Advancing drug development for atrial fibrillation by prioritising findings from human genetic association studies.

BACKGROUND: Drug development for atrial fibrillation (AF) has failed to yield new approved compounds. We sought to identify and prioritise potential druggable targets with support from human genetics, by integrating the available evidence with bioinformatics sources relevant for AF drug development. METHODS: Genetic hits for AF and related traits were identified through structured search of MEDLINE. Genes derived from each paper were cross-referenced with the OpenTargets platform for drug interactions. Confirmation/validation was demonstrated through structured searches and review of evidence on MEDLINE and ClinialTrials.gov for each drug and its association with AF. FINDINGS: 613 unique drugs were identified, with 21 already included in AF Guidelines. Cardiovascular drugs from classes not currently used for AF (e.g. ranolazine and carperitide) and anti-inflammatory drugs (e.g. dexamethasone and mehylprednisolone) had evidence of potential benefit. Further targets were considered druggable but remain open for drug development. INTERPRETATION: Our systematic approach, combining evidence from different bioinformatics platforms, identified drug repurposing opportunities and druggable targets for AF. FUNDING: KK is supported by Barts Charity grant G-002089 and is mentored on the AFGen 2023-24 Fellowship funded by the AFGen NIH/NHLBI grant R01HL092577. RP is supported by the UCL BHF Research Accelerator AA/18/6/34223 and NIHR grant NIHR129463. AFS is supported by the BHF grants PG/18/5033837, PG/22/10989 and UCL BHF Accelerator AA/18/6/34223 as well as the UK Research and Innovation (UKRI) under the UK government's Horizon Europe funding guarantee EP/Z000211/1 and by the UKRI-NIHR grant MR/V033867/1 for the Multimorbidity Mechanism and Therapeutics Research Collaboration. AF is supported by UCL BHF Accelerator AA/18/6/34223. CF is supported by UCL BHF Accelerator AA/18/6/34223.

Long-term incidence and risk factors of cardiovascular events in Asian populations: systematic review and meta-analysis of population-based cohort studies.

BACKGROUND: Scientific studies on cardiovascular disease (CVD) burden and risk factors are predominantly based on short-term risk in Westerner populations, and such information may not be applicable to Asian populations, especially over the longer term. This review aims to estimate the long-term (>10 years) CVD burden, including coronary heart disease (CHD) and stroke, as well as associated risk factors in Asian populations. METHODS: PubMed, Embase and Web of Science were systematically searched, and hits screened on: Asian adults, free of CVD at baseline; cohort study design (follow-up >10 years). Primary outcomes were fatal and non-fatal CVD events. Pooled estimates and between-study heterogeneity were calculated using random effects models, Q and I2 statistics. RESULTS: Overall, 32 studies were eligible for inclusion (follow-up: 11-29 years). The average long-term rate of fatal CVD is 3.68 per 1000 person-years (95% CI 2.84-4.53), the long-term cumulative risk 6.35% (95% CI 4.69%-8.01%, mean 20.13 years) and the cumulative fatal stroke/CHD risk ratio 1.5:1. Important risk factors for long-term fatal CVD (RR, 95% CI) were male gender (1.49, 1.36-1.64), age over 60/65 years (7.55, 5.59-10.19) and current smoking (1.68, 1.26-2.24). High non-HDL-c, and ß- and γ-tocopherol serum were associated only with CHD (HR 2.46 [95% CI 1.29-4.71] and 2.47 [1.10-5.61] respectively), while stage 1 and 2 hypertensions were associated only with fatal stroke (2.02 [1.19-3.44] and 2.89 [1.68-4.96] respectively). CONCLUSIONS: Over a 10 year + follow-up period Asian subjects had a higher risk of stroke than CHD. Contrary to CVD prevention in Western countries, strategies should also consider stroke instead of CHD only.