Pathology of Cardiac Valve Disease : Surgical and Interventional Anatomy [1 ed.] 9783031354977, 9783031354984

Citation preview

Gaetano Thiene · Cristina Basso · Stefania Rizzo · Mila Della Barbera · Marialuisa Valente · Uberto Bortolotti   Editors

Pathology of Cardiac Valve Disease Surgical and Interventional Anatomy

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Pathology of Cardiac Valve Disease

Gaetano Thiene • Cristina Basso Stefania Rizzo  •  Mila Della Barbera Marialuisa Valente • Uberto Bortolotti Editors

Pathology of Cardiac Valve Disease Surgical and Interventional Anatomy

Editors Gaetano Thiene Istituto di Anatomia Patologica University of Padua PADOVA, Padova, Italy Stefania Rizzo Cardiovascular Pathology, Department of Cardiac Thoracic and Vascular Sciences and Public. Health University of Padua Padova, Padova, Italy Marialuisa Valente Istituto di Anatomia Patologica University of Padua PADOVA, Padova, Italy

Cristina Basso Cardiovascular Pathology, Department of Cardiac Thoracic and Vascular Sciences and Public. Health University of Padua Padova, Padova, Italy Mila Della Barbera Cardiac-Thoracic-Vasc. Sc. and P. Health AOU University of Padua Medical School Padova, Italy Uberto Bortolotti Cardio-Thoracic and Vascular Department Cardiac Surgery Unit University of Pisa Padova, Padova, Italy

ISBN 978-3-031-35497-7    ISBN 978-3-031-35498-4 (eBook) https://doi.org/10.1007/978-3-031-35498-4 © 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

Foreword

Pathology of cardiac native and prosthetic valves.

I first met Gaetano Thiene and Uberto Bortolotti in 1981 at the National Heart, Lung, and Blood Institute (NIH) at Bethesda, where I was a fellow. Gaetano and Uberto were visiting speakers. Gaetano and I were involved in the establishment of the Society for Cardiovascular Pathology. We also shared an interest in cardiovascular prosthetic devices. Gaetano Thiene, an accomplished cardiovascular pathologist, has spent his career teaching pathology to generations of students and doing research at the University of Padua. He is now Professor Emeritus at the University of Padua, Italy, with numerous scientific publications on cardiovascular pathology, as well as book chapters and books to his credit. One of Gaetano “seminal” papers was on arrhythmogenic right ventricular dysplasia (ARVD, now termed arrhythmogenic cardiomyopathy), following a review of autopsied cases of sudden death in the young. He is a founder of the European Association of Cardiovascular Pathology, and his influence on the teaching and practice of cardiovascular pathology has been very impressive. Uberto Bartolotti is a seasoned cardiovascular surgeon and colleague of Dr. Thiene. He has numerous scientific publications and book chapters to his credit. He is now a retired Full Professor of Cardiovascular Surgery at the University of Pisa, Italy. They are both outstanding teachers, clinicians, and researchers. Pathology, as in any part of Medicine, remains as much a science as an art. Like good wine, it needs years of experience to mature and acquire its unique qualities. It is a pleasure to see this book, a compilation of numerous years of expertise in the management of valvular heart disease. This book, an atlas of valvular heart disease, native and prosthetic, shows its “maturity” in the concise text and high-quality images. With the significant changes in interventional management of heart valve disease in the last decade, this book, with its section on trans-catheter heart valve technologies, is a timely atlas and will likely be “one of its kind” for years to come. The authors give a brief historical overview of the pathology of native valve diseases, the development of prosthetic heart valves, followed by native and prosthetic valve pathology in a concise and well-illustrated manner. Images of failed transcatheter aortic valve implantation valves are likely to be especially valuable since there is little published about the pathology of these devices. As one would expect, there are always some things “more” that could be added to the atlas and this would include a more consistent approach to each valve, language that is easier to understand, and the pathology of native valve repair (a niche area, but nonetheless one with good clinical results).

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Foreword

Cardiovascular pathology is a niche area, with a small number of practitioners worldwide. This atlas will be a resource for many who need to report the pathology of native and prosthetic valve disease. The concise format and the excellent quality of the illustrations suggest that the book will be well received by residents, fellows, pathologists, cardiologists, and cardiovascular surgeons as a good reference and a great addition to institutional and personal libraries. Jagdish Butany Professor Emeritus, Faculty of Medicine University of Toronto Toronto, ON, Canada

Contents

1 Introduction�����������������������������������������������������������������������������������������������������������������   1 Gaetano Thiene and Uberto Bortolotti 2 Story  Telling of Prosthetic Cardiac Valves���������������������������������������������������������������   3 Uberto Bortolotti and Gaetano Thiene 3 Anatomy  of Native Heart Valves�������������������������������������������������������������������������������   7 Gaetano Thiene and Stefania Rizzo 4 Non  Infections Pathology of Native Heart Valves ���������������������������������������������������  31 Cristina Basso and Gaetano Thiene 5 Congenital  Anomalies of the Cardiac Valves�����������������������������������������������������������  63 Carla Frescura and Gaetano Thiene 6 Infective Endocarditis�������������������������������������������������������������������������������������������������  87 Gaetano Thiene, Cristina Basso, and Uberto Bortolotti 7 Pathology  of Mechanical Prosthetic Cardiac Valves����������������������������������������������� 105 Uberto Bortolotti, Mila Della Barbera, Tomaso Bottio, and Gaetano Thiene 8 Pathology  of Biological Prosthetic Cardiac Valves ������������������������������������������������� 117 Gaetano Thiene, Mila Della Barbera, Aldo Milano, Stefania Rizzo, Uberto Bortolotti, and Marialuisa Valente 9 Anticalcification  Strategies to Increase Bioprosthetic Valve Durability ��������������� 153 Marialuisa Valente, Mila della Barbera, Uberto Bortolotti, and Gaetano Thiene

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Introduction Gaetano Thiene and Uberto Bortolotti

Until the late 1950s, heart valve diseases could be treated only by closed-chest procedures, such as mitral valve commissurotomy or dilatation of stenotic pulmonary valves. Despite satisfactory results, such operations were palliative with only temporary benefit. It was in 1960, by replacing the mitral and aortic diseased valves with mechanical prostheses, thanks to the milestone operations performed by Nina Braunwald, Albert Starr and Dwight E.  Harken, that the prognosis of patients affected by deadly valvular diseases changed dramatically. Within years, prosthetic valve replacement has progressively become an almost routine operation with excellent early and long-term results. This has been certainly due also to definite improvements in patient selection, intraoperative management and postoperative care, which have occurred during various decades. However, a crucial role has been undoubtedly played by the tremendous technical progress which has been achieved in the manufacture of cardiac valve substitutes. With the initial prosthetic models, cardiac surgery pioneers have demonstrated their talent but also their ingenuity. However, it was also evident that a still very long and winding road would have been expected to obtain the ideal device to be safely used in any kind of patient and native pathology. It was soon realized that mechanical prostheses were associated with thrombotic, thromboembolic and hemorrhagic complications related to the often incorrect use and management of life-long anticoagulants, while bioprosthetic valves had the major drawback in a limited structural durability. The various causes of prosthetic valve failure were

clearly identified by a continuous research in this field, with the results shared with the scientific community through numerous reports. Accordingly, it was possible to precisely highlight the typical modes of failure of each specific device, introduced in the market and made clinically available, either mechanical or biological. This information has been of pivotal importance for the industry, since each involved company started to modify their early models based upon the findings observed and provided by clinicians and pathologists. This allowed to introduce important innovations in the prosthesis manufacturing process and to eliminate structural weakness, to increase biocompatibility, to minimize thrombogenicity of mechanical prostheses, and to improve hemodynamic performance, favoring ease of implantation and extending durability for biological counterparts. Owing to the great progress in prosthetic technology, after over 60  years from the first implant of a caged-ball mechanical prosthesis and more than 50 years of a stented porcine bioprosthesis, we can say that a new generation of extremely reliable and effective cardiac valve substitutes is now available. Despite this, it must be also recognized that the ten commandments for what should be considered the ideal prosthetic valve, devised by Dwight E. Harken many years Table 1.1  The ten commandments for the ideal prosthetic valvea 1. It must not propagate emboli 2. It must be chemically inert and not damage blood elements 3. It must offer no resistance to physiological flows 4. It must close promptly (less than 0.05 second) 5. It must remain closed during the appropriate phase of the cardiac cycle 6. It must have lasting physical and geometric features 7. It must be inserted in a physiological site (generally the normal anatomic site) 8. It must be capable of permanent fixation 9. It must not annoy the patient 10. It must be technically practical to insert

G. Thiene (*) Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padua Medical School, and Cardiovascular Pathology Unit, University Hospital of Padua, Padua, Italy e-mail: [email protected] U. Bortolotti Section of Cardiac Surgery, Cardio-thoracic and Vascular Department, University Hospital of Pisa, Pisa, Italy e-mail: [email protected]

as originally defined by DE Harken

a

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 G. Thiene et al. (eds.), Pathology of Cardiac Valve Disease, https://doi.org/10.1007/978-3-031-35498-4_1

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ago (Table 1.1), are not yet totally fulfilled, witnessing that probably there is still considerable research to be carried out in the field of prosthetic heart valves. The present book, in the form of an illustrated text atlas on the surgical anatomy and pathology of native and prosthetic heart valves, appears timely not only historically but also of practical utility for all involved in this field. The aim of this book is to provide the reader with clear images of the valve anatomy and pathology, including views from a cardiac surgeon’s perspective and pictures of most heart prosthetic models and their typical mode of failure. All the materials included in this publication derived from the collection of the Unit of Cardiovascular Pathology of the University of Padua Medical School. The huge amount of specimens gathered through the years and shared here will help to demonstrate the importance of this contribution to the progress in mechanical and bioprosthetic technology and to the improvement in the care of prosthetic heart valve recipients. In the era of rapid and increasingly advancing trans-

G. Thiene and U. Bortolotti

catheter procedures, the present overview will also help to understand the role of surgical valve replacement that with the current available prosthetic models certainly cannot be considered a yet outdated procedure.

Further Reading Bortolotti U, Milano AD, Valente M, Thiene G.  The stented porcine bioprosthesis. A 50-year journey through hopes and realities. Ann Thorac Surg. 2019;108:304–8. De Martino A, Milano AD, Thiene G, Bortolotti U. Diamond anniversary of mechanical heart valve prostheses. A tale of cages, balls and discs. Ann Thorac Surg. 2020;110:1427–33. De Martino A, Milano AD, Thiene G, Della Barbera M, Bortolotti U. The caged-ball prosthesis 60 years later. Historical review of a cardiac surgery milestone. Texas Heart Inst J. 2022;49:e207267. Harken DE. Heart valves: ten commandments and still counting. Ann Thorac Surg. 1989;48: (3 Suppl): S18-9:S18. Lefrak EA, Starr A, editors. Cardiac valve prostheses. New  York: Appleton-Century-Crofts; 1979.

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Story Telling of Prosthetic Cardiac Valves Uberto Bortolotti and Gaetano Thiene

The history of cardiac prosthetic valves starts in September 1952 when Charles A. Hufnagel implanted, at Georgetown University, in Washington, DC, USA, the first cardiac prosthesis, a ball valve made of methyl metachrylate, into the descending aorta in a patient with aortic valve incompetence. Unavailability at that time of the cardiopulmonary bypass forced this unusual application which, however, had very limited clinical benefits. Mitral valve replacement had been attempted in July 1955 by Judson Chesterman in Sheffield, UK, using a prosthesis made of Perspex®, an acrylic material, which worked on the principles of a car engine valve. The patient survived 14 h and died because of sudden prosthetic failure. In March 1960, 8 years from Hufnagel’s operation, Dwight E.  Harken at the Harvard Medical School in Boston, MA, USA, performed the first orthotopic implantation of a caged-ball prosthesis in subcoronary position for aortic stenosis, while 1  day later, Nina Braunwald, at the National Institutes of Health, in Bethesda, MD, USA, replaced for the first time an incompetent mitral valve using a prosthesis made from two leaflets of polyurethane connected to the papillary muscles by strips of Teflon; this prosthesis was implanted in a 44-year-old woman with mitral regurgitation who survived the operation but died 4 months later, most likely for arrhythmia. Albert Starr in Portland, OR, USA, is credited for the first successful mitral valve replacement performed with a caged-ball prosthesis in September 1960 in a patient with mitral stenosis. Such operations started the modern era of prosthetic valve replacement, and during the following decades, a wide variety of

U. Bortolotti (*) Section of Cardiac Surgery, Cardio-thoracic and Vascular Department, University Hospital of Pisa, Pisa, Italy e-mail: [email protected] G. Thiene Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padua Medical School, and Cardiovascular Pathology Unit, University Hospital of Padua, Padua, Italy e-mail: [email protected]

mechanical prostheses became available with significant improvements in materials, structural design, shapes, and hemodynamic concepts. Major concerns with the use of mechanical devices, represented by anticoagulant-related complications such as thromboembolism and hemorrhages, led to conceive biological alternatives for valve replacement which would eliminate or minimize the burden and risks of chronic anticoagulation. The first heterologous bioprosthesis was implanted in Paris by Binet in 1965 who employed a porcine aortic valve inserted with the free-hand technique to replace a diseased aortic valve. Subsequently, a stent was added to the porcine valve to avoid tissue ingrowth, and glutaraldehyde was used for tissue fixation to stabilize the collagen cross-links, reduce tissue antigenicity, and provide sterilization of the heterograft. These innovations represented the beginning of the bioprosthetic era during which failures and successes have been witnessed by a multitude of clinical and pathological reports. Currently, due the widespread development of valve repair techniques, the use of prosthetic valves has been confined to specific conditions. Due to the increasing age of the population referred for surgical valve replacement, employment of mechanical devices is extremely limited in favor of tissue valves, while expanding indications for transcatheter aortic valve implantation has led to development of a further generation of bioprostheses to be implanted with less invasive methods. A wide variety of cardiac valve substitutes has been introduced clinically in the last 60 years. Mechanical prostheses have undergone most significant improvements not only in design but also in the use of different materials to obtain devices resistant to mechanical stress and structural wear. Conversely, in biological prosthesis manufacture, major modifications have involved tissue selection, methods of fixation, and the use of various anticalcification treatments, while design variations have played an important role as well. The valve prosthesis portfolio has recently been implemented by the manufacture of sutureless bioprostheses made

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 G. Thiene et al. (eds.), Pathology of Cardiac Valve Disease, https://doi.org/10.1007/978-3-031-35498-4_2

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of bovine pericardium, in the attempt to minimize the intraoperative ischemic times and counterbalance the ­ increasing impact of transcatheter valve implantation.

Evolution of Mechanical Prostheses In reviewing the history of prosthetic valves, it appears evident how many improvements and technical advances have been obtained in this field. Looking to the past, it must also be underlined how some old concepts, which can be considered quite revolutionary for those years, clearly indicate the great skill of those who conceived them. The Hufnagel principle was substantially derived from the patent of the bottle stopper dating back to 1858, which was later transferred to the Starr-Edwards caged-ball prosthesis which has been in clinical use for many years with extremely long-term longevity. It is however interesting to recall that the Hufnagel principle was revisited almost 40 years later by implanting a tilting-disc prosthesis in the descending aorta of patients with a failing aortic prosthetic valve considered otherwise inoperable. Another unique mechanical prosthesis was developed in Cape Town, South Africa, by Christiaan Barnard in 1962. It consisted of a double cone-shaped poppet resembling a toilet plunger from which the idea was taken. A modification of such design was adopted by others to reduce the high rate of thromboembolic complications, obtaining a disc valve resembling a collar button. Currently the only mechanical prostheses available in the market are those who incorporate the bileaflet mechanism. Again, this concept is only apparently modern since it was pioneered by Vincent Gott in 1963 while developing a central-­hinging bileaflet valve with a polycarbonate housing and leaflets made of silicone rubber and Teflon fabric. This device has demonstrated unexpected durability with apparently no reported cases of structural failures. In 1968, Walton Lillehei developed an all titanium bileaflet prosthesis with improved hemodynamics in vitro owing to a central laminar flow. This prosthesis was implanted in mitral position only in a patient who did not survive the operation and then abandoned. In the continuous effort to provide a prosthesis with reduced resistance to flow, the bileaflet model has been consistently revitalized in more recent years yielding various mechanical prostheses with excellent hemodynamic performances and no reports of structural failures in the recent models. These devices are the only still in the market and, after an initial skepticism, are now considered extremely reliable with unsurpassed records of durability. Failures of some early bileaflet prostheses, with episodes of leaflet rupture and embolization, were mainly referred to a faulty design.

U. Bortolotti and G. Thiene

Another milestone in mechanical prostheses manufacturing is represented by the introduction of pyrolytic carbon, which eliminated the risk of deformation or wear of other materials such as Delrin®, an acetyl resin, used in some prosthetic models. Interestingly, pyrolytic carbon was first used to manufacture the poppet of the DeBakey-Surgitool caged-ball prosthesis. Sorin Biomedica (Saluggia, Italy) was particularly active in this field, under the leadership of Franco Vallana, producing both tilting disc and bileaflet prostheses with excellent results and absence of mechanical failures. Subsequently, a new technology yielded the Carbofilm®, a thin film of turbostratic carbon to cover the sewing ring and other valve components, with the potential to reduce thrombogenicity. More recently, a bileaflet prosthesis has been approved for clinical use which has been designed to function with a lower anticoagulation level than previously recommended.

Evolution of Biological Prostheses In addition, biological prostheses have undergone a wide variety of changes, before obtaining definite acceptance, favored by the superior resistance to structural valve deterioration in third-generation devices. Indiscriminate use of commercially manufactured porcine and pericardial bioprostheses led surgeons to face an increasingly frequent number of reoperations for valve failures. Calcific cusp degeneration in porcine and fatigue-induced lesions in pericardial bioprostheses were soon identified as the main modes of failure. Important advances in bioprosthetic technology allowed to minimize or even eliminate such complications. Among these, replacement of a rigid stent with a flexible one in porcine xenografts reduced mechanical stresses particularly on the commissures. Although the use of buffered glutaraldehyde in tissue fixation was an important achievement, by obtaining stability of collagen cross-links, it also caused xenograft cell death by providing the initial sites for the calcific cascade. Thereafter, numerous anticalcification treatments, mostly based on removal during manufacturing of cell debris or glutaraldehyde residuals, have been added to tissue processing and many of which have been shown to have an effective antimineralization action both in experimental and in clinical settings. Furthermore, the concept of low to zero pressure fixation was accepted for its fundamental role in maintaining normal collagen waviness of the fibrosa in the porcine aortic cusps, preserving their elasticity and function. All such modifications have led to the manufacture of various new models of bioprostheses which represent an ideal substitute especially in an elderly population where such devices are expected to outlive their recipient owing to

2  Story Telling of Prosthetic Cardiac Valves

a prolonged durability. These considerations appear undoubtedly important considering the rapid growth of transcatheter procedures employing prostheses of bovine pericardium, which could render surgical valve replacement obsolete in a near future. In the attempt to counteract or delay this trend, sutureless and rapid deployment bioprostheses have been introduced in the clinical practice. Such devices have demonstrated to allow a significant reduction of implantation time and cardiopulmonary bypass length and consequently of myocardial ischemia, being therefore particularly useful and indicated in high-risk, critical patients. Dysfunctioning biological prostheses, in the past replaced with standard reoperations, are currently managed in many cases by implantation of transcatheter devices in a valve-in-­ valve fashion. Accordingly, the industry has adapted to this trend by developing more flexible, resilient pericardial bioprostheses which have the potential to facilitate possible future valve-in-valve procedures.

Conclusion In reviewing the history of prosthetic valves, it appears evident how many improvements and technical advances have been obtained in this field. Looking to the past, it must also be underlined how some old concepts, which could be considered quite revolutionary for that time, clearly indicate the great skill and ingenuity of those who conceived them. Both mechanical and biological prostheses have gone a long way before reaching their current reliability, which is the result of both lessons and mistakes from the past. Nevertheless, in reviewing the early and more recent years and recognizing the many steps forward in prosthetic valve evolution, one cannot ignore that history sometimes repeats itself, and this is once again demonstrated by the revival of old and initially unsuccessful concepts.

Further Reading Amrane M, Soulat G, Carpentier A, Jouan J.  Starr-Edwards aortic valve: 50+ years and still going strong: a case report. Eur Heart J– Case Rep. 2017;1:1–3. Arbustini E, Jones M, Moses RD, Eidbo EE, Carrol RJ, Ferrans VJH.  Modification of the Hancock T6 process of calcification of bioprosthetic cardiac valves implanted in sheep. Am J Cardiol. 1984;53:1388–96. Arru P, Rinaldi S, Stacchino C, Vallana F. Wear assessment in bileaflet heart valves. J Heart Valve Dis. 1996;5(Suppl. I):S133–43. Baldus S, Mauri V. Valve-in-valve TAVI: the new standard therapy for failing bioprosthetic valves? Euro Intervention. 2022;17:1197–8. Barnard CN, Schrire V, Goosen CC.  Total aortic valve replacement. Lancet. 1963;2:856. Binet JP, Duran CG, Carpentier A, Langlois J.  Heterologous aortic valve transplantation. Lancet. 1965;2:1275. Borkos JC.  Carbon in prosthetic heart valves. Ann Thorac Surg. 1989;48:S49–50.

5 Bortolotti U, Milano AD, Valente M, Thiene G.  The stented porcine bioprosthesis. A 50-year journey through hopes and realities. Ann Thorac Surg. 2019;108:304–8. Braunwald NS, Cooper TC, Morrow AG. Complete replacement of the mitral valve. J Thorac Cardiovasc Surg. 1960;40:1–11. Cale ARJ, Sang CTM, Campanella C, Cameron EWJ. Hufnagel revisited: a descending thoracic aortic valve to treat prosthetic valve insufficiency. Ann Thorac Surg. 1993;55:1218–21. Carpentier A, Lemaigre G, Robert J, Carpentier S, Dubost C. Biological factors affecting long-term results of valvular heterografts. J Thorac Cardiovasc Surg. 1969;58:467–83. Celiento M, Filaferro L, Milano AD, Anastasio G, Ferrari G, Bortolotti U.  Single center experience with the Sorin Bicarbon prosthesis. A 17-year clinical follow-up. J Thorac Cardiovasc Surg. 2014;148:2039–44. Celiento M, Ravenni G, Tomei L, Pratali S, Milano A, Bortolotti U. Excellent durability of the mosaic aortic porcine bioprosthesis at extended follow up. J Heart Valve Dis. 2018;27:93–103. Chaikof EL.  The development of prosthetic heart valves–lessons in form and function. N Engl J Med. 2007 Oct 4;357(14):1368–71. D’Onofrio A, Salizzoni S, Filippini C, et  al. Surgical aortic valve replacement with new generation bioprostheses: sutureless Perceval-S versus rapid-deployment Intuity. J Thorac Cardiovasc Surg. 2020;159:432–42. David TE, Armstrong S, Maganti M.  Hancock II bioprosthesis for aortic valve replacement: the gold standard of bioprosthetic valves durability? Ann Thorac Surg. 2010;90:775–81. Davis PK, Myers JL, Pennock JL, Thiele BL. Strut fracture and disc embolization in Björk-Shiley mitral valve prostheses: diagnosis and management. Ann Thorac Surg. 1985;40:65–8. De Martino A, Falcetta G, Milano AD, Bortolotti U. Modern concepts from old ideas in manufacture of cardiac valve prostheses. Ind J Thorac Cardiovasc Surg. 2020a;36:502–5. De Martino A, Milano AD, Della Barbera M, Thiene G, Bortolotti U. The caged-ball prosthesis 60 years later. Historical review of a cardiac surgery milestone. Texas Heart Inst J. 2022;49:e207267. De Martino A, Milano AD, Thiene G, Bortolotti U. Diamond anniversary of mechanical cardiac valve prostheses: a tale of cages, balls, and discs. Ann Thorac Surg. 2020b Oct;110(4):1427–33. Ellis FH Jr, Healy RW, Alexander S. Mitral valve replacement with the modified University of Cape Town (UCT) prosthesis: clinical and hemodynamic results. Ann Thorac Surg. 1977;23:26–31. Emery RW, Krogh CC, Arom KV, et al. The St. Jude Medical cardiac valve prosthesis: a 25-year experience with single valve replacement. Ann Thorac Surg. 2005;79:776–82. Gabbay S, Bortolotti U, Wasserman F, Factor S, Strom J, RWM F.  Fatigue-induced failure of the Ionescu-Shiley pericardial xenograft in the mitral position: In vivo and in  vitro correlation and a proposed classification. J Thorac Cardiovasc Surg. 1984a;87:836. Gott VL, Alejo DE, Cameron D. Mechanical heart valves: 50 years of evolution. Ann Thorac Surg. 2003;76:S2230–9. Gott VL, Daggett RL, Whiffen JD, Koeple DE, Rowe GG, Young WP. A hinged-leaflet valve for total replacement of the human aortic valve. J Thorac Cardiovasc Surg. 1964;48:713–25. Gott VL, Daggett RL, Young WP.  Development of a carbon-coated, central-hinging bileaflet valve. Ann Thorac Surg. 1989;48:S28–30. Harken DE, Soroff HS, Taylor WJ, Lefemine AA, Gupta SK, Lunzer S. Partial and complete prostheses in aortic insufficiency. J Thorac Cardiovasc Surg. 1960;40:744–62. Hufnagel CA, Harvey WP.  The surgical correction of aortic regurgitation. Preliminary report. Bull Georgetown Univ Med Center. 1954;6:60–1. Lillehei CW, Nakib A, Kaster RL, Kalke BR, Rees JR. The origin and development of three new mechanical valve designs: toroidal disc, pivoting disc, and rigid bileaflet cardiac prostheses. Ann Thorac Surg. 1989;48:S35–7.

6 Mattews AM. The development of the Starr-Edwards heart valve. Texas Heart Inst J. 1998;25:282–93. Mazzucco A, Morea P, Milano A, Bortolotti U. Concentric wear of the Delrin disc of a Björk-Shiley prosthesis: an uncommon cause of prosthetic incompetence. J Thorac Cardiovasc Surg. 1994;107:318–9. Milano A, Bortolotti U, Mazzucco A, et  al. Heart valve replacement with the Sorin tilting-disc prosthesis. A 10-year experience. J Thorac Cardiovasc Surg. 1992;103:267–75. Milano A, Bortolotti U, Mazzucco A, Gallucci V.  Extended survival after mitral valve replacement with a Gott-Daggett prosthesis. Am J Cardiol. 1984a;54:1147. Milano A, Bortolotti U, Talenti E, Valfrè C, Arbustini E, Valente M, Mazzucco A, Gallucci V, Thiene G.  Calcific degeneration as the main cause of porcine bioprosthetic valve failure. Am J Cardiol. 1984b;53:1066–70. Norman AF.  The first mitral valve replacement. Ann Thorac Surg. 1991;51:525–6. Percy E, Harloff M, Aranki SF. The future of a former valve: inspiring, resilient, or both? J Thorac Cardiovasc Surg. 2021;162:1487–8. Pibarot P, Dumesnil JG.  Prosthetic heart valves. Selection of the optimal prosthesis and long-term management. Circulation. 2009;119:1034–48. Reis RL, Hancock WD, Yarbrough JW, Glancy DL, Morrow AG. The flexible stent. A new concept in the fabrication of tissue heart valve prostheses. J Thorac Cardiovasc Surg. 1971;62:683–9.

U. Bortolotti and G. Thiene Schoen FJ, Levy RJ, Nelson AC, Bernhard WF, Nashef A, Hawley M. Onset and progression of experimental bioprosthetic heart valve calcification. Lab Investig. 1985;52:523–32. Schoen FJ, Titus JL, Lawrie GM.  Durability of pyrolytic carbon-­ containing heart valve prostheses. J Biomed Mater Res. 1982;16:559–70. Starr A, Edwards ML. Mitral replacement: clinical experience with a ball-valve prosthesis. Ann Surg. 1961;154:726–40. Starr A. A cherry blossom moment in the history of heart valve replacement. J Thorac Cardiovasc Surg. 2010 Dec;140(6):1226–9. Valente M, Bortolotti U, Thiene G.  Ultrastructural substrates of dystrophic calcification in porcine bioprosthetic valve failure. Am J Pathol. 1985;119:12–21. Van Steenbergen GGJ, Tsang QHY, van der Heyde SM, Verkroost MWA, Li WWL, Morshujs WJ. Spontaneous leaflet fracture resulting in embolization from mechanical valve prostheses. J Card Surg. 2019;34:124–30. Veseli I. Analysis of the Medtronic intact bioprosthetic valve. Effects of “zero pressure” fixation. J Thorac Cardiovasc Surg. 1991;91: 90–9. Villafana MA. “It will never work”–the St. Jude valve. Ann Thorac Surg. 1989;48:S53–4. Whitlock RP, Bhatt DL, Eikelboom JW. Reduced-intensity anticoagulation for mechanical aortic valve prostheses. J Am Coll Cardiol. 2018;71:2727–30.

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Anatomy of Native Heart Valves Gaetano Thiene and Stefania Rizzo

Aortic Valve Leonardo Da Vinci compared the aortic valve to a gate and depicted the blood flow through the aortic orifice with vortexes starting to close the cusps at the end of the ventricular systole. The aortic cusps are located within the sinusal portion of the ascending aorta (Fig. 3.1). The aortic sinuses, known as sinuses of Valsalva, were first described by Antonio Maria Valsalva in his book Opera

Fig. 3.1  The aortic valve apparatus within the sinusal part of the ascending aorta

Omnia, published posthumous in 1740 by his pupil Giovanni Battista Morgagni. The aortic valve apparatus consists of cusps, commissures, intercuspal triangles, and the aortic wall (Fig. 3.2). The cusps are three semilunar, swallow’s nest in shape, one posterior and two anterior (right and left) (Fig. 3.3). The right aortic cusp lies over the ventricular septum, the left aortic cusp on the antero-lateral myocardial band, whereas the posterior cusp is in fibrous continuity with the anterior mitral leaflet (Figs. 3.3, 3.4 and 3.5). Triangles indicate interleaflet triangles. Aortic Valve Apparatus

• Sinuses of Valsalva Diameter of sinus of valsalva

• Cusps • Commissures

Height of LMS • Intercusp triangles • Aortic wall Aortic valve annulus, maximum and minimum dimensions

Diameter of LVOT

G. Thiene · S. Rizzo (*) Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padua Medical School, and Cardiovascular Pathology Unit, University Hospital of Padua, Padua, Italy e-mail: [email protected]; [email protected] © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 G. Thiene et al. (eds.), Pathology of Cardiac Valve Disease, https://doi.org/10.1007/978-3-031-35498-4_3

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a

Commissural Ring (Sinutubular junction)

Aortic wall within ventricle (interleaflet triangle)

Ventriculo- arterial ring and junction Basal ring

Ventricle within sinus

b

Fig. 3.3  The aortic cusps are similar to swallow nests. Note the coronary ostia (arrows) located just below the sinotubular junction. L, P, R = left, posterior, right cusps

The aortic root is located in between the mitral and tricuspid valves (Fig. 3.6). The top confluence of the semilunar cusps, where they approximate to each other, represents the commissures. At variance with the mitral and tricuspid valves, the semilunar cusps at the commissures are in discontinuity (Fig. 3.3). Histologically, the aortic cusps show three layers: (a) a thin ventricularis facing the ventricular cavity and consisting of fibro-elastic fibers; (b) the fibrosa facing the aortic wall side, consisting of collagen bundles, and (c) the spongiosa in between with extracellular matrix made by myxoid ground substance (Fig. 3.7).

Fig. 3.2  Schematic representation of the aortic valve apparatus and its components, together with the various anatomical and functional rings

The coronary arteries originate just below the sinotubular junction, with a variability up to 2.5 mm, in the right and left sinuses of Valsalva (Figs. 3.8 and 3.9), facing the main pulmonary artery. There are several aortic anatomic and functional “rings” at the root of the aorta (Fig. 3.8): the “surgical” one, corresponding to the lowest part of cuspal attachment; the contact border of cuspal closure, namely, the physiological virtual ring separating the aorta and ventricular cavity during diastole; the “crown-like” attachment of the cusps to the aortic wall; the sinotubular junction separating the sinusal and tubular portions of the ascending aorta; and the anatomic ventricular myocardium in discontinuity with the aortic wall. The membranous septum is situated under the commissure between the posterior and the anterior right cusps, with the His bundle coursing in the posteroinferior rim (Fig. 3.10). The aortic wall structure (an intrinsic component of the aortic valve apparatus) consists of intima, media, and adventitia (Fig. 3.11). The intima is composed by an endothelial lining and a myointimal layer with smooth muscle cells. The tunica media is made by lamellar elastic units (Figs. 3.12 and 3.13), approximately 50–60 in the ascending aorta, which include smooth muscle cells (Fig. 3.14) within an extracellular matrix consisting of collagen fibers and ground substance. The smooth muscle cells of the lamellar units represent the “parenchyma” of the aorta, which should be considered a real “organ.”

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a

c

d

NC Sinus

RC Sinus

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S

Fig. 3.4 (a, b, d) The aortic valve partially lies over the myocardium. In particular, the right coronary cusp (RC) lies over the ventricular septum (S), the left coronary cusp over the anterolateral band and the noncoronary (NC) one is in fibrous continuity with the anterior mitral leaflet (c) Fig. 3.5  The aortic cusps seen from the ventricular cavity (a). Note the aortic fibrous continuity between the anterior mitral leaflet and the posterior noncoronary cusp (b)

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Fig. 3.6  The aortic valve is wedged between the mitral (M) and tricuspid (T) valves. A, P, S = anterior, posterior, and septal leaflets of the T valve

S

A P

3  Anatomy of Native Heart Valves Fig. 3.7 (a) The three layers of an aortic cusp: fibrosa (up), ventricularis (down) and spongiosa (middle). (b) Crimping of the collagen in systole

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a

b collagen crimp corrugations

elastin

Systole

Diastole

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Fig. 3.8  The several anatomic and functional “rings” of an aortic valve apparatus

Fig. 3.9  The coronary ostia are located just below the sinotubular junction. Gross view of the left infundibular outflow and aorta valve apparatus (a). Histology at the left coronary ostium (b)

a

b

Sinotubular junction

LC Sinus

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b b

Fig. 3.12  The concept of aortic lamellar units ((a), elastic lamellae; (b), smooth muscle cells in between) according to Wolinsky H and Glagov S. From Circulation Research, Vol. 20, January 1967 Fig. 3.10  The course of the atrioventricular conduction system, seen from the right (a) and left (b) sides. Note the relationship with the membranous septum transilluminated and the aortic valve

Aortic Wall • TunicaI INTIMA • Tunica MEDIA • The nomber of elastic lamellae is maximum in the ascending aorta (about 56) and gradually decreases distally, with a minimum in the abdominal aorta (about 28); • Tunica ADVENTITIA

Fig. 3.11  Schematic representation of the aortic wall layers with number of elastic lamellae in ascending and abdominal aorta

14 Fig. 3.13 Histology (Weigert-Van Gieson stain) (a) and immunohistochemistry (smooth muscle actin) (b) of the wall of the ascending aorta. Note the lamellar units in the tunica media with smooth muscle cells within

Fig. 3.14  The lamellar units consist of elastic fibers (Elastin), encompassing smooth muscle cells (VSMC) and extracellular matrix (ECM). From El-Hamamsy I, Yacoub MH, Nature Reviews Cardiology, 2009

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Mitral Valve The mitral valve is a complex apparatus consisting of annulus, orifice, leaflets, chordae tendineae, and papillary muscles (Fig.  3.15). Moreover, the left ventricular free wall, where the papillary muscles are implanted, should be regarded as an intrinsic part of the mitral valve apparatus. The origin of the name “mitral” is attributed to Andreas Vesalius, who, in De Humani Corporis Fabrica, published in 1543, stated “one could not inappropriately compare to a Bishop miter” (Fig. 3.16). (a) The mitral annulus is an atrioventricular circular fibrous structure where both left atrial and left ventricular myocardial free wall are attached (Fig. 3.17). It represents a barrier preventing electrical connection between the atria and ventricles, aside the specialized atrioventricular conduction system of Tawara. An evident fibrous annulus is present only at the attachment of the posterior (mural) leaflet of the mitral valve, while the anterior leaflet is in fibrous continuity with the posterior noncoronary cusp of the aortic valve and with the right and left fibrous trigons (Fig.  3.18). The fibrous mitral annulus is thicker than that of the tricuspid valve. Whereas tricuspid valve regurgitation increases with the progressive rise of the pulmonary arterial pressure, this phenomenon does not occur in the left side where myocardial hypertrophy, secondary to systemic hypertension, reinforces the sphincteric contraction at the annulus, maintaining mitral valve competence. (b) The mitral orifice is the passage of blood between the leaflets, which opens during ventricular diastole with atrial systole and closes during ventricular systole and atrial diastole. The nearing of the leaflets during ventricular systole contributes to the closure of the orifice, by 20% of which is ascribable to a sphincteric contraction of the annulus (Fig. 3.19). Occlusion of the mitral Mitral Valve A. Anulus B. Orifice C. Leaflets D. Chordae tendineae E. Papillary muscles F. Left ventricle

Fig. 3.15  The mitral valve apparatus consists of leaflets, annulus, orifice, chordae tendineae, papillary muscles, and left ventricular wall (PM posteromedial; AL anterolateral)

...mitrae episcopali non admodum inepte contuleris....

Figure 9 Book VI

One could not inappropriately compare [these membranes] to a Bishop miter

Andreas Vesalius, De Humani corporis fabrica, 1543, Book VI, Chapter XIII (De undecim membranulis quatuor orificiorum cordis – The 11 membranes of the heart’s four orifices), p. 592.

Fig. 3.16  Picture from the book of Andreas Vesalius: the name “mitral” derives from the bishop’s miter

orifice may occur in peculiar situations as in case of ball thrombus or a myxoma in the left atrium (see mitral pathology). (c) Leaflets: Basically there are two leaflets, one anterior and one posterior (Fig. 3.20). This is the reason why the mitral valve is considered “bicuspid” when compared to the “tricuspid” right atrioventricular valve. However, the posterior (mural) leaflet generally shows three scallops, so the mitral valve should be considered as a quadricuspid structure. The three scallops are particularly evident in mitral valve prolapse (see pathology of mitral valve chapter). The anterior leaflet is deep and narrow, whereas the posterior one is large and less deep, in so far as the area of the two is equal, which means that they equally share the closure of the orifice during ventricular systole (Fig. 3.20). Both anterior and posterior leaflets show a rough zone on their ventricular side where second-order chordae tendineae insert (Figs. 3.18 and 3.20). (d) Chordae tendineae: These are fibrous tendons that arise from the top of the papillary muscles, branch twice, and reach the leaflets to ensure the excursion and an adequate approximation during ventricular systole. The classification of Roberts-Perloff is perhaps the most useful from the pathophysiological view point; 20 to 25 chordae tendineae (“first-order” chordae) take origin from the top of the papillary muscles, divide in “second-­order,” and finally attach to the leaflets in the “third order” chordae (Fig. 3.21). Another classification refers to the site where the chordae tendineae connect to the leaflets: “first-order” chordae insert into the free margin, “second-order” into

16 Fig. 3.17  A ring of the mitral valve (a) does exist only in correspondence of the posterolateral (mural) leaflet (b)

Fig. 3.18  The mitral valve belongs to the left ventricle, without any relationship with the ventricular septum (a). Schematic representation (b)

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b

a

a

b

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Fig. 3.19  The sphincteric contraction of the annulus (a) contributes by 20% of the orifice closure during ventricular systole (b)

a

b

a

b

Fig. 3.21 Roberts-Perloff classification of the chordae tendineae according to branching

Fig. 3.20  The shape of the mitral leaflets (a) is different; however, the size is equal (b). A, P = anterior, posterior leaflets. AL, PM = anterior and posterior papillary muscle

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the rough zone on the ventricular side of the leaflet, 1–2 centimeters from the free margin (Fig. 3.22). Among the “second-order” chordae to the anterior leaflet, there are long thick tendons (“strut chordae”), playing the important role to cope with the systolic strain (Fig.  3.23). “Third-order” chordae tendineae are present in the posterior leaflet, arising from minute papillary muscles or directly from the endocardium to insert to the basal part of the leaflet, quite close to the annulus (Fig. 3.22).

Fig. 3.22  View of the various orders of chordae tendineae according to the site of insertion: 1 = first order, free margin; 2 = second order, rough zone; 3 = third order, base of the mural, posterolateral fibrous ring

Fig. 3.23 (a) View of the mitral valve and left ventricle. (b) Note a strut chorda to the anterior leaflet and mitro-­ aortic fibrous continuity. Ao = aorta; cf = fibrous continuity; A = anterior leaflet; P = posterior leaflet; * = strut chordae

a

“First-order” chordae inserting at the commissures exhibit a peculiar shape (“fan-like chordae”) (Fig. 3.24). At histology, the leaflets show three layers (Fig. 3.25): (a) A thick fibrosa, facing the ventricle and made by collagen bundles. The chordae tendineae insert directly to the cusp fibrosa and are also made exclusively by collagen (Fig. 3.26). (b) A thin auricularis consisting of a fibroelastic component. (c) A spongiosa in between, made by extracellular matrix, mostly ground substance. (e) Papillary muscles: There are two main papillary muscles of the mitral valve—the anterolateral and the posteromedial (Fig. 3.20). They arise from the free wall of the left ventricle without any relationship with the ventricular septum (Fig. 3.18). The anterolateral is a single pillar, giving origin to chordae tendineae for both the leaflets. The posteromedial consists of a group of stems (Fig. 3.17), from which originate several chordae including “fan-like” chordae inserting into the commissures of the scallops (Fig. 3.20). Blood supply to the anterolateral papillary muscle is provided by a diagonal branch of the anterior descending coronary artery. The posteroseptal group of papillary muscles are perfused by the dominant coronary artery, most frequently by the right coronary or the left circumflex.

b

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a

b

Fig. 3.24  Fan-like commissural chordae, all attaching to the free margin (“first order”)

a

b

Fig. 3.25  The three layers of an av valve leaflet: a thick fibrosa (collagen), facing the ventricle, a thin fibroelastic fascicular facing the atrium, and a spongiosa in between (consisting of ground substance). Note the chordae tendineae attaching to the fibrosa. (a) Azan Mallory stain, (b) Weigert-Van Gieson stain

Fig. 3.26  The chordae tendineae consists of collagen fibers and connect with the fibrosa. (a) Azan Mallory stain, (b) Weigert-Van Gieson stain

Tricuspid Valve Moreover, the right atrioventricular valve is a ventricular structure, consisting of three leaflets (“tricuspid”) (septal, anterior, and posterior), orifice, annulus, chordae tendineae, papillary muscles, and ventricular wall as a platform of papillary muscles attached to the right ventricular free wall and septum (Figs. 3.27 and 3.28). The fibrous annulus separates the right atrium from the right ventricle. The right ventricular free wall is thinner than that of the left ventricle (Fig. 3.28). This explains why tricuspid valve incompetence occurs frequently in pulmonary hypertension as a consequence of annular dilatation. In addition, the degree of sphincteric contraction of the tricuspid annulus is much less than that of the mitral valve, being the atrial and ventricular walls thinner than the left-sided structures (Fig. 3.29). Unlike the mitral valve, the tricuspid valve is attached with its septal leaflet to the ventricular septum (Figs. 3.28, 3.30 and 3.31). Moreover, the moderator band joins the septomarginal trabecula to the anterior papillary muscle (Fig. 3.32). The septal leaflet is attached to the septum by small papillary muscles or directly through chordae tendineae (Figs. 3.28, 3.30 and 3.31) and to the septal annulus of the

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a

b

LPM APM IPM

Fig. 3.27  Open tricuspid valve (a). Unlike mitral valve, the septal leaflet of tricuspid valve is attached to the ventricular septum by small papillary muscles or directly by chordae tendineae (b). APM anterior papillary muscle; IPM inferior papillary muscle; LPM Lancisi papillary muscle Fig. 3.28  Comparison of right (a) vs left (b) atrioventricular ring. The right one is tiny. Note also that the right ventricular mass attaching to the av ring is thinner than the left one

atrioventricular junction, from the anteroseptal to the posteroseptal commissures (Fig. 3.27). The former is just close of the membranous septum (Fig. 3.28) and consists of fan-­ like chordae tendineae originating from the conal (“Lancisi”) papillary muscle which is implanted on the pulmonary infundibulum (Fig. 3.32). The posteroseptal commissure is marked by chordae tendineae originating from a group of posterior papillary muscles (Figs. 3.27 and 3.31). The anterior tricuspid leaflet is a large curtain from the anteroseptal to the anteroposterior commissures. The anterior papillary muscle is a big pillar from the top of which chordae tendineae arise connecting by branching both anterior and posterior leaflets, the base of which is attached to the atrioventricular ring of the anterior free wall (Figs. 3.32 and 3.33). Roughly, by external view the acute margin of the heart corresponds to the commissure in between the anterior and posterior leaflets (anteroposterior commissure of the tricuspid valve) (Fig. 3.31). Moreover, the tricuspid valve commissures are the confluence between the leaflets where the distance from the atrioventricular ring is shorter. Usually, the cusps show continuity with the exception of the anteroseptal commissure where discontinuity is observed in 10–20% of cases (Fig. 3.31). In

Right AV Ring

a

Left AV Ring

b

3  Anatomy of Native Heart Valves Fig. 3.29 (a) Right side of the ventricular septum, to which the septal leaflet of the tricuspid valve is directly attached. (b) Drawing of the trabecula septomarginalis (TSM) connected to the anterior papillary muscle by moderator band

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a

b

Fig. 3.30  Open right ventricle and view of the tricuspid valve with anterior, septal, and posterior leaflets. Note fan-like chordae, arising from the conal (“Lancisi”) muscle and branching to the anteroseptal commissure. The septal leaflet is split in correspondence of the membranous septum

Fig. 3.31  View of the pulmonary infundibulum (right ventricular outflow track) with the anterior leaflet of the tricuspid valve and marginal band linking the trabecula septomarginalis to the anterior papillary muscle

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At histology, the leaflets, like those of the mitral valve, show three layers: a thick fibrosa, made by collagen bundles and facing the right ventricle, to which the chordae tendineae are connected and made of collagen bundles; a thin auricularis facing the atrium and consisting of fibro-elastic fibers; and a spongiosa in between, mostly made by ground substance extracellular matrix.

Pulmonary Valve Similar to the aortic valve, the pulmonary valve apparatus also consists of cusps, commissures, interleaflet triangles, and pulmonary artery (Fig.  3.34). The pulmonary valve has three cusps: two posterior, facing the aortic root, and one anterior. The shape of the cusps is semilunar with a swallow nest shape. The pulmonary valve differs from the aortic one for several structural features:

Fig. 3.32  View of conal (“Lancisi”) muscle, trabecula septomarginalis, anterior papillary muscle, and anterior leaflet of the tricuspid valve

(a) The pulmonary artery is anterior and it takes origin from the right ventricle. (b) There are no coronary ostia. (c) All the cusps lie over the infundibular myocardium. At variance with the mitral valve, no fibrous continuity exists between the anterior tricuspid leaflet and the posterior pulmonary right semilunar cusp, since the crista superventricularis is wedged between the tricuspid and pulmonary valves (Figs. 3.35, 3.36 and 3.37).

Fig. 3.33  The close relationship between the His bundle, membranous septum, and anteroseptal commissure of the tricuspid valve

the latter condition, the underlying membranous septum appears bare on the posteroinferior aspect where the His bundle runs (Fig. 3.33). The chordae tendineae of the tricuspid valve do not differ from those of the mitral valve, including the presence of fan-­ like chordae at the commissural level (Fig. 3.31).

Fig. 3.34  Normal pulmonary valve with three semilunar, swallow nest-like cusps. The pulmonary artery arises from the ventricular outflow tract (pulmonary infundibulum). Note the crista supraventricularis separating tricuspid and pulmonary valves. Look at the conal (“Lancisi”) papillary muscle

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Fig. 3.35  The pulmonary valve seen from below. (a) It lies over the ventricular myocardium, at difference from the aortic valve (b), which is in fibrous continuity with the anterior leaflet of the mitral valve

a

Fig. 3.36 Comparison between right (a) and left (b) ventricular outflows. Unlike anterior leaflet of the mitral valve, which is in fibrous continuity with the aortic valve (b), the anterior leaflet of the tricuspid valve shows muscular discontinuity with the pulmonary valve, because of crista supraventricularis (a)

a

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Fig. 3.37  Diagram representing the right-sided ventricular septum with the septomarginal trabecula, branching in two parts to wedge the crista supraventricularis

(d) With the fall of pulmonary arterial pressure after birth, the pulmonary artery wall loses progressively elastic lamellar units becoming flattened like a vein, as to be called in the past “arteria venosa.” To all effects, during fetal life with the patency of the ductus arteriosus, the pulmonary artery behaves like a second aorta.

Fig. 3.38  Transducer position (subxiphoid, apical, parasternal long axis) (illustration by Anna Rambaldo)

Echo Transthoracic View Tomographic cross sections of transthoracic two-­dimensional echo include long- and short-axis parasternal views and fourto five-chamber apical views (Figs. 3.38 and 3.39). They are an excellent, noninvasive scan of cardiac valves. The long-axis parasternal view beautifully explores both inflow and outflow of the left ventricle, including aortic and mitral valves with the entire apparatus (leaflets, chordae tendineae, and papillary muscles). In addition, the pulmonary infundibulum is well visible (Fig. 3.40). The short-axis parasternal tomographic sections may scan the heart from apex to base including cross sections of both ventricles and the apparatus of both atrioventricular valves (Figs. 3.41 and 3.42). The parasternal short axis at the base of the heart beautifully discloses the aortic root, the pulmonary artery, and its bifurcation (Fig. 3.43). The apical four-chamber view in longitudinal tomographic section allows to see both ventricles and atria, with the corresponding atrioventricular valves (Figs. 3.44 and 3.45).

Fig. 3.39  Diagram with multiple tomographic sections (illustration by Anna Rambaldo)

3  Anatomy of Native Heart Valves

Diagram of long axis view

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Parasternal long axis view

Anatomical specimen with long axis view

Fig. 3.40  Parasternal long-axis view left atrium, inflow and outflow left ventricle, aorta and pulmonary infundibulum. AA ascending aorta, LV left ventricle, RV right ventricle, LA left atrium, MV mitral valve

Diagram

Short axis view at the mid ventricular section

Anatomical specimen

Fig. 3.41  Parasternal short-axis view. Midventricular section with left and right ventricles, mitral and tricuspid valves. LV left ventricle; RV right ventricle

Diagram of parasternal short axis

View at the papillary muscle level

Anatomical specimen of short axis view

Fig. 3.42  Apical short axis, showing the papillary muscles of the mitral valve. IVS  =  interventricular septum; LV left ventricle; RV right ventricle

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Diagram of short axis view

Parasternal short axis

Anatomical specimen

Fig. 3.43  Parasternal short axis at the level of the great arteries’ root. Note the semilunar aortic valve and pulmonary artery bifurcation. AV anterior valve; LA left atrium; PA pulmonary artery; RA right atrium; RV right ventricle

Diagram

Apical four chamber view

Anatomical specimen

Fig. 3.44  Apical four-chamber tomographic section. LA left atrium; LV left ventricle; MV mitral valve; RA right atrium; RV right ventricle; TV tricuspid valve

By slightly enhancing the transducer, a five-chamber view may be obtained, namely, the four cardiac chambers plus the left ventricular outflow tract up to the ascending aorta (Fig. 3.46).

Moreover, from the apical longitudinal approach, a two-­ chamber view (left atrium, mitral valve, left ventricle) may be achieved (Fig. 3.47).

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Fig. 3.45  Other apical four-chamber tomographic section. LA left atrium; LV left ventricle; RA right atrium; RV right ventricle

Fig. 3.46  Five-chamber apical tomographic section

Fig. 3.47  Apical tomographic section with two-chamber view. LA left atrium; LAA left atrial appendages; LV left ventricle; MV mitral valve

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Conduction System The atrioventricular (AV) conduction system, discovered by Tawara (Fig. 3.48), is in close proximity to the cardiac valves. The AV node is located inside the triangle of Koch, consisting of the following sides: the tendon of Todaro (within the crista dividens), the fibrous annulus of the septal tricuspid valve leaflet, and the ostium of the coronary sinus (Fig. 3.49). The AV node is a right-sided structure of the atrial septum which lies just above the septal leaflet of the tricuspid valve (Fig. 3.50). The His bundle penetrates the central fibrous body (Fig. 3.51) and runs underneath the membranous septum, on the crest of the ventricular septum, just in front of the anteroseptal commissure of the tricuspid valve (Fig. 3.52); then, it bifurcates upon the crest of the ventricular septum, dividing into right and left branches (Fig. 3.52). The sinoatrial node is located at the junction of the superior vena cava and right atrium, quite far from the AV valves and the aortic root. The pulmonary and mitral valves do not have a relation with the AV conduction system in the normal heart.

Membranous septum

Right coronary aortic leaflet

Left bundle branch

Fig. 3.48  The av conduction system, discovered by Tawara, seen from the left ventricle

Cardiovascular Pathology, University of -Italy Padua

Fig. 3.49  The triangle of Koch: the av node is located in front of the ostium of the coronary sinus. The His bundle penetrates the central fibrous body and runs underneath the transilluminated membranous septum

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Fig. 3.50  The av node is located on the right side of the central fibrous body, below the endocardium of the atrial septum. It is quite far from the mitral valve, just over the tricuspid septal leaflet (a). Panoramic view and (b) closeup of the av node

a

Fig. 3.51 (a) The His bundle penetrates the central fibrous body from the right side, far from the mitral valve. (b) Common His bundle on the right side of the atrial septum, fully surrounded by the collagen of the central fibrous body, close to the septal leaflet of the tricuspid valve

a

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Fig. 3.52  Relationship of the conduction system with the aortic and tricuspid valve. (a) The His bundle runs and bifurcates under the membranous septum (transilluminated), in correspondence to the anteroseptal commissure of the tricuspid valve. (b) The His bundle is just below (4–5 mm) the commissure between the aortic right and posterior noncoronary semilunar cusps of the aorta

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Further Reading Anderson RH, Becker AE.  Cardiac anatomy. An integrated text and color atlas. Edinburgh: Grover Medical Publishing, Churchill Livingstone; 1986. Anderson RH, Yen HS. The anatomy of the heart. Cordis International SA Training & Development; 1995. Ho SY. Anatomy of the mitral valve. Heart. 2002 Nov;88(Suppl 4):iv5– 10, 5iv. Pistolesi GF, Thiene G, Casolo F.  L’imaging diagnostico del cuore. Cittadella: Edizioni libreria Cortina Verona; 1985. Rajamannan NM.  Cardiac valvular medicine. Chap. 19. London: Springer-Verlag; 2012. Taramasso M, Pozzoli A, Basso C, Thiene G, Denti P, Kuwata S, Nietlispach F, Alfieri O, Hahn RT, Nickenig G, Schofer J, Leon MB, Reisman M, Maisano F. Compare and contrast tricuspid and mitral valve anatomy: interventional perspectives for transcatheter tricuspid valve therapies. EuroIntervention. 2018;13(16):1889–98.

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Non Infections Pathology of Native Heart Valves Cristina Basso and Gaetano Thiene

Aortic Valve Rhe

Rheumatic Valve Disease

C. Basso · G. Thiene (*) Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padua Medical School, and Cardiovascular Pathology Unit, University Hospital of Padua, Padua, Italy e-mail: [email protected]; [email protected]

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ase

Incidence

Rheumatic valve disease is still the leading cause of aortic valve disease in developing countries, while it is declining in the Western world in favor of degenerative forms (Fig. 4.1). The acute rheumatic valvulitis consists of noninfective small vegetations (verrucae) arising on the contact border of the cusps. The acute inflammation consists of a granulomatous phenomenon including “owl” cells (Aschoff) and “spider cells” (Aničkov), without perforation or fraying of the leaflets. The organization of such vegetations leads to cusp fibrous thickening and retraction (Fig. 4.2) with commissural fusion (Fig.  4.3), a feature which is considered pathognomonic of the disease. In the chronic stage, presence of vascularization at histology is the marker of previous rheumatic valvulitis (Fig. 4.2), since normal valves are not vascularized. Calcification of the cusps is another consequence of rheumatic valve disease (Fig. 4.4). As far as the pathophysiologic consequence, aortic stenosis occurs when commissural fusion predominates (Fig. 4.3), whereas incompetence originates when cusp retraction prevails (Fig. 4.2). The combination of the two (commissural fusion and cusp retraction) accounts for aortic steno-incompetence. Chronic regurgitation leads to traumatic reaction of the subaortic septal endocardium with swallow nest formation, which is considered a pathognomonic gross hallmark of rheumatic aortic valve incompetence. Nowadays, valve disease due to primary dystrophic calcification is by far the main cause of aortic stenosis (Fig. 4.4).

uma

ase e valve dise Degenerativ disease g valve Emergin Time

Fig. 4.1  The diagram shows the decline of rheumatic valve pathology and the increase of degenerative one, as current trend of aortic valve disease in the developed countries

It is easily distinguishable from rheumatic stenosis, because of coarse intrinsic calcific deposits in the absence commissural fusion. The calcium deposits may be so exuberant to appear as nodular cauliflower-like excrescences (Figs.  4.5 and 4.6). Calcification may involve the membranous septum and the His bundle bifurcation, with onset of AV block. The dystrophic calcific phenomenon of the aortic valve is frequently associated with calcification of the mitral ring (Fig. 4.5) and atherosclerotic disease of the aorta (Fig. 4.6). Aortic valve stenosis implies systolic overload with ventricular hypertrophy (Fig.  4.7) and myocardial blood flow discrepancy, even in the absence of obstructive coronary artery disease. It is the cause of subendocardial myocardial ischemia, with myocytolysis and fibrosis (Fig. 4.8). The term atherosclerotic aortic stenosis was used in the past; however, atheromasia of the aortic cusps is rare. Another frequent cause of calcific aortic stenosis is the bicuspid aortic valve, a congenital defect silent until adult-

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 G. Thiene et al. (eds.), Pathology of Cardiac Valve Disease, https://doi.org/10.1007/978-3-031-35498-4_4

31

32 Fig. 4.2 (a) Drawing normal aortic valve. (b) Drawing rheumatic aortic incompetence. (c) Rheumatic aortic valve incompetence: note the thickened and retracted cusps (d) vascularization at histology

Fig. 4.3  Rheumatic aortic stenosis with commissural fusion. (a) Drawing. (b) Surgical pathology specimen

a

C. Basso and G. Thiene

a

c

b

d

a

b

b

c

Fig. 4.4  Senile aortic stenosis by dystrophic calcification (a). Note the absence of commissural fusion (b). The histology shows nodular intrinsic calcification, in the absence of inflammation or neovascularization (c)

4  Non Infections Pathology of Native Heart Valves Fig. 4.5  Senile aortic valve stenosis (a) associated with dystrophic calcification of the mitral annulus (b)

33

a

a

b

b

c

Fig. 4.6  Senile aortic valve stenosis by dystrophic calcification (a) associated with severe atherosclerosis of the aorta (b). Close-up (c)

Fig. 4.7  Senile aortic valve stenosis (a) with concentric left ventricular hypertrophy (b)

a

b

34

a

C. Basso and G. Thiene Surgical pathology of 181 consecutive stenotic aortic valves 110 M, 71 F, mean age 71 ± 9 15%

22% 63% TAV

b

BAV

RVD

Fig. 4.9  Nowadays, the prevalent aortic valve stenosis is dystrophic senile calcification of a tricuspid aortic valve (TAV tricuspid aortic valve; BAV bicuspid aortic valve; RVD rheumatic valve disease)

Fig. 4.8  Subendocardial ischemic injury with replacement type fibrosis (a) and myocytolysis (b)

hood (Fig. 4.9). It becomes manifest about 10 years earlier than the senile tricuspid aortic stenosis. The pathogenesis is probably similar, namely, chronic mechanical stress on a normal (tricuspid) and abnormal (bicuspid) aortic valve (Fig. 4.10).

Fig. 4.10  Aortic stenosis by bicuspid valve with dystrophic calcification and a raphe

4  Non Infections Pathology of Native Heart Valves

Other Causes of Aortic Valve Incompetence Aortic valve incompetence may occur even in the setting of normal aortic cusps, when the sinus portion of the ascending aorta enlarges because of aortopathy (Figs.  4.11 and 4.12). The latter, first reported by Corrigan from Dublin in the famous article “Permanent patency of the mouth of the aorta” (Fig. 4.13), is another cause of aortic valve incompetence following rheumatic (Fig. 4.2), infective endocarditis (Fig. 4.14) and syphilis (Fig. 4.15). The free margin of the cusps appears thickened with a “drum stick” appearance (Fig. 4.16). The tunica media of the aorta shows cystic medionecrosis with loss of smooth muscle cells and elastic fragmentation of the lamellar units (Figs. 4.16 and 4.17).

Fig. 4.11  Aortic valve incompetence due to dilatation of the sinusal portion of the ascending aorta and enlarged annulus. (a) drawing; (b) autopsy specimen

a

35

Aortic valve incompetence may be associated with bicuspid aortic valve in the setting of aortopathy, with dilatation of the sinusal part of the ascending aorta and the aortic annulus. Strands (“chordae tendineae”) attached to the commissural raphe of a bicuspid aortic valve may suddenly rupture and account for abrupt aortic incompetence with pulmonary edema (Fig. 4.18). Downward extension of acute aortic dissection may cause aortic incompetence because of commissural detachment (Fig. 4.19). Overall, according to surgical pathology experience, degenerative aortopathy is becoming the prevalent cause of aortic valve regurgitation (Fig. 4.20).

b

36 Fig. 4.12 Aortic incompetence because of aortopathy and dilatation of both sinusal and ascending aorta: angiography (a); the same, viewed at surgery (b)

C. Basso and G. Thiene

a

Fig. 4.13  Corrigan, the discoverer of aortic incompetence with normal semilunar cusps and dilatation of the ascending aorta due to aortopathy

b

4  Non Infections Pathology of Native Heart Valves Fig. 4.14 Aortic incompetence due to infective endocarditis with cusp disruption. (a) drawing; (b) autopsy specimen

a

Fig. 4.15 Aortic incompetence because of syphilis of the ascending aorta. Note the paved intima (a) and the pathognomonic histologic landmark of plasma cell vasculitis of the vasa vasorum in the adventitia (b). (c) Immunohistochemistry CD38

a

37

b

b

c

38

C. Basso and G. Thiene

a

c

b

d

Fig. 4.16  Aortic incompetence by aortopathy. The cusps are normal (a), with a drum stick feature (b). The aortic tunica media shows elastic fragmentation (c) and cystic medial necrosis (d)

Fig. 4.17  Aortic valve incompetence due to aortopathy of the ascending aorta. Note the dilatation of the sinusal aorta at angiography (a) and loss of elastic lamellar units in the aortic wall (b)

a

b

4  Non Infections Pathology of Native Heart Valves

39

Fig. 4.18  Sudden rupture of an aortic valve strand (“chorda tendinea”), detached from a raphe in bicuspid aortic valve

a

b

c

Fig. 4.19  Drawings of aortic dissection with detachment of the valve commissures by downward extension of the dissection (a), with aortic incompetence (b, c)

C. Basso and G. Thiene

40

Etiology of Aortic Regurgitation Surgical Pathology Studies Author, Year

Country

Olsen et al., 1984

USA

Guiney et al., 1987

RHD %

Deg. %

I.E. %

BAV %

Others %

225

46

21

9

20

4

UK

72

26

34

21

9

10

Italy

254

20

59

11

7

3

France

313

38

35

11

5

11

Turri et al., 1990 Michel et al., 1991

N.

a

Fig. 4.20  Prevalence of aortic valve incompetence due to aortopathy, from different surgical pathology experiences. BAV bicuspid aortic valve; Deg degeneration disease; I.E. infective endocarditis; RHD rheumatic disease

b

Mitral Valve Acquired mitral valve disease may be classified as inflammatory, degenerative, ischemic, neoplastic, toxic, traumatic, and functional (secondary).

Inflammatory Disease Rheumatic valve disease has been the leading cause of mitral valve disease worldwide and is currently confined to third-­ world countries. It is the consequence of an autoimmune phenomenon, due to streptococcal pharyngitis. Rheumatic valvulitis affects first the mitral valve with aseptic verrucae (Fig. 4.21), granulomatous inflammation including Aschoff and Aničkov (“owl” and “spider”) cells, in the absence of any disrupting lesions like cusp perforation or chordal rupture. The healing process determines valve remodeling with stenosis by cuspal thickening, commissural fusion, and calcific deposits with intact chordae (valvular stenosis) (Figs. 4.22, 4.23 and 4.24) or with chordal fusion, disappearance, of interchordal spaces and fusion of papillary muscles with the leaflets (subvalvular stenosis) (Figs. 4.25 and 4.26). Both recurrent valvulitis and organization of thrombus formation at the commissures account for disease progression (Fig. 4.27). Histology reveals fibrosis and neovascularization due to previous valvulitis (Fig. 4.28). Atrial enlargement with thrombus formation, either within the left atrial appendage or a free-floating ball, source of systemic emboli (“embolizing rheumatic mitral stenosis”), is a regular occurrence (Figs. 4.29 and 4.30).

Fig. 4.21 (a) Rheumatic valvulitis of the mitral valve with sterile verrucae. (b) Histology

Splitting of fused commissures, accomplished surgically by a finger, represented historically a mode of palliative relief of rheumatic mitral stenosis, currently replaced by the use of transcatheter ballooning in selected cases (Fig. 4.31). However, all these closed-chest and blind procedures imply the risk of valve apparatus disruption (Fig. 4.32). Pure rheumatic valve incompetence is rare and consists of chordal and cusp retraction in the absence of commissural fusion, with the mitral orifice remaining patent during ventricular systole (Figs. 4.33 and 4.34). Mitral steno-incompetence is the most frequent disease as the consequence of post-rheumatic mitral valve remodeling. Mitral valve involvement by Libman-Sacks endocarditis in lupus erythematosus or phospholipid syndrome consists also of sterile verrucae, quite similar to those of rheumatic disease albeit without the histological hallmark of granulomatous inflammation. Also in this setting, the sequelae of the healing process may account for valve deformity and valve dysfunction.

4  Non Infections Pathology of Native Heart Valves

41

Fig. 4.23  Rheumatic mitral stenosis in an autopsy specimen: note the fusion of the commissures and thrombosis

Fig. 4.22  Schematic representation of rheumatic mitral stenosis by commissural fusion with cusp calcification

Fig. 4.24  Surgical specimen of mitral rheumatic stenosis, view from left atrial and ventricular sides: note the valve thickening and commissural fusion (a), with normal subvalvular apparatus (b)

a

Fig. 4.25 Subvalvular rheumatic stenosis: fusion of the chordae tendineae and commissures, with valve thickening. a = drawing, (b) specimen

a

b

b

42

C. Basso and G. Thiene

a

b

Fig. 4.26  Autopsy specimen with subvalvular rheumatic mitral stenosis (ventricular view): note the fused chordae with disappearance of interchordal spaces

Fig. 4.27  Rheumatic mitral stenosis with left atrial enlargement and valve thrombosis (a). Histology of a commissure with thrombus deposition which contributes to progression of commissural fusion (b)

Fig. 4.28  The histological hallmark of chronic rheumatic valve disease is neovascularization

4  Non Infections Pathology of Native Heart Valves Fig. 4.29  Rheumatic mitral stenosis: (a) thrombosis of the left atrial appendage and (b) free-floating ball thrombus

a

Fig. 4.30  Rheumatic mitral stenosis with thrombi in the left atrial appendage and free-floating ball thrombus inside a huge dilatation of the left atrium

43

b

44 Fig. 4.31 Balloon intervention (a) splitting the fused mitral commissures (b)

C. Basso and G. Thiene

a

b

Fig. 4.32  Ballooning split of commissural fusion in mitral stenosis, complicated by valve disruption with chordal rupture Fig. 4.33  Surgical specimen of rheumatic mitral incompetence. Note the retracted cusps and chordae tendineae

4  Non Infections Pathology of Native Heart Valves Fig. 4.34  Rheumatic mitral incompetence. (a) Drawing, (b) autopsy specimen with wide orifice by retracted cusps, (c) neovascularization at histology

a

45

b

c

Degenerative Disease

Ischemic Disease

Mitral valve prolapse is currently the hallmark of the leading degenerative disease, accounting for 2/3 of cases of mitral incompetence. It consists of ballooning and “billowing” of cusps and scallops, prolapsing into the atrial cavity during systole and resulting in various degrees of valve incompetence (Figs. 4.35, 4.36, 4.37 and 4.38). At histology the cusp fibrosa appears infiltrated by myxoid tissue with loss of collagen fibers (Fig. 4.39). The chordae tendineae may also show myxoid degeneration. They progressively elongate and break suddenly, with acute valve incompetence (Figs.  4.40, 4.41 and 4.42) and lung edema, requiring emergency intervention (valve replacement or repair) (Fig. 4.43). The cause of progressive myxoid degeneration may be the chronic trauma of the leaflets, due to congenital defective disjunction of the posterior leaflet to the annulus. Congenital absence of third-order chordae tendineae has been postulated (Fig. 4.44). Mitral valve prolapse can be part of the phenotype expression of Marfan syndrome, associated with aneurysm of the ascending aorta and aortic incompetence (Fig.  4.45). However, non-Marfan mitral prolapse has not been proved to be a genetically determined valve disease.

Acute mitral incompetence with pulmonary edema may occur in the first week after myocardial infarction due to papillary muscle rupture (Figs. 4.46, 4.47 and 4.48), involving either the anterior (in the setting of an anteroseptal infarction) or the posterior papillary muscle (in the setting of a posterolateral infarction). Simultaneous rupture of both papillary muscles (Fig. 4.49) has never been reported before, to the best of our knowledge. The rupture may involve the whole pillar of the papillary muscle causing abrupt mitral regurgitation and pulmonary edema or only one head of the papillary muscle, with less severe mitral valve incompetence (Fig. 4.50). Post-necrotic scarring may cause retraction of a papillary muscle with chronic mitral valve incompetence (Figs. 4.50 and 4.51). A peculiar degenerative disease of the mitral valve apparatus is represented by dystrophic calcification of the annulus, at the insertion of the posterior leaflet (Fig. 4.52). Annular mineralization may be huge and soft (Fig. 4.53). The disease may lead to mitral regurgitation, since calcium deposits may hinder the annular sphincteric contraction.

46 Fig. 4.35  Mitral valve prolapse with ballooning of cusps—scallops and mild incompetence. (a) drawing, (b) view from the left atrium in an autopsy specimen

C. Basso and G. Thiene

a

b

Fig. 4.36  Much more severe ballooning of the cusps in mitral valve prolapse of an autopsy specimen Fig. 4.38 Schematic representation of progression of mitral valve prolapse up to clinical regurgitation and chordal rupture. LA left atrium; LV left ventricle

Fig. 4.37  Severe mitral incompetence with hooding and thickning of the leaflets–scallops in an autopsy specimen

Floppy mitral valve LA

LV

Billowing

Floppy

Prolapse

Floppy and flail

4  Non Infections Pathology of Native Heart Valves

47

a

b

Fig. 4.39  Histology of a prolapsing cusp: note the remarkable replacement of collagen bundles of the fibrosa by mucoid ground substance (a); closeup (b)

Fig. 4.40  Drawing of a chordal rupture in mitral valve prolapse (a). The mucoid degeneration involves the core of the chorda tendinea (b)

a

b

48

C. Basso and G. Thiene

Fig. 4.41  Mitral valve prolapse in an autopsy specimen of a patient died by acute pulmonary edema: note the chordal rupture of a prolapsed cusp

Fig. 4.43 (a) Chordal rupture of a prolapsing mitral valve, removed at surgery (surgical valve replacement). (b) Segmental resection of prolapsed cusp by chordal rupture (surgical valve repair)

a

Fig. 4.42  Mitral valve prolapse in another autopsy specimen: note the free-floating cusp due to chordae rupture

b

4  Non Infections Pathology of Native Heart Valves

49

a

Fig. 4.44  Third-order chordae tendineae: the missed development may compromise anchorage of the posterior leaflet of the mitral valve

b

a

Fig. 4.46  Postinfarction papillary muscle rupture in autopsy specimens. Rupture of the anterior (a) and posterior (b) papillary muscles

b a

Fig. 4.45  Aortic (a) and mitral (b) valves surgically removed in a patient with Marfan syndrome, who underwent to mitro-aortic valve replacement due to incompetence

b

Fig. 4.47  Schematic representation of postinfarction papillary muscle rupture (a). Surgical specimen of posterior mitral papillary muscle rupture (b)

50

C. Basso and G. Thiene

a

b

Fig. 4.48  Postinfarction rupture of the posteromedial papillary muscle of the mitral valve (a). Histology of the ruptured papillary muscle: note the diffuse myocytolysis (b)

Fig. 4.49  Myocardial infarction with contemporary rupture of both anterior and posterior papillary muscles of the mitral valve

4  Non Infections Pathology of Native Heart Valves

51

b

a

c

d

Fig. 4.50  Papillary muscle in chronic ischemic mitral valve incompetence. (a, c) Fibrosis and tethered posteromedial papillary muscle. (b, d) Rupture of the tip of the posteromedial papillary muscle

52

C. Basso and G. Thiene

a

b Fig. 4.51  Mitral incompetence due to tethered ischemic papillary muscle. (a) Regurgitation at echo doppler, (b) autopsy specimen of the same patient

Fig. 4.52  Mild calcification of the mitral ring with impaired sphincteric contraction and valve incompetence. (a) X-Ray, (b) gross view of the autopsy specimen, (c) histology of the mitral ring

a

b

c

4  Non Infections Pathology of Native Heart Valves

a

53

a

b b

Fig. 4.53  Huge, soft calcification of the mitral annulus in an autopsy specimen. (a) panoramic view, (b) closeup

“ Toxic” Disease (See Also Tricuspid Valve Pathology) Carcinoid valve disease usually spares the left side of the heart because serotonin is lysed while crossing the lung circulation, with the exception of a right-to-left shunt as in case of patent foramen ovale. However, exposure to drugs like ergotamine, methysergide, and fen-phen may involve the left heart valves. Cardiomyopathy Systolic motion of the anterior mitral leaflet accounts for the so-called systolic click in hypertrophic cardiomyopathy. Contact of the anterior leaflet with septal asymmetric hypertrophy leads to the onset of endocardial plaques as well as leaflet thickening contributing to mitral incompetence (Fig. 4.54).  unctional (“Secondary”) Chronic Mitral F Incompetence It refers to mitral incompetence in the setting of a normal mitral valve apparatus (leaflets, chordae tendineae, papillary muscles).

Fig. 4.54  Mitral valve incompetence in hypertrophic cardiomyopathy. (a) Drawing, (b) panoramic view: note the contact in between the anterior mitral leaflet and the ventricular septum, with endocardial fibrotic plaque

It may occur in dilated cardiomyopathy due to dilatation of the mitral annulus (Fig. 4.55a) and in ischemic heart disease when the papillary muscles are implanted into an area of previous myocardial infarction (Fig. 4.55b). Tethering of the mitral leaflets occurs in ventricular dysfunction by displaced papillary muscles (Fig. 4.56).

Traumatic Mitral Valve Incompetence Papillary muscle quite rarely may rupture following a blunt thoracic trauma.

Neoplastic Disease A huge left atrial myxoma may herniate into the mitral orifice, causing severe mitral stenosis and even occlusion (Fig. 4.57). It has been a cause of sudden death in the presurgical, angiographic, and echocardiographic era with cardiogenic shock and pulmonary edema (Fig. 4.58). In such cases, at surgical pathology or autopsy examination, the myxoma appears hanged with a circular sign of strangulation, because

54 Fig. 4.55  Functional mitral valve incompetence in dilated cardiomyopathy because of annular dilatation (a) and in postinfarction scarring, with remodeling of left ventricular cavity (b)

C. Basso and G. Thiene

a

b

Fig. 4.56  Schematic drawings of left ventricle cavity with a displaced papillary muscle and tethering. AO aorta; LA left atrium; LV left ventricle

Fig. 4.57  Left atrial myxoma with smooth muscle herniating into the mitral valve orifice. (a) 2D echo. (b) View of the specimen after successful surgical removal

a

b

4  Non Infections Pathology of Native Heart Valves

55

of the annular sphincteric contraction around it (Fig. 4.59). Since the risk of neoplastic or thrombotic embolism with stroke is high, left atrial myxomas should be removed surgically on an urgent/emergency basis. Before availability of echocardiography, 25% of surgically resected myxomas were incidentally found at surgery, with a clinical diagnosis of rheumatic mitral valve stenosis. Endocardial papillary fibroelastomas may grow up in the mitral apparatus and account for valve dysfunction (Fig. 4.60).

Fig. 4.58  Giant villous left atrial myxoma, with obstruction of the mitral valve orifice, cardiogenic shock, pulmonary edema, and death, occurred in pre echocardiography era

Fig. 4.59  Left atrial myxoma strangulated by sphincteric contracting of the mitral annulus. (a) echo and (b) surgical pathology view

a

b

56

a

C. Basso and G. Thiene

b

c

Fig. 4.60  Left ventricular papillary fibroelastoma (a) echo view; (b) gross appearance following surgical removal; (c) fibroelastic arborization at histology. LV left ventricle; RV right ventricle

Tricuspid Valve Acquired pathology of the tricuspid valve can be divided into primary (Table 4.1) and secondary:

“Primary” Rheumatic Tricuspid Valve Disease The tricuspid valve may be involved by rheumatic valvulitis, although much less frequently than mitral and aortic valves and never as an isolated form. Rheumatic abacterial verrucae are located in the contact borders of the leaflets, the site of traumatic endocardial erosion during systolic closure. Organization of valvulitis is similar to that occurring in the mitral valve: thickening and retraction of the leaflets with neovascularization, commissural fusion, shortening, and fusion of the chordae tendineae (Figs. 4.61 and 4.62) resulting in stenotic, steno-­incompetent, and incompetent tricuspid valve. Involvement of the tricuspid valve occurs in the setting of triple rheumatic valve disease (Fig. 4.63).

Table 4.1  Classification of acquired tricuspid valve diseases “Primary” structural tricuspid valve disease Congenital See chapter congenital valve disease Acquired Post-inflammatory • Rheumatic •  Infective endocarditis Carcinoid and carcinoid-like syndromes Traumatic Neoplastic

Carcinoid Valve Disease Carcinoid tumor of the small intestine, mostly the appendix, is an endocrine neoplasm secreting serotonin, 5-­ hydroxytryptophan, histamine, bradykinins, and prostaglandins (Table  4.2). in addition, tumor metastases to the liver via the portal vein may release toxic substances. Before reaching the lungs, these toxic agents cross the right cardiac chambers and damage the endocardium of right atrium, tricuspid valve, right ventricle, and pulmonary valve, which represent the target of their action as part of a carcinoid syndrome (Fig. 4.64).

4  Non Infections Pathology of Native Heart Valves

57

a

b Fig. 4.62  Severe rheumatic tricuspid valve disease with remarkable cusp thickening and fusion of the anteroseptal commissure

Fig. 4.63 Multivalvular rheumatic disease (a) mitro-aortic; (b) tricuspid Table 4.2  Toxic chemical agents secreted by carcinoid tumor, accounting for endocardium damage

Fig. 4.61 Rheumatic tricuspid valve disease. Note: commissural fusion, cusp thickening, and chordal retraction-fusion with steno-incompetence

The reaction of the involved structures is represented by smooth muscle cell proliferation with onset of endocardial plaques (Fig.  4.65) as well as thickening and retraction of tricuspid and pulmonary leaflets with valve incompetence. The damage occurs on the endocardium of the right-sided cavities (Fig.  4.65): the auricularis of the tricuspid leaflets (Fig.  4.66), the chordae tendineae, and the ventricularis of the pulmonary cusps (Fig. 4.67). If the metastases reach the lungs and the neoplastic tissue continues to secrete, the left-sided cardiac valves may also be involved, developing similar lesions. Serotonin-like drugs (ergotamine, methysergide, fenfluramine-phentermine) account for the so-called “fen-phen” phenomenon (Table 4.3).

Carcinoid disease Tumor products •  5-hydroxytryptamine (serotonin) • 5-hydroxytryptophan • Histamine • Bradykinins • Tachykinins • Prostaglandins

Ischemic Postinfarction rupture of a papillary muscle of the tricuspid valve occurs quite rarely. A healed posteroinferior myocardial infarction may retract the base of papillary muscles causing distortion of the valve apparatus with secondary incompetence (Fig. 4.68).

Traumatic Blunt chest traumas may cause rupture of a papillary muscle with tricuspid valve incompetence. The most vulnerable

C. Basso and G. Thiene

58

Fig. 4.66  Remarkable involvement of the tricuspid valve in carcinoid syndrome, with thickening and retraction of the leaflets as well as fused chordae tendineae with disappearance of interchordal spaces

Fig. 4.64  Carcinoid syndrome with schematic representation of heart involvement. CS coronary sinus; IVC inferior vena cava; LA left atrium; LV left ventricle; MV mitral valve; RA right atrium; RV right ventricle; SVC superior vena cava

Fig. 4.67  Histology of a carcinoid plaque of a semilunar pulmonary cusp on the side of fibrosa. Note also thickening around chordae tendineae of the tricuspid valve

Table 4.3  “Carcinoid-like” valvular disease exposure to serotoninlike drugs

Fig. 4.65 Carcinoid infundibulum

endocardial

plaque

in

the

pulmonary

“Carcinoid-like” Valvular disease Exposure to serotonin-like drugs • Ergotamine • Methysergide •  Fenfluramine-phentermine (“fen-phen” disease)

4  Non Infections Pathology of Native Heart Valves

59

a

b

c

d

Fig. 4.68 (a) Secondary tricuspid valve incompetence due to postinfarct ventricular dilatation and myocardial translucent scarring. (b) Arrhythmogenic right ventricular cardiomyopathy, with the pathognomonic transilluminated aneurysm of the posterior wall

structure is the tiny conal (Lancisi) papillary muscle (Fig.  4.69) accounting for acute tricuspid insufficiency, which is initially well tolerated, being often discovered late after the traumatic event, when signs of right heart failure appear.

Neoplastic Angiosarcoma of the heart usually arises at the level of right AV junction and invades the tricuspid valve orifice and apparatus with steno-incompetence (Fig. 4.70). Endocardial papillomas may grow upon the tricuspid valve leaflets (Fig. 4.71). These are benign tumors, at the risk of embolization, both neoplastic and thrombotic, the latter because of thrombus lining the surface. Since the embolus is of small size, the effect of a pulmonary infarct is negligible,

Fig. 4.69  Traumatic rupture of the conal (Lancisi) papillary muscle

60

C. Basso and G. Thiene

a

c

b

d

Fig. 4.70  Tricuspid valve incompetence by cardiac angiosarcoma with typical growth at the right av junction at echo (a). Endomyocardial biopsy immunohistochemistry stains in keeping with angiosarcoma (b, c, d) from Poletti et al., Cardiovascular Pathology 1991

unlike leiomyosarcoma of the pulmonary infundibulum, the size of which may simulate a massive pulmonary thromboembolism.

Secondary: “Functional” There are some acquired myocardial diseases which may cause tricuspid insufficiency due to tethering of a still intact valve apparatus. This is the case with healed right ventricular myocardial infarction (Fig. 4.68a) and arrhythmogenic cardiomyopathy (Fig. 4.68b).

Currently, the most frequent cause of functional tricuspid valve incompetence is pulmonary arterial hypertension, whether primary or secondary to chronic increase of left sided venous pressure like mitral valve disease or left ventricular failure. The reason why the right AV annulus dilates with enlargement of the tricuspid valve orifice is the existence of a tiny fibrous AV ring, much thinner than that of the mitral valve (Fig.  4.72). The more the pulmonary arterial hypertension, the more the tricuspid valve regurgitation.

4  Non Infections Pathology of Native Heart Valves Fig. 4.71 Endocardial fibroelastoma of the septal tricuspid valve leaflet at echo (a) and after surgical removal (b). AD right atrium; VD right ventricle; F fibroelastoma; VS left ventricle

Fig. 4.72 Comparison between gross (a) and histology (b) of right (tricuspid) and left (mitral) av rings: the right one is thinner. Myocardial ventricular mass attached to the annulus is less at tricuspid level, accounting for smaller sphincteric constriction

61

a

b

a

b

Right AV Ring

Left AV Ring

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Further Reading Anderson RH, Becker AE. The heart: structure in health and disease. London: Gower Medical Publishing; 1992. Basso C, Valente M, Thiene G. Cardiac tumor pathology. New York: Humana Press; 2013. Becker AE, Anderson RH.  Cardiac pathology: an integrated text and colour atlas. Hon Kong: Gower Medical Publishing; 1983. Buja LM, Butany J.  Cardiovascular pathology, 5th ed. Elsevier Academic Press; 2022. Burke A, Virmani R.  Atlas of tumor pathology. Tumors of the Heart and Great Vessels. Washington DC: Armed Forces Institute of Pathology; 1996. Davies MJ.  Colour atlas of cardiovascular pathology. 1st ed. United States: Harvey Miller Publishers–Oxford University Press; 1986. Edwards JE. Atlas of acquired diseases of the heart and great vessels, vol. 1. United States of America: Saunders; 1961a. Edwards JE. Atlas of acquired diseases of the heart and great vessels, vol. 2. United States of America: Saunders; 1961b. Edwards JE. Atlas of acquired diseases of the heart and great vessels, vol. 3. United States of America: Saunders; 1961c. Gallucci V, Bini RM, Thiene G.  Selected topics in cardiac surgery. Bologna: Pàtron Editore Bologna; 1980. Gould SE.  Patologia Del Cuore E Dei Vasi Sanguigni. Ed. italiana a cura di Cavallero C. Vol. 1. Padova: Piccin Editore; 1972a. Gould SE.  Patologia Del Cuore E Dei Vasi Sanguigni. Ed. italiana a cura di Cavallero C. Vol. 2. Padova: Piccin Editore; 1972b. Lucena JS, García-Pavía P, Suarez-Mier MP, Alonso-Pulpon LA.  Clinico-pathological atlas of cardiovascular pathology. Switzerland: Springer; 2015. Masson & Cie, Paris, Roth & Cie, Lausanne editors. Mahaim I.  Les Tumeurs et les polypes du Coeur. Etude anatomo-clinique. Lausanne. 1945;132(15):959.

C. Basso and G. Thiene McAllister HA, Fenoglio JJ.  Tumors of the cardiovascular system. (Atlas of Tumor Pathology, Second Series, Fascicle 15). Washington DC: Armed Forces Institute of Pathology; 1978. McManus BM (vol. editor). Braunwald E (Series editor). Atlas of cardiovascular pathology for the clinician, 2nd edition. Springer: China; 2008. Pomerance A, Davies MJ, editors. The pathology of the heart. Great Britain: Blackwell Scientific Publications; 1975. Romero JL, Garcia-Pavia P, Suarez-Mier MP, Alonso-Pulpon L, editors. Atlas clínico-patológico de enfermedades cardiovasculares. Barcelona: Esmon Publicidad; 2013. Schoen FJ.  Interventional and surgical cardiovascular pathology. Clinical correlations and basic principles. United States of America: Saunders; 1989. Shenasa M, Hindricks G, Callans DJ, Miller JM, Josephson ME, editors. Cardiac Mapping. 5th ed. John Wiley & Sons Ltd; 2019. Silver MD, editor. Cardiovascular pathology, vol. I. 2nd ed. United Stated of America: Churchill Livingstone; 1991a. Silver MD, editor. Cardiovascular pathology, vol. II. 2nd ed. United Stated of America: Churchill Livingstone; 1991b. Silver MD, Gotlieb AI, Schoen FJ, editors. Cardiovascular pathology. 3rd ed. New York: Churchill Livingstone; 2001. Silver MD. Cardiovascular pathology, vol. 1. United Stated of America: Churchill Livingstone; 1983a. Silver MD. Cardiovascular pathology, vol. 2. United Stated of America: Churchill Livingstone; 1983b. Silver MD. Patologia Cardiovascolare, 2° edizione. Vol 1. Ed. italiana a cura di Baroldi G, Gallo P, Thiene G. Padova: McGraw-Hill; 1994. Silver MD. Patologia Cardiovascolare, 2° edizione. Vol 2. Ed. italiana a cura di Baroldi G, Gallo P, Thiene G. Padova: McGraw-Hill; 1994. Virmani R, Atkinson JB, Fenoglio JJ. Cardiovascular pathology. United States of America: Saunders; 1991. Virmani R, Burke A, Farb A. Atlas of cardiovascular pathology. United States of America: Saunders; 1996.

5

Congenital Anomalies of the Cardiac Valves Carla Frescura and Gaetano Thiene

Mitral Valve The congenital malformations of the mitral valve can affect the mitral leaflets and/or the subvalvular apparatus (Table 5.1). Parachute deformity of the mitral valve is characterized by the presence of a single papillary muscle to which the chordae tendineae of both the mitral leaflets are connected (Fig.  5.1a, b). The mitral valve looks like a parachute. All chordae tendineae are usually attached to the posteromedial papillary muscle, with the anterolateral papillary muscle hypoplastic or even absent. The leaflets and chordae are well differentiated, and the interchordal spaces represent the effective valvular orifice. If the leaflets or tensor apparatus are dysplastic, the valve appears severely stenotic. This malformation is rarely isolated. More frequently it is associated with ventricular septal defect and obstruction of the aortic arch (Fig. 5.1c). Mitral arcade (known also as the “congenital mitral stenosis”) is a malformation characterized by absent or defective differentiation of the chordae tendineae originating from the tip of the papillary muscles, with preservation of the embryonic muscularization (Fig.  5.2). The muscularization of the chordae from the apex of both the papillary muscles to the anterior leaflet gives the valve the look of an arcade mimicking “rheumatic” mitral disease. The leaflets lose their movement and there is absence of the interchordal spaces. The cleft of the anterior leaflet of the mitral valve is rarely an isolated defect. It can be observed in association with atrial or ventricular septal defects, tetralogy of Fallot, and transposition of the great arteries. The cleft is usually located in the central part of the anterior mitral leaflet and is shaped like an inverted “V” with the apex pointing toward the valvular anulus (Fig.  5.3). The C. Frescura (*) · G. Thiene Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padua Medical School, and Cardiovascular Pathology Unit, University Hospital of Padua, Padua, Italy e-mail: [email protected]

extension of the cleft from the free margin of the leaflet to the anulus is variable. The deeper and wider the cleft, the more the valve results insufficient. The cleft is also part of partial atrioventricular septal defect (also known as ostium primum defect), characterized by interatrial communication and mitral valve insufficiency (Fig. 5.4). Two types of double orifice mitral valve can be found: the “bridge type” and the “hole type.” In the “bridge type,” the mitral valve is divided into two orifices because of the partial fusion of the anterior and posterior leaflets as to form a fibrous bridge (Fig. 5.5). In the “hole-type” double orifice, there is a variable deficiency in the substance of a valvular leaflet (Fig. 5.6). Usually, the affected leaflet is the anterior one. In both cases, the accessory orifice shows along the circumference the insertion of chordae tendineae arising from papillary muscles. In addition, the double orifice mitral valve rarely is an isolated anomaly, more often being associated with atrioventricular or ventricular septal defects and obstruction of the aortic arch. The supravalvular mitral ring is a circumferential fibrous ring located in the left atrium, a few mm over the mitral valve and below the mouth of left atrial appendage (Figs. 5.7 and 5.8). The ring is associated with a central orifice that allows the transit of blood flow from the atrium to the left ventricle. Depending upon the diameter of the orifice, various degrees of obstruction may result. The ring reduces the effective orifice of the mitral valve. In some cases, a supravalvular mitral ring is associated with a parachute mitral valve and aortic isthmic coarctation (so-called Shone malformation). Cases exist where the ring is located around the same mitral leaflets (Fig. 5.8). Quite rare is the occurrence of the “Ebstein”-type anomaly of the mitral valve. The “mitral” Ebstein must be distinguished from the Ebstein of the tricuspid valve in hearts with left-sided tricuspid valve due to the development of an

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 G. Thiene et al. (eds.), Pathology of Cardiac Valve Disease, https://doi.org/10.1007/978-3-031-35498-4_5

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64 Table 5.1  Congenital anomalies of the mitral valve Frequent forms •  Parachute mitral valve •  Arcade mitral valve •  Cleft of the anterior mitral leaflet •  Double orifice mitral valve •  Supravalvular mitral ring •  Ebstein anomaly of the mitral valve Rare forms •  Mucoid dysplasia of the leaflets •  Short/absent chordae tendineae

a

b

Fig. 5.1  Parachute mitral valve. (a) Drawing of a parachute mitral valve: all the chordae tendineae to the mitral leaflets originate from a single papillary muscle. The valve is stenotic with a parachute appearance. (b) View of the left cardiac chambers: the chordae tendineae of

l-­ ventricular loop (corrected transposition of the great arteries). The short chordae tendineae (Fig. 5.9) impair the mobility of the mitral valve leaflets and interfere with the closure of the valve, causing valvular insufficiency. Incompetence of the mitral valve is also present when the chordae tendineae are absent (Fig. 5.10). Elongated chordae tendineae with redundant and prolapsing leaflets (mitral valve prolapse) are rarely present in infancy and children. c

both the mitral leaflets are attached to the posteromedial papillary muscle. The mitral valve takes the shape of a parachute. The anterior papillary muscle is hypoplastic. (c) External view of the same specimen: note an aortic isthmic coarctation with a patent ductus arteriosus

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Fig. 5.2  Mitral arcade. (a) Drawing of the muscularization of the mitral leaflets. The abnormal differentiation of the chordae tendineae gives an “arcade-­ like” appearance to the valve. (b) View of the left cardiac chambers: the mitral valve is dysplastic with muscularization of the chordae tendineae and of the free margin of the leaflets. The interchordal spaces are absent. The valve looks like rheumatic

a

b

Fig. 5.3  Isolated cleft of the mitral valve. (a) Drawing of a mitral cleft, which consists of a “V-shaped” incision in the anterior mitral leaflet. The apex of the incision points to anulus. The cleft is the cause of mitral valve insufficiency. (b) Anatomical view of the left cardiac chambers. The arrow indicates the cleft in the anterior mitral leaflet. Note the deep incision reaching the anulus and the presence of chordae tendineae anchoring the two parts of the anterior leaflet to the ventricular septum

a

b

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Fig. 5.4  Mitral cleft with ostium primum defect. A mitral cleft is part of partial atrioventricular septal defect, a malformation characterized by an ostium primum atrial septal defect, mitral cleft, and insufficiency of the mitral valve. (a) View of the left cardiac chambers: a large atrial septal defect is present at the atrioventricular junction. Note the mitral cleft (arrow). (b) View from the right ventricle: note the large ostium primum septal defect. A patent foramen ovale is also present (arrow)

a

Fig. 5.5  Double orifice mitral valve. (a) Drawing of a mitral valve with double orifice. The double orifice is due to the partial fusion of the anterior and posterior leaflets that determine the formation of a fibrous bridge (“bridge-­ type” double orifice). (b) Anatomical view of the left cardiac chambers: a “bridge-type” double orifice is present, associated with a cleft of the anterior mitral leaflet

a

Fig. 5.6  Double orifice mitral valve. The “hole-type” double orifice is characterized by a hole within one of the mitral leaflets. (a) Anatomical specimen with an accessory mitral orifice in the anterior mitral leaflet. The orifice shows a tensor apparatus. (b) Closeup of the same specimen that evidences the morphology of the “holetype” double orifice

a

b

b

b

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a

b

c

Fig. 5.7  Supravalvular mitral ring. (a) Drawing of supravalvular mitral ring which consists of a fibrous diaphragm with a central orifice located in the left atrium, over the mitral valve (arrows). The mitral valve may be normal or the leaflets may be distorted and fused with the fibrous diaphragm. (b) View from the enlarged left atrium: the mitral valve is

not recognizable due to the presence of a circumferential fibrous diaphragm with a restrictive orifice. (c) View from the left ventricle: the mitral valve is small with short chordae tendineae and small interchordal spaces. A perimembranous ventricular septal defect is present (arrow)

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Fig. 5.9  Mitral valve with short chordae tendineae. The mitral leaflets are normal while the chordae tendineae are short and few, thus impairing the leaflet motion and causing incompetence

Fig. 5.8  Valvular mitral ring. View of left atrium and ventricle: note a ridge within the anterior mitral leaflet. The morphology of the mitral valve is distorted with dysplastic leaflets and short chordae tendineae

5  Congenital Anomalies of the Cardiac Valves Fig. 5.10  Mitral valve with absent chordae tendineae and severe incompetence. (a) View from the left atrium of the incomplete mitral valve. The surgically repair of the mitral valve failed. Note the enlarged left atrium. (b) Outflow tract of the left ventricle: the mitral leaflets show the absence of chordae tendineae, cause of valve insufficiency. A small perimembranous ventricular septal defect is also present (arrow)

a

Tricuspid Valve Congenital malformations of the tricuspid valve, such as focal or diffuse thickening of the valve leaflets, deficient development of chordae tendineae and papillary muscles, adherence of valve leaflets to the ventricular wall, and focal agenesis of valvular tissue are collectively termed as “tricuspid valve dysplasia.” The most important morbid entity within the spectrum of tricuspid dysplasia is represented by the Ebstein anomaly. In this congenital cardiac malformation, the septal and sometimes the posterior leaflets of the tricuspid valve do not attach normally the valvular annulus, being adherent to the musculature of the right ventricle (Figs.  5.11 and 5.12). Therefore, the effective tricuspid orifice is displaced downward into the right ventricular cavity, at the junction of the inlet and apical trabecular components. The point of maximum displacement is located at the commissure between the septal and posterior leaflets. The anterior leaflet usually is not involved in the process of apical displacement. The degree of displacement of the leaflets may vary from cases with minimal displacement to cases where the entire inlet portion of the right ventricle becomes part of the right atrium

69

b

(“auricularization of the right ventricle”). The displaced leaflets are usually dysplastic. Sometimes the leaflets are firmly adherent to the right ventricular wall. The displaced tricuspid valve divides the right ventricle in two portions: one, the inlet portion, is functionally integrated in the right atrium (“atrialized ventricle”), and the other, comprising the trabecular and outlet portions, constitutes the functional hypoplastic right ventricle. The atrialized portion of the right ventricle presents a thin and fibrotic parietal wall, sometimes missing myocardial tissue, with pronounced dilatation. The right atrium and the right atrial appendage are dilated. Ebstein anomaly of the tricuspid valve can appear single or in association with other cardiac malformations. Usually an atrial septal defect, fossa ovalis type, or a patent foramen ovale is present accounting for a right-to-left shunt. In addition, more severe malformations can be associated, such as pulmonary atresia with intact ventricular septum. In some cases of Ebstein anomaly, the presence of accessory atrioventricular connections, located in the septum or in the lateral part of the right atrioventricular sulcus, does exist as a substrate of reentry arrhythmias in the setting of ventricular preexcitation (Wolff-Parkinson-White syndrome).

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a

b

Fig. 5.11  Ebstein anomaly of the tricuspid valve. (a) Drawing of the Ebstein anomaly of the tricuspid valve: the septal and posterior leaflets of the tricuspid valve are displaced toward the apex of right ventricle. The right ventricle is reduced in size and the atrium is abnormally enlarged, including the atrialized portion of the right ventricle. A fossa

Fig. 5.12  Ebstein anomaly of the tricuspid valve. (a) View of the right ventricle. A prosthetic valve is inserted at the atrioventricular junction. The tricuspid leaflets are displaced into the right ventricle. The right ventricle is dilated with a thin wall. (b) Closeup of the same specimen showing the displacement of the tricuspid leaflets

a

Common Atrioventricular Valve During the embryological life, the common atrioventricular valve does not differentiate in two separated valves and orifices (tricuspid and mitral). The postnatal persistence of the common valve is usually associated with a huge septal defect in the atrioventricular region (Fig. 5.13) with both interatrial and interventricular communication. This anatomical complex, known as complete atrioventricular canal, was classified

ovalis-type interatrial septal defect is present with a right to left shunt (arrow). (b) Anatomical view of the right cardiac chambers: note the enlarged right atrium and the abnormal insertion of the anterior and posterior tricuspid leaflets down into the right ventricle. Note the atrialized portion of the right ventricle

b

by Rastelli et al. in three different types according to the morphology of the anterior leaflet of the common atrioventricular valve. The type A is characterized by a subdivided anterior leaflet with chordal insertions to the crest of ventricular septum (Fig. 5.14). In type C the common anterior leaflet is not subdivided and is overriding the ventricular septum (Fig. 5.15). Type B is rare and the common anterior leaflet attached to an abnormal papillary muscle of the right ventricle (Fig. 5.16), without chordal insertion to the ventricular septum.

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a

b

Fig. 5.13  Common atrioventricular valve. (a) Schematic representation of the common valve and atrioventricular septal defect. The presence of a common atrioventricular valve in association with an atrioventricular septal defect constitutes the so-called complete atrioventricular defect (also known as complete atrioventricular canal). (b)

a

b

Fig. 5.14  Common atrioventricular valve, type A. (a) View of the left outflow tract: a common atrioventricular valve is present with insertion of chordae tendineae on the crest of the ventricular septum. Note the large atrioventricular septal defect. (b) View from the right cardiac Fig. 5.15 Common atrioventricular valve, type C. (a) View from the right atrium: the anterior leaflet of the common atrioventricular valve is overriding the interventricular septum, without chordal insertions. (b) View of the left outflow of the same specimen showing a large atrioventricular septal defect and a common atrioventricular valve without chordal insertion to the crest of the ventricular septum

View from the right cardiac chambers: a large atrioventricular septal defect is present in association with a common atrioventricular valve showing chordal insertion to the crest of the ventricular septum (complete atrioventricular canal type A of Rastelli classification)

a

chambers of the same specimen: a large atrioventricular septal defect is associated with a fossa ovalis defect (arrow). Note the common atrioventricular valve with chordal insertion to the crest of the ventricular septum

b

72 Fig. 5.16 Common atrioventricular valve, type B. (a) View from the right cardiac chambers: an atrioventricular septal defect is associated with a common atrioventricular valve without chordal insertion to the crest of the ventricular septum. (b) View of the right ventricular outflow: the anterior leaflet of the common atrioventricular valve is attached to an abnormal papillary muscle of the right ventricle (complete atrioventricular canal)

C. Frescura and G. Thiene

a

Anomalies of the Semilunar Valves Aortic Valve The stenosis of the aortic valve may manifest in infancy with a dysplastic tricuspid, bicuspid, or unicuspid shape (Table 5.2). In the congenital tricuspid aortic valve stenosis, the three cusps present nodular myxoid dysplasia, and endocardial fibroelastosis may be associated (Fig. 5.17). The unicuspid aortic valve is the most severe type of congenital aortic stenosis. The unicuspid aortic valve may be unicommissural or acommisuural (Table 5.2). The unicommissural aortic valve shows a single leaflet with a single commissure and an eccentric orifice (Fig. 5.18). In the acommissural valve, distinct cusps did not develop and only short raphes are identifiable in the site of failed division of the cusps (Fig. 5.19). In unicuspid valve, the anulus is hypoplastic and the ascending aorta shows a reduced diameter. The concomitant presence of hypoplastic left ventricle or ­endocardial fibroelastosis (Fig. 5.20) aggravates the clinical presentation. The bicuspid aortic valve is the most frequent congenital heart disease, with a prevalence in the autopsy studies of general population varying from 0.5 to 1.2%. Isolated bicuspid aortic valve may be silent until adulthood, the presence of a bicuspid aortic valve being revealed at the onset of complications along the natural history.

b

Table 5.2  Malformations of the aortic valve •  Unicuspid aortic valve − Unicommissural − Acommissural •  Bicuspid aortic valve •  Tricuspid myxoid aortic valve •  Quadricuspid aortic valve

The anatomical characteristic of bicuspid aortic valve is the presence of two cusps (Figs. 5.21 and 5.22). Usually, a raphe is located in one of the two sinuses of Valsalva and most probably derived by an “aborted” commissure (Figs. 5.22 and 5.23). Under the raphe, there is no interleaflet triangle. Cases of bicuspid valve without raphe are rare (Fig. 5.21). The aortic cusps may be in anteroposterior or laterolateral position (Fig. 5.24). When the cusps are in anteroposterior position, a raphe is present in the anterior sinus, due to embryonic fusion of anterior right and left cushions. In this setting, both the coronary arteries originate from the anterior sinus (Figs.  5.25 and 5.27). When the cusps are placed in laterolateral position, the raphe is located in the left sinus and results from the fusion of right and posterior cushions. The coronary arteries originate each from the opposite sinus (Fig. 5.26). The anteroposterior position of the cusps is the more frequent occurrence, accounting for 70% of cases. The bicuspid aortic valve may be an isolated malformation or may be associated with other congenital heart dis-

5  Congenital Anomalies of the Cardiac Valves Fig. 5.17  Tricuspid stenotic and dysplastic aortic valve. (a) Schematic representation of a stenotic tricuspid aortic valve with dysplastic myxoid degeneration of the cusps. (b) Corresponding anatomical specimen: note the thickened cusps with nodular myxoid excrescences. The left ventricle is hypertrophic with endocardial fibroelastosis

a

Fig. 5.18 Unicuspid, unicommissural aortic valve. (a) Drawing of unicuspid and unicommissural aortic valve: only one aortic cusp and a single commissure are present. The orifice is eccentric and usually left posterior. (b) Anatomical specimen with an aortic valve with a single dysplastic cusp and commissure with myxoid nodular excrescences

a

eases like ventricular septal defect and/or aortic arch coarctation (Figs. 5.27, 5.28 and 5.29). Familial reurrence of bicuspid aortic valve happens in approximately 9% of cases. Inheritance is consistent with an autosomal dominant pattern with reduced penetrance. Echocardiographic screening is recommended for first-­ degree relatives of patients with bicuspid aortic valve.

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b

b

A role of neural crest in the development of bicuspid aortic valve has been postulated, because of the frequent association with isthmic coarctation. In young age a bicuspid aortic valve may remain asymptomatic, but, with time, the malformation is prone to multiple complications. The natural history of bicuspid valve is indeed characterized by progressive calcification of the cusps

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Fig. 5.19  Unicuspid acommissural aortic valve. View of the aortic root from above: the aortic valve is unicuspid and there is no commissure (acommissural valve). Three short raphes are recognizable remnants of the aborted commissures. A small, central orifice is present

a

b

Fig. 5.20  Aortic valve stenosis with hypoplastic, fibroelastic left ventricle. (a) View of the left cardiac chambers: a diminutive mitral valve connects the left atrium with the hypoplastic left ventricle. (b) View of the left ventricular outflow tract: a dysplastic aortic valve is present.

with stenosis, high risk of endocarditis, aortopathy because of wall degenerate with dilation of the ascending aorta, valve incompetence, and aortic dissection at risk of sudden death (Table 5.3). Aortic stenosis of bicuspid aortic valve is the consequence of calcific degeneration of the cusps (Fig. 5.30), similar to senile calcific aortic stenosis. The onset of calcification in bicuspid valve occurs earlier and more severely than in a normal tricuspid aortic valve. More than the 30% of patients with aortic stenosis, requiring surgical replacement of the aortic valve, shows a bicuspid valve. The bicuspid aortic valve represents a well-known risk factor for infective endocarditis (see chapter on endocarditis), and antibiotic prophylaxis is recommended also for minimal surgical or invasive procedures. Infective endocarditis involves the cusps, with disruption and vegetations, and the valvular annulus, accounting for abscesses and aneurysms in the Valsalva sinuses. The vegetations are composed of platelets, fibrin, inflammatory cells, and microorganisms.

c

Note the remarkable endocardial fibroelastosis. (c) Closeup of the same specimen: the aortic cusps show multiple nodular myxoid excrescences

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With time, aortopathy develops in nearly 50% of patients with bicuspid aortic valve. The sinusal and tubular ascending aorta show an aneurismal dilatation due to disruption of elastic fibers of the tunica media with loss of wall elasticity (Figs.  5.31, 5.32 and 5.33). At histology, the degenerative disease affects the tunica media with noninflammatory loss of smooth muscle cells (medionecrosis), fragmentation of the elastic fibers, and increased extracellular ground substance in the lamellar units (cystic medionecrosis) (Fig. 5.32).

Fig. 5.21  Bicuspid aortic valve. View of the outflow tract of the left ventricle and ascending aorta. The aortic valve shows two intact cusps without raphe. The colored triangle delimitates the area of the membranous septum

Fig. 5.23  Bicuspid aortic valve. (a) Anatomical view from the left ventricle showing a bicuspid aortic valve with latero-lateral (side-by-side) arrangement of the aortic cusps. The coronary arteries take origin from the opposite sinuses. (b) The arrow indicates the raphe in the left coronary sinus of Valsalva. The colored triangle identifies the membranous septum

a

Fig. 5.22  Bicuspid aortic valve. Anatomical specimen with bicuspid aortic valve: the cusps are in anteroposterior position, and both the coronary arteries take origin from the anterior sinuses of Valsalva. A fibrous raphe is present inside the anterior sinus of Valsalva (arrow). The colored triangle indicates the membranous septum

b

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a

b

Fig. 5.24  Bicuspid aortic valve and cusps arrangement. (a) Schematic representation of bicuspid valve. The aortic leaflets may be located in anteroposterior or latero-lateral position. In the former situation, both the coronary arteries take origin from the anterior sinus of Valsalva,

a

b

Fig. 5.25  Bicuspid aortic valve with anteroposterior position of the cusps. (a) Left ventricular outflow tract with a bicuspid aortic valve: the membranous septum is transilluminated and delineated by a colored triangle. Both the coronary arteries take origin from the anterior aortic sinus. (b) Schematic representation of a bicuspid aortic valve with anteroposterior position of the cusps: note the location of the membra-

LC L

R

nous septum (white area), the fibrous continuity of the posterior aortic cusp with the anterior mitral leaflet, and the origin of both the coronary arteries (white spots) from the anterior sinus of Valsalva. The dotted line indicates the aortic raphe in the anterior aortic sinus. A anterior aortic cusp; AML anterior mitral leaflet; P posterior aortic cusp

P

NC RC

whereas in the latter the coronary arteries take origin from opposite sinuses. (b) Anatomical view from above: a bicuspid, dysplastic aortic valve is present with cusps in anteroposterior position and with both coronary arteries originating from the anterior sinus of Valsalva

LC RC

LC L

RC A

Fig. 5.26  Development of bicuspid aortic valve and origin of the coronary arteries. (a) The normal aortic valve shows three cusps and the origin of the right coronary artery from the right anterior aortic sinus and of the left coronary artery from the left anterior aortic sinus. L, left cusp; LC, left coronary artery; NC, not coronary cusp; R, right cusp; RC, right coronary artery. (b) In the bicuspid valve with anteroposterior position of the cusps, both the coronary arteries originate from the

R

anterior sinus. The valve is the result of the embryonic fusion of anterior right and left cushions. A, anterior cusp; LC, left coronary artery; P, posterior cusp¸ RC, right coronary artery. (c) In the bicuspid valve with latero-lateral position of the cusps, the coronary arteries originate from opposite sinuses. The bicuspid valve derives from the fusion of right and posterior embryological cushions. L, left cusp; LC, left coronary artery; R, right cusp; RC, right coronary artery

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a

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b

Fig. 5.27  Bicuspid aortic valve with aortic isthmic coarctation. (a) A bicuspid aortic valve with intact ventricular septum and severe aortic isthmic coarctation. Note the presence of diffuse and severe atheromatosis of the ascending aorta and the subocclusion of the left atheroscle-

Fig. 5.28  Bicuspid aortic valve with ventricular septal defect and aortic isthmic coarctation. (a) View of the left ventricular outflow and aorta: a bicuspid aortic valve is associated with a large perimembranous ventricular septal defect (arrow). (b) Aortic arch and descending aorta of the same specimen: the arrow indicates the site of severe aortic isthmic coarctation

Fig. 5.29  Bicuspid aortic valve, isthmic coarctation, and aortic dissection. (a) Bicuspid aortic valve with an intimal tear. (b) Severe aortic isthmic coarctation

a

a

rotic coronary artery (arrow). The patient died by rupture of postcoarctation mycotic aneurysm. (b) Closeup of the same specimen showing a coarctation of the aorta in the isthmic region and mycotic aneurysm

b

b

C. Frescura and G. Thiene

78 Table 5.3  Bicuspid aortic valve: complication in the natural history •  Aortic stenosis •  Infective endocarditis •  Dilatation of the ascending aorta (aortopathy) •  Aortic valve incompetence •  Aortic dissection

Fig. 5.30  Stenotic bicuspid aortic valve by dystrophic calcification. (a) Schematic representation of bicuspid aortic valve with calcific degeneration. (b) Anatomical specimen of a bicuspid valve with calcific degeneration. The cusps of the valve are in anteroposterior position. Note the raphe within the anterior sinus of Valsalva

a

Fig. 5.31  Aortopathy with bicuspid aortic valve. (a) The sinus portion of ascending aorta appears dilated. (a) At histology, the aortic wall shows loss of lamellar units and elastic fiber disruption (Weigert-Van Gieson stain)

a

The consequences of the aortic wall degeneration are aortic valve incompetence (Fig. 5.33) and even aortic dissection (Figs. 5.34 and 5.35) with risk of sudden death. Rare is the occurrence of a quadricuspid aortic valve (Fig. 5.36) that usually is the cause of aortic regurgitation.

b

b

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79

b

Fig. 5.32  Degenerative pathology of the aortic wall tunica media in bicuspid aortic valve. (a) Noninflammatory loss of smooth muscle cells (medionecrosis) (hematoxylin-eosin stain). (b) Fragmentation of the

Fig. 5.33  Aortopathy and bicuspid aortic valve incompetence. (a) Anatomical view of the left ventricle and ascending aorta: note a dilated aorta and aortic annulus, due to degenerative disease of the aortic tunica media. The aortic valve is bicuspid and incompetent. (b) Histology of the wall of the ascending aorta showing loss of the elastic fibers in the tunica media (Weigert-Van Gieson stain)

a

c

elastic fibers (Weigert-Van Gieson stain). (c) Pools of basophilic ground substance (cystic medial necrosis) (Alcian PAS stain)

b

80

C. Frescura and G. Thiene

Fig. 5.34  Bicuspid aortic valve and aortic dissection. (a) Aorta and outflow tract of the left ventricle with bicuspid aortic valve and dissection of the ascending aorta. The patient died at rest due to cardiac tamponade by aortic rupture. (b) Histology of the wall of the ascending aorta with severe elastic loss (Weigert-Van Gieson stain)

a

Fig. 5.35  Bicuspid aortic valve and aortic dissection. (a) Outflow of the left ventricle and aorta: a bicuspid aortic valve is present. Note the dilatation of the ascending aorta and the intimal tear just above the sinotubular junction. (b, c) Histology of the aortic wall showing the dissecting hematoma and elastic fragmentation of the tunica media (Weigert-Van Gieson stain)

a

b

b

c

81

5  Congenital Anomalies of the Cardiac Valves

a

b

c

Fig. 5.36  Quadricuspid aortic valve. (a) Drawing of a quadricuspid aortic valve. (b) Anatomical specimen: the valve consists of four dysplastic cusps. Usually, the valve is incompetent. Under the aortic valve,

a fibrous endocardial thickening is also present, due to chronic aortic regurgitation. (c) Closeup of the (b)

The quadricuspid aortic valve may be an isolated anomaly or may be associated with other cardiac malformations, including ventricular septal defect, discrete subaortic stenosis, and supravalvular aortic stenosis.

Table 5.4  Pulmonary valve morphology

Pulmonary Valve The pulmonary valve can be stenotic in the presence of unicuspid, bicuspid, or tricuspid valve (Table 5.4). The unicuspid valve (Fig. 5.37) is the most severe and frequent form of pulmonary stenosis and consists of a single membrane and small central orifice. In the bicuspid and tricuspid pulmonary valves (Figs. 5.38 and 5.39), the stenosis is due to the dysplasia of the cusps. Pulmonary valve stenosis may be isolated or associated with tetralogy of Fallot.

•  Unicuspid pulmonary valve •  Bicuspid pulmonary valve •  Tricuspid pulmonary valve •  Quadricuspid pulmonary valve

The quadricuspid pulmonary valve (Fig. 5.40) is rare and usually a benign anomaly without clinical symptoms. Only sporadic cases of quadricuspid pulmonary valve stenosis or insufficiency are reported.

82

C. Frescura and G. Thiene

Fig. 5.37 Unicuspid congenital pulmonary valve stenosis. It is the most frequent and severe form of valve stenosis. (a) Schematic representation: the pulmonary valve shows a single cusp, formed by a fibrous membrane with a small central orifice. (b) Anatomical specimen: the unicuspid pulmonary valve shows a central orifice and tiny raphes which indicate the site of aborted commissures

a

Fig. 5.38 Bicuspid pulmonary valve. (a) Diagram of a bicuspid pulmonary valve. It may show normally functioning or fibroticdysplastic leaflets with stenosis. (b) The pulmonary valve, anterior and to the left of the aortic valve, shows two thickened cusps

a

Fig. 5.39  Tricuspid, stenotic pulmonary valve. (a) Diagram of a slightly stenotic tricuspid pulmonary valve: the mild valvular stenosis is due to thickened cusps. (b) Outflow of the right ventricle showing a tricuspid pulmonary valve with thickened cusps. Note the post-stenotic dilatation of the pulmonary artery

a

b

b

b

5  Congenital Anomalies of the Cardiac Valves Fig. 5.40 Quadricuspid pulmonary valve. (a) Schematic representation. (b) Anatomical specimen with quadricuspid pulmonary valve: all the four cusps are thickened. A subvalvular pulmonary stenosis is also present, due to hypertrophy of the trabecula septo-marginalis and crista supraventricularis

a

Polyvalvular Disease Congenital polyvalvular disease is a severe cardiac malformation, characterized by maldevelopment and dysfunction of multiple cardiac valves with congenitally dysplastic features (Fig. 5.41). The anomaly affects not only leaflets but also commissures, chordae tendineae, and papillary muscles. The atrioventricular valve leaflets appear redundant with

83

b

nodular myxoid thickening, and the semilunar valve may present also abnormalities in the number of cusps. This malformation can be observed in otherwise normal hearts or be associated with other cardiac defects, like ventricular septal defect, and with extracardiac malformations. Cases with chromosomal anomalies are reported. A high incidence of congenital polyvalvular disease is present in patients with trisomy 18.

84

a

C. Frescura and G. Thiene

b

c

Fig. 5.41  Congenital polyvalvular disease. In polyvalvular disease the atrioventricular and semilunar valves are involved in a myxoid dysplastic process. (a) View of the left ventricle with a mitral valve showing redundant leaflets and myxoid grape-like excrescences. The aortic

valve is also dysplastic. (b) View of the dysplastic mitral leaflets from the left atrium. (c) View of the right cardiac chambers: note the dysplastic leaflets of the tricuspid valve with myxoid excrescences

References

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85 Larson EW, Edwards WD. Risk factors for aortic dissection: a necropsy study of 161 cases. Am J Cardiol. 1984;53:849–55. Layman TE, Edwards JE. Anomalous mitral arcade. A type of congenital mitral insufficiency. Circulation. 1967;35:389–95. Leung PL, McKey R, Smith A, Anderson RH, Arnold R. Critical aortic stenosis in early infancy. Anatomic and echocardiographic substrates of successful open valvulotomy. J Thorac Cardiovasc Surg. 1991;101:526–35. Lev M, Gibson S, Miller RA. Ebstein's disease with Wolff-Parkinson-­ white syndrome. Am Heart J. 1955;49:724–41. Lev M, Liberthson R, Joseph RH, Seten CE, Kunske R, Eckner FAO, Miller RA. The pathologic anatomy of Ebstein’s disease. Arch Path. 1970;90:3334–43. McKey R, Smith A, Leung MP, Arnold R, Anderson RH. Morphology of the ventriculoaortic junction in critical aortic stenosis. Implications for hemodynamic function and clinical management. J Thorac Cardiovasc Surg. 1992;104:434–42. Michelena HI, Della Corte A, Prakash SK, Milewicz DM, Evangelista A, Enriquez-Sarano M.  Bicuspid aortic valve aortopathy in adults: incidence, etiology, and clinical significance. Int J Cardiol. 2015;201:400–7. Michelena HI, Khanna AD, Mahoney D, Margaryan E, Toplsky Y, Suri RM, Edwards WD, Sundt TM, Enriquez-Sarano M.  Incidence of aortic complications in patients with bicuspid aortic valves. JAMA. 2011;306:1104–12. Moller JH, Edwards JE. Anomalies associated with the parachute mitral valve: a pathologic analysis of 52 cases. Can J Cardiol. 1986;2:278–81. Nistri S, Basso C, Marzari C, Mormino P, Thiene G.  Frequency of bicuspid aortic valve in young male conscripts by echocardiogram. Am J Cardiol. 2005;96:718–21. Nistri S, Basso C, Thiene G.  Bicuspid aortic valve. G Ital Cardiol. 2012;13:25–37. Nistri S, Sorbo MD, Marin M, Palisi M, Scognamiglio R, Thiene G. Aortic root dilatation in young men with normally functioning bicuspid aortic valves. Heart. 1999;82:19–22. Rastelli GC, Kirklin JW, Titus JL. Anatomic observations on complete form of persistent common atrioventricular canal with special reference to atrioventricular valves. Mayo Clin Proc. 1966;41:296–308. Roberts WC, Ko JM. Frequency by decades of unicuspid, bicuspid, and tricuspid aortic valves in adults having isolated aortic valve replacement for aortic stenosis, with or without associated aortic regurgitation. Circulation. 2005;111:920–5. Roberts WC, Morrow AG.  Congenital aortic stenosis produced by a unicommisural valve. Br Heart J. 1965;27:505–10. Roberts WC.  The congenitally bicuspid aortic valve. A study of 85 autopsy cases. Am J Cardiol. 1970;26:72–83. Roberts WC. Valvular, subvalvular and supravalvular stenosis: morphologic features. Cardiovasc Clin. 1973;5:79–126. Robicsek F, Thubrikar MJ, Cook JW, Fowler B. The congenital bicuspid aortic valve: how does it function? Why does it fail? Ann Thorac Surg. 2004;77:177–85. Rosenquist GC, Stark J, Taylor JF. Congenital mitral valve disease in transposition of the great arteries. Circulation. 1975;51:731–7. Rosenquist GC. Congenital mitral valve disease associated with coarctation of the aorta. A spectrum that includes parachute deformity of the mitral valve. Circulation. 1974;49:985–93. Rossi L, Thiene G. Mild Ebstein's anomaly associated with supraventricular tachycardia and sudden death: clinicomorphologic features in 3 patients. Am J Cardiol. 1984;53:332–4. Sans-Coma V, Cardo M, Durán AC, Franco D, Fernandez B, Arque JM. Evidence for a quantitative genetic influence on the formation of aortic valves with two leaflets in the Syrian hamster. Cardiol Young. 1993;3:132–40. Sans-Coma V, Fernández B, Durán AC, Thiene G, Arqué JM, Muñoz-­ Chápuli R, Cardo M. Fusion of valve cushions as a key factor in the

86 formation of congenital bicuspid aortic valves in Syrian hamsters. Anat Rec. 1996;244:490–8. Sans-Coma V, Fernández MC, Fernández B, Durán AC, Anderson RH, Arqué JM. Genetically alike Syrian hamsters display both bifoliate and trifoliate aortic valves. J Anat. 2012;220:92–101. Sievers HH, Sievers HL.  Aortopathy in bicuspid aortic valve disease–genes or hemodynamics? Or Scylla and Charybdis? Eur J Cardiothorac Surg. 2011;39:803–4. Stamm C, Anderson RH, Ho SY. Clinical anatomy of the normal pulmonary root compared with that in isolated pulmonary valve stenosis. J Am Coll Cardiol. 1988;31:1420–5. Stefani G, Cocco P, Sans-Coma V, Corrado D, Thiene G.  Juvenile sudden death from spontaneous aortic rupture. G Ital Cardiol. 1993;23:55–61. Thareja SK, Frommelt MA, Lincoln J, Lough JW, Mitchell ME, Tomita-Mitchell A. A systematic review of Ebstein's anomaly with left ventricular noncompaction. J Cardiovasc Dev Dis. 2022 Apr 13;9(4):115. Thiene G, Basso C. Pathology and pathogenesis of infective endocarditis in native heart valves. Cardiovasc Pathol. 2006;15:256–63. Thiene G, Frescura C, Daliento L. The pathology of the congenitally malformed mitral valve. In: Marcelletti G, Anderson RH, Becker AE, et al., editors. Pediatric cardiology, vol. 6. Edinburgh: Churchill Livingstone; 1986. p. 225–39. Thiene G, Frescura C, Di Donato R, Gallucci V.  Complete atrioventricular canal associated with cono-truncal malformations: anatomical observations in 13 specimens. Europ J Cardol. 1979;9:199–213. Tribouilloy C, Rusinaru D, Sorel C, Thuny F, Casalta JP, Riberi A, Jeu A, Gouriet F, Collart F, Caus T, Raoult D, Habib G.  Clinical characteristics and outcome of infective endocarditis in adults with bicuspid aortic valves: a multicenter observational study. Heart. 2010;96:1723–9. Tsang MYC, Abudiab MM, Ammash NM, Tasneem Z, Naqvi TZ, Edwards WD, Nkomo VT, Pellikka PA. Quadricuspid aortic valve: characteristics associated structural cardiovascular abnormalities and clinical outcomes. Circulation. 2016;133:312–9. Van Praagh S, Porras D, Oppido G, Geva T, Van Praagh R. Cleft mitral valve without ostium primum defect: anatomic data and surgical considerations based on 41 cases. Ann Thorac Surg. 2003;75:1752–62. Vasudev R, Shah P, Bikkina M, Shamoon F. Quadricuspid aortic valve: a rare congenital cause of aortic insufficiency. J Clin Imaging Sci. 2016;30(6):10.

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6

Infective Endocarditis Gaetano Thiene, Cristina Basso, and Uberto Bortolotti

Definition Infective endocarditis (IE) (Fig. 6.1) is an infection of cardiovascular structures including the large intrathoracic vessels (Fig.  6.2) and mural and valvular  heart  endocardium. Formerly known as bacterial endocarditis, endocardial infections are currently named IE, in order to include both bacterial and fungal microorganisms as causative agents.

Pathogenesis and Predisposition Sterile, tiny endocardial thrombotic vegetations are considered the crucial lesions for the development of IE, since they serve as a predisposing milieu for bacterial adhesion on valve surfaces. Endothelial injury and erosion are the most likely factors leading to platelet deposition. Hemodynamic and mechanical stresses seem to play an important role in development of the initial lesions and location of the infection. The favorite site of IE growth is the valve coaptation line of closure, due to the continuous trauma, which also explains the prevalent involvement of the high pressure left-sided valves. Entry of microorganisms into circulation due to focal infection or trauma ultimately converts thrombotic noninfective deposits into IE. Events that traumatize the oral mucosa, particularly the gums and the genitourinary and gastrointestinal tracts, are associated with an increased risk of bacteriemia. Grampositive microorganisms have the propensity to adhere to valvular surfaces, whereas Gram-negative germs adhere

much less. This justifies the prevalence of Gram-positive microorganisms as etiologic agents in IE (Fig. 6.3). In addition, the decrease of host defense mechanisms most probably plays a major role. Variations in the local blood flow patterns, as a result of change of the valve remodeling, concur to thrombus formation, microorganism adhesion during bacteremia and eventually onset of IE (injury-thrombusinfection theory). The microorganisms then can grow and induce further thrombus formation and neutrophils chemiotaxis (Fig.  6.4). Thus, an underlying valve disease with a deformed leaflet surface is the main risk factor of IE. Likewise, jet or friction lesions of the endocardium, as seen on the left ventricular outflow tract in aortic incompetence and hypertrophic cardiomyopathy, are well-known triggers of infective colonization. Most Gram-positive bacteria are resistant to the bactericidal activity of the serum, whereas Gram-negative are not. Viral endocarditis has never been reported. Fungal infections are mostly indolent processes, may be culture negative, and are common in patients with prosthetic valves or intracardiac catheters, in intravenously drug abusers and immunosuppressed people. Candida is the most frequent fungal infective agent, followed by Aspergillus and Histoplasma species. Although hematoxylin-eosin may be enough, employment of special stains is necessary to distinguish Gram-positive (most frequent) from Gram-negative (rare) microorganisms. Following treatment with antibiotics, bacteria may lose their sensitivity to Gram staining, and the histologic diagnosis of infection becomes hard. Findings at gross inspection like cusp disruption and perforation are per sè diagnostic of a previous infection.

G. Thiene · C. Basso (*) Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padua Medical School, and Cardiovascular Pathology Unit, University Hospital, Padua, Italy e-mail: [email protected]; [email protected]

 athology and Complications of Native Valve P Endocarditis

U. Bortolotti Section of Cardiac Surgery, Cardio-thoracic and Vascular Department, University Hospital, Pisa, Italy e-mail: [email protected]

From the pathological viewpoint, IE is a local process, characterized mainly by valvular and perivalvular destruction, and may present with peripheral spread, due to detachment

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 G. Thiene et al. (eds.), Pathology of Cardiac Valve Disease, https://doi.org/10.1007/978-3-031-35498-4_6

87

88

Fig. 6.1  Infective endocarditis of the aortic valve with huge vegetations and cusp disruption

of septic vegetations with embolism, metastatic infection and septicemia. Local complications of IE occur in the valve components (Figs.  6.5 and 6.6) or in the perivalvular region, and they also vary, based on whether atrioventricular or semilunar

G. Thiene et al.

valves are affected (Table  6.1). Vegetations are usually attached to the atrial side of atrioventricular valves and to the ventricular side of semilunar valves, at the valve line closure. IE may present with vegetations of various sizes, which in the acute phase consist of septic thrombi entrapping microorganisms and neutrophil infiltrates (Fig.  6.4). Sometimes, vegetations may be so small as to be overlooked by the pathologist. Distal complications of IE differ whether infection is right-sided or left-sided (Table  6.2). Right-sided IE  can be complicated with pulmonary artery embolism and lung infarcts, pneumonia, and abscesses. Left-sided IE  can be complicated with systemic embolism with cerebral, splenic (Fig. 6.7), renal (Fig. 6.8), myocardial (Fig. 6.9), and bowel infarcts, with possible subsequent abscesses formation. Embolic events are the most common extracardiac IE-related complication, being reported with an incidence ranging from 22 to 43%. Vegetations may be huge with massive emboli such to occlude the aortic carrefour (Fig. 6.10). The size of vegetations seems to be a significant risk factor for embolism, mostly in case of Streptococcus viridans IE. Cerebrovascular accidents are observed in nearly 10% of left-sided IE. Paradoxical emboli may also occur in congenital heart disease with right-to-left shunt. Metastatic infection may lead to apostematous meningitis, myocarditis (Fig.  6.9), and pyelonephritis. Splenic abscesses (Fig. 6.7) are at risk of rupture, so abdominal computed tomography is indicated for monitoring splenic involvement requiring splenectomy. Septicemia may stimulate disseminated intravascular coagulation, while deposition of circulating complexes may account for diffuse or focal glomerulonephritis (Fig.  6.8). Mycotic aneurysms may involve both large to medium-sized arteries and small vessels.

6  Infective Endocarditis

a

c

89

b

d

Fig. 6.2 (a) Gross view of mycotic aneurysm of the ascending aorta. (b) Histology, low panoramic view, Azan stain. (c) Same of (b), stained with Weigert-Van Gieson. (d) High magnification of the septic abscess. Hematoxylin-eosin

90

G. Thiene et al.

Infective Endocarditis of Native Valve Microorganisms Müller (1964-82)

Johnson Awadallah (1950-79) (1970-90)

Streptococcus viridans

35%

28%

29%

Streptococci, others

10%

-

-

Staphylococcus aureus

20%

38%

27%

Staphylococcus epidermidis

3%

6%

-

Fungi

5%

2%

6%

Others

14%

14%

27%

Negative culture

23%

12%

11%

Fig. 6.3  Causative microorganisms of infective endocarditis in native valves (from three published historical series)

Fig. 6.5  Ulcero-vegetative infective endocarditis of the aortic valve

Fig. 6.4  Histology of a septic vegetation: note colonies of microorganisms surrounded by neutrophils (hematoxylin-eosin) Fig. 6.6  Ulcero-vegetative infective endocarditis of the mitral valve with chordal rupture

6  Infective Endocarditis

91

Table 6.1  Infective endocarditis: Local complications

Vegetations Perforations Aneurysms, annular abscesses, tunnel, fistulae Chordal rupture

Aortic valve ++ ++ ++

Mitral valve ++ ++ −

−

+

Table 6.2  Infective endocarditis: distal complications Side Right

Left

Complications – Pulmonary infarcts – Pneumoniae – Lung abscesses – Systemic infarcts – Myocarditis – Pericarditis – Meningitis – Glomerulonephritis – Splenic abscess – Multiorgan failure – Mycotic aneurysms – Occlusion of the abdominal aortic carrefour

Fig. 6.7  Large spleen infarcts at risk of rupture due to septic embolism of infective endocarditis

Fig. 6.8  Segmental embolic glomerulitis in left-sided infective endocarditis (hematoxylin-eosin)

92 Fig. 6.9 (a) Panoramic histologic view of septic embolism of a coronary artery. (b) Myocarditis due to embolic dissemination of septic vegetation. Hematoxylin-eosin

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Fig. 6.10 (a) Huge septic vegetation of the mitral valve with perforation (probe) of a leaflet. (b) Massive embolism, occluding the abdominal aortic carrefour

In Vivo Diagnosis At present, evidence of endocardial vegetations through echocardiography plays a major role for an in vivo clinical diagnosis (“Duke criteria”) (Table 6.3), even in the absence of positive blood cultures. A molecular approach, by employing polymerase chain reaction either on excised valves or blood, may enhance the diagnosis of valvular IE. Cusp disruption with loss of substance accounts for tearing, fraying, perforation, and bulging, even in the absence of vegetations, especially when the causative microorganism is a Staphylococcus (Fig. 6.5). Valve incompetence is the usual hemodynamic complication with left ventricular decompensation and congestive heart failure. It may be associated with stenosis if vegetations are huge, as it is the case of fungal infections causing valve obstruction. In the subacute-chronic phase, microorganisms may disappear, replaced by granulomatous inflammation including giant cells, and vegetations may transform into coarse calcific deposits. Local spread of infection includes extension to the aortic wall that may lead to development of sinus of Valsalva aneurysms, ring abscess, tunnels, and fistulae to the surrounding cardiac chambers (right and left atria and ventricles) (Fig. 6.11). Rupture into the pericardial cavity with tamponade may occur. Transesophageal echocardiography is highly accurate in the detection of complications, such as paravalvular abscesses or mycotic aneurysms. Aortic root complications carry an

increased operative mortality and a high incidence of postoperative recurrence. Homografts are generally preferred to treat these complications. Extension of IE from the aortic to the mitral valve occurs through mitro-aortic fibrous continuity. A marker of such complication is the development of a septic aneurysm in the anterior leaflet of the mitral valve (satellite infection or “kiss” lesion), with or without perforation (Fig. 6.12). Involvement of the atrioventricular conduction system may account for atrioventricular block, while extension to the membranous septum with rupture may create ventricular septal defect with interventricular or ventriculoatrial communications. Apart from cusp vegetations and perforations, which do not differ substantially from those occurring in the semilunar valves, IE of atrioventricular valves is peculiar in so far as the subvalvular apparatus (chordae tendineae and papillary muscles) may also be involved (Fig.  6.13). Papillary muscles rupture may occur, either due to septic localization on their tip or to myocardial necrosis because of coronary embolism. Perivalvular extension of the infection and ring abscesses are rare if IE is localized at atrioventricular valves. Healed endocarditis is characterized by indentation of the free margin and/or perforation of the body of the cusps with thickened edges (Fig. 6.14a), cusp aneurysms and ruptured chordae tendineae. Neovascularization (Fig.  6.14b), giant cells inflammation, and calcification are pathognomic histologic hallmarks, even with disappearance of microorganisms.

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94 Table 6.3  Duke criteria for diagnosis of infective endocarditisa: two or one major + three minor or five minor criteria are required Major Positive blood culture Evidence of endocardial involvement – Positive echocardiogram – New valvular regurgitation

a

Minor Predisposing heart condition or intravenous drug use Fever >38° Vascular phenomena Immunological phenomena Microbiological evidencea Echocardiograma

Consistent with infective endocarditis but not meeting major criteria

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Fig. 6.11 (a) Annular abscess complicating infective endocarditis of aortic valve. (b) Right-sided heart: spread of the infection from the right anterior Valsalva sinus into the right atrial septum Fig. 6.12 (a) Ulcero-­ vegetative infective endocarditis of the aortic valve (b) “kiss” lesion to the anterior leaflet of the mitral valve, with septic aneurysm and perforation

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Fig. 6.13  Ulcero-vegetative endocarditis of mitral valve prolapse with cusp perforation and chordal rupture. (a) Drawing; (b) surgical pathology specimen. (c) Colonies of microorganisms at histology (Gram stain)

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Fig. 6.14 (a) Healed endocarditis of the aortic valve: note a hole within a cusp with thickened borders; (b) valve repair with fibrosis and neovascularization at histology. Hematoxylin-eosin

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 ardiac Conditions/Patients at Risk C (Table 6.4) Rheumatic valve disease (Fig. 6.15) has been considered for years the major risk factor for IE, account in the first 20–25% of cases. In the 1980s, this figure dropped to 7–10%. As previously mentioned, sterile thrombus formation on the surface of deformed valves, with altered blood flow dynamics and inflammatory endothelial injury, is the main mechanism for both microbial settlement and valve disease progression. Although the frequency of rheumatic valve disease has Table 6.4  Cardiac conditions at risk of infective endocarditis Prosthetic heart valves, catheters Complex congenital cyanotic heart diseases Previous infective endocarditis Surgical systemic or pulmonary conduits Acquired valvular heart diseases Mitral valve prolapse with valvular regurgitation or severe valve thickening Noncyanotic congenital heart diseases (except for secundum-type atrial septal defect), including bicuspid aortic valves Hypertrophic cardiomyopathy

diminished in Europe and North America, it is still endemic in third world countries where it represents by far the leading predisposing factor, especially in children (Table 6.5). With increasing of life expectancy, currently acquired degenerative heart diseases are becoming the most common condition at risk for IE. Mitral valve prolapse has emerged as predominant predisposing structural abnormality and accounts for 7–30% of cases of native valve IE in Western countries. The risk is almost entirely confined to patients with regurgitation (Figs. 6.13 and 6.16), particularly those with valve ­redundancy and thickened mucoid leaflets. The incidence of IE in patients with mitral valve prolapse is ten times than in the general population. IE on a prolapsing mitral valve may lead to chordal rupture (Fig. 6.13) Table 6.5  Infective endocarditis: underlying predisposing heart disease in 186 Indian patients (Choudhury at al., 1992) Rheumatic heart disease Congenital heart diseasea Normal valve Uncertain etiology Floppy mitral valve Prosthetic valve a

a

Bicuspid aortic valve in 25

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Fig. 6.15 (a) Rheumatic mitral valvulitis with commissural fusion and (b) verruca at histology. Hematoxylin-eosin

79 (42%) 62 (33%) 17 (9%) 24 (13%) 2 (1%) 2 (1%)

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and only histologic evidence of microorganisms, inflammatory infiltrates, and/or neovascularization may allow to differentiate chordal rupture secondary to IE from spontaneous rupture complicating myxoid degeneration. Dystrophic calcification of the mitral valve, a common finding at autopsy and surgery in elderly patients, usually presents with some degree of valve incompetence due to cusp and annular rigidity and impaired valve closure. Vegetations of infective endocarditis are found on the base of the posterior (mural) leaflet (Fig. 6.17) rather than related to its line of closure and are often associated with leaflet ulceration. The bicuspid aortic valve, which represents nowadays one of the main risk factors of IE, is the most common congenital defect, being present in 0.5–2% of the general population. IE may superimpose not only on a stenotic, symptomatic bicuspid valve in adult and elderly patients but also in the young subjects where this condition is clinically silent, the aortic valve is still normally functioning, and IE may represent the first manifestation of the disease. Wear and tear mechanisms of the unnatural closing of the bicuspid valve account for predisposition to infection (Figs. 6.18, 6.19 and 6.20). Hypertrophic cardiomyopathy, an inherited heart muscle disease with gene mutations encoding defective sarcomeric proteins, may complicate with IE in 5–9% of cases, especially in patients with subaortic stenosis. Hemodynamic and anatomic alterations of the left ventricular outflow tract, by contact between the ventricular septum bulging and the anterior leaflet of the mitral valve due to systolic anterior motion, cause microtraumatisms with endocardial injury (plaques). The latter may represent the nidus for thrombus deposition and microbial seeding during bacteremia (Fig. 6.21), involving both aortic and mitral valve leaflets. Other congenital heart diseases may be a predisposing risk factor of IE in children (75–90%), in the young (10– 20%), and in adults (8–10%). Ventricular septal defect,

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tetralogy of Fallot (Fig.  6.22), discrete subaortic stenosis, patent ductus arteriosus, and coarctation of the aorta are the most common predisposing congenital defects. Secundum atrial septal defect is not associated with an increased risk of IE, probably because of the low-pressure, nontraumatic left-­ to-­right shunt (Table 6.4). Ventricular septal defect is at par-

Fig. 6.17  Vegetative infective endocarditis, complicating huge dystrophic calcification of the mitral annulus

Fig. 6.16  Ulcero-vegetative endocarditis of a mitral valve prolapse with perforation of the posterior leaflet

Fig. 6.18  Infective endocarditis of bicuspid aortic valve with vegetations in a drug addict

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ticular risk if small or associated with aortic regurgitation. In case of isthmic coarctation and patent ductus arteriosus, infection may involve the great vessels with development of mycotic aneurysms. Bicuspid aortic valve and mitral valve prolapse have been identified in surgical pathology specimens as the most frequent predisposing factor in 23% and 18% of cases, respectively. Finally, native valve IE may develop upon normal valves in up to 30% of cases (Fig. 6.23). Whether such valves are indeed normal has been questioned. Risk factors, like intravenous drug use, alcoholism, and immunodeficiencies, may play a major risk factor in otherwise normally structured hearts. Intravenous drug users can introduce several microorganisms of the skin flora, such as cocci and fungi. Right-sided heart structures are typically involved in this setting, particularly the tricuspid valve (Fig. 6.24) and even the Eustachian valve. Hidden bicuspid aortic valve is particularly at risk in drug addicts (Fig. 6.18). Among neonates, IE typically affects the tricuspid valve of a structurally normal heart as the consequence of infected intravenous feading right-sided catheters. IE may complicate the implant of cardiac devices like endocardial pacemakers (Fig. 6.25) or defibrillators leads or valve prostheses. Among the latter, IE may occur early (perioperative), mostly due to hospital infection, or late (postoperative), due to bacteremia risk factors, equal to those of native endocarditis. In mechanical prostheses recipients, the substrate is represented by microthrombi on the sewing ring and suture lines. Infection can detach the annular stiches, creating perivalvular leaks with various degrees of prosthesis incompetence and hemolysis, according to the number and dimensions of the leaks (Fig. 6.26). When the involvement of the annulus by IE is extensive, even complete detachment of the prosthesis and dislodgement may occur, presenting with acute, massive incompetence, and sudden death by pulmonary edema (Fig. 6.27). Moreover, exuberant septic vegetations may embolize or interfere with the prosthetic valve dysfunction. In bioprosthetic valve recipients, IE rarely presents with annular involvement. Usually, the microorganisms involve directly the biological tissue with cusp infiltration, necrosis, and perforation, commissural dehiscence, and septic vegetations, features similar to those observed in native valve IE. Microorganisms may be detected either within the thrombotic vegetations or deep in the porcine (Fig. 6.28) or bovine (Fig. 6.29) pericardial leaflets. Dissemination of IE with septic emboli, annular abscesses, and annular detachment may also occur. In case of fungal IE, obstruction of the bioprosthetic valve  orifice has been reported (Fig.  6.30). When infection spreads to the His bundle from an infected aortic prosthesis, complete atrioventricular block may ensue.

b

Fig. 6.19 (a) Infective endocarditis of bicuspid aortic valve. (b) Colonies of Gram-positive microorganisms at histology. Gram stain

Fig. 6.20  Healed infective endocarditis of bicuspid aortic valve with a chronic hole within one cusp

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Fig. 6.21 (a) Infective endocarditis complicating hypertrophic cardiomyopathy. The anterior mitral leaflet shows perforation and vegetation. (b) View of the left ventricular outflow track with asymmetric hypertro-

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phy of the basal ventricular septum and anterolateral wall. Note the perforation of the anterior leaflet of the mitral valve (“kissing lesion”)

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Fig. 6.22  Infective endocarditis in tetralogy of Fallot. (a) Vegetations and disruption of the pulmonary valve. (b) The aortic valve is also involved

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Fig. 6.23  Infective aortic valve endocarditis over a normal aortic valve: gross view of huge vegetation

Fig. 6.25 (a) Infective vegetative endocarditis upon pacemaker catheter of the right ventricle. (b) Fungal (Candida) at histology

Fig. 6.24  Giant polypous septic vegetations of the anterior leaflet of the tricuspid valve in a drug addict

Fig. 6.26  Extensive leak of mechanical prosthetic aortic valve by endocarditis annulus

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b Fig. 6.27  Severe endocarditis of prosthetic mechanical aortic valve with total annular detachment of the device

Fig. 6.28 (a) Vegetative infective endocarditis of a porcine bioprosthetic valve explant. (b) Colonies of microorganisms, deep into the core of a cusp (Gram stain)

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Fig. 6.29 (a) Histology of a bovine pericardial cusp with vegetative infective endocarditis. (b) Microorganisms within the vegetations (Gram stain)

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Fig. 6.30 (a, b) Vegetative infective endocarditis of bioprosthetic valve with orifice occlusion. (c) Hyphae of aspergilli at histology (hematoxylin and eosin) and (d) at scanning electron microscopy

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Further Reading Alessandri N, Pannarale G, Del Monte F, Moretti F, Marino B, Reale A. Hypertrophic obstructive cardiomyopathy and infective endocarditis: a report of seven cases and a review of the literature. Eur Heart J. 1990;11:1041–8. Atkinson JB, Virmani R.  Infective endocarditis: changing trends and general approach for examination. Hum Pathol. 1987;18:603–8. Auclair F. Update on pathogenesis of infective endocarditis. Cardiovasc Pathol. 1995;4:265–8. Bacchion F, Cukon S, Rizzoli G, et al. Infective endocarditis in bicuspid aortic valve: atrioventricular block as sign of perivalvular abscess. Cardiovasc Pathol. 2007;4:252–5. Basso C, Boschello M, Perrone C, et  al. Epidemiology of bicuspid aortic valve: an echocardiogarphic survey in an apparently healthy children population. Am J Cardiol. 2004;93:661–3. Blasi S, De Martino A, Levantino M, Pratali S, Anastasio G, Bortolotti U.  Splenectomy and valve replacement in patients with infective endocarditis and splenic abscesses. Ann Thorac Surg. 2016;102:e253–5. Bortolotti U, Thiene G, Milano A, Panizzon G, Valente M, Gallucci V. Pathological study of infective endocarditis on Hancock porcine bioprostheses. J Thorac Cardiovasc Surgery. 1981;6:934–42. Breitkopf C, Hammel D, Scheld HH, Peters G, Becker K.  Impact of a molecular approach to improve the microbiological diagnosis of infective heart valve endocarditis. Circulation. 2005;111:1415–21. Castonguay MC, Burner KD, Edwards WD, Baddour LM, Maleszewski JJ. Surgical pathology of native valve endocarditis in 310 specimens from 287 patients (1985-2004). Cardiovasc Pathol. 2013;22:19–27. Choudhury R, Grover A, Varma J, et  al. Active infective endocarditis observed in an Indian hospital 1981-1991. Am J Cardiol. 1992;70:1453–8. Davies MJ. Pathology of cardiac valves. London: Butterworths; 1980. Delahaye JP, Poncet PH, Malquarti V, Beaune J, Garè JP, Mann JM.  Cerebrovascular accidents in infective endocarditis: role of anticoagulation. Eur Heart J. 1990;11:1074–8. Dressler FA, Roberts WC. Infective endocarditis in opiate addicts: analysis of 80 cases studied at necropsy. Am J Cardiol. 1989;63:1240–57. Durack DT, Lukes AS, Bright DK. New criteria for diagnosis of infective endocarditis: utilization of specific echocardiographic findings. Duke Endocarditis Service. Am J Med. 1994;96:200–9. Grant RT, Wood JE, Jones TD. Heart valve irregularities in relation to subacute bacterial endocarditis. Heart. 1928;14:247–61. Griffin MR, Wilson WR, Edwards WD, O'Fallon WM, Kurland LT.  Infective endocarditis: Olmstead County, Minnesota, 1950 through 1981. JAMA. 1985;254:1199–202. Horstkotte D, Follath F, Gutschik E, et  al. Guidelines on prevention, diagnosis and treatment of infective endocarditis. Executive sum-

103 mary. The task force on infective endocarditis of the European Society of Cardiology. Eur Heart J. 2004;25:267–76. John RMJ, Treasure T, Sturridge MF, Swanton RH. Aortic root complications of infective endocarditis: influence on surgical outcome. Eur Heart J. 1991;12:241–8. Karchmer AW.  Infective endocarditis. In: Braunwald E, editor. Heart disease. 6th ed. Philadelphia: WB Saunders; 2001. p. 1723–50. Lepeschkin E. On the relation between the site of valvular involvement in endocarditis and the blood pressure resting on the valve. Am J Med Sci. 1952;224:318–9. MacMahon SW, Hickey AJ, Wilcken DE, Wittes JT, Feneley MP, Hickie JB. Risk of infective endocarditis in mitral valve prolapse with and without precordial systolic murmurs. Am J Cardiol. 1987;59:105–8. Maizza AF, Thiene G.  Infective endocarditis. Curr Opinion Cardiol. 1992;7:482–7. McKinsey DS, Ratts TE, Bisno A. Underlying cardiac lesions in adults with infective endocarditis: the changing spectrum. Am J Med. 1987;82:681–8. Michel PL, Acar J.  Native cardiac disease predisposing to infective endocarditis. Eur Heart J. 1995;16:2–6. Musci M, Weng Y, Hübler M, Amiri A, Pasic M, Kosky S, Stein J, Siniawski H, Hetzer R. Homograft aortic root replacement in native or prosthetic active infective endocarditis: twenty-year single-center experience. J Thorac Cardiovasc Surg. 2010;139(3):665–73. Osler W.  Malignant endocarditis. Br Med J. 1885;467–70, 522–6, 577–9. Roberts WC. Characteristics and consequences of infective endocarditis (active or healed or both) learned from morphologic studies. In: Rahimtoola SH, editor. Infective endocarditis. Orlando, FL: Grune & Stratton; 1978. p. 55. Spirito P, Rapezzi C, Bellone P, et al. Infective endocarditis in hypertrophic cardiomyopathy: prevalence, incidence, and indications for antibiotic prophylaxis. Circulation. 1999;99:2132–7. Stekelberg JM, Murphy JG, Ballard D, et al. Emboli in infective endocarditis: the prognostic value of echocardiography. Ann Intern Med. 1991;114:635–40. Thiene G, Basso C. Pathology and pathogenesis of infective endocarditis in native heart valves. Cardiovasc Pathol. 2006;15:256–63. Ting W, Silverman NA, Arzouman DA, Levitsky S.  Splenic septic emboli in endocarditis. Circulation. 1990;82:IV;105-9. Van der Meer JTM, Thompson J, Valkenburg HA, Michel MF. Epidemiology of bacterial endocarditis in The Netherlands. I Patient characteristics. Arch Intern Med. 1992;152:1863–8. Watanakunakorn C, Burkert T.  Infective endocarditis at a large community teaching hospital, 1980-1990: a review of 210 episodes. Medicine. 1993;72:90–102. Watanakunakorn C.  Staphylococcus aureus endocarditis on the calcified mitral valve. Am J Med Sci. 1973;266:219–23.

7

Pathology of Mechanical Prosthetic Cardiac Valves Uberto Bortolotti, Mila Della Barbera, Tomaso Bottio, and Gaetano Thiene

With the advent of extracorporeal circulation in the early 1950s, surgical repair of many acquired and congenital cardiac diseases became possible. In those years, rheumatic disease was very common, with a frequent involvement of cardiac valves. Until then, most surgical procedures were confined to the treatment of mitral valve stenosis by means of closed commissurotomy. Prosthetic valve replacement became a reality when the first mechanical devices were available to be used in orthotopic position. The first commercially manufactured models were constructed based on the “ball-in-a-­cage” concept where a spherical occluder (poppet) was allowed to move freely into a metallic cage; the prostheses had a cloth-covered sewing ring to facilitate the implant in the native annuli (Fig.  7.1). Caged-ball prostheses were followed by other models, aimed to improve the hemodynamic performance and reduce thrombogenicity, including

specific changes in design. These were represented by caged-­ disc, tilting-disc, and bileaflet prostheses (Fig. 7.2). The first models of mechanical prostheses showed an evident suboptimal hemodynamics characterized by the presence of high transprosthetic gradients, especially when small-sized devices were implanted. This was the consequence of the specific design of caged-ball and caged-disc valves producing lateral flows due to the central presence of the occluder. Switching later to the tiling-disc concept and then to the bileaflet design improved significantly the hemodynamic performance providing a central, physiological blood flow. Availability of mechanical prostheses had a great impact in the management of patients with valvular heart disease. Nevertheless, soon some important complications related to their use, pertaining to all of them and some being typical of specific models, started to be observed.

U. Bortolotti Section of Cardiac Surgery, Cardio-thoracic and Vascular Department, University Hospital of Pisa, Pisa, Italy e-mail: [email protected] M. Della Barbera (*) · G. Thiene Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padua Medical School, and Cardiovascular Pathology Unit, University Hospital of Padua, Padua, Italy e-mail: [email protected]; [email protected] T. Bottio Division of Cardiac Surgery, Emergency and Transplant Department, University Hospital of Bari, Bari, Italy © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 G. Thiene et al. (eds.), Pathology of Cardiac Valve Disease, https://doi.org/10.1007/978-3-031-35498-4_7

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Fig. 7.1  The Starr-Edwards caged-ball prosthesis. (a) The original model used for the first mitral valve replacement (left) was made of a lucite cage, a silicone rubber (Silastic) ball, and a Teflon sewing ring.

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(b) The last model of the same prosthesis consisted in a metallic cage made of stellite, a cobalt-chromium-molybdenum-nickel alloy and a Silastic ball with a silicone rubber and sponge in the sewing ring

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a

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Fig. 7.2  Different blood flow patterns through the various models of mechanical prostheses. (a) Caged-ball; (b) caged-disc with lateral transprosthetic flow; (c) tilting-disc; and (d) bileaflet models with both central and lateral flows

Thrombosis and Thromboembolism The major drawback of mechanical prostheses, regardless of their specific model, is represented by the occurrence of thrombus deposition on the surface of the fabric and metallic components. Thrombosis is extremely dangerous since it may extend to interfere with the movement of the occluders, causing sudden, acute malfunction (Fig.  7.3). Moreover, systemic embolization may also occur with ischemic complications and severely debilitating or even lethal consequences (Figs.  7.4 and 7.5). Implant of

mechanical prostheses, both in mitral and aortic positions, requires lifelong administration of oral anticoagulants. Anticoagulation management is sometimes difficult due to absence of patient compliance, associated diseases, or drug interference. Most cases of prosthetic thrombosis are related to inadequate anticoagulant treatment or its arbitrary suspension; conversely, an excessive anticoagulation may cause hemorrhagic complications with possible fatal sequelae. Pyrolytic carbon (Carbofilm) was introduced to prevent thrombus formation by coating the poppet, the struts and even the sponge of the sewing ring.

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Fig. 7.3  Thrombosis of three different mechanical prosthetic models. (a) caged-disc, (b) tilting-disc, and (c) bileaflet. In all cases thrombus deposition interfered with the occluder movements, causing blockage and dysfunction

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Fig. 7.4 (a) Cerebral ischemia in a patient with a mechanical prosthesis, who died of a thromboembolic stroke. (b) Embolic occlusion of a coronary artery. (c) Myocardial infarction at the histology. Haematoxylin-eosin disclosing infarction

7  Pathology of Mechanical Prosthetic Cardiac Valves Fig. 7.5  Gross aspect of the kidney in a patient who died of mechanical prosthesis-­ related thromboembolism. Acute infarction shown on the kidney surface (a) and in the parenchyma (b)

a

Fibrous Tissue Overgrowth Excessive reaction by the host tissue may occur at the prosthetic sewing ring and native valvular annulus as expression of a healing process. This is represented by formation of fibrous tissue which can cover the fabric ring, protruding on

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the valve orifice with reduction of the prosthetic effective orifice area (Fig.  7.6). This process starts with progressive deposition of platelets fibrin and formation of a thrombotic lining which subsequently becomes organized in fibrous tissue overgrowth (Fig. 7.7).

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Fig. 7.6  Fibrous tissue overgrowth in a patient reoperated because of severe stenosis of a Starr-Edwards caged-ball prosthesis implanted in aortic position. Fibrous tissue is present on the ventricular view (a), covering entirely the sewing ring and significantly reducing the effective prosthetic of the orifice. On the aortic view (b), the fibrous pannus climbs the lower part of the cage struts, interfering with ball excursion

a

Fig. 7.7 (a, b) Two explanted tilting-disc mechanical valve prostheses with evidence of thrombotic deposition close to the sewing ring and fibrous tissue overgrowth. Thrombus and fibrous tissue apposition clearly interfere with the disc movements. The organization of continuous thrombus formation may explain the growth of the fibrous pannus

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7  Pathology of Mechanical Prosthetic Cardiac Valves

Structural Deterioration The first models of caged-ball prostheses contained a silicone poppet which was noted to undergo with time to swelling due to absorption of plasma proteins and lipids from the blood stream. This caused a variation in the structure, size, and shape of the occluder, a phenomenon known as ball variance which interfered with the ball movements (Fig. 7.8). Despite being constructed with apparently strong and fatigue-resistant materials, some of the mechanical prostheses implanted clinically showed failures due to wear or rupture of part of their structural elements.

Fig. 7.8 (a, b) Caged-ball prostheses with ball variance; in both cases the ball becomes swollen and larger than the initial size, so that cage may be unable to contain it. (c) In another caged-ball valve, the occluder shows an evident fracture indicating an impending risk of embolization

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Rupture of components of a mechanical prosthesis, such as the metallic struts of the cage, have been observed in the past. As a consequence, cases of fatal valve dysfunction with systemic ball embolization have occurred (Fig. 7.9). Occasionally, wear of the disc has been observed in some models with erosion sites due to contact with the cage with eventual disc embolization (Fig. 7.10). In some tilting-disc and bileaflet prostheses, rupture of some components has occurred with frequent fatal consequences due to sudden and acute device failure (Fig. 7.11). Such failures have been attributed to faulty prosthetic designs which have required recall of such devices from the market.

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Fig. 7.9 (a) Fracture of the cage struts of an aortic prosthesis; (b) a pyrolytic carbon ball escaped from the ruptured cage and was found at necropsy in the aortic carrefour

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Fig. 7.10 (a, b) Wear (arrows) of the disc of caged-disc prostheses occurred by contact with the stent. (c) Escape of the disc

7  Pathology of Mechanical Prosthetic Cardiac Valves

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Fig. 7.11 (a, b) Fracture of one of the retaining struts from the ring of Bjork-Shiley tilting-disc prosthesis. Rupture occurred at the welding points (arrowheads) with fatal disc embolization. Subsequent models eliminated this complication since the struts were not fused to the ring but obtained from a single piece of metal as integral part of the ring itself

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 RI-Tech Bileaflet Prostheses and Leaflet T Escape The TRI-Tech valve was a low-profile mechanical bileaflet cardiac valve prosthesis with pyrolytic carbon (Fig.  7.12). The two leaflets were designed to reduce both turbulence and the transvalvular gradient. The leaflets were housed in the orifice ring by two tabs inserted into orifice hinges, while a metal band reinforced the housing system. The polyester-­ made swing ring was covered by a small ledge of pyrolytic carbon, on both the inflow and outflow surfaces. The catastrophic structural deterioration of this mechanical valve model was tab fracture, due to tab height asymmetry (Figs. 7.13 and 7.14), with sudden leaflet escape. For this reason, the implantation program was interrupted with even prophylactic prosthetic replacement. The valve was withdrawn from the market. Among a total of almost 5550 TRI-Tech prostheses implanted worldwide, leaflet escape has been reported in 9 cases. In Padua, this complication occurred in three patients, two aortic and one mitral, 10 days, 40 days, and 22 months after surgery, respectively. A 52-year-old male underwent uneventful implantation of a 25 mm TRI-Tech aortic valve with ascending aorta replacement and died suddenly at home, 10  days postoperatively. The predischarge echocardiogram had shown a normal prosthetic valve function (mean gradient 12 mmHg). At autopsy, an escaped leaflet was found in the descending thoracic aorta.

b

Fig. 7.12  The unimplanted bileaflet mechanical TRI-Tech valve prosthesis, in both closed (a) and open (b) positions

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Fig. 7.13 (a) The escaped leaflet found in the thoracic aorta. Note the fracture of a pivot system with 0.55 mm asymmetry of the tabs height (0.75 mm of fractured tab versus 1.30 mm of nonfractured tab). (b) Close-up, which highlights the fractured pivot

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Fig. 7.14 (a) The successfully replaced mitral TRI-Tech prosthetic valve with one missing leaflet. (b) The missing leaflet, found in the left common iliac artery, with tab asymmetry of 0.33 mm

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Fig. 7.15 (a) TRI-Tech valve leaflet, escaped from the aortic position for valve tab fracture and found at the bifurcation of the left common iliac artery (b) Close-up of (a). (c) The TRI-Tech valve in the aortic

position: a leaflet is missing. (d) The missing leaflet, found in the left common iliac artery, had a tab asymmetry of 0.41 mm

Another patient, a 53-year-old man who was submitted to mitral valve replacement with a 31  mm TRI-Tech, experienced sudden dyspnea with pulmonary edema, 22  months postoperatively, and underwent a successful emergency prosthetic valve replacement. The third patient, a 68-year-old man, who had undergone 25  mm TRI-Tech aortic valve implantation and had refused prophylactic prosthetic valve

replacement, died suddenly while driving. The escaped leaflet was found in the left common iliac artery (Fig. 7.15) with tab asymmetry of 0.41 mm. Tab asymmetry, with postoperative risk of fracture of the pivoting system, leaflet escape, and embolization, were clearly a manufactural error.

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Paravalvular Leak

Further Reading

Apart from prosthetic thrombosis and fibrous tissue overgrowth, another well-known cause of nonstructural failure of mechanical valve devices is detachment from the prosthetic annulus. This complication is most commonly related to annular disruption by sewing ring sutures, precipitated by infectious endocarditis or caused by extreme weakness of the native annulus due to significant calcification. Technical factors during the surgical procedure may also play a role. As a ­consequence, formation of single or multiple regurgitant jets occurs which may cause both various degrees of hemolysis and severe valve insufficiency (Fig. 7.16).

Bottio T, Casarotto D, Thiene G, Caprili L, Angelini A, Gerosa G. Leaflet escape in a new bileaflet mechanical valve: TRI Technologies. Circulation. 2003;107:2303–6. Cianciulli TF, Fairman EB, Saccheri MC, Llanos Dethinne SD, Prezioso HA. Retrieval of a leaflet escaped in a TRI-Technologies bileaflet mechanical prosthetic valve. Eur J Echocardiogr. 2007a;9:65–8. Cianciulli TF, Lax JA, Saccheri MC, Redruello HJ, Belforte SM, Picone VP, Prezioso HA.  Acute mitral valve dysfunction due to leaflet escape in a TRI-Technologies bileaflet mechanical valve. Eur J Echocardiogr. 2007b;8:63–6. De Martino A, Milano AD, Thiene G, Bortolotti U. Diamond anniversary of mechanical heart valve prostheses. A tale of cages, balls and discs. Ann Thorac Surg. 2020;110:1427–33. De Martino A, Milano AD, Thiene G, Della Barbera M, Bortolotti U. The caged-ball prosthesis 60 years later. Historical review of a cardiac surgery milestone. Texas Heart Inst J. 2022;49:e207267. Della Barbera M, Bottio T, Angelini A, Cresce GD, Montisci M, Gerosa G, Valente M, Thiene G.  The pathology of TRI-tech valve leaflet escape. J Heart Valve Dis. 2012;21(2):241–6. Dikmengil M, Sucu N, Aytacoglu BN, Mavioglu I.  Leaflet escape in a TRI bileaflet rotatable mitral valve. J Heart Valve Dis. 2004;13:638–40. Edmunds LH. Thromboembolic complications of current cardiac valvular prostheses. Ann Thorac Surg. 1982;34:96–106. Gerosa G, Carta R, Montisci M, Leoni L, Iliceto S, Rizzoli G, Di Marco F. How to deal with recipients of valves prone to structural failure in the 2000s: Padua experience with the TRI Technologies valve. Ann Thorac Surg. 2006;82:858–64. Harken DE, Soroff HS, Taylor WJ, Lefemine AA, Gupta SK, Lunzer S. Partial and complete prostheses in aortic insufficiency. J Thorac Cardiovasc Surg. 1960;40:744–62. Kliger C, Eiros R, Isasti G, et al. Review of surgical prosthetic paravalvular leaks: diagnosis and catheter-based closure. Eur Heart J. 2013;34:638–48. Lindblom D, Bjork VO, Semb BKH. Mechanical failure of the Bjork-­ Shiley valve. Incidence, clinical presentation and management. J Thorac Cardiovasc Surg. 1986;92:894–907. Roudaut R, Serri K, Lafitte S. Thrombosis of prosthetic heart valves: diagnosis and therapeutic considerations. Heart. 2007;93:137–42. Starr A, Edwards ML. Mitral replacement: clinical experience with a ball-valve prosthesis. Ann Surg. 1961;154:726–40. Weisse AB.  The surgical treatment of mitral stenosis: the first heart operation. Am J Cardiol. 2009;103:143–7.

Fig. 7.16  Tilting-disc mechanical valve prosthesis implanted in mitral position with evident detachment from the native annulus (arrow). Another periprosthetic leak is indicated by a probe, passing through the sewing ring-annulus interface (asterisk). The prosthesis had been implanted using a continuous suture technique. The patient had a mitral prolapse regurgitation, and the leaks might have been favored by the weakness of the annulus related to the underlying disease

8

Pathology of Biological Prosthetic Cardiac Valves Gaetano Thiene, Mila Della Barbera, Aldo Milano, Stefania Rizzo, Uberto Bortolotti, and Marialuisa Valente

Stented At present, approximately 80% of surgical valve replacements are performed employing bioprostheses, obtained either from the porcine aortic valve or made of bovine pericardium, the latter molded to simulate a tricuspid aortic valve (Fig. 8.1).

Porcine Bioprostheses Glutaraldehyde fixation ensures tissue stabilization by strengthening collagen cross-linking, masking recipient immunological response, and assuring tissue sterilization (Fig. 8.2). Porcine valves are mounted on a stent, which in the initial models was made by rigid metallic alloys, and then replaced by flexible plastic material such as polypropylene in most recent models; the stent is covered with a fabric cloth and provided with a sewing ring to facilitate prosthesis implantation (Fig. 8.3). Normal porcine aortic cusps consist of three layers (Fig. 8.4): (a) “Ventricular,” facing the ventricular cavity with elastic fibers. (b) “Spongiosa,” with extracellular matrix, mostly ground substance. G. Thiene (*) · M. D. Barbera · S. Rizzo · M. Valente Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padua Medical School, and Cardiovascular Pathology Unit, University Hospital of Padua, Padua, Italy e-mail: [email protected]; [email protected]; [email protected]; [email protected] A. Milano Division of Cardiac Surgery, Emergency and Transplant Department, University Hospital of Bari, Bari, Italy e-mail: [email protected] U. Bortolotti Section of Cardiac Surgery, Cardio-thoracic and Vascular Department, University Hospital of Pisa, Pisa, Italy e-mail: [email protected]

(c) “Fibrosa,” facing the sinus of Valsalva, with collagen bundles; this layer crimps during ventricular systole and flattens during diastole. Unfortunately, in the first-generation models without an effective antimineralization treatment, structural deterioration of the valve tissue occurred with time so that nearly 50% of patients required prosthetic valve replacement within 10–12 years from implant (Fig. 8.5) and almost 100% within 20 years. Causes and mechanisms of structural deterioration of bioprosthetic valves may be divided into host-related and graft-­ related (Table  8.1). Among the former, fibrous tissue overgrowth consists of exuberant healing at the annulus invading the orifice and overlaying the cusps, thus creating valve stenosis (Fig.  8.6). Lipid insudation from the recipient’s blood may also occur, at times being so great to determine cusp fragility with tearing and prosthetic valve incompetence, even in the absence of calcification (Fig. 8.7). Among the graft-related causes of structural valve deterioration, inward banding (Fig.  8.8a) due to creeping of the stent, may occur with prosthetic stenosis  (Fig.  8.8b). Occasionally, sudden collapse of the frame by fracture of the post (Fig.  8.8c) may even cause acute prosthetic valve incompetence. Cuspal hematomas are hematic dissections of the porcine cusps (Fig.  8.9), probably due to blood entering through stitches at the annulus. Commissural dehiscence, with detachment of the cusp commissures from the xenograft aortic wall, results in valve incompetence (Fig. 8.10). The right cusp of a porcine aortic valve includes a myocardial shelf. An immune reaction with macrophage phagocytosis of the glutaraldehyde-fixed pig cardiomyocytes may cause perforation of the muscle shelf with prosthetic incompetence (Fig. 8.11). Thrombus formation may fill the Valsalva sinuses impairing cusp distensibility and causing valve stenosis (Fig. 8.12).

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 G. Thiene et al. (eds.), Pathology of Cardiac Valve Disease, https://doi.org/10.1007/978-3-031-35498-4_8

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Fig. 8.1 (a) Porcine aortic valve and (b) pericardial aortic valve, tricuspid molded from a sheet of bovine pericardium Fig. 8.2 Glutaraldehyde fixation with collagen cross linking

Cells

Bundles of fibers Cross linking

GLUTARALDEHYDE

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8  Pathology of Biological Prosthetic Cardiac Valves Fig. 8.3  Porcine (a) and pericardial (b) valves, after being mounted in the stent

Fig. 8.4 (a) Histology of an aortic porcine cusp with three layers (ventricularis, spongiosa and fibrosa), (b) note the collagen crimping of the fibrosa during systole and flatting in diastole

Porcine stented

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100 80 60 40 20

Porcine: MetaAnalysis - 5,837 patients CE Pericardial Perimount: 8 studies - 2,902 patients “Porcine Limits”

0 0

5 10 15 Years Post-PHV Implant

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Fig. 8.5  Longevity of porcine and pericardial valve. After 7–8 years, the actuarial Meyer curve freedom from structural valve deterioration starts to decline

Table 8.1  Host-related and graft-related causes of structural valve deterioration

Fig. 8.6  Severe stenosis of mitral porcine BP valves by fibrous tissue overgrowth. (a) Gross view from the left atrium; (b) histology. Weigert-Van Gieson stain

However, dystrophic calcification of the xenograft cusps is the major cause of the structural valve deterioration in porcine bioprostheses. Blood calcium of the recipient combines with phospholipids of the cell membrane debris of the xenograft valve, thus precipitating calcium phosphate formation. Calcification leads either to cusp stiffness and rigidity with valve stenosis (Fig. 8.13a) or commissural and cusp tearing with incompetence (Fig. 8.13b). Cusp mineralization accounts for almost 90% of cases of structural deterioration in porcine bioprosthetic valves recipients. The valve commissures are particularly prone to mineralization as to be the early sites of calcification, being the structures bearing the maximal mechanical stress during opening and closing of the cusps (Fig. 8.14).

Structural valve deterioration of bioprosthetic valves Host-related • Fibrous pannus • Lipid insudation Graft-related • Stent creeping or fracture • Cuspal hematoma • Commissural dehiscence • Thrombus formation • Tears, primary • Mineralization

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Fig. 8.7 (a) Yellow cusps of a porcine valve, (b) spontaneous tearing at the commissure in the absence of X-ray calcification, (c) insudation with cholesterol needles and foreign body inflammatory. Haematoxylin-eosin stain

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122 Fig. 8.8 (a, b) Creeping and (c) fracture with collapse of plastic stent in porcine bioprosthetic valves

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Fig. 8.9  Huge hematoma of the cusps, hindering the orifice opening and creating severe stenosis. (a) Gross view of a mitral device from the atrium; (b) histology of the hematoma (arrow). Azan Mallory stain

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Fig. 8.10 (a) Commissural dehiscence by detachment from xenograft aortic wall. (b) Closeup

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Fig. 8.11 (a) Porcine bioprosthetic valve perforation of the right aortic cusp muscle shelf with valve incompetence. (b) At transmission electron microscopy, a macrophage phagocytoses a sarcomere from a cardiomyocite

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Fig. 8.12  Porcine valve sinuses fulfilled by a thrombus and creating valve stenosis. (a) Gross view; (b) histology. Weigert-Van Gieson stain

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Fig. 8.13 (a) Stenosis of bioprosthetic porcine valve by massive dystrophic calcification with stiffened cusps. (b) Calcification may affect only the commissure and create tearing with even acute incompetence

Pericardial Bioprostheses Pericardial bioprosthetic valves, made of bovine parietal pericardium, represent an alternative to porcine bioprostheses. The parietal pericardium consists of a mesothelium layer, facing originally the pericardial cavity, compact fibrosa with parallel, slightly crimped collagen fibers and a few scattered pericardiocytes (interstitial cells) (Fig. 8.15).

Mechanical stress and abrasion of the pericardium by contact with the stent were considered responsible of commissural tearing in the first-generation pericardial devices, with prosthetic regurgitation both in tricuspid (Fig. 8.16a, b) and monocusp models (Fig. 8.16c), even in the absence of mineralization. This “Achilles heel” was corrected in the second generation of pericardial bioprostheses, by changing the valve

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Fig. 8.14 (a) X-ray showing a calcification starting at the commissures, enough to create tearing and severe acute valve incompetence. X-ray; (b) histology of a commissure, von Kossa stain

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Fig. 8.15 (a) Histology; (b) scanning electron microscopy, and (c, d) transmission electron microscopy pictures of unimplanted pericardium. Note the collagen fibers and bundles (b, c) and perfectly fixed interstitial cell

126 Fig. 8.16 (a) Commissural tearing of pericardial bioprosthetic valve (Ionescu-­ Shiley device) and (b) the same in Hancock pericardial valve device. (c) Commissural tearing of monocusp pericardial valve device. Note the absence of calcification at X-ray in all

G. Thiene et al.

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design with the use of a single sheet of bovine pericardium mounted on the stent to create a tricuspid valve model and a second sheet covering the stent to prevent abrasion (Fig.  8.17). When dystrophic calcification occurred in second-­generation pericardial bioprosthetic valves, mineralization involved all the cups with stenosis, without isolated commissural calcification and tearing (Fig. 8.18).

However, defective glutaraldehyde fixation of bovine pericardium occurred in the second-generation Mitroflow pericardial bioprosthetic valve, accounting for collagen denaturation (“fibrinoid necrosis”) and accelerated mineralization (Fig. 8.19).

8  Pathology of Biological Prosthetic Cardiac Valves Fig. 8.17  Change of the design in second-generation bovine pericardial valve xenografts. A single sheet is employed for molding all the three cusps. Second sheet covers the stent, to avoid abrasion

Fig. 8.18 Second-generation pericardial valve, gross view and X-Ray. (a) Prophylactic early explant: neither calcification nor tearing at the commissures. (b) Massive calcification with stenosis at distance with calcification of all the cusps, without tearing at commissure

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Stentless Stentless bioprosthetic valves (SLBPVs) have represented an important evolution in the history of surgical treatment of aortic valve stenosis. The advantage for the use of these devices, even in patients less than 65 years of age, is the lack of prosthetic frame, to mimic the native aortic valve and to minimize both commissural hemodynamic stress and postoperative transvalvular gradient. Postoperative regression of left ventricular hypertrophy occurs. The negative aspect is the extensive suturing requiring long-time cross-clamping, with the risk of not optimal myocardial protection and the need of peculiar skill by the surgeon, with long learning curve. Stentless bioprostheses are made from the porcine aortic valve or constructed with bovine pericardium (Fig. 8.20); both are fixed in glutaraldehyde and not mounted on a frame. They are implanted in a free-hand fashion using three separate sutures to fix the valve to the native aortic annulus. This procedure may be time consuming and therefore such devices have not been universally accepted as alternative to stented bioprostheses. In porcine SLBPVs, following the removal of the native diseased cusps, the commissures remain attached to the porcine xenograft aortic wall and sutured to the recipient one. a

c

The most typical mode of dysfunction of porcine SLBPVs is usually incompetence while for pericardial SLBPVs is stenosis. Porcine SLBPVs degenerate in a peculiar mode, namely, pinpoint calcification at the commissures, which can lead to tearing and ever sudden incompetence (Fig. 8.21). Valve tissue degradation may consist also of lipid insudation, tissue disruption, and fraying of collagen fibers. Lipid insudation (“atheromasia”) is well visible at gross examination by a yellowish appearance of the cusps. Histology and transmission electron microscopy show cholesterol clefts (Figs. 8.22 and 8.23). In stentless pericardial xenografts the cusps are molded from a single pericardial sheet, which is then sutured to a second external pericardial sheet. In pericardial SLBPVs, calcification phenomenon can be massive at both cusps commissures and belly, leading to stenosis for cusp stiffening and regurgitation due to cusp tears. In addition, pericardial SLBPVs may also show focal yellow spots, like fatty streaks (“atheromasia”). Histology reveals intrinsic calcification and focal mononuclear cell infiltrates, mostly macrophages positive at immunohistochemistry markers (Fig. 8.24).

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Fig. 8.19 (a, b) Severe early calcification at gross and X-ay examination of a Mitroflow pericardial valve. Poor glutaraldehyde fixation with collagen denaturation, is well visible both at light (c, d) (haematoxylin-

e

eosin and Azan Mallory stains) and ultrastructural transmission electron microscopy (e)

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Pericardial stentless

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Fig. 8.21  Cryolife-O’Brien porcine stentless valve removed by emergency operation, following an abrupt incompetence due to Ca++ commissural tearing. Gross (a) and X-ray (b) views of the removed cusps with pin point mineralization at the commissures

Mineralization was proven to occur ever in the midterm, similar to stented valves, particularly at commissural levels of porcine SLBPVs, as to account for an even abrupt tearing and valve incompetence (Figs. 8.23, 8.24, 8.25 and 8.26). Thus, tissue mineralization is the nightmare also of SLBPVs. Even pinpoint calcification at the commissure and belly, especially in porcine devices, may be dangerous enough to cause abrupt cuspal tearing and sudden incompetence. Lipid insudation contributes to SVD as well. Overall,

aortic valve replacement with Toronto porcine stented valve resulted with an optimal patient survival but suboptimal valve durability. Treatment with effective anticalcific agents should increase long-term durability. Moreover, nowadays, TAVI with “valve-in-valve” procedure is a valid alternative to surgical prosthetic valve replacement and reoperation in case of SVD.

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Fig. 8.22  Cryolife-O’Brien porcine stentless valve. The cusp appears yellow at gross examination (a–c). Coarse calcification at X-ray (d–f) and lipid insudation at histology with intrinsic calcification (g–i). Von Kossa stain Fig. 8.23 (a, b) Transmission electron microscopy of a porcine cusp (same case of Fig. 8.23). Note lipid droplet and cholesterol needles (asterisks)

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Fig. 8.24  Removed cusps of Solo stentless pericardial valve (a) with pinpoint calcific deposits at X-ray (b). Note massive lipid insudation with cholesterol clefts surrounded by CD68-positive macrophages (c)

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Fig. 8.25  Gross (a, b, c), X-ray (d, e, f) with microscopic histologic findings (g, h, i) of a Toronto porcine SLBPV, explanted after 115 mos because of incompetence due to calcium-related commissural tearing. The explanted cusps show yellow appearance due to lipid insudation and commissural tearing (arrow). (a–f) Corresponding X-ray; note the

bright signal at a commissure (d) (arrow), due to calcifications with tearing and incompetence. Histologic sections of the cusps with intrinsic calcium deposits and the cholesterol clefts by lipid insudation (g–i). Hematoxylin-eosin stain (g, h) and von Kossa stain (i)

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Fig. 8.26  Gross (a–c), radiographic (d–f), and microscopic findings (g–i) of a Freedom Solo pericardial SLBPV, explanted after 83 mos because of stenosis due to calcific dystrophy. (a–c) Gross features of the cusps: note the thickening due to massive calcifications. (d–f)

Corresponding X-ray; diffuse bright signal due to mineralization. (g–i) Histological sections with von Kossa stain: massive cuspal intrinsic calcium deposits

Sutureless

Since implantation requires collapse of the valve followed by ballooning (Fig.  8.28), pericardial damage was feared during this procedure. This phenomenon has been excluded by scanning electron microscopy studies, detecting neither collagen periodicity changes nor architectural fibers deformation after collapsing and ballooning in  vitro (Figs.  8.29 and 8.30). Thus, collapsing and ballooning during deployment of Perceval S do not damage the xenograft pericardial collagen. Collagen crimping appeared unaltered. Neither tear and perforations of the pericardial cusps nor stent deformation fractures have been observed.

Sutureless valve devices were introduced in the clinical setting to expedite valve implant even with a thoracoscopy approach, as to avoid sternotomy. Unlike with TAVI, in which the native calcific valve is left in situ, sutureless valve implant procedure consists of cusp excision, avoiding risk of calcium nodular embolization and paravalvular leak. The sutureless Perceval valve model is composed by a nitinol frame, adapted around the pericardial stentless Solo bioprosthesis, and by an anchorage clothed annulus (Fig. 8.27).

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Fig. 8.27  Perceval S sutureless bioprosthetic valve. A self-expandable nitinol network surrounds a pericardial stentless valve

Ready to implant

Valve is collapsed to a reduced diameter First step valve deployment

Fig. 8.28  The two steps of valve implantation valve are as follows: collapsed to reduce the diameter and then deployed

However, in the mid to long term, both mineralization and fibrous pannus (Figs. 8.31 and 8.32) occurred. Fibrous tissue overgrowth with stenosis took place progressively overtime with a plateau around 20  months after implant. Structural valve deterioration by mineralization with stenosis was observed in some patients in the midterm follow-up as to require redo with bioprosthesis valve replacement. Nowadays, valve-in-valve TAVI procedure is a reliable alternative to surgical reintervention, avoiding anesthesia, sternotomy, and cross-clamping. Effective anticalcification treatment and stent remodeling will be mandatory to improve long-term durability of Pericardial sutureless valve bioprosthesis. Moreover, the implant procedure has to pay attention on the His bundle, which is only 5–6  mm far from the aortic annulus. A newly introduced anticalcification treatment is expected to enhance valve durability, preventing early mineralization. A second-generation Perceval (Perceval Plus) with antimineralization processing has been manufactured and it is now in the market.

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Collagen wave length (µm) 25 17.47±2.50

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Fig. 8.30  A 3-hour collapse of the pericardial valve did not alter collagen periodicity. Note the comparison with no collapse controls. Histogram displaying collagen wave length at different collapsing times, in comparison with controls (no collapse). All values are expressed as mean ± standard deviation

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Fig. 8.31  Fibrous tissue overgrowth (pannus) narrows the orifice with stenosis, 59 months after implant (a, b). Coarse calcification is also visible at X-ray (c). Fibrous tissue climbs onto the stent (d), (e) histology of the pannus. Hematoxylin-Eosin stain

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Fig. 8.32  Severe calcification (a–c) of a Perceval S, 53 months after implant. Note the severe calcification at X-Ray (d) and histology (von Kossa stain). Note fibrous tissue overgrowth climbing the nitinol strut at gross view (c) and histology (f) (Azan Mallory stain 200x)

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The lack of long-distance results represents still a drawback, which does not allow definitive conclusions. Comparison with transcatheter valve (TAVI) aftermath is warranted.

Interventional Transcatheter interventional therapy of valve disease has expanded therapeutic options. It includes less invasive approaches such as transcatheter aortic valve implantation (TAVI), edge-to-edge repair, or even atrioventricular valve implantation. TAVI represented a revolutionary approach to repair aortic valve stenosis with minimally invasive treatment. The procedure consists of implanting a pericardial aortic valve device through femoral artery. After expansion of the stenotic aortic valve, which is left in situ, the device is deployed into the aortic annulus. Originally, there were three models with different deployment systems (Fig. 8.33): (a) The Edwards Sapien with expandable balloon. (b) The Core valve with self-expandable nitinol frame. (c) Cardio Intuity with expandable balloon. An alternative approach is surgical (Fig. 8.34), from the apex of the left ventricle (“transapical”), or through the ascending aorta on a beating heart, both without cardiopulmonary bypass. When the interventional bioprosthesis is

a

b

implanted in failed bioprosthesis, rather than in a native valve, the procedure is called “valve-in-valve.” In any case, the valve is a three-leaflet bovine pericardial bioprosthesis with fibrosa much thicker than fibrosa of porcine pericardium (Fig. 8.35). Moreover, experiments with porcine valve showed rupture of the porcine leaflets, because of crack of the fibrosa with the ballooning, suggesting that porcine valve xenograft is not suitable to cope with this purpose (Fig. 8.36). The operation is not free from complications, mostly related to the blind procedure and the leaving in situ the native calcified valve (Fig. 8.37). Complications consist of the following: (a) The catheter along abdominal, ascending aorta as well as the aortic arch may encounter atherothrombotic plaques (Fig. 8.38) with the risk of embolism. The catheter crossing the aortic arch and ascending aorta is at risk of cerebral embolism and stroke. (b) Vascular access complications like femoral artery dissection or rupture. (c) Extrinsic calcific vegetations of the native aortic valve, by forcing to open the orifice during device deployment, may detach nodular calcific deposits with coronary and cerebral embolism (Fig. 8.39). (d) The presence of marked calcific deposits at the aortic annulus may be of obstacle to the deployment of the device and to achieve perfect adhesion, accounting for perivalvular leak and aortic regurgitation.

c

Fig. 8.33  Three models of TAVI, all employing glutaraldehyde fixed pericardial cusps. (a) Sapien, requiring ballooning for deployment. (b) Core valve with nitinol self-expandable frame. (c) Cardio Intuity with expandable balloons

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Fig. 8.34  Transarterial (a) vs transapical (b) valve implantation (TAVI), the latter from the apex of the left ventricle, both with beating heart and no need of cardiopulmonary bypass. (c) Sapien in situ after deployment

Fig. 8.35  The thickness of bovine pericardium fibrosa is nearly three times than that of porcine pericardium. Azan Mallory stain

Bovine Pericardium

Porcine Pericardium

Bovine Pericardial is a strong and resistant tissue Pericardial Tissue Yield Strength [Newtons] 25 20 15 10 5 0

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Fig. 8.36  TAVI employing porcine aortic cusps (a, b). The deployment and ballooning create fracture of the thin leaflet fibrosa (c, d). Azan Mallory stain Fig. 8.37  The native senile aortic valve stenosis by nodular dystrophic calcification (a) which appears intrinsic at histology (b). Azan Mallory stain

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Fig. 8.38  Senile aortic valve stenosis (a) in a patient with severe atherothrombosis of the aorta; (b) panoramic view; (c) closeup of the thoracic aorta Fig. 8.39  Embolism of the right anterior cerebral artery due to detachment of a calcific nodule from a native aortic cusp, occurred during Sapien bioprosthetic valve deployment with ballooning. (a) Panoramic view. (b) Closeup: note the calcific embolic fragment occluding the right anterior cerebral artery. Arrow indicates the calcific embolism

a

(e) Native valve calcific deposits may involve the right and left fibrous trigons with the risk of perforation during the traumatic bioprosthetic valve deployment (Figs.  8.40 and 8.41). (f) The AV conduction system is just below the aortic annulus (5–6 mm at distance) (Fig. 8.42). Site of sub-annular stent insertion should not exceed 2–3 mm; otherwise, the subvalvular nitinol network may compress the His bundle and the left bundle branch, with onset of complete

b

AV block if a right bundle branch block pre-exists (Fig. 8.43). Interference with the anterior leaflet of the mitral valve can also occur in the setting of a downward deployment into the left ventricular outflow tract (Fig. 8.43). (g) The abovementioned complications are pathognomonic of TAVI procedure. Of course, other complications like endocarditis may occur as in any bioprosthetic valve (Fig. 8.44).

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(h) Thrombus formation, blocking the cusp opening (Fig. 8.45), has been reported, quite similar to that originally observed in surgically implanted porcine bioprostheses. (i) Dystrophic calcification at mid to long term can occur also in the pericardial leaflets of TAVI (Fig. 8.46). Valve-­ in-­valve procedure is now available to treat structural valve deterioration by calcific degeneration. It has been already employed for structural valve deterioration of surgical stented bioprosthetic valves, both porcine and pericardial. Fig. 8.40  Calcification in native senile aortic stenosis, extended to the right and left fibrous trigones (arrows), at risk of external rupture during TAVI ballooning and deployment

a RVOT

LC PC

b

*

Fig. 8.41 (a) The Sapien prosthesis appears correctly implanted with no interference with the right and left coronary ostia, the anterior mitral valve leaflet, and the conduction system of the subaortic membranous ventricular septum. Note the aortic annulus rupture (probe inside) at the nadir of the left coronary cusp. (b) View of the left ventricular outflow tract, after removal of the aortic valve prosthesis: note the amount of calcification distributed along the mitroaortic fibrous continuity, particularly at the level of the right and left fibrous trigones. A perforation (asterisk) is visible at the nadir of the left coronary cusp, 1 cm below the coronary ostium (arrow), in correspondence of a calcific deposits which were detached during the TAVI procedure. LC  =  left anterior aortic cusp; PC  =  posterior, noncoronary cusp; RVOT = right ventricular outflow tract

In addition, atrioventricular valves can  be a target for interventional therapy. Until recently, valve surgical replacement or repair was the only feasible treatment for mitral regurgitation. Currently, invasive percutaneous methods include narrowing the orifice by clipping the leaflets or implanting bioprostheses into the native mitral orifice or in the lumen of failed bioprosthetic valves (the valve-in-valve procedure), via a transapical or a transseptal atrial approach (all in beating heart without extracorporeal circulation), with low complication rate and high procedural performance. The most used interventional method of treating mitral valve incompetence is nowadays the MitraClip device. This device is a V-shaped, fabric covered clip, which captures the free edge of both mitral leaflets and creates a double orifice valve, a procedure similar to the “Alfieri” surgical repair. In porcine model experimental studies, endothelialization of the clips occurred as early as 4 weeks, with 100% of clips by 17 weeks. Complications may be procedure or device related. As for procedure-related complications, thromboembolic events and vascular approach dissection may occur. Device-­ related complications include functional (persistent mitral regurgitation, mitral stenosis) and structural device failure (clip detachment with possible embolization, injury of leaflets or subvalvular apparatus, endocarditis). Transcatheter valve therapies enlarge the limited treatment options also to tricuspid regurgitation and include percutaneous tricuspid annuloplasty, to reduce the orifice area of the tricuspid valve, by edge-to-edge clip repair (Figs. 8.47 and 8.48).

8  Pathology of Biological Prosthetic Cardiac Valves Fig. 8.42 (a) Normal AV conduction system with distance of His bundle from the aortic annulus. (b) Safe subaortic distance of the bioprosthetic annular stent should not exceed 2–3 mm. L = left anterior aortic cusp; R = right anterior aortic cusp; NC = non coronary aortic cusp

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Fig. 8.43  AV block (b, c) by compression of the left bundle branch in patient with preoperative right bundle branch and sub-annular stent. The deep implantation of the TAVI device into the left ventricular out-

flow tract (a, d, e) can interfere also the anterior mitral valve leaflet. A = aorta; LV = left ventricle; MS = membranous septum. From Fraccaro et al., Am J Cardiol. 2011

144 Fig. 8.44  Infective fungal endocarditis in TAVI. (a, b) At gross examination, note a prosthetic valve stenosis by polypous and friable vegetations that block a pericardial cusp and extends along the mitroaortic fibrous continuity. (c, d) Histologic examination shows clusters of Candida-type yeasts, hyphae, and pseudohyphae entrapped, within a fibrin network platelets, red cells, and granulocytes ((c), HE; (d), PAS; insert, Grocott stains). From Santos M et al., Eur Heart J. 2011

G. Thiene et al.

a

b

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Fig. 8.45 (a, b) TAVI showing massive thrombotic vegetations blocking the valve leaflets. On histological examination, the thrombotic material consists of mixture of fibrin and platelet aggregates  (c).

Coronary artery embolization occurred (d). (c) Hematoxylin-eosin stain. (d) Azan Mallory stain

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Fig. 8.46 Valve-in-valve transcatheter mitral valve implantation (TMVI): atrial view of the mitral porcine bioprosthetic valve with cusps in open position (a) in a 54-year-old woman. High-resolution X-ray with heavy calcifications demonstrated by the bright signal (b). Histological section of a cusp: note intrinsic calcium deposits (black) (c). Atrial view of Sapien XT bioprosthesis with heavy nodular calcifi-

a

cations of the cusps. Fibrous tissue overgrowth involves the metallic stent (d). High-resolution X-ray showing heavy calcifications demonstrated by the bright signal (e). Histological section of the sampling of (d). Intrinsic nodular calcium deposits (black) are detected (f) (c, g von Kossa staining). From Tessari C et al., Card Surg. 2021

b

Fig. 8.47  Mitral clips in mitral incompetence by acute myocardial infarction with partial papillary muscle rupture. (a) atrial view; (b) ventricular view

8  Pathology of Biological Prosthetic Cardiac Valves

a

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Fig. 8.48  Mitral clip in chronic ischemic heart disease with congestive heart failure. (a) atrial view; (b) ventricular view

Further Reading  Akins CW, Miller DC, Turina MI, Kouchoukos NT, Blackstone EH, Grunkemeier GL, Takkenberg JJ, David TE, Butchart EG, Adams DH, Shahian DM, Hagl S, Mayer JE, Lytle BW, STS; AATS; EACTS. Guidelines for reporting mortality and morbidity after cardiac valve interventions. Ann Thorac Surg. 2008;85(4):1490–5. Ali A, Halstead JC, Cafferty F, et al. Are stentless valves superior to modern stented valves? A prospective randomized trial. Circulation. 2006;114(1 Suppl):I535–40. Alvarez JR, Sierra J, Vega M, Adrio B, Martinez-Comendador J, Gude F, Martinez-Cereijo J, Garcia J.  Early calcification of the aortic Mitroflow pericardial bioprosthesis in the elderly. Interact Cardiovasc Thorac Surg. 2009;9(5):842–6. Arbustini E, Bortolotti U, Valente M, et al. Cusp disruption by massive lipid infiltration. A rare cause of porcine valve dysfunction. J Thorac Cardiovasc Surg. 1982;84(5):738–43. Bach DS, Kon ND, Dumesnil JG, Sintek CF, Doty DB. Ten-year outcome after aortic valve replacement with the freestyle stentless bioprosthesis. Ann Thorac Surg. 2005;80(2):480–7. Baumgartner H.  Transcatheter valve-in-valve implantation in failed aortic bioprosthetic valves: a word of caution in times of euphoria. Eur Heart J. 2020;41(29):2743–6. Bejko J, Della Barbera M, Valente M, Pettenazzo E, Gregori D, Basso C, Thiene G. Morphologic investigation on Perceval S, a sutureless

147 pericardial valve prosthesis: collagen integrity after collapsing-ballooning and structural valve deterioration at distance. Int J Cardiol. 2021;(341):62–7. Belluschi I, Buzzatti N, Castiglioni A, De Bonis M, Maisano F, Alfieri O. Aortic and mitral bioprosthetic valve dysfunction: surgical or percutaneous solutions? Eur Heart J Suppl. 2021;23(Suppl E):E6–E12. Berkovitz BKB.  Crimping of collagen in the intra-articular disc of the temporomandibular joint: a comparative study. J Oral Rehabil. 2000;27:608–13. Biancari F, Barbanti M, Santarpino G, et al. Immediate outcome after sutureless versus transcatheter aortic valve replacement. Heart Vessel. 2016;31(3):427–33. Blasi S, Ravenni G, Celiento M, De Martino A, Milano AD, Bortolotti U.  Durability of the mitroflow pericardial prosthesis: influence of patient-prosthesis mismatch and new anticalcification treatment. Thorac Cardiovasc Surg. 2020 Mar;68(2):131–40. Bleiziffer S, Simonato M, Webb JG, Rodés-Cabau J, Pibarot P, Kornowski R, Windecker S, Erlebach M, Duncan A, Seiffert M, Unbehaun A, Frerker C, Conzelmann L, Wijeysundera H, Kim WK, Montorfano M, Latib A, Tchetche D, Allali A, Abdel-Wahab M, Orvin K, Stortecky S, Nissen H, Holzamer A, Urena M, Testa L, Agrifoglio M, Whisenant B, Sathananthan J, Napodano M, Landi A, Fiorina C, Zittermann A, Veulemans V, Sinning JM, Saia F, Brecker S, Presbitero P, De Backer O, Søndergaard L, Bruschi G, Franco LN, Petronio AS, Barbanti M, Cerillo A, Spargias K, Schofer J, Cohen M, Muñoz-Garcia A, Finkelstein A, Adam M, Serra V, Teles RC, Champagnac D, Iadanza A, Chodor P, Eggebrecht H, Welsh R, Caixeta A, Salizzoni S, Dager A, Auffret V, Cheema A, Ubben T, Ancona M, Rudolph T, Gummert J, Tseng E, Noble S, Bunc M, Roberts D, Kass M, Gupta A, Leon MB, Dvir D.  Long-term outcomes after transcatheter aortic valve implantation in failed bioprosthetic valves. Eur Heart J. 2020;41(29):2731–42. Borger MA, Carson SM, Ivanov J, et al. Stentless aortic valves are hemodynamically superior to stented valves during mid-term follow-up: a large retrospective study. Ann Thorac Surg. 2005;80(6):2180–5. Bortolotti U, Gallucci V, Casarotto D, Thiene G. Fibrous tissue overgrowth on Hancock mitral xenografts: a cause of late prosthetic stenosis. J Thorac Cardiovasc Surg. 1979;27:316–8. Bortolotti U, Milano A, Mazzucco A, Valfre C, Fasoli G, Valente M, Thiene G, Gallucci V.  Longevity of the formaldehyde-preserved Hancock porcine heterograft. J Thorac Cardiovasc Surg. 1982;84(3):451–3. Bottio T, Thiene G, Pettenazzo E, Ius P, Bortolotti U, Rizzoli G, Valfré C, Casarotto D, Valente M. Hancock II bioprosthesis: a glance at the microscope in mid-long-term explants. J Thorac Cardiovasc Surg. 2003;126(1):99–105. Bottio T, Valente M, Rizzoli G, et al. Commissural dehiscence: a rare and peculiar cause of porcine valve structural deterioration. J Thorac Cardiovasc Surg. 2006;132:1017–22. Butany J, Collins MJ, Nair V, Leask RL, Scully HE, Williams WG, David TE.  Morphological findings in explanted Toronto stentless porcine valves. Cardiovasc Pathol. 2006;15(1):41–8. Butany J, Zhou T, Leong SW, Cunningham KS, Thangaroopan M, Jegatheeswaran A, Feindel C, David TE.  Inflammation and infection in nine surgically explanted Medtronic freestyle stentless aortic valves. Cardiovasc Pathol. 2007;16(5):258–67. Butany J, Feng T, Luk A, Law K, Suri R, Nair V.  Modes of failure in explanted mitroflow pericardial valves. Ann Thorac Surg. 2011;92(5):1621–7. Butany J, Feng T, Suri R, Law K, Christakis G. Mitroflow pericardial bioprosthesis: structured failure at 4.5 years. Cardiovasc Pathol. 2012;21(6):506–10. Capodanno D, Petronio AS, Prendergast B, et al. Standardized definitions of structural deterioration and valve failure in assessing longterm durability of transcatheter and surgical aortic bioprosthetic valves: a consensus statement from the European Association of

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Anticalcification Strategies to Increase Bioprosthetic Valve Durability Marialuisa Valente, Mila della Barbera, Uberto Bortolotti, and Gaetano Thiene

Mineralization is the main cause of structural valve deterioration of xenograft bioprosthetic valves. In the time interval 1975–2000, 411 valve xenografts were explanted at surgical redo at the University of Padua because of failure. Calcific structural deterioration was detected in 368 (89.5%) (Table 9.1). Glutaraldehyde fixation is certainly needful and at present still unique for achieving stabilization by collagen crosslinking, prevention of immune reaction, and tissue sterilization (Fig. 9.1). After more than 50 years of its employment, no suitable alternative was found. Free aldehyde residuals with toxic effect on the recipient cells are considered the culprits. Moreover, after glutaraldehyde fixation and valve bioprosthesis implantation, a cascade of events occurs leading to cusp stiffness by mineralization. First, phosphorus of cell membrane links with calcium present in the interstitium and recipient blood, giving origin to calcification by apatite crystals formation and prosthetic valve failure (Fig. 9.2). The phenomenon has been observed by both spectroscopy and transmission electron microscopy. Energy dispersion analysis demonstrated a Ca++/Ph ratio correspondent to apatite (calcium phosphate). Transmission electron microscopy showed that origin of calcification starts upon cell membrane debris (Fig. 9.3). Lipid extraction by solvents is believed to be the best anticalcification treatment. For this reason, sodium dodecyl sulfate was employed in the second-generation porcine Hancock valve, ethanol in

Table 9.1  Calcification accounted for structural valve deteriorations in 89.5% of 411 porcine bioprosthetic valve explants for redo Mean time of function (mos) 124.8 ± 51.8

N. Explants 411

Ca++ SVD (%) 368 (89.5%)

(SVD: structural valve deterioration) From Bottio T. and Thiene G., unpublished

Glutataraldheyde Fixation PRO • Tissue stabilization by collagen cross-linking • Host-immunological response masking • Tissue sterilization CONS • Graft cell devitalization • Free aldehyde residuals with toxic effects on host cells

Fig. 9.1  Glutaraldehyde fixation pros vs. cons

porcine Epic link of St. Jude Medical, Tween80-ethanol in Carpentier Edwards bioprosthetic valves (Fig. 9.4). Freedom from structural valve deterioration (SVD) of Hancock Standard vs. Hancock II valves showed a significant gain in the durability (Fig. 9.5).

M. Valente (*) · M. d. Barbera · G. Thiene Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padua Medical School, and Cardiovascular Pathology Unit, University Hospital of Padua, Padua, Italy e-mail: [email protected]; [email protected]; [email protected] U. Bortolotti Section of Cardiac Surgery, Cardio-thoracic and Vascular Department, University Hospital of Pisa, Pisa, Italy e-mail: [email protected] © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 G. Thiene et al. (eds.), Pathology of Cardiac Valve Disease, https://doi.org/10.1007/978-3-031-35498-4_9

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Cell death of BP tissue

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Phosphorus of membrane phospholipids from cell debris

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Fig. 9.2  Cascade of events leading to structural deterioration of bioprosthetic valves

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Fig. 9.3  Calcium deposits upon cell debris at transmission electron microscopy (a). Spectroscopy of mineralization: the ratio between calcium and phosphorus content is in keeping with apatite (b). From Thiene G, Valente M, J Heart Valve Dis, 2011

9  Anticalcification Strategies to Increase Bioprosthetic Valve Durability Fig. 9.4 Anticalcification strategies in different bioprosthetic valve models

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1.00 0.90 0.80 0.70 Freedom from SVD

Fig. 9.5  Actuarial freedom from structural valve deterioration (SVD) of the Hancock II vs. Hancock I porcine bioprosthetic valves in patients aged 65 years or older. SVD appears much later in Hancock II than in Hancock I. From Valfrè et al., J Thorac Cardiovasc Surg, 2006

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Anticalcification Strategies The mitigation of bioprosthetic valve calcification can be achieved in two main ways: • Free aldehyde neutralization: It is possible to prevent the toxic effects of free aldehyde residuals by bonding unsaturated glutaraldehyde groups with amino-terminal amino acids, such as amino-oleic or other advanced patented technologies that involve also glycol as preventive medium. They neutralize the “killing” action of the aldehyde residuals against host endothelial cells, allowing the graft surface to be cell covered and thereby decreasing any propensity to mineralization. • Lipid extraction: this method aims to remove the phosphorus component of the early nuclei of calcification by means of solvents/surfactants. Examples include sodium dodecyl sulfate (T6), alcohols, polysorbate 80 (Tween 80), or a combination of polysorbate 80 and ethanol as in Edwards XenoLogiX treatment (Fig. 9.4).

Preclinical Testing The efficacy of these anticalcification agents may be monitored preclinically in several ways:

M. Valente et al.

• Subdermal rat implantation: This rapid method involves the subcutaneous implantation of tissue pieces (glutaraldehyde-­ fixed bovine pericardium or porcine cusps) into the back of Sprague-Dawley rats. Usually, four round or square pieces—two treated and two untreated—are applied to the same animal, with the implant position being rotated in different rats. The ideal implantation time should be no less than 10–12 weeks. • Circulatory implantation in large animals: This is the second compulsory step for the preclinical testing of any novel bioprosthetic device, with an orthotopic intracardiac implant (usually atrioventricular) replacing the native valve. Mitral valve replacement in juvenile sheep (aged 20 weeks), with an implant time of at least 140–150 days, is considered the best accelerated calcification model for circulatory implants and is recommended by the FDA. The orthotopic aortic position in animals is used to test transarterial or transapical aortic valve implants with bioprosthetic devices (TAVI). • In vitro: Accelerated calcification can be accomplished through a pulsatile testing device. In this case, the stented valve—either porcine or pericardial—is inserted into a device within a rapid synthetic calcification solution [Ca × P = 130(mg/dl)2], with full opening and closure of the valve cusps being conducted at 300 cycles per minute (Fig.  9.6). This system has been shown to reproduce intrinsic calcium phosphate mineralization after 19 × 106 cycles, with results suggesting the presence of apatite crystals by diffractometry.

9  Anticalcification Strategies to Increase Bioprosthetic Valve Durability

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Fig. 9.6  Accelerated intrinsic calcification achieved in  vitro through pulsatile testing with a rapid synthetic calcification solution, viewed at X-ray (a) and histology (b). Imaging with scanning electron micros-

copy (c) and diffractometry (d) revealed the calcification to be apatite crystals. From Pettenazzo et al., J Thorac Cardiovasc Surg, 2001

Clinical Trials

immunohistochemistry investigations, transmission and scanning electron microscopy, and atomic absorption spectroscopy for monitoring both calcium and phosphorus levels. Energy-dispersive analysis and diffractometry are also recommended (Fig. 9.6).

Testing the efficacy of anticalcific agents in new-generation bioprosthetic xenografts in clinical setting requires at least 10–15 years of follow-up, with echocardiographic monitoring (possibly with the addition of computed tomography) to detect early mineralization in  vivo (Fig.  9.5). A thorough study of the explants at the time of reoperation or death is mandatory, not only to establish the cause and mode of failure but also to distinguish the primary causes of SVD (such as calcification, fibrous tissue overgrowth, primary tears, lipid infiltration, thrombus formation, cusp hematoma, commissural dehiscence, stent fracture or bending) from secondary causes (such as endocarditis or paravalvular leak). A rigorous study protocol for pathological investigations is compulsory, both in animals and in the clinical experience. This would include gross examination, X-ray, histology,

 reclinical and Clinical Tests of New P Anticalcification Agents: The Padua Experience  ree Aldehyde Radical Neutralization F (Homocysteic Acid Detoxification) The pericardium was fixed in glutaraldehyde for crosslinking, treated with homocysteic acid to bind unsaturated aldehyde groups, and then preserved with a buffered

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Fig. 9.7  Subdermal implant with free aldehyde radical neutralization achieved by homocysteic acid. After 12  weeks, pinpoint calcification was observed in treated pericardial discs, vs. massive in untreated peri-

cardial discs, at both X-ray (a) and histology with von Kossa stain (b = pinpoint, c = massive). The diffractometry results were in keeping with apatite mineralization (d)

glutaraldehyde-free solution. Four discs of pericardium (two treated, two untreated) were implanted subcutaneously into the back of 24 Sprague-Dawley rats for 14, 28, 56, and 84 days and then submitted to pathology study. Dystrophic calcification was shown to commence at 28  days and increased with time in both the treated and untreated animals, with a significant difference between the two at 84 days (p = 0.01). Mineralization was intrinsic to the graft tissue and involved both cell debris and collagen. Apatite crystals were identified at diffractometry (Fig. 9.7). The same test was then conducted in the large animal circulatory model (orthotopic tricuspid position). Although the results were satisfactory, the choice of the tricuspid position rendered the results questionable, as the right-sided heart is a low-pressure system and hence unreliable for promoting calcification. The overall results were so convincing, with regard to homocysteic acid potential to mitigate dystrophic calcification, that new-generation pericardial prosthetic

valves had been created: the Pericarbon More and the stentless Freedom Solo. They were manufactured by Sorin and introduced to the market for clinical use.

α-Amino-oleic Acid Detoxification α-Amino-oleic acid treatment is currently employed in the manufacture of the Mosaic bioprosthetic valve, a new-­ generation porcine valve (Medtronic Inc.). The experiments were conducted in the mitral position of the sheep model, comparing Hancock Standard versus Mosaic valve prostheses. As requested by the FDA protocol, the prostheses were in place for 20 weeks. Overall, the degree of mineralization was low in both cases, most likely because the sheep at implant were relatively old; nonetheless, the difference in calcium content of the two valve prostheses after 20 weeks was statistically significant between the Mosaic and the Hancock Standard (p