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Contribution of changes in myocardial collagen cross-linking toward cardiac dysfunction and remodelling in cardiac hypertrophy

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dc.contributor.advisor Norton GR en
dc.contributor.advisor Woodiwiss AJ en
dc.contributor.author Tsotetsi OJ en
dc.date.accessioned 2016-09-22T11:14:14Z
dc.date.available 2016-09-22T11:14:14Z
dc.date.created 1994 en
dc.date.submitted 2001 en
dc.identifier.uri http://hdl.handle.net/20.500.11892/106389
dc.description.abstract A principal cardiac change in heart failure is cardiac hypertrophy. Left ventricular (LV) hypertrophy (LVH) is associated with heterogenous tissue remodelling (myocardial fibrosis). Myocardial fibrosis is thought to contribute toward diastolic heart failure (through increases in myocardial stiffness) and the progression from compensated LVH to cardiac dilatation and systolic heart failure. However, there is some question as to whether myocardial fibrosis represents a marker of progressive cardiac disease or whether fibrosis contributes toward cardiac dysfunction. The researcher investigated whether qualitative rather than quantitative changes in myocardial collagen could explain cardiac dysfunction and decompensation in LVH. As the phenotypic qualities of myocardial collagen, including the predominant subtype and the cross-linked properties, determine the stability and tensile strength of the collagen fibrillar arrangement, the researcher reasoned that qualitative myocardial collagen changes, which would modify interstitial tensile strength and stability, could contribute to alterations in diastolic myocardial performance and cardiac geometry in heart disease. <br><br> Using the spontaneously hypertensive rat (SHR) as a model of LVH, and pharmacological manipulations that modify the cardiac interstitium in different ways, increases in myocardial stiffness in hypertensive-induced concentric LVH were shown to be associated with increments in collagen cross-linking, but not with myocardial fibrosis or changes in myocardial collagen type I-to-III ratios. These results suggest that increments in myocardial collagen cross-linking could contribute toward myocardial stiffness in LVH. <br><br> SHRs with concentric LV chamber remodelling and compensated cardiac hypertrophy had increases in cross-linked, but not in non-cross-linked myocardial collagen. In contrast, a decline in LV concentricity (mediated through LV dilatation) that accompanies cardiac failure in SHRs was associated with increments in the amount of the weaker and less stable non-cross-linked collagen molecule, but not with changes in cross-linked collagen. Both type I and III myocardial collagen concentrations were enhanced in compensated, and decompensated cardiac hypertrophy in SHRs. The increases in non-cross-linked myocardial collagen in heart failure in SHRs was attributed to the preferential accumulation of this collagen phenotype. These data suggest that alterations in myocardial collagen cross-linking may, in-part, determine cardiac chamber geometry in hypertension. <br><br> Although alterations in myocardial collagen cross-linking could explain LV dilatation in cardiac hypertrophy, cardiomyocyte size, rather than changes in the interstitium, could account for modifications in cardiac chamber geometry following pressure overload LV hypertrophy (POH). Administration of hydralazine to SHRs for approximately 20 months, until an age when.signs of heart failure develop in untreated SHRs, prevented the reduction in myocardial collagen cross-linking, the development of LV dilatation and the signs of cardiac failure noted in untreated SHRs, but failed to alter the degree of LVH. Moreover, a pharmacological agent that reduced LV cardiomyocyte weight to control values, but maintained the decline in myocardial collagen cross-linking when administered to rats with POH and established LV dilatation induced by suprarenal aortic band, failed to modulate the degree of LV dilatation. These results support a role for alterations in myocardial collagen cross-linking, but not for cardiomyocyte growth, as an important determinant of LV dilatation in POH. <br><br> If alterations in the extent of myocardial collagen cross-linking associated with cardiac decompensation in SHRs were important in modulating LV geometry, then these changes should be a common feature of ail models of LV dilatation. Indeed, in a model of isoproterenol-induced LVH, the myocardial collagen change associated with LV dilatation was a decrease in myocardial collagen cross-linking rather than alterations in either myocardial collagen concentrations or type I-to-III ratios. <br><br> In conclusion, the results of this work suggest that increments in myocardial collagen cross-linking contribute toward diastolic dysfunction but maintain a concentric chamber geometry, whereas a decrease in myocardial collagen cross-linking accounts for eccentric chamber remodelling and LV dilatation in cardiac hypertrophy. Moreover, results are presented indicating that the degree of cardiomyocyte growth is not an important determinant of LV dilatation. These findings underscore the need to identify the molecular and cellular mechanisms responsible for changes in myocardial collagen cross-linking in different forms of cardiac hypertrophy. en
dc.language English en
dc.title Contribution of changes in myocardial collagen cross-linking toward cardiac dysfunction and remodelling in cardiac hypertrophy en
dc.type Doctoral degree en
dc.description.degree PhD (Med) en


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