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M.Sc.(Med.), Faculty of Health Sciences, University of the Witwatersrand, 2010 / The progression from compensated cardiac hypertrophy to decompensation and cardiac failure is accompanied by cardiac dilatation. As cardiac failure has a poor prognosis, it is imperative to prevent the progression to cardiac dilatation and heart failure. In this regard, an understanding of the mechanisms of cardiac dilatation is vital to guide optimal therapy to prevent heart failure. Although a number of factors have been shown to contribute to the development of cardiac dilatation, to date the role of alterations in cardiac myocyte dimensions remains unclear. Hence, the aim of the current study was to determine whether changes in cardiac myocyte dimensions contribute to the process of cardiac dilatation. Methods: Two models of cardiac dilatation in pressure-overload induced cardiac hypertrophy were assessed. One model was a natural progression model, in which 18 spontaneously hypertensive rats (SHR), were assessed at 23 months of age (an age when left ventricular hypertrophy is noted to have progressed to left ventricular decompensation, dilatation and heart failure in approximately 50% of rats). The second model, a pharmacological model, was induced in 14 month old SHR (n=9) by chronic beta-adrenoreceptor activation [0.02mg/kg isoproterenol (ISO) twice daily for 4.5 months]. Chronic beta-adrenoreceptor activation in SHR, enhances the progression from compensated left ventricular hypertrophy to left ventricular dilatation. Nine normotensive Wistar Kyoto (WKY) rats were the controls for both models. Left ventricular dilatation was defined as an increase in left ventricular radius determined at controlled filling pressures using piezo-electric transducers. The classification of rats as being in heart failure was based upon the presence of pleuropericardial effusions and / or atrial thrombi. Cardiac myocytes were isolated and dimensions determined using both light microscopy and flow cytometry. Results: Left ventricular radius was increased in SHR-Failure compared to SHR-Non-Failure (p<0.01), and in SHR-ISO compared to SHR-Control (saline administration) (p<0.01), hence confirming the presence of cardiac dilatation in both models. Although, cardiac myocyte length vi was increased in all SHR groups compared to WKY (p<0.001), no differences were observed between SHR-Failure and SHR-Non-Failure, or between SHR-ISO and SHR-Control. No differences in cell length:width ratios or in cell widths were evident between the groups. The flow cytometry data confirmed the results obtained for cardiac myocyte lengths using microscopy. Moreover, a linear correlation (r=0.46, p=0.002) between flow cytometry and microscopy cardiac myocyte lengths was observed. Importantly, no relationships were evident between left ventricular radius and cardiac myocyte length (r=0.12, p=0.42 and r=0.14, p=0.35 for microscopic and flow cytometry lengths respectively). Conclusion: The results from the present study show that although pressure-overload hypertrophy is associated with lengthening of cardiac myocytes, no further changes occur with cardiac dilatation. Hence, alterations in cardiac myocyte dimensions do not contribute to the development of cardiac dilatation in pressure-overload models.

p38-mitogen activated protein kinases (p38-MAPKs) are stress activated serine/threonine kinases that are activated during several different cardiac pathologies. Classically, studies have focused solely on p38α signaling in the heart. However, there is also high cardiac expression of the p38γ isoform but little is known about its cardiac function. The aim of this study was to elucidate the signaling pathway of p38γ, with a particular focus on its role in the progression of pathological cardiac hypertrophy. Comparisons of cardiac function and structure of wild type (WT) and p38γ knock out (KO) mice, in response to abdominal aortic banding, found that KO mice developed less ventricular hypertrophy than their corresponding WT controls, and have preserved cardiac function. Basal p38γ myocardial staining was primarily localised at the membranes and throughout the cytoplasm. Following aortic constriction, nuclear staining of p38γ increased, but no accumulation of p38α was observed. This suggests that the two isoforms play distinct roles in the heart. To elucidate its signaling pathway, we generated an analogue sensitive p38γ, which is mutated at a gatekeeper residue, to specifically track and identify its endogenous substrates in the myocardium. The mutation allows only the mutant kinase, but not WT kinases, to utilise analogues of ATP that are expanded at the N6 position and contain a detectable tag on the γ-phosphate. Transfer of this tag to substrates allows subsequent isolation and identification. Furthermore, unlike other p38-MAPKs, p38γ contains a C-terminal PDZ domain interacting motif. We have utilised this motif in co pull-down assays to identify interacting proteins of p38γ in the heart. Using these techniques we have identified, amongst other substrates, LDB3 and calpastatin as novel substrates of p38γ and we have determined the residues that are targeted for phosphorylation. Lastly we have shown that phosphorylation of calpastatin reduces its efficiency as a calpain inhibitor in vitro, hence proposing a mechanism by which p38γ may mediate its pro-hypertrophic role.

Heart failure (HF) is a pathological state indicating insufficient blood supply to the peripheral tissues from the heart. The pathophysiology of HF is multifactorial like cardiac remodeling including cardiac hypertrophy, perivascular fibrosis and apoptosis to compensate for the heart’s inability to pump enough blood. Cardiac hypertrophy is initially adaptive to hemodynamic overload; however, it chronically contributes to heart failure and sudden cardiac death. The extracellular regulatory factors and intracellular signaling pathways involved in the cardiac remodeling are not yet fully clear. PI3-kinase is an important intracellular kinase in organ size control. Cardiac overexpression of Class I PI3-kinase caused heart enlargement in transgenic mice. Autophagy as a dynamic process involving the degradation of damaged mitochondria prevents ROS overproduction which leads to the cardiac remodeling. Therefore, our aim was to study the relationship between PI3-kinases and Ang II-induced cardiac remodeling via an autophagy-dependent mechanism. Ang II significantly increased autophagy with two distinctive phases: an increasing phase at low doses and a decreasing phase at high doses in cardiomyocytes. The Ang II-induced autophagic depression was attenuated by a Class I PI3-kinase inhibitor and potentiated by Class III PI3-kinase inhibitor. Besides, Ang II-induced cardiac hypertrophy and mitochondria ROS generation were attenuated via blockade of Class I PI3-kinase or mTOR. To further validate our in vitro data, we studied the role of Class I PI3-kinase in Ang II-induced cardiac remodeling in vivo. We successfully transferred Lv-DNp85 (Class I PI3-kinase blockade) and Lv-GFP (control) into adult rat hearts and found that cardiac transfer of Lv-DNp85 did not alter Ang II-induced pressor effect, but attenuated Ang II-induced cardiac hypertrophy, perivascular fibrosis and cardiac dysfunction. Ang II-induced cardiac remodeling was associated with impaired autophagy and mitochondrial ROS overproduction, which were significantly attenuated by Lv-DNp85-induced blockade of Class I PI3-kinase. Taken together, these data suggest that Class I PI3-kinase is involved in Ang II-induced impairment of autophagy via Akt/mTOR pathway, leading to mitochondrial ROS overproduction and cardiac remodeling. These results are not only highly significant from a pathophysiological perspective, but also have important pharmacological implications in the control of cardiac hypertrophy to prevent decompensation and failure in cardiac function. / National Institute of Neurological Disorders and Stroke / National Institutes of Health (NIH, NS55008)

Catecholamines have been implicated in the regulation of cardiac hypertrophy. The serial injection of a catecholamine (epinephrine, norepinephrine or isoproterenol) will increase cardiac muscle mass. In a canine model of left ventricular hypertrophy secondary to aortic coarctation, the endogen

published_or_final_version / Community Medicine / Master / Master of Philosophy

Hormonal regulation of growth and of macromolecular synthesis in a variety of tissues is now well established. This dissertation addresses the role of circulating hormones, particularly epinephrine, in the physiological regulation of myocardial mass. Following hemodynamic overload of the right ventricle, the circulating epinephrine concentration increased significantly, and blood epinephrine exhibited a significant positive correlation with myocardial mass. Further, a nonspecific β-antagonist, propranolol, blocked the usual myocardial hypertrophy that occurs in response to hemodynamic overload. These studies strongly implicate β-adrenoceptors in the regulation of myocardial mass. Theoretically, a circulating myocardial trophic hormone should result in biventricular hypertrophy. We found that a selective hemodynamic overload of the right ventricle produced significant hypertrophy of both the right and the left ventricles. A biochemical marker of β-receptor activity, ornithine decarboxylase, a key regulatory enzyme in growth, showed elevated activity in both the right and left ventricles following hemodynamic overload of the left ventricle. To further evaluate possible circulating myocardial trophic hormones, we studied hypertrophy in a donor heart transplanted into the abdomen of a recipient animal. Myocardial hypertrophy of the donor heart occurred independently of innervation and of any hemodynamic parameters. Alteration in myocardial mass paralleled the extent of β-receptor activity as assessed by the administration of exogenous β-agonists or by the modulation of β-receptor number by denervation. β-Receptor activity was assessed by the ability of isoproterenol to elevate ornithine decarboxylase activity in either the donor or the recipient heart. Finally, alterations in the levels of circulating endogenous hormones in response to pulmonary artery banding of the recipient rat heart resulted in concomitant hypertrophy of both recipient and donor hearts. These studies suggest that myocardial mass is regulated by the concentration of circulating epinephrine through its effect on myocardial β-adrenoceptors. This effect may be modified by the level of other hormones such as thyroid hormone, but does not appear to be altered to any extent by myocardial innervation or by the alteration of hemodynamic parameters except as they affect the circulating level of catecholamines.

The purpose of this study was to compare the myocardial structure and function among endurance athletes (n.12), powerlifters/steroid users (n=5), powerlifters/non-steroid users (n=6), and sedentary controls (n=4). All subjects had a M-mode echocardiographic examination of their left ventricles under resting conditions. The echocardiographic measurements recorded and analyzed were of the left ventricular posterior wall at diastole and systole, left ventricular internal diameter at diastole and systole, and inter-ventricular septal thickness at diastole and systole. Myocardial function measurements consisting of left ventricle ejection time, left ventricular mass, mean ventricular contractile force, and percent fractional shortening were also recorded and analyzed. A One Way Analysis of Variance was used to analyze the data for statistical significance. A Tukey's HSD post-hoc test was used to determine statistical significance between the groups. A significant difference (p =0.02) was found for inter-ventricular septal thickness during diastole. All three athletic groups had significantly thicker inter-ventricular septa' thickness during diastole as compared to the controls. Power lifters/steroid users had the thickest inter-ventricular septal thickness (18.7 mm), followed by endurance athletes (18.6 mm), and powerlifters/nonsteroid users (16.5 mm). Overall, powerlifters/steroid users had the thickest walls at systole and diastole, while endurance athletes had the greatest internal diameters relative to the size of the left ventricle. Statistically significant differences among the groups were found for all four myocardial functional parameters: left ventricular ejection time (p = 0.03), left ventricular mass (p = 0.002), mean ventricular contractile force of (p 0.0013), and percent fractional shortening (p = 0.05). Power lifters/steroid users had the fastest left ventricular ejection times, largest left ventricular mass, greatest mean ventricular contractile force, and greatest percent fractional shortening. Endurance athletes had the slowest left ventricular ejection times, second largest left ventricular mass, lowest mean ventricular contractile force, and third lowest percent fractional shortening. The results indicated that not all individuals participating in high level endurance or powerlifting training and competition demonstrated complete adaptations in myocardial structure and function. Power lifters/steroid users however, demonstrated myocardial functional adaptations that were significantly different from powerlifters/non-steroid users, endurance athletes, and controls. The results of this study cannot attribute these changes either to the use of large amounts of anabolic steroids, or long-term, high-intensity training and competition in powerlifting. However, the study identified alterations in myocardial functions in powerlifters/steroid users, and contributes to the existing body of knowledge regarding the use of anabolic steroids by athletes. / Graduation date: 1990

Thesis (Ph. D.)--University of Hawaii at Manoa, 1982. / Bibliography: leaves 260-277. / Microfiche. / xiv, 277 leaves, bound ill. 29 cm