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.
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.
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.
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.
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.
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.
Abstract Constitutive nitric oxide synthases (NOSs) are ubiquitous enzymes that play a pivotal role in the regulation of myocardial function in health and disease. The discovery of both a neuronal ...NOS (nNOS) and an endothelial NOS (eNOS) isoform in the myocardium and the availability of genetically modified mice with selective eNOS or nNOS gene deletion have been of crucial importance for understanding the role of constitutive nitric oxide (NO) production in the myocardium. eNOS and nNOS are homologous in structure and utilize the same co-factors and substrates; however, they differ in their subcellular localization, regulation, and downstream signaling, all of which may account for their distinct effects on excitation–contraction coupling. In particular, eNOS-derived NO has been reported to increase left ventricular (LV) compliance, attenuate beta-adrenergic inotropy and enhance parasympathetic/muscarinic responses, and mediate the negative inotropic response to β3 adrenoreceptor stimulation via cGMP-dependent signaling. Conversely, nNOS-derived NO regulates basal myocardial inotropy and relaxation by inhibiting the sarcolemmal Ca2+ current ( ICa ) and promoting protein kinase A-dependent phospholamban (PLN) phosphorylation, independent of cGMP. By inhibiting the activity of myocardial oxidase systems, nNOS regulates the redox state of the myocardium and contributes to maintain eNOS “coupled” activity. After myocardial infarction, up-regulation of myocardial nNOS attenuates adverse remodeling and prevents arrhythmias whereas uncoupled eNOS activity in murine models of left ventricular pressure overload accelerates the progress towards heart failure. Here we review the evidence in support of the idea that NOS subcellular localization, mode of activation, and downstream signaling account for the diverse and highly specialized actions of NO in the heart. This article is part of a Special Issue entitled “Local Signaling in Myocytes”.
To investigate sex differences in acute myocardial infarction (AMI) guideline-indicated care as defined by the European Society of Cardiology (ESC) Acute Cardiovascular Care Association (ACCA) ...quality indicators.
Nationwide cohort study comprising 691 290 AMI hospitalisations in England and Wales (n=233 hospitals) from the Myocardial Ischaemia National Audit Project between 1 January 2003 and 30 June 2013.
There were 34.5% (n=238 489) women (median age 76.7 (IQR 66.3-84.0) years; 33.9% (n=80 884) ST-elevation myocardial infarction (STEMI)) and 65.5% (n=452 801) men (median age 67.1 (IQR 56.9-77.2) years; 42.5% (n=192 229) STEMI). Women less frequently received 13 of the 16 quality indicators compared with men, including timely reperfusion therapy for STEMI (76.8% vs 78.9%; p<0.001), timely coronary angiography for non-STEMI (24.2% vs 36.7%; p<0.001), dual antiplatelet therapy (75.4% vs 78.7%) and secondary prevention therapies (87.2% vs 89.6% for statins, 82.5% vs 85.6% for ACE inhibitor/angiotensin receptor blockers and 62.6% vs 67.6% for beta-blockers; all p<0.001). Median 30-day Global Registry of Acute Coronary Events risk score adjusted mortality was higher for women than men (median: 5.2% (IQR 1.8%-13.1%) vs 2.3% (IQR 0.8%-7.1%), p<0.001). An estimated 8243 (95% CI 8111 to 8375) deaths among women could have been prevented over the study period if their quality indicator attainment had been equal to that attained by men.
According to the ESC ACCA AMI quality indicators, women in England and Wales less frequently received guideline-indicated care and had significantly higher mortality than men. Greater attention to the delivery of recommended AMI treatments for women has the potential to reduce the sex-AMI mortality gap.
There are concerns that the COVID-19 pandemic has had a negative effect on cancer care but there is little direct evidence to quantify any effect. This study aims to investigate the impact of the ...COVID-19 pandemic on the detection and management of colorectal cancer in England.
Data were extracted from four population-based datasets spanning NHS England (the National Cancer Cancer Waiting Time Monitoring, Monthly Diagnostic, Secondary Uses Service Admitted Patient Care and the National Radiotherapy datasets) for all referrals, colonoscopies, surgical procedures, and courses of rectal radiotherapy from Jan 1, 2019, to Oct 31, 2020, related to colorectal cancer in England. Differences in patterns of care were investigated between 2019 and 2020. Percentage reductions in monthly numbers and proportions were calculated.
As compared to the monthly average in 2019, in April, 2020, there was a 63% (95% CI 53–71) reduction (from 36 274 to 13 440) in the monthly number of 2-week referrals for suspected cancer and a 92% (95% CI 89–95) reduction in the number of colonoscopies (from 46 441 to 3484). Numbers had just recovered by October, 2020. This resulted in a 22% (95% CI 8–34) relative reduction in the number of cases referred for treatment (from a monthly average of 2781 in 2019 to 2158 referrals in April, 2020). By October, 2020, the monthly rate had returned to 2019 levels but did not exceed it, suggesting that, from April to October, 2020, over 3500 fewer people had been diagnosed and treated for colorectal cancer in England than would have been expected. There was also a 31% (95% CI 19–42) relative reduction in the numbers receiving surgery in April, 2020, and a lower proportion of laparoscopic and a greater proportion of stoma-forming procedures, relative to the monthly average in 2019. By October, 2020, laparoscopic surgery and stoma rates were similar to 2019 levels. For rectal cancer, there was a 44% (95% CI 17–76) relative increase in the use of neoadjuvant radiotherapy in April, 2020, relative to the monthly average in 2019, due to greater use of short-course regimens. Although in June, 2020, there was a drop in the use of short-course regimens, rates remained above 2019 levels until October, 2020.
The COVID-19 pandemic has led to a sustained reduction in the number of people referred, diagnosed, and treated for colorectal cancer. By October, 2020, achievement of care pathway targets had returned to 2019 levels, albeit with smaller volumes of patients and with modifications to usual practice. As pressure grows in the NHS due to the second wave of COVID-19, urgent action is needed to address the growing burden of undetected and untreated colorectal cancer in England.
Cancer Research UK, the Medical Research Council, Public Health England, Health Data Research UK, NHS Digital, and the National Institute for Health Research Oxford Biomedical Research Centre.
The recent discovery of a NOS1 gene product (i.e. a neuronal-like isoform of nitric oxide synthase or nNOS) in the mammalian
left ventricular (LV) myocardium has provided a new key for the ...interpretation of the complex experimental evidence supporting
a role for myocardial constitutive nitric oxide (NO) production in the regulation of basal and β-badrenergic cardiac function.
Importantly, nNOS gene deletion has been associated with more severe LV remodelling and functional deterioration in murine
models of myocardial infarction, suggesting that nNOS-derived NO may also be involved in the myocardial response to injury.
To date, the mechanisms by which nNOS influences myocardial pathophysiology remain incompletely understood. In particular,
it seems over simplistic to assume that all aspects of the myocardial phenotype of nNOS knockout (nNOS â/â ) mice are a direct consequence of lack of NO production from this source. Emerging data showing co-localisation of xanthine
oxidoreductase (XOR) and nNOS in the sarcoplasmic reticulum of rodents, and increased XOR activity in the nNOS â/â myocardium, suggest that nNOS gene deletion may have wider implications on the myocardial redox state. Similarly, the mechanisms
regulating the targeting of myocardial nNOS to different subcellular compartments and the functional consequences of intracellular
nNOS trafficking have not been fully established. Whether this information could be translated into a better understanding
and management of human heart failure remains the most important challenge for future investigations.
Oxidative stress plays a critical role in the vascular complications of type 2 diabetes. We examined the effect of type 2 diabetes on NADPH oxidase in human vessels and explored the mechanisms of ...this interaction. Segments of internal mammary arteries (IMAs) with their perivascular adipose tissue (PVAT) and thoracic adipose tissue were obtained from 386 patients undergoing coronary bypass surgery (127 with type 2 diabetes). Type 2 diabetes was strongly correlated with hypoadiponectinemia and increased vascular NADPH oxidase-derived superoxide anions (O2˙(-)). The genetic variability of the ADIPOQ gene and circulating adiponectin (but not interleukin-6) were independent predictors of NADPH oxidase-derived O2˙(-). However, adiponectin expression in PVAT was positively correlated with vascular NADPH oxidase-derived O2˙(-). Recombinant adiponectin directly inhibited NADPH oxidase in human arteries ex vivo by preventing the activation/membrane translocation of Rac1 and downregulating p22(phox) through a phosphoinositide 3-kinase/Akt-mediated mechanism. In ex vivo coincubation models of IMA/PVAT, the activation of arterial NADPH oxidase triggered a peroxisome proliferator-activated receptor-γ-mediated upregulation of the adiponectin gene in the neighboring PVAT via the release of vascular oxidation products. We demonstrate for the first time in humans that reduced adiponectin levels in individuals with type 2 diabetes stimulates vascular NADPH oxidase, while PVAT "senses" the increased NADPH oxidase activity in the underlying vessel and responds by upregulating adiponectin gene expression. This PVAT-vessel interaction is identified as a novel therapeutic target for the prevention of vascular complications of type 2 diabetes.
Health information technology can support the development of national learning health and care systems, which can be defined as health and care systems that continuously use data-enabled ...infrastructure to support policy and planning, public health, and personalisation of care. The COVID-19 pandemic has offered an opportunity to assess how well equipped the UK is to leverage health information technology and apply the principles of a national learning health and care system in response to a major public health shock. With the experience acquired during the pandemic, each country within the UK should now re-evaluate their digital health and care strategies. After leaving the EU, UK countries now need to decide to what extent they wish to engage with European efforts to promote interoperability between electronic health records. Major priorities for strengthening health information technology in the UK include achieving the optimal balance between top-down and bottom-up implementation, improving usability and interoperability, developing capacity for handling, processing, and analysing data, addressing privacy and security concerns, and encouraging digital inclusivity. Current and future opportunities include integrating electronic health records across health and care providers, investing in health data science research, generating real-world data, developing artificial intelligence and robotics, and facilitating public–private partnerships. Many ethical challenges and unintended consequences of implementation of health information technology exist. To address these, there is a need to develop regulatory frameworks for the development, management, and procurement of artificial intelligence and health information technology systems, create public–private partnerships, and ethically and safely apply artificial intelligence in the National Health Service.
Adiponectin is an adipokine with potentially important roles in human cardiovascular disease states. We studied the role of adiponectin in the cross-talk between adipose tissue and vascular redox ...state in patients with atherosclerosis.
The study included 677 patients undergoing coronary artery bypass graft surgery. Endothelial function was evaluated by flow-mediated dilation of the brachial artery in vivo and by vasomotor studies in saphenous vein segments ex vivo. Vascular superoxide (O2(-)) and endothelial nitric oxide synthase (eNOS) uncoupling were quantified in saphenous vein and internal mammary artery segments. Local adiponectin gene expression and ex vivo release were quantified in perivascular (saphenous vein and internal mammary artery) subcutaneous and mesothoracic adipose tissue from 248 patients. Circulating adiponectin was independently associated with nitric oxide bioavailability and O2(-) production/eNOS uncoupling in both arteries and veins. These findings were supported by a similar association between functional polymorphisms in the adiponectin gene and vascular redox state. In contrast, local adiponectin gene expression/release in perivascular adipose tissue was positively correlated with O2(-) and eNOS uncoupling in the underlying vessels. In ex vivo experiments with human saphenous veins and internal mammary arteries, adiponectin induced Akt-mediated eNOS phosphorylation and increased tetrahydrobiopterin bioavailability, improving eNOS coupling. In ex vivo experiments with human saphenous veins/internal mammary arteries and adipose tissue, we demonstrated that peroxidation products produced in the vascular wall (ie, 4-hydroxynonenal) upregulate adiponectin gene expression in perivascular adipose tissue via a peroxisome proliferator-activated receptor-γ-dependent mechanism.
We demonstrate for the first time that adiponectin improves the redox state in human vessels by restoring eNOS coupling, and we identify a novel role of vascular oxidative stress in the regulation of adiponectin expression in human perivascular adipose tissue.
PDF
