Ulrik Wisløff

Aims Resting heart rate (RHR) is associated with cardiovascular disease (CVD) and mortality. This study aimed to identify genetic loci associated with RHR, develop a genome-wide polygenic risk score (PRS) for RHR, and assess associations between the RHR PRS and CVD outcomes, to better understand the biological mechanisms linking RHR to disease. Sex-specific analyses were conducted to potentially elucidate different pathways between the sexes. Methods and results We performed a genome-wide meta-analysis of RHR (n = 550 467) using two independent study populations, The Trøndelag Health Study (HUNT) and the UK Biobank (UKB), comprising 69 155 and 481 312 participants, respectively. We also developed a genome-wide PRS for RHR using UKB and tested for association between the PRS and 13 disease outcomes in HUNT. We identified 403, 253, and 167 independent single nucleotide polymorphisms (SNPs) significantly associated with RHR in the total population, women, and men, respectively. The sex-specified analyses indicated differences in the genetic contribution to RHR and revealed loci significantly associated with RHR in only one of the sexes. The SNPs were mapped to genes enriched in heart tissue and cardiac conduction pathways, as well as disease-pathways, including dilated cardiomyopathy. The PRS for RHR was associated with increased risk of hypertension and dilated cardiomyopathy, and decreased risk of atrial fibrillation. Conclusion Our findings provide insight into the pleiotropic effects of the RHR variants, contributing towards an improved understanding of mechanisms linking RHR and disease. In addition, the sex-specific results might contribute to a more refined understanding of RHR as a risk factor for the different diseases.

Aims Left atrial (LA) and ventricular (LV) remodelling is thought to be balanced in healthy individuals, and the LA end-systolic volume (LAV) to LV end-diastolic volume (LVEDV) ratio (LA:LV) could help discriminate between pathological and physiological LA enlargement. We aimed to assess LA:LV and its associations with age, sex, and cardiovascular risk factors HbA1C, body mass index (BMI), systolic blood pressure, and peak oxygen uptake (VO2peak). The association to measures of LV diastolic function and filling pressures were compared with LAV and LA reservoir strain. Methods and results Cardiopulmonary exercise testing and measurement of risk factors 10 years apart and echocardiography at follow-up was performed in 1348 healthy adults [52% women, mean (SD) age 59 (12) years] prospectively included in a large population study. All risk factors were significantly associated with LA:LV in univariate analyses, while BMI and VO2peak were significantly associated with LA:LV in adjusted models. A higher LA:LV was associated with increased odds ratio (OR) of diastolic dysfunction [OR (95% CI) 2.6 (2.1, 3.3)]. Measures of LV filling pressures were more closely associated with LA:LV than LAV and LA reservoir strain, but LA reservoir strain was more closely related to some diastolic function measures. In individuals with LAV > 34 mL/m2, the LA:LV explained 29% of variance in VO2peak (P < 0.001). Conclusion A higher LA:LV was associated with, and may improve, assessment of diastolic dysfunction and filling pressures. The LA:LV differentiates VO2peak in individuals with enlarged LAV and may have a role in evaluating whether LA enlargement reflects pathology.