top) and SPECT (bottom) imaging. Discrepancy between the degree of cardiac uptake and cardiac involvement by CMR is noted

Case 3: Hereditary ATTR Cardiac Amyloidosis

of CA (1058 ms) [18] with normal T2. Post-contrast images showed the absence of LGE and elevated ECV (35%) in keeping with an early CA. She was started on patisiran in 2020. After 2 years, she is tolerating the treatment well and echocardiogram, CMR and NT-proBNP (870 ng/L) are stable.

A 58-year-old lady with a family history of ATTR amyloidosis associated with T60A TTR variant developed sensory peripheral neuropathy and effort dyspnea. Gene testing confirmed the presence of T60A TTR variant, 99mTc-DPD scan showed a grade 1 cardiac uptake and no monoclonal proteins were identified (Fig.  7.3b); therefore, she was referred to CMR.  Echocardiogram revealed normal wall thickness (MWT 9 mm) and biventricular systolic function (LVEF 65%, TAPSE 22 mm). At CMR (Fig. 7.3a), native T1 value were within the intermediate range of probabilities for the presence

Learning Point

CMR with T1 mapping and ECV measurement can be used to assess early cardiac amyloid infiltration in patients with TTR variants.

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Fig. 7.3 (a) Top raw: late gadolinium enhancement imaging. Middle raw: native myocardial T1 mapping imaging. Bottom raw: ECV imaging. (b) Bone tracer scintigraphy with planar (top) and SPECT (bottom) imaging

Case 4: AL Cardiac Amyloidosis A 63-year-old gentleman presented with recent onset HF with NYHA class II and echocardiographic findings suggesting CA. He had a recent stroke. 99mTc-DPD scan ­demonstrated the absence of cardiac uptake, which was confirmed at SPECT/CT, and he was referred to CMR (Fig.  7.4). Cine SSFP images showed an increased biventricular wall thickness (MWT 18  mm) with reduced longitudinal function (MAPSE 8 mm, TAPSE 13 mm). Native T1 was increased and a borderline elevated T2 was found. Diffuse transmural LGE and elevated ECV were noted. A left atrial appendage (LAA) thrombus was detected on early gadolinium enhancement images, and he was started on anticoagulation. Blood tests showed the presence of two paraproteins (IgG and IgM) and increased serum lambda light chains (192 mg/L). Fat pad

biopsy was positive for amyloid of AL type, and he was diagnosed with systemic AL amyloidosis with predominant cardiac involvement. He achieved a complete hematological response after five cycles of cyclophosphamide-bortezomib-­ dexamethasone (CyBorD) therapy with significant reduction in NT-proBNP (from 5630 to 715 ng/L).

Learning Point

This represents a typical case of cardiac AL amyloidosis, with characteristic changes in structure, function, and tissue characterization. This case also illustrates the potential of CMR with dedicated early gadolinium enhancement images of the LAA in identifying thrombi.

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Fig. 7.4  Top raw: early gadolinium enhancement imaging with left atrial appendage thrombus (white and black arrows). Second raw: late gadolinium enhancement imaging. Third raw: native myocardial T1 and T2 mapping imaging. Bottom raw: ECV imaging

Case 5: AL Cardiac Amyloidosis A 67-year-old lady with biopsy-proven renal AL amyloidosis due to an IgA lambda secreting multiple myeloma was referred to CMR to assess for the presence of cardiac involvement. Her ECG and echocardiogram were normal. Her NT-proBNP was 364  pg/mL and FLCs were normal. Cine SSFP images showed normal biventricular dimensions, wall thickness and systolic function with mild biatrial dilatation (Fig. 7.5, top row). On tissue characterization, T1 was mildly elevated (n.v. 50% within the wall thickness of compacted myocardium during diastole, perpendicular to the endocardial border, and with evidence of subtotal or total obliteration during systole [16]. Differently from cardiac diverticula, myocardial crypts do not extend beyond the epicardial boundary.

9  Crypts, Diverticula, and Left Ventricular Noncompaction

Case 1. LVNC + Ebstein Anomaly A 55 years old male who underwent transthoracic echocardiography due to mild-to-moderate dyspnea presented increased biventricular trabeculation. Cardiac MRI was performed and confirmed severe LV hyper-trabeculation fulfilling the CMR diagnostic criteria for LVNC: Petersen with NC/C ratio > 2,3:1 (3,4:1 in this case) and Jacquier with a non-compacted myocardial mass  >  20% of total LV mass

Fig. 9.1  Cardiac MRI—cine images

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(38% in this case) (Fig. 9.1 panel a and b). Moreover, an apical displacement of septal tricuspidal leaflet was evident, reaching the criteria for Ebstein anomaly (a distance between mitral and tricuspidal implantation site >8 mm/m2) (Fig. 9.1 panel b and c). Of interest, septal midwall non-ischemic late gadolinium enhancement was present (Fig.  9.2 short axis view panle a and d, long axis view panel b and c). A diagnosis of LVNC combined to a congenital heart disease was reached and the patients is still on clinical follow-up.

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Case 2. LVNC with Non-ischemic Fibrosis A 57-year-old man with palpitations was referred to cardiological evaluation. His Holter ECG confirmed 9000 PVCs in 24 h, without complex ventricular arrhythmias. A cycloergometer stress ECG showed negative T waves in V5-V6 at baseline, that normalized during exercise, with no demonstration of stress-induced ventricular arrhythmias. Transthoracic echocardiography showed apical akinesia. Cardiac MRI was then suggested and demonstrated

ventricular hyper-trabeculation reaching the diagnostic criteria for LVNC, i.e., Petersen’s criteria with NC/C ratio  >  2.3:1 (3.2:1  in this case) and Jacquier’s criteria with non-­compacted myocardial mass > 20% (32% in this case) of the myocardial mass (Fig. 9.3 panel a to c). Both LV and RV EF were normal. LGE images resulted to be positive with midwall septal distribution (non-ischemic pattern), supporting the diagnosis of cardiomyopathy with LVNC (Fig. 9.3 panel d).

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Case 3. Congenital Diverticulum A 54-year-old female with non-sustained ventricular tachycardia at Holter ECG and a normal transthoracic echocardiography was referred to MRI, which showed a congenital diverticulum in the interventricular septum (Fig. 9.4 panel a and b), with preserved systolic contrac-

tion. Both left and right ventricle ejection fractions were normal. No sign of any shunt was detected (Qp:Qs 1:1) and no myocardial fibrosis was evident at LGE imaging. (Fig. 9.4 panel c and d). Of interest an apical localization of the postero-medial papillary muscle was detected. These specific findings enabled to differentiate this condition from wall thinning due to myocardial scar.

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Case 4. Congenital Diverticulum A 79-year-old asymptomatic woman with occasional finding of possible ventricular septal defect at transthoracic echocardiography and no clear shunt at color Doppler analysis was referred to CMR. A congenital diverticulum of the mid-­ventricular por-

tion of the interventricular septum was identified and described in both long- (Fig. 9.5 panel a and b) and short-axis (Fig. 9.5 panel c and d) views. LV EF and RV EF were normal. No signs of intraventricular shunt was evident and Qp:Qs was 1. All these findings, together with a preserved systolic contraction of the septal outpouching allowed the diagnosis of diverticulum.

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Case 5. Congenital Aneurysm A 19-year-old asymptomatic male presenting with negative T waves at resting ECG underwent transthoracic echocardiography, which showed focal akinesia of the inferior left ventricular wall. Cardiac MRI was suggested and demonstrated a congenital aneurysm of the inferior

left ventricular wall (Fig. 9.6 panel a and b). LV EF and RV EF were normal. Despite the regional akinesia of the thinned myocardium, no myocardial fibrosis was evident at LGE imaging (Fig.  9.6 panel c and d). This specific finding enabled to differentiate this condition from wall thinning due to myocardial scar (e.g., from an acquired post-infarction aneurysm).

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Case 6. Saw-Tooth Cardiomyopathy A 51-year-old male athlete with a previous history of isolated PVCs had undergone several transthoracic echocardiography in the past, showing LVNC with associated hypertrophic phenotype. The presence of ventricular septal defect was also sug-

gested in the past. CMR images d­ emonstrated multiple crypts in the interventricular septum, possibly related to the spontaneous closure of small muscular ventricular septal defects during childhood. LV EF and RV EF were normal. Overall this phenotype may also be classified as saw-tooth cardiomyopathy that represents a very rare form of LVNC (Figs. 9.7 and 9.8).

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Case 7. Ventricular Crypt A 50-year-old asymptomatic male practicing competitive sport activity with normal echocardiography (LVEF 56%) developed ventricular ectopic beats with superior axis (single and couplets) during exercise (Fig.  9.9). He was then referred to CMR. Cine SSFP showed eccentric remodeling with mild increase of ventricular volumes (LVEDVi = 113 mL/ m2; RVEDVi = 104 mL/m2) and preserved systolic function (LVEF = 56%; RVEF = 63%). Cine SSFP in the 2-chamber and short-axis views documented a deep invagination of the myocardium consistent with a myocardial crypt extending through the entire wall thickness at the conjunction point between the mid posterior septum and inferior wall (Fig. 9.10, arrow). There was no evidence of segmental wall motion abnormality and almost subtotal obliteration of the crypt during systole (Fig. 9.10). LGE images showed focal areas of patchy midwall myocardial fibrosis in the basal inferior wall adjacent to the myocardial crypt and at the level of the mid lateral wall of non-ischemic etiology (Fig.  9.11, thin arrow points to myocardial crypt with increased blood-pool signal, wide arrows indicate myocardial fibrosis). Fig. 9.7  Cardiac MRI—bSSFP cine images

Fig. 9.8  Cardiac MRI—bSSFP cine images

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9  Crypts, Diverticula, and Left Ventricular Noncompaction

 ase 8. LVNC-DCM with Multiple Regions C of Fibrosis A 53-year-old male was admitted because of worsening dyspnea on exertion. Echocardiography showed eccentric remodeling and reduced LV systolic function. Coronary angiography demonstrated non-obstructive disease. CMR was later requested to address cardiomyopathy etiology. Cine SSFP images showed a dilated LV with mild systolic dysfunction (LVEDVi = 112 mL/m2; LVEF = 42%) and prominent trabeculations at the level of mid and apical ­segments. On cine SSFP imaging, measurement of NC/C ratios in 3-chamber, 4-cham-

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ber, and 2-chamber longitudinal views in end-diastole were  >  2.3 (max 2.9) which satisfied Petersen’s criteria for LVNC (Fig. 9.12, red lines represent measurement of trabeculations and yellow lines indicate the compacted myocardium). The non-compacted myocardium was >20% of LV mass which also satisfied Jacquier’s CMR criteria for LVNC (Fig.  9.13 panel a, b and c, compacted myocardium (yellow line) vs. NC in multiple short-axis views (red line)). Delayed imaging showed multiple areas of patchy and linear midwall fibrosis of non-­ischemic etiology (Fig. 9.14). CMR phenotype was consistent with an overlapping phenotype between LVNC and DCM, subsequently confirmed by positive genetic testing.

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Fig. 9.12  Cine SSFP imaging in 3-chamber, (a), 4-chamber, (b), and 2-chamber, (c), views

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Case 9. LVNC-HCM A 55-year-old black male underwent a cardiology outpatient evaluation due to the development of dyspnea on exertion. The ECG showed T-wave inversion in the precordial leads (Fig.  9.15). The echocardiogram showed increased wall thickness and consequently a CMR exam was requested on suspicion of hypertrophic cardiomyopathy (HCM). Cine SSFP images showed asymmetric hypertrophy mostly involving the interventricular septum (Fig. 9.16, white line measuring maximum wall thickness of 22 mm), no evidence of left ventricular outflow obstruction or systolic anterior motion (SAM) of the mitral leaflets/chords, and mildly

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reduced left ventricular ejection fraction (LVEF  =  46%). Moreover, prominent trabeculations involved the mid and the apical segments satisfying Petersen’s criteria for left ventricular noncompaction (LVNC): measurement of non-­ compacted/compacted myocardium ratios in 4-chamber, 2-chamber, and 3-chamber longitudinal views in end-­diastole were  >  2.3 (Fig.  9.16, red lines represent measurement of trabeculations and yellow lines indicate compacted myocardium). Delayed enhancement imaging documented prominent areas of patchy midwall myocardial fibrosis in multiple segments (Fig.  9.17, arrows). Together these findings indicated overlapping phenotype between LVNC and HCM, diagnosis later confirmed by genetic testing.

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 ase 10. Congenital vs. Acquired Left C Ventricular Apical Aneurysm A 76-year-old subject underwent a cardiological evaluation for hypertension and mitral regurgitation of rheumatic etiology. His ECG was unremarkable (Fig.  9.18a). A cardiac magnetic resonance was requested to evaluate the degree of mitral regurgitation as echocardiography had suboptimal quality. Cine SSFP images showed normal systolic function and volumes and mild to moderate MR (LVEDVi = 101 mL/ m2, LVEF = 55%). There was also an incidental finding of a circular well-demarcated apical aneurysm of the LV measuring 28 × 25 mm shown on 2-chamber and off-axis 4-chamber cine images (Fig.  9.19a, b, arrows). 3D strain analysis showed normal contraction of all myocardial segments except for a prominent systolic bulging of the aneurysm (Fig. 9.19c, arrow indicates systolic excursion).

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On the other hand, a young 41-year-old male with a strong family history for coronary artery disease underwent a cardiological evaluation for a late presentation of an anterior myocardial infarction, ventricular dilatation, and reduced systolic function. The ECG documented anterior myocardia necrosis (Fig.  9.18b). Cine SSFP images showed severely enlarged LV and mild systolic dysfunction secondary to LAD territory wall motion abnormality (LVEDVi = 147 mL/m2, LVEF = 41%). The LV apex was aneurysmatic with evidence of low-intensity formation within the aneurysm (Fig. 9.20 arrow). On delayed enhancement imaging, there was a prominent transmural scar of ischemic etiology involving the entire territory of the LAD artery and confirmation of a thrombotic formation within the LV aneurysm (Fig.  9.20, arrows point to myocardial scar and star indicates thrombotic formation).

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Fig. 9.18  ECG (precordial leads) of a patient with congenital left ventricular aneurysm (a) and of a patient with post-ischemic left ventricular aneurysm (b)

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Fig. 9.19  Cine SSFP imaging in 2-chamber, (a), off-axis 4-chamber, (b), and 3D strain (c)

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Fig. 9.20  Cine SSFP imaging in 4-chamber, (a), delayed imaging in 3-chamber, (b), and 2-chamber (c)

Pearls and Pitfalls • Among patients with CMR criteria of LVNC, LV fibrosis is a robust-independent predictor of poor prognosis; moreover, patients with LV dilation and reduced LVEF and LVSV, a phenotype classified as dilated cardiomyopathy (DCM)-like, present a high rate of cardiovascular events. • Among patients with CMR criteria of LVNC, normal ECG, preserved systolic function, no LGE, and negative familial screening are associated with low rate of adverse cardiovascular events. • In 70% of patients with an LV diverticulum, there are associated midline thoraco-abdominal defects or other congenital cardiac malformations, while the remaining 30% of patients present without other congenital defects. • Left ventricular diverticula are muscular contractile outpouchings and typically originate from left ventricular apex, inferior or posterior wall while ventricular aneurysms are fibrous, akinetic/dyskinetic outpouchings. • Myocardial crypts are blood-filled invaginations within the compacted left ventricular myocardium which have also previously been referred to as clefts or fissures. • While no standard definition exists, crypts are usually defined as structural abnormalities consisting of narrow, deep blood-filled invaginations extending >50% within the wall thickness of contiguous normal compacted myocardium during diastole, perpendicular to the endocardial border, and evidence of subtotal or total obliteration during systole. • Evidence of any clinical significance remains elusive and crypts are generally thought to represent a benign variant although they are significantly more common in HCM, first-degree family members of subjects with HCM, and hypertensive CM.

Conclusions CMR should be considered as the gold standard for the anatomical evaluation of non-compacted ventricular myocardium and for the identification of myocardial crypts or diverticula. All these conditions could be considered as rare; thus, an expert evaluation is needed for appropriate evaluation and clinical management in order not to overdiagnose or mis-diagnose these rare clinical entities. In this regard, CMR is able to provide myocardial tissue characterization with identification of myocardial fibrosis presence that is associated with cardiovascular prognosis. The accurate identification of those patients with higher probability of cardiovascular events is of fundamental importance in the setting of rare anatomical patterns that could be identified both in patients with cardiomyopathy and in patients without any defined heart structural disease. Moreover, CMR is able to accurately identify the presence of LV thrombosis that could be associated with LVNC or LV aneurysm, whose identification is of utmost clinical importance. Finally, it should be underlined that CMR findings should be considered together with a comprehensive clinical evaluation, including ECG monitoring and exercise ECG testing for the identification of ventricular arrhythmias, that is of fundamental importance for an appropriate prognostic stratification of the patients.

References 1. Jenni R, Oechslin EN, van der Loo B.  Isolated ventricular non-­ compaction of the myocardium in adults. Heart. 2007;93:11–5. 2. Arbustini E, Weidemann F, Hall JL.  Left ventricular non-­ compaction: a distinct cardiomyopathy or a trait shared by different cardiac disease? J Am Coll Cardiol. 2014;64:1840–50.

9  Crypts, Diverticula, and Left Ventricular Noncompaction 3. Zaragoza MV, Arbustini E, Narula J.  Noncompaction of the left ventricle: primary cardiomyopathy with elusive genetic etiology. Curr Opin Pediatr. 2007;19:619–27. 4. Gati S, Chandra N, Bennet RL, et al. Increased left ventricular trabeculation in highly trained athletes: do we need more stringent criteria for the diagnosis of left ventricular non-compaction in athletes? Heart. 2013;99:401–8. 5. Captur G, Zemrak F, Muthurangu V, et al. Fractal analysis of myocardial trabeculations in study participants: multi-ethnic study of atherosclerosis. Radiology. 2015;277:707–15. 6. Nucifora G, Aquaro GD, Pingitore A, Masci PG, Lombardi M. Myocardial fibrosis in isolated left ventricular noncompaction and its relation to disease severity. Eur Heart Fail. 2011;13:170–6. 7. Petersen SE, Selvanayagam JB, Wiesmann F, et al. Left ventricular noncompaction insights from cardiovascular magnetic resonance imaging. J Am Coll Cardiol. 2005;46:101–5. 8. Jacquier A, Thuny F, Jop B, et  al. Measurement of trabeculated left ventricular mass using cardiac magnetic resonance imaging in the diagnosis of left ventricular noncompaction. Eur Heart J. 2010;31:1098–104. 9. Andreini D, Pontone G, Bogaert J, et  al. Long term prognostic value of cardiac magnetic resonance in left ventricle noncompaction: a prospective multicenter study. J Am Coll Cardiol. 2016;68:2166–81.

171 10. Grigoratos C, Barison A, Ivanov A, et  al. Meta-analysis of the prognostic role of late gadolinium enhancement and global systolic impairment in left ventricular noncompaction. J Am Coll Cardiol Img. 2019;12:2141–51. 11. Casas G, Limeres J, Oristrell G, et  al. Clinical risk prediction in patients with left ventricular myocardial noncompaction. J Am Coll Cardiol. 2021;78(7):643–62. 12. Takahashi M, Nishikimi T, Tamano K, et al. Multiple left ventricular diverticula detected by second harmonic imaging: a case report. Circ J. 2003;67(11):972–4. 13. Chang CH. Total correction of a syndrome consisting of left ventricular diverticulum, atrial septal defect, tetralogy of Fallot and midline thoracoabdominal defect. Cardiovasc Dis. 1974;1(2):105–8. 14. Bunch TJ, Oh JK, Click RL.  Subepicardial aneurysm of the left ventricle. J Am Soc Echocardiogr. 2003;16(12):1318–21. 15. Child N, Muhr T, Sammut E, et al. Prevalence of myocardial crypts in a large retrospective cohort study by cardiovascular magnetic resonance. J Cardiovasc Magn Reson. 2014;16:66. 16. Erol C, Koplay M, Olcay A, et al. Congenital left ventricular wall abnormalities in adults detected by gated cardiac multidetector computed tomography: clefts, aneurysms, diverticula and terminology problems. Eur J Radiol. 2012;81:3276–81.

Iron Overload Cardiomyopathies

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Alessia Pepe, Paola Sormani, Antonella Meloni, and Camilla Torlasco

Introduction Iron overload cardiomyopathy (IOC) is a secondary form of cardiomyopathy occurring in the setting of iron accumulation in the myocardium. IO is cytotoxic and with time it can induce organ damage and failure. Primary IO is caused by an underlying genetic defect that alters a protein involved in the regulation of iron absorption. Secondary IO is primarily observed for high parenteral iron administration in association with inherited anemias such as hemoglobinopathies (thalassemia and sickle-cell disease) or acquired anemias (i.e., myelodysplastic syndromes, leukemias, stem cell transplantations, chronic kidney disease). Other conditions associated with secondary IO include chronic liver diseases, Friedreich ataxia, and extreme dietary intake [1]. Two phenotypes of IOC have been identified: the dilated phenotype, characterized by left ventricular (LV) remodelling resulting into chamber dilation and depressed LV ejection fraction (LVEF), and the restrictive phenotype, characterized by diastolic LV dysfunction with restrictive filling, preserved LVEF, pulmonary hypertension, and subse-

Supplementary Information The online version contains supplementary material available at https://doi.org/10.1007/978-­3-­031-­32593-­9_10. A. Pepe (*) Department of Medicine, Institute of Radiology, University of Padua, Padua, Italy e-mail: [email protected] P. Sormani ASST GOM Niguarda, De Gasperis Cardio Center, Milan, Italy e-mail: [email protected] A. Meloni Fondazione Toscana Gabriele Monasterio, Pisa-Massa, Italy e-mail: [email protected] C. Torlasco Department of Cardiology, Istituto Auxologico Italiano, IRCCS, Milan, Italy e-mail: [email protected]

quent right ventricular (RV) dilation [2]. Today, the dilated phenotype is the most frequent presentation, and it is supported by the prevalence of a high cardiac output state due to the anemia respect to the MIO. The quantification of the myocardial iron overload (MIO) is the cornerstone of the clinical diagnosis and management of patients with IOC.  To date, cardiac magnetic resonance (CMR) is the only technique that quantitatively and noninvasively assesses MIO. The presence of myocardial iron deposits causes microscopic magnetic field inhomogeneities and reduces all relaxation times. The T2* technique at 1.5  T is currently the mainstay for the quantitative assessment of cardiac iron deposition [3]. In the single-slice approach, the T2* value is evaluated in the mid-ventricular septum as representative of the T2* value for the whole heart [4]. The multislice approach allows a global and segmental analysis of the whole LV by identifying early heterogeneous and preferential patterns of iron distribution, correlated with clinical endpoints [5, 6]. At 3  T, T2* quantification limited to the mid-ventricular septum is feasible and reproducible, but a segmental heart T2* analysis is a challenge due to significantly higher susceptibility artifacts [7]. The T2* technique at 1.5 T has been proved to be reproducible and transferable among different scans [8]. The validation against healthy subjects and human biopsy has clearly demonstrated that the universally accepted cut off of 20 ms is extremely conservative: the real T2* cut off for an iron free heart is about >30 ms [9]. The T2* CMR has revolutionized the clinical management of patients with IO conditions, allowing to tailor the iron chelation therapy, aimed to prevent or to eliminate iron deposition, and to monitor its efficacy. Actually, the observed survival improvement in thalassemia major (TM) is significantly attributable to the introduction of CMR-T2* imaging into clinical practice [10]. In fact, cardiac T2* values convey a prognostic role, enabling the early identification of patients at risk for heart failure and needing an intensification of chelation therapy [6]. Moreover, it is recommended to quantify also liver [4] and pancreatic [11] iron using a single stop T2* MR approach. In this way, it is possible to tailor the therapy

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 A. Barison et al. (eds.), Case-based Atlas of Cardiovascular Magnetic Resonance, https://doi.org/10.1007/978-3-031-32593-9_10

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also considering the specific effects of the chelators for the different organs. One of the main limitations of the T2* CMR is the reduced sensitivity for detection of changes associated with mild or early MIO, but T1 mapping has been proved useful in overcoming this drawback [12, 13]. Indeed, T1 mapping appears to be able to identify even small amounts of iron accumulating in the heart and, in this scenario, it can have a higher sensitivity than the T2* technique, in particular for the ferritin form. Due to the heterogenous iron distribution in the heart, a segmental approach is strongly suggested for quantifying iron by T1 mapping. However, native T1 is less specific than T2* for MIO detection, given that myocardial fat and fibrosis can influence T1 values. CMR can uniquely detect replacement fibrosis by the late gadolinium enhancement (LGE) technique and diffuse myocardial fibrosis by accurately measuring the extracellular volume (ECV), which is calculated from pre- and post-­contrast T1 values. Replacement myocardial fibrosis was demonstrated to be a relatively common finding among adult TM patients and in the current era it is emerged as the strongest CMR predictor for heart failure and cardiac complications, thanks to the reduced prevalence of MIO by the improvement in the clinical management [6]. In TM children, free of complications which have been proved to predispose to replacement myocardial fibrosis in adult (such as diabetes mellitus or hepatitis C virus infection), a significant link between heart iron and replacement myocardial fibrosis has been demonstrated [14]. Moreover, it has recently been shown that ECV by CMR is significantly increased in TM patients who had prior MIO as compared with healthy subjects [15]. These findings seem to confirm that MIO may play a key pathophysiological role in the development of myocardial fibrosis. Native myocardial T1 mapping is considered superior to T2 mapping for MIO detection. In patients with low or normal MIO, iron may not be dominant in affecting T2 values and its effects may be counterbalanced by inflammation. T2 mapping can circumvent all the limitations of T2-weighted imaging, and it can provide additional insights into the subclinical myocardial involvement also in patients with hemochromatosis. In fact, these patients have increased susceptibility to infections that are the most common cause of myocarditis [16].

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Beyond tissue characterization, the assessment of biventricular volumes and function is crucial for the detection of heart damage and a consistent number of hemochromatosis patients show heart dysfunction without evidence of heart iron [17]. CMR is the gold standard for quantifying biventricular function parameters, thanks to its high accuracy and reproducibility. Anyway, it is recommended to apply appropriate “normal” reference ranges to anemic patients to avoid misdiagnosis of cardiomyopathy due to a basal high-output state characterized by heart chambers’ dilatation and a hypernormal function [18]. The routinely acquired cine images can also be used for detecting the morphological criteria for non-compaction (NC) and for quantifying myocardial deformation by ventricular strain feature tracking (FT) CMR. Due to an adverse heart remodelling mainly supported by the chronic anemia, it is strongly suggested to apply planimetric morphologic criteria to improve the specificity of LVNC diagnosis and to differentiate the NC from a hypertrabeculation [19]. The more relevant use of strain lies in its ability to assess the effect of MIO and other factors on contractility. When performed serially, FT-CMR can add insights into the rapid deterioration of an asymptomatic patient [20].

Case 1: Thalassemia Major A CMR scan in a 28-year-old patient with TM and severe cardiac iron overload (T2* 6.3  ms, T1 420 ms [v.n. 918– 1038 ms]) displayed increased LV size (LV EDV = 144 mL; LV EDVi  =  110  mL/m2) and reduced systolic function based on the specific reference values in anemic patients (LV EF = 52%) (Fig. 10.1, top panel). After increasing chelation therapy (from deferoxamine to combined deferoxamine and deferasirox) a 12-month follow-up scan demonstrated a significant reduction in iron overload (T2* = 12 ms, T1 mapping = 650 ms) associated to LV size reduction (LV EDV = 107 mL; LV EDVi = 82 mL/m2) and systolic function improvement (LV EF = 64%) (Fig. 10.1, bottom panel; Video 10.1 short-axis cines). This is a paradigmatic case of tailored chelation therapy effective in removing heart iron with a concordant positive effect on cardiac function.

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Fig. 10.1  Top panel: first scan. Bottom panel: follow-up scan after chelation therapy intensification. Both panels, from left to right: long-­ axis cine (top row: diastole; bottom row: systole); mid-ventricular

short-axis slice T1 mapping by MOdified Lock-Locker Inversion recovery (MOLLI); mid-ventricular short-axis slice T2* (Top panel: T2* map; Bottom panel: dark-blood T2*)

Case 2: Thalassemia Intermedia

based on the specific reference values in anemic patients (Fig. 10.2, Video 10.2 short-axis cines). Mid-ventricular septum T2* showed normal values (T2* = 27 ms), suggesting no iron overload. Conversely, native T1 mapping (MOLLI) was reduced (885  ms, n.v. 918–1038  ms), suggesting for the ­presence of mild iron overload (Fig. 10.3) and for its higher sensitivity in detecting MIO .

A 23-year-old patient with thalassemia intermedia, who required repeated blood transfusions, underwent routine CMR scans every 2 years. Cine SFFP images demonstrated normal LV size (EDV = 135 mL; EDVi = 84 mL/m2) with a low-normal systolic function (LV EF = 59%, GLS = 16.5%)

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10  Iron Overload Cardiomyopathies

 ase 3: Iron Overload with Acute Myocardial C Damage A 20-year-old male with hyperferritinemia due to newly diagnosed hemochromatosis (H63D mutation) and history of acute leukemia requiring multiple transfusions, developed moderate left ventricular dysfunction. He underwent CMR imaging to evaluate myocardial and hepatic iron load, cardiac function, and late gadolinium enhancement. At cardiac cine SSFP sequences, diffuse hypokinesia with mild global left ventricular dysfunction was evident (LVEF 43%) (Fig.  10.4a, Video 10.3). Myocardial global longitudinal strain was reduced (−14%). Myocardial T2* was mildly reduced in the septal region, suggesting the presence of mild myocardial iron overload with preserved values in the anteFig. 10.4 (a) Cine SSFP 4-chambers view (b) BB T2* mid-ventricular short-axis view (c) STIR T2W mid-ventricular short-axis view (d) STIR T2W 3-chamber view

Fig. 10.5 (a) T1 mapping mid-ventricular short-axis view by MOLLI sequence, (b) ECV mid-ventricular short-axis view

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rior segments (Fig.  10.4b). T2-weighted STIR images showed subepicardial signal hyperintensity of the left ventricular inferolateral wall (Fig.  10.4d), while other regions were unremarkable (Fig. 10.4c). Native T1 mapping images showed diffuse reduction of myocardial T1 (mid value 896  ms) with focal areas of further reduction (lower value 740  ms) (Fig.  10.5a). Delayed enhancement imaging after paramagnetic gadolinium-based contrast medium showed extensive subepicardial enhancement with variable intramyocardial extension (nonischemic pattern) matching the areas with lower T1 mapping values (Fig. 10.6). ECV was significantly increased in the areas with LGE (up to 50%) (Fig. 10.5b). A likely explanation of these findings could be the presence of localized ferritin deposition due to acute myocardial damage in the context of diffuse mild myocardial

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iron overload. This case shows well the value of a CMR multiparametric approach in order to fully address the heart damage in patients with hemochromatosis.

 ase 4: Thalassemia Major with Extensive C Myocardial Fibrosis A 38-year-old female with TM underwent routine CMR to quantify MIO by T2*. At cine SSFP images, global LVEF was normal (61%) but distal apical left ventricular akinesis with wall thinning was found (Fig.  10.7a, c, Video 10.4). Myocardial global longitudinal strain was reduced (−15%) (Fig. 10.7b, Video 10.5). Due to these findings, a complete tissue characterization including contrast enhancement was applied. T2-weighted STIR images were unremarkable. T1-weighted images showed a focal apical area of fat infiltration/metaplasia (Fig.  10.7d). Delayed enhancement

i­maging after paramagnetic contrast showed a full-thickness enhancement matching with the apical akinetic region (Fig. 10.8, blue arrows) and subepicardial and intramyocardial enhancement of the inferolateral and distal septal walls (Fig. 10.8, yellow arrows). Myocardial T2* was within normal values (23 ms in the mid-ventricular septum) following the conservative cut off of 20 ms (Fig. 10.9a), but T1 mapping values were reduced (867  ms in the mid-ventricular ­septum) based on the normal reference values in our CMR site (Fig. 10.9b), suggesting an initial myocardial iron overload. Liver T2* was reduced, suggesting moderate iron overload (2.7 ms). A CMR scan was repeated after 1 year and the patient developed mild global left ventricular dysfunction (LVEF 51%), considering the specific cut off in the anemic patients. This case underscores the important prognostic role of late gadolinium enhancement in predicting left ventricular dysfunction also in patients with thalassemia.

10  Iron Overload Cardiomyopathies Fig. 10.7 (a) Cine SSFP 4-chamber view, (b) 4-chamber view STRAIN image, (c) Cine SSFP 2-chamber view, (d) T1W TSE 2-Chamber view image

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 ase 5: Thalassemia Major with Mild LV C Systolic Dysfunction A 20-year-old male TM patient with an autoimmune history (arthritis and hemolytic anemia) was referred to MR before the scheduled follow-up due to a mild reduction of the LV systolic function in order to understand the cause (myocarditis or/and MIO?). Cine images documented normal LV and RV volumes (93 mL/m2 and 87 mL/m2, respectively) with a preserved RV systolic function (EF 59%) and a mild reduction of the systolic function (EF 52%) taking into account the normal reference cut off in anemic patients (Fig. 10.10a and d, shortaxis cines in Video 10.6). Cardiac index was elevated (4.3 L/

min/m2). T2-weighted STIR (Fig. 10.10b, c) and PSIR LGE images (Fig. 10e, f) were unremarkable. Considering the specific laboratory reference values based on sex and age, T1 and T2 mapping were reduced at global level (683 and 38  ms, respectively), and at segmental level (Fig.  10.11a and b, respectively). Severe and diffuse MIO was detected based on T2* multislice technique (global heart = 9 ms, basal, mid and distal ventricular septum 9 ms) (Fig. 10.12). The extracellular volume was mildly elevated (33%). Thanks to a multiparametric mapping approach (T2*, T1, and T2), myocarditis has been excluded, while a severe and diffuse MIO was confirmed: the patient stopped deferasirox and started combined desferrioxamine and deferiprone chelation therapy.

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 ase 6: Thalassemia Major with Biventricular C Dilation A 16-year-old male TM patient was referred to MR for a scheduled follow-up. He was asymptomatic and reported no infections in the previous 6 months. Cine images documented severe dilated LV and RV volumes (133 mL/m2 and 135 mL/ m2, respectively) with a preserved LV and RV systolic function (EF 59% and 62%, respectively) and mild pericardial effusion (Fig.  10.13a, b, short-axis cines in Video 10.7). Cardiac index was elevated (5.02 L/min/m2). By a multislice approach, heart T2* values were normal: global heart = 40 ms; T2* in the basal, mid and distal ventricular septum were, respectively, 41, 42, and 39 ms (Fig. 10.14). Considering the

Fig. 10.13  Cine SSFP 2-chamber end diastolic phase (a) and end systolic phase (b), PSIR LGE basal-mid-­ ventricular short-axis view (c–d)

specific laboratory normal reference values by sex and age, native T1 values were reduced at global (889 ms) and segmental level (Fig. 10.15a). The extracellular volume was normal (26%). Despite low native T1 values due to iron, T2 values were mildly elevated at global (53 ms) and segmental level, with the exception of the inferior, anterior, and infero-septal basal segments (Fig. 10.15b). PSIR LGE images showed mild intramyocardial enhancement in the inferior and inferolateral wall at mid-basal level (Fig. 13c, d). Thanks to a multiparametric approach (T2*, T1, T2 mapping, and LGE), a subclinical mild acute/subacute myocardial involvement was unveiled by impacting in the clinical management of the patients. Moreover, the elevated cardiac index associated to severe dilated ventricles stressed for a higher transfusional regimen.

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Pearls and Pitfalls • Multiparametric CMR combines quantitative tissue characterization, morphological and functional assessment, and plays a key role in identifying subclinical and overt cardiac involvement in patients with hemochromatosis [6]. • The T2* technique for quantifying myocardial iron overload is a biomarker for tailoring the chelation therapy [10]. It has been proved to be fast, reproducible, transferable, and validated against human biopsy [9]. • T1 mapping seems more sensitive than T2* mapping for MIO detection, but it is less specific, more dependent on sequence type and protocol parameters, and more difficult to transfer among different scanners. On site, normal reference values are mandatory [12, 13]. • The iron-induced oxidative stress and the increased risk of infections in regularly transfused patients can trigger myocardial inflammation that can be detected by T2 mapping. • In a non-negligible percentage of hemochromatosis patients, heart dysfunction coexists without myocardial iron overload: it is of utmost importance to look for other causes of heart damage by T2 and post-contrast sequences [6, 16]. • Hypertrabeculated hearts are relatively frequent in patients with hemochromatosis due to adverse remodelling: it is recommended to apply planimetric morphologic criteria to improve the specificity of LVNC diagnosis [19]. • FT-CMR may detect subclinical disturbances in strain before the development of overt cardiac dysfunction [20]. • In the current era, myocardial fibrosis is emerging as the strongest CMR predictor for cardiac complications also in hemochromatosis: it is advisable to administer gadolinium contrast medium in patients older than 10 years, in particular in the presence of cardiovascular risk factors, heart dysfunction, and MIO [3, 6]. • In hemochromatosis, the first CMR for iron quantification should be performed as soon as the child can cooperate without sedation. It should be repeated annually, even though in patients with no significant MIO it can be performed every 2  years, while in patients at high risk (T2*  1) (Fig. 11.18 and Videos 11.13, 11.14, and 11.15). LV ejection fraction was increased (79%) with systolic obliteration of the LV apex. Both atrial dimensions were within normal limits. No areas of LGE were found on post-contrast sequences (Fig.  11.19). The relative apical LV hypertrophy, the super-­normal ejection fraction, the latesystolic apical obliteration are features not associated with athlete heart. Even if current criteria for HCM were not fulfilled, an early form was suspected.

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 ase 8: Palpitation in Young Female C Adolescent: Left Ventricular Non-compaction A 15-year-old female volleyball player was referred to Cardiology Department for palpitation. Rest electrocardiogram was normal. She has no relevant medical history and no family history of cardiomyopathy or sudden cardiac death. Echocardiogram showed normal LV and RV volumes and function with increased LV trabeculations. The 12-lead 24 h ambulatory ECG monitoring demonstrated isolated ventricular beats with rare couplets.

The patient was referred to CMR.  Cine images showed increased LV trabeculation with the ratio of non-compacted myocardium to compacted myocardium greater than 2.3 in diastolic frames (Fig. 11.20 and Video 11.16). RV trabeculation was also pronounced in the apical portion. Volume quantification showed mildly dilated LV volume with mild reduction of the LV function. These features are not part of the athlete’s heart and a diagnosis of LV non-compaction was made. LGE imaging detects no areas of LV enhancement (Fig.  11.21). The patient started low dosage of beta-­ blockers and cardiopulmonary test for exercise prescription was done.

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 ase 9: Exercise-Related Syncope in Football C Player: Arrhythmogenic Cardiomyopathy

Fig. 11.20  Cine SSFP imaging in 4-chamber view, end-diastolic still-frame

Fig. 11.21  LGE imaging in short-axis views

A 22-year-old male football player was referred to CMR because of exercise-induced syncope. The grandfather died suddenly at 50  years old. His past medical history was negative. Resting ECG showed right axis deviation (Fig. 11.22 and Video 11.17). On ECG Holter monitoring, premature ventricular contractions were polymorphic, complex, and exercise induced. Echocardiography was unremarkable. CMR showed mildly unbalanced LV dilatation (LVEVD/RVEDV ratio 1.19) with preserved systolic biventricular function (Fig. 11.23). T2-weighted and T2 mapping sequences showed no areas of edema. Nonischemic LGE with sub-epicardial distribution was documented in inferior and inferolateral LV walls at the mid-basal segments and apically at the inferior segment (Fig. 11.24). He underwent an electrophysiological study without induction of any ventricular tachycardia. The electro-anatomic study confirmed the presence of scar at the LV level. The genetic evaluation revealed a mutation in the 5′ region of the JUP (junction plakoglobin) gene labeled as variant of uncertain significance. The most

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likely diagnosis is an arrhythmogenic cardiomyopathy involving the LV. Competitive sport was not recommended based on the presence of structural disease (left-dominant

arrhythmogenic cardiomyopathy) along with polymorphic ventricular arrhythmias and exercise-induced syncope.

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 ase 10: Abnormal Electrocardiogram C in a 12-Year-Old Football Player: Arrhythmogenic Cardiomyopathy

and dyskinesia of the LV inferior and infero-lateral mid-­ basal wall and multiple aneurisms of the RV-free wall (Fig.  11.26, Videos 11.19 and 11.20). The post-contrast images revealed a non-ischemic LGE with sub-epicardial A 13-year-old male football athlete was referred for pre-­ distribution at the mid-basal segments of inferior and infero-­ participation screening. His past medical history and family lateral LV walls, with transmural involvement at the level of history for sudden cardiac death were negative. Resting ECG the dyskinetic area (Fig.  11.27). No fat infiltration was showed right axis deviation with non-specific intraventricu- detected by CMR. Electroanatomic mapping revealed low-­ lar right delay. Echocardiography showed biventricular dila- voltage areas at the level of the RV. Genetic analysis revealed tation and systolic impairment with dyskinesia of the LV a pathogenic mutation of the desmoplakin genes. Sport parlateral wall. CMR was requested and showed biventricular ticipation restriction was recommended and an ICD was dilatation with RV predominance (Fig. 11.25, Video 11.18). implanted. After 6 months from the ICD implant, he had an Both ventricles presented systolic dysfunction with thinning appropriate DC shock for sustained ventricular tachycardia.

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11  Cardiac Remodeling Versus Cardiomyopathies in Athletes

Pearls and Pitfalls • Sport-induced cardiac adaptations may vary in relation to different sport discipline and training volume. Information related to sport (specific discipline, training volume and intensity) should be collected for a correct interpretation of the cardiac imaging findings. • Normative reference range for sedentary subjects should not be used when studying athletes with cardiac imaging techniques. • Although some differences between sports categories are relevant, the general principle of balanced adaptation should be always taken into account. • The predominant dilatation of one ventricle, a wall hypertrophy without concomitant LV dilatation, focal hypertrophy, a disproportion between cardiac remodeling and the sport activity should always raise the suspicion of an underlying cardiomyopathy. • Extreme endurance sport induces cardiac adaptations with marked biventricular dilatation, possible mild RV prevalence and low-normal biventricular ejection fraction. In such cases, the stroke volumes should be high-­ normal. Atria is usually mildly dilated. • The presence of ancillary, even non-diagnostic, features associated with cardiomyopathy further increase the likelihood of pathology. These include papillary muscle abnormalities, myocardial clefts, supra-normal ejection fraction, markedly increased sphericity index. • LGE limited to the RV insertion points is a common benign finding in the athletic population if present as an isolated finding. However, the possible extension to the intraventricular septum and the LV-free wall should be considered as a pathologic finding. • Native myocardial T1 mapping in the athlete’s heart should be toward the lower limits of the normal range. ECV should not be increased. • CMR has indication for the differential diagnosis between athlete’s heart and cardiomyopathy or in case of abnormal ECG, symptoms, or arrhythmias if echocardiogram is sub-optimal or non-diagnostic.

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Conclusion CMR is a valuable tool for the differential diagnosis between athlete’s heart and cardiomyopathy. In the case of non-­ diagnostic echocardiogram, CMR can provide information on the morphology and function of cardiac chambers. CMR has some limitations related to the lack of sport-specific normative range for volumes and function. The principle related to the harmonic adaptation of the chambers, combined with a full consideration of additional clinical and instrumental hints, can be used for a correct interpretation of the imaging findings. Furthermore, providing tissue characterization, CMR may reveal myocardial abnormalities that are not part of the athlete’s heart spectrum.

References 1. Pelliccia A, Sharma S, Gati S, et al. 2020 ESC guidelines on sports cardiology and exercise in patients with cardiovascular disease. Eur Heart J. 2021;42:17–96. 2. Pelliccia A, Maron BJ, Spataro A, Proschan MA, Spirito P.  The upper limit of physiologic cardiac hypertrophy in highly trained elite athletes. N Engl J Med. 1991;324:295–301. 3. Luijkx T, Cramer MJ, Prakken NH, et  al. Sport category is an important determinant of cardiac adaptation: an MRI study. Br J Sports Med. 2012;46:1119–24. 4. D'Ascenzi F, Anselmi F, Piu P, et  al. Cardiac magnetic resonance normal reference values of biventricular size and function in male Athlete's heart. J Am Coll Cardiol Img. 2019;12:1755–65. 5. Zorzi A, Perazzolo Marra M, Rigato I, et al. Nonischemic left ventricular scar as a substrate of life-threatening ventricular arrhythmias and sudden cardiac death in competitive athletes. Circ Arrhythm Electrophysiol. 2016;9:9. 6. McDiarmid AK, Swoboda PP, Erhayiem B, et al. Athletic cardiac adaptation in males is a consequence of elevated myocyte mass. Circ Cardiovasc Imaging. 2016;9:e003579. 7. Pelliccia A, Caselli S, Sharma S, et  al. European Association of Preventive Cardiology (EAPC) and European Association of Cardiovascular Imaging (EACVI) joint position statement: recommendations for the indication and interpretation of cardiovascular imaging in the evaluation of the athlete's heart. Eur Heart J. 2018;39:1949–69.

Myocarditis and Inflammatory Cardiomyopathies

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Giovanni Camastra, Federica Ciolina, Manuel De Lazzari, and Cristina Basso

Introduction

and diagnosis [1]. Chronic inflammatory cardiomyopathy (chronic infl-CMP) indicates persistent myocardial inflammaMyocarditis is an inflammatory disease of the myocardium tion and is a relatively common cause of sudden cardiac death with a heterogenous etiology and different clinical presenta- (SCD) in young people [2]. In some patients, inflammation tion. Usually caused by viral infections, it can also be induced may cause extensive scarring that triggers left ventricular (LV) by other pathogens (i.e., bacterial or protozoal), as well as remodeling, inducing eventually dilated cardiomyopathy mediated by toxic or hypersensitivity drug reactions, or by (DCM) or alternatively a predominant hypokinetic non-dilated auto-immunity and systemic immune-mediated diseases phenotype of cardiomyopathy. (i.e., sarcoidosis). The clinical presentation of acute myocarEndomyocardial biopsy is considered the reference standitis (AM) is heterogeneous: the typical onset is with infarct-­ dard for the diagnosis of definite myocarditis [3] with well-­ like symptoms usually associated with dynamic ECG established histological, immunological, and changes; other times it may begin as recent-onset heart fail- immunohistochemical criteria. However, since it is an invaure or with arrhythmic events. When myocarditis is associ- sive procedure that prefigures some risks, it is not a routine ated with cardiac dysfunction and ventricular remodeling, it practice and current recommendations restrict its use in speis referred to as inflammatory cardiomyopathy. The varying cific clinical scenarios (i.e., heart failure, life-threatening clinical features and the overlap with other acute/subacute arrhythmias, incomplete healing), not encompassing the cardiac conditions make its diagnosis challenging. most frequent clinical presentation such as infarct-like myoMyocarditis may present in acute, fulminant, subacute, and carditis. In this latter setting, if the patients are hemodynamichronic forms. AM can be defined as a period of 1–3 months between symptom onset to detect signs of myocardial inflammation with high accuracy, including tissue edema, myocardial hyperemia and Supplementary Information The online version contains supplementary areas of myocardial necrosis. Myocardial injury in myocarmaterial available at https://doi.org/10.1007/978-­3-­031-­32593-­9_12. ditis is localized in the epicardial or mid-myocardial layers with sparing of the subendocardial layers, while, in ischemic G. Camastra (*) · F. Ciolina heart disease, myocardial damage is mostly localized in the MG Vannini Hospital, Rome, Italy subendocardial layers or with a transmural pattern. Currently, e-mail: [email protected]; CMR is the recommended diagnostic tool in patients with [email protected] clinically suspected AM or in patients with chest pain, norM. De Lazzari · C. Basso mal coronaries, and raised troponin, for the differential diagUniversity of Padova Medical School, Padova, Italy nosis of ischemic versus non-ischemic origin [7, 8]. CMR e-mail: [email protected]; [email protected] © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 A. Barison et al. (eds.), Case-based Atlas of Cardiovascular Magnetic Resonance, https://doi.org/10.1007/978-3-031-32593-9_12

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sensitivity is high for infarct-like, low for cardiomyopathic, and very low for arrhythmic clinical presentations [9]. While CMR is able to detect inflammatory cardiopathy in vivo easily, it is not able to identify the underlying etiology. In 2009, a consensus group published the original Lake Louise Criteria, which identified three hallmarks of myocardial inflammation with corresponding CMR markers [10]: hyperemia, that is an intense signal in early gadolinium enhancement images; tissue edema, that is an increased myocardial T2 relaxation time or an increased signal intensity in T2-weighted images; and necrosis/fibrosis detected by LGE. If two of these three criteria are present, AM can be diagnosed with 74% sensitivity and 86% specificity. In recent years, parametric mapping, which allows direct quantification of myocardial tissue magnetic parameters (primarily T1 and T2), has been increasingly applied in myocarditis with high sensitivity. The Lake Louise Criteria have been recently updated including T2 mapping for edema and native T1, as well as extracellular volume mapping, for inflammatory injuries [11]. Based on the cell types infiltrating, myocarditis can be classified as lymphocytic, eosinophilic, giant cells, or granulomatous. The true incidence of myocarditis is unknown. Among patients presenting to the emergency department, AM represents the second most common cardiac cause of chest pain. The review of the literature reveals a great variability in the incidence of myocarditis among patients initially labeled as myocardial infarction with nonobstructed coronary arteries [7, 8]. AM mostly affects relatively young patients, more frequently men than women. Immune check-point inhibitor (ICI)-associated myocarditis is a recently recognized entity, whose rate of diagnosis has increased due to larger awareness and to the larger population of patients with eligible for treatment with ICI [12, 13]. Infection with SARS-CoV2, the virus causing coronavirus disease 2019 (COVID-19), is associated with several cardiac complications including myocarditis [14]. Eosinophilic myocarditis (EM) is associated with systemic conditions, hypersensitivity reactions to drugs or parasitic infection; EM is not common but its incidence may be underestimated and present peculiar CMR features [15]. Sarcoidotic myocarditis occurs in 5% of patients with systemic sarcoidosis and up to 20% of cardiac sarcoidosis is isolated, hence the importance of the clinician’s suspicion and the knowledge of the hallmarks [16]. Giant cell myocarditis is a severe and rare form of myocarditis with a poor prognosis; immunosuppressive therapy should be initiated promptly and for this reason endomyocardial biopsy (EMB) is mandatory.

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EMB has a pivotal role in identifying the underlying etiology and deciding therapy in specific clinical subsets, both in AM and chronic infl-CMP, but actually it remains underutilized also in the recommended settings. Of note, EMB must be taken into account when clinical features and CMR features are atypical, unconclusive or pose concerns: myocardial edema associated with LGE with a non-ischemic pattern could be the common pathway of other different and specific myocardial diseases requiring a completely different approach (i.e., hot phases of arrhythmogenic cardiomyopathy) [16–18]. The role of CMR is also crucial for the prognostic assessment even during the acute phase. The onset of negative T waves during acute myocarditis has been linked with a transmural extent but transient myocardial edema, without leading to ventricular dysfunction during follow-up [16]. Moreover, in the setting of AM patients presenting with normal left ventricular ejection fraction, the presence of LGE suggests an increased risk of adverse cardiovascular events and unfavorable evolution, despite a normal LVEF [4–6]. The extent of LGE is a dynamic process in AM, mainly related to tissue edema and necrosis in the acute phase that progressively vanishes over time, whereas in the late phase, LGE mainly reflects post-inflammatory replacement fibrosis. Hence, the added prognostic value of repeating a CMR scan after 6  months [17]: the presence of LGE without edema at 6-month CMR is associated with a worse prognosis, particularly when distributed with a midwall septal pattern. The presence of LGE without edema could represent definite fibrosis, whereas the presence of edema suggests a residual chance of recovery. Larger prospective trials could help standardize the diagnostic and therapeutics strategies in myocarditis [18].

 ase 1: Acute Myocarditis with Infarct-Like C Presentation A 21-year-old patient was transferred to our coronary care unit from a peripheral hospital for chest pain associated with fever and elevated troponin values. The patient was asymptomatic with normal electrocardiogram and echocardiogram. During hospitalization, he experienced chest pain recurrence with significant ST elevation in the inferior leads. For this reason, urgent coronary angiography was performed with normal coronary arteries. A few hours after coronary angiography, he experienced a new episode of chest pain with ST elevation in the inferior, posterior, and lateral leads (Fig. 12.1) as well as the appearance of supra-

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ventricular tachycardia and ventricular ectopic beats on the monitor. His echocardiogram showed a marked reduction in global contractility (EF 30%); akinesia of the anterior wall, the interventricular septum (IVS) and the inferior wall. After 24 h, his control echocardiogram showed an EF 45%; persistent akinesia of mid-basal IVS; anterior and inferior mid-basal hypokinesia. His CMR confirmed the EF reduction (Fig.  12.2a–c and Videos 12.1, 12.2, and 12.3) and documented the presence of edema and midwall/subepicardial late enhancement in the septum, ­anterior and inferior walls, compatible with recent necrosis of non-isch-

emic origin (Fig. 12.2d–h). Furthermore, there was pericardial effusion (asterisk in Fig.  12.2h). His autoantibody profile tested positive for different Coxsackievirus strains. On the ECG Holter: numerous isolated BEVs, some couples and a triplet. At the pre-discharge echocardiogram revealed a recovery in contractility (EF 50%). CMR after 3  months of follow-up showed normal contractility (Fig. 12.3d, e and Videos 12.4 and 12.5), a slight reduction in the areas of LGE (Fig. 12.3g–i) and a significant reduction of edema (Fig. 12.3a–c). In the follow-up, there were no adverse events.

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 ase 2: Acute Myocarditis with Infarct-Like C Presentation

Chest X-ray was normal. His viral serology tested negative. He undertook therapy with high-dose anti-inflammatory drugs and was referred to CMR (Figs.  12.4 and 12.5 and A 28-year-old patient, without cardiovascular risk factors, Videos 12.6 and 12.7), which documented the presence of came to the emergency department complaining of chest edema and LGE in the antero-septal, anterior and antero-­ pain, fever, significant enzymatic movement with high-­ lateral walls, with some LGE also in the inferior wall and sensitivity troponin 2154 pg/mL (normal value below 14 pg/ trace pericardial effusion. The clinical course was uneventful mL) and ST elevation in V1-V2 at ECG. Coronary angiogra- and there was a progressive reduction in the indexes of myophy revealed normal coronary arteries. The echocardiogram cardial and inflammatory necrosis. In the follow-up, there showed a left ventricle of normal size with normal wall were no adverse events and CMR (Fig. 12.6) documented the thickness, normal global kinetics without regional wall disappearance of edema and the reduction of the necrosis motion abnormalities, some pericardial hyperechogenicity. area.

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Fig. 12.6  Follow-up: STIR images on basal (a), mid (b), and apical (c) short-axis view and LGE on basal (d), mid (e), and apical (f) short-axis view

 ase 3: Immune Check-Point Inhibitor Acute C Myocarditis with Infarct-Like Presentation A 70-year-old man presented to the emergency department because of new-onset dyspnea. His past medical history included lung cancer for which therapy with check-point inhibitor atezolizumab had been started a week earlier. At admission, his ECG showed mild ST-segment elevation in infero-lateral leads, while echocardiography revealed mild hypokinesis of the infero-lateral wall. Coronary angiography showed patent epicardial coronary arteries. Troponin values were elevated, with a peak hs-Troponin T 500 pg/mL (normal value below 14  pg/mL). On day 3 from admission, a

CMR was performed. T2-stir sequences revealed a mild infero-lateral epicardial hyperintensity suggestive of edema (Fig.  12.7). Native T1 and T2 mapping showed increased values in the infero-lateral wall (Fig. 12.8). Cine sequences confirmed echocardiographic findings and late gadolinium enhancement (LGE) images revealed the presence of replacement fibrosis in the same areas (Fig. 12.9 and Videos 12.8, 12.9, 12.10). The recent administration of atezolizumab suggested the diagnosis of immune check-point inhibitor myocarditis (ICI-M). In this context, T1 and T2 mapping constitute a useful tool, allowing more reliable detection of myocardial edema as compared to T2-STIR sequence and detection of myocardial involvement in ICI-M.

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 ase 4: COVID-19 Acute Myocarditis C with Infarct-Like Presentation

context of a clinically suspected myocarditis, he was referred to CMR, which confirmed a global hypokinesia with systolic dysfunction (Ejection Fraction: 40%; Videos 12.11 and A 55-year-old man was referred to our COVID-19-dedicated 12.12). T2 STIR (Fig. 12.10a–d) and native T2 mapping images coronary care unit because of typical chest pain, nonspecific (Fig. 12.10f) revealed a diffuse signal increase, suggestive of electrocardiographic ST-T wave changes and increased high-­ sensitive cardiac troponin T levels (peak: 3540 ng/L; normal myocardial edema. Native T1 mapping images (Fig. 12.11a) value  1, the pulmonary flow surpasses systemic flow, and a systemic-to-­ pulmonary (left-to-right) shunting occurs. Conversely, when Qp/Qs  1  cm above the sinotubular junction), the patient was treated with beta-­ • blockers and a routine follow-up. Pearls and Pitfalls • The common technical problems encountered during a CMR examination are amplified when examining children; therefore, the imaging protocols should be centered

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on the achievement of crucial diagnostic information, especially in case of limited patient cooperation. The usage of small field-of-views and thinner slices, required for small anatomical structures, leads to a reduced signal-to-noise ratio. This can be balanced by increasing the number of acquisitions at the disadvantage of an increased scan time. A dedicated extremity (i.e., knee coil) should also be used in neonates or children. Children usually have faster heart rates than adults and consequently shorter R-R times. Sequences that utilize longer repetition times than R-R can be acquired by triggering the second or third R wave. For cineSSFP images, the number of phase-encode steps can be reduced for each frame and decrease the acquisition period. This improves the temporal resolution and image sharpness at the expense of an increment in scan time. The habitual low temperatures in the CMR scanning room may lead to hypothermia, particularly in small infants undergoing anesthesia. A close monitor of patient temperature is required, and wrapping them with blankets may be helpful. Prolonged, multiple breath holds are required. This can cause hypoxia in ACHD; an adequate pause for ventilation control between breath holds is mandatory.

Fig. 17.20  Whole-heart axial view. The AAOCA retro aortic course of Cx is marked with a white arrow (the lowest) in Panel A. The RCA is marked in Panel A with the highest white arrow. The LCA is marked with a white arrow in the Panel B. Aorta (Ao), Pulmonary artery (Plm)

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2. Ombelet F, Goossens E, Van De Bruaene A, Budts W, Moons P.  Newly developed adult congenital heart disease anatomic and physiological classification: first predictive validity evaluation. CMR is an essential tool in the multimodality assessment of J Am Heart Assoc. 2020;9(5):e014988. https://doi.org/10.1161/ JAHA.119.014988. CHD and ACHD patients. It provides a detailed structural 3. Budts W, Miller O, Babu-Narayan SV, Li W, Valsangiacomo diagnosis and an accurate volumetric and flow analysis. The Buechel E, Frigiola A, van den Bosch A, Bonello B, Mertens implementation of 4D flow sequences provides additional L, Hussain T, Parish V, Habib G, Edvardsen T, Geva T, Roos-­ hemodynamic information; these are essential in evaluating Hesselink JW, Hanseus K, Dos Subira L, Baumgartner H, Gatzoulis M, Di Salvo G. Imaging the adult with simple shunt lesions: posiand managing patients with CHD. CMR can be safely used tion paper from the EACVI and the ESC WG on ACHD. Endorsed for longitudinal follow-up as a radiation-free exam. It is recby AEPC (Association for European Paediatric and Congenital ommended in the presence of clinical worsening, non-­ Cardiology). Eur Heart J Cardiovasc Imaging. 2021;22(6):e58–70. diagnostic echo findings, and before surgery or transcatheter https://doi.org/10.1093/ehjci/jeaa314. 4. Verheugt CL, Uiterwaal CS, van der Velde ET, Meijboom FJ, Pieper intervention. CMR imaging in CHD neonates and children PG, van Dijk AP, Vliegen HW, Grobbee DE, Mulder BJ. Mortality may be challenging, and some common technical problems in adult congenital heart disease. Eur Heart J. 2010;31(10):1220–9. encountered during a routine CMR examination can be https://doi.org/10.1093/eurheartj/ehq032. amplified when examining these patients. The implementa5. Saremi F.  Cardiac CT and MR for adult congenital heart disease. New  York: Springer; 2014. https://doi. tion of dedicated acquisition protocols or preparatory exam org/10.1007/978-­1-­4614-­8875-­0. strategies is mandatory. CCT may be complementary to 6. Sridharan JS, Price G, Tann O, Hughes M, Muthurangu V, Taylor CMR scans and sometimes may follow a CMR examination, AM.  Cardiovascular MRI in congenital heart disease. Cham: especially when needing to increase spatial resolution or the Springer; 2010. https://doi.org/10.1007/978-­3-­540-­69837-­1. 7. Secinaro A, Ait-Ali L, Curione D, Clemente A, Gaeta A, Giovagnoni exam is limited or impeded by technical restraints. A, Esposito A, Alaimo A, Tchana B, Sandrini C, Bennati E, Angeli CMR frequency should be determined by the individual E, Bianco F, Ferroni F, Pluchinotta F, Rizzo F, Secchi F, Spaziani patient’s underlying defect and clinical status. Intervals G, Trocchio G, Peritore G, Puppini G, Inserra MC, Galea N, between scans depend on the risk profile, findings at the first Stagnaro N, Ciliberti P, Romeo P, Faletti R, Marcora S, Bucciarelli V, Lovato L, Festa P.  Recommendations for cardiovascular magCMR study, and the expected rate of change. Due to their netic resonance and computed tomography in congenital heart anatomical and technical peculiarities, CMR studies in CHD disease: a consensus paper from the CMR/CCT working group of should be supervised and reported by appropriately trained the Italian Society of Pediatric Cardiology (SICP) and the Italian CHD and ACHD specialists. College of Cardiac Radiology endorsed by the Italian Society of Medical and Interventional Radiology (SIRM) part I. Radiol Med. 2022;127:788. https://doi.org/10.1007/s11547-­022-­01490-­9. Acknowledgments  We thank Dr. Mario Raguso (Radiology 8. Di Salvo G, Miller O, Babu Narayan S, Li W, Budts W, Department, Policlinico Casilino, Roma) for providing clinical and Valsangiacomo Buechel ER, Frigiola A, van den Bosch AE, imaging material of the cases no. 3 and 6. Bonello B, Mertens L, Hussain T, Parish V, Habib G, Edvardsen T, Geva T, Baumgartner H, Gatzoulis MA.  Imaging the adult with congenital heart disease: a multimodality imaging approach-­ position paper from the EACVI. Eur Heart J Cardiovasc Imaging. References 2018;19(10):1077–98. https://doi.org/10.1093/ehjci/jey102. 9. Brothers JA, Frommelt MA, Jaquiss RDB, Myerburg RJ, Fraser CD, 1. Franklin RCG, Beland MJ, Colan SD, Walters HL, Aiello VD, Tweddell JS. Expert consensus guidelines: anomalous aortic origin Anderson RH, et  al. Nomenclature for congenital and paediatof a coronary artery. J Thorac Cardiovasc Surg. 2017;153(6):1440– ric cardiac disease: the International Paediatric and Congenital 57. https://doi.org/10.1016/j.jtcvs.2016.06.066. Cardiac Code (IPCCC) and the Eleventh Iteration of the 10. Srichai MB, Mason D. Coronary artery anomalies. In: Cardiac CT International Classification of Diseases (ICD-11). Cardiol and MR for adult congenital heart disease. Cham: Springer; 2014. Young. 2017;27(10):1872–938. https://doi.org/10.1017/ p. 603–34. https://doi.org/10.1007/978-­1-­4614-­8875-­0_27. S1047951117002244.

Complex Congenital Heart Diseases

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Pierluigi Festa, Paolo Ciancarella, Lamia Ait Ali, and Aurelio Secinaro

Introduction Complex congenital heart disease (CHD) represents a wide spectrum of anatomical anomalies, characterized by an association of cardiac and extracardiac anomalies including situs anomalies, atrioventricular and/or ventriculo-arterial connections, and/or additional intra-and extracardiac defects leading to variable physiopathology and clinical dysfunction. Most of complex CHD are diagnosed at birth and in the recent area during the fetal life; however, some of them may be diagnosed late in life and sometimes didn’t require any treatment. However, most of complex CHD undergo more than one surgical procedure and/or palliation. The “unnatural history” of complex CHD is still evolving in parallel with the progress of the surgical/percutaneous techniques. This could be symbolized by the surgical history of the transposition of the great artery [1] starting from the Blalock Hanlon palliation in the ‘50 s to the physiological correction (atrial switch in the ‘60 s) until to the arterial switch in the late ‘80 s. Also, the history of the functionally single ventricle evolves overtime with the ongoing evolution of the staged palliations. Prior to initial treatment, most neonates can be imaged adequately by transthoracic echocardiography (TTE). Advanced non-invasive imaging is necessary in selected Supplementary Information The online version contains supplementary material available at https://doi.org/10.1007/978-3-031-32593-9_18. P. Festa (*) Fondazione Toscana Gabriele Monasterio, Pisa-Massa, Italy e-mail: [email protected] P. Ciancarella · A. Secinaro Advanced Cardiothoracic Imaging Unit, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy e-mail: [email protected]; [email protected] L. Ait Ali Institute of Clinical Physiology, National Research Institute, Pisa, Italy e-mail: [email protected]

cases mainly to define complex anatomy (as in Case 5.) when TTE is not exhaustive. Both CMR and cardiac computed tomography (CCT) are excellent options: CCT may be preferred for its easier and faster acquisition protocol in critical newborns while CMR has the advantage of providing additional functional parameters, including flow patterns, without using ionizing radiation [2] and without needing sedation using the “feed and wrap” technique [3]. In people with a functionally single ventricle, subsequent diagnostic flow-chart includes traditionally cardiac catheterization. However, ongoing studies report the usefulness of CMR in combination or in substitution to catheterization before Glenn anastomosis and before Fontan intervention [4, 5]. Moreover, there is consensus that patients with complex CHD require lifetime follow-up to monitor residual sequels and to guide clinical management [6]. Recent guidelines recommend lifelong follow-up with serial CMR imaging in most complex adult congenital heart [7, 8]. As a matter of fact, CMR provides complete morphological information about intra- and extracardiac anatomy as well as functional and hemodynamic assessment. Intra and extracardiac anatomy: Multiple anatomical anomalies may coexist in complex CHD.  CMR provides high-resolution imaging of intracardiac and extracardiac anatomy in any imaging plane without the restrictions of acoustic windows, scar tissue and exposure to ionizing radiation, or the morbidity associated with invasive diagnostic catheterization [9, 10]. Ongoing developments in MR technology have greatly impacted on the anatomic evaluation enabling high-quality imaging at short acquisition times also in children [11]. Besides cine (steady-state free precession, SSFP) and GRE images, high-contrast black blood images could be useful for morphological assessment of cardiac structures in particular in patients with ferro-magnetic devices such as stents or occluder devices. Three-dimensional contrast-­enhanced MR angiography (MRA) is usually performed for the vessels assessment. In selected CHD as postFontan palliation patients or post physiological correction of

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TGA and suspected systemic venosus stenosis, time resolved MRA is sometimes preferred as it resolves the problem of contrast timing and adds diagnostic information such as the visualization of intra- and extracardiac shunts [11]. The anatomy visualization and vessels measurements can be also performed without using contrast medium using non-contrast-enhanced volume acquisition. Free-breathing 3-D SSFP with or without respiratory movement correction is currently the most used. Moreover, this ECG-gated isotropic sequence suits for 3D modeling, with rapid prototyping useful for surgical/interventional planning in complex CHD [9]. Although TTE is superior to CMR in the evaluation of atrioventricular valves, CMR could be useful in Ebstein’s anomaly because of its capability to prescribe unlimited planes to visualize the tricuspid valve structure in addition to the direct or indirect quantification of tricuspid valve regurgitation and the evaluation of ventricular volumes and function [12]. Ventricular volumes and function: CMR is the gold standard for the evaluation of bi-ventricular volume and function. Of particular importance in complex CHD is the evaluation of the RV. As a matter of fact, dilatation and/or hypertrophy of the right ventricle (RV) is frequent in children and adults with congenital heart disease secondary to volume overload in shunt lesions, congenital or acquired tricuspid and pulmonary valve regurgitation, or to pressure overload due to pulmonary pathway stenosis [9], such as Tetralogy of Fallot, Truncus arteriosus, and Ebstein’s anomaly. Moreover, in some patients with CHD (congenitally corrected TGA, TGA post physiological repair), the systemic ventricle is the RV.  Therefore, it’s not surprising that the decision process of many complex CHD is based on a comprehensive CMR study in patient with univentricular heart, where ventricular volumes are predictor of death or heart transplant [13]. For this reason, the assessment of ventricular function and volumes is a key element in the management of patients after the Fontan procedure [14]. CMR is superior to TEE in the evaluation of univentricular volumes and function [14]. Another emerging CMR technique is the evaluation of myocardial strain with FT-CMR: ongoing studies are evaluating its potential usefulness for risk stratification in adult with complex CHD [15]. Flow imaging (velocity-encoded phase contrast (PC) sequences) is a major asset of CMR scanning in complex CHD allowing the quantification of shunt, semilunar valve regurgitation, flow distribution in pulmonary branches (of umost importance in TOF, truncus arteriosus, TGA, or single ventricles), the contribution of inferior vena cava conduit-­ pulmonary artery in Fontan hemodynamic, the evaluation of aortopulmonary collaterals in single ventricles; all these elements can explore the underlying pathophysiological mechanism that contribute to the outcome of these patients [5]. CMR in combination with invasive catheterization can also evaluate pulmonary vascular resistance.

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Traditionally, flow evaluation in CMR is assessed by 2D Flow. Recently, 4D flow sequence allows a retrospective evaluation of flow volumes and velocities of any site of the acquired volume, hence it is increasingly used in CHD [16]. Moreover, 4D flow allows the visualization of flows and other promising advanced parameters that contribute to a major increase of the knowledge of the complex and unique hemodynamics in complex CHD. Tissue characterization: A further strength of CMR is its ability to perform tissue characterization, which enables the assessment of focal myocardial fibrosis [17]. The prognostic value of the fibrosis in complex CHD is still not completely elucidated. Late gadolinium enhancement CMR for focal fibrosis and T1 mapping imaging for interstitial fibrosis are increasingly used in complex CHD for their potential prognostic value. CMR is also useful for identifying thrombosis, particularly in post-Fontan patients. Myocardial perfusion. CMR contrast myocardial perfusion imaging (MPI) is a validated technique to investigate myocardial ischemia and coronary artery disease. In complex CHD, the role of MPI has been investigated in patients undergoing reimplantation of the coronary arteries, such as in the arterial switch operation for the transposition of the great arteries, the double switch operation in congenitally corrected transposition of the great arteries, the Ross procedure, and in anomalous origin of the left coronary artery from the pulmonary artery [18]. Overall, thanks to its multiple anatomical and functional assets CMR is a very useful tool for the diagnosis and monitoring of complex CHD.  However, the heterogeneity and complexity of the diseases require an expertise not only in the CMR techniques but also of congenital heart diseases in general and of the scheduled patient in particular [19].

Case 1: Repaired Tetralogy of Fallot (TOF) A 36-year-old man with Tetralogy of Fallot (TOF) post-­ surgical repair was referred to CMR in order to decide the timing and the modality of pulmonary valve implant. At the age of 4  years after a previous surgical palliation with Waterston shunt, he had undergone intracardiac repair with pulmonary valvulotomy, reconstruction of the right ventricle outflow tract (RVOT) with monocuspid transannular patch, and closure of the residual ventricular septal defect (VSD). He experienced a sustained ventricular tachycardia at the age of 35, which was successfully ablated. His baseline ECG showed a QRS length of 200 msec, his cardiopulmonary test confirmed a quite good functional capacity (peak VO2 = 70% of the predicted). Standard cine CMR in 2 and 4 chamber of the left ventricle (LV) (Fig.  18.1a–c), in 3 chamber of the right ventricle (RV) (Fig. 18.1d, e), and biventricular short axis (Fig. 18.1f–h) showed a mildly dilated left atrium (LA),

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normal LV volumes and EF and confirmed the dilation of both the right atrium (RA) and right ventricle (RV), with RV systolic dysfunction, also because of a huge dyskinetic infundibulum. Late gadolinium enhancement images showed late enhancement of the RV free wall, infundibulum, VSD patch, the right side of the interventricular septum (Fig. 18.2a–c), and also at the level of the anterior septum with transmural extension (Fig.  18.2c, blue arrow). Parasagittal (Fig.  18.3a) and 2-chamber (Fig.  18.3b) RV SSFP acquisitions showed residual pulmonary cusps (white a

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arrow) and severe regurgitation fraction (44%). The maximum pulmonary diameter in systole was 26  ×  25  mm. Pulmonary branches were not stenotic (3D reconstruction of CEMRA images in Fig.  18.3c, axial SSFP sequence in Fig. 18.3d). CEMRA images showed also the absence of the right superior vena cava, and the presence of the left superior vena cava (LSVC) draining into a dilated coronary sinus (Fig. 18.3e, f, red arrow). The patient was scheduled for percutaneous PV implant.

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Fig. 18.3  RVOT and systemic venous drainage illustration

Case 2: Ebstein’s Anomaly A 22-year-old woman with Ebstein’s anomaly and patent foramen ovale (PFO), diagnosed when she was 3 years old, was scheduled for CMR examination. She had a reduced functional capacity (peak VO2/kg around 50–60% of the predicted), a peripheral O2Sat of 99% at rest, dropping to 75% during exercise. At echocardiography, she showed progressive increasing of the tricuspid valve (TV) regurgitation. A non-contrast CMR was performed for the evaluation of the right atrium (RA), atrialized right ventricle (aRV), biventricular volumes and function, and TV structure. Standard cine SSFP sequences were prescribed in left ventricular (LV) 2-chamber (Fig. 18.4a) and 4-chamber (Fig. 18.4b, c), right ventricular (RV) 3-chamber (Fig.  18.4d) and ventricular short axis (SA) extended to the atria (Fig. 18.4e, f); from the latter stack, atrial and ventricular volumes and function were calculated. The RV was also evaluated in axial cine acquisition (Fig. 18.4g), where it is easier to delineate the TV and

RV volumes and function can be assessed with higher reproducibility than the short axis [12, 13]. The functional RV was not dilated: indexed end-diastolic volume 100/96  mL/m2 (short/long axis) with an EF of 49%; the LV volumes and EF were normal; the RA including the aRV was dilated (ESVi: 92 mL/m2). Tricuspid valve structure was imaged through multiplane of contiguous stack, in short axis (Fig. 18.5a, Fig. 18.6b, f), parasagittal (Fig.  18.5b, Fig.  18.6a, e), paracoronal (Fig. 18.5c, Fig. 18.6d, h), and axial view (Fig. 18.5c, g). The functional annulus of the TV was displaced and rotated toward the right ventricular outflow tract (Fig. 18.6a–h red line), the anterior leaflet (al) was elongated, a small septal (sl) and inferior/posterior leaflet (il) were tethered, respectively, to the septum and to the RV free wall. The suboptimal ­coaptation and an additional fenestration in the al caused a moderate tricuspid regurgitation. A follow-up was advised with monitoring of functional capacity, O2 peripheral saturation, and RV volumes and function,

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 ase 3: Truncus Arteriosus Post-­Surgical C Repair—Pulmonary Artery Branch Stenosis A 27-year-old man had been operated on for the correction of a truncus arteriosus at the age of 18 months by means a RVpulmonary artery conduit; subsequently he had undergone reconstruction of the RVOT.  At follow-up, a progressive RVOT and pulmonary branches stenosis had been diagnosed by echocardiography. He was referred to CMR for the evaluation of the anatomy and flow of the pulmonary branches, pulmonary valve, truncal valve, and biventricular volumes and function (Video 18.1). CMR cine SSFP images in 2-chamber (Fig. 18.7a), 4-chamber (Fig. 18.7b), right ventricular paracoronal (Fig. 18.7c), and short-axis acquisitions (Fig.  18.7d) showed a dilated right atrium (RA), hypertrophic right ventricle (RV) with volumes at the upper limits and preserved global RV systolic function. An akinetic anterior free wall at the level of previous ventriculostomy was visualized in cine imaging with positive late

enhancement, suggesting presence of fibrosis (Fig. 18.7e, blue arrow). The left ventricle had normal volumes and systolic function (Fig.  18.7f). Long axis left ventricular outflow (Fig. 18.8a) and short-axis truncal valve (Fig. 18.8b) show a mildly dilated aortic root and a bicuspid truncal valve with trivial regurgitation. Cine GRE (Fig. 18.8c) and black blood sequence (Fig. 18.8d) illustrated the RVOT. Multiparametric CMR assessment of the pulmonary arteries (Fig.  18.9) included MRA MIP reconstruction (Fig. 18.9a, b) and MRA volume rendering reconstruction (Fig.  18.9g), cine GRE (Fig. 18.9d, e), black blood (Fig. 18.9c, f) confirming the stenosis and hypoplasia of the right pulmonary artery (RPA). He successfully underwent a Melody pulmonary percutaneous implant and stent angioplasty of the RPA. CMR post interventional procedure demonstrated reduced RA and RV volume and improvement of the RPA flow from 10% of the total pulmonary flow to 30% after stent angioplasty. Figure 18.8 illustrate the post CMR imaging of pulmonary arteries (black blood sequence (Fig. 18.9h, j) cine GRE (Fig. 18.9i), 4D flow sequence (Fig. 18.9k), MRA MIP reconstruction (Fig. 18.9l)).

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Fig. 18.9  Pulmonary branches evaluation pre- and post-stent angioplasty

 ase 4: Functionally Univentricular Heart C Post Fenestrated Fontan Palliation

Superior Vena Cava (LSVC) and the left pulmonary artery (LPA) and the connection of the inferior vena cava (IVC) to the pulmonary arteries through a fenestrated conduit, while A 9-year-old boy with a functionally single ventricle post-­ the right pulmonary artery (RPA) is hypoplastic. The 4D flow Fontan palliation with a fenestrated extra-cardiac conduit sequence allowed the calculation of the flow in all arterial and was scheduled for CMR for anatomical and functional evalu- venous vessels (Fig.  18.12); in particular as illustrated in ation of the Fontan circuit. His CMR scan confirmed the (Fig.  18.12e), the difference of the flow between the caudal diagnosis of visceral/bronchial/atrial situs inversus and cranial conduit was similar to the flow at the fenestration. The 4D flow allowed also the visualization of the Fontan cir(Fig. 18.10a–c) and dextrocardia (panel d). Cine RM in four-chamber view (Fig. 18.11a) and in ven- cuit (Fig.  18.12a–c and Video 18.2), flow direction tricular short axis (Fig. 18.11b) highlighted the common atrio- (Fig. 18.12c), and the streamlines distribution (Fig. 18.12d, f). ventricular valve (white arrow) with two ventricles and a large A post-processing segmentation quantifies the streamlines ventricular septal defect (blue arrow); the aorta (Ao) originates concluding that LSVC flow was mainly distributed to the RPA from the anterior ventricle (Fig. 18.11c). MIP from a 3D SSFP (65%) whereas the conduit flow to the LPA (80%) (Fig. 18.12g). (Fig.  18.11d–f) illustrates the anastomosis between the left

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Fig. 18.12 4D-flow

Case 5: Double Outlet Right Ventricle A 1-year-old boy with diagnosis of double outlet right ventricle (DORV), ventricular septal defect (VSD), pulmonary stenosis (PS) was scheduled for CMR in order to plan the surgical correction. At the age of 1 month, he had undergone a right modified Blalock Taussig shunt (mBT). Echocardiography (Fig. 18.13a) and CMR (Fig. 18.13b–e) confirmed a large oval subpulmonary VSD (red asterisk) with posterior extension as apparent from cine SSFP (Fig. 18.13b–e) and from reformatted 3D SSFP (Fig. 18.13d). Both the left (LV) and right ventricle (RV) had normal volumes and systolic function; the aorta (AO) arises from the RV, anterior to the pulmonary artery (PA) (Fig. 18.13d and Fig.  18.14a, b). Cine CMR and echocardiography showed a PA stenosis secondary, also, to accessory sub-

valvular tissue (Fig. 18.13a, b). MR angiography MIP and volume rendering reconstruction (Fig. 18.14c, d) depicted the stenosis of the right modified BT shunt at the RPA anastomosis. Because of the discrepancy between AO annulus and VSD dimensions, the surgical decision-making was challenging. Therefore from an isotropic 3D SSFP (voxel size: 1.3 × 1.3 × 1.3), a 3D model was segmented and then printed. The surgeon evaluated the virtual model (Fig.  18.15a–c) and the printed one (Fig.  18.15d–f) to better understand the relationship between the AO and the LV.  Because of the discrepancy between the Ao and the VSD and the position of the great arteries, it was not possible to baffle the LV toward the Ao, therefore the child, successfully underwent a Nikaido intervention (surgical transposition of the aortic root to the LV outflow tract).

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Fig. 18.15  Tridimensional model of the congenital defect. 3D modeling was elaborated and printed by BioCardioLab of FTGM

 ase 6: Transposition of the Great Arteries C Following Atrial Switch Operation A 27-year-old female patient with a diagnosis of D-TGA treated with atrial switch operation was referred to CMR for a comprehensive assessment before getting pregnant becouse previous TTE evaluation was considered difficult and incomplete due to suboptimal acoustic window. Morpho-functional evaluation showed moderate dilatation and hypertrophy of the systemic right ventricle (RVEDVi 135 mL/m2), with preserved systolic function (EF 50%) (Fig.  18.16a, b). Cine imaging clearly depicted leftward shift of the interventricular septum (Fig. 18.16c), due to systemic RV pressure, associated with functional tricuspid regurgitation and dynamic left ventricular outflow obstruction, with systolic anterior motion

of the mitral valve. 3D time resolved MR angiography revealed obstruction of the superior caval vein baffle (Fig.  18.17a–c, arrows), with compensatory dilatation and inverted flow in azygos and hemiazygos veins, which carried the venous return of the upper half of the body into the abdominal venous system (Fig. 18.17a, b, arrowheads). Cine SSFP imaging confirmed SVC obstruction (Fig. 18.17c) and also identified mild stenosis of the inferior caval vein tunnel (Fig. 18.17d). The patient underwent interventional stenting procedure to restore SVC baffle patency, thus reducing abdominal venous congestion. One-year follow-up CT scan obtained after an uneventful pregnancy with successful delivery, confirmed the correct position and normal caliber of the caval stent (Fig. 18.18).

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Fig. 18.16  Cine SSFP imaging in 2-chamber (a), 4-chamber (b), and short-axis (c) view

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Fig. 18.17  3D time resolved MR angiography coronal and sagittal MIP reconstruction (a, b); cine SSFP long axis views of SVC baffle (c) and IVC intra-atrial tunnel (d)

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Fig. 18.18  Pre and post-procedural angiographic images (a, b); coronal CT image (c)

 ase 7: Transposition of the Great Arteries C Following Arterial Switch Operation A 3 years-old patient with a diagnosis of D-TGA and anomalous intramural course of the right coronary artery underwent arterial switch operation with unroofing of the right coronary ostium early after birth. During follow-up, ventricular ectopic beats were found on ECG and hypokinesia of the inferior wall of the LV was documented at TTE. The patient was referred to adenosine stress perfusion CMR under general anesthesia for suspected ischemia. Stress first pass perfusion imaging documented transmural perfusion defect of the inferoseptal and inferior wall of the LV (Fig. 18.19a–d, arrows), without perfusion abnormalities on rest images (Fig. 18.19e–h). Cine sequences showed normal ­biventricular volumes (LVEDVi

75 mL/m2, RVEDVi 85 mL/m2) and systolic function (LVEF 58%, RVEF 60%), without regional wall motion abnormalities (Fig. 18.20a, b). No myocardial scar was found on LGE imaging (Fig. 18.20c, d). 3D SSFP images clearly depicted the left coronary button (Fig.  18.20e, arrow), whereas the right coronary ostium was not recognizable (Fig.  18.20e, arrowhead). There was also moderate obstruction of the neopulmonary root (Fig. 18.20f, arrow), stretching of the pulmonary arteries without relevant narrowing (Fig.  18.20g), and dilation of the neo-aortic root (Fig.  18.20h). Severe right coronary artery stenosis was confirmed at coronary angiography (Fig.  18.21a, arrow). Surgical coronary button reconstruction was successfully performed, as documented at follow-up CT scan (Fig. 18.21b, c, arrows).

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Fig. 18.19  Stress first pass perfusion short-axis images (a, b) and upslope color maps (c, d); rest first pass perfusion short-axis images (e, f) and upslope color maps (g, h)

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Fig. 18.20  Cine SSFP 2-chamber (a) and 4-chamber view (b) and corresponding LGE imaging (c, d); 3D ECG-gated SSFP image at the level of the reimplanted coronary ostia (e); cine SSFP RVOT (f); branch pulmonary arteries (g); and LVOT views (h)

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Fig. 18.21  Angiographic image of the right coronary (a); curved multiplanar and 3D volume rendering CT reconstruction

 ase 8: Congenitally Corrected Transposition C of the Great Arteries (ccTGA) A 9 years-old male patient with ccTGA and tricuspid dysplasia presented at medical follow-up with recent onset of heart failure symptoms. TTE showed severe tricuspid regurgitation with RV dilatation and dysfunction. The patient was referred to CMR for further assessment. Cardiovascular anatomy was characterized by atrio-ventricular and ventriculo-­arterial discordance with left-sided systemic RV, right-sided subpulmonary LV, and levo-transposition of the great arteries (Fig.  18.22). Dilatation of the RV (RVEDVi 130  ml/m2) with leftward systolic bowing of the interventricular septum (Fig. 18.22c) was associated with tricuspid annular enlargement and displacement of papillary muscles,

with tethering of dysplastic leaflets causing severe valve regurgitation (regurgitant fraction 45%) (Fig.  18.22a, b, arrows). The patient underwent surgical palliative procedure of pulmonary artery banding in order to increase left ventricular pressure and reduce leftward shift of the IVS, thus decreasing tricuspid regurgitation. After surgery he showed significant improvement in his clinical condition. Pressure in the subpulmonary LV was half systemic at TTE. At 1 year follow-up CMR, pulmonary banding was tight, without impinging pulmonary valve or branch pulmonary arteries (Fig.  18.23d, arrow). Flattened shape of IVS was able to reduce tricuspid insufficiency (RF 20%), with decrease in RV volume (RVEDV 105 mL/m2) and improvement of systolic function (EF 55% vs 47%) (Fig. 18.23a–c).

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Fig. 18.22  Preoperative cine SSFP 4-chamber (a), right ventricle 2-chamber (b), short axis (c), and left ventricle 3-chamber (d) view

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Fig. 18.23  Postoperative cine SSFP 4-chamber (a), right ventricle 2-chamber (b), short axis (c), and left ventricle 3-chamber (d) view

 ase 9: Pulmonary Atresia and Ventricular C Septal Defect (PA/VSD) and Major Aortopulmonary Collateral Arteries (MAPCAs) A 6 years-old child diagnosed with unrepaired PA/VSD, confluent hypoplastic pulmonary arteries, and MAPCAs was referred to our center because of failure to thrive and progressive reduction in exercise tolerance. Echocardiographic evaluation showed good bi-ventricular systolic function with dilated left chambers. The 16  kg patient underwent cardiac CT with 3D reconstruction of the mediastinal anatomy (Video 18.3) and cardiac catheterization under general anesthesia; both techniques showed large unobstructed MAPCAs and high pulmonary pressure was detected during selective angiography. Based on invasive oximetry, the estimated Qp/Qs was around 1, with high pulmonary vascular resistances (11 WU/m2) with sign of

good vasoactive response during hyperoxia. To confirm hemodynamic status, awake CMR scan was performed in a free-breathing technique; the study was targeted to delineate the vascular anatomy with 3D Contrast-Enhanced Magnetic Resonance Angiography (CEMRA) (Fig. 18.24a, b) and for Qp/Qs quantification using Phase Contrast flow analysis (high spatial/temporal resolution and increased number of signal averaging/experiments NSA/NEX). Aorta (Ao), Superior Vena Cava (SVC), and Inferior Vena Cava (IVC) flows were sampled with calculated AO flow of 120 mL/beat and a Qs (SVC + IVC flows) of 24 mL/beat. Derived Qp (AO  −  SVC  +  IVC) was 96  mL/beat with a calculated Qp/Qs around 4 (96 mL/24), suggesting significant pulmonary overflow (Fig. 18.25). Based on Qp/Qs calculation, CMR guided surgical management and single stage correction were successfully performed with no major complications and favorable estimated post-op RV pressure from TR of 30 mmHg.

334 Fig. 18.24 Contrast-­ enhanced magnetic resonance angiography (CEMRA) showing well-developed aortopulmonary collaterals

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Fig. 18.25  Qp/Qs calculation from aortic flow and systemic venous return

 ase 10: Polymalformative Syndrome C with Complete Atrioventricular Septal Defect (AVSD), Pulmonary Artery Sling (PAS), Complex Tracheal Stenosis, and Duodenal Atresia A newborn girl in good general conditions diagnosed with complete AVSD, appearance of ventricular disproportion, and associated duodenal atresia underwent pre-operative assessment with CMR under general anesthesia for the evaluation of bi-ventricular dimensions. CMR Cine images confirmed mesocardia with levo-apex and mildly left dominant complete AVSD (LVEDVi 72 mL/m2 vs RVEDVi 69 mL/m2,

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RVEDV/LVEDV of 0.9 with normal value of 1–1.1) (Fig. 18.26a–d and Video 18.4) with preserved bi-ventricular systolic function (Fig. 18.26a in the diastolic phase and panel D in the systolic phase), poorly formed antero-lateral dominant papillary muscle (Fig. 18.26e) and a mild valvular pulmonary stenosis. Anatomical evaluation performed with a black blood 3D TSE sequence with Variable Flip Angle revealed a non-communicating persistent left superior vena cava (LSVC Fig. 18.27e) draining into an unroofed coronary sinus, right-sided aortic arch (RAA Fig. 18.27c, d) with mirror image branching with left persistent ductus arteriosus (PDA, Fig. 18.27f), and a type IIA PAS (Figs. 18.27a, b and 18.28a, b). PAS is characterized by left pulmonary artery (LPA) originating from the proximal right pulmonary artery (RPA) coursing between esophagus (Fig.  18.27a orange oval) and the trachea (Fig. 18.27b red oval/line); in addition there is congenital stenosis of the distal trachea due to complete airway cartilaginous ring (Fig.  18.27a red oval). The tracheal anatomy was further investigated with cardio-thoracic CT and mediastinal relationship detailed by volume rendering reconstructions (Fig. 18.28). Flow evaluation with velocity-­encoded phase contrast imaging quantified significant ­pulmonary overflow with a calculated Qp/Qs of 2.7. The patient successfully underwent single stage surgical correction of the congenital intracardiac anomaly, PDA ligation, left pulmonary artery reimplantation, and slide tracheoplasty.

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Pearls and Pitfalls • Performing and interpreting CMR in Complex CDH require deep knowledge of CMR technique and all clinical and surgical aspects of the patient; this is particularly important for safety reasons in case of difficult scan conditions (poor collaborating patients, arrhythmias, general anesthesia, electronic devices). • CMR is currently the gold standard technique for RV volume and ejection fraction calculation; both are crucial for the timing of patient treatment, therefore short-axis evaluation compared with flow calculation is recommended. In Ebstein’s anomaly, RV volumes and function can be evaluated also in transversal orientation. • Echocardiography is generally superior in the evaluation of AV valve, however in some complex CHD (Ebstein’s anomaly, AVSD) multiplane AV junction views are useful. • In complex CHD, an accurate estimation of flows and hemodynamic parameters is necessary to guide management; tailored parameters (geometry, velocity encoding scale, spatial/temporal resolution) are crucial to avoid

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aliasing phenomena and for accurate flow volume estimation. 4D flow sequence is a promising technology in the evaluation of complex CHD, in particular when multiple arterial and venous quantifications are required (e.g., functionally single ventricle in pre and post Fontan palliation and Pulmonary atresia + VSD with MAPCAs). Cine gradient-echo sequences should be preferred to standard cine bSSFP in the evaluation of stenotic vessels, in the presence of calcifications or metallic object (e.g., stents). 3D time resolved MR angiography is useful in some complex CHD, especially when multiple angiographic phases are needed to investigate simultaneously anatomy and stream of flow of both arterial and venous structures (e.g., post-atrial switch when a superior baffle stenosis is suspected). 3D anatomical evaluation with whole-heart sequences, including both bright and black blood techniques, is very accurate; however, in selected cases when coronary artery details or additional airway information are needed, complimentary cardiovascular CT should be performed.

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Fig. 18.27  3D black blood fast spin echo CMR imaging Fig. 18.28  3D reconstruction of thoracic computed tomography

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• 3D reconstruction (including volume rendering, modeling, and rapid prototyping) can be used as a point of care; however, caution should be made in evaluating vessels stenosis with this approach. • CMR stress with adenosine is useful in CHD patients after surgical manipulation of coronary arteries, especially in TGA after arterial switch operation when myocardial ischemia is suspected.

337 Acknowledgements We thank all the radiographers and nurses of FTGM and Bambin Gesu Hospital CMR-Lab for their dedication. We thanks the bioengineers Nicola Martini (FTGM) and Luca Borro (Bambin Gesù Hospital) for supporting us to improve the CMR assessment of this population of complex CHD and the bioengineers Simona Celi, Katia Capelli and Emanuele Gasparotti and collaborators of the BioCardiolab of FTGM for their valuable contribution in the 3D modeling of complex CHD.

References Conclusions In this chapter, we illustrated CMR application in some complex CHD.  The anatomic and hemodynamic heterogeneity does not allow to illustrate all possible scenarios. We tried to figure out the most frequently complex CHD cases usually scheduled for CMR evaluation. In patients with complex CHD, TTE is often sufficient before the first surgery or palliation, however in selected cases when TTE is not exhaustive, CMR is indicated to allow accurate pre-op anatomical evaluation for better surgical planning, for instance: –– In case of DORV, as illustrated in case 5; –– When hemodynamic evaluation could help management as in PA/VSD/MAPCAs, as illustrated in case 9. –– When extracardiac defects, not accurately visualized at TTE, are suspected (complex AVSD with pulmonary sling illustrated in case 10). –– For RV volumes and function when RV is concerned as in congenitally corrected TGA (illustrated in the case 8) or in Ebstein’s anomaly (illustrated in the case 2). Moreover, CMR has become also increasingly used in the interstage evaluation of complex CHD with a single ventricle and in the follow-up of this population. In addition, CMR, thanks to its unique ability for functional evaluation, contributes significantly to the indication of reintervention, as illustrated in the case 1 dealing with a post repair-Tetralogy di Fallot patient. CMR is a time-consuming examination, especially in patients with heterogeneous and complex anatomy, therefore CMR image acquisition and interpretation usually requires technical knowledge and expertise in CHD.  Finally, the advantage of newer technological improvement (such as 4D flow, rapid imaging acquisition etc) will allow in the near future to reduce the acquisition time and to improve the hemodynamic evaluation of patients with complex CHD.

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P. Festa et al. 17. Broberg CS, Burchill LJ.  Myocardial factor revisited: the importance of myocardial fibrosis in adults with congenital heart disease. Int J Cardiol. 2015;189:204–10. 18. Raimondi F, et al. Cardiac magnetic resonance myocardial perfusion after arterial switch for transposition of great arteries. JACC Cardiovasc Imaging. 2018;11(5):778–9. 19. Secinaro A, et  al. Recommendations for cardiovascular magnetic resonance and computed tomography in congenital heart disease: a consensus paper from the CMR/CCT working group of the Italian Society of Pediatric Cardiology (SICP) and the Italian College of Cardiac Radiology endorsed by the Italian Society of Medical and Interventional Radiology (SIRM) Part I.  La radiologia medica. 2022;127:1–15.