Fibrosis, Myocyte Degeneration and Heart Failure in Chronic Experimental Aortic Regurgitation

Abstract

Myocardial fibrosis and myocyte degeneration have been reported in patients with chronic aortic regurgitation (AR), and may be related to the pathophysiology of congestive heart failure (CHF) in this disease. To define the relationship between myocardial histopathologic variations and CHF in chronic AR, we performed gross and microscopic evaluations of postmortem tissue from a rabbit model of chronic AR manifesting left ventricular (LV) responses to AR similar to those in humans. Moderate-to-severe chronic AR (echocardiographic regurgitant fraction = 52 ± 13%) was induced by closed-chest aortic valve perforation in 11 New Zealand White rabbits; 5 control rabbits were sham operated. Six of the 11 AR rabbits died 1.5 ± 0.8 years (range 0.6–2.8 years) after AR induction; all 6 had gross and histologic anatomic evidence of CHF at necropsy. The remaining 5 AR rabbits survived until sacrifice at 2.9 ± 0.1 years of AR; none had pathologic evidence of CHF. Cardiac hypertrophy and the extent of LV fibrosis and myocyte necrosis all were greatest among the 6 AR CHF rabbits. No inflammatory response was apparent in any animal. Moderate-to-severe chronic experimental AR frequently results in CHF which is strongly associated with myocardial fibrosis and necrosis, without evidence of inflammation. These histopathologic variations may be pathophysiologically related to CHF development.

Myocardial Fibrosis in Chronic Aortic Regurgitation

“…Our results in cultured AR fibroblasts, plus earlier findings of histologically evident fibrosis in the absence of CHF 4 and, occasionally, in the absence of apparent myocyte damage, suggest that myocardial fibrosis in AR may be, at least in part, a primary response to volume overload. This is supported by our finding of similar cellular/molecular abnormalities in cultured AR fibroblasts and in normal fibroblasts subjected for several days (beyond the time of immediate gene expression changes) to dynamic, cyclical strain modeling that of AR.…”

“…This is consistent with our earlier report of histologically evident fibrosis in experimental animals with chronic AR. 4,5 In these animals, myocardial collagen content was normal despite exuberant fibrosis in some animals; noncollagen ECM proteins were not assessed.…”

“…[1][2][3] With an animal model system that closely mimicked the pathophysiology of chronic AR in humans, we recently reported data consistent with these clinical observations, finding that fibrosis precedes CHF and is particularly marked when CHF has developed. 4 The myocardium in these experimental animals revealed normal collagen content 5 despite histologically severe fibrosis, suggesting disproportionate accumulation of noncollagen elements within the fibrotic myocardium. Subsequent exploratory analysis with differential display polymerase chain reaction in cardiac fibroblasts (CFs) from animals with chronic AR indicated upregulated expression of several genes that code for noncollagen extracellular matrix (ECM) proteins.…”

Intrauterine growth restriction coupled with hyperglycemia: effects on cardiac structure in adult rats

“…Although cardiac fibrosis is a well known cause of altered contractility of the myocardium (30,31), left-ventricular contractility appears to be adequately maintained at this stage, as seen from the finding that FS of the cardiac muscle did not differ between the LPD and NPD offspring. It appears likely that the left-ventricular hypertrophy observed in the IUGR offspring leads to encroachment on the left ventricle chamber size during systole, as judged from the significant decrease in end-systolic dimensions in the hearts of IUGR animals.…”

Study of Left Ventricular Diastolic Diameter–peak Stress Relationship Before and After Valve Replacement Operation for Patients With Chronic Aortic Regurgitation

“…For cases with chronic AR, histological study has demonstrated that LV fibrosis and myocyte necrosis were in proportion to the hemodynamic burden in rabbit model even in early period. 10 In another study, AR-induced myocardial damage was demonstrated to occur even before functional deterioration.…”