Alteration in function of the cardiac autonomic nervous system has proved to be a powerful predictor of cardiac death or serious arrhythmia in patients with cardiac disease, yet little is known about the mechanisms by which this system is regulated. Recent evidence suggests that the gaseous molecule nitric oxide (NO) may act as an important mediator in this pathway. Histochemical staining techniques have identified neuronal populations that contain NO synthase within medullary cardio-regulatory sites and their peripheral autonomic pathways. Drugs that modulate the NO pathway (administered both systemically and into the central nervous system) cause changes in pre- and post-ganglionic sympathetic nerve activity that imply that NO serves to inhibit central sympathetic outflow. There is also evidence that NO may attenuate cardiovascular end-organ responses to sympathetic stimulation. Studies suggest that NO modulates cardiac vagal control, increasing the activity of central vagal motoneurons and, more contentiously, contributing to the bradycardic effects of vagal stimulation. NO also modulates so-called 'indirect' vagal inhibition of sympathetic cardiac responses. Additionally, central attenuation of baroreflex-mediated vagal control has been described. There is relatively little information available on the importance of NO in the regulation of human cardiovascular autonomic control. Further well-controlled studies are required.

Background Acute kidney injury (AKI) is a serious global public health problem. We aimed to quantify the risk of AKI associated with estimated glomerular filtration rate (eGFR), albuminuria (albumin-creatinine ratio [ACR]), age, sex, and race (African American and Caucasian). Study Design Collaborative meta-analysis. Setting & Population 8 general population cohorts (1,285,049 participants) and 5 chronic kidney disease (CKD) cohorts (79,519 participants). Selection Criteria for Studies Available eGFR, ACR, and ≥50 AKI events. Predictors Age, sex, race, eGFR, urine ACR, and interactions. Outcome Hospitalized with or for AKI, using Cox proportional hazards models to estimate HRs of AKI and random effects meta-analysis to pool results. Results 16,480 (1.3%) general population cohort participants had AKI over a mean follow-up of 4 years; 2,087 (2.6%) CKD participants had AKI over mean follow-up of 1 year. Lower eGFR and higher ACR were strongly associated with AKI. Compared with eGFR 80 ml/min/1.73 m2, the adjusted HR of AKI at eGFR 45 ml/min/1.73 m2 was 3.35 (95% CI, 2.75–4.07). Compared with ACR 5 mg/g, the risk of AKI at ACR 300 mg/g was 2.73 (95% CI, 2.18–3.43). Older age was associated with higher risk of AKI, but this effect was attenuated in lower eGFR or higher ACR. Male sex was associated with higher risk of AKI, with a slight attenuation in lower eGFR but not in higher ACR. African Americans had higher AKI risk at higher levels of eGFR and most levels of ACR. Limitations Only 2 general population cohorts could contribute to analyses by race; AKI identified by diagnostic code. Conclusions Reduced eGFR and increased ACR are consistent, strong risk factors for AKI whereas the associations of AKI with age, sex, and race may be weaker in more advanced stages of CKD.

for the Rate Control Therapy Evaluation in Permanent Atrial Fibrillation (RATE-AF) Team IMPORTANCE There is little evidence to support selection of heart rate control therapy in patients with permanent atrial fibrillation, in particular those with coexisting heart failure.OBJECTIVE To compare low-dose digoxin with bisoprolol (a β-blocker). DESIGN, SETTING, AND PARTICIPANTSRandomized, open-label, blinded end-point clinical trial including 160 patients aged 60 years or older with permanent atrial fibrillation (defined as no plan to restore sinus rhythm) and dyspnea classified as New York Heart Association class II or higher. Patients were recruited from 3 hospitals and primary care practices in England from 2016 through 2018; last follow-up occurred in October 2019. INTERVENTIONS Digoxin (n = 80; dose range, 62.5-250 μg/d; mean dose, 161 μg/d) or bisoprolol (n = 80; dose range, 1.25-15 mg/d; mean dose, 3.2 mg/d). MAIN OUTCOMES AND MEASURESThe primary end point was patient-reported quality of life using the 36-Item Short Form Health Survey physical component summary score (SF-36 PCS) at 6 months (higher scores are better; range, 0-100), with a minimal clinically important difference of 0.5 SD. There were 17 secondary end points (including resting heart rate, modified European Heart Rhythm Association [EHRA] symptom classification, and N-terminal pro-brain natriuretic peptide [NT-proBNP] level) at 6 months, 20 end points at 12 months, and adverse event (AE) reporting.RESULTS Among 160 patients (mean age, 76 [SD, 8] years; 74 [46%] women; mean baseline heart rate, 100/min [SD, 18/min]), 145 (91%) completed the trial and 150 (94%) were included in the analysis for the primary outcome. There was no significant difference in the primary outcome of normalized SF-36 PCS at 6 months (mean, 31.9 [SD, 11.7] for digoxin vs 29.7 [11.4] for bisoprolol; adjusted mean difference, 1.4 [95% CI, −1.1 to 3.8]; P = .28). Of the 17 secondary outcomes at 6 months, there were no significant between-group differences for 16 outcomes, including resting heart rate (a mean of 76.9/min [SD, 12.1/min] with digoxin vs a mean of 74.8/min [SD, 11.6/min] with bisoprolol; difference, 1.5/min [95% CI, −2.0 to 5.1/min]; P = .40). The modified EHRA class was significantly different between groups at 6 months; 53% of patients in the digoxin group reported a 2-class improvement vs 9% of patients in the bisoprolol group (adjusted odds ratio, 10.3 [95% CI, 4.0 to 26.6]; P < .001). At 12 months, 8 of 20 outcomes were significantly different (all favoring digoxin), with a median NT-proBNP level of 960 pg/mL (interquartile range, 626 to 1531 pg/mL) in the digoxin group vs 1250 pg/mL (interquartile range, 847 to 1890 pg/mL) in the bisoprolol group (ratio of geometric means, 0.77 [95% CI, 0.64 to 0.92]; P = .005). Adverse events were less common with digoxin; 20 patients (25%) in the digoxin group had at least 1 AE vs 51 patients (64%) in the bisoprolol group (P < .001). There were 29 treatment-related AEs and 16 serious AEs in the digoxin group vs 142 and 37, ...