International Elsevier
CARD10
Journal of Cardiology,
30 (1991) 9-13
01177
Review
Pathogenesis of hypertrophic cardiomyopathy: another viewpoint Shyam Sunder Kothari Institute
of Cardiology, New Civil Hospital, Ahmedabad,
(Received
21 June 1990; revision
accepted
Kothari SS. Pathogenesis of hypertrophic cardiomyopathy:
3 August
India 1990)
another viewpoint. Int J Cardiol 1991;30:9-13.
A genetically determined error in the handling of catecholamines by the developing heart has been speculated to cause hypertrophic cardiomyopathy. A critical appraisal of the published literature reveals that there is little actual experimental or clinical evidence favouring the role of catechohunines in the pathogenesis of hypertrophic cardiomyopathy. Other factors seem to be more important. An abnormality of myocardial growth, either induced by excessive growth promoting substance, or a genetically determined abnormality in myocardial responses to normal growth factors during life (but not in the fetal handling of cathecholamines) is likely to be responsible for hypertrophic cardiomyopathy. Key words: Hypertrophic
cardiomyopathy;
Catecholamines;
Introduction
The ‘catecholamine
A genetically determined error in the handling of catecholamines by the developing heart has been speculated to cause hypertrophic cardiomyopathy [l]. Perloff extended this hypothesis by adding some experimental and clinical evidence [2]. Subsequently there has been little evidence to support the hypothesis, and many studies have belied the presumptions made in the ‘catecholamine hypothesis’. Notwithstanding, it continues to enjoy the status of an almost accepted hypothesis [3,4]. It is the purpose of this review to redress the ‘catecholamine hypothesis’ and integrate the available information into a more plausible explanation for the pathogenesis of hypertrophic cardiomyopathy.
Correspondence to: Dr. S.S. Kothari, MD, DM., Inst. of Cardiology, New Civil Hospital, Ahmedabad, India 380 016.
0167-5273/91/$03.50
8 1991 Elsevier Science Publishers
Growth factors
Experimental
hypothesis’
evidence
The reported experimental evidence favouring the hypothesis include the following observations: (a) The earlier observation that sympathetic innervation and noradrenaline content were increased in fresh septal myocardium removed from patients with hypertrophic cardiomyopathy undergoing operation [5]. This was subsequently found to be incorrect [6]. (b) Chronic infusion of norepinephrine in mature dogs in subhypertensive doses caused cardiac hypertrophy 171. In these experiments, ventricular wall hypertrophy was induced with short term infusion of norepinephrine. However, there was no septal hypertrophy and the histopathology was not examined. (c) Production of ventricular hypertrophy simulating idiopathic hypertrophic subaortic stenosis
B.V. (Biomedical
Division)
10
with long term infusion of norepinephrine in conscious dogs were reported [8]. The similarity to hypertrophic cardiomyopathy was only in the production of a hypercontractile state in which outflow gradients were observed. This should not be equated to hypertrophic cardiomyopathy since such a state can be induced with catecholamines in normal and otherwise hypertrophied hearts as well [9]. (d) As an extension of the above work, the same group of investigators implicated catecholamines in the pathogenesis of the disease based on the observation of increased beta-adrenergic receptors and reduced cyclic AMP in canine myocardium in response to long term catecholamine infusion [lo]. The alterations were different in the septum and free walls and occurred before ventricular hypertrophy was evident. This observation should have limited implications by itself, but the authors hypothesised that depleted stores of cyclic AMP may be one of the mechanisms involved in the pathogenesis of hypertrophic cardiomyopathy. This has been extended as an evidence in favour of the role of catecholamines in the pathogenesis [4]. (e) Long-term beta-blockade in rabbits caused a reduction in the rate of cardiac growth [ll]. In young rabbits long term beta-blockade caused reduction in cardiac weight and decrease in number of mitochondria in these experiments. This was probably in response to reduced oxygen requirements. While it is true that catecholamines may influence myocyte growth [12], and may be important in adaptive cardiac hypertrophy [13], this does not automatically implicate catecholamines in the pathogenesis of hypertrophic cardiomyopathy. Other studies It is relevant that in more recent studies, no abnormalities in the myocardial norepinephrine concentration [6,14], in the number of beta-adrenoceptors, or in the level of catecholamine sensitive adenylate cyclase [15] have been determined in patients with hypertrophic cardiomyopathy. Thus, there is no actual experimental evidence support-
ing the role of catecholamines in the pathogenesis of hypertrophic cardiomyopathy. Clinical evidence The second line of reasoning was related to occasional occurrence of hypertrophic cardiomyopathy in a group of otherwise unrelated disorders that were presumed to be disorders of catecholamines and sympathetic nervous system [2]. Subsequent studies have suggested that hypertrophic cardiomyopathy in most of these could be explained by factors other than catecholamines. (a) Disorders of neural crest derivatives: The hypertrophic cardiomyopathy in the disorders of neural crest derivatives like lentigenosis and neurofibromatosis was linked to catecholamines, as either due to excessive catecholamine precursors synthesised by melanocytes, or due to excessive nerve growth factor. Hypertrophic cardiomyopathy induced by injection of nerve growth factor in the experimental animals was not well documented [16]. Normal catecholamine concentrations were found in patients with these disorders [17,18]. Of course, these observations do not rule out participation of catecholamines in the pathogenesis. However, it appears simplistic, if not illogical, to implicate catecholamines in these patients as the neural crest disorders like neurofibromatosis are primary disorders of cell growth and differentiation [19] with potentials of localised growth, hamartoma and neoplasia in various organs. Nerve growth factor structurally resembles insulin. Nerve growth factor (or some other similar peptides) may also have effects on myocytes irrespective of catecholamines. As recently shown, the growth peptides have multifunctional potentials [20]. Phaeochromocytoma: Excessive catecholamines cause myocardial cell necrosis and histopathological picture resembling dilated cardiomyopathy [21]. The rare occurrence of asymmetric septal hypertrophy with phaeochromocytoma, and its reversal after removal of the tumour has been reported [22]. As discussed earlier, catecholamines may induce some cardiac hypertrophy. However, the tumour tissue may secrete various other peptides [23] which may presumably influence the cardiac hypertrophy. Associated multiple endo-
11
crinopathy may also be responsible for hypertrophy in some of the cases. (b) Friedreich’s ataxia: Hypertrophic cardiomyopathy in patients with Friedreich’s ataxia was thought to be common. A comprehensive study by Child and coworkers has shown that cardiac abnormalities in this disease include segmental myocardial dystrophy, global left ventricular hypokinesia, and, rarely, ventricular hypertrophy and asymmetric septal hypertrophy [24]. The myocardial cellular disarray, or propensity to ventricular arrhythmias was not seen in these patients. A number of metabolic abnormalities have been observed in patients with Friedreich’s ataxia [25]. The mitochondrial mahc enzyme deficiency may explain both the neural and cardiac involvement. It is reasonable to suggest that hypertrophic cardiomyopathy in Friedreich’s ataxia represents a metabolic myopathy. Hypertropbic cardiomyopathy also rarely occurs in other metabolic myopathies [26]; these are not discussed here. (c) Hyperthyroidism: The administration of TRIAC (diethanolamine salt of triodothyroacetic acid) to pregnant rats induced wide spread cellular disarray and ventricular hypertrophy akin to hypertrophic cardiomyopathy in the offspring [27]. This observation and the clinical occurrence of hypertrophic cardiomyopathy with hyperthyroidism [28] was hypothesised to have resulted from the adrenergic stimulus that accompanied hyperthyroidism [2]. However, subsequent studies by Pearse et al. [29] using the TRIAC model, have clarified that hypertrophy was prevented by drugs with membrane stabilising effects and was unrelated to their adrenergic blocking efficacy. Thus thyroid hormone rather than catecholamines seem to be responsible for hypertrophy. Thyroxine has also been shown to have myocyte growth-promoting effects in isolated cell culture studies [12]. (d) Hypercalcemia: Since catecholamines may increase intracellular calcium concentrations, the occurrence of hypertrophic cardiomyopathy with hypercalcemia was suggested as favouring the catecholamine hypothesis. However, parathyroid hormone, and not calcium, has been shown to be responsible for hypertrophy [30]. Increased concentration of parathyroid hormone measured by radioimmunoassay was found in one third of pa-
tients with hypertrophic cardiomyopathy. A direct effect of parathyroid hormone or a similar peptide measured in the immunoassay was thought to be responsible for the ventricular hypertrophy [30]. (e) Infants of diabetic mothers: Reversible hypertrophic cardiomyopathy seen in infants of diabetic mothers [31] was postulated to result from increased intrauterine adrenergic responses to fetal hypoglycemia [2]. Similar hypertrophy has been observed in infants with total lipodystrophy [32], in leprechaunism [33] and with Beckwith-Weidemann syndrome [34]. Hyperinsulinism rather than hypoglycemia is responsible for hypertrophy [31,33]. Insulin has growth-promoting effects [35] and the fetal heart is rich in insulin receptors. The recent observation of insulin action on fetal insulin-like growth factor (IGF-II) receptors, even with genetic resistance to insulin receptors [33] lends credence to the fact that insulin in fetus causes myocardial hypertrophy. Thus, there is no clear clinical evidence to support the assertion that abnormalities of catecholamine concentration or of adrenergic receptors are responsible for the pathogenesis of hypertrophic cardiomyopathy. Therefore, this speculation should be de-emphasized.
Alternative hypothesis During normal embryogenesis the ventricular septum is disproportionately thicker than the ventricular walls [36]. Mild cellular disarray is seen in normal infants [36], in hearts of primitive animals like crustaceans [37], and in organ culture of beating salamander myocardium [38]. This may be a feature of dedifferentiated growth [37]. Abnormal myocardial growth in the fetus due to excessive growth-promoting substances (like insulin, thyroxine, and other peptide regulatory factors) may result in excessive septal hypertrophy and cellular disarray. The septum may retain a greater ability to respond to growth factors with hypertrophy later in life as well. Thus exuberant hypertrophy in response to growth-promoting substances may result in asymmetric septal hypertrophy frequently seen in acromegaly [39], hyperparathyroidism [30], and hyperinsulinism [32]. A variable degree of cellular disarray accompanies
12
hypertrophy in these situations. Why some patients with these disorders develop pattern similar to hypertrophic cardiomyopathy and others develop concentric ventricular hypertrophy needs to be determined. Genetically determined abnormal myocardial cell responses to normal growth factors may be responsible for pathogenesis of hypertrophic cardiomyopathy in other instances. When the abnormality is already established in infancy, the clinical course of the disease is much more malignant [40]. Alternatively, the hypertrophy may occur later in life with body growth, as suggested by Maron and coworkers [41]. In serial echocardiographic studies, these workers have demonstrated progressive and striking ventricular hypertrophy during adolescence in children with hypertrophic cardiomyopathy. In some of these children, the previous echo was entirely normal. Whether cellular disarray was present without hypertrophy is not known. However, the hypertrophy often accompanied the pubertal growth spurt. It is tempting to speculate that the more common occurrence of hypertrophic cardiomyopathy in males despite an autosomal dominant pattern of inheritance [42] may be related to growth-promoting effects of male sex hormones that potentiate the effects of growth factors in susceptible individuals. The nature of primary myocardial abnormality is not known. The various antenatal and postnatal growth-promoting substances, hormones and other peptide regulatory factors, may be finally acting through some common pathways [43] which are altered in patients with genetic variety of hypertrophic cardiomyopathy. The recent findings of increased calcium channels in the septum [43], and increased calcium antagonist receptors in the atrial tissues [45] of patients with hypertrophic cardiomyopathy may be relevant. Furthermore, the finding of a DNA locus on chromosome 14, responsible for familial hypertrophic cardiomyopathy is very provocative [46]. The relationship of growthpromoting substances to the calcium fluxes remains to be determined. Thus, an abnormality of myocardial growth either induced by excessive growth-promoting substances, or a genetically determined abnormal-
in the myocardial responses to growth-promoting substances during life (but not in the fetal handling of catecholamines), is likely to be responsible for the pathogenesis of hypertrophic cardiomyopathy. ity
References 1 Goodwin JF. Prospects and predictions for the cardiomyopathies. Circulation 1974;50:210-219. 2 Perloff JK. Pathogenesis of hypertrophic cardiomyopathy:hypotheses and speculations. Am Heart J 1981;lOl: 219-226. 3 Davis MJ. The cardiomyopathies: a review of terminology, pathology and pathogenesis. Histopathology 1984;8:363393. 4 Wenger NK, Abelmann WH, Roberts WC. Cardiomyopathy and specific heart muscle disease. In: Hurst JW, Schlant RC, Rackley CE, Sonnenblick CH, Wenger NH eds. The heart arteries and veins. 7th ed. New York: 1990; McGraw Hill, 1278-1347. 5 Pearse AGE. The histochemistry and electron microscopy of obstructive cardiomyopathy. In: Wolstenholme GEW, M O’Connor, eds. Ciba Foundation Symposium on Cardiomyopathies. London: Churchill, 1964; 132-164. 6 Van Noorden S. Olsen EGJ, Pearse AGE. Hypertrophic obstructive cardiomyopathy, a histological, histochemical and ultrastructural study of biopsy material. Cardiovasc Res 1971;5:118-131. 7 Laks MM, Morady F, Swan HJC. Myocardial hypertrophy produced by chronic infusion of subhypertensive doses of norepmephrine in the dog. Chest 1973;64:75-78. 8 Blaufuss AH, Laks MM, Gamer D, Ishomoto, Criley JM. Production of ventricular hypertrophy simulating idiopathic hypertrophic subaortic stenosis (IHSS) by subhypertensive infusion of norepinephrine in conscious dogs. Clin Res 1975;23:77A. 9 Come PC, Bulkley BH, Goodman ZD, Hutchins GM, Pitt B, Fortuin NJ. Hypercontractile cardiac states simulating hypertrophic cardiomyopathy. Circulation 1977;55:901908. 10 Raum WJ, Larks MM, Garner D, Swerdoff S. B-adrenergic receptors and cyclic AMP alterations in the canine ventricular septum during long term norepinephrine infusion: implications for hypertrophic cardiomyopathy. Circulation 1983;68:693-697. Vaughan Williams EM, Tasgal J, Rain AEG. Morphomettic changes in rabbit ventricular myocardium produced by long-term beta-adrenoceptor blockade. Lancet 1977:2:850852. Simpson P, McGrath A, Savion S. Myocyte hypertrophy in neonatal rat heart cultures and its regulation by serum and by catecholamines. Circ Res 1982;51:787-801. Ostman-Smith I. Cardiac sympathetic nerves as the final common pathways in the induction of adaptive cardiac hypertrophy. Clin Sci 1981;61:265-272.
13 14 Kawai
15
16
17
18 19
20 21 22
23
24
25 26
27 28
29
C, Yui Y, Hishino T, Sasayama S, Matsumori A. Myocardial catecholamines in hypertropbic and dilated (congestive) cardiomyopathy: a biopsy study. J Am Co11 Cardiol 1983;2:834-840. Golf S, Myhre E, Abdelnoor M, Andersen D, Hansson V. Hypertrophic cardiomyopathy characterized by beta-adrenoceptor density, relative amount of beta-adrenoceptor subtypes and adenylate cyclase activity. Cardiovasc Res 1985;19:693-699. Witzke DJ, Kaye MP. Hypertrophic cardiomyopathy induced by administration of nerve growth factor. Circulation 1976;53/54:11-88. Elliot CM, Tajik AJ, Giuliani ER, Gordon H. Idiopathic hypertrophic subaortic stenosis associated with cutaneous neurofibromatosis. Report of a case. Am Heart J 1976;92: 368-372. Polani PE, Moynahan EJ: Progressive cardiomyopathic lentigenosis. Quart J Med 1972;41:205-225. Bolande RP. Neurofibromatosis: the quintessential neurocristopathy: pathogenic concepts and relationships. Adv Nemo1 1981;29:67-75. Sporn MB, Roberts AB. Peptide growth factors are multifunctional. Nature 1988;330:484-486. Garcia R. Jennings JM. Phaeochromocytoma masquerading as a cardiomyopathy. Am J Cardiol 1972;29:568-572. Miranda CME, Garcia PJ. Casas E, deSoria RF. Oliver J, Dela Marina AJR. Hipertrofia miocardica septal asimetri. Med Clin 1989;92:701-704. Viale G. Dell’orto P, Moro E. Cozzaglio L, Coggi G. Vasoactive intestinal polypeptide, somatostatin and calcitonin producing adrenal phaeochromocytoma associated with watery diarrhoea syndrome. Cancer 1985;55: 109991106. Child JS, Perloff JK. Bach PM, Wolfe AD. Perlman S, Kark AP. Cardiac involvement in Friedreich’s ataxia. A clinical study of 75 patients. J Am Co11 Cardiol 1986;7: 1370-1378. Stumpf DA. Friedreich’s disease: a metabolic cardiomyopathy. Am Heart J 1982;104:887-888. Kohlschiitter A, Hausdorf G. Primary (genetic) cardiomyopathy in infancy. A survey of possible disorders and guidelines for diagnosis. Eur J Pediatr 1986;145:454-459. Olsen EGJ, Symons C, Hawkey C. Effect of triac on the developing heart. Lancet 1977;2:221-223. Symons C. Richardson PJ, Feizi 0. Hypertrophic cardiomyopathy and hyperthyroidism: A report of three cases. Thorax 1974;29:713-719. Pearce PC, Hawkey CM, Symons C. Effect of triac and /3-adrenergic blocking agents in the myocardium of developing rats. Cardiovasc Res 1983;17:7-14.
30 Symons C, Fortune F, Greenbaum RA, Dandona P. Cardiac hypertrophy, hypertrophic cardiomyopathy and hyperparathyroidism: an association. Br Heart J 1985:54:539542. 31 Breitweser JA, Meyer RA, Sperling MA et al. Cardiac septal hypertrophy in hyperinsulinemic infants. J Pediatr 1980;96:535-539. 32 Rheuban KS, Blizzard RM, Parker MA et al. Hypertrophic cardiomyopathy in total lipodystrophy. J Pediatr 1986; 109:301-302. 33 Geffner ME, Nersch N, Kaplan SA et al. Leprechaunism: insulin action despite genetic insulin resistance. Pediatr Res 1986:20:329A. 34 Ryan CA. Boyle MH. Burggraf. Reversible obstructive hypertrophic cardiomyopathy in the Beckwith-Wiedemann syndrome. Pediatr Cardiol 1989;10:225-228. 35 Picon L. Effect of insulin on growth and biochemical composition of the rat fetus. Endocrinology 1967;81:14191421. 36 Maron BJ, Verter J. Kapur S. Disproportionate ventricular septal thickening in the developing normal human heart. Circulation 1978:57:520-526. 37 Ferrans VJ. Morrow AG, Roberts WC. Myocardial ultrastructure in idiopathic hypertrophic subaortic stenosis. Circulation 1972;45:765-792. 38 Millhouse EW, Chiakulas JJ, Scheving LE. Long-term organ culture of the salamander heart. J Cell Biol 1971;48:1-14. 39 Smallridge RC, Rajfer S, Davia J, Schaaf M. Acromegaly and the heart: an echocardiographic study. Am J Med 1979;66:22-27. 40 Maron BJ. Tajik AJ, Ruttenberg HD et al. Hypertrophic cardiomyopathy in infants: clinical features and natural history. Circulation 1982;65:7-17. 41 Maron BJ, Spirit0 P. Wesley Y. Arce J. Development and progression of left ventricular hypertrophy in children with hypertrophic cardiomyopathy. N Engl J Med 1986;315: 610-614. 42 Maron BJ. The genetics of hypertrophic cardiomyopathy. Ann Intern Med 1986;105:610-613. 43 Michell RH. Peptide regulatory factors. Post receptor signalling pathways. Lancet 1989;1:765-767. 44 Ferry DR. Kaumann AJ. Relationship between P-adrenoceptors and calcium channels in human ventricular myocardium. Br J Pharmacol 1987:90:447-457. 45 Wagner JA, Sax FL, Weisman HF et al. Calcium antagonist receptors in the atria1 tissue of patients with hypertrophic cardiomyopathy. N Engl J Med 1989;320:755-761. 46 Jarcho JA. McKenna W. Pare JAP et al. Mapping a gene for familial hypertrophic Cardiomyopathy to chromosome 14ql. N Engl J Med 1989. 321:1372-1378.
CARD10
Journal of Cardiology,
30 (1991) 9-13
01177
Review
Pathogenesis of hypertrophic cardiomyopathy: another viewpoint Shyam Sunder Kothari Institute
of Cardiology, New Civil Hospital, Ahmedabad,
(Received
21 June 1990; revision
accepted
Kothari SS. Pathogenesis of hypertrophic cardiomyopathy:
3 August
India 1990)
another viewpoint. Int J Cardiol 1991;30:9-13.
A genetically determined error in the handling of catecholamines by the developing heart has been speculated to cause hypertrophic cardiomyopathy. A critical appraisal of the published literature reveals that there is little actual experimental or clinical evidence favouring the role of catechohunines in the pathogenesis of hypertrophic cardiomyopathy. Other factors seem to be more important. An abnormality of myocardial growth, either induced by excessive growth promoting substance, or a genetically determined abnormality in myocardial responses to normal growth factors during life (but not in the fetal handling of cathecholamines) is likely to be responsible for hypertrophic cardiomyopathy. Key words: Hypertrophic
cardiomyopathy;
Catecholamines;
Introduction
The ‘catecholamine
A genetically determined error in the handling of catecholamines by the developing heart has been speculated to cause hypertrophic cardiomyopathy [l]. Perloff extended this hypothesis by adding some experimental and clinical evidence [2]. Subsequently there has been little evidence to support the hypothesis, and many studies have belied the presumptions made in the ‘catecholamine hypothesis’. Notwithstanding, it continues to enjoy the status of an almost accepted hypothesis [3,4]. It is the purpose of this review to redress the ‘catecholamine hypothesis’ and integrate the available information into a more plausible explanation for the pathogenesis of hypertrophic cardiomyopathy.
Correspondence to: Dr. S.S. Kothari, MD, DM., Inst. of Cardiology, New Civil Hospital, Ahmedabad, India 380 016.
0167-5273/91/$03.50
8 1991 Elsevier Science Publishers
Growth factors
Experimental
hypothesis’
evidence
The reported experimental evidence favouring the hypothesis include the following observations: (a) The earlier observation that sympathetic innervation and noradrenaline content were increased in fresh septal myocardium removed from patients with hypertrophic cardiomyopathy undergoing operation [5]. This was subsequently found to be incorrect [6]. (b) Chronic infusion of norepinephrine in mature dogs in subhypertensive doses caused cardiac hypertrophy 171. In these experiments, ventricular wall hypertrophy was induced with short term infusion of norepinephrine. However, there was no septal hypertrophy and the histopathology was not examined. (c) Production of ventricular hypertrophy simulating idiopathic hypertrophic subaortic stenosis
B.V. (Biomedical
Division)
10
with long term infusion of norepinephrine in conscious dogs were reported [8]. The similarity to hypertrophic cardiomyopathy was only in the production of a hypercontractile state in which outflow gradients were observed. This should not be equated to hypertrophic cardiomyopathy since such a state can be induced with catecholamines in normal and otherwise hypertrophied hearts as well [9]. (d) As an extension of the above work, the same group of investigators implicated catecholamines in the pathogenesis of the disease based on the observation of increased beta-adrenergic receptors and reduced cyclic AMP in canine myocardium in response to long term catecholamine infusion [lo]. The alterations were different in the septum and free walls and occurred before ventricular hypertrophy was evident. This observation should have limited implications by itself, but the authors hypothesised that depleted stores of cyclic AMP may be one of the mechanisms involved in the pathogenesis of hypertrophic cardiomyopathy. This has been extended as an evidence in favour of the role of catecholamines in the pathogenesis [4]. (e) Long-term beta-blockade in rabbits caused a reduction in the rate of cardiac growth [ll]. In young rabbits long term beta-blockade caused reduction in cardiac weight and decrease in number of mitochondria in these experiments. This was probably in response to reduced oxygen requirements. While it is true that catecholamines may influence myocyte growth [12], and may be important in adaptive cardiac hypertrophy [13], this does not automatically implicate catecholamines in the pathogenesis of hypertrophic cardiomyopathy. Other studies It is relevant that in more recent studies, no abnormalities in the myocardial norepinephrine concentration [6,14], in the number of beta-adrenoceptors, or in the level of catecholamine sensitive adenylate cyclase [15] have been determined in patients with hypertrophic cardiomyopathy. Thus, there is no actual experimental evidence support-
ing the role of catecholamines in the pathogenesis of hypertrophic cardiomyopathy. Clinical evidence The second line of reasoning was related to occasional occurrence of hypertrophic cardiomyopathy in a group of otherwise unrelated disorders that were presumed to be disorders of catecholamines and sympathetic nervous system [2]. Subsequent studies have suggested that hypertrophic cardiomyopathy in most of these could be explained by factors other than catecholamines. (a) Disorders of neural crest derivatives: The hypertrophic cardiomyopathy in the disorders of neural crest derivatives like lentigenosis and neurofibromatosis was linked to catecholamines, as either due to excessive catecholamine precursors synthesised by melanocytes, or due to excessive nerve growth factor. Hypertrophic cardiomyopathy induced by injection of nerve growth factor in the experimental animals was not well documented [16]. Normal catecholamine concentrations were found in patients with these disorders [17,18]. Of course, these observations do not rule out participation of catecholamines in the pathogenesis. However, it appears simplistic, if not illogical, to implicate catecholamines in these patients as the neural crest disorders like neurofibromatosis are primary disorders of cell growth and differentiation [19] with potentials of localised growth, hamartoma and neoplasia in various organs. Nerve growth factor structurally resembles insulin. Nerve growth factor (or some other similar peptides) may also have effects on myocytes irrespective of catecholamines. As recently shown, the growth peptides have multifunctional potentials [20]. Phaeochromocytoma: Excessive catecholamines cause myocardial cell necrosis and histopathological picture resembling dilated cardiomyopathy [21]. The rare occurrence of asymmetric septal hypertrophy with phaeochromocytoma, and its reversal after removal of the tumour has been reported [22]. As discussed earlier, catecholamines may induce some cardiac hypertrophy. However, the tumour tissue may secrete various other peptides [23] which may presumably influence the cardiac hypertrophy. Associated multiple endo-
11
crinopathy may also be responsible for hypertrophy in some of the cases. (b) Friedreich’s ataxia: Hypertrophic cardiomyopathy in patients with Friedreich’s ataxia was thought to be common. A comprehensive study by Child and coworkers has shown that cardiac abnormalities in this disease include segmental myocardial dystrophy, global left ventricular hypokinesia, and, rarely, ventricular hypertrophy and asymmetric septal hypertrophy [24]. The myocardial cellular disarray, or propensity to ventricular arrhythmias was not seen in these patients. A number of metabolic abnormalities have been observed in patients with Friedreich’s ataxia [25]. The mitochondrial mahc enzyme deficiency may explain both the neural and cardiac involvement. It is reasonable to suggest that hypertrophic cardiomyopathy in Friedreich’s ataxia represents a metabolic myopathy. Hypertropbic cardiomyopathy also rarely occurs in other metabolic myopathies [26]; these are not discussed here. (c) Hyperthyroidism: The administration of TRIAC (diethanolamine salt of triodothyroacetic acid) to pregnant rats induced wide spread cellular disarray and ventricular hypertrophy akin to hypertrophic cardiomyopathy in the offspring [27]. This observation and the clinical occurrence of hypertrophic cardiomyopathy with hyperthyroidism [28] was hypothesised to have resulted from the adrenergic stimulus that accompanied hyperthyroidism [2]. However, subsequent studies by Pearse et al. [29] using the TRIAC model, have clarified that hypertrophy was prevented by drugs with membrane stabilising effects and was unrelated to their adrenergic blocking efficacy. Thus thyroid hormone rather than catecholamines seem to be responsible for hypertrophy. Thyroxine has also been shown to have myocyte growth-promoting effects in isolated cell culture studies [12]. (d) Hypercalcemia: Since catecholamines may increase intracellular calcium concentrations, the occurrence of hypertrophic cardiomyopathy with hypercalcemia was suggested as favouring the catecholamine hypothesis. However, parathyroid hormone, and not calcium, has been shown to be responsible for hypertrophy [30]. Increased concentration of parathyroid hormone measured by radioimmunoassay was found in one third of pa-
tients with hypertrophic cardiomyopathy. A direct effect of parathyroid hormone or a similar peptide measured in the immunoassay was thought to be responsible for the ventricular hypertrophy [30]. (e) Infants of diabetic mothers: Reversible hypertrophic cardiomyopathy seen in infants of diabetic mothers [31] was postulated to result from increased intrauterine adrenergic responses to fetal hypoglycemia [2]. Similar hypertrophy has been observed in infants with total lipodystrophy [32], in leprechaunism [33] and with Beckwith-Weidemann syndrome [34]. Hyperinsulinism rather than hypoglycemia is responsible for hypertrophy [31,33]. Insulin has growth-promoting effects [35] and the fetal heart is rich in insulin receptors. The recent observation of insulin action on fetal insulin-like growth factor (IGF-II) receptors, even with genetic resistance to insulin receptors [33] lends credence to the fact that insulin in fetus causes myocardial hypertrophy. Thus, there is no clear clinical evidence to support the assertion that abnormalities of catecholamine concentration or of adrenergic receptors are responsible for the pathogenesis of hypertrophic cardiomyopathy. Therefore, this speculation should be de-emphasized.
Alternative hypothesis During normal embryogenesis the ventricular septum is disproportionately thicker than the ventricular walls [36]. Mild cellular disarray is seen in normal infants [36], in hearts of primitive animals like crustaceans [37], and in organ culture of beating salamander myocardium [38]. This may be a feature of dedifferentiated growth [37]. Abnormal myocardial growth in the fetus due to excessive growth-promoting substances (like insulin, thyroxine, and other peptide regulatory factors) may result in excessive septal hypertrophy and cellular disarray. The septum may retain a greater ability to respond to growth factors with hypertrophy later in life as well. Thus exuberant hypertrophy in response to growth-promoting substances may result in asymmetric septal hypertrophy frequently seen in acromegaly [39], hyperparathyroidism [30], and hyperinsulinism [32]. A variable degree of cellular disarray accompanies
12
hypertrophy in these situations. Why some patients with these disorders develop pattern similar to hypertrophic cardiomyopathy and others develop concentric ventricular hypertrophy needs to be determined. Genetically determined abnormal myocardial cell responses to normal growth factors may be responsible for pathogenesis of hypertrophic cardiomyopathy in other instances. When the abnormality is already established in infancy, the clinical course of the disease is much more malignant [40]. Alternatively, the hypertrophy may occur later in life with body growth, as suggested by Maron and coworkers [41]. In serial echocardiographic studies, these workers have demonstrated progressive and striking ventricular hypertrophy during adolescence in children with hypertrophic cardiomyopathy. In some of these children, the previous echo was entirely normal. Whether cellular disarray was present without hypertrophy is not known. However, the hypertrophy often accompanied the pubertal growth spurt. It is tempting to speculate that the more common occurrence of hypertrophic cardiomyopathy in males despite an autosomal dominant pattern of inheritance [42] may be related to growth-promoting effects of male sex hormones that potentiate the effects of growth factors in susceptible individuals. The nature of primary myocardial abnormality is not known. The various antenatal and postnatal growth-promoting substances, hormones and other peptide regulatory factors, may be finally acting through some common pathways [43] which are altered in patients with genetic variety of hypertrophic cardiomyopathy. The recent findings of increased calcium channels in the septum [43], and increased calcium antagonist receptors in the atrial tissues [45] of patients with hypertrophic cardiomyopathy may be relevant. Furthermore, the finding of a DNA locus on chromosome 14, responsible for familial hypertrophic cardiomyopathy is very provocative [46]. The relationship of growthpromoting substances to the calcium fluxes remains to be determined. Thus, an abnormality of myocardial growth either induced by excessive growth-promoting substances, or a genetically determined abnormal-
in the myocardial responses to growth-promoting substances during life (but not in the fetal handling of catecholamines), is likely to be responsible for the pathogenesis of hypertrophic cardiomyopathy. ity
References 1 Goodwin JF. Prospects and predictions for the cardiomyopathies. Circulation 1974;50:210-219. 2 Perloff JK. Pathogenesis of hypertrophic cardiomyopathy:hypotheses and speculations. Am Heart J 1981;lOl: 219-226. 3 Davis MJ. The cardiomyopathies: a review of terminology, pathology and pathogenesis. Histopathology 1984;8:363393. 4 Wenger NK, Abelmann WH, Roberts WC. Cardiomyopathy and specific heart muscle disease. In: Hurst JW, Schlant RC, Rackley CE, Sonnenblick CH, Wenger NH eds. The heart arteries and veins. 7th ed. New York: 1990; McGraw Hill, 1278-1347. 5 Pearse AGE. The histochemistry and electron microscopy of obstructive cardiomyopathy. In: Wolstenholme GEW, M O’Connor, eds. Ciba Foundation Symposium on Cardiomyopathies. London: Churchill, 1964; 132-164. 6 Van Noorden S. Olsen EGJ, Pearse AGE. Hypertrophic obstructive cardiomyopathy, a histological, histochemical and ultrastructural study of biopsy material. Cardiovasc Res 1971;5:118-131. 7 Laks MM, Morady F, Swan HJC. Myocardial hypertrophy produced by chronic infusion of subhypertensive doses of norepmephrine in the dog. Chest 1973;64:75-78. 8 Blaufuss AH, Laks MM, Gamer D, Ishomoto, Criley JM. Production of ventricular hypertrophy simulating idiopathic hypertrophic subaortic stenosis (IHSS) by subhypertensive infusion of norepinephrine in conscious dogs. Clin Res 1975;23:77A. 9 Come PC, Bulkley BH, Goodman ZD, Hutchins GM, Pitt B, Fortuin NJ. Hypercontractile cardiac states simulating hypertrophic cardiomyopathy. Circulation 1977;55:901908. 10 Raum WJ, Larks MM, Garner D, Swerdoff S. B-adrenergic receptors and cyclic AMP alterations in the canine ventricular septum during long term norepinephrine infusion: implications for hypertrophic cardiomyopathy. Circulation 1983;68:693-697. Vaughan Williams EM, Tasgal J, Rain AEG. Morphomettic changes in rabbit ventricular myocardium produced by long-term beta-adrenoceptor blockade. Lancet 1977:2:850852. Simpson P, McGrath A, Savion S. Myocyte hypertrophy in neonatal rat heart cultures and its regulation by serum and by catecholamines. Circ Res 1982;51:787-801. Ostman-Smith I. Cardiac sympathetic nerves as the final common pathways in the induction of adaptive cardiac hypertrophy. Clin Sci 1981;61:265-272.
13 14 Kawai
15
16
17
18 19
20 21 22
23
24
25 26
27 28
29
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