Raja Jayaram

Atrial sources of reactive oxygen species vary with the duration and substrate of atrial fibrillation: implications for the antiarrhythmic effect of statins.

Background— An altered nitric oxide–redox balance has been implicated in the pathogenesis of atrial fibrillation (AF). Statins inhibit NOX2-NADPH oxidases and prevent postoperative AF but are less effective in AF secondary prevention; the mechanisms underlying these findings are poorly understood. Methods and Results— By using goat models of pacing-induced AF or of atrial structural remodeling secondary to atrioventricular block and right atrial samples from 130 patients undergoing cardiac surgery, we found that the mechanisms responsible for the NO-redox imbalance differ between atria and with the duration and substrate of AF. Rac1 and NADPH oxidase activity and the protein level of NOX2 and p22phox were significantly increased in the left atrium of goats after 2 weeks of AF and in patients who developed postoperative AF in the absence of differences in leukocytes infiltration. Conversely, in the presence of longstanding AF or atrioventricular block, uncoupled nitric oxide synthase activity (secondary to reduced BH4 content and/or increased arginase activity) and mitochondrial oxidases accounted for the biatrial increase in reactive oxygen species. Atorvastatin caused a mevalonate-reversible inhibition of Rac1 and NOX2-NADPH oxidase activity in right atrial samples from patients who developed postoperative AF, but it did not affect reactive oxygen species, nitric oxide synthase uncoupling, or BH4 in patients with permanent AF. Conclusions— Upregulation of atrial NADPH oxidases is an early but transient event in the natural history of AF. Changes in the sources of reactive oxygen species with atrial remodeling may explain why statins are effective in the primary prevention of AF but not in its management.

Atrial Sources of Reactive Oxygen Species Vary With the Duration and Substrate of Atrial Fibrillation

Background— An altered nitric oxide–redox balance has been implicated in the pathogenesis of atrial fibrillation (AF). Statins inhibit NOX2-NADPH oxidases and prevent postoperative AF but are less effective in AF secondary prevention; the mechanisms underlying these findings are poorly understood. Methods and Results— By using goat models of pacing-induced AF or of atrial structural remodeling secondary to atrioventricular block and right atrial samples from 130 patients undergoing cardiac surgery, we found that the mechanisms responsible for the NO-redox imbalance differ between atria and with the duration and substrate of AF. Rac1 and NADPH oxidase activity and the protein level of NOX2 and p22phox were significantly increased in the left atrium of goats after 2 weeks of AF and in patients who developed postoperative AF in the absence of differences in leukocytes infiltration. Conversely, in the presence of longstanding AF or atrioventricular block, uncoupled nitric oxide synthase activity (secondary to reduced BH4 content and/or increased arginase activity) and mitochondrial oxidases accounted for the biatrial increase in reactive oxygen species. Atorvastatin caused a mevalonate-reversible inhibition of Rac1 and NOX2-NADPH oxidase activity in right atrial samples from patients who developed postoperative AF, but it did not affect reactive oxygen species, nitric oxide synthase uncoupling, or BH4 in patients with permanent AF. Conclusions— Upregulation of atrial NADPH oxidases is an early but transient event in the natural history of AF. Changes in the sources of reactive oxygen species with atrial remodeling may explain why statins are effective in the primary prevention of AF but not in its management.

Perioperative Rosuvastatin in Cardiac Surgery.

BACKGROUND Complications after cardiac surgery are common and lead to substantial increases in morbidity and mortality. Meta-analyses of small randomized trials have suggested that perioperative statin therapy can prevent some of these complications. METHODS We randomly assigned 1922 patients in sinus rhythm who were scheduled for elective cardiac surgery to receive perioperative rosuvastatin (at a dose of 20 mg daily) or placebo. The primary outcomes were postoperative atrial fibrillation within 5 days after surgery, as assessed by Holter electrocardiographic monitoring, and myocardial injury within 120 hours after surgery, as assessed by serial measurements of the cardiac troponin I concentration. Secondary outcomes included major in-hospital adverse events, duration of stay in the hospital and intensive care unit, left ventricular and renal function, and blood biomarkers. RESULTS The concentrations of low-density lipoprotein cholesterol and C-reactive protein after surgery were lower in patients assigned to rosuvastatin than in those assigned to placebo (P<0.001). However, the rate of postoperative atrial fibrillation did not differ significantly between the rosuvastatin group and the placebo group (21.1% and 20.5%, respectively; odds ratio 1.04; 95% confidence interval [CI], 0.84 to 1.30; P=0.72), nor did the area under the troponin I-release curve (102 ng×hour per milliliter and 100 ng×hour per milliliter, respectively; between-group difference, 1%; 95% CI, -9 to 13; P=0.80). Subgroup analyses did not indicate benefit in any category of patient. Rosuvastatin therapy did not result in beneficial effects on any of the secondary outcomes but was associated with a significant absolute (±SE) excess of 5.4±1.9 percentage points in the rate of postoperative acute kidney injury (P=0.005). CONCLUSIONS In this trial, perioperative statin therapy did not prevent postoperative atrial fibrillation or perioperative myocardial damage in patients undergoing elective cardiac surgery. Acute kidney injury was more common with rosuvastatin. (Funded by the British Heart Foundation and others; STICS ClinicalTrials.gov number, NCT01573143.).

Quality of Reporting in Randomized Trials Published in High-Quality Surgical Journals

BACKGROUND Randomized controlled trials (RCTs) in surgery can provide valuable evidence of the efficacy of interventions if they are well-designed, appropriately executed, and adequately reported. Adequate reporting of methodology in surgical RCTs is known to be poor, and adverse-event reporting in surgical research is inconsistent. The Consolidated Standards of Reporting Trials (CONSORT) statement is a framework to help authors report their findings in a transparent manner. Extensions to the CONSORT statement have been published recently to address deficiencies in adverse-event reporting and in reporting of specific criteria related to nonpharmacologic treatments. The aim of this study was to assess the quality of reporting of trial methodology and adverse events in a sample of general surgical RCTs published in high-quality surgical journals using the criteria specified in the CONSORT statements. STUDY DESIGN We used impact factor to identify the top three ranked surgical journals in 2004. We then obtained information on all RCTs published in these journals in the 2005 calendar year. We assessed quality of reporting using Jadad score, compared the quality of RCTs from CONSORT-endorsing journals with nonendorsers, and assessed the number of RCTs adequately reporting key generic methodologic, adverse-event-related, and specific nonpharmacologic criteria. RESULTS Of 42 RCTs analyzed, only 40% (17 of 42) had a Jadad score > or = 3. There was no significant difference in the number of high-quality RCTs published in CONSORT-endorsing journals compared with nonendorsers (p = 0.3). The median percentage of RCTs adequately reporting generic methodologic, adverse-event-related, and specific nonpharmacologic criteria was 32.5%, 17%, and 36.5%, respectively. CONCLUSIONS Quality of reporting of generic methodologic, adverse-event-related, and specific nonpharmacologic criteria in surgical RCTs is poor. Increased attention to quality of reporting of surgical RCTs is required if studies are to meet published criteria.

Myocardial Redox State Predicts In-Hospital Clinical Outcome After Cardiac Surgery Effects of Short-Term Pre-Operative Statin Treatment

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).

Regulation of Endothelial Nitric Oxide Synthase (NOS) S-Glutathionylation by Neuronal NOS: Evidence of a Functional Interaction between Myocardial Constitutive NOS isoforms

Background: Whether neuronal nitric-oxide synthase (nNOS) plays a role in the endothelial NOS (eNOS)-dependent negative inotropic effect of β3-adrenergic stimulation remains to be established. Results: nNOS knock-out or inhibition leads to increased superoxide production, eNOS uncoupling, and abrogation of β3-adrenergic responses. Conclusion: Disabling nNOS disrupts eNOS function and downstream signaling. Significance: nNOS plays a crucial role in preserving myocardial nitroso-redox balance and coupled eNOS activity. Myocardial constitutive No production depends on the activity of both endothelial and neuronal NOS (eNOS and nNOS, respectively). Stimulation of myocardial β3-adrenergic receptor (β3-AR) produces a negative inotropic effect that is dependent on eNOS. We evaluated whether nNOS also plays a role in β3-AR signaling and found that the β3-AR-mediated reduction in cell shortening and [Ca2+]i transient amplitude was abolished both in eNOS−/− and nNOS−/− left ventricular (LV) myocytes and in wild type LV myocytes after nNOS inhibition with S-methyl-l-thiocitrulline. LV superoxide (O2̇̄) production was increased in nNOS−/− mice and reduced by l-Nω-nitroarginine methyl ester (l-NAME), indicating uncoupling of eNOS activity. eNOS S-glutathionylation and Ser-1177 phosphorylation were significantly increased in nNOS−/− myocytes, whereas myocardial tetrahydrobiopterin, eNOS Thr-495 phosphorylation, and arginase activity did not differ between genotypes. Although inhibitors of xanthine oxidoreductase (XOR) or NOX2 NADPH oxidase caused a similar reduction in myocardial O2̇̄, only XOR inhibition reduced eNOS S-glutathionylation and Ser-1177 phosphorylation and restored both eNOS coupled activity and the negative inotropic and [Ca2+]i transient response to β3-AR stimulation in nNOS−/− mice. In summary, our data show that increased O2̇̄ production by XOR selectively uncouples eNOS activity and abolishes the negative inotropic effect of β3-AR stimulation in nNOS−/− myocytes. These findings provide unequivocal evidence of a functional interaction between the myocardial constitutive NOS isoforms and indicate that aspects of the myocardial phenotype of nNOS−/− mice result from disruption of eNOS signaling.

Cost of intensive care in India

Critical care is often described as expensive care. However, standardized methodology that would enable determination and international comparisons of cost is currently lacking. This article attempts to review this important issue and develop a framework through which cost of critical care in India could be analyzed.

Up-regulation of miR-31 in human atrial fibrillation begets the arrhythmia by depleting dystrophin and neuronal nitric oxide synthase

Atrial microRNA-31 up-regulation causes dystrophin and nNOS depletion, which in turn contributes to the electrical phenotype of atrial fibrillation. Rhythm remodeling traced to tiny RNA Atrial fibrillation (AF) is characterized by abnormal heart rhythms and can be caused by a variety of risk factors ranging from obesity to diabetes. Although treatments exist, AF is famously able to recur by “remodeling” the heart tissue electrically and structurally to maintain its unsteady beat. Reilly et al. have discovered a small noncoding RNA, miR-31, that is responsible for a string of signals that allow for such remodeling. An increase in miR-31 led to depletion of neuronal nitric oxide synthase (nNOS) and repression of dystrophin (which binds nNOS in muscle cells) in the fibrillating atrial myocardium of both humans and goats. These mechanistic findings were further explored in mice. Because up-regulation of miR-31 and the resulting loss of dystrophin and nNOS in AF are specific to the atrium, it may be possible to target interventions to this remodeling pathway, thus providing a safer therapeutic option for patients with AF than those that are currently available, including ablation and ion channel blockers. Atrial fibrillation (AF) is a growing public health burden, and its treatment remains a challenge. AF leads to electrical remodeling of the atria, which in turn promotes AF maintenance and resistance to treatment. Although remodeling has long been a therapeutic target in AF, its causes remain poorly understood. We show that atrial-specific up-regulation of microRNA-31 (miR-31) in goat and human AF depletes neuronal nitric oxide synthase (nNOS) by accelerating mRNA decay and alters nNOS subcellular localization by repressing dystrophin translation. By shortening action potential duration and abolishing rate-dependent adaptation of the action potential duration, miR-31 overexpression and/or disruption of nNOS signaling recapitulates features of AF-induced remodeling and significantly increases AF inducibility in mice in vivo. By contrast, silencing miR-31 in atrial myocytes from patients with AF restores dystrophin and nNOS and normalizes action potential duration and its rate dependency. These findings identify atrial-specific up-regulation of miR-31 in human AF as a key mechanism causing atrial dystrophin and nNOS depletion, which in turn contributes to the atrial phenotype begetting this arrhythmia. miR-31 may therefore represent a potential therapeutic target in AF.

Management of cerebral venous thrombosis in a patient with Lane-Hamilton syndrome and coeliac disease, epilepsy and cerebral calcification syndrome

We describe a case of cerebral venous thrombosis presenting in a patient with Lane-Hamilton syndrome and coeliac disease epilepsy cerebral calcification syndrome. This is a first reported occurrence of this combination. Delayed anticoagulation with early external ventricular drain insertion for life-threatening raised intracranial pressure resulted in a successful outcome.

142 Atrial sources of reactive oxygen species vary with the substrate and duration of atrial fibrillation: implications for the antiarrhythmic effect of statins

Background Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and is associated with altered nitric oxide (NO)-redox balance. The molecular mechanisms and implications of this phenomenon in the management of patients with AF are poorly understood. Statins improve NO-redox imbalance and decrease the occurrence of postoperative AF but are less effective in the secondary prevention of AF, suggesting that the sources of reactive oxygen species might vary with the substrate and duration of AF. Methods and Results We investigated atrial tissue from 130 patients undergoing cardiac surgery (26 with permanent AF, 32 who developed AF post-operatively and 72 who were in normal sinus rhythm before and after surgery), and from goats in sinus rhythm (SR, n=19) with or without atrial structural remodelling secondary to surgical AV block (AVB, n=10) or after 2 weeks (2W, n=15) or 6 months (6M, n=10) of pacing-induced AF. Atrial NADPH oxidase activity (chemiluminescence and 2-OH ethidium, Abstract 142 figures 1 and 2), NOX2 & p22phox protein level were increased after 2W-AF and in patients who developed AF post-operatively (n=32). In contrast, the increased superoxide production in atrial tissue from goats with AVB or 6M-AF was exclusively driven by mitochondrial oxidases and uncoupled NOS (secondary to a reduction in atrial BH4 level and an increase in arginase activity). These findings were recapitulated in the right atrial appendage of patients. Increase in basal superoxide production in postoperative AF was associated with an apocynin-reversible increase in NADPH oxidase activity and protein level of the NOX2 and p22phox subunits. NOS activity remained coupled despite the increase in superoxide production. In line with this, atrial BH4 content was unaltered. In contrast, in patients with permanent AF, increased superoxide production was not reversed by apocynin, and was maintained by mitochondrial oxidases and uncoupled NOS (secondary to BH4 deplition). Ex-vivo inhibition of HMG-CoA reductase with atorvastatin (20 μMol/l) inhibited NADPH oxidase activity (via reducing activity of Rac1 and membrane translocation of cytosolic subunit p47phox and p67phox of NADPH oxidase) and caused a mevalonate-reversible reduction in superoxide release in atrial samples of patients with post-operative AF but had no effect in patients with permanent AF. Similarly, atorvastatin did not induce a mevalonate-reversible changes in the atrial BH4 concentration and NOS uncoupling in neither group. Conclusions Together, these findings indicate that upregulation of NOX2-NADPH oxidases is an early but transient event in the natural history of AF, as mitochondrial oxidases and uncoupled NOS account for the statin-resistant increase in atrial superoxide production in permanent AF. Variation in atrial sources of reactive oxygen species with the duration and substrate of AF may explain the reported variability in the effectiveness of statins in the prevention and management of AF.