Andrea P. Babick

Cardiac remodeling and subcellular defects in heart failure due to myocardial infarction and aging

Although several risk factors including hypertension, cardiac hypertrophy, coronary artery disease, and diabetes are known to result in heart failure, elderly subjects are more susceptible to myocardial infarction and more likely to develop heart failure. This article is intended to discuss that cardiac dysfunction in hearts failing due to myocardial infarction and aging is associated with cardiac remodeling and defects in the subcellular organelles such as sarcolemma (SL), sarcoplasmic reticulum (SR), and myofibrils. Despite some differences in the pattern of heart failure due to myocardial infarction and aging with respect to their etiology and sequence of events, evidence has been presented to show that subcellular remodeling plays a critical role in the occurrence of intracellular Ca2+-overload and development of cardiac dysfunction in both types of failing heart. In particular, alterations in gene expression for SL and SR proteins induce Ca2+-handling abnormalities in cardiomyocytes, whereas those for myofibrillar proteins impair the interaction of Ca2+ with myofibrils in hearts failing due to myocardial infarction and aging. In addition, different phosphorylation mechanisms, which regulate the activities of Ca2+-cycling proteins in SL and SR membranes as well as Ca2+-binding proteins in myofibrils, become defective in the failing heart. Accordingly, it is suggested that subcellular remodeling involving defects in Ca2+-handling and Ca2+-binding proteins as well as their regulatory mechanisms is intimately associated with cardiac remodeling and heart failure due to myocardial infarction and aging.

Antiplatelet therapy attenuates subcellular remodelling in congestive heart failure

Antiplatelet agents, sarpogrelate (SAR), a 5‐HT2A receptor antagonist, and cilostazol (CIL), a phosphodiesterase III (PDE‐III) inhibitor, are used for the treatment of peripheral vascular disease. We tested whether these agents affect cardiac function and subcellular remodelling in congestive heart failure (CHF) induced by myocardial infarction (MI). Three weeks after MI, rats were treated daily with 5 mg/kg SAR or CIL as well as vehicle for 5 weeks. Sham‐operated animals served as controls. At end of the treatment period, haemodynamic measurements were performed and the left ventricle was processed for the determination of sarcoplasmic reticulum (SR) Ca2+‐uptake and ‐release activities, and expression of SR Ca2+‐pump, phospholamban and ryanodine receptors, as well as myofibrillar ATPase activities, expression of α‐ and β‐myosin heavy chain (MHC) isoforms, and phosphorylation of phospholamban and cardiac troponin‐I (c Tn‐I). Marked haemodynamic changes in the MI‐induced CHF were associated with depressions in SR Ca +‐uptake and ‐release activities as well as in protein content and gene expression for SR proteins. Furthermore, myofibrillar Ca2+‐stimulated ATPase activity, as well as protein content and gene expression for α‐MHC were decreased whereas those for β‐MHC were increased in the failing heart. Also, phosphorylation levels of phospholamban and cTn‐I were reduced in failing hearts. The MI‐associated changes in cardiac function, SR and myofibillar activities, as well as SR and myofibrillar protein and gene expression were attenuated by treatment with SAR or CIL. The results suggest that SAR and CIL improve cardiac function by ameliorating subcellular remodelling in the failing heart and indicate the potential therapy of CHF with antiplatelet agents.

Role of Subcellular Remodeling in Cardiac Dysfunction due to Congestive Heart Failure

Although alterations in the size and shape of the heart (cardiac remodeling) are considered in explaining cardiac dysfunction during the development of congestive heart failure (CHF), there are several conditions including initial stages of cardiac hypertrophy, where cardiac remodeling has also been found to be associated with either an increased or no change in heart function. Extensive studies have indicated that cardiac dysfunction is related to defects in one or more subcellular organelles such as myofibrils, sarcoplasmic reticulum and sarcolemma, depending upon the stage of CHF. Such subcellular abnormalities in the failing hearts have been shown to occur at both genetic and protein levels. Blockade of the renin-angiotensin system has been reported to partially attenuate changes in subcellular protein, gene expression, functional activities and cardiac performance in CHF. These observations provide support for the role of subcellular remodeling (alterations in molecular and biochemical composition of subcellular organelles) in cardiac dysfunction in the failing heart. On the basis of existing knowledge, it appears that subcellular remodeling during the process of cardiac remodeling plays a major role in the development of cardiac dysfunction in CHF.

TNF‐α‐mediated signal transduction pathway is a major determinant of apoptosis in dilated cardiomyopathy

Although J2N‐k strain of cardiomyopathic hamsters is an excellent model of dilated cardiomyopathy, the presence and mechanisms of apoptosis in the hearts of these genetically modified animals have not been investigated. This study examined the hypothesis that cardiac dysfunction and apoptosis in the cardiomyopathic hamsters were associated with tumour necrosis factor‐alpha (TNF‐α)‐mediated signalling pathway involving the activation of some pro‐apoptotic proteins and/or deactivation of some antiapoptotic proteins. Echocardiographic assessment of 31‐week‐old hamsters indicated an increase in the internal dimension of the left ventricle as well as decreases in the ejection fraction, fractional shortening and cardiac output without any evidence of cardiac hypertrophy. Increased level of TNF‐α and apoptosis in cardiomyopathic hearts were accompanied by increased protein content for protein kinase C (PKC) ‐α and ‐ɛ isozymes as well as caspases 3 and 9. Phosphorylated protein content for p38 MAPK and NFκB was increased whereas that for Erk1/2, BAD and Bcl‐2 was decreased in cardiomyopathic hearts. These results support the view that TNF‐α and PKC isozymes may promote apoptosis due to the activation of p38 MAPK and deactivation of Erk1/2 pathways, and these changes may contribute toward the development of cardiac dysfunction in dilated cardiomyopathy.

Reversal of cardiac dysfunction and subcellular alterations by metoprolol in heart failure due to myocardial infarction

In order to examine the reversibility of heart failure due to myocardial infarction (MI) by β‐adrenoceptor blockade, 12 weeks infarcted rats were treated with or without metoprolol (50 mg/kg/day) for 8 weeks. The depressed left ventricular (LV) systolic pressure, positive and negative rates of changes in pressure development, ejection fraction, fractional shortening and cardiac output, as well as increased LV end‐diastolic pressure in 20 weeks MI animals were partially reversed by metoprolol. MI‐induced decreases in septum (systolic) thickness as well as increase in LV posterior wall thickness and LV internal diameter were partially or fully reversible by metoprolol. Treatment of MI animals with metoprolol partially reversed the elevated levels of plasma norepinephrine and dopamine without affecting the elevated levels of epinephrine. Although sarcoplasmic reticular (SR) Ca2+‐uptake, as well as protein content for SR Ca2+‐pump and phospholamban, were reduced in the infarcted hearts; these changes were partially reversible with metoprolol. Depressed myofibrillar Ca2+‐stimulated ATPase activity, as well as mRNA levels for SR Ca2+‐pump, phospholamban and α‐myosin heavy chain, were unaffected whereas increased mRNA level for β‐myosin heavy chain was partially reversed by metoprolol. The results suggest that partial improvement of cardiac performance by β‐adrenoceptor blockade at advanced stages of heart failure may be due to partial reversal of changes in SR Ca2+‐pump function whereas partial to complete reverse cardiac remodeling may be due to partial reduction in the elevated levels of plasma catecholamines. J. Cell. Physiol. 228: 2063–2070, 2013.

Reversal of subcellular remodelling by losartan in heart failure due to myocardial infarction

This study tested the reversal of subcellular remodelling in heart failure due to myocardial infarction (MI) upon treatment with losartan, an angiotensin II receptor antagonist. Twelve weeks after inducing MI, rats were treated with or without losartan (20 mg/kg; daily) for 8 weeks and assessed for cardiac function, cardiac remodelling, subcellular alterations and plasma catecholamines. Cardiac hypertrophy and lung congestion in 20 weeks MI‐induced heart failure were associated with increases in plasma catecholamine levels. Haemodynamic examination revealed depressed cardiac function, whereas echocardiographic analysis showed impaired cardiac performance and marked increases in left ventricle wall thickness and chamber dilatation at 20 weeks of inducing MI. These changes in cardiac function, cardiac remodelling and plasma dopamine levels in heart failure were partially or fully reversed by losartan. Sarcoplasmic reticular (SR) Ca2+‐pump activity and protein expression, protein and gene expression for phospholamban, as well as myofibrillar (MF) Ca2+‐stimulated ATPase activity and α‐myosin heavy chain mRNA levels were depressed, whereas β‐myosin heavy chain expression was increased in failing hearts; these alterations were partially reversed by losartan. Although SR Ca2+‐release activity and mRNA levels for SR Ca2+‐pump were decreased in failing heart, these changes were not reversed upon losartan treatment; no changes in mRNA levels for SR Ca2+‐release channels were observed in untreated or treated heart failure. These results suggest that the partial improvement of cardiac performance in heart failure due to MI by losartan treatment is associated with partial reversal of cardiac remodelling as well as partial recovery of SR and MF functions.

Hormonal Mechanisms of Cardiac Remodeling in Heart Failure

It is now generally accepted that cardiac dysfunction in congestive heart failure (CHF) is due to cardiac remodeling as a consequence of changes in the size and shape of the heart. Furthermore, both the sympathetic nervous system (SNS) and the renin–angiotensin system (RAS) are activated, and the circulating levels of catecholamines and angiotensin II are elevated in CHF. Experimental and clinical studies have revealed that the blockade of SNS by different adrenoceptor (AR) antagonists improve cardiac function and attenuate cardiac remodeling. In addition to modifying β-AR-mediated signal transduction, β-AR antagonists have been shown to depress the elevated levels of catecholamines in CHF. On the contrary, the improvement of cardiac function and cardiac remodeling in CHF due to the blockade of RAS by angiotensin-converting enzyme inhibitors and angiotensin receptor blockers were associated with a reduction in the formation of angiotensin and antagonism of the angiotensin-receptor-mediated signal transduction, respectively. Blockade of either SNS or RAS prevented subcellular remodeling upon modifying changes in cardiac gene expression, reduced the development of intracellular Ca2+-overload, and attenuated the occurrence of oxidative stress in the failing heart. These observations are consistent with the view that the activation of both SNS and RAS plays a crucial role in the genesis of cardiac remodeling and cardiac dysfunction in CHF.

Reversal of Cardiac Remodeling and Subcellular Defects by Prazosin in Heart Failure Due to Myocardial Infarction

Background: This study was undertaken to test if α-Adrenoceptor (AR) blockade with prazosin reverses cardiac remodeling and ameliorates subcellular defects in heart failure due to Myocardial Infarction (MI). Methods: Heart failure in rats was induced by MI for 12 wks and then treated with or without prazosin (10 mg/kg/ day) for 8 wks. Both control and experimental animals were assessed hemodynamically and echocardiographically for evaluating changes in heart function and cardiac remodeling, respectively. Left Ventricle (LV) was used for determining biomedical and molecular activities. Results: Cardiac dysfunction, as evident from depressed LV systolic pressure, rates of changes in pressure development and decay, cardiac output, ejection fraction and fractional shortening as well as increased LV end diastolic pressure, in 20 wks infarcted animals, was corrected partially by prazosin treatment. Different parameters of cardiac remodeling including increased LV posterior wall thickness and LV systolic diameter in failing hearts were fully or partially reversed whereas increased LV diastolic diameter was unaltered by prazosin therapy. Reversal of lung congestion and cardiac hypertrophy in MI animals by prazosin was associated with depression in the elevated levels of plasma norepinephrine, unlike epinephrine or dopamine. Depressions in Sarcoplasmic Reticular (SR) Ca2+-uptake activity as well as protein content for Ca2+-pump ATPase and phospholamban in failing hearts were reversed partially whereas depressed SR Ca2+-release activity and myofibrillar Ca2+-stimulated ATPase activity were not affected by prazosin. Alterations in mRNA levels for SR Ca2+-pump ATPase, SR Ca2+-release channels, and α-myosin heavy chain and β-myosin heavy chain in MI-induced heart failure were not influenced by prazosin treatment. Conclusions: It is suggested that the activation of α-AR system may be associated with cardiac remodeling and heart failure and the reverse cardiac remodeling by α-AR blockade may improve cardiac performance by attenuating defects in SR Ca2+-pump.