Preconditioning limits myocardial infarct size in hypercholesterolemic rabbits

doi:10.1016/S0021-9150(99)00389-5

Atherosclerosis

Volume 150, Issue 1, May 2000, Pages 81-89

https://doi.org/10.1016/S0021-9150(99)00389-5 Get rights and content

Abstract

Background: Hypercholesterolemia predisposes to coronary artery disease and causes endothelial dysfunction; some reports suggest that endothelial derived substances are involved in ischemic preconditioning. Objective: Our aim was to examine the possibility that preconditioning maybe attenuated in a clinically relevant animal model of hypercholesterolemia with atherosclerosis. Methods: Male rabbits were fed with cholesterol enriched diet and then divided into two groups (A and B) without and with preconditioning, respectively. A second series of rabbits fed a normal diet were similarly divided into two groups (C and D) without and with preconditioning, respectively. All the animals were subjected to 30 min ischemia and 180 min reperfusion. Blood samples were collected for cholesterol assessment; arterial and heart samples were harvested at the end for histopathological examination. Infarct (I) and risk areas (R) were delineated with Zn–Cd particles and TTC staining. Results: Cholesterol in groups A and B was 58.3±8.7 mg% at baseline and 1402±125 mg% at 8 weeks (P<0.0001) and in groups C and D 57.5±5.8 mg% before the surgical procedure. I/R% was 39.3±6.3% in group A, 16.7±3.9% in B (P<0.01), 41.4±7.5% in C and 10.8±3.3% in D (P<0.01). Conclusion: We conclude that preconditioning is unlikely to be attenuated by hypercholesterolemia.

Introduction

Elevations in total cholesterol are a major factor predisposing to atherosclerosis, with vulnerable plaques causing acute myocardial infarction [1]. Currently, the most efficient method of reducing mortality in this condition is to achieve rapid reperfusion by lysis or mechanical disruption of the occlusive thrombus and plaque [2]. The mortality from acute myocardial infarction under these circumstances is inversely related to the amount of myocardial salvage achieved by reperfusion [2], therefore agents that slow the rate of ischemic necrosis are likely to save many lives [3].

Ischemic preconditioning describes the resistance to ischemic injury that follows brief periods of myocardial ischemia. The brief ischemic trigger delays the onset and slows the rate of necrosis occurring in response to subsequent prolonged ischemia. The resulting level of protection is profound, with a typical 4-fold reduction in the volume of infarction after relatively short periods of coronary occlusion. This striking level of protection has resulted in preconditioning being ranked second only to reperfusion in ability to reduce infarction [4]. The possibility therefore exists that ischemic preconditioning, by profoundly slowing the rate of necrosis, increases the amount of myocardial salvage on reperfusion. This is certainly consistent with the finding that patients with pre-infarction angina tend to have a more benign course and smaller enzyme derived infarct sizes than those with unheralded infarction [3].

However, there is also evidence that nitric oxide is involved in some animal models in the antiarrhythmic effect of preconditioning [5]. In addition, it is also known that hypercholesterolemia impairs endothelial relaxation and nitric oxide production [6]. The possibility therefore exists that hypercholesterolemia predisposes patients to myocardial infarction, whilst depriving them of the endogenous protection offered by ischemic preconditioning.

The aim of this study was to examine the possibility that preconditioning is attenuated in a clinically relevant animal model where hypercholesterolemia predisposes to atherosclerosis.

Section snippets

Methods

Thirty-six New Zealand White male rabbits were divided into two series of experiments each composing of two groups. All animals received proper care in compliance with the ‘Principles of Laboratory Animal Care’, formulated by the National Society for Medical Research, and the ‘Guide for the Care and Use of Laboratory Animals’, prepared by the National Academy of Sciences and published by the National Institutes of Health (NIH publication no. 86-23, revised 1985). The first series consisted of

Animals and exclusions

One rabbit from the first experimental series died prior to surgery whilst on the cholesterol diet. Two animals (one from group A and one from group B) died from intractable ventricular fibrillation, respectively during ischemia and the final period of reperfusion. Two other animals (one from group B and one from group C) died of progressive hypotension during the final period of reperfusion. Thus, 16 animals from the first experimental series and 15 from the second series completed the study.

Hemodynamic variables

Discussion

Our study demonstrates that preconditioning is able to confer protection against myocardial infarction in both normally fed and hypercholesterolemic rabbits with atherosclerosis.

Progress in research and new therapeutic developments have revealed that apart from the restoration of blood flow there are also ‘endogenous mechanisms of protection’ which render the heart more tolerant to prolonged ischemia [7], [8]. Preconditioning is one of these protective mechanisms and a great number of in vivo

Acknowledgements

This work was made possible in part by a grant from EEC (Biomed II Concerted Action BMH4-CT 95-0838).

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Preconditioning limits myocardial infarct size in hypercholesterolemic rabbits

Abstract

Introduction

Section snippets

Methods

Animals and exclusions

Hemodynamic variables

Discussion

Acknowledgements

Lancet

J. Mol. Cell Cardiol.

J. Mol. Cell. Cardiol.

J. Am. Coll. Cardiol.

Int. J. Cardiol.

J. Mol. Cell. Cardiol.

J. Mol. Cell. Cardiol.

Atherosclerosis

Molecular bases of the acute coronary syndromes

Circulation

Treatment of myocardial infarction, unstable angina, and angina pectoris

Br. Med. J.

Angina reassessed: pain or protector?

Lancet

Medical and cellular implications of stunning, hibernation and preconditioning. An NHLBI Workshop

Circulation

Preconditioning of the ischemic myocardium; involvement of the l-arginine nitric oxide pathway

Br. J. Pharmacol.

The pathogenesis of atherosclerosis; a perspective for the 1990s

Nature