Chronic Treatment With Allopurinol Boosts Survival and Cardiac Contractility in Murine Postischemic Cardiomyopathy

Abstract

Abstract-Oxidative stress is a hallmark of systemic illnesses, including heart failure. Nevertheless, the overall importance of radical production in the heart remains conjectural; is it merely a marker of illness, or can intervention alter the progression of disease? This question was addressed by blocking xanthine oxidase (XO), a superoxide-generating enzyme that is upregulated in animal models of heart failure. In a randomized prospective trial design, we administered the XO inhibitor allopurinol orally to mice that had undergone massive myocardial infarction (MI). Cardiac XO activity was elevated in untreated mice after MI; allopurinol suppressed the XO activity to levels comparable to those in sham-operated mice. Eighty-one percent of untreated mice died of advanced heart failure over 2 to 4 weeks of follow-up. Survival doubled in the allopurinol-treated mice, whereas cardiac contractile function (both in vivo and in isolated muscle) was markedly improved. Response to isoproterenol was restored to near-normal levels in the allopurinol group but was attenuated in untreated mice. Oxidative modifications to proteins were prevented in the allopurinol-treated mice. Key Words: heart failure Ⅲ mice Ⅲ myocardial contraction Ⅲ oxygen H eart failure, a condition that afflicts up to 8 million Americans, is accompanied by excessive free radical production. 1 However, it is not clear whether the relationship is associative in nature or, alternatively, whether oxidative stress figures prominently in the pathogenesis of heart failure. Xanthine oxidase (XO), a superoxide-generating enzyme, is upregulated in animals 1,2 and in humans 3 with heart failure. Acute administration of the XO inhibitor allopurinol improves the mechanical efficiency of the failing heart; 4,5 contractility increases, whereas oxygen consumption paradoxically decreases. Direct XO inhibition in cardiac muscle leads to increased force generation by the myofilaments at any given level of activator calcium. 6 Despite the striking and distinctive acute effects of allopurinol, it remains unclear whether chronic treatment with an XO inhibitor is beneficial in the treatment of heart failure. This study is different from any previous work because XO inhibition by allopurinol was continuous for 28 days after myocardial infarction (MI) and was delivered orally, which is a clinically relevant delivery method. The goal of this study was to determine if the acute effects of allopurinol could be sustained long-term and also whether XO inhibition alters the natural history of heart failure.We find that in a mouse model of postischemic cardiomyopathy, allopurinol delivered in the drinking water markedly enhances survival after MI and also improves global cardiac function. Investigation into the mechanistic implications revealed that oral allopurinol acts as a calcium sensitizer, increasing force generation without augmenting calcium handling. Furthermore, we show that modification of proteins by the lipid peroxidation product 4-hydroxy-2-nonenal (HNE), evident in the ...

Xanthine Oxidase Inhibition and Heart Failure

“…24 It is important to note, however, that in all these experimental models of heart failure, the beneficial effects of XO inhibition were achieved because XO activities were increased within the myocardium; treatment with either allopurinol or oxypurinol restored XO activity to baseline levels and myocardial function was restored. 19,21,22,[25][26][27] These findings, therefore, suggest that by limiting oxidant stress to maintain levels of ROS required for ambient signaling, XO inhibition abrogates the destructive effects of ROS on various intracellular mechanisms that maintain function and integrity in the working cardiomyocyte. In addition, it has also been suggested that decreases in uric acid levels seen with XO inhibition have an antiinflammatory effect on the cardiovascular system.…”

“…On a functional level, there is strong evidence that XO inhibition enhances the responsiveness of the myofilaments to calcium. 21 The study by Minhas et al additionally shows that XO inhibition enhanced SERCA2a levels while decreasing expression of the sodium-calcium exchanger to increase contractility. 24 It is important to note, however, that in all these experimental models of heart failure, the beneficial effects of XO inhibition were achieved because XO activities were increased within the myocardium; treatment with either allopurinol or oxypurinol restored XO activity to baseline levels and myocardial function was restored.…”

“…20 Prolonged inhibition of XO with allopurinol in rodent models of post-infarction heart failure has also been shown to prolong survival, improve contractile function, and prevent ventricular remodeling. 21,23 These effects are believed to result from allopurinol-mediated XO inhibition and a resultant decrease in ROS levels.In this issue of Circulation Research, Minhas et al extend these findings and demonstrate that XO inhibition initiates reverse remodeling in rats with established dilated cardiomyopathy. 24 In these studies, the authors used a rat model of heart failure, the spontaneously hypertensive/Heart Failure (SHHF) model and inhibited XO with oxypurinol.…”

“…20 Prolonged inhibition of XO with allopurinol in rodent models of post-infarction heart failure has also been shown to prolong survival, improve contractile function, and prevent ventricular remodeling. 21,23 These effects are believed to result from allopurinol-mediated XO inhibition and a resultant decrease in ROS levels.…”

“…These findings corroborate positive results seen in other studies that demonstrated improved contractile parameters in heart failure with XO inhibition. 19,21,22,[25][26][27] The positive inotropy induced by XO inhibition in the setting of heart failure differs significantly from standard clinically used pharmacological inotropes. Unlike cAMPmodulating inotropes, XO inhibition decreases myocardial oxygen consumption, thereby sparing energy expenditure in the energy-deprived failing heart.…”