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Pathologic evidence of extensive left ventricular involvement in arrhythmogenic right ventricular cardiomyopathy
Pathologic Evidence of Extensive left Ventricular Involvement in Arrhythmogenic Right Ventricular Cardiomyopathy PIETRO GALLO, MD, GIULIA D’AMATI, MD, AND F RANCESCO PELLICCIA, MD Arrhythmogenic right ventricular cardiomyopathy (also known as arrhythmogenic right ventricular dysplasia) is characterized by adipose or fibroadipose tissue replacement of the right ventricular myocardium, whereas the left ventricle is substantively spared. Two cases of the disease with evidence of extensive left ventricular involvement at pathologic examination are described. Hearts from two patients who died suddenly showed full-thickness right ventricular fatty infiltration associated with extensive left ventricular involvement (>50% of myocardial thickness). These findings might explain the reported clinical features of left ventricle dysfunction in a subset of patients with arrhythmogenic right ventricular cardiomyopathy. In view of the biventricular involvement of the disease, it should simply be termed “arrhythmogenic cardiomyopathy.” HUM PATHOL 23:948-952. Copyright 0 1992 by W.B. Saunders Company
plasia) is characterized by episodes of ventricular tachycardia with a QRS configuration that is typical of left ventricular delay and by the presence of ventricular postexcitation waves and global wall motion abnormalities of the right ventricle. Some cases of left ventricular dysfunction are described. Sudden death during exercise is a common presenting symptom of this cardiomyopathy. From a pathologic standpoint the disease is characterized by adipose or fibroadipose tissue replacement of right ventricular myocardium,’ which accounts for the electrical instability of the right ventricle. The left ventricle is said to be substantially spared.’ We describe two cases of the disease with evidence of extensive left ventricular involvement at pathologic examination.
FIGURE 1. Case no. 1. Free wall of the right ventricle showing full-thickness adipose replacement. Remnants of myocardium are present in the subendocardial area (top) and scattered through the wall. (Hematoxylin-eosin stain; magnification X5.)
Arrhythmogenic right ventricular (also known as arrhythmogenic right
cardiomyopathy ventricular dys-
From the Department of Experimental Medicine, University of L’Aquila, L’Aquila, Italy; and the Department of Human Biopathology and the Institute of Cardiac Surgery, “La Sapienza” University of Rome, Rome, Italy. Accepted for publication October 15, 1991. Key word..s: right ventricular cardiomyopathy, arrhythmogenic cardiomyopathy, cardiomyopathies, pathology. Address correspondence and reprint requests to Pietro Gallo, MD, Dipartimento di Biopatologia Umana, Sea. Anatomia Patologica, Universita “La Sapienza”, Viale Regina Elena 324, 00161 Roma, Italy. Copyright 0 1992 by W.B. Saunders Company 0046~8177/92/2308-0019$5.00/O
FIGURE 2. Case no. I. Free wall of the left ventricle at the same magnification and orientation (epicardium at the bottom) as in Fig 1. The adipose replacement is thicker than in the right ventricle and comprises some myocardial remnants (see also Figs 3 and 4). (Hematoxylin-eosin stain; magnification X5.)
948
ARRHYTHMOGENIC
RIGHT VENTRICULAR
CARDIOMYOPATHY
(Gallo et al)
replaced by adipose tissue, with the exclusion of trabeculae carneae. The left ventricle was 16-mm thick and showed adipose infiltration involving the free wall. The thickness of fatty replacement ranged from 7 mm (at the basal region) to 10 mm (next to the apex); only the subendocardial layers were spared. Histologic examination of the right ventricle confirmed a full-thickness replacement of myocardium by mature adipose tissue (Fig 1). Myocytes persisted only in a slight and discontinuous subendocardial strip and in the trabeculae carneae; additional myocardial cells were scattered, as isolated cells or small strands, among the fat cells of the parietal wall. The histologic slides showed an irregular, fatty substitution of left ventricular myocardium. The relative amount of subepicardial adipose tissue was remarkably variable: in the midventricular portion it was nearly absent, whereas toward the apex it was 1O-mm thick and entrapped a few residual myocytes as isolated cells or small round clusters (Figs 2 through 4). In another portion of the wall a nest of adipose tissue appeared to be isolated within the ventricular wall, completely encircled by myocardial tissue (Fig 5). Subendocardial left ventricular myocardium was hypertrophied, with focal areas of intracellular edema. Among the bundles of myocardial cells a slight amount of fibroadipose tissue was focally present. In conclusion, the
FIGURE 3. Case no. 1. Enlarged detail of Fig 2 showing clusters of myocardial cells entrapped within the adipose tissue. Some groups of myocytes also exhibit fibrous replacement. (Hematoxylin-eosin stain; magnification X.50.)
MATERIALS
AND METHODS
The hearts of two subjects who died suddenly were referred to our institution for detailed morphologic study. Autopsy had previously ruled out any noncardiac cause of sudden death. Gross examination of the hearts included measurements of heart weight and wall thickness. Valvular, congenital, and coronary heart disease was absent. Multiple sections from right and left ventricular myocardium were processed for routine histologic analysis.
CASE
REPORTS
Case No. 1 The patient was a 32-year-old man in whom sudden death was apparently the first sign of disease. The heart weighed 550 g and the external examination suggested an overall increase of subepicardial fat, although the patient was neither obese nor did he have excessive fat deposits elsewhere. The right ventricle was slightly enlarged; on the cut surface, the right ventricular myocardium (thickness, 11 mm) was totally
FIGURE 4. Case no. I. Outer portion of the left ventricular free wall showing a small round remnant of myocytes (left) and isolated myocardial cells (right) entrapped within the adipose tissue. (Hematoxylin-eosin stain; magnification x50.)
949
HUMAN PATHOLOGY
Volume 23, No. 8 (August
1992)
cardial cells, some lymphocytes, a few plasma cells, and lipofuscinic pigment. In the subepicardial and midparietal zones small clusters of myocardial cells and scattered lymphocytes were evident within the fat tissue. Subendocardial left ventricular myocardium appeared to be thinned (Fig 7), with focal intracellular edema and necrosis of myocytes and fibrous or fibroadipose replacement. On the subepicardial side the fat tissue entrapped scant isolated myocytes and small myocardial nests, surrounded by or intermingled with fibrous tissue (Fig 8). Residual myocytes were mainly associated with branches of subepicardial vessels. In conclusion, the pathologic features of this heart are diagnostic of right ventricular arrhythmogenic cardiomyopathy and consistent with its fibroadipose pattern, and show a similar lesion to be present in the left ventricle as well.
DISCUSSION Since the early observations of Fontaine et al” and Marcus et al4 arrhythmogenic, right ventricular cardiomyopathy has been extensively reported. The hallmark of the disease is the adipose and/or fibroadipose replacement of right ventricular myocardium, which is usually associated with ventricular arrhythmias and sudden death.’ Several investigators have reported clinical features of left ventricular dysfunction in a subset of
FIGURE 5. Case no. I. In this portion of the left ventricular wall the amount of subepicardial fat (bottom) is within normal limits, but an offshoot of adipose tissue (elsewhere contiguous with the outer zone) spreads through the myocardium, replacing it. (Hematoxylin-eosin stain; magnifkation X5.)
gross and microscopic appearance of this heart is diagnostic of the adipose pattern of right ventricular arrhythmogenic cardiomyopathy. The same kind of lesion was also demonstrated in the left ventricle.
Case
No. 2
The patient was a 36-year-old man. He had previously experienced a syncopal episode, but no cardiac abnormality could be diagnosed prior to death. The heart weight was 480 g. On external examination, an increased amount of subepicardial fat was apparent, but this patient was neither obese nor had excessive fat deposits elsewhere. The right ventricle showed a moderate cavity enlargement and a full-thickness (9 mm) fatty infiltration of its walls. The left ventricle was 1 lmm thick with a marked thinning at the apex; there was adipose replacement (thickness, 6 mm) involving the outer half of the free wall and the apex, whereas the interventricular septum was spared. Microscopic examination of the right ventricle confirmed the almost complete replacement of nontrabecular myocardium by adipose tissue (Fig 6). Beneath the endocardium there was a laminar sclerosis comprising residual myo-
FIGURE 6. Case no. 2. Free wall of the right ventricle. The adipose substitution extends from the epicardium (left) to the endocardium (right). The subendocardial remnants and the trabecular myocardium show an irregular fibrous replacement. (Hematoxylin-eosin stain; magnification X5.)
950
ARRHYTHMOGENIC
RIGHT VENTRICULAR
CARDIOMYOPATHY
(Gallo et al)
patients with arrhythmogenic right ventricular cardiomyopathy; no pathologic findings, however, were available in those cases5-’ We report extensive adipose and fibroadipose infiltration of the left ventricle (>50% of myocardial thickness) in two hearts showing the typical features of arrhythmogenic right ventricular cardiomyopathy. Pathologic studies previously have disclosed fibroadipose infiltration of both riBEOand left ventricular myocardium in isolated cases. 3 3 Left ventricular abnormalities, however, were limited to the subepicardial layers,’ especially in the anterior and posterior paraseptal regionsg In addition, histology usually revealed fibrosis of the left ventricle rather than adipose replacement.*!” To our knowledge, only Letac et al’” described a case of histologically proven fatty infiltration of the left ventricular myocardium that was not confined to the subepicardial layers. Our own and Letac et al’s pathologic findings of extensive fatty infiltration of both ventricles in arrhythmogenic right ventricular cardiomyopathy are consistent with a wider spectrum of the disease than has been recognized previously. Thus, ar-
FIGURE 8. Case no. 2. Subepicardial zone of the left ventricular wall. Fibroadipose replacement of myocardium, entrapping residual myocardial nests, is apparent. (Hematoxylin-eosin stain; magnification X20.)
rhythmogenic right ventricular cardiomyopathy should simply be called “arrhythmogenic cardiomyopathy,” since it seems to be the more appropriate way to term the disease. We observed myocardial remnants, as both isolated cells and small strands or nests, in the subepicardial and midparietal portions of the free wall of both ventricles. This observation suggests that myocardial replacement by adipose or fibroadipose tissue progresses from the subepicardium to the trabecular myocardium, which is usually spared. The absence of full-thickness involvement of the left ventricle could be due to the greater thickness of its walls. REFERENCES
FIGURE 7. Case no. 2. Free wall of the left ventricle at the same magnification and with a mirror-like orientation (epicardium on the right) compared with Fig 6. There is a marked subepicardial adipose substitution with scattered areas of fibrous replacement. Toward the apex (bottom) the ventricular wall appears to be thinned. (Hematoxylin-eosin stain; magnification X5.)
1. Boffa GM, Thiene G, Nava A, et al: Cardiomyopathy: A necessary revision of the WHO classification. Int J Cardiol 30:1-7, 1991 2. Thiene G, Nava A, Corrado D, et al: Right ventricular cardiomyopathy and sudden death in young people. N Engl J Med 3 18: 129133, 1988
951
HUMAN PATHOLOGY
Volume 23, No. 8 (August
3. Fontaine R, Guiradon G, Frank R, et al: Arrhythmogenic right ventricular dysplasia. A previously unrecognized syndrome. Circulation 52:65, 1979 (suppl 2) (abstr) 4. Marcus FI, Fontaine GH, Cuiraudon G, et al: Right ventricular dysplasia: A report of 24 adult cases. Circulation 65:384-398, 1982 5. Webb JG, Kerr CR, Huckell VF, et al: I.eft ventricular abnormalities in arrhythmogenic right ventricular dysplasia. Am J Cardiol 58:560-570, 1986 6. Blomstrom-Lundqvist C, Sahel KG, Ollsson SB: A long-term follow-up of 15 patients with arrhythmogenic right ventricular dysplasia. Br Heart J 58:477-488, 1987 7. Daubert G, Descaves C, Foulgoc JL, et al: Critical analysis of
1992)
cineangiogt-aphic criteria for diagnosis of arrhythmogenicright ventricular dysplasia. Am Heart J 115:448-459, 1988 8. Manyari DE, Klein GJ, Gulamhusein S, et al: Arrhythmogenic right ventricular dysplasia: A generalized cardiomyopathy? Circulation 68:251-257, 1983 9. Fontaine G, Fontaliran F, de la Salle ME, er al: Righ’ ventricular dysplasias, in Aliot E, Lazara R (eds): Ventricular Tachycardias: From Mechanism to Therapy. The Hague, The Netherlands, Martinus Nijoff; 1987, pp 113-133 10. I.etac B, Tayot J, Barthes I’: Infiltration graisseuse du coem et maladie de Uhl (A propos d’une observation de lipomatose cardiaque). Arch Mal Coeur 70: 107-t 13, 1977
952
plasia) is characterized by episodes of ventricular tachycardia with a QRS configuration that is typical of left ventricular delay and by the presence of ventricular postexcitation waves and global wall motion abnormalities of the right ventricle. Some cases of left ventricular dysfunction are described. Sudden death during exercise is a common presenting symptom of this cardiomyopathy. From a pathologic standpoint the disease is characterized by adipose or fibroadipose tissue replacement of right ventricular myocardium,’ which accounts for the electrical instability of the right ventricle. The left ventricle is said to be substantially spared.’ We describe two cases of the disease with evidence of extensive left ventricular involvement at pathologic examination.
FIGURE 1. Case no. 1. Free wall of the right ventricle showing full-thickness adipose replacement. Remnants of myocardium are present in the subendocardial area (top) and scattered through the wall. (Hematoxylin-eosin stain; magnification X5.)
Arrhythmogenic right ventricular (also known as arrhythmogenic right
cardiomyopathy ventricular dys-
From the Department of Experimental Medicine, University of L’Aquila, L’Aquila, Italy; and the Department of Human Biopathology and the Institute of Cardiac Surgery, “La Sapienza” University of Rome, Rome, Italy. Accepted for publication October 15, 1991. Key word..s: right ventricular cardiomyopathy, arrhythmogenic cardiomyopathy, cardiomyopathies, pathology. Address correspondence and reprint requests to Pietro Gallo, MD, Dipartimento di Biopatologia Umana, Sea. Anatomia Patologica, Universita “La Sapienza”, Viale Regina Elena 324, 00161 Roma, Italy. Copyright 0 1992 by W.B. Saunders Company 0046~8177/92/2308-0019$5.00/O
FIGURE 2. Case no. I. Free wall of the left ventricle at the same magnification and orientation (epicardium at the bottom) as in Fig 1. The adipose replacement is thicker than in the right ventricle and comprises some myocardial remnants (see also Figs 3 and 4). (Hematoxylin-eosin stain; magnification X5.)
948
ARRHYTHMOGENIC
RIGHT VENTRICULAR
CARDIOMYOPATHY
(Gallo et al)
replaced by adipose tissue, with the exclusion of trabeculae carneae. The left ventricle was 16-mm thick and showed adipose infiltration involving the free wall. The thickness of fatty replacement ranged from 7 mm (at the basal region) to 10 mm (next to the apex); only the subendocardial layers were spared. Histologic examination of the right ventricle confirmed a full-thickness replacement of myocardium by mature adipose tissue (Fig 1). Myocytes persisted only in a slight and discontinuous subendocardial strip and in the trabeculae carneae; additional myocardial cells were scattered, as isolated cells or small strands, among the fat cells of the parietal wall. The histologic slides showed an irregular, fatty substitution of left ventricular myocardium. The relative amount of subepicardial adipose tissue was remarkably variable: in the midventricular portion it was nearly absent, whereas toward the apex it was 1O-mm thick and entrapped a few residual myocytes as isolated cells or small round clusters (Figs 2 through 4). In another portion of the wall a nest of adipose tissue appeared to be isolated within the ventricular wall, completely encircled by myocardial tissue (Fig 5). Subendocardial left ventricular myocardium was hypertrophied, with focal areas of intracellular edema. Among the bundles of myocardial cells a slight amount of fibroadipose tissue was focally present. In conclusion, the
FIGURE 3. Case no. 1. Enlarged detail of Fig 2 showing clusters of myocardial cells entrapped within the adipose tissue. Some groups of myocytes also exhibit fibrous replacement. (Hematoxylin-eosin stain; magnification X.50.)
MATERIALS
AND METHODS
The hearts of two subjects who died suddenly were referred to our institution for detailed morphologic study. Autopsy had previously ruled out any noncardiac cause of sudden death. Gross examination of the hearts included measurements of heart weight and wall thickness. Valvular, congenital, and coronary heart disease was absent. Multiple sections from right and left ventricular myocardium were processed for routine histologic analysis.
CASE
REPORTS
Case No. 1 The patient was a 32-year-old man in whom sudden death was apparently the first sign of disease. The heart weighed 550 g and the external examination suggested an overall increase of subepicardial fat, although the patient was neither obese nor did he have excessive fat deposits elsewhere. The right ventricle was slightly enlarged; on the cut surface, the right ventricular myocardium (thickness, 11 mm) was totally
FIGURE 4. Case no. I. Outer portion of the left ventricular free wall showing a small round remnant of myocytes (left) and isolated myocardial cells (right) entrapped within the adipose tissue. (Hematoxylin-eosin stain; magnification x50.)
949
HUMAN PATHOLOGY
Volume 23, No. 8 (August
1992)
cardial cells, some lymphocytes, a few plasma cells, and lipofuscinic pigment. In the subepicardial and midparietal zones small clusters of myocardial cells and scattered lymphocytes were evident within the fat tissue. Subendocardial left ventricular myocardium appeared to be thinned (Fig 7), with focal intracellular edema and necrosis of myocytes and fibrous or fibroadipose replacement. On the subepicardial side the fat tissue entrapped scant isolated myocytes and small myocardial nests, surrounded by or intermingled with fibrous tissue (Fig 8). Residual myocytes were mainly associated with branches of subepicardial vessels. In conclusion, the pathologic features of this heart are diagnostic of right ventricular arrhythmogenic cardiomyopathy and consistent with its fibroadipose pattern, and show a similar lesion to be present in the left ventricle as well.
DISCUSSION Since the early observations of Fontaine et al” and Marcus et al4 arrhythmogenic, right ventricular cardiomyopathy has been extensively reported. The hallmark of the disease is the adipose and/or fibroadipose replacement of right ventricular myocardium, which is usually associated with ventricular arrhythmias and sudden death.’ Several investigators have reported clinical features of left ventricular dysfunction in a subset of
FIGURE 5. Case no. I. In this portion of the left ventricular wall the amount of subepicardial fat (bottom) is within normal limits, but an offshoot of adipose tissue (elsewhere contiguous with the outer zone) spreads through the myocardium, replacing it. (Hematoxylin-eosin stain; magnifkation X5.)
gross and microscopic appearance of this heart is diagnostic of the adipose pattern of right ventricular arrhythmogenic cardiomyopathy. The same kind of lesion was also demonstrated in the left ventricle.
Case
No. 2
The patient was a 36-year-old man. He had previously experienced a syncopal episode, but no cardiac abnormality could be diagnosed prior to death. The heart weight was 480 g. On external examination, an increased amount of subepicardial fat was apparent, but this patient was neither obese nor had excessive fat deposits elsewhere. The right ventricle showed a moderate cavity enlargement and a full-thickness (9 mm) fatty infiltration of its walls. The left ventricle was 1 lmm thick with a marked thinning at the apex; there was adipose replacement (thickness, 6 mm) involving the outer half of the free wall and the apex, whereas the interventricular septum was spared. Microscopic examination of the right ventricle confirmed the almost complete replacement of nontrabecular myocardium by adipose tissue (Fig 6). Beneath the endocardium there was a laminar sclerosis comprising residual myo-
FIGURE 6. Case no. 2. Free wall of the right ventricle. The adipose substitution extends from the epicardium (left) to the endocardium (right). The subendocardial remnants and the trabecular myocardium show an irregular fibrous replacement. (Hematoxylin-eosin stain; magnification X5.)
950
ARRHYTHMOGENIC
RIGHT VENTRICULAR
CARDIOMYOPATHY
(Gallo et al)
patients with arrhythmogenic right ventricular cardiomyopathy; no pathologic findings, however, were available in those cases5-’ We report extensive adipose and fibroadipose infiltration of the left ventricle (>50% of myocardial thickness) in two hearts showing the typical features of arrhythmogenic right ventricular cardiomyopathy. Pathologic studies previously have disclosed fibroadipose infiltration of both riBEOand left ventricular myocardium in isolated cases. 3 3 Left ventricular abnormalities, however, were limited to the subepicardial layers,’ especially in the anterior and posterior paraseptal regionsg In addition, histology usually revealed fibrosis of the left ventricle rather than adipose replacement.*!” To our knowledge, only Letac et al’” described a case of histologically proven fatty infiltration of the left ventricular myocardium that was not confined to the subepicardial layers. Our own and Letac et al’s pathologic findings of extensive fatty infiltration of both ventricles in arrhythmogenic right ventricular cardiomyopathy are consistent with a wider spectrum of the disease than has been recognized previously. Thus, ar-
FIGURE 8. Case no. 2. Subepicardial zone of the left ventricular wall. Fibroadipose replacement of myocardium, entrapping residual myocardial nests, is apparent. (Hematoxylin-eosin stain; magnification X20.)
rhythmogenic right ventricular cardiomyopathy should simply be called “arrhythmogenic cardiomyopathy,” since it seems to be the more appropriate way to term the disease. We observed myocardial remnants, as both isolated cells and small strands or nests, in the subepicardial and midparietal portions of the free wall of both ventricles. This observation suggests that myocardial replacement by adipose or fibroadipose tissue progresses from the subepicardium to the trabecular myocardium, which is usually spared. The absence of full-thickness involvement of the left ventricle could be due to the greater thickness of its walls. REFERENCES
FIGURE 7. Case no. 2. Free wall of the left ventricle at the same magnification and with a mirror-like orientation (epicardium on the right) compared with Fig 6. There is a marked subepicardial adipose substitution with scattered areas of fibrous replacement. Toward the apex (bottom) the ventricular wall appears to be thinned. (Hematoxylin-eosin stain; magnification X5.)
1. Boffa GM, Thiene G, Nava A, et al: Cardiomyopathy: A necessary revision of the WHO classification. Int J Cardiol 30:1-7, 1991 2. Thiene G, Nava A, Corrado D, et al: Right ventricular cardiomyopathy and sudden death in young people. N Engl J Med 3 18: 129133, 1988
951
HUMAN PATHOLOGY
Volume 23, No. 8 (August
3. Fontaine R, Guiradon G, Frank R, et al: Arrhythmogenic right ventricular dysplasia. A previously unrecognized syndrome. Circulation 52:65, 1979 (suppl 2) (abstr) 4. Marcus FI, Fontaine GH, Cuiraudon G, et al: Right ventricular dysplasia: A report of 24 adult cases. Circulation 65:384-398, 1982 5. Webb JG, Kerr CR, Huckell VF, et al: I.eft ventricular abnormalities in arrhythmogenic right ventricular dysplasia. Am J Cardiol 58:560-570, 1986 6. Blomstrom-Lundqvist C, Sahel KG, Ollsson SB: A long-term follow-up of 15 patients with arrhythmogenic right ventricular dysplasia. Br Heart J 58:477-488, 1987 7. Daubert G, Descaves C, Foulgoc JL, et al: Critical analysis of
1992)
cineangiogt-aphic criteria for diagnosis of arrhythmogenicright ventricular dysplasia. Am Heart J 115:448-459, 1988 8. Manyari DE, Klein GJ, Gulamhusein S, et al: Arrhythmogenic right ventricular dysplasia: A generalized cardiomyopathy? Circulation 68:251-257, 1983 9. Fontaine G, Fontaliran F, de la Salle ME, er al: Righ’ ventricular dysplasias, in Aliot E, Lazara R (eds): Ventricular Tachycardias: From Mechanism to Therapy. The Hague, The Netherlands, Martinus Nijoff; 1987, pp 113-133 10. I.etac B, Tayot J, Barthes I’: Infiltration graisseuse du coem et maladie de Uhl (A propos d’une observation de lipomatose cardiaque). Arch Mal Coeur 70: 107-t 13, 1977
952