We have previously shown that chronic mitral regurgitation (MR) increases the rate of left ventricular early diastolic filling. These changes in chamber diastolic function were felt to be secondary to alterations in left ventricular loading conditions. Therefore, cellular diastolic function measured in cardiac muscle cells (cardiocytes) isolated from animals with chronic MR (absent alterations in loading conditions) was expected to be normal. However, chronic MR caused a decrease in sarcomere lengthening rate. The purpose of the current study was to define the mechanisms causing this decreased sarcomere lengthening rate in chronic MR cardiocytes and to explain the apparent dichotomy between chamber and cellular diastolic properties. Accordingly, sarcomere motion was measured using laser diffraction techniques in enzymatically isolated cardiocytes from seven control dogs and 11 dogs with chronic MR (produced by closed-chest transection of the mitral chordae). In the MR cardiocytes, there were abnormalities in cellular systolic function (decreased extent and velocity of shortening) and in cellular diastolic function (decreased velocity of sarcomere lengthening). Because studies in papillary muscles have shown that there is a direct relation between abnormal diastolic function (decreased velocity of muscle lengthening) and abnormal systolic function (decreased extent of muscle shortening), it was unclear whether the changes in cellular relaxation rate observed in chronic MR merely reflected a concomitant decrease in the extent of shortening or instead reflected an impairment in intrinsic relaxation properties. To make this distinction, the relation between relaxation velocity (measured as peak sarcomere lengthening rate) and sarcomere shortening extent was examined in MR cardiocytes and compared with that in control cardiocytes. There was a direct relation between sarcomere relaxation velocity and sarcomere shortening extent in both control and MR cardiocytes. Over a wide range of shortening extent, the slopes and y intercepts of this relation were similar in control and MR cardiocytes (slope, 27.7 sec-1 in control cells versus 28.1 sec-1 in MR cells; y intercept, -1.1 μm/sec in control cells versus - 1.7 μm/sec in MR cells; p=NS). At any common shortening extent, relaxation velocity was the same in control and MR cardiocytes. To prove that this relation could detect abnormalities in the intrinsic myocardial relaxation process, interventions known to produce primary alterations in the intrinsic myocardial relaxation process were examined: the effects of hypothermia (30°C) and isoproterenol (10-6 M) on the relaxation velocity-shortening extent relation were studied in normal and MR cardiocytes. In normal cardiocytes, hypothermia decreased relaxation velocity at any common shortening extent and decreased the slope of this direct relation (slope, 24.4 sec-1 at 37°C versus 13.9 sec-1 at 30°C; p<0.05), whereas isoproterenol increased relaxation velocity at any common shortening extent and increased the slope of this direct relation (slope, 24.5 sec-1 before versus 29.8 sec-1 during isoproterenol; p<0.05). Similarly, in MR cardiocytes, hypothermia decreased the slope of the relaxation velocity- shortening extent relation, whereas isoproterenol increased the slope of this relation. Thus, in isolated cardiocytes from both control and chronic MR dogs, there was a direct relation between sarcomere relaxation velocity and the extent of sarcomere shortening. Changes in the slope of this relation accurately reflected changes in the intrinsic myocardial relaxation process. The slope of the relation between relaxation velocity and shortening extent was the same in control cardiocytes and chronic MR cardiocytes. Thus, the abnormalities in cellular diastolic function seen in chronic MR resulted from a decrease in systolic function leading to a decrease in the extent of shortening and diminished restoring forces. Changes in cellular diastolic function did not result from a primary impairment of the intrinsic myocardial relaxation process.
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