ABSTRACT
OBJECTIVES: The purpose of this study was to evaluate the role of the myocardial redox state in the development of in-hospital complications after cardiac surgery and the effect of statins on the myocardial redox state. BACKGROUND: Statins improve clinical outcome after cardiac surgery, but it is unclear whether they exert their effects by modifying the myocardial redox state. METHODS: We quantified myocardial superoxide anion (O(2)(-)) and peroxynitrite (ONOO(-)) and their enzymatic sources in samples of the right atrial appendage (RAA) from 303 patients undergoing cardiac surgery who were followed up until discharge, and in 42 patients who were randomized to receive 3-day treatment with atorvastatin 40 mg/d or placebo before surgery. The mechanisms by which atorvastatin modifies myocardial redox state were investigated in 26 RAA samples that were exposed to atorvastatin ex vivo. RESULTS: Atrial O(2)(-) (derived mainly from nicotinamide adenine dinucleotide phosphate [NADPH] oxidases) and ONOO(-) were independently associated with increased risk of atrial fibrillation, the need for post-operative inotropic support, and the length of hospital stay. Pre-operative atorvastatin treatment suppressed atrial NADPH oxidase activity and myocardial O(2)(-) and ONOO(-) production. Ex vivo incubation of RAA samples with atorvastatin induced a mevalonate-reversible and Rac1-mediated inhibition of NADPH oxidase. CONCLUSIONS: There is a strong independent association between myocardial O(2)(-)/ONOO(-) and in-hospital complications after cardiac surgery. Both myocardial O(2)(-) and ONOO(-) are reduced by pre-operative statin treatment, through a Rac1-mediated suppression of NADPH oxidase activity. These findings suggest that inhibition of myocardial NADPH oxidases may contribute to the beneficial effect of statins in patients undergoing cardiac surgery. (Effects of Atorvastatin on Endothelial Function, Vascular and Myocardial Redox State in High Cardiovascular Risk Patients; NCT01013103).
Subject(s)
Cardiac Surgical Procedures/methods , Heptanoic Acids/administration & dosage , Hydroxymethylglutaryl-CoA Reductase Inhibitors/administration & dosage , Oxidation-Reduction/drug effects , Pyrroles/administration & dosage , Aged , Atorvastatin , Cardiac Surgical Procedures/adverse effects , Cardiac Surgical Procedures/mortality , Confidence Intervals , Coronary Artery Bypass/adverse effects , Coronary Artery Bypass/methods , Coronary Artery Bypass/mortality , Dose-Response Relationship, Drug , Drug Administration Schedule , Female , Follow-Up Studies , Hospital Mortality/trends , Humans , Kaplan-Meier Estimate , Lipid Peroxidation/drug effects , Male , Middle Aged , Myocardium/metabolism , Postoperative Complications/prevention & control , Predictive Value of Tests , Preoperative Care/methods , Proportional Hazards Models , Prospective Studies , Survival Analysis , Treatment OutcomeABSTRACT
BACKGROUND: Treatment with statins improves clinical outcome, but the exact mechanisms of pleiotropic statin effects on vascular function in human atherosclerosis remain unclear. We examined the direct effects of atorvastatin on tetrahydrobiopterin-mediated endothelial nitric oxide (NO) synthase coupling in patients with coronary artery disease. METHODS AND RESULTS: We first examined the association of statin treatment with vascular NO bioavailability and arterial superoxide (O(2)(·-)) in 492 patients undergoing coronary artery bypass graft surgery. Then, 42 statin-naïve patients undergoing elective coronary artery bypass graft surgery were randomized to atorvastatin 40 mg/d or placebo for 3 days before surgery to examine the impact of atorvastatin on endothelial function and O(2)(·-) generation in internal mammary arteries. Finally, segments of internal mammary arteries from 26 patients were used in ex vivo experiments to evaluate the statin-dependent mechanisms regulating the vascular redox state. Statin treatment was associated with improved vascular NO bioavailability and reduced O(2)(·-) generation in internal mammary arteries. Oral atorvastatin increased vascular tetrahydrobiopterin bioavailability and reduced basal and N-nitro-l-arginine methyl ester-inhibitable O(2)(·-) in internal mammary arteries independently of low-density lipoprotein lowering. In ex vivo experiments, atorvastatin rapidly improved vascular tetrahydrobiopterin bioavailability by upregulating GTP-cyclohydrolase I gene expression and activity, resulting in improved endothelial NO synthase coupling and reduced vascular O(2)(·-). These effects were reversed by mevalonate, indicating a direct effect of vascular hydroxymethylglutaryl-coenzyme A reductase inhibition. CONCLUSIONS: This study demonstrates for the first time in humans the direct effects of statin treatment on the vascular wall, supporting the notion that this effect is independent of low-density lipoprotein lowering. Atorvastatin directly improves vascular NO bioavailability and reduces vascular O(2)(·-) through tetrahydrobiopterin-mediated endothelial NO synthase coupling. These findings provide new insights into the mechanisms mediating the beneficial vascular effects of statins in humans. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01013103.
Subject(s)
Biopterins/analogs & derivatives , Coronary Artery Disease/metabolism , Coronary Vessels/drug effects , Coronary Vessels/metabolism , Heptanoic Acids/pharmacology , Nitric Oxide Synthase Type III/metabolism , Nitric Oxide/metabolism , Pyrroles/pharmacology , Aged , Atorvastatin , Biological Availability , Biopterins/metabolism , Coronary Artery Bypass , Coronary Artery Disease/surgery , Double-Blind Method , Endothelium, Vascular/drug effects , Endothelium, Vascular/physiology , Female , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Male , Middle Aged , Oxidation-Reduction , Oxidative Coupling/drug effects , Oxygen/metabolism , Superoxides/metabolismABSTRACT
We explored the role of asymmetrical dimethylarginine (ADMA) as a cause of endothelial dysfunction induced by systemic inflammation. In vitro data suggest that ADMA bioavailability is regulated by proinflammatory stimuli, but it is unclear whether ADMA is a link between inflammation and endothelial dysfunction in humans. In study 1 we recruited 351 patients with coronary artery disease (CAD) and 87 healthy controls. In study 2 we recruited 69 CAD, 69 healthy, and 10 patients with rheumatoid arthritis, whereas in study 3, 22 healthy and 70 CAD subjects were randomly assigned to Salmonella typhii vaccination (n=11 healthy and n=60 CAD) or placebo (n=11 healthy and n=10 CAD). Circulating interleukin 6/ADMA and flow-mediated dilation (FMD) were measured at 0 and 8 hours. In study 1, ADMA was inversely correlated with FMD in healthy individuals and CAD patients (P<0.0001 for both). However, interleukin 6 was inversely correlated with FMD (P<0.0001) in healthy subjects but not in CAD patients. The positive correlation between ADMA and interleukin 6 was stronger in healthy (r=0.515; P<0.0001) compared with CAD (r=0.289; P=0.0001) subjects. In study 2, both patients with rheumatoid arthritis and CAD had higher interleukin 6 (P<0.0001) and ADMA (P=0.004) but lower FMD (P=0.001) versus healthy subjects. In study 3, vaccination increased interleukin 6 in healthy (P<0.001) and CAD (P<0.001) subjects. FMD was reduced in healthy subjects (P<0.05), but its reduction in CAD was borderline. Vaccination increased ADMA only in healthy subjects (P<0.001). Systemic, low-grade inflammation leads to increased ADMA that may induce endothelial dysfunction. This study demonstrated that ADMA may be a link between inflammation and endothelial dysfunction in humans.
