Elevated uric acid levels predict allograft vasculopathy in cardiac transplant recipients.

BACKGROUND: Cardiac allograft vasculopathy (CAV) poses the greatest threat to the long-term survival of cardiac transplant recipients, and these individuals often exhibit elevated levels of uric acid (UA), a stimulator of T cells. We hypothesized that hyperuricemia is associated with CAV in cardiac transplant recipients. METHODS: UA levels were measured in cardiac transplant recipients between January 2003 and January 2005. Surveillance cardiac catheterizations performed 3 months to 1 year after UA measurement were reviewed. The relationship between UA and CAV was adjusted for possible confounders with propensity scores and confirmed with goodness-of-fit tests. RESULTS: The 105 patients included in this study were a median 63.3 months post-transplant and their left heart catheterizations were performed a median 5.6 months after UA measurement. Focal stenosis was evident in 25 angiograms and 31 showed distal pruning of the coronary arteries. Compared with the lowest quartile of UA, the highest quartile had an increased risk of CAV: odds ratio (OR) 6.11 (95% CI 1.47 to 25.5; p = 0.013) for focal stenosis and OR 4.60 (95% CI 1.34 to 15.8; p = 0.015) for distal pruning. After adjustment, this relationship persisted for both focal stenosis (OR 5.53, 95% confidence interval [CI] 1.29 to 23.7; p = 0.021) and distal pruning (OR 4.21, 95% CI 1.15 to 15.4; p = 0.029). CONCLUSIONS: Elevated UA confers an increased risk of CAV. This association may be causal, with pathophysiologic implications for the role of hyperuricemia in allograft failure and, if substantiated, could have clinical implications for the use of xanthine oxidase inhibitors in cardiac transplant recipients.

Positive inotropic and lusitropic effects of HNO/NO- in failing hearts: independence from beta-adrenergic signaling.

Nitroxyl anion (HNONO(-)), the one-electron reduced form of nitric oxide (NO), induces positive cardiac inotropy and selective venodilation in the normal in vivo circulation. Here we tested whether HNO/NO(-) augments systolic and diastolic function of failing hearts, and whether contrary to NO/nitrates such modulation enhances rather than blunts beta-adrenergic stimulation and is accompanied by increased plasma calcitonin gene-related peptide (CGRP). HNO/NO(-) generated by Angelis' salt (AS) was infused (10 microg/kg per min, i.v.) to conscious dogs with cardiac failure induced by chronic tachycardia pacing. AS nearly doubled contractility, enhanced relaxation, and lowered cardiac preload and afterload (all P < 0.001) without altering plasma cGMP. This contrasted to modest systolic depression induced by an NO donor diethylamine(DEA)NO or nitroglycerin (NTG). Cardiotropic changes from AS were similar in failing hearts as in controls despite depressed beta-adrenergic and calcium signaling in the former. Inotropic effects of AS were additive to dobutamine, whereas DEA/NO blunted beta-stimulation and NTG was neutral. Administration of propranolol to nonfailing hearts fully blocked isoproterenol stimulation but had minimal effect on AS inotropy and enhanced lusitropy. Arterial plasma CGRP rose 3-fold with AS but was unaltered by DEA/NO or NTG, supporting a proposed role of this peptide to HNO/NO(-) cardiotropic action. Thus, HNO/NO(-) has positive inotropic and lusitropic action, which unlike NO/nitrates is independent and additive to beta-adrenergic stimulation and stimulates CGRP release. This suggests potential of HNO/NO(-) donors for the treatment of heart failure.

Imbalance between xanthine oxidase and nitric oxide synthase signaling pathways underlies mechanoenergetic uncoupling in the failing heart.

Inhibition of xanthine oxidase (XO) in failing hearts improves cardiac efficiency by an unknown mechanism. We hypothesized that this energetic effect is due to reduced oxidative stress and critically depends on nitric oxide synthase (NOS) activity, reflecting a balance between generation of nitric oxide (NO) and reactive oxygen species. In dogs with pacing-induced heart failure (HF), ascorbate (1000 mg) mimicked the beneficial energetic effects of allopurinol, increasing both contractility and efficiency, suggesting an antioxidant mechanism. Allopurinol had no additive effect beyond that of ascorbate. Crosstalk between XO and NOS signaling was assessed. NOS inhibition with N(G)-monomethyl-L-arginine (L-NMMA; 20 mg/kg) had no effect on basal contractility or efficiency in HF, but prevented the +26.2+/-3.5% and +66.5+/-17% enhancements of contractility and efficiency, respectively, observed with allopurinol alone. Similarly, improvements in contractility and energetics due to ascorbate were also inhibited by L-NMMA. Because of the observed NOS-XO crosstalk, we predicted that in normal hearts NOS inhibition would uncover a depression of energetics caused by XO activity. In normal conscious dogs, L-NMMA increased myocardial oxygen consumption (MVO2) while lowering left ventricular external work, reducing efficiency by 31.1+/-3.8% (P<0.005). Lowered efficiency was reversed by XO inhibition (allopurinol, 200 mg) or by ascorbate without affecting cardiac load or systemic hemodynamics. Single-cell immunofluorescence detected XO protein in cardiac myocytes that was enhanced in HF, consistent with autocrine signaling. These data show that both NOS and XO signaling systems participate in the regulation of myocardial mechanical efficiency and that upregulation of XO relative to NOS contributes to mechanoenergetic uncoupling in heart failure.