Case 3 -

Sudden Death and ARVC Jagdish Butany, University of Toronto and Toronto General Hospital, Toronto, Ontario, Canada

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Case 3 - Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Case 3 - Slide 2 Click to view with ImageScope Click to view with a Web-Based Viewer "If it were done when its done, then 'twere well it were done quickly" (Macbeth, Act 1,Scene1.) While a quick death is likely to be preferred by everyone of us, for who wants to linger at that painful time, it can be devastating when it occurs in the young, and unexpectedly at that. However, this quick death, is unlikely to be of any comfort to the family of persons believed to be in excellent health, athletic and dying suddenly while competing, exercising or perhaps in-bed. This session is geared primarily to these sudden and unexpected deaths. Sudden death (SD) is a not an uncommon event and it can be due to numerous conditions, many related to structural cardiac disease. When one excludes the common ones, such as coronary artery disease, accidents and infections, one is left with sudden unexpected cardiac death. A cause of death in young people, often during physical activity and often in people in the prime of their lives. This sudden death is defined in many different ways and was defined by Goldstein et al [1] as "Death occurring within one hour of the onset of symptoms". A subcategory of SD is "instantaneous death is defined as "acute collapse and death without any symptoms". A subcategory of this is called "intermediate sudden death" which includes those patients who die within one to twenty-four hours after onset of symptoms. Haerem [2] in a study of 81 patients, divided deaths into the following groups: 1. Sudden cardiac death: 47 of 81 patients died instantly or within 10 minutes after the onset of pain, having no other recent clinical disease. 2. Chronic coronary disease: 21 out of 81 patients, who had been treated for myocardial infarction six months to several years previously. 3. Non-coronary disease: 13 patients without known cardiac disease. (In this series all deaths were witnessed.) There are many different definitions of sudden death and the Scientific Council on Atherosclerosis and Ischemic Heart Disease of the International Society of Cardiology and the Councils on Atherosclerosis and Epidemiology of the HAH and the WHO recommended the following definition of SD: "Sudden (unexpected) natural death is defined as death occurring instantaneously or within an estimated 24 hours of the onset of symptoms or signs" [3]. In some contrast is the definition of a WHO pathological study: "A non-violent death occurring unexpectedly within six hours in an apparently healthy subject, or in a sick person whose condition is steady or improving". [3] It is essential to have a definition in mind when assigning a death to the category of sudden death, especially sudden unexpected death. At this evening's symposium, we are discussing some causes of sudden unexpected cardiac death. These include the channelopathies such as long QT syndrome, right ventricular cardiomyopathy, myocarditis, rare and unusual causes and anomalies of the coronary arteries leading to sudden unexpected death. Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVD/C) This condition has had many synonyms starting with arrhythmogenic right ventricular dysplasia, arrhythmogenic right ventricular cardiomyopathy (ARVC) to conditions such as arrhythmogenic cardiomyopathy and right ventricular dysplasia and perhaps at the opposite end of the spectrum - Uhl's anomaly( a different entity). Definition: Arrhythmogenic right ventricular cardiomyopathy / dysplasia (ARVC/D): a heart muscle disorder characterized by progressive fibrofatty replacement of right ventricular myocardium, initially with typical regional and later global right and some left ventricular involvement with relative sparing of the septum (WHO classification, 1995) [4] ARVC/D, is accepted, as a genetic cause of sudden cardiac arrest. In this condition there is progressive change in the myocardium, resulting in the normal myocardial tissue being replaced with fat and fibrous tissue with the proportions of these two tissues being variable. This occurs predominantly in the right ventricle (RV) and to a lesser degree, about 50% of cases, in the left ventricle. The septum is less commonly involved and the trabeculae carneae are either not involved or far less commonly involved (personal experience). Its incidence varies from country to country and ranges from 1:1000 to 1:5000 individuals. Reportedly the incidence is higher in Italy as compared to North America. This, however, may be related to many causes. The reasons for these discrepancies are that the diagnosis is often difficult to make and the disease is commonly mistaken for other entities, most commonly dilated cardiomyopathy. The biggest reason for its significance, even though it is a relatively uncommon condition, is that sudden unexpected death occurs often in the prime of their life, usually 30 years of age or younger, and has been estimated to be the cause in 20% of young people dying suddenly. The incidence is likely higher(12.5 -25%) amongst young athletes, under 35 years of age, in Italy. [5] Genetics: ARVC is a disease with low penetrance and while reportedly having a 30% (to 50%) incidence of genetic abnormalities in families, this may actually be an underestimation. The gene expression is often variable and sometimes difficult to trace along a family line. The genetic abnormality may be one of autosomal dominance or autosomal recessive. The autosomal dominant form (AD) is more common and here each individual with the gene abnormality will have this syndrome [6]. Additionally, the children of these individuals would have at least a 50% chance of inheriting it from their affected parent. Autosomal recessive form (AR) is less common and an individual must receive the mutant genes from both parents, otherwise remaining a silent carrier with no physical manifestation. It has recently been reported that the AR form is commonly associated with the Naxos Syndrome in which ARVD is seen along with abnormalities of the skin (hyperkeratosis) and of the hair [7]. Genotyping of individuals suspected of the disease helps to identify them and genotyping of the family then helps to efficiently screen the immediate family and the extended family if necessary. Good screening leads to positive results in approximately 50% of cases. The mutant genes, regardless of AD or AR, code for the same proteins and these are the desmosomes. Desmosomes are the cell junctions which keep cardiac muscle fibers attached together, and are essential for maintaining cardiac structural integrity. With defective desmosomes, mechanical stress, such as exercise often can lead to detachment of these intercellular junctions and to cell death. This is associated with inflammation, scarred formation and fat deposition. These fibrofatty islands predispose this individual to arrhythmias. While the disease is initially localized, it can gradually spread from discrete areas involving the rest of the right ventricle. Left ventricular involvement is usually seen late. [8] (For a list of reported genetic abnormalities, please see Table 1.) Clinical Manifestations: Clinical features generally often occur at or around 30 years of age or younger (10 - 50 years) and there is often no difference in involvement of men vs. women, though the overall reported incidence of ARVD/Cis higher in Men. The most common symptom is an arrhythmia, usually a tachyarrhythmia. This may include palpitation, dizziness, shortness of breath, syncope, etc. It must be kept in mind that sudden cardiac arrest may also be the presenting feature. Given the previous comments about the genetics, clearly some patients may be asymptomatic at the time of investigation and the diagnosis of ARVC suspected following a screening for the disease. The screening tools that may be used are commonly an electrocardiogram or echocardiograms [9]. Diagnosis: The diagnosis of ARVC may present a challenge. Normal hearts do have some degree of fat and fibrous tissue and the hearts of those who are even moderately obese often have fairly significantly increased amounts of adipose tissue. Management: There is no definitive treatment, for curing the disease! The aim of management is to prevent sudden death from ventricular tachycardia and sudden cardiac arrest. This can be accomplished by the implantation of an ICD (Implanted cardioverted-defibrillator). These devices today are fairly small, can continuously monitor the heart's electrical functioning and detect life threatening arrhythmias, at which time the device automatically shocks or cardioverts the individual back to a normal rhythm. This is generally recommended for those with a documented episode of sustained VT. Its success in converting life threatening arrhythmias is pretty good. Medication per se are not absolutely effective in preventing VT, and therefore SCD. These are not as effective and are reserved for those not felt to be suitable candidates for ICD implantation. Anti-arrhythmic agents of course, may be used. Individuals at high risk: are young patients, who present with syncope or a history of cardiac arrest or sustained ventricular tachycardia, patients with signs of right ventricular failure, etc. Prognosis: At this time, the prognosis of ARVD is not clear. As expected, patients with mild disease and short episodes of VT may have a better prognosis than those with severe disease, history of sustained VT or evidence of right or left heart failure. [7] Morphologic diagnosis of ARVC/D: The autopsy diagnosis of ARVC/D is based on gross and histologic examination of heart obtained at autopsy and today increasingly from hearts obtained at transplantation. The clinical diagnosis on most of these cases is generally dilated cardiomyopathy. It is only the detailed examination of these hearts (gross more so than the histology), which helps define the underlying disease, while the histology will confirm the gross suspicion. The heart weight may be normal for body size, gender and age, but is usually associated with apparent right ventricular enlargement and dilatation which may range from mild to moderate to severe. The gross weight of the heart, as previously mentioned may be within normal limits or be mildly to moderately increased. [9, 10] The gross examination helps to guide the appropriate sections to be taken for histology. One of the tools that are helpful is holding the right ventricle chamber against the light, anterior wall, apex and posterobasal region, to see if it is transilluminant, suggesting that there is a significant increase in adipose tissue and a decrease in myocardium, grossly consistent with the features of ARVC/D. These right ventricular aneurysms, usually multiple (generally three) and occasionally single are considered pathonomic of ARVC/D and are at times referred to as the "Triangle of dysplasia". The right ventricular changes can be diffuse or segmental. The left ventricular involvement may be noted on gross examination as fairly significant areas of fibrosis or scarring, often subepicardial and band-like or subepicardial, but equally often may not be seen on gross examination and end up being underestimated. The ventricular septum is involved in only about 20% of cases and the left ventricle in about 50% of cases. The left ventricle is often not involved or at least at light microscopy appears not to be involved. For obvious reasons, in young people with sudden unexpected death, the heart, if it shows no significant abnormality, must be given a far more detailed examination to exclude small areas of fibrofatty change. Inflammation: Patchy areas of interstitial inflammatory infiltrates may be seen at different points and may be associated with loss of cardiac muscle fibers. A mild degree of epicardial inflammation may also be seen and in both cases the inflammatory cells are comprised of lymphocytes and some macrophages. These infiltrates may be a response to cell death. Patchy areas of endocardial fibrosis are often seen, but are not as striking as those that one sees in other forms of dilated cardiomyopathy or even ARVD/C in older individuals. They likely are a result of hemodynamic changes, the formation and organization of small endocardial thrombi. The type of change described above can be categorized into two groups: fatty and fibrofatty ARVC/D. In the fatty type, the adipose tissue reaches the endocardium and there is therefore a full thickness or transmural fatty infiltration with the wall thickness appearing normal or even increased but the cut edge of the wall shows the fatty appearance and does not show the typical tan color of the presence of the myocardium. Small amounts of interstitial fibrous tissue will usually be seen, although they may be focal and one may have to hunt for them. These, if not easily seen, should be looked for at different magnifications. [9, 10] Fibrofatty or cardiomyopathic type: In this the right ventricular wall is thinner, often parchment like and significantly translucent, accounting for the aneurysm seen in the three areas mentioned earlier (a feature often known as the "triangle of dysplasia" and a finding considered pathonomic of ARVC/D). In both forms, there is significant myocyte death, hypertrophy of residual myocytes and degeneration of these myocytes [9, 10]. The appearance suggests that there is ongoing myocyte or tissue injury, repair and replacement. Immunohistochemistry in these cases often shows the presence of CD43, CD45, CD3 positive T-lymphocytes. Macrophages (CD68 positive cells) are often associated with these areas. Myocardial apoptosis has been reported in post-mortem samples, as well as endomyocardial biopsies of ARVC/D patients. This apoptosis as well as inflammation may be brought on by many factors and may well represent an epiphenomenon or a secondary phenomenon rather than a primary feature of disease [11]. Left ventricular involvement: Left ventricular free wall involvement by lesions similar to those of right ventricle involvement is variable. Some authors [15] reported the left ventricular changes in about half of all cases with the change being fibrofatty in appearance. In addition, older patients were usually associated with a clinical picture of congestive heart failure. Others have found an even more increase in left ventricular involvement [16]. A Canadian Study found 45% of hearts showed left ventricular scars [17, 18]. In other studies, Burke et al [19] found LV involvement in 64% of their cases, while D'Amati et al, found biventricular involvement in 87% of cases [20] In our own series of cases [17, 18] left ventricular involvement was far less likely to be seen at gross inspection than right ventricular involvement and remained more or less the same in the involved areas. In our series there was the total absence of full thickness left ventricular involvement, and left ventricular aneurysms were not seen. Myocardial changes, fibrosis and variable fatty involvement were much more likely to be subepicardial and mid wall than at other points. It is worth keeping this in mind since these changes can easily be missed. In cases of sudden death, especially unexpected death and unexpected cardiac failure, septal and free wall sections should be taken somewhat more generously. [12, 19] Features to keep in mind: The criteria for the diagnosis of ARVC/D are not yet etched in stone. They are evolving. As more morphological reports and larger numbers of cases are reported, firmer diagnostic criteria will evolve. With this in mind, it is less likely that ARVC may be under or over diagnosed. The gross features of ARVC/D may be minimal possibly more commonly seen in cases of young people than in the hearts examined at forensic autopsy. What is essential is the generous sampling of the right ventricle, as well as left ventricle myocardium, in all cases of sudden cardiac death. [12] Uhl's anomaly should be distinguished from ARVC/D. [13] Essential: In view of the availability of genetic analyses for mutations, tissue from autopsy should be taken for genetic analysis. If mutations are found, this helps the examination of the family members of individuals dying a sudden death. The Fatty Heart: Many hearts examined in detail, especially those from older and variably obese individuals show fat in the myocardium. [14] Reported the presence of fatty infiltration without fibrosis and stated that the myocardium was of normal or increased thickness with the left ventricle largely normal with no myocyte changes. In these cases of fatty infiltration, the myocytes, if one looks at them closely, show the features of being pushed aside rather than replaced by the fatty tissue and there is little suggestion of fibrosis. Significant Pathologic Features of ARVC/D (gross and histologic) Gross Features: normal to mildly increased weight. apparent significant increase in adiposity over the right ventricle RV dilatation and areas of translucency of the myocardium normal thickness to marked thinning of the wall Microscopic Features: fatty infiltration with fibrosis replacement fibrosis myocyte hypertrophy and myocytes showing degenerative changes minimal to mild presence of adipocytes small foci of chronic inflammation Trabeculae carneae, largely normal Table 1: Genes Associated with ARVD/C* Gene Locus Inheritance 1. Plakophillin-2 (PKP2) 12q11 AD/AR 2. Desmoglein-2 (DSG2) 18q12 AD/AR 3. Desmoplakin (DSP) 6p24 AD 4. Desmocollin-2 (DSC2) 18q12 AD 5. TGF beta 3 14a24.3 AD 6. Plakoglobin (JVP) 17q21 AD (1 Family) 7. Plakoglobin (JVP) 17q21 AR (Naxos family) 8. Desmoplakin (DSP) 6p24 AR 9. Cardiac Ryanodine Receptors (RYR2) 1Q42 AD 10. Transmembrane Protein 43 3p25 AD AD-Autosomal Dominant; AR-Autosomal Recessive *Modified from John Hopkins website: ARVD.com References: Goldstein S, et al. Aspirin myocardial infarction study research group. 1984. Timing Mechanism and Clinical Setting of Witnessed deaths in post myocardial patients. JACC 3:111-17 Haerem JW. Myocardial lesions in sudden unexpected coronary death. 1975. Am Art J, 90:562 - 68. Pisa Z. Sudden death - a worldwide problem. In Sudden death - developments in cardiovascular medicine. Ed Kalbertus HE and Bellins HJJ. 1980. The Hague: M Nijhoff, pp 3 -10. Richardson P, McKenna WJ, Bristol M et al. Report of 1995 WHO / ISFC Task force on the definition of cardiomyopathy. Circulation. 1996 93: 841-842. Arrhythmogenic RV cardiomyopathy / dysplasia, Recent advances. 2008, Ed, Marcus FI, Nava A, Thiene G. Springer Verlag Italia Milano. Nava A, Bauce B, Basso C et al Clinical profile and long-term follow-up of 37 families with arrhythmogenic right ventricular cardiomyopathy. J Am Coll Cardiol. 2000 Dec;36(7):2226-33. McCoy G, Protonotarious N, Crosby A et al. Identification of a deletion of plaqueoglobin in arrhythmogenic right ventricular cardiomyopathy with Palmoplantar keratoderma in wooly hair (Naxos disease). Lancet 2000 355:2119 - 2124 Hamid MS, et al. Prospective evaluation of relatives for familial arrhythmogenic right ventricular dilated cardiomyopathy / dysplasia - the need to broaden diagnostic criteria JACC; 16 (2002) (40): 1445 - 1450). Thiene G, Nava A, Corrado D et al. Right ventricular cardiomyopathy and sudden death in young people. N Engl J Med. 1988; 318: 129-133 Basso C, Thiene G, Corrado D, et al. Arrhythmogenic right ventricular cardiomyopathy. Dysplasia, dystrophy or myocarditis? Circulation 1996; 94: 983-991 Thiene G, Basso C. Arrhythmogenic right ventricular cardiomyopathy. An update. Cardiovasc Pathol 2001; 10: 109-111 d'Amati G, Leone O, di Gioia CR et al. Arrhythmogenic right ventricular cardiomyopathy: clinicopathologic correlation based on a revised definition of pathologic patterns. Hum Pathol. 2001 Oct;32(10):1078-86. Grils LM, Schmidt-Ott SC, Ho SY Dysplastic conditions of the right ventricular myocardium: Uhl's anomaly vs arrhythmogenic right ventricular dysplasia. Br Heart J. 1993 Feb;69(2):142-50 Basso C, Thiene G. Adiopositas Chordis. Fatty infiltration Adipositas cordis, fatty infiltration of the right ventricle, and arrhythmogenic right ventricular cardiomyopathy. Just a matter of fat? Cardiovasc Pathol. 2005 Jan-Feb;14(1):37-41. Basso C, Victor C, Daniele GA et al. Arrhythmogenic right ventricular cardiomyopathy: clinical registry and database, evaluation of therapies, pathology registry, DNA banking. Eur Heart J. 2004 Mar;25(6):531-4. Corrado D, Basso C, Thiene G et al. Spectrum of clinicopathologic manifestations of arrhythmogenic right ventricular cardiomyopathy/dysplasia: a multicenter study. J Am Coll Cardiol. 1997 Nov 15;30(6):1512-20. Lobo FV, Heggtveit HA, Butany J et al. Right ventricular dysplasia: morphological findings in 13 cases. Can J Cardiol. 1992 Apr;8(3):261-8. Lobo F, Silver MD, Butany J et al. Left ventricular involvement in right ventricular dysplasia/cardiomyopathy. Can J Cardiol. 1999 Nov;15(11):1239-47. Burke AB, Farb A, Tashko G et al. Arrhythmogenic right ventricular cardiomyopathy and fatty replacement of the right ventricular myocardium: are they different diseases? Circulation. 1998 Apr 28;97(16):1571-80.