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Cardiovascular disease is the leading cause of mortality worldwide, affecting a wide range of patients at different stages across the cardiovascular continuum. Hypertension is one of the earliest risk factors in this continuum and can be controlled in most patients with currently available antihypertensive agents. However, goals are often not met because treatments are not optimized in terms of tailoring therapy to individual patients based on their hypertension subclass and cardiovascular risk profile and initiating early use of adapted-dose, single-pill combinations. In this context, beta-blockers in combination with angiotensin-converting enzyme (ACE) inhibitors are of special interest as a result of their complementary actions on the sympathetic nervous system and renin–angiotensin–aldosterone system, two interlinked pathways that influence cardiovascular risk and disease outcomes. In addition to their antihypertensive actions, beta-blockers are used to manage arrhythmias and treat angina pectoris and heart failure, while ACE inhibitors provide cardioprotection in patients with acute coronary syndromes and treat congestive heart failure. A broad range of patients may therefore receive the combination in routine clinical practice. This paper examines the supporting evidence for beta-blockers and ACE inhibitors in each of the above indications and considers the rationale for combining these agents into a single pill, using data from bisoprolol and perindopril randomized controlled trials as supporting evidence. Combining these established antihypertensive agents into a single pill continues to provide effective blood pressure lowering and improved cardiovascular outcomes while allowing a greater proportion of patients to rapidly achieve treatment targets.

Background Participants in clinical research studies often do not reflect the populations for which healthcare interventions are needed or will be used. Enhancing representation of under-served groups in clinical research is important to ensure that research findings are widely applicable. We describe a multicomponent workstream project to improve representation of under-served groups in clinical trials. Methods The project comprised three main strands: (1) a targeted scoping review of literature to identify previous work characterising under-served groups and barriers to inclusion, (2) surveys of professional stakeholders and participant representative groups involved in research delivery to refine these initial findings and identify examples of innovation and good practice and (3) a series of workshops bringing together key stakeholders from funding, design, delivery and participant groups to reach consensus on definitions, barriers and a strategic roadmap for future work. The work was commissioned by the UK National Institute for Health Research Clinical Research Network. Output from these strands was integrated by a steering committee to generate a series of goals, workstream plans and a strategic roadmap for future development work in this area. Results ‘Under-served groups’ was identified and agreed by the stakeholder group as the preferred term. Three-quarters of stakeholders felt that a clear definition of under-served groups did not currently exist; definition was challenging and context-specific, but exemplar groups (e.g. those with language barriers or mental illness) were identified as under-served. Barriers to successful inclusion of under-served groups could be clustered into communication between research teams and participant groups; how trials are designed and delivered, differing agendas of research teams and participant groups; and lack of trust in the research process. Four key goals for future work were identified: building long-term relationships with under-served groups, developing training resources to improve design and delivery of trials for under-served groups, developing infrastructure and systems to support this work and working with funders, regulators and other stakeholders to remove barriers to inclusion. Conclusions The work of the INCLUDE group over the next 12 months will build on these findings by generating resources customised for different under-served groups to improve the representativeness of trial populations.

We tested whether genetic factors distinctly contribute to either development of coronary atherosclerosis or, specifically, to myocardial infarction in existing coronary atherosclerosis. We did two genome-wide association studies (GWAS) with coronary angiographic phenotyping in participants of European ancestry. To identify loci that predispose to angiographic coronary artery disease (CAD), we compared individuals who had this disorder (n=12 393) with those who did not (controls, n=7383). To identify loci that predispose to myocardial infarction, we compared patients who had angiographic CAD and myocardial infarction (n=5783) with those who had angiographic CAD but no myocardial infarction (n=3644). In the comparison of patients with angiographic CAD versus controls, we identified a novel locus, ADAMTS7 (p=4·98×10 −13). In the comparison of patients with angiographic CAD who had myocardial infarction versus those with angiographic CAD but no myocardial infarction, we identified a novel association at the ABO locus (p=7·62×10 −9). The ABO association was attributable to the glycotransferase-deficient enzyme that encodes the ABO blood group O phenotype previously proposed to protect against myocardial infarction. Our findings indicate that specific genetic predispositions promote the development of coronary atherosclerosis whereas others lead to myocardial infarction in the presence of coronary atherosclerosis. The relation to specific CAD phenotypes might modify how novel loci are applied in personalised risk assessment and used in the development of novel therapies for CAD. The PennCath and MedStar studies were supported by the Cardiovascular Institute of the University of Pennsylvania, by the MedStar Health Research Institute at Washington Hospital Center and by a research grant from GlaxoSmithKline. The funding and support for the other cohorts contributing to the paper are described in the webappendix.

AimsACE inhibition reduces mortality and morbidity in patients with heart failure after acute myocardial infarction (AMI). However, there are limited randomised data about the long-term survival benefits of ACE inhibition in this population.MethodsIn 1993, the Acute Infarction Ramipril Efficacy (AIRE) study randomly allocated patients with AMI and clinical heart failure to ramipril or placebo. The duration of masked trial therapy in the UK cohort (603 patients, mean age=64.7 years, 455 male patients) was 12.4 and 13.4 months for ramipril (n=302) and placebo (n=301), respectively. We estimated life expectancy and extensions of life (difference in median survival times) according to duration of follow-up (range 0–29.6 years).ResultsBy 9 April 2019, death from all causes occurred in 266 (88.4%) patients in placebo arm and 275 (91.1%) patients in ramipril arm. The extension of life between ramipril and placebo groups was 14.5 months (95% CI 13.2 to 15.8). Ramipril increased life expectancy more for patients with than without diabetes (life expectancy difference 32.1 vs 5.0 months), previous AMI (20.1 vs 4.9 months), previous heart failure (19.5 vs 4.9 months), hypertension (16.6 vs 8.3 months), angina (16.2 vs 5.0 months) and age >65 years (11.3 vs 5.7 months). Given potential treatment switching, the true absolute treatment effect could be underestimated by 28%.ConclusionFor patients with clinically defined heart failure following AMI, ramipril results in a sustained survival benefit, and is associated with an extension of life of up to 14.5 months for, on average, 13 months treatment duration.

ObjectiveTo study the association of cardiac rehabilitation and physical activity with temporal changes in health-related quality of life (HRQoL) following acute myocardial infarction (AMI).MethodsEvaluation of the Methods and Management of Acute Coronary Events-3 is a nationwide longitudinal prospective cohort study of 4570 patients admitted with an AMI between 1 November 2011 and 17 September 2013. HRQoL was estimated using EuroQol 5-Dimension-3 Level Questionnaire at hospitalisation, 30 days, and 6 and 12 months following hospital discharge. The association of cardiac rehabilitation and self-reported physical activity on temporal changes in HRQoL was quantified using inverse probability of treatment weighting propensity score and multilevel regression analyses.ResultsCardiac rehabilitation attendees had higher HRQoL scores than non-attendees at 30 days (mean EuroQol 5-Visual Analogue Scale (EQ-VAS) scores: 71.0 (SD 16.8) vs 68.6 (SD 19.8)), 6 months (76.0 (SD 16.4) vs 70.2 (SD 19.0)) and 12 months (76.9 (SD 16.8) vs 70.4 (SD 20.4)). Attendees who were physically active ≥150 min/week had higher HRQoL scores compared with those who only attended cardiac rehabilitation at 30 days (mean EQ-VAS scores: 79.3 (SD 14.6) vs 70.2 (SD 17.0)), 6 months (82.2 (SD 13.9) vs 74.9 (SD 16.7)) and 12 months (84.1 (SD 12.1) vs 75.6 (SD 17.0)). Cardiac rehabilitation and self-reported physical activity of ≥150 min/week were each positively associated with temporal improvements in HRQoL (coefficient: 2.12 (95% CI 0.68 to 3.55) and 4.75 (95% CI 3.16 to 6.34), respectively).ConclusionsCardiac rehabilitation was independently associated with temporal improvements in HRQoL at up to 12 months following hospitalisation, with such changes further improved in patients who were physically active.

Peter Donnelly and colleagues report fine mapping of 14 susceptibility loci in 8,000 cases and controls for type 2 diabetes, coronary artery disease and Graves' disease. They apply a new Bayesian method for analysis of fine-mapping data sets, using this to define sets of SNPs likely to contain causal disease-associated variants. To further investigate susceptibility loci identified by genome-wide association studies, we genotyped 5,500 SNPs across 14 associated regions in 8,000 samples from a control group and 3 diseases: type 2 diabetes (T2D), coronary artery disease (CAD) and Graves' disease. We defined, using Bayes theorem, credible sets of SNPs that were 95% likely, based on posterior probability, to contain the causal disease-associated SNPs. In 3 of the 14 regions, TCF7L2 (T2D), CTLA4 (Graves' disease) and CDKN2A - CDKN2B (T2D), much of the posterior probability rested on a single SNP, and, in 4 other regions ( CDKN2A - CDKN2B (CAD) and CDKAL1 , FTO and HHEX (T2D)), the 95% sets were small, thereby excluding most SNPs as potentially causal. Very few SNPs in our credible sets had annotated functions, illustrating the limitations in understanding the mechanisms underlying susceptibility to common diseases. Our results also show the value of more detailed mapping to target sequences for functional studies.

Background The ‘My Experience of Taking Medicines’ (MYMEDS) questionnaire is a self-reporting tool for identifying modifiable adherence barriers among individuals prescribed post-myocardial infarction (MI) secondary prevention medicines (SPM) in clinical practice. It was found to be a useful tool to support the conduction of patient-centred consultation in cardiology outpatient leading to improved outcomes including better adherence to SPM and patient satisfaction. This study describes the rationale and development of the MYMEDS tool, its performance and usefulness in identifying modifiable barriers to adherence in cardiology medical practice including user feedback of 204 consecutive post-MI patients who completed an evaluation based on MYMEDS. Methods Modifiable non-adherence factors were initially identified based on literature review and stakeholder feedback. A draft MYMEDS questionnaire was piloted in 10 patients and adapted accordingly. The final version comprises six sections, covering current medicines, understanding and satisfaction with medicines, concerns about medicines, practical adherence barriers, fitting medicines into daily routine, and adherence to individual SPMs. The questionnaire was mailed to post-MI patients who then attended an outpatient medicines optimisation clinic. Results Mean age was 70.5 years and 67.6% were male. The tool was effective in revealing modifiable adherence barriers that could be addressed during the consultation. There were high rates of concern that SPMs could be harmful (33.2%) or overprescribed (43.2%), practical issues with swallowing medicines (8.2%), opening packaging (7.3%) or accessing repeat prescriptions (5.2%), forgetfulness (19.7%), and concerns about inconvenience (13.5%). Mean number of barriers per patient was 1.8 ± 1.5. The medications most commonly associated with non-adherence were statins (21.5%), angiotensin II receptor blockers (21.1%), and antiplatelet agents (18.5%). In total, 42.5% of patients acknowledged non-adherence behaviour. Patient feedback on MYMEDS was positive, with near-unanimous agreement that it was simple, clear and not too long, and that it enabled them to raise any concerns they had about their medicines. Patients reported that their individual medicines related needs were better addressed. Conclusions MYMEDS is a practical tool that can successfully identify modifiable barriers to SPM adherence which can be addressed in a clinical setting. It can be easily rolled out in daily clinical practice to enable individualised person-centred medicines optimisation consultation.

Two private, heterozygous mutations in two functionally related genes, GUCY1A3 and CCT7 , are identified in an extended family with myocardial infarction; these genes encode proteins that work together to inhibit platelet activation after nitric oxide stimulation, suggesting a link between impaired nitric oxide signalling and myocardial infarction risk. Signal failure raises cardiac disease risk Next-generation sequencing in families with multiple affected individuals has revolutionized the identification of rare and private (single family or limited group) mutations. Here, the authors identify two private, heterozygous mutations in two functionally related genes, GUCY1A3 and CCT7 , in an extended family with myocardial infarction. The products of these genes work together to induce vasodilation and inhibit platelet activation upon stimulation with nitric oxide. Starting with a severely affected family, this work identifies a link between impaired nitric oxide signalling and myocardial infarction risk, possibly through accelerated thrombus formation. Reversal of this signalling defect may provide a new therapeutic strategy for reducing the risk of myocardial infarction. Myocardial infarction, a leading cause of death in the Western world 1 , usually occurs when the fibrous cap overlying an atherosclerotic plaque in a coronary artery ruptures. The resulting exposure of blood to the atherosclerotic material then triggers thrombus formation, which occludes the artery 2 . The importance of genetic predisposition to coronary artery disease and myocardial infarction is best documented by the predictive value of a positive family history 3 . Next-generation sequencing in families with several affected individuals has revolutionized mutation identification 4 . Here we report the segregation of two private, heterozygous mutations in two functionally related genes, GUCY1A3 (p.Leu163Phefs*24) and CCT7 (p.Ser525Leu), in an extended myocardial infarction family. GUCY1A3 encodes the α1 subunit of soluble guanylyl cyclase (α1-sGC) 5 , and CCT7 encodes CCTη, a member of the tailless complex polypeptide 1 ring complex 6 , which, among other functions, stabilizes soluble guanylyl cyclase. After stimulation with nitric oxide, soluble guanylyl cyclase generates cGMP, which induces vasodilation and inhibits platelet activation 7 . We demonstrate in vitro that mutations in both GUCY1A3 and CCT7 severely reduce α1-sGC as well as β1-sGC protein content, and impair soluble guanylyl cyclase activity. Moreover, platelets from digenic mutation carriers contained less soluble guanylyl cyclase protein and consequently displayed reduced nitric-oxide-induced cGMP formation. Mice deficient in α1-sGC protein displayed accelerated thrombus formation in the microcirculation after local trauma. Starting with a severely affected family, we have identified a link between impaired soluble-guanylyl-cyclase-dependent nitric oxide signalling and myocardial infarction risk, possibly through accelerated thrombus formation. Reversing this defect may provide a new therapeutic target for reducing the risk of myocardial infarction.