Mechanisms underlying ischemic diastolic dysfunction: relation between rigor, calcium homeostasis, and relaxation rate

Abstract

Varma, Niraj, James P. Morgan, and Carl S. Apstein. Mechanisms underlying ischemic diastolic dysfunction: relation between rigor, calcium homeostasis, and relaxation rate. Am J Physiol Heart Circ Physiol 284: H758-H771, 2003. First published October 31, 2002 10.1152/ajpheart.00286. 2002-Increased diastolic chamber stiffness (1DCS) during ischemia may result from increased diastolic calcium, rigor, or reduced velocity of relaxation. We tested these potential mechanisms during severe ischemia in isolated red blood cell-perfused isovolumic rabbit hearts. Ischemia (coronary flow reduced 83%) reduced left ventricular (LV) contractility by 70%, which then remained stable. DCS progressively increased. When LV end-diastolic pressure had increased 5 mmHg, myofilament calcium responsiveness was altered with 50 mmol/l NH4Cl or 10 mmol/l butanedione monoxime. These affected contractility (i.e., a calcium-mediated force) but not 1DCS. Second, quick length changes reversed 1DCS, supporting a rigor mechanism. Third, ischemia increased the time constant of isovolumic pressure decline from 47 Ϯ 3 to 58 Ϯ 3 ms (P Ͻ 0.02) but concomitantly abbreviated the contraction-relaxation cycle, i.e., pressure dissipation occurred earlier without diastolic tetanization. Finally, to assess any link between rate of relaxation and 1DCS, hearts were exposed to 10 mmol/l calcium. Calcium doubled contractility and accelerated relaxation velocity, but without affecting 1DCS. Thus 1DCS developed during ischemia despite severely reduced contractility via a rigor (and not calcium mediated) mechanism. Calcium resequestration capacity was preserved, and reduced relaxation velocity was not linked to 1DCS.stiffness; left ventricular end-diastolic pressure; quick length change; heterogeneity ACUTE DIASTOLIC heart failure, characterized by reduced rate of relaxation and increased diastolic chamber stiffness, occurs in angina, left ventricular (LV) hypertrophy, and hypertension (where subendocardial ischemia may be important) (12, 15) with pulmonary sequelae (27) that may ultimately produce edema (12, 25). The underlying etiology remains unclear, but persistently increased diastolic calcium (6, 18), disturbed high-energy phosphate metabolism (16, 36), and reduced relaxation velocity (7) have all been implicated. However, the precise nature of the ischemic insult, i.e., "supply" or "demand," may determine the mechanisms underlying diastolic dysfunction (3,5,15,26,35). Demand ischemia, where tachycardia occurs during moderately reduced coronary flow, characteristically results in an upward shift of the pressure-volume loop, i.e., increased diastolic stiffness, whereas contractile function remains preserved. Intracellular calcium has not been measured during demand ischemia, but we (37) recently reported a rigor-bond mechanism underlying increased diastolic stiffness in an experimental model. In contrast, supply ischemia, e.g., during acute coronary thrombosis or experimental ligation, results in contractile failure and an initial increase in diastolic disten...

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