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EXPERIMENTAL STUDY

Left ventricular diastolic dysfunction during demand ischemia: rigor underlies increased stiffness without calcium-mediated tension. Amelioration by glycolytic substrate

^a Boston University School of Medicine, Boston, Massachusetts, USA

Manuscript received September 11, 2000; revised manuscript received February 22, 2001, accepted March 1, 2001.

Reprint requests and correspondence: Dr. Niraj Varma, Cardiac Muscle Research Laboratory, X720, Whitaker Cardiovascular Institute, Boston University School of Medicine, 650 Albany Street, Boston, Massachusetts 02118
nxv11{at}po.cwru.edu

OBJECTIVES

The goal of this study was to determine the subcellular mechanism(s) underlying increased left ventricular (LV) diastolic chamber stiffness (DCS) during angina (demand ischemia).

BACKGROUND

Increased DCS may result from increased diastolic myocyte calcium concentration and/or rigor. Therefore, we assessed the effects of direct alterations of both calcium-activated tension and high-energy phosphates on increased DCS.

METHODS

Demand ischemia was reproduced in isolated, isovolumic, red-cell perfused rabbit hearts by imposing low-flow ischemia and pacing tachycardia. This resulted in increased DCS. Interventions were performed after LV end-diastolic pressure had increased approximately 7 mm Hg. Initially, to determine the effects of altered calcium concentration or myofilament calcium responsiveness, hearts received either: 1) 5 or 14 mmol/L calcium chloride; 2) 8 mmol/L egtazic acid; 3) 5 mmol/L butane-dione-monoxime (BDM); or 4) 50 mmol/L ammonium chloride (NH₄Cl). Then, to assess the contribution of decreased high-energy phosphate supply, hearts received 5) glucose (25 mmol/L) and insulin (400 µU/ml).

RESULTS

1) Calcium chloride, 5 and 14 mmol/L, increased LV systolic pressure by 42% and 70%, respectively (p < 0.001), indicating increased calcium-activated tension, but did not further increase DCS, implying intact diastolic calcium resequestration. 2) Egtazic acid reduced LV systolic pressure by 30% (p < 0.001), indicating reduced intracellular calcium, but failed to reduce increased DCS. 3) Butane-dione-monoxime and NH₄Cl chloride affected contractile function (i.e., a calcium-driven force) but did not alter increased DCS. 4) Glucose and insulin, which increase high-energy phosphates during ischemia, reduced increased DCS by 50% (p < 0.001).

CONCLUSIONS

Increased DCS during demand ischemia was insensitive to maneuvers altering intracellular calcium concentration or myofilament calcium-responsiveness, that is, evidence against an etiology of calcium-activated tension. In contrast, increased glycolytic substrate ameliorated increased DCS, supporting a primary mechanism of rigor-bond formation.

Abbreviations and Acronyms   ATP = adenosine triphosphate   BDM = butane-dione-monoxime   Ca++ = calcium chloride   EGTA = egtazic acid   G + I = glucose and insulin   LV = left ventricle or left ventricular   LVEDP = left ventricular end-diastolic pressure   NH4Cl = ammonium chloride   N Sal = normal saline   +dP/dt = peak positive derivative of left ventricular pressure   –dP/dt = peak negative derivative of left ventricular pressure

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