IMPORTANCE It has been hypothesized that angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs) may make patients more susceptible to coronavirus disease 2019 and to worse outcomes through upregulation of the functional receptor of the virus, angiotensin-converting enzyme 2.OBJECTIVE To examine whether use of ACEI/ARBs was associated with COVID-19 diagnosis and worse outcomes in patients with COVID-19. DESIGN, SETTING, AND PARTICIPANTSTo examine outcomes among patients with COVID-19, a retrospective cohort study using data from Danish national administrative registries was conducted. Patients with COVID-19 from February 22 to May 4, 2020, were identified using ICD-10 codes and followed up from day of diagnosis to outcome or end of study period (May 4, 2020). To examine susceptibility to COVID-19, a Cox regression model with a nested case-control framework was used to examine the association between use of ACEI/ARBs vs other antihypertensive drugs and the incidence rate of a COVID-19 diagnosis in a cohort of patients with hypertension from February 1 to May 4, 2020.EXPOSURES ACEI/ARB use was defined as prescription fillings 6 months prior to the index date. MAIN OUTCOMES AND MEASURESIn the retrospective cohort study, the primary outcome was death, and a secondary outcome was a composite outcome of death or severe COVID-19. In the nested case-control susceptibility analysis, the outcome was COVID-19 diagnosis. RESULTSIn the retrospective cohort study, 4480 patients with COVID-19 were included (median age, 54.7 years [interquartile range, 40.9-72.0]; 47.9% men). There were 895 users (20.0%) of ACEI/ARBs and 3585 nonusers (80.0%). In the ACEI/ARB group, 18.1% died within 30 days vs 7.3% in the nonuser group, but this association was not significant after adjustment for age, sex, and medical history (adjusted hazard ratio [HR], 0.83 [95% CI, 0.67-1.03]). Death or severe COVID-19 occurred in 31.9% of ACEI/ARB users vs 14.2% of nonusers by 30 days (adjusted HR, 1.04 [95% CI, 0.89-1.23]). In the nested case-control analysis of COVID-19 susceptibility, 571 patients with COVID-19 and prior hypertension (median age, 73.9 years; 54.3% men) were compared with 5710 age-and sex-matched controls with prior hypertension but not COVID-19. Among those with COVID-19, 86.5% used ACEI/ARBs vs 85.4% of controls; ACEI/ARB use compared with other antihypertensive drugs was not significantly associated with higher incidence of COVID-19 (adjusted HR, 1.05 [95% CI, 0.80-1.36]). CONCLUSIONS AND RELEVANCEPrior use of ACEI/ARBs was not significantly associated with COVID-19 diagnosis among patients with hypertension or with mortality or severe disease among patients diagnosed as having COVID-19. These findings do not support discontinuation of ACEI/ARB medications that are clinically indicated in the context of the COVID-19 pandemic.

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AimsHeart failure (HF) is increasingly prevalent among the growing number of elderly people, but not well studied. We sought to evaluate disease pattern and importance of prognostic factors among very elderly patients with HF. Methods and resultsAmong 8507 patients screened for entry into two studies on HF, we analysed the clinical characteristics, major comorbidities and prognostic factors in 825 patients older than 85 years (very elderly) compared with younger age groups. Adjusted hazard ratios [HR (95% confidence intervals)] of long-term mortality were calculated using Cox models. The very elderly were more often female (60 vs. 26%) and had a higher prevalence of preserved ejection fraction (53 vs. 36%) compared with patients younger than 65 years (P , 0.001). The prevalence of cardiovascular comorbidities increased with advancing age only until the seventh decade and then declined, resulting in the lowest prevalence of diabetes (12 vs. 16%, P , 0.001), hypertension (20 vs. 26%, P , 0.001), ischaemic heart disease (42 vs. 53%, P , 0.001), and peripheral artery disease (4 vs. 6%, P ¼ 0.017) among the very elderly compared with patients aged ,85 years. Non-cardiovascular comorbidities generally increased linearly with age. Long-term mortality was associated with atrial fibrillation [HR ¼ 1.30 (1.06-1.60), P ¼ 0.013] with greater prognostic importance in the very elderly, while ejection fraction, diabetes [HR ¼ 1.31 (1.01-1.61), P ¼ 0.04], and renal insufficiency [HR ¼ 1.36 (1.13-0.63), P , 0.0001] had less prognostic importance than in younger patients (P for interactions ,0.003). ConclusionThe prevalence of cardiovascular comorbidities is lower in very elderly HF patients and has different prognostic importance.--

BackgroundPhysical activity is associated with several health benefits, including lower cardiovascular disease risk. The independent influence of physical activity on cardiac and vascular function in the community, however, has been sparsely investigated.Measures and ResultsWe related objective measures of moderate‐ to vigorous‐intensity physical activity (MVPA, assessed by accelerometry) to cardiac and vascular indices in 2376 participants of the Framingham Heart Study third generation cohort (54% women, mean age 47 years). Using multivariable regression models, we related MVPA to the following echocardiographic and vascular measures: left ventricular mass, left atrial and aortic root sizes, carotid–femoral pulse wave velocity, augmentation index, and forward pressure wave. Men and women engaged in MVPA 29.9±21.4 and 25.5±19.4 min/day, respectively. Higher values of MVPA (per 10‐minute increment) were associated with lower carotid–femoral pulse wave velocity (estimate −0.53 ms/m; P=0.006) and lower forward pressure wave (estimate −0.23 mm Hg; P=0.03) but were not associated with augmentation index (estimate 0.13%; P=0.25). MVPA was associated positively with loge left ventricular mass (estimate 0.006 loge [g/m2]; P=0.0003), left ventricular wall thickness (estimate 0.07 mm; P=0.0001), and left atrial dimension (estimate 0.10 mm; P=0.01). MVPA also tended to be positively associated with aortic root dimension (estimate 0.05 mm; P=0.052). Associations of MVPA with cardiovascular measures were similar, in general, for bouts lasting <10 versus ≥10 minutes.ConclusionsIn our community‐based sample, greater physical activity was associated with lower vascular stiffness but with higher echocardiographic left ventricular mass and left atrial size. These findings suggest complex relations of usual levels of physical activity and cardiovascular remodeling.

Aim To determine the incidence, patient characteristics, and related events associated with new-onset atrial fibrillation (AF) during a national COVID-19 lockdown. Methods and results Using nationwide Danish registries, we included all patients, aged 18–90 years, receiving a new-onset AF diagnosis during the first 3 months of 2019 and 2020. The main comparison was between patients diagnosed during lockdown (12 March 12–1 April 2020) and patients diagnosed in the corresponding period 1 year previously. We found a lower incidence of new-onset AF during the 3 weeks of lockdown compared with the corresponding weeks in 2019 [incidence rate ratios with 95% confidence intervals (CIs) for the 3 weeks: 0.66 (0.56–0.78), 0.53 (0.45–0.64), and 0.41 (0.34–0.50)]. There was a 47% drop in total numbers (562 vs. 1053). Patients diagnosed during lockdown were younger and with a lower CHA2DS2-VASc score, while history of cancer, heart failure, and vascular disease were more prevalent. During lockdown, 30 (5.3%) patients with new-onset AF suffered an ischaemic stroke and 15 (2.7%) died, compared with 45 (4.3%) and 14 (1.3%) patients during the corresponding 2019 period, respectively. The adjusted odds ratio of a related event (ischaemic stroke or all-cause death) during lock-down compared with the corresponding weeks was 1.41 (95% CI 0.93–2.12). Conclusions Following a national lockdown in Denmark, a 47% drop in registered new-onset AF cases was observed. In the event of prolonged or subsequent lockdowns, the risk of undiagnosed AF patients developing complications could potentially translate into poorer outcomes in patients with AF during the COVID-19 pandemic.

Abstract Background and objectives Male sex has been associated with severe Coronavirus disease 2019 (Covid-19) infection. We examined the association between male sex and severe Covid-19 infection and if an increased risk remains after adjustment for age and comorbidities. Methods Nationwide register-based follow-up study of Covid-19 patients in Denmark until May 16, 2020. Average risk ratio comparing 30-day composite outcome of all-cause death, severe Covid-19 diagnosis or intensive care unit (ICU) admission for men versus women standardized to the age and comorbidity distribution of all patients were derived from multivariable Cox regression. Included covariates were age, hypertension, diagnoses including obesity, alcohol, sleep apnea, diabetes, chronic obstructive pulmonary disease, previous myocardial infarction (MI), ischemic heart disease (IHD), heart failure (HF), atrial fibrillation (AF), stroke, peripheral artery disease, cancer, liver-, rheumatic-, and chronic kidney disease (CKD). Results Of 4,842 Covid-19 patients, 2,281 (47.1%) were men. Median age was 57 [25%-75% 43-73] for men versus 52 [38-71] for women (P&lt;0.001); however, octogenarians had equal sex distribution. Alcohol diagnosis, diabetes, hypertension, sleep apnea, prior MI and IHD (all P&lt;0.001) as well as AF, stroke and HF (all P=0.01) were more often seen in men, and so was CKD (P=0.03). Obesity diagnosis (P&lt;0.001) were more often seen in women. Other comorbidity differences were insignificant (P&gt;0.05). The fully adjusted average risk ratio was 1.63 [95% CI 1.44-1.84]. Conclusions Men with Covid-19 infection have &gt;50% higher risk of all-cause death, severe Covid-19 infection, or ICU admission than women. The excess risk was not explained by age and comorbidities.

Background & Aims A genome wide association study (GWAS) of 280 cases identified the hepatic cholesterol transporter ABCG8 as a locus associated with risk for gallstone disease, but findings have not been reported from any other GWAS of this phenotype. We performed a large-scale meta-analysis of GWASs of individuals of European ancestry with available prior genotype data, to identify additional genetic risk factors for gallstone disease. Methods We obtained per-allele odds ratio (OR) and standard error estimates using age- and sex-adjusted logistic regression models within each of the 10 discovery studies (8720 cases and 55,152 controls). We performed an inverse variance weighted, fixed-effects meta-analysis of study specific estimates to identify single nucleotide polymorphisms (SNPs) that were independently associated with gallstone disease. Associations were replicated in 6489 cases and 62,797 controls. Results We observed independent associations for 2 SNPs at the ABCG8 locus: rs11887534 (OR = 1.69; 95% confidence interval [CI], 1.54–1.86; P=2.44×10−60) and rs4245791 (OR=1.27; P=1.90×10−34). We also identified and/or replicated associations for rs9843304 in TM4SF4 (OR=1.12; 95% CI, 1.08–1.16; P=6.09×10−11), rs2547231 in SULT2A1 (encodes a sulfo-conjugation enzyme that acts on hydroxysteroids and cholesterol-derived sterol bile acids), (OR=1.17, 95% CI, 1.12– 1.21;P=2.24×10−10), rs1260326 in GCKR (encodes a glucokinase regulator) (OR=1.12; 95% CI, 1.07–1.17; P=2.55×10−10), and rs6471717 near CYP7A1 (encodes an enzyme that catalyzes conversion of cholesterol to primary bile acids) (OR=1.11; 95% CI, 1.08–1.15; P=8.84×10−9). Among individuals of African American and Hispanic American ancestry, rs11887534 and rs4245791 were positively associated with gallstone disease risk, while the association for the rs1260326 variant was inverse. Conclusions In this large-scale GWAS of gallstone disease, we identified 4 loci in genes that have putative functions in cholesterol metabolism and transport, and sulfonylation of bile acids or hydoxysteroids.

Aims The study aimed to estimate the risk of cardiac events in immune checkpoint inhibitor (ICI)-treated patients with lung cancer or malignant melanoma. Methods and results The study included consecutive patients with lung cancer or malignant melanoma in 2011–17 nationwide in Denmark. The main composite outcome was cardiac events (arrhythmia, peri- or myocarditis, heart failure) or cardiovascular death. Absolute risks were estimated and the association of ICI and cardiac events was analysed in multivariable Cox models. We included 25 573 patients with lung cancer. Of these, 743 were treated with programmed cell death-1 inhibitor (PD1i) and their 1-year absolute risk of cardiac events was 9.7% [95% confidence interval (CI) 6.8–12.5]. Of the 13 568 patients with malignant melanoma, 145 had PD1i and 212 had cytotoxic T-lymphocyte-associated protein-4 inhibitor (CTLA-4i) treatment. Their 1-year risks were 6.6% (1.8–11.3) and 7.5% (3.7–11.3). The hazard rates of cardiac events were higher in patients with vs. without ICI treatment. Within 6 months from 1st ICI administration, the hazard ratios were 2.14 (95% CI 1.50–3.05) in patients with lung cancer and 4.30 (1.38–13.42) and 4.93 (2.45–9.94) in patients with malignant melanoma with PD1i and CTLA-4i, respectively. After 6 months, HRs were 2.26 (1.27–4.02) for patients with lung cancer and 3.48 (1.91–6.35) for patients with malignant melanoma and CTLA-4i. Conclusions Among patients with lung cancer and malignant melanoma, ICI treated had increased rates of cardiac events. The absolute risks were higher in these data compared with previous pharmacovigilance studies (e.g. 1.8% peri-/myocarditis 1-year risk).