901-91 Diastolic Dysfunction During Demand Ischemia is due to a Reversible Rigor Force and is not a Calcium (Ca2+) Activated Tension

Abstract

Exercise-induced angina (demand ischemia (D1)) causes an acute increase in LV diastolic chamber stiffness (↑DCS), via a mechanism that may involve i) diastolic persistence of excessive cytosolic Ca 2+ (particularly from incomplete resequestration by an energy limited sarcoplasmic reticulum (SR)) with continued cross-bridge cycling, or ii) rigor force from ATP depletion. Aim To determine the nature of the tension underlying ↑DCS in DI. A) Diastolic anginal physiology was created in isolated isovolumic (balloon-in-LV) blood perfused rabbit hearts. Tachyardia (T: 7 Hz) imposed during restricted coronary blood flow (30% of baseline) increased DCS (ie isovolumic LVEOP) 7–9 mmHg after 15 ± 1 min (n = 381, increased lactate production (pre-T vs post-T: 0.12 ± 0.03 vs 0.45 ± 0.03 μM/min/gL Vww, p < 0.001) without increasing oxygen extraction. ↑DCS was reversible on reperfusion, similar to patients with angina. B) During the state of ↑DCS, brief intracoronary (ic) infusion of saline (S, n = 7) was compared to 50 mM ammonium chloride (NH 4 C1, n = 7) and to 14 mM Ca 2 + (n = 6). Function was similar during low-flow ischemia pre-T (LV systolic pressure (LVSP)/LVEDP S = 67/18 vs NH 4 CI 58/17 vs Ca 2 + 67/17 mmHg, NS) and post-T (S = 38/25 vs NH 4 C1 39/26 vs Ca 2 + 43/24 mmHg, NS). i) NH 4 CI exerted a biphasic effect on LVSP over 2.5 min (LVSP maximum increase to 70 ± 4, P < 0.001, followed by decrease to minimum 52 ± 2mmHg, p < 0.001) commensurate with an action as an intracellular alkalinising and then acidifying agent, to alternately increase and decrease myofilament Ca 2+ sensitivity. However LVEDP remained unaffected suggesting ↑DCS was not Ca 2+ dependent. ii) Ca 2+ increased LVSP (S vs Ca 2+ 57 ± 3 vs 97 ± 5 mmHg, p < 0.001). decreased DCS (LVEOP S vs Ca 2+ 25 ± 1 vs 21 ± 1 mmHg, p i 0.001). and increased relaxation rate (–dP/dt/P 13 ± 1 vs 10 ± l/s, p < 0.005). Hence Ca 2+ resequestration capacity during a state of ↑DCS was intact and capable of acceleration, consistent with a functional and responsive SR. C) To further investigate the nature of ↑DCS we applied a method novel to the isolated heart with a quick (0.5s) stretch-release (QSR) of 25% of intraventricular balloon volume in three groups of hearts with ↑DCS i) classic rigor with zero-flow ischemia ii) ic infusion of 5 mM caffeine and 5 mMCa 2+ (producing Ca 2+ activated ↑DCS) and iii) in D1. QSR instantly lysed increased diastolic tension during zero-flow ischemia (LVEDP pre-vs post-QSR 27 ± 1 vs 17 ± 1 mmHg, p < 0.001), and also in D1 (27 ± 2 to 15 ± 1 mmHg, p < 0.001). By contrast, LVEDP was unaffected by QSR during Ca 2+ activated ↑DCS (28 ± 1 to 26 ± 1 mmHg, NS). Hence, ↑DCS in D1 behaved as a rigor tension with QSR. In D1, neither does ↑ DCS behave as a Ca 2+ activated tension nor is subcellular Ca 2+ reuptake disabled. Rather, ↑DCS displays properties of a rigor force which may produce ischemic diastolic dysfunction in D1.