This editorial refers to ‘Transient reduction in myocardial free oxygen radical levels is involved in the improved cardiac function and structure after long-term allopurinol treatment initiated in established chronic heart failure’† by V. Mellin et al., on page 1544
Mellin et al.1 report that short- and long-term xanthine oxidase (XO) inhibition with allopurinol, initiated in rats with chronic heart failure due to myocardial infarction, improves cardiac haemodynamics and function and reverses left ventricular remodelling. Rats with established left ventricular dysfunction induced by left coronary artery ligation received a 5-day or 10-week treatment with allopurinol starting 18 or 8 weeks, respectively, after the initial injury. Both short- and long-term allopurinol treatment increased cardiac output without changing arterial pressure consistent with an afterload reducing effect, but only long-term allopurinol treatment reduced left ventricular end-diastolic pressure and the left ventricular time-constant of relaxation. Importantly, chronic allopurinol produced clear reverse remodelling, decreasing left-ventricular systolic and diastolic diameters, weight, and collagen density.
Interestingly, a reduction in reactive oxygen species determined using electron spin resonance spectroscopy was detectable only in the group receiving 5 days of allopurinol, and thiobarbituric acid reactive substances (TBARS) were not reduced in either group. These findings substantially extend prior work performed in mouse models in which XO inhibition administered immediately following infarction had beneficial effects on remodelling prevention2 and mortality.3 Although the effects following acute infarction were predictable based on findings from stunned myofilaments,4 the effects on reverse remodelling of established ischaemic cardiomyopathy had not been previously addressed. The current study not only raises extremely interesting questions regarding the role of oxidative stress in heart failure, but also offers new support for a novel class of heart failure therapeutics: the XO inhibitors.
Pathophysiological role of XO pathway in heart failure
There is strong evidence supporting a pathophysiological role for the XO pathway in heart failure.5 XO, which is physiologically present in the heart,6 catalyses the two terminal steps of purine metabolism, from hypoxanthine to xanthine and xanthine to uric acid. Both steps also generate superoxide, and this ability to generate excess reactive oxygen species when the enzyme is upregulated is central to the role of XO in heart failure. From a functional standpoint, increased XO activity causes cardiac mechanoenergetic uncoupling and vascular dysfunction in the failing circulation.5
Mechanoenergetic uncoupling refers to an imbalance between left ventricular performance and myocardial energy consumption. In heart failure, despite markedly impaired left ventricular work, the oxygen consumed for myocardial contraction remains relatively unchanged, resulting in a decrease in the mechanical efficiency of contraction.7,8 The clinical relevance of this phenomenon is inferred from studies of inotropic agents, which further worsen myocardial energetic efficiency by increasing left ventricular work at the expense of disproportionate increases in myocardial oxygen consumption, offering a possible explanation for the increased mortality associated with long-term inotropic therapy.9
Reactive oxygen species participate in mechanoenergetic uncoupling through effects involving both enhanced oxygen utilization at the level of the whole heart6,8 and myofilament responsiveness to activator calcium.4 In dogs with pacing-induced heart failure, XO inhibition with allopurinol decreases myocardial oxygen consumption and increases myocardial contractility at rest8 and in response to β-adrenergic stimulation and exercise.10 In humans with heart failure, allopurinol infusion into the coronary circulation also improves myocardial efficiency by diminishing oxygen consumption without impairing cardiac function.6
Interaction between XO and nitric oxide pathways
XO impacts mechanoenergetic uncoupling and myocardial contractility via cross-talk with cardiac nitric oxide (NO) signalling pathways. For example, although dogs with pacing-induced heart failure demonstrate increased contractility and myocardial efficiency after receiving allopurinol, this response is blocked by NO synthase (NOS) inhibition. Conversely, in normal dogs (with low XO activity), NOS inhibition causes mechanoenergetic uncoupling that can be reversed with subsequent XO inhibition.7 Together, these findings indicate an important interaction between XO and NO signalling systems with regard to mechanoenergetic uncoupling in heart failure. We have since discovered that there is a direct protein–protein interaction between XO and neuronal NOS (NOS1) in the sarcoplasmic reticulum of the cardiac myocyte that accounts in large part for the cross-talk between these signalling pathways.11
Another link between XO and NO signalling is seen in the role of XO in vascular dysfunction. Endothelial dysfunction and vasodilator reactivity to exercise are significantly impaired in heart failure, and this dysfunction is mediated, in part, by oxidative stress, disrupting normal NO signalling and post-translational protein modification.12 XO-derived oxygen free radical production causes endothelial dysfunction, as has been demonstrated in patients with coronary artery disease.13 Furthermore, administration of allopurinol to chronic heart failure patients improves endothelial dysfunction while reducing markers of oxidative stress.14
Anti-oxidant effect of XO inhibition
Mellin et al.1 show a reduction in superoxide formation measured by EPR, but not a reduction in maldonialdehyde (MDA), a low molecular weight fragment of polyunsaturated fatty acid that results from oxidative damage, measured using TBARS. This finding, coupled with the amassing functional data reviewed earlier, is consistent with an interpretation that XO inhibition exerts favourable effects by reducing ROS formation, and that this does not necessarily reduce end-stage markers of cellular damage, which may be non-specific.12 The fact that the EPR signal is not reduced in the animals receiving long-tem allopurinol suggests breakthrough of other sources of ROS formation. Clearly, however, there is specificity in inhibiting XO long-term as the favourable effects on cardiac architecture were maintained. Together, these findings support the notion that sources of ROS formation exert precise effects most likely in specific subcellular domains and that blockade of these specific sources can have beneficial effects which exceed non-specific anti-oxidant approaches.11,12
Pathophysiological and clinical roles of uric acid in heart failure
Beyond XO activity, recent experimental studies suggest that uric acid itself may have a role in cardiovascular pathophysiology. In heart failure, hyperuricaemia is a marker of impaired oxidative metabolism15 and the levels of uric acid reflect the degree of circulating XO activity. Thus, it is not surprising that elevated levels of uric acid predict mortality and the need for heart transplantation in patients with congestive heart failure, even when combined with measures of cardiac function and patient functional status.16
Although uric acid predicts clinical outcomes in heart failure, the clinical utility of this is still not clear. Given its relation to XO activity, uric acid may be a causal and potentially clinically useful marker in the pathophysiology of heart failure. If this is true, uric acid levels should change in response to heart failure therapy in a manner than could predict clinical outcome, and therapies directed at hyperuricaemia via XO inhibition might benefit heart failure patients.
Clinical utility of XO inhibitors in heart failure
Allopurinol and its active metabolite oxypurinol are XO inhibitors which have enjoyed widespread clinical use in the treatment of a variety of conditions characterized by hyperuricaemia, notably gout and haematological malignancies. The metabolism of allopurinol to oxypurinol is catalysed by XO itself, resulting in the generation of reactive oxygen species, and thus the conversion of allopurinol to oxypurinol may actually enhance free radical production. For this and other reasons relating to the pharmacokinetics of these XO inhibitors, oxypurinol may have enhanced efficacy in heart failure relative to allopurinol.
Growing evidence that XO inhibition favourably affects myocardial energetics and vascular function in animal models of acute and chronic heart failure and in human heart failure has culminated in the OPT-CHF trial.17 This is a Phase II–III prospective, randomized, double-blind, placebo-controlled study of long-term oxypurinol added to standard therapy in patients with chronic heart failure. The overall objective of OPT-CHF is to demonstrate the safety and efficacy of oxypurinol vs. placebo in patients with moderate-to-severe symptomatic heart failure receiving standard therapy. To date, enrollment is completed on a total of 400 patients from United States and Canadian centres. We eagerly anticipate the results of this ground-breaking study, introducing a potential new class of drugs into the management of heart failure patients. Furthermore, the current findings of Mellin et al.1 and those of Engberding et al.2 and Stull et al.3 suggest that XO inhibition has the potential to play a therapeutic role in patients with both acute and chronic post-myocardial infarction left-ventricular dysfunction, in addition to their role in patients with established heart failure due to non-ischaemic causes.
XO inhibition in heart failure is an excellent example of translation from basic science to a clinical level. From beneficial effects in mouse, rat, and dog models of heart failure to acute physiological benefits in human heart failure, inhibition of XO improves myocardial energetics and vascular function, whereas uric acid levels, a marker of XO activity, have the potential to offer prognostic information in heart failure patients. These findings have culminated in a randomized clinical trial to test the science behind XO inhibition in heart failure, which, if positive, could usher into clinical use a new class of drugs for the treatment of heart failure.
This research is supported by NIH Grant 5RO1-HL-065455 (to J.M.H.). J.M.H. is a recipient of a Paul Beeson Physician Faculty Scholars in Aging Research Award. M.M.K. is a recipient of the Pearl M. Stetler Research Fund for Women Physicians Fellowship Award.
Conflict of interest
J.M.H. discloses that he is a consultant at Cardiome Pharma, Vancouver, Canada. The terms of this arrangement are being managed by the Johns Hopkins University in accordance with its conflict of interest policies.
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