oxypurinol and Cardiomyopathies

Cachexia is a common complication of cancer and may be responsible for 22% of all cancer-related deaths. The exact cause of death in cancer cachexia patients is unknown. Recently, atrophy of the heart has been described in cancer cachexia animal models, which resulted in impaired cardiac function and is likely to contribute to mortality. In cancer patients hyperuricaemia independent of tumour lysis syndrome is often associated with a worse prognosis. Xanthine oxidase (XO) metabolizes purines to uric acid and its inhibition has been shown to improve clinical outcome in patients with chronic heart failure.. The rat Yoshida AH-130 hepatoma cancer cachexia model was used in this study. Rats were treated with 4 or 40 mg/kg/d oxypurinol or placebo starting one day after tumour-inoculation for maximal 15 days. Cardiac function was analyzed by echocardiography on day 11.. Here we show that inhibition of XO by oxypurinol significantly reduces wasting of the heart and preserves cardiac function. LVEF was higher in tumour-bearing rats treated with 4 mg/kg/d (61±4%) or 40 mg/kg/d (64±5%) oxypurinol vs placebo (51±3%, both p<0.05). Fractional shortening was improved by 4 mg/kg/d (43±3%) oxypurinol vs placebo (30±2, p<0.05), while 40 mg/kg/d oxypurinol (41±5%) did not reach statistical significance. Cardiac output was increased in the 4 mg/kg/d dose only (71±11 mL/min vs placebo 38±4 mL/min, p<0.01).. Inhibition of XO with oxypurinol has beneficial effects on cardiac mass and function in a rat model of severe cancer cachexia, suggesting that XO might be a viable drug target in cancer cachexia.

Topics: Animals; Cachexia; Cardiomyopathies; Liver Neoplasms; Liver Neoplasms, Experimental; Male; Oxypurinol; Rats; Rats, Wistar; Xanthine Oxidase

An R120G mutation in alphaB-crystallin (CryAB(R120G)) causes desmin-related myopathy (DRM). In mice with cardiomyocyte-specific expression of the mutation, CryAB(R120G)-mediated DRM is characterized by CryAB and desmin accumulations within cardiac muscle, mitochondrial deficiencies, activation of apoptosis, and heart failure (HF). Excessive production of reactive oxygen species (ROS) is often a hallmark of HF and treatment with antioxidants can sometimes prevent the progression of HF in terms of contractile dysfunction and cardiomyocyte survival. It is unknown whether blockade of ROS is beneficial for protein misfolding diseases such as DRM. We addressed this question by blocking the activity of xanthine oxidase (XO), a superoxide-generating enzyme that is upregulated in our model of DRM. The XO inhibitor oxypurinol was administered to CryAB(R120G) mice for a period of 1 or 3 months. Mitochondrial function was dramatically improved in treated animals in terms of complex I activity and conservation of mitochondrial membrane potential. Oxypurinol also largely restored normal mitochondrial morphology. Surprisingly, however, cardiac contractile function and cardiac compliance were unimproved, indicating that the contractile deficit might be independent of mitochondrial dysfunction and the initiation of apoptosis. Using magnetic bead microrheology at the single cardiomyocyte level, we demonstrated that sarcomeric disarray and accumulation of the physical aggregates resulted in significant changes in the cytoskeletal mechanical properties in the CryAB(R120G) cardiomyocytes. Our findings indicate that oxypurinol treatment largely prevented mitochondrial deficiency in DRM but that contractility was not improved because of mechanical deficits in passive cytoskeletal stiffness.

Topics: alpha-Crystallin B Chain; Animals; Apoptosis; Cardiomyopathies; Compliance; Desmin; Disease Models, Animal; Enzyme Inhibitors; Free Radical Scavengers; Hemorheology; Membrane Potential, Mitochondrial; Mice; Mice, Transgenic; Mitochondria, Heart; Mutation; Myocardial Contraction; Myocytes, Cardiac; Oxidative Stress; Oxypurinol; Protein Folding; Reactive Oxygen Species; Sarcomeres; Ventricular Function, Left; Xanthine Oxidase

Reactive oxygen species, in particular superoxide, have been closely linked to the underlying pathophysiology of ischemic cardiomyopathy: superoxide not only mediates mechanoenergetic uncoupling of the myocyte but also adversely impacts on myocardial perfusion by depleting endothelial-derived nitric oxide bioavailability. Xanthine oxidase generates superoxide upon oxidation of hypoxanthine and xanthine and has been detected in cardiac myocytes and coronary endothelial cells of patients with ischemic heart disease. Here we investigated the effects of oxypurinol, a xanthine oxidase inhibitor, on myocardial contractility in patients with ischemic cardiomyopathy. Twenty patients (19 males, 66+/-8 years) with stable coronary disease, severely suppressed systolic function (left ventricular ejection fraction 22+/-2%), and nonelevated uric acid plasma levels received a single intravenous dose of oxypurinol (400 mg). Cardiac MRI studies, performed before and 5.2+/-0.9 h after oxypurinol administration, revealed a reduction in end-systolic volumes (-9.7+/-4.2%; p=0.03) and an increase in left ventricular ejection fraction (+17.5+/-5.2%; p=0.003), whereas 6 patients (6 males, 63+/-3.8 years, ejection fraction 26+/-5%) who received vehicle only did not show significant changes in any of the parameters studied. Oxypurinol improves left ventricular function in patients with ischemic cardiomyopathy. These results underscore the significance of reactive oxygen species as important pathophysiological mediators in ischemic heart failure and point toward xanthine oxidase as an important source of reactive species that serve to modulate the myocardial redox state in this disease.

Topics: Aged; Cardiomyopathies; Cardiotonic Agents; Enzyme Inhibitors; Female; Humans; Hypoxanthine; Magnetic Resonance Imaging, Cine; Male; Middle Aged; Myocardial Contraction; Myocardial Ischemia; Oxypurinol; Reactive Oxygen Species; Uric Acid; Xanthine; Xanthine Oxidase