Current Concepts in Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia

by Corinna Brunckhorst (Editor), Firat Duru (Editor), Ardan M. Saguner (Editor)

Overview

Edited and written by internationally recognized authorities, Current Concepts in Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia (ARVC/D) presents important insights to all aspects of this unique disease and will serve as a valuable guide to help readers provide the best possible care for their patients. Discussion of ARVC/D by the experts includes: Basic and clinical science. Pathophysiology, molecular mechanisms, and genetic background. The mechanisms of disease progression leading to a diversity of disease phenotypes. Challenges in the clinical setting with respect to diagnosis, risk stratification, and therapy. "The editors...have enlisted as authors those who first recognized and named the disease, and most of those responsible for the recent advances in this fascinating area. The result is an excellent, comprehensive but very readable text dealing with this increasingly important spectrum of diseases. It is a unique book that should be found on the shelves of everyone who seeks to manage patients with cardiac arrhythmia because amongst those who seek advice there are sure to be patients with this challenging disease."

Product Details

ISBN-13:	9781935395928
Publisher:	Cardiotext Publishing
Publication date:	08/15/2014
Product dimensions:	7.10(w) x 10.20(h) x 0.60(d)

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Current Concepts in Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia

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By Corinna Brunckhorst, Firat Duru

Cardiotext Publishing, LLC

Copyright © 2014 Corinna Brunckhorst, Firat Duru
All rights reserved.
ISBN: 978-1-935395-92-8

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CHAPTER 1

Discovery of Right Ventricular Cardiomyopathies

Guy H. Fontaine, MD, PhD, HDR, Robert Frank, MD, Jean-Louis Hébert, MD, Françoise Hidden-Lucet, MD, and Michel Komajda, MD

Introduction

Famed French cardiologist Pierre-Charles Potain said, "Doctors do not discover diseases. Diseases are as old as the world. What doctors discover are small signs previously unnoticed." As the diseases are as old as the world, it was interesting to search the medical literature for unrecognized cases of right ventricular dysplasia. This disease was not recognized because of the small number of cases seen by a single physician, as well as the lack of dissemination of scattered observations on the behavior of the right ventricle.

The chapter that follows describes how the experiences of various physicians and scientists contributed to the gradual recognition of ARVC/D as a specific disease, an entity of itself. Much of the description is written from the point of view of the lead author, Dr. Guy Fontaine, and it is to him that the narrative refers when first-person discussions arise.

The Renaissance

Leonardo da Vinci

During a visit to the Science Museum of London, I saw one of the famous anatomical drawings by Leonardo da Vinci (Figure 1.1). It shows the body of a young woman who died for no apparent cause, since there were no signs suggesting trauma or major organ disease. The unexpected death may have been the reason for the autopsy. Since there were no pathologi- cal findings at autopsy, the doctors of Milan, who knew of Leonardo's interest in anatomy, presented him with her exceptional case.

The picture is fascinating. The heart was cut in the horizontal plane, showing clearly the two ventricles separated by the interventricular septum. In other drawings, Leonardo showed a communication between the two ventricles, but on this one plate, there is a perfect anatomical representation of the interventricular septum separating the two cavities. This was contrary to the dogma at that time that physiologic direct communication existed between the two ventricles in the adult. If we focus on the walls of the heart where the epicardium and endocardium are carefully drawn, we can see the configuration of the right ventricle as compared to the left ventricle. The right ventricle is blatantly dilated. The right ventricular wall is much thinner and shows segmental abnormalities. In this anatomical description, it is possible that the patient had arrhythmogenic right ventricular dysplasia (ARVD) that could have led to sudden death.

This anatomical projection by Leonardo can be currently obtained by 4-chamber echocardiography. An echocardiographer who is aware of this disease would assume the diagnosis by looking at the sketch of the master of Milan. The epicardial fat, which is a characteristic of dysplasia, is absent on this drawing. It may have been intentionally removed in order to simplify the drawing, similar to the absence of fat in all the other organs in this picture. Leonardo interpreted the anatomy more as a scientist than as an artist. He sought an obvious anatomical reality leading to the understanding of the physiology rather than making a purely artistic design.

William Harvey (1578–1657)

In Leonardo's time, the mechanism of blood flow was not yet elucidated. Since the heart was known to contract forcefully, it was suspected to drive the blood through the body, and it was known that these contractions were essential to life. However, it was not until William Harvey, a physician from England who resided for several years at the University of Padua, Italy, at the turn of the 17th century, demonstrated the pulmonary and systemic circulation including the arteries, veins, and cardiac chambers so that the human circulation was defined. The French philosopher René Descartes had systematically criticized Harvey's findings based on pure, logical reasoning. Descartes's comments were disturbing to Harvey, and he was forced to make new experiments that resulted in information to the complete satisfaction of Descartes. The result was that the mechanism of blood flow was finally elucidated.

Giovanni Maria Lancisi (1654–1720)

The first clinical description of ARVD was made by the Italian physician Giovanni Maria Lancisi, who was interested in heart aneurysms and reported typical familial cases studied over four generations and one additional family member with autopsy.*

Twentieth Century

Massachusetts General Clinicopathological Exercises (1952)

In the modern era, a comparison of clinical and pathological data as a cause of ARVD was discussed at the Massachusetts General Hospital in 1952. The discussion's chairmen were Dr. Benjamin Castleman, pathologist, and Dr. Howard B. Sprague, clinician. Another participant was Dr. Paul Dudley White. The meeting concerned a 24-year-old woman admitted for abdominal swelling and fever. Ten years earlier, her brother died at the age of 17, one year after the onset of heart failure.

At the age of 20, the patient had experienced 4- to 5-minute episodes of rapid heartbeat associated with discomfort. Clinical examination suggested a dilated heart extending to the anterior axillary line. The rhythm was regular with some extrasystoles and episodes of bigeminy. A week after discharge from Massachusetts General Hospital, she was admitted to Good Samaritan Hospital with acute heart failure. The ECG revealed low voltage with inverted T waves in leads I, II, and III, and in the precordial leads. In addition, she had frequent ventricular extrasystoles. An esophageal lead showed that she had atrial tachycardia at a rate of 220 beats per minute with a ventricular rate of 110. The patient was discharged from the hospital after 3 months, and for the next 14 months, she was confined to her home and had many cardiac consultations. She was treated with cardiotonics, procainamide, and diuretics. During the last few months of her life, she had 2 episodes of palpitations associated with nausea and chest pain. An x-ray taken 3 months before her death showed a right pleural effusion as well as considerable enlargement of the cardiac silhouette. She died at home.

The case discussion was conducted by Dr. Sprague. He stressed the difficulty of diagnosis in this young woman, who had edema in her legs for 11 months, fever, dyspnea, and cough. She died suddenly, but had severe heart failure. Rheumatic fever was excluded, and the possibility of a common congenital disease could not be confirmed. In the discussion, a systemic disease such as von Gierke's was considered. There was no evidence for a collagen vascular disease. The possibility of amyloidosis or granulomatous myocarditis was considered. The most likely diagnosis was myocarditis of unknown etiology, complicated by ventricular tachycardia and possibly pulmonary embolism. However, this did not explain the history of her brother, who died at age 17 due to heart failure. The clinical diagnosis proposed by Dr. Sprague was that of myocarditis of unknown etiology associated with a ventricular ectopicrhythm. The pathological analysis by Dr. Castleman indicated that the patient had extreme dilation of the right side of the heart. This ventricle, and the right atrium as well, were huge and thin, "the thinnest in [his] personal experience." In some areas, the thickness of the ventricular myocardium was no more than a millimeter. Dr. White then asked if there was fibrous tissue, but Dr. Castleman had seen very little, and only around the vessels. The volume of the right ventricle was estimated to be five times that of the left ventricle. In both chambers, there were small mural thrombi. The valves were normal, and the coronary arteries were not occluded. Dr. White again asked if a literature study had been done to try to diagnose this disease. The only answer was a reference to a heart belonging to the collection of Osler. However, Dr. Castleman insisted that the Osler case was different. In that specimen, both right and left ventricles were "paper thin"; in the present case, the left ventricle was normal in size and thickness both pathologically and on microscopic examination. A congenital disease seemed most likely. In particular, he stressed the absence of signs of myocarditis because there were no inflammatory cells. The septum was also quite normal.

Dr. Sprague concluded that the patient had a congenital heart defect that was not previously described. Dr. Castleman asked if they should propose the term "isolated ectasia of the right ventricle." Dr. Castleman highlighted the presence of concomitant atrial dilation and concluded the presentation.

In my opinion, this was a typical case of ARVD, possibly complicated by healed inflammation leading to right heart failure. The description of the ECG during sinus rhythm was highly suggestive of this disease, with inverted T waves and the presence of both atrial and ventricular arrhythmias that could explain the patient's sudden death. The familial nature of the disease, with the death of a brother at the age of 17, although not sudden, was also in favor of ARVD. The severe dilation of the right ventricle with a thin wall is consistent with this diagnosis. Although the presence of fat was not mentioned, this could have been insignificant. The presence of mural thrombus in the atrium and in the ventricle are well known in patients with late stages of this disease. Dilation of the right atrium can be explained as a result of tricuspid regurgitation due to right ventricular dilation.

Hemodynamics of Certain Cardiomyopathies of the Right Ventricle (1961)

In the 1960s, considerable progress was made in cardiology. It became possible to measure the pressures in various cardiac chambers using catheters introduced in veins and arteries. Variations of these pressures during the cardiac cycle could be recorded on photographic paper, and it became possible to evaluate the hemodynamic status and establish a precise diagnosis and to determine possible surgical interventions.

It then became possible for Dalla Volta et al to evaluate and describe a hemodynamic syndrome called "auricularization of the pressure curves of the right ventricle," observed in two patients with a fibroblastic cardiomyopathy. One patient had a myocardial infarction mainly involving the right ventricle. In the other, the diagnosis was confirmed at autopsy.

This report focused on the consequences produced by incompetence of the right ventricle. The atrium was hemodynamically able to partially replace the function of the failing right ventricle, and the result was the presence of a pressure wave in the right ventricle contemporary with an increase in right atrial pressure. These patients died due to right heart failure, and no arrhythmias were reported. Death was described as "sudden" in one of them.

In a second publication in the French Journal of Cardiology (Archives des Maladies du Coeur et des Vaisseaux), two additional cases were reported. These were classified as "unknown cardiomyopathy" leading to the same hemodynamic syndrome that Dalla Volta established, suggesting a "true clinical entity." These two patients were still alive; however, the diagnosis of one of the patients was not sufficiently established except for the hemodynamic study that was not consistent with dysplasia. The last case is indeed in favor of typical ARVD, since for me the ECG showed obvious prolongation of the QRS complexes in leads V1 and V2, an Epsilon wave in V1, and T-wave inversions in the right precordial leads in a young woman, who is the only one of the four cases to have presented with palpitations (Figure 1.2).

The First Epicardial Mapping in Europe (1971)

In 1968, an abstract reported the first surgical treatment of tachycardia in Wolff-Parkinson-White (WPW) syndrome that was performed at Duke University. I was convinced that this method could be used to treat the most severe cases of ventricular tachycardia resistant to all other forms of treatment including antiarrhythmic drugs and pacemakers. I recalled a statement of my mentor, Professor Jean Facquet, who indicated that I should not continue to pass the examinations in academic medicine since my accomplishments in the field of cardiac pacemakers were already significant. He suggested that I pursue investigations of "these new techniques that the Americans have and that we do not have." Since I was trained in electrical engineering before studying medicine, and I was convinced that the surgical treatment of the WPW syndrome needed extensive electronic participation during surgery to guide this surgical approach, I discussed this approach with Professor Facquet, who suggested that I meet with the chief of the cardiovascular surgical department, Professor Cabrol, and with his assistant, Professor Gérard Guiraudon. After an interview with Gérard, we decided to work together on this project one afternoon every week in the department of experimental heart surgery.

After six months, the technique of epicardial mapping was perfected in dogs with a special stimulator that I designed in order to activate the heart and to mimic the various forms of abnormal epicardial activation in the WPW syndrome. We performed the first successful European surgical procedure for the treatment of WPW syndrome in 1971, and a report of this case was published in 1972.

It was then that I decided that the same technique of epicardial mapping could be applied to other forms of life-threatening arrhythmias such as ventricular tachycardia (VT). Four patients with VT due to remote myocardial infarction or idiopathic dilated cardiomyopathy were operated on with the same success before we attempted this procedure on the first patient with ARVD.

The First Successful Surgical Treatment of ARVD (1973)

The first patient, a 65-year-old man, did not have coronary artery disease but had had recurring episodes of ventricular tachycardia for 10 years. These episodes were resistant to treatment with all antiarrhythmic drugs. These tachycardias seemed to originate from the right ventricle as judged by the morphology of the ECG during VT. This was of great interest, since VT originated from the left ventricle in the four preceding patients. In addition, the left ventricular contractility was normal, with the exception of a slight anomaly on the anterior wall near the apex. Since the rate of tachycardia was decreased by drug therapy, it could be studied by epicardial mapping. All the documented episodes of VT had the same morphology, suggesting a single area of origin. The surgical procedure took place on October 30, 1973. As soon as the heart was exposed, the surgeon noted that the right ventricle was moderately dilated, hypokinetic, and covered by a prominent layer of fat.

The first epicardial map during sinus rhythm was almost normal (Figure 1.3). The anterior aspect of the right ventricle was activated normally, but with a 10-ms delay. The VT was easily induced by electrical stimulation. Mapping was completed in less than 20 minutes and revealed that the "site of origin" was in the mid-right ventricular free wall as suspected by the electrocardiographic morphology. It was decided to perform a "simple ventriculotomy" along the border of the RV from apex to base. This large incision facilitated an extensive view of the right ventricular cavity, which appeared normal. The histology of the fragment taken from the free wall, studied several years later, was essentially normal with no signs of inflammation. When the ventricle was closed and the extracorporeal circulation was withdrawn, it became clear that the tachycardia was no longer inducible. Subsequently, he had no further arrhythmias and no longer needed antiarrhythmic drugs.

This case was initially considered as "idiopathic tachycardia," and the case report was one of four published in a book chapter after presentation of these cases in 1975 during a scientific meeting in Amsterdam. It was the first time that this innovative surgical treatment for VT was described. Our team was convinced we had discovered a new method of surgical treatment of resistant VT. The patient died at the age of 86 from heart failure without any new episodes of VT.

Left Ventricular Involvement in Right Ventricular Dysplasia (1975)

One of the first ARVD patients operated on for the treatment of VT had a significant ventricular epicardium in addition to that in the right ventricle. This was a 42-year-old man referred for VT resistant to all antiarrhythmic drugs. The VTs occurred each month and led to a loss of consciousness. These VTs had the same left bundle branch block morphology, except for some short episodes of nonsustained VT with right bundle branch block observed only after induction by stimulation. Angiography showed akinesia of the left ventricular apex with a discrete area of dyskinesia. The anterior interventricular artery was short, suggesting a probable old thrombosis of this vessel, which could explain the akinesia at the apex of the left ventricle. It could also be due to narrowing of the vessel caused by hypertrophy of the leiomyocytes of this vessel (a well-known feature of ARVD). Surgical therapy for VT was performed on January 7, 1975.

(Continues...)

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Excerpted from Current Concepts in Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia by Corinna Brunckhorst, Firat Duru. Copyright © 2014 Corinna Brunckhorst, Firat Duru. Excerpted by permission of Cardiotext Publishing, LLC.
All rights reserved. No part of this excerpt may be reproduced or reprinted without permission in writing from the publisher.
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Table of Contents

Contents

Contributors, ix,
Foreword, xi,
Preface, xiii,
Chapter 1 Discovery of Right Ventricular Cardiomyopathies Guy H. Fontaine, Robert Frank, Jean-Louis Hébert, Françoise Hidden-Lucet, Michel Komajda, 1,
Chapter 2 Disease Mechanisms in Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia: From the Macro- to the Nanoscale Esperanza Agullo-Pascual, Marina Cerrone, Mario Delmar, 19,
Chapter 3 Genetic Background of Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia Judith Groeneweg, Richard Hauer, 31,
Chapter 4 Genetic Counseling for Patients and Relatives Argelia Medeiros-Domingo, 43,
Chapter 5 Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia: Clinical Presentation, Differential Diagnosis, and Diagnostic Challenges Rajesh Janardhanan, Frank I. Marcus, 49,
Chapter 6A The Role of Echocardiography in Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia Alessandra Vecchiati, Felix C Tanner, 59,
Chapter 6B The Role of Cardiac Magnetic Resonance Imaging in Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia Robert Manka, Markus Niemann, 69,
Chapter 7 Drug Therapy in Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia: When and How to Use Which Drugs Thomas Wichter, 79,
Chapter 8 The Role of Implantable Defibrillators and Catheter Ablation in the Management of Patients with Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia Florence Porterfield, Hugh Calkins, 93,
Chapter 9 Risk Stratification and Prognosis Alessandro Zorzi, Domenico Corrado, 105,
Chapter 10 The Zurich ARVC Program Ardan M. Saguner, 117,
Case 1 Difficult-to-Treat Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia Richard Kobza, Paul Erne, 127,
Case 2 Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia in Sports: Rare Incident or the "Tip of the Iceberg"? Christian M. Schmied, 133,
Impressions from the First Zurich ARVC/D Symposium, 141,
Index, 145,