Abstract-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 ϩ26.2Ϯ3.5% and ϩ66.5Ϯ17% 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 (MV O 2 ) while lowering left ventricular external work, reducing efficiency by 31.1Ϯ3.8% (PϽ0.005). 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. Key Words: xanthine oxidase Ⅲ oxidative stress Ⅲ nitric oxide Ⅲ heart failure Ⅲ ascorbate T he failing heart displays substantial energetic inefficiency in both isolated muscle 1,2 and intact chambers. [3][4][5] This phenomenon can be best described as "mechanoenergetic uncoupling," given that the depression of contractile force is not matched by a concomitant depression of energy consumption. Among the proposed mechanisms is enhanced oxidative stress stemming from mitochondrial 6 and cytosolic free radical generating systems. 7 Xanthine oxidase (XO) is prominent among these enzymes, because it produces superoxide as a byproduct of the terminal two steps of purine metabolism. 3 XO is upregulated in failing myocardium of experimental animals 3,8 and humans, 9 and its inhibition by allopurinol improves the mechanical efficiency (the ratio between ventricular work performed and oxygen consumed) of intact failing hearts 3,9 ; such an effect was predicted by the initial observations that allopurinol and oxypurinol augment calcium-activated force without increasing activator Ca 2ϩ in isolated cardiac muscle. 2 To date, however, the signal transduction mechanisms of the salutary effects o...

We appreciate the thoughtful comments of Drs Almonedro-Delia, Galvez-Acebal, and Rodriguez-Bano regarding our recent publication, "Association Between Surgical Indications, Operative Risk, and Clinical Outcome in Infective Endocarditis: a Prospective Study From the International Collaboration on Endocarditis." 1 These authors raise important issues for evaluating the impact of surgery on patient outcomes, particularly survival. We strongly agree that treatment selection bias and survivor bias are major issues when evaluating the impact of surgery on mortality and that the use of appropriate statistical methodologies is necessary to quantify an unbiased and causal association of the effect of surgical treatment on outcome. In our previous studies on the impact of surgery on mortality, we have used such methods, including propensity scores, 2 to account for selection bias and Cox proportional hazards models with surgery entered as a time-dependent covariate 3,4 for survivor bias adjustment. However, the objective of the current study was to evaluate the differences in clinical characteristics comparing patients treated with and without cardiac surgery for infective endocarditis, and to evaluate the relationship between surgical indications, operative risk (by using the Society of Thoracic Surgeons operative risk score), and outcome. Our results emphasize the relevance of specific surgical indications in treatment decisions in infective endocarditis, and the relationship between the Society of Thoracic Surgeons operative risk score and outcome, as well. The purpose of our study was not to determine the prognostic influence of surgery in comparison with medical therapy alone in infective endocarditis.

Background Suspected coronary artery disease (CAD) is one of the most common, potentially life threatening diagnostic problems clinicians encounter. However, no large outcome-based randomized trials have been performed to guide the selection of diagnostic strategies for these patients. Methods The PROMISE study is a prospective, randomized trial comparing the effectiveness of two initial diagnostic strategies in patients with symptoms suspicious for CAD. Patients are randomized to either: 1) functional testing (exercise electrocardiogram, stress nuclear imaging, or stress echocardiogram); or 2) anatomic testing with >=64 slice multidetector coronary computed tomographic angiography. Tests are interpreted locally in real time by subspecialty certified physicians and all subsequent care decisions are made by the clinical care team. Sites are provided results of central core lab quality and completeness assessment. All subjects are followed for ≥1 year. The primary end-point is the time to occurrence of the composite of death, myocardial infarction, major procedural complications (stroke, major bleeding, anaphylaxis and renal failure) or hospitalization for unstable angina. Results Over 10,000 symptomatic subjects were randomized in 3.2 years at 193 US and Canadian cardiology, radiology, primary care, urgent care and anesthesiology sites. Conclusion Multi-specialty community practice enrollment into a large pragmatic trial of diagnostic testing strategies is both feasible and efficient. PROMISE will compare the clinical effectiveness of an initial strategy of functional testing against an initial strategy of anatomic testing in symptomatic patients with suspected CAD. Quality of life, resource use, cost effectiveness and radiation exposure will be assessed. Clinical trials.gov identifier NCT01174550