Mini Review Creative Commons, CC-BY
The Role of Hyperaldosteronism in the Pathogenesis of Neuroleptic Cardiomyopathy
*Corresponding author:Volkov V P, Tver center of judicial examinations, Tver, Russia
Received:September 13, 2019;Published: September 26, 2019
A brief review of the literature deals with the role of aldosterone in the pathogenesis of neuroleptic cardiomyopathy due to the side effects of cardiotoxic antipsychotic drugs. Various physiological and pathophysiological effects of aldosterone, its effect on myocardium and participation in cardiac remodeling during morphogenesis of neuroleptic cardiomyopathy are considered.
Keywords: Neuroleptic cardiomyopathy; Pathogenesis; Aldosterone
Neuroleptic cardiomyopathy (NCMP) is a little-studied iatrogenic pathology of the heart due to the side cardiotoxic effects of antipsychotic (neuroleptic) drugs [1-4]. Along with the fact that the etiology of the disease is quite clearly defined, its pathogenesis remains not fully studied. Analysis of the literature data on the development of different types of cardiomyopathies allows us to make some assumptions about the pathogenesis of NCMP. One of the possibilities of heart damage with long-term use of antipsychotics is their indirect effect through the influence of these drugs on the overall metabolism in the body. So, it is well known that one of the most serious side effects of neuroleptic therapy is metabolic syndrome [5-9]. One of the links of neuroendocrine dysfunction in metabolic syndrome is hypercorticism, that is, an increase in the formation and excretion of all steroid hormones of the adrenal cortex , including aldosterone, which plays a certain and, presumably, a significant role in the pathogenesis of NCMP . This brief review of the literature is devoted to this issue.
First, it is necessary to highlight several pathophysiological aspects related to this hormone. Thus, aldosterone is a mineralocorticoid produced mainly in the glomerular zone of the adrenal cortex and in smaller quantities - in the brain, myocardium, vascular endothelium [12-14]. The main activator of the synthesis of aldosterone is the renin - angiotensin system. Inhibit the formation and secretion of the hormone primarily atrial and brain natriuretic peptides . The main effects of aldosterone are an increase in sodium reabsorption in the distal tubules of the kidneys and the associated fluid retention; the consequence of reducing natriuresis is an increase in potassium excretion in the urine [11-16]. Aldosterone also increases the severity of local intravascular inflammation, causes damage to the endothelium of peripheral vessels, increases the number of receptors for angiotensin II in vessels, accelerates apoptosis of cardiomyocytes and potentiates the effects of reninangiotensin system [11,13,17,18]. In this regard, it is important to note that, in addition to the distal renal tubules, aldosterone receptors are present in endothelial cells, cardiomyocytes and fibroblasts of the heart muscle [11,13,19]. It was found that the interaction of aldosterone with these receptors directly affects the state of the extracellular matrix of the myocardium, causes an acceleration of fibroblast proliferation, as well as an increase in the synthesis and accumulation of collagen types I and III, resulting in myocardial fibrosis [19,20-27], which plays a leading role in the appearance of diastolic dysfunction induced by the action of this hormone . It should be emphasized that the development of fibrosis of the heart muscle under the action of aldosterone is not mediated by sodium and fluid retention but is a consequence of direct stimulation of myocardial receptors . This effect is realized primarily by increasing the synthesis of aldosterone not in the adrenal glands, but in the myocardium [29,30], in the aorta and in the coronary sinus . It is also believed that aldosterone which is namely locally synthesized and fixed to the membrane receptors of the heart plays an important role in the processes of ventricular remodeling [31,32]. The triggering effect of aldosterone in relation to fibrosis of the heart muscle is likely determined by the influence of this hormone on the activity of collagenase.
According to CG Brilla et al. , aldosterone enhances the expression of type III collagen gene in cardiac fibroblasts by inhibiting the activity of this enzyme. In addition, many authors have revealed the direct influence of hyperaldosteronism on the processes of cardiac remodeling and hypertrophy [34-37] and demonstrated a direct correlation of aldosterone level with myocardial mass [38,39]. One of the mechanisms of aldosterone participation in cardiac remodeling is its induction of generalized inflammation and oxidative stress [24,25,40], as well as increased activity of matrix metalloproteinases [22&40]. All this is accompanied by an increase in the ultrasonic density of the myocardium, an increase in the stiffness of the walls of the left ventricle, violations of its filling and the appearance of diastolic dysfunction due to the development of extensive fibrosis [22,41,42]. These phenomena accelerate the progression of heart failure, increase the electrical heterogeneity of the myocardium, which underlies the mechanisms of re-entry and reduce the threshold for the occurrence of life-threatening ventricular arrhythmias . The elongation of the QT interval is observed on the electrocardiogram [41,42]. It is appropriate to recall that this electrophysiological phenomenon is a very characteristic feature of the cardiotoxic action of neuroleptics and developing NCMP [43-48]. Diastolic dysfunction induced by the action of aldosterone has been found by many researchers [35,37,42,49,50]. Myocardial fibrosis plays a leading role in its development [50,51]. Hyperaldosteronism entails a decrease in the number of contractile elements per unit volume of the myocardium, the development of tissue hypoxia and disruption of the synchronous operation of cardiomyocytes . At the same time, one of the mechanisms of the negative effect of aldosterone on the structure of the heart muscle is its ability to activate cardiomyocyte apoptosis [22,52]. This process is known to be of importance in the pathogenesis of cardiac remodeling [53-58]. Aldosterone can influence on the development of cardiovascular diseases, including NCMP, through the formation of endothelial dysfunction [22,59]. The development of aldosterone-induced endothelial dysfunction is associated with decreased bioavailability of NO and activity of NO-synthase . At the cellular level, aldosterone alters signals from the transcriptional nuclear factor NF-kB, induces oxidative stress and enhances the penetration of reactive oxygen species into the vascular wall, which is a serious importance in the genesis of endothelial dysfunction [25,61].
Thus, in addition to the direct cardiotoxic side effect of neuroleptic drugs, their indirect effect on the overall metabolism of the body, the development of neuroendocrine dysfunction and metabolic syndrome, an important component of which is hyperaldosteronism, is essential in the pathogenesis of NCMP. The diverse damaging effect of aldosterone on the heart plays an important role in the development of NCMP .
- Buckley NA, Sanders P (2000) Cardiovascular adverse effects of antipsychotic drugs. Drug Saf 23(3): 215-228.
- Coulter DM, Bate A, Meyboom RHB (2001) Antipsychotic drugs and heart muscle disorder in international pharmacovigilance: data mining study. Br Med J 322(7296): 1207-1209
- Volkov VP (2010) Cardiotoxicity of phenothiazine neuroleptics (review of literature). Psichiat psychopharmacother 12(2): 41-45
- Volkov VP (2009) Phenothiazine dilated cardiomyopathy: some aspects of clinic and morphology. Klin Med 87(8): 13-16.
- Bernstein JG (1987) Induction of obesity by psychotropic drugs. Ann NY Acad Sci 499: 203-215
- Cygankov BD, Agasaryan ET (2010) Analysis of efficacy and safety of modern and classical antipsychotic drugs. Zhurn. nevropatologii i psihiatrii im. SS Korsakova 110(9): 64-70
- Gorobec LN (2007) Neuroendocrine dysfunction and neuroleptic therapy. Moscow: Medpraktika-M Publ Pp.312
- Gorobec LN (2005) Neuroendocrine dysfunction in patients with schizophrenia. Soc Klin Psihiatriya 15(1): 89-99.
- Mosolov SN, Kabanov SO (2003) Metabolic disorders in antipsychotic therapy. Soc Klin Psihiatriya 13(2): 162-171.
- Metabolic syndrome
- Volkov V (2014) On the role of metabolic syndrome in the pathogenesis of neuroleptic cardiomyopathy. Vrach 4: 76-77.
- Janiak PC, Lewis SJ, Brody MJ (1990) Role of central mineralocorticoid binding sites in development of hypertension. Am J Physiol - Regul Integr Comp Physiol 259(5, Pt 2): R1025-R1034
- Karpov YuA (2012) Application of eplerenone in cardiology. Some aspects of the pathophysiology of postinfarction period. The role of aldosterone blockade in postinfarction therapy. AtmosferA. Novosti kardiologii 2: 18-22.
- Mortensen RM, Williams GH (2001)Aldosterone action. In: De Groot LJ, Jameson JL, Burger HG et al. Endocrinology. 4th edn.: WB Saunders Publ, Philadelphia, USA, 1783-1790
- McMachon EG (2001) Recent studies with eplerenone, a novel selective aldosterone receptor antagonist. Curr Opin Pharmacol 1(2): 190–196.
- Parhimovich RM (1973) Adrenal hormones; biosynthesis, its regulation, metabolism, biological role in the body. In: Aleshin BV, Genes SG, Vogralik V.G. (eds). Rukovodstvo po endokrinologii. Medicine Publ, Moskow, Russia, pp. 65-82.
- Kapustin AV, Panfilenko OA, Serebryakova BG. Significance of myocardial changes for forensic diagnosis of death from alcoholic cardiomyopathy
- Lapshina LA, Kravchun PG, Lepeeva EA (2006) The role of aldosterone in the process of myocardial remodeling. Ukr kardіol zhurn 2: 90-96
- Weber K T, Brilla C G (1992) Myocardial fibrosis and the renin-angiotensin- aldosterone system. J Cardovasc Pharmacology 20(Suppl 1): 48-54.
- Brilla CG, Zhou G, Matsubara L (1994) Collagen metabolism in cultured adult rat cardiac fibroblasts: response to angiotensin II and aldosterone. J Moll Cell Cardiol 26(7): 809-820
- Brilla CG, Zhou G, Weber KT (1992) Aldosterone-mediated stimulation of collagen synthesis in cultured cardiac fibroblasts. J Hypertens 10(4): 7-10.
- Bubnova MG (2013) Improved survival after myocardial infarction with left ventricular dysfunction and signs of heart failure: focus on aldosterone antagonists.
- Nunes VL, Ramires FJ, Pimentel Wde S (2006) The role of storage of interstitial myocardial collagen on the overlife rate of patients with idiopathic and Сhagasic dilated cardiomyopathy. Arq Bras Cardiol 87(6): 757-762.
- Rocha R, Rudolph AE, Frierdich GE (2002) Aldosterone induces a vascular inflammatory phenotype in the rat heart. Am J Physiol - Heart Circ Physiol 283(5): H1802-H1810
- Sun Y, Zhang J, Lu L (2002) Aldosterone-induced inflammation in the rat heart: role of oxidative stress. Am J Pathol 161(5): 1773-1781
- Weber KT, Brilla CG (1991) Pathological hypertrophy and cardiac interstitium. Fibrosis and renin-angiotensin-aldosterone system. Circulation 83(6): 1849-1865.
- Young M, Fullerton M, Dilley R (1994) Mineralocorticoids, hypertension, and cardiac fibrosis. J Clin Invest 93(6): 2578-2583
- Sato A, Funder JW (1996) High glucose stimulates aldosterone-induced hypertrophy via type I mineralocorticoid receptors in neonatal rat cardiomyocytes. Endocrinology 137(10): 4145-4153.
- Lindpaintner K, Niedermaier N, Drexler H (1992) Left ventricular remodelling after myocardial infarction: does the cardiac renin-angiotensin system play a role. J Cardovasc Pharmacol 20(Suppl 1): S41-S47.
- Hayashi M, Tsutamoto T, Wada A (2003) Immediate administration of mineralocorticoid receptor antagonist spironolactone prevents post-infarct left ventricular remodelling associated with suppression of a marker of myocardial collagen synthesis in patients with first anterior acute myocardial infarction. Circulation 107(20): 2559-2565.
- Chai W, Garrelds IM, de Vries R (2006) Cardioprotective effects of eplerenone in the rat heart: interaction with locally synthesized or blood-derived aldosterone? Hypertension 47(4): 665-670.
- Silvestre JS, Heymes C, Oubénaïssa A (1991) Activation of cardiac aldosterone production in rat myocardial infarction: effect of angiotensin II receptor blockade and role in cardiac fibrosis. Circulation 99(20): 2694- 2701
- Brilla CG, Matsubara LS, Weber KT (1993) Anti-aldosterone treatment and the prevention of myocardial fibrosis in primary and secondary hyperaldosteronism. J Mol Cell Cardiol 25(5): 563-575.
- Matsumura K, Fujii K, Oniki H (2006) Role of aldosterone left ventricular hypertrophy in hypertension. Am J Hypertens 19(1): 13-18.
- Rossi GP, Sacchetto A, Visentin P (1996) Changes in left ventricular anatomy and function in hypertension and primary aldosteronism. Hypertension 27(5): 1039-1045.
- Shigematsu Y, Hamada M, Okayama H (1997) Left ventricular hypertrophy precedes other target-organ damage in primary aldosteronism. Hypertension 29(3): 723-727.
- Shustov SB, Baranov VL, Kadin DV (2000) Condition of cardiac muscle in patients operated on for Kon syndrome. Vestn VMA 1: 40-44.
- Duprez DA, Bauwens FR, De Buyzere ML (1993) Influence of arterial blood pressure and aldosterone on left ventricular hypertrophy in moderate essential hypertension. Am J Cardiol 71(3): 17A-20A.
- Schunkert H, Hense HW, Muscholl M (1997) Association between circulating components of the rennin-angiotensine-aldosterone system and left ventricular mass. Br Heart J 77(1): 24-31.
- Rude MK, Duhaney TA, Kuster GM (2005) Aldosterone stimulates matrix metalloproteinases and reactive oxygen species in adult rat ventricular cardiomyocytes. Hypertention 46(3): 555-561.
- Brilla CG, Janicki JS, Weber KT (1991) Impaired diastolic function and coronary reserve in genetic hypertension. Role of interstitial fibrosis and medial thickening of intramyocardial coronary arteries. Circ Res 69(1): 107-115.
- Rossi GP, Sacchetto A, Pavan E (1997) Remodeling of the left ventricle in primary aldosteronism due to Conn’s adenoma. Circulation 1997; 95(6): 1471-1478.
- Volkov V (2018) Cardiotoxicity of neuroleptics: clinical aspects. LAP Lambert Acad Publ, Beau Bassin, Pp.205.
- Volkov VP (2018) Cardiotoxicity of antipsychotic drugs. Tver: Triada Publ Pp.622.
- Volkov VP (2009) ECG features in phenothiazine cardiomyopathy. Verhnevolzhskij med zhurn 7(4): 3-7.
- Volkov VP (2012) Electrocardiographic manifestations of neuroleptic cardiomyopathy in patients with schizophrenia at the stages of its morphogenesis. Verhnevolzhskij med zhurn 10(1): 13-15.
- Volkov VP (2016) Myocardial morphology in comorbid course of neuroleptic malignant syndrome and neuroleptic cardiomyopathy: information analysis. In: Innovacii v nauke: sb. st. po mater. LIV mezhdunar nauch - prakt konf NO 2(51), SibAK Publ, Novosibirsk, pp: 47-56.
- Volkov VP (2012) To morphogenesis of neuroleptic cardiomyopathy: morphometric and electrocardiographic correlations. Sib med zhurn (Tomsk) 27(4): 29-33.
- TA Sakhnova, GG Arabidze, FU Hajayeva (1995) Computer electrocardiographic assessment of the left heart in patients with primary hyperaldosteronism. Cardiology 35(8): 25-29.
- Yurenev AP, Devereux RB, Goncharova LN (1997) Assessment of the functional state of the myocardium in patients with hypertension and hyperaldosteronism. Kardiologiya 37(9): 22-25.
- Sanderson JE, Cockram CS, Yu CM (1761) Myocardial fibrosis and hyperaldosteronism [letter]. Eur Heart J 1996; 17(11): 1761–1762.
- Mano A, Tatsumi N, Shiraishi J (2004) Aldosterone directly induces myocyte apoptosis through calcineurin-dependent pathways. Circulation 110(3): 317-323.
- Glukhov AA (1999) Clinical and morphological comparisons of dilated and ischemic cardiomyopathy: autoref. Dis kand, med sci, SPb pp. 24.
- Liu T, Wu W, Feng Z (2001) Apoptosis of myocardial cells in dilated cardiomyopathy. Zhonghua Nei Ke Za Zhi 40(9): 602-604.
- Narula J, Arbustini E, Chandrashekhar Y (2001) Apoptosis and the systolic dysfunction in congestive heart failure. Story of apoptosis interruptus and zombie myocytes. Cardiol Clin 19(1): 113-126.
- Nerheim P, Krishnan SC, Olshansky D (2001) Apoptosis in the genesis of cardiac rhythm disorders. Cardiol Clin 19(1): 155-163.
- Shumakov VI, Hubutiya MSh, Ilyinsky IM (2003) Dilated cardiomyopathy. Tver: Triada Publ Pp.448.
- Singh K, Xiao L, Remondino A (2001) Adrenergic regulation of cardiac myocyte apoptosis. J Cell Physiol 189(3): 257-265.
- Duprez D, De Buyzere M, Rietzschel ER (2000) Aldosterone and vascular damage. Curr Hypertens Rep 2(3): 327-334.
- Mitchell BM, Smith AD, Webb RC (2003) Aldosterone decreases endothelium- dependent relaxation by down-regulating GTP cyclohydrolase. Hypertension 42: 435.
- Rajagopalan S, Duquaine D, King S (2002) Mineralocorticoid receptor antagonism in experimental atherosclerosis. Circulation 105(18): 2212- 2216.