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Am J Physiol Heart Circ Physiol 284: H758-H771, 2003. First published October 31, 2002; doi:10.1152/ajpheart.00286.2002
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Vol. 284, Issue 3, H758-H771, March 2003

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

Niraj Varma1,2, James P. Morgan2, and Carl S. Apstein1

1 Boston University School of Medicine, Boston 02118; and 2 Cardiovascular Division, Beth Israel Hospital, Harvard Medical School, Boston, Massachusetts 02215

Increased diastolic chamber stiffness (up-arrow DCS) 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 up-arrow DCS. Second, quick length changes reversed up-arrow DCS, supporting a rigor mechanism. Third, ischemia increased the time constant of isovolumic pressure decline from 47 ± 3 to 58 ± 3 ms (P < 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 up-arrow DCS, hearts were exposed to 10 mmol/l calcium. Calcium doubled contractility and accelerated relaxation velocity, but without affecting up-arrow DCS. Thus up-arrow DCS 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 up-arrow DCS.

stiffness; left ventricular end-diastolic pressure; quick length change; heterogeneity


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