Diastolic Dysfunction During Demand Ischemi is due to Reversible Rigor Force and is not Calcium (Ca2+) Activated Tension

Background: Exercise-induced angin (demand ischemi (DI)) causes an acute increase in LV diastolic chamber stiffness (↑ DCS), vi mechanism that may involve i) diastolic persistence of excessive cytosolic Ca2+ (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. Methods and Results: A) Diastolic anginal physiology was created in isolated isovolumic (balloon-in-LV) blood perfused rabbit hearts. Tachyardi (T: 7 Hz) imposed during restricted coronary blood flow (30% of baseline) increased DCS (ie isovolumic LVEDP) 7-9 mmHg after 15 ± 1 min (n = 38), 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 (NH4Cl, N = 7) and to 14 mM Ca2+ (n = 6). Function was similar during low-flow ischemi pre-T (LV systolic pressure (LVSP)/LVEDP S = vs NH4Cl vs Ca2+ mmHg, NS) and post-T (S = vs NH4Cl vs Ca2+ mmHg, NS). i) NH4Cl exerted biphasic effect on LVSP over 2.5min (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 Ca2+ sensitivity. However LVEDP remained unaffected suggesting ↑ DCS was not Ca2+ dependent. ii) Ca2+ increased LVSP (S vs Ca2+ 57 ± 3 vs 97 ± 5 mmHg, p < 0.001), decreased DCS (LVEDP S vs Ca2+ 25 ± 1 vs 21 ± 1 mmHg, p i 0.001), and increased relaxation rate (−dP/dt/P 13 ± 1 vs 10 ± 1/s, p < 0.005). Hence Ca2+ resequestration capacity during state of ↑ DCS was intact and capable of acceleration, consistent with functional and responsive SR. C) To further investigate the nature of ↑ DCS we applied method novel to the isolated heart with 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 ischemi ii) ic infusion of 5 mM caffeine and 5 mMCa2+ (producing Ca2+ activated ↑ DCS) and iii) in DI. QSR instantly lysed increased diastolic tension during zero-flow ischemi (LVEDP pre-vs post-QSR 27 ± 1 vs 17 ± 1 mmHg, p < 0.001), and also in DI (27 ± 2 to 15 ± 1 mmHg, p < 0.001). By contrast, LVEDP was unaffected by QSR during Ca2+ activated ↑ DCS (28 ± 1 to 26 ± 1 mmHg, NS). Hence, ↑ DCS in DI behaved as rigor tension with QSR. Conclusion In DI, neither does ↑ DCS behave as Ca2+ activated tension nor is subcellular Ca2+ reuptake disabled. Rather, ↑ DCS displays properties of rigor force which may produce ischemic diastolic dysfunction in DI.