Cellular and ventricular contractile dysfunction in experimental canine mitral regurgitation.

Abstract

This study was designed to answer two questions. First, does the left ventricular contractile dysfunction resulting from mitral regurgitation (MR) reflect a primary defect in the cardiac muscle cell? Second, what is the basis for any change in cellular contractile function that might be observed? Left ventricular volume overload was produced in 10 dogs by catheter transection of mitral chordae tendineae. Three months later in these and in seven control dogs, left ventricular contractile function was characterized by the end-ejection stress-volume relation (EESVR). Investigators who were blinded to these results then characterized the contractile performance of cardiac muscle cells, or cardiocytes, from these same left ventricles in terms of the viscosity (graded external load)-velocity relation. Finally, the tissue and cellular components of these same left ventricles were analyzed morphometrically. Both the left ventricles from the MR group and their constituent cardiocytes showed marked contractile abnormalities. By matching ventricles with cells from the same MR dogs, ventricular EESVR was correlated with cardiocyte peak sarcomere shortening velocity (SSV). The correlation coefficient between EESVR and SSV was 0.63, but between a size-independent measure of active ventricular stiffness and SSV, it was 0.88. No change in left ventricular interstitial volume fraction was found in MR dogs, but both ventricular and cellular contractile dysfunction strongly correlated with a decreased volume fraction of cardiocyte myofibrils. Last, in an attempt to relate the degree of contractile dysfunction to the hypertrophic response, left ventricular mass in the MR dogs was correlated with both cellular and ventricular contractile indexes; no significant correlation was found. Three conclusions are warranted by these studies. First, chronic left ventricular volume overload from mitral regurgitation leads to contractile defects at both the ventricular and cellular levels, the extent of which correlates well in individual animals. Second, no quantitative interstitial change resulted from MR. Taken together, these two findings strongly suggest that the contractile defect is intrinsic to the cardiocyte. Third, while the contractile abnormality in MR remains undefined, the most basic defects appear to be a combination of myofibrillar loss with the failure of compensatory hypertrophy to occur in response to progressive decrements in cellular and ventricular function.

Pathologic Manifestations on Surgical Biopsy and Their Correlation with Clinical Indices in Dogs with Degenerative Mitral Valve Disease

“…Myocardial systolic or diastolic dysfunction accrues from histopathologic changes that cause myocardial decompensation, which in turn induces clinical signs such as cough, dyspnea, and exercise intolerance 3, 4, 8, 9, 10. However, knowledge is incomplete regarding the pathologic progression of myocardial degeneration and attendant difficulties in evaluating myocardial dysfunction in DMVD.…”

“…These microenvironmental changes worsen myocardial function by inducing pathologic degeneration characterized by loss of myofibrils, myocardial necrosis, and severe deposition of interstitial connective tissue 6, 8, 9, 10, 11. Also, cardiogenic pulmonary congestion, a result of backward failure, causes pulmonary pathologic changes, such as thickened alveolar septa, the presence of heart failure cells, and hyperplasia of type II pneumocytes 12, 13.…”

Experimental Impact of Mucopolysaccharidosis on Right Atrial Contractile Capacity of Skinned Fibers

“…Furthermore the right ventricle and atrium might not yet be affected of the MS by missing atrial afterload so far. Another explanation give Urabe and Cooper, who suggest that the right ventricle tend s to tolerate volume overload well and pressure overload poorly, whereas the left ventricle tends to tolerate volume overload poorly and pressure overload well [16,17]. But nevertheless the correlation of "normal" left ventricular function (in our cases EF > 50%) and contractility of atrial fibers is not sufficiently examined in literature.…”

Dobutamine Stress Echocardiography for Assessment of Systolic Function in Dogs with Experimentally Induced Mitral Regurgitation

“…Systolic function has been suggested to decrease in dogs with naturally acquired MMVD2, 3 and in dogs with experimentally induced MR 20, 21. However, identification of systolic dysfunction is challenging in dogs with MMVD22; EF, FS, and PEP/ET at rest and dobutamine infusion could not detect systolic dysfunction.…”