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 ß-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) Ca(2+)-uptake, as well as protein content for SR Ca(2+)-pump and phospholamban, were reduced in the infarcted hearts; these changes were partially reversible with metoprolol. Depressed myofibrillar Ca(2+)-stimulated ATPase activity, as well as mRNA levels for SR Ca(2+)-pump, phospholamban and α-myosin heavy chain, were unaffected whereas increased mRNA level for ß-myosin heavy chain was partially reversed by metoprolol. The results suggest that partial improvement of cardiac performance by ß-adrenoceptor blockade at advanced stages of heart failure may be due to partial reversal of changes in SR Ca(2+)-pump function whereas partial to complete reverse cardiac remodeling may be due to partial reduction in the elevated levels of plasma catecholamines.

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) Ca(2+)-pump activity and protein expression, protein and gene expression for phospholamban, as well as myofibrillar (MF) Ca(2+)-stimulated ATPase activity and α-myosin heavy chain mRNA levels were depressed, whereas ß-myosin heavy chain expression was increased in failing hearts; these alterations were partially reversed by losartan. Although SR Ca(2+)-release activity and mRNA levels for SR Ca(2+)-pump were decreased in failing heart, these changes were not reversed upon losartan treatment; no changes in mRNA levels for SR Ca(2+)-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.

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 Ca(2+)-overload and development of cardiac dysfunction in both types of failing heart. In particular, alterations in gene expression for SL and SR proteins induce Ca(2+)-handling abnormalities in cardiomyocytes, whereas those for myofibrillar proteins impair the interaction of Ca(2+) with myofibrils in hearts failing due to myocardial infarction and aging. In addition, different phosphorylation mechanisms, which regulate the activities of Ca(2+)-cycling proteins in SL and SR membranes as well as Ca(2+)-binding proteins in myofibrils, become defective in the failing heart. Accordingly, it is suggested that subcellular remodeling involving defects in Ca(2+)-handling and Ca(2+)-binding proteins as well as their regulatory mechanisms is intimately associated with cardiac remodeling and heart failure due to myocardial infarction and aging.

TNF-alpha-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-alpha)-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-alpha and apoptosis in cardiomyopathic hearts were accompanied by increased protein content for protein kinase C (PKC) -alpha and -epsilon isozymes as well as caspases 3 and 9. Phosphorylated protein content for p38 MAPK and NF kappaB was increased whereas that for Erk1/2, BAD and Bcl-2 was decreased in cardiomyopathic hearts. These results support the view that TNF-alpha 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.

Antiplatelet therapy attenuates subcellular remodelling in congestive heart failure.

Antiplatelet agents, sarpogrelate (SAR), a 5-HT(2A) 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) Ca(2+)-uptake and -release activities, and expression of SR Ca(2+)-pump, phospholamban and ryanodine receptors, as well as myofibrillar ATPase activities, expression of alpha- and beta-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 Ca(2+)-stimulated ATPase activity, as well as protein content and gene expression for alpha-MHC were decreased whereas those for beta-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.

Gender differences in the modulation of cardiac gene expression by dietary conjugated linoleic acid isomers.

In an earlier study, we showed that dietary conjugated linoleic acid (CLA) isomers can exert differential effects on heart function in male and female rats, but the underlying mechanisms for these actions are not known. Cardiomyocyte Ca2+ cycling is a key event in normal cardiac contractile function and defects in Ca2+ cycling are associated with cardiac dysfunction and heart disease. We therefore hypothesized that abnormalities in the sarcolemmal (SL) and sarcoplasmic reticulum (SR)-mediated regulation of intracellular Ca2+ contribute to altered cardiac contractile function of male and female rats owing to dietary CLA isomers. Healthy male and female Sprague-Dawley rats were fed different CLA isomers, (cis-9, trans-11 (c9,t11) and trans-10, cis-12 (t10,c12)) individually and in combination (50:50 mix as triglyceride or fatty acids) from 4 to 20 weeks of age. We determined the mRNA levels of sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA) 2a, ryanodine receptor, phospholamban, calsequestrin, Na+-Ca2+-exchanger (NCX), and L-type Ca2+ channel in the left ventricle (LV) by RT-PCR. The SR function was assessed by measurement of Ca2+-uptake and -release. Significant gender differences were seen in the LV NCX, L-type Ca2+ channel, and ryanodine receptor mRNA expression levels in control male and female rats. Dietary CLA isomers in the various forms induced changes in the mRNA levels of SERCA 2a, NCX, and L-type Ca2+ channel in the LV of both male and female hearts. Whereas protein contents of the Ca2+ cycling proteins were altered, changes in SR Ca2+-uptake and -release were also detected in both male and female rats in response to dietary CLA. The results of this study demonstrate that long-term dietary supplementation can modulate cardiac gene expression and SR function in a gender-related manner and may, in part, contribute to altered cardiac contractility.

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.

Differential changes in beta-adrenoceptor signal transduction in left and right ventricles of infarcted rats.

Although different experimental and clinical studies have revealed varying degrees of defects in beta-adrenoceptors (beta-ARs) during the development of heart failure, the mechanisms for differences in beta-AR signal transduction between the left (LV) and right ventricle (RV) are not understood. Because biochemical alterations in the myocardium depend on the stage of heart disease, this study was undertaken to assess the status of beta-ARs in the LV and RV at different stages of heart failure. Myocardial infarction was induced in rats by occluding the left coronary artery for 8 and 24 weeks. The beta-AR signal transduction was monitored by measuring beta1-AR density, the isoproterenol-induced positive inotropic effect, the increase in [Ca2+]i in cardiomyocytes, and the activation of adenylyl cyclase. The beta-AR signal transduction parameters in the 8- and 24-week failing LV were depressed, whereas the RV showed upregulation at 8 weeks and downregulation at 24 weeks of these mechanisms. These results suggest that beta-AR-mediated signal transduction in the LV and RV are differentially regulated and are dependent upon the stage of development of congestive heart failure due to myocardial infarction.

A comparative serial echocardiographic analysis of cardiac structure and function in rats subjected to pressure or volume overload.

Heart failure is a leading cause of death that is reaching epidemic proportions. It is a clinical syndrome attributable to a multitude of factors that begins with a compensatory response known as hypertrophy, followed by a decompensatory response that eventually results in failure. Heart failure can be triggered when the heart is subjected to extended periods of pathological pressure overload (PO) or volume overload (VO). To date there have been no comparative serial echocardiographic studies outlining the progression of hypertrophy in PO versus VO rats. We hypothesized that PO or VO would induce differential cardiac remodeling leading to contractile dysfunction with subsequent heart failure. To address this hypothesis we used echocardiography to study the serial progression of heart structure and function in rat models of both PO- and VO-induced hypertrophy. PO or VO were induced by performing abdominal aortic banding or aortocaval shunt procedures, respectively, while cardiac structure and function were assessed in both models by M-mode and Doppler echocardiography at key time intervals. PO rats showed progressive wall thickening consistent with concentric hypertrophy, while VO rats showed marked left ventricular dilatation consistent with eccentric hypertrophy. Systolic dysfunction occurred early in VO compared to PO. Diastolic dysfunction was evident in PO, while VO showed signs of enhanced diastolic function. PO and VO induced differential changes in cardiac structure and function during the progression of compensated hypertrophy to decompensated heart failure.

Cardiac contractile dysfunction in J2N-k cardiomyopathic hamsters is associated with impaired SR function and regulation.

Although dilated cardiomyopathy (DCM) is known to result in cardiac contractile dysfunction, the underlying mechanisms are unclear. The sarcoplasmic reticulum (SR) is the main regulator of intracellular Ca2+ required for cardiac contraction and relaxation. We therefore hypothesized that abnormalities in both SR function and regulation will contribute to cardiac contractile dysfunction of the J2N-k cardiomyopathic hamster, an appropriate model of DCM. Echocardiographic assessment indicated contractile dysfunction, because the ejection fraction, fractional shortening, cardiac output, and heart rate were all significantly reduced in J2N-k hamsters compared with controls. Depressed cardiac function was associated with decreased cardiac SR Ca2+ uptake in the cardiomyopathic hamsters. Reduced SR Ca2+ uptake could be further linked to a decrease in the expression of the SR Ca(2+)-ATPase and cAMP-dependent protein kinase (PKA)-mediated phospholamban (PLB) phosphorylation at serine-16. Depressed PLB phosphorylation was paralleled with a reduction in the activity of SR-associated PKA, as well as an elevation in protein phosphatase activity in J2N-k hamster. The results of this study suggest that an alteration in SR function and its regulation contribute to cardiac contractile dysfunction in the J2N-k cardiomyopathic hamster.