Asian Cardiovasc Thorac Ann 1998;6:41-44
© 1998 Asia Publishing EXchange Pte Ltd
Catecholamine Cardiomyopathy: An Autopsy Study
Kamaraju Suguna Ratnakar, MD,
Challa Sundaram, MD,
Angajala Rajasekhar, MD,
Krishnamoorthy Gayathri, MD,
Aruna K Prayag, MD,
Sadasiva Jaishankar, MD,1,
Bhoopathiraju Soma Raju, MD,1
Department of Pathology
1 Department of Cardiology Nizam's Institute of Medical Sciences Hyderabad, India
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For reprint information contact: Kamaraju Suguna Ratnakar, MD Department of Pathology Nizam's Institute of Medical Sciences Panjagutta, Hyderabad 500482, India Tel:91 40 39 9519 Ext. 151 Fax:91 40 22 9316
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ABSTRACT
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Pheochromocytoma, an uncommon intra-abdominal tumor of the sympathetic nervous system, is associated with episodic hypertension. Cardiac complications infrequently occur as the principal presenting symptoms and may account for the morbidity and mortality. The role of catecholamines, mainly noradrenaline, in ventricular hypertrophy and cardiac dysfunction is well documented. This report documents two autopsy cases, one of adrenal pheochromocytoma and the other of extra-adrenal pheochromocytoma, with manifestations primarily of cardiac etiology. The changes described indicate catecholamine cardiomyopathy.
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INTRODUCTION
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The World Health Organization and International Society and Federation of Cardiology Task Force on the definition and classification of cardiomyopathies observed in its 1995 report that myocardial dysfunction due to cardiac disorders of specific causes or of unknown etiology could be considered as cardiomyopathies.1 Under the group of specific cardiomyopathies, metabolic cardiomyopathy encompasses a wide range of etiologies including pheochromocytoma, which could affect the myocardium.
Pheochromocytoma presenting with cardiac complications is well recorded in the literature.2 Ventricular hypertrophy occurring in cases of pheochromocytoma is attributed to hypertension secondary to catecholamine release. However, the cardiac dysfunction is disproportionate to the increase in blood pressure, both in degree and duration and in spite of treatment, which necessitates consideration of cardiomyopathy due to catecholamines. We report here an autopsy study of two cases of pheochromocytoma associated with cardiac dysfunction.
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MATERIALS AND METHODS
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CASE 1
A 26-year-old male was admitted with episodic attacks of chest pain, palpitation, and giddiness with hypertension (210/140 mm Hg) of two months duration. Ultrasound revealed a mass over the upper pole of the left kidney. Fundoscopy showed grade 1 retinal changes. The electrocardiogram showed left ventricular hypertrophy and two-dimensional echocardiography revealed concentric hypertrophy with an ejection fraction of 54%. A computed tomography scan confirmed the ultrasound findings. Urinary vanillylmandelic acid was 26 mg per day (normal less than 8 mg per day). The patient underwent surgery and the suprarenal mass was dissected and removed. Early postoperative recovery went well with careful monitoring. However, 16 hours after surgery there was a precipitous fall in blood pressure and the patient died of cardiac arrest.
At autopsy, the heart weighed 450 g, the right ventricular wall thickness was 8 mm, the left ventricular wall thickness was 18 mm, and microscopy revealed marked anisonucleosis with panfascicular hypertrophy. There was no increase in collagen in the interstitium and the coronary vessels showed medial thickening of a moderate degree. The suprarenal mass weighed 25 g and was found to be more medial with normal adrenal adjacent to it on both sides, hence the mass was extra-adrenal. Microscopy showed that the mass contained a mixed pattern of trabecular and alveolar arrangements of polygonal cells with abundant granular acidophilic cytoplasm. Cut sections exposed to formalin vapor and dichromate solutions showed an intense brown (chromaffin) reaction indicating the presence of catecholamines. There was no mitosis or vascular invasion. In addition, there was marked pulmonary edema (Figure 1
). Extraadrenal pheochromocytoma with marked ventricular hypertrophy and pulmonary edema was the final diagnosis at autopsy.
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Figure 1. Ventricular hypertrophy characterized by marked anisonucleosis and hypochromasia. No significant intrafascicular or interfascicular fibrosis is seen.
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CASE 2
A 19-year-old male student was admitted with a history of shortness of breath functional class II for 1.5 years. Examination revealed hypertension (220/120 mm Hg). Routine hematology and biochemical studies were negative. Two-dimensional echocardiography showed a dilated left ventricle, global hypokinesia with mild mitral regurgitation and severe left ventricular dysfunction. A computed tomography scan indicated a right suprarenal mass. Urinary vanillylmandelic acid was elevated to 22.4 mg per day. The electrocardiogram showed left atrial enlargement and left ventricular hypertrophy, T-segment inversion in lead AVL, and poor R-wave progression on leads V2 to V4. While being prepared for surgery, the patient suddenly collapsed and died following a trivial injury to his abdomen.
At autopsy the heart weighed 500 g, the left ventricular wall thickness was 18 mm, and the right ventricular wall thickness was 5 mm. Microscopic examination revealed marked panfascicular hypertrophy characterized by anisonucleosis and an increase in myofibrillary mass (Figure 2). The interstitium including perivascular areas showed no increase in collagen. The coronary arteries were patent with mild medial thickening. The right adrenal mass weighed 45 g, it was lobulated with a gray-tan cut surface that became dark tan in formalin-dichromate solution. Microscopically, the morphology was typical of a pheochromocytoma characterized by sheets of polygonal cells with granular cytoplasm and oval to round nuclei (Figure 3). The cells were arranged in nests and trabeculae. There was no vascular or capsular invasion. A diagnosis was made of pheochromocytoma with marked cardiac hypertrophy and dilatation.
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Figure 2. Intrafascicular neoangionesis seen in a section of left ventricle (hematoxylin and eosin stain, original magnification x600).
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Figure 3. Sections from the tumor showing polyhedral cells in typical nests with granular cytoplasm and central dark nuclei (hematoxylin and eosin stain, original magnification x400).
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DISCUSSION
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This autopsy study of pheochromocytoma in 2 young males (19 and 26 years of age) revealed four important histological features in the heart: panfascicular hypertrophy with marked anisonucleosis (grade 3) with a proportionate sarcoplasmic increase; minimal increases of intrafascicular reticulin or collagen; neovascularization abutting and or involving muscle bundles; and an absence of focal or diffuse scarring. These changes are distinctly different from hypertensive hypertrophy that is grossly indistinguishable but histologically characterized by marked intrafascicular arteriolar thickening, and interfascicular as well as intrafascicular focal or diffuse perivascular and plexiform scarring. This scarring may vary according to the severity and duration of hypertension as well as the treatment modalities.
The role of catecholamines in ventricular hypertrophy is not completely understood. Proponents of hypertension as the principal pathologic mechanism in hypertrophy argue that ventricular wall tension rises due to increased afterload, resulting in hypertrophy.3 However, Laks and colleagues4 using a subhypertensive dose of noradrenaline clearly demonstrated the direct role of norepinephrine in increasing cardiac mass. There is compelling evidence that cardiac noradrenaline increases in physiological states such as exercise, triggering a hypertrophic process. An increase in cardiac size of approximately 7% and a rise of cardiac noradrenaline of 16% were found following 15 weeks of exercise in rats.5 Noradrenaline generation in the myocardium during conditions of preload or afterload stress is postulated to be from the sympathetic nervous system or neural reflexes. The molecular events necessary for hypertrophy are triggered by noradrenaline locally.6 However, in chronic states, it is found to result in exhaustion with a decrease of myocardial noradrenaline and the onset of decompensation. In clinical and experimental congestive cardiac failure, the myocardial content of noradrenaline has been reported to be low.7 The rise followed by a fall in catecholamine levels is considered to elicit hypertrophy and cardiac decompensation. Subsequently, as the stimulant activity to hypertrophy ceases, the hypertrophic heart rapidly deteriorates in function. This hypothesis explains the preload and afterload ventricular wall tension in various etiologies but it fails to explain sufficiently the morphological and functional status of the heart in a patient with a pheochromocytoma.
Cardiac hypertrophy requires elucidation based on the alteration in structure and function of the myocyte and nonmyocyte units of the myocardium. While the muscle component occupies over 75% of the myocardium, the remainder is represented by nonmyocyte elements such as fibroblasts, vascular endothelial cells, and smooth muscle cells.8 The cardiac fibroblasts are the sources of collagen type I and III, the principal collagen types of the cardiovascular system. The complex cardiac interstitium enveloping both groups and individual cardiac sarcomeres serves to maintain cardiac structural and functional integrity in controlling both contraction and expansion. The left ventricular hypertrophy that occurs in essential hypertension becomes maladoptive when the balance of myocytes to fibroblasts is disturbed.8 It is interesting to note that in conditions such as experimental systemic hypertension and right ventricular pressure overloads, a reactive interstitial fibrosis with accumulation of collagen in the absence of myocyte necrosis is seen. This comprises: interstial fibrosis resulting from thickening of normally positioned status (fibrillar collagen also appears in intermuscular spaces previously devoid of collagen); perivascular fibrosis (accumulation of collagen within the adventitium of intramyocardial coronary arteries and arterioles); and plexiform fibrosis associated with muscle fiber disarray.8
The myocardial histology in the patients studied here was distinct from the ventricular hypertrophy encountered in essential hypertension. There were no microscopic or gross areas of interstitial fibrosis. Hence, the cardiac decompensation or congestive cardiac failure that typically follows ventricular hypertrophy was probably not responsible for the terminal event in catecholamine cardiomyopathy. It is probably rhythm abnormalities such as ventricular arrhythmias that account for morbidity and mortality.
Pheochromocytoma is an uncommon intra-abdominal tumor with an incidence of less than two per million in the general population and one per ten thousand in cases of abdominal surgery.9,10 Improved investigative modalities and increased awareness have reduced the incidence of patients dying or surviving with serious complications as a result of unsuspected pheochromocytoma. Histologically these tumors consist of polyhedral cells with a granular cytoplasm and oval to round nuclei. These patterns are recognized as trabecular, alveolar, and mixed, with the mixed variant being most commonly encountered.11 The normal adrenal medulla synthesizes principally adrenaline whereas a pheochromocytoma secretes primarily noradrenaline with lesser quantities of adrenaline. A French study recently concluded that the triad of headache, palpitations, and sweating in patients with hypertension predicts pheochromocytoma with 93.8% specificity and 90.9% sensitivity.12
Increased plasma noradrenaline levels are found in patients with congestive cardiac failure.13 The increase in cardiac myocyte mass is a reflection of possible direct or indirect effects of noradrenaline on cell protein synthesis. Angiotensin II, which is known to be released by noradrenaline, acts on membrane receptors associated with phosphorylation of proteins related to DNA and RNA transcription of several protooncogenes that code for cell growth and development.14 This may be the mechanism responsible for increased cardiac myocyte growth in conditions of high noradrenaline levels. Similarly, the angiogenesis seen in this study can also be explained. It is therefore postulated that catecholamine cardiomyopathy is a result not of load mechanisms but of a direct noradrenaline-induced synthesis of cardiac myocyte protein.
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ABSTRACT
INTRODUCTION
