CELL GEOMETRY AND CONTRACTILE ABNORMALITIES OF MYOCYTES FROM FAILING HUMAN LEFT-VENTRICLE

Objectives: Systolic and diastolic dysfunction of the failing human he art may be due to changes in myocyte function, or to extracellular inf luences such as necrosis, fibrosis or repositioning of viable cells. I n order to determine the contribution of cellular factors we have char acterised the contraction amplitudes, and contraction and relaxation v elocities of single myocytes isolated from failing human left ventricl e. Methods: Myocytes were enzymatically isolated from the left ventric les of 42 subjects, superfused at 32 degrees C and paced at 0.2 Hz. Us ing a video/edge tracking system we obtained contraction amplitude and contraction and relaxation velocities as well as times to peak contra ction (TTP) and to 50% and 90% relaxation (R50 and R90). Concentration -response curves to Ca2+ were constructed for each cell. Results: Ther e was little difference in contraction amplitude at any Ca2+ concentra tion between cells from failing and non-failing hearts at this low fre quency. At maximally activating Ca2+ concentrations (6-20 mM) there wa s a 30% slowing of relaxation velocity in myocytes from patients with both mild-moderate (P < 0.001) and severe (P < 0.001) congestive heart failure. Contraction and relaxation times were increased in myocytes from failing hearts [TTP: 0.46 +/- 0.02 s (n = 34 patients) vs. 0.35 /- 0.02 s (n = 6), P < 0.01 and R50: 0.25 +/- 0.02 s (n = 34) vs. 0.16 +/- 0.02 s (n = 6), P < 0.001]. Impaired relaxation was seen with mos t etiologies, including ischemic and dilated cardiomyopathies and mitr al valve disease. Myocytes from failing hypertrophied ventricles were more severely affected than those from failing non-hypertrophied heart s for both contraction and relaxation velocities. Cells from failing h ypertrophied ventricles had a significantly larger area than from non- failing or failing non-hypertrophied ventricles, although cell length and sarcomere length were similar between groups. Larger myocytes did not show a more pronounced change in relaxation velocity than normally sized cells from the same hypertrophied ventricle. Conclusions: Signi ficant impairment of relaxation can be observed in ventricular myocyte s from failing human heart under conditions where contraction amplitud e appears normal. The defect is not confined to one etiology of diseas e, but is exacerbated during hypertrophy. An increase in cell size, al though observed in myocytes from hypertrophied ventricle, does not its elf account for changes in relaxation. Cellular changes contribute to diastolic dysfunction in the failing human heart.