Loss Of Contractile Mass Research Articles

Mouse SIRT3 attenuates hypertrophy-related lipid accumulation in the heart through the deacetylation of LCAD.

Cardiac hypertrophy is an adaptive response to pressure, volume stress, and loss of contractile mass from prior infarction. Metabolic changes in cardiac hypertrophy include suppression of fatty acid oxidation and enhancement of glucose utilization, which could result in lipid accumulation in the heart. SIRT3, a mitochondrial NAD+-dependent deacetylase, has been demonstrated to play a crucial role in controlling the acetylation status of many enzymes participating in energy metabolism. However, the role of SIRT3 in the pathogenesis of hypertrophy-related lipid accumulation remains unclear. In this study, hypertrophy-related lipid accumulation was investigated using a mouse cardiac hypertrophy model induced by transverse aortic constriction (TAC). We showed that mice developed heart failure six weeks after TAC. Furthermore, abnormal lipid accumulation and decreased palmitate oxidation rates were observed in the hypertrophic hearts, and these changes were particularly significant in SIRT3-KO mice. We also demonstrated that the short form of SIRT3 was downregulated in wild-type (WT) hypertrophic hearts and that this change was accompanied by a higher acetylation level of long-chain acyl CoA dehydrogenase (LCAD), which is a key enzyme participating in fatty acid oxidation. In addition, SIRT3 may play an essential role in attenuating lipid accumulation in the heart through the deacetylation of LCAD.

A Translational Approach to Hypertensive Heart Disease

The spectrum of the cardiac complications of arterial hypertension includes heart failure (HF), sudden death, and cardiac dysrhythmias, as well as the exacerbation of coincidental diseases (ie, atherosclerosis and chronic renal disease).1 However, knowledge of the cardiac impact of chronic elevation of arterial pressure has so evolved that hypertensive heart disease (HHD) may be thought as those consequences derived from left ventricular (LV) responses to fundamental disease mechanisms triggered by mechanical overload and neurohumoral stimuli.2 For instance, the long-held views are that LV hypertrophy (LVH), as the result of cardiomyocyte growth in response to pressure overload, serves to restore heart muscle economy back to normal and to preserve LV function.3 However, a number of alterations of the cardiomyocyte and the noncardiomyocyte components of the myocardium (including apoptosis, fibrosis, and changes in the microcirculation) also develop in HHD that lead to pathological myocardial remodeling not only in the left ventricle but also the left atrium and right ventricle.2 These alterations may explain the overall risk of LVH and its associated cardiac and noncardiac complications in hypertensive patients.4 Although LVH may be detected early and accurately in hypertensive patients by electrocardiography and echocardiography, newer cardiac imaging methods and the monitoring of several circulating biomarkers hold promise as noninvasive tools for the diagnosis of myocardial remodeling. Numerous clinical studies have shown that effective long-term antihypertensive treatment may be associated with a decreased LV mass (LVM), which has been attributed to diminished risk. However, no large study (or meta-analysis) has demonstrated that diminished risk from the contemporary reduction of arterial pressure by virtue of its a priori design. Therefore, because overall risk remains unacceptably high, especially from HF, new therapeutic strategies aimed not only to decrease arterial pressure and LVM but also to repair and even prevent myocardial remodeling …

The Potential of Soluble Epoxide Hydrolase Inhibition in the Treatment of Cardiac Hypertrophy

The Potential of Soluble Epoxide Hydrolase Inhibition in the Treatment of Cardiac Hypertrophy

Does load-induced ventricular hypertrophy progress to systolic heart failure?

Ventricular hypertrophy develops in response to numerous forms of cardiac stress, including pressure or volume overload, loss of contractile mass from prior infarction, neuroendocrine activation, and mutations in genes encoding sarcomeric proteins. Hypertrophic growth is believed to have a compensatory role that diminishes wall stress and oxygen consumption, but Framingham and other studies established ventricular hypertrophy as a marker for increased risk of developing chronic heart failure, suggesting that hypertrophy may have maladaptive features. However, the relative contribution of comorbid disease to hypertrophy-associated systolic failure is unknown. For instance, coronary artery disease is induced by many of the same risk factors that cause hypertrophy and can itself lead to systolic dysfunction. It is uncertain, therefore, whether ventricular hypertrophy commonly progresses to systolic dysfunction without the contribution of intervening ischemia or infarction. In this review, we summarize findings from epidemiologic studies, preclinical experiments in animals, and clinical trials to lay out what is known-and not known-about this important question.

Increase in G(i alpha) protein accompanies progression of post-infarction remodeling in hypertensive cardiomyopathy.

Hypertensive cardiac hypertrophy and myocardial infarction (MI) are clinically relevant risk factors for heart failure. There is no specific information addressing signaling alterations in the sequence of hypertrophy and post-MI remodeling. To investigate alterations in beta-adrenergic receptor G-protein signaling in ventricular remodeling with pre-existing hypertrophy, MI was induced by coronary artery ligation in Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). Ten weeks after the induction of MI, the progression of left ventricular dysfunction and increases in plasma atrial natriuretic peptide (ANP) and cardiac ANP mRNA were more pronounced in SHR than WKY. In addition, the impaired contractile response to beta-adrenergic stimulation was observed in the noninfarcted papillary muscle isolated from SHR. Immunochemical G(s alpha) protein and beta-adrenoceptor density were not significantly altered by MI in both strains. However, immunochemical G(i alpha) was increased (1.5-fold) in the noninfarcted left ventricle of the SHR in which infarction had been induced when compared with that in SHR that underwent sham operation. This increase was observed especially in rats with a high plasma ANP level. Furthermore, there was a positive correlation between G(i alpha) and the extent of post-MI remodeling in WKY. A similar correlation between G(i alpha) and the extent of hypertensive hypertrophy was observed in SHR. In conclusion, the vulnerability of hypertrophied hearts to ischemic damage is greater than that of normotensive hearts. An increase in G(i alpha) could be one mechanism involved in the transition from cardiac hypertrophy to cardiac failure when chronic pressure overload and loss of contractile mass from ischemic heart disease coexist.

Ventricular radius reduction without resection: a computational analysis.

Reducing a dilated left ventricle's radius by wedge resection lowers wall stress, improving performance. However, compliance falls, stroke volume improvement is limited, and, later, both functional deterioration and serious dysrhythmias are frequent. These all may result from loss of circumference, loss of contractile mass, and myocardial trauma, none of which would occur in geometric remodeling. One specific technique is bimeridianal restraint, which uses two indenting bars to remodel the left ventricle (LV) as two widely communicating "lobes" of reduced radius. Computational analysis of this technique, applied to the dilated ventricular dimensions of four pretransplant patients, showed that 20% radius reduction would be accomplished by two < or =18 mm wide bars, indenting the epicardium < or =8.3 mm with < or =6.4 mm greatest outward displacement. Projected stroke volume (SV) for the subject ventricles was then modeled and compared with projections for resected ventricles. Assuming that equally improved contractile fraction will follow equal radius reduction, however that reduction is accomplished, improvement is dramatic: if postresection remodeling SV were 1.0, 1.2, or 1.5 times baseline, then postgeometric remodeling SV would be 1.36+/-0.06, 1.66+/-0.05, or 2.14+/-0.04 times baseline, respectively. These results, preservation of contractile mass and circumferential length, complete reversibility, and minimal operative trauma, warrant study of implementing mechanical designs.

Expression of specific white adipose tissue genes in denervation-induced skeletal muscle fatty degeneration

Denervation of skeletal muscle results in rapid atrophy with loss of contractile mass and/or progressive degeneration of muscle fibers which are replaced to a greater or lesser degree by connective and fatty tissues. In this study, we show that denervated rabbit muscles are transformed into a white adipose tissue, depending on their fiber types. This tissue does express LPL, G3PDH and particularly the ob gene, a white adipose tissue-specific marker, and does not express the brown adipose tissue molecular marker UCP1 mRNA.

Myocardial ischemia and infarction: Anatomic and biochemical substrates for ischemic cell death and ventricular arrhythmias

Myocardial ischemia is a widespread cause of morbidity and the number one cause of death in the economically developed countries of the world. In the United States, approximately 25 per cent of all deaths are at tr ibuted to hear t attacks; of these deaths, about one half occur suddenly outside the hospital setting. Although there are many possible causes of sudden unexpected death, the majority undoubtedly are cardiogenic, owing to ventricular arrhythmias that occur either in the setting of transient myocardial ischemia or in some phase of an evolving myocardial infarct. Following hospitalization for an acute myocardial infarct, the majority of deaths have anatomically definable explanations (i.e., loss of sufficient myocardium to cause cardiac pump failure or specific anatomic complications of infarction such as cardiac rupture). In addition, despite the development of many potent antiarrhythmic drugs, some patients still die of ventricular fibrillation during the acute phase of myocardial infarction; others, even after the infarct has undergone replacement by scarring, st iffer f rom recu r r en t chronic ventr icular tachycardia that can lead to hemodynamic collapse and/or ventricular fibrillation. The reduction of overall cardiac pump function in myocardial infarction may have several contributory causes; the most important cause surely is the loss of contractile mass. It has been shown, for example, that among patients with fatal myocardial infarcts, those who had died o f cardiogenic shock usually had lost at least 30 per cent and often 40 per cent or more of their left ventricular mass) Some of the gross anatomic determinants of myocardial infarct size are known, as are many subcellular biochemical and structural consequences of acute ischemic injury. However, the subcellular conditions dictating that an ischemic myocyte has become irreversibly and thus destined for necrosis have not been defined completely. The electrophysiologic explanations for most ventricular arrhythmias are reentrant conduction, enhanced automaticity of an injured focus, or triggered activity of an injured focus. 2 However, the underlying anatomic and/or biochemical explanations