Telomeres, the end fragments of chromosomes, play key roles in cellular proliferation and senescence. Here we characterize the genetic architecture of naturally occurring variation in leukocyte telomere length (LTL) and identify causal links between LTL and biomedical phenotypes in 472,174 well-characterized UK Biobank participants. We identified 197 independent sentinel variants associated with LTL at 138 genomic loci (108 new). Genetically determined differences in LTL were associated with multiple biological traits, ranging from height to bone marrow function, as well as several diseases spanning neoplastic, vascular and inflammatory pathologies. Finally, we estimated that, at the age of 40 years, people with an LTL >1 s.d. shorter than the population mean had a 2.5-year-lower life expectancy compared with the group with ≥1 s.d. longer LDL. Overall, we furnish new insights into the genetic regulation of LTL, reveal wide-ranging influences of LTL on physiological traits, diseases and longevity, and provide a powerful resource available to the global research community.

Leukocyte telomere length (LTL) is a proposed marker of biological age. Here we report the measurement and initial characterization of LTL in 474,074 participants in UK Biobank. We confirm that older age and male sex associate with shorter LTL, with women on average ~7 years younger in "biological age" than men. Compared to white Europeans, LTL is markedly longer in African and Chinese ancestries. Older paternal 5 age at birth is associated with longer individual LTL. Higher white cell count is associated with shorter LTL, but proportions of white cell subtypes show weaker associations. Age, ethnicity, sex and white cell count explain ~5.5% of LTL variance. Using paired samples from 1,351 participants taken ~5 years apart, we estimate the within-individual variability in LTL and provide a correction factor for this. This resource provides opportunities to investigate determinants and biomedical consequences of variation in LTL.

Telomeres, the end fragments of chromosomes, play key roles in cellular proliferation and senescence. Here we characterize the genetic architecture of naturally-occurring variation in leucocyte telomere length (LTL) and identify causal links between LTL and biomedical phenotypes in 472,174 well-characterized participants in UK Biobank. We identified 197 independent sentinel variants associated with LTL at 138 genomic loci (108 novel). Genetically-determined differences in LTL were associated with multiple biological traits, ranging from height to bone marrow function, as well as several diseases spanning neoplastic, vascular, and inflammatory pathologies. Finally, we estimated that at age 40 years, people with >1-SD shorter compared to ≥1-SD longer LTL than the population mean had 2.5 years lower life expectancy. Overall, we furnish novel insights into the genetic regulation of LTL, reveal LTL's wide-ranging influences on physiological traits, diseases, and longevity, and provide a powerful resource available to the global research community.

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ObjectiveTo investigate percutaneous coronary intervention (PCI) practice in an international cohort of patients with spontaneous coronary artery dissection (SCAD). To explore factors associated with complications and study angiographic and longer term outcomes.MethodsSCAD patients (n=215, 94% female) who underwent PCI from three national cohort studies were investigated and compared with a matched cohort of conservatively managed SCAD patients (n=221).ResultsSCAD-PCI patients were high risk at presentation with only 8.8% undergoing PCI outside the context of ST-elevation myocardial infarction/cardiac arrest, thrombolysis in myocardial infarction (TIMI) 0/1 flow or proximal dissections. PCI complications occurred in 38.6% (83/215), with 13.0% (28/215) serious complications. PCI-related complications were associated with more extensive dissections (multiple vs single American Heart Association coronary segments, OR 1.9 (95% CI: 1.06–3.39),p=0.030), more proximal dissections (proximal diameter per mm, OR 2.25 (1.38–3.67), p=0.001) and dissections with no contrast penetration of the false lumen (Yip-Saw 2 versus 1, OR 2.89 (1.12–7.43), p=0.028). SCAD-PCI involved long lengths of stent (median 46mm, IQR: 29–61mm). Despite these risks, SCAD-PCI led to angiographic improvements in those with reduced TIMI flow in 84.3% (118/140). Worsening TIMI flow was only seen in 7.0% (15/215) of SCAD-PCI patients. Post-PCI major adverse cardiovascular and cerebrovascular events (MACCE) and left ventricular function outcomes were favourable.ConclusionWhile a conservative approach to revascularisation is favoured, SCAD cases with higher risk presentations may require PCI. SCAD-PCI is associated with longer stent lengths and a higher risk of complications but leads to overall improvements in coronary flow and good medium-term outcomes in patients.

Aims Most patients who receive implantable cardioverter defibrillators (ICDs) for primary prevention do not receive therapy during the lifespan of the ICD, whilst up to 50% of sudden cardiac death (SCD) occur in individuals who are considered low risk by conventional criteria. Machine learning offers a novel approach to risk stratification for ICD assignment. Methods and results Systematic search was performed in MEDLINE, Embase, Emcare, CINAHL, Cochrane Library, OpenGrey, MedrXiv, arXiv, Scopus, and Web of Science. Studies modelling SCD risk prediction within days to years using machine learning were eligible for inclusion. Transparency and quality of reporting (TRIPOD) and risk of bias (PROBAST) were assessed. A total of 4356 studies were screened with 11 meeting the inclusion criteria with heterogeneous populations, methods, and outcome measures preventing meta-analysis. The study size ranged from 122 to 124 097 participants. Input data sources included demographic, clinical, electrocardiogram, electrophysiological, imaging, and genetic data ranging from 4 to 72 variables per model. The most common outcome metric reported was the area under the receiver operator characteristic (n = 7) ranging between 0.71 and 0.96. In six studies comparing machine learning models and regression, machine learning improved performance in five. No studies adhered to a reporting standard. Five of the papers were at high risk of bias. Conclusion Machine learning for SCD prediction has been under-applied and incorrectly implemented but is ripe for future investigation. It may have some incremental utility in predicting SCD over traditional models. The development of reporting standards for machine learning is required to improve the quality of evidence reporting in the field.

Aims The optimal timing of an invasive strategy (IS) in non-ST-elevation acute coronary syndrome (NSTE-ACS) is controversial. Recent randomized controlled trials (RCTs) and long-term follow-up data have yet to be included in a contemporary meta-analysis. Methods and results A systematic review of RCTs that compared an early IS vs. delayed IS for NSTE-ACS was conducted by searching MEDLINE, Embase, and Cochrane Central Register of Controlled Trials. A meta-analysis was performed by pooling relative risks (RRs) using a random-effects model. The primary outcome was all-cause mortality. Secondary outcomes included myocardial infarction (MI), recurrent ischaemia, admission for heart failure (HF), repeat re-vascularization, major bleeding, stroke, and length of hospital stay. This study was registered with PROSPERO (CRD42021246131). Seventeen RCTs with outcome data from 10 209 patients were included. No significant differences in risk for all-cause mortality [RR: 0.90, 95% confidence interval (CI): 0.78–1.04], MI (RR: 0.86, 95% CI: 0.63–1.16), admission for HF (RR: 0.66, 95% CI: 0.43–1.03), repeat re-vascularization (RR: 1.04, 95% CI: 0.88–1.23), major bleeding (RR: 0.86, 95% CI: 0.68–1.09), or stroke (RR: 0.95, 95% CI: 0.59–1.54) were observed. Recurrent ischaemia (RR: 0.57, 95% CI: 0.40–0.81) and length of stay (median difference: −22 h, 95% CI: −36.7 to −7.5 h) were reduced with an early IS. Conclusion In all-comers with NSTE-ACS, an early IS does not reduce all-cause mortality, MI, admission for HF, repeat re-vascularization, or increase major bleeding or stroke when compared with a delayed IS. Risk of recurrent ischaemia and length of stay are significantly reduced with an early IS.