Nitric oxide (NO) donors inhibit sympathetic neurotransmission and baroreceptor activity and can directly stimulate heart rate (HR) in vitro. To assess whether exogenous NO affects cardiovascular autonomic control in humans, we tested the baroreceptor-cardiac reflex [baroreflex sensitivity (BRS)] and the arterial blood pressure (BP) and HR variability during an infusion of the NO donor sodium nitroprusside (SNP, 2 μg ⋅ kg −1 ⋅ min −1 ) or 5% glucose in 16 healthy subjects. The hypotensive action of SNP was prevented by phenylephrine (PE, 0.9 ± 0.15 μg ⋅ kg −1 ⋅ min −1 ). The SNP + PE infusion did not affect BRS or HR variability, but it caused a significant reduction in the diastolic and systolic BP low-frequency power. In addition, SNP + PE caused a sustained 12% increase in HR in the absence of changes in brachial and aortic BP. In conclusion, SNP had no effect on the cardiac-vagal limb of the baroreflex in humans but caused a substantial reduction in BP low-frequency power consistent with a decreased baroreflex/sympathetic control of peripheral resistance. The increase in HR in the absence of baroreceptor downloading confirms our previous finding of a direct positive chronotropic effect of NO donors.
Atrial fibrillation (AF) is the most common sustained arrhythmia, currently affecting over 33 million individuals worldwide, and its prevalence is expected to more than double over the next 40 years. AF is associated with a twofold increase in premature mortality, and important major adverse cardiovascular events such as heart failure, severe stroke and myocardial infarction. Significant effort has been made over a number of years to define the underlying cellular, molecular and electrophysiological changes that predispose to the induction and maintenance of AF in patients. Progress has been limited by the realisation that AF is a complex arrhythmia that can be the end result of various different pathophysiological processes, with significant heterogeneity between individual patients (and between species). In this focused Review article, we aim to succinctly summarise for the non-specialist the current state of knowledge regarding the mechanisms of AF. We address all aspects of pathophysiology, including the basic electrophysiological and structural changes within the left atrium, the genetics of AF and the links to comorbidities and wider systemic and metabolic perturbations that may be upstream contributors to development of AF. Finally, we outline the translational implications for current and future rhythm control strategies in patients with AF.
Women with Turner's syndrome (TS) have a threefold increase in mortality, primarily as a result of their cardiovascular complications. Recently, the risk of fatal aortic dissection has come to light as a major cause of mortality in women with TS. The aim of this study was to assess the prevalence of aortic root dilatation in a group of women with TS and to investigate the factors contributing to its development. Thirty-eight women with TS attending a dedicated adult Turner clinic were examined clinically and by M-mode and two-dimensional echocardiography on at least one occasion. Aortic root dilatation was defined as an aortic root diameter greater than the 95th centile for body surface area. Fasting serum lipid concentrations were measured in all women. Additionally, 18 subjects underwent noninvasive assessment of central arterial stiffness using applanation tonometry. Fifty percent of subjects were hypertensive and a similar number had an abnormal echocardiogram. A bicuspid aortic valve was present in 33% of subjects, 16 women (42%) had ascending aortic root dilatation. This was associated with a bicuspid aortic valve in four women and hypertension in 11. Two women had isolated aortic root dilatation. Aortic root diameter was significantly associated with systolic blood pressure (r = 0.5, P = 0.003) and left ventricular thickness (r = 0.5, P = 0.02). There was no association with serum lipids or arterial compliance. Structural cardiac abnormalities are present in up to 50% of women with Turner's syndrome. Aortic root dilatation is a significant risk in women with Turner's syndrome and is closely dependent on blood pressure. Aortic root dilatation does not appear to be related to atherosclerosis and is more likely to be due to a mesenchymal defect. Regular surveillance of the aortic root diameter is essential in all women with Turner's syndrome and hypertension should be treated aggressively when present in order to minimize the risk of potentially fatal aortic dissection.
Abstract Background Visceral obesity is directly linked to increased cardiovascular risk, including heart failure. Purpose We explored the ability of human epicardial adipose tissue (EAT)-derived microRNAs (miRNAs) to regulate the myocardial redox state and clinical outcomes. Methods The 5 study arms included 466 patients undergoing cardiac surgery to perform: 1) the discovery phase in which we screened for 351 miRNAs expressed and released from human EAT; 2) correlation analyses between EAT microRNAs and myocardial expression of their targets or myocardial superoxide production in paired EAT/atrial biopsies; 3) genome-wide association screening for miR-92a-3p expression in EAT to test causality/directionality; 4) ex vivo experiments to investigate the underlying mechanisms that were also studied in vitro and in vivo; 5) an 8-year follow-up study to test the prognostic value of the discovered miRNA. Superoxide (O2.-) generation was measured by lucigenin chemiluminescence with NADPH 100μM stimulation as indicator of NADPH-oxidases activity. Vas2870 400 μM (a specific pan-NADPH oxidase inhibitor) was used to obtain the Vas2870-inhibitable O2.- signal which constitutes a more specific index of NADPH oxidase activity. Activation of Rac1, a key NADPH-oxidases subunit, was evaluated by a commercially available kit. Differentiated H9c2 cells were used as an in vitro model of cardiomyocytes. Doxycycline-inducible Wnt5a-overexpressing mice were used for in vivo experiments. Results The EAT secretome profiling on study 1 patients led us to identify 3 microRNAs both expressed and released by EAT whose levels in EAT correlated with oxidative stress in human myocardium. Among these miRNAs only miR-92a-3p reduced NADPH-oxidase-derived superoxide (O2.-) in cardiomyocytes (A). A genetic screening identified 7 SNPs that were associated with high miR-92a-3p levels in EAT (EAT-miR-92a-3p SNPs) and were related to lower myocardial superoxide production (B). miR-92a-3p decreased both activation of Rac1 (not shown) and Wnt5a protein levels in vitro (C). Patients with high EAT miR-92a-3p levels had lower WNT5A levels in the myocardium (not shown). Ex vivo, in vivo and in vitro experiments showed opposite effects of Wnt5a on Rac1-mediated NADPH-oxidases activity (D and not shown). Finally, we found an association of miR-92a-3p levels in EAT with lower relative risk of adverse cardiovascular events (E). Conclusions EAT-derived miRNAs exert paracrine effects on the human heart. Indeed miR-92a-3p suppresses the Wnt5a/Rac1/NADPH oxidase axis and improves myocardial redox state. EAT-derived miR-92a-3p is related with improved clinical outcomes and is a rational therapeutic target for the prevention and treatment of obesity-related heart disease.
BACKGROUND: Several countries affected by the COVID-19 pandemic have reported a substantial drop in the number of patients attending the emergency department with acute coronary syndromes and a reduced number of cardiac procedures. We aimed to understand the scale, nature, and duration of changes to admissions for different types of acute coronary syndrome in England and to evaluate whether in-hospital management of patients has been affected as a result of the COVID-19 pandemic. METHODS: We analysed data on hospital admissions in England for types of acute coronary syndrome from Jan 1, 2019, to May 24, 2020, that were recorded in the Secondary Uses Service Admitted Patient Care database. Admissions were classified as ST-elevation myocardial infarction (STEMI), non-STEMI (NSTEMI), myocardial infarction of unknown type, or other acute coronary syndromes (including unstable angina). We identified revascularisation procedures undertaken during these admissions (ie, coronary angiography without percutaneous coronary intervention [PCI], PCI, and coronary artery bypass graft surgery). We calculated the numbers of weekly admissions and procedures undertaken; percentage reductions in weekly admissions and across subgroups were also calculated, with 95% CIs. FINDINGS: Hospital admissions for acute coronary syndrome declined from mid-February, 2020, falling from a 2019 baseline rate of 3017 admissions per week to 1813 per week by the end of March, 2020, a reduction of 40% (95% CI 37-43). This decline was partly reversed during April and May, 2020, such that by the last week of May, 2020, there were 2522 admissions, representing a 16% (95% CI 13-20) reduction from baseline. During the period of declining admissions, there were reductions in the numbers of admissions for all types of acute coronary syndrome, including both STEMI and NSTEMI, but relative and absolute reductions were larger for NSTEMI, with 1267 admissions per week in 2019 and 733 per week by the end of March, 2020, a percent reduction of 42% (95% CI 38-46). In parallel, reductions were recorded in the number of PCI procedures for patients with both STEMI (438 PCI procedures per week in 2019 vs 346 by the end of March, 2020; percent reduction 21%, 95% CI 12-29) and NSTEMI (383 PCI procedures per week in 2019 vs 240 by the end of March, 2020; percent reduction 37%, 29-45). The median length of stay among patients with acute coronary syndrome fell from 4 days (IQR 2-9) in 2019 to 3 days (1-5) by the end of March, 2020. INTERPRETATION: Compared with the weekly average in 2019, there was a substantial reduction in the weekly numbers of patients with acute coronary syndrome who were admitted to hospital in England by the end of March, 2020, which had been partly reversed by the end of May, 2020. The reduced number of admissions during this period is likely to have resulted in increases in out-of-hospital deaths and long-term complications of myocardial infarction and missed opportunities to offer secondary prevention treatment for patients with coronary heart disease. The full extent of the effect of COVID-19 on the management of patients with acute coronary syndrome will continue to be assessed by updating these analyses. FUNDING: UK Medical Research Council, British Heart Foundation, Public Health England, Health Data Research UK, and the National Institute for Health Research Oxford Biomedical Research Centre.
To assess the relative roles of neural and nonneural mechanisms in respiratory sinus arrhythmia (RSA) at rest and during exercise (steady-state supine cycle ergometry at 25% of peak oxygen uptake), we studied 10 healthy men (mean age 21 +/- 1 yr) before (control) and during ganglion blockade (GB) with trimetaphan camsylate (3-5 mg/min i.v.). GB was confirmed by the abolition of the reflex bradycardia in response to intravenous phenylephrine and of the blood pressure rise with the cold pressor test. RSA was calculated from the power of the spectral component of the R-R interval variability centered at the breathing frequency. GB decreased but did not abolish RSA. At rest, this nonneural component of RSA was negligible, accounting for < 1% of the control RSA. During GB, exercise did not affect RSA significantly. However, because control RSA was decreased by exercise, the proportion of nonneural RSA increased by 32% (range from 17 to 75%). These results indicate that as the vagal tone decreases with exercise, an increasing proportion of RSA is due to nonneural mechanisms.
Background—Sympathetic activation may limit exercise performance by restraining muscle blood flow or by negatively affecting skeletal muscle metabolic behavior. To test this hypothesis, we studied the effect of thoracoscopic sympathetic trunkotomy (TST) on forearm exercise duration, blood flow, and muscle bioenergetics in 13 patients with idiopathic palmar hyperhidrosis. Methods and Results—Heart rate and beat-by-beat mean arterial pressure were recorded at rest and during right and left rhythmic handgrip before and 4 to 7 weeks after right TST. Forearm blood flow was measured bilaterally at rest and on the right during exercise. Right forearm muscle phosphocreatine content and intracellular pH were assessed by 31phosphorus magnetic resonance spectroscopy. After right TST, exercise duration increased from 8.9±1.4 to 13.4±1.8 minutes (P<0.0001) with the right forearm and from 5.7±0.4 to 7.6±0.9 minutes (P<0.05) with the left (P<0.05 for the interaction between treatment and side). Right forearm blood flow ...
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