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Aims Treatment with sodium-glucose co-transporter 2 (SGLT2)-inhibitors reduces the risk of cardiovascular disease and mortality, but the mechanism is unclear. We hypothesized that a functional genetic variant in solute carrier family 5 member 2 (SLC5A2), known to be associated with familial renal glucosuria, would mimic pharmacological SGLT2-inhibition, and thus provide an opportunity to examine potential mediators of the effects on lower risk of cardiovascular disease and mortality. Methods and results We examined 112 712 individuals from the Copenhagen City Heart Study and Copenhagen General Population Study (CCHS + CGPS), 488 687 from the UK Biobank, and 342 499 from FinnGen, genotyped for SLC5A2 rs61742739, c.1961A > G; p.(Asn654Ser). The 2.0% heterozygotes and 0.01% homozygotes were pooled as carriers and compared with the 98% non-carriers. First, we examined the risk of cardiovascular disease and mortality; second, whether carrying the variant was associated with potential mediators of the effect; and third, whether identified potential mediators could explain the observed reduced risk of cardiovascular disease and mortality. In the CCHS + CGPS, carriers vs. non-carries had a 31% lower risk of heart failure, 21% lower risk of myocardial infarction, 16% lower risk of ischaemic heart disease, and 22% lower risk of all-cause mortality. Corresponding values in meta-analyses of the three studies combined were lower risk by 10%, 6%, 6%, and 10%, respectively. The SLC5A2 rs61742739 variant was not associated with a risk of ischaemic stroke or cardiovascular mortality. Of the lower risks observed in CCHS + CGPS, lower plasma glucose mediated 2.0%(P = 0.004) on heart failure, 3.1%(P = 0.09) on myocardial infarction, 4.1%(P = 0.02) on ischaemic heart disease, and 6.0%(P = 0.39) on all-cause mortality; corresponding values in the UK Biobank were 2.9%(P = 0.70), 1.5%(P = 0.77), 4.1%(P = 0.23), and 3.1%(P = 0.21), respectively. Conclusion A functional genetic variant in SLC5A2 , mimicking SGLT2-inhibition, was associated with a lower risk of heart failure, myocardial infarction, ischaemic heart disease, and all-cause mortality. These effects were at most minimally mediated through lower plasma glucose. [ABSTRACT FROM AUTHOR]

Aims Recent evidence suggest that the lipoprotein(a)-associated risk of atherosclerotic cardiovascular disease (ASCVD) may be observed only in individuals with low-grade systemic inflammation. It was hypothesized that high lipoprotein(a) is a main driver for the risk of ASCVD, myocardial infarction, and aortic valve stenosis irrespective of C-reactive protein levels. Methods and results A total of 68 090 individuals from the Copenhagen General Population Study, a prospective cohort study, were included. During a median follow-up of 8.1 years, 5104 individuals developed ASCVD, 2432 myocardial infarction, and 1220 aortic valve stenosis. The risk of ASCVD, myocardial infarction, and aortic valve stenosis increased with higher values of both lipoprotein(a) and C-reactive protein. For individuals with lipoprotein(a) in the 91st–100th percentiles (≥70 mg/dl, ≥147 nmol/l) vs. the 1st–33rd percentiles (≤6 mg/dl, ≤9 nmol/l), the multivariable-adjusted hazard ratio for ASCVD was 1.61 (95% confidence interval 1.43–1.81) for those with C-reactive protein <2 mg/l and 1.57 (1.36–1.82) for those with C-reactive protein ≥2 mg/l (P for interaction = 0.87). The corresponding values were 2.08 (1.76–2.45) and 1.65 (1.34–2.04) for myocardial infarction, and 2.01 (1.59–2.55) and 1.73 (1.31–2.27) for aortic valve stenosis, respectively (P for interaction = 0.15 and = 0.18). The highest absolute 10-year risks were found in men aged 70–79 years with lipoprotein(a) levels in the 91st–100th percentiles and C-reactive protein ≥2 mg/l, with 34% for ASCVD, 19% for myocardial infarction, and 13% for aortic valve stenosis. The corresponding values in women were 20%, 10%, and 8%, respectively. Conclusion High lipoprotein(a) was a main driver for the risk of ASCVD, myocardial infarction, and aortic valve stenosis independent of C-reactive protein levels. [ABSTRACT FROM AUTHOR]

Aims  We tested the hypothesis that high directly measured remnant cholesterol is associated with increased risk of ischaemic heart disease (IHD) and myocardial infarction (MI) in the general population. We also explored whether directly measured vs. calculated remnant cholesterol is superior in identifying individuals at increased risk. Methods and results  Overall, 16 207 individuals from the Copenhagen General Population Study with both directly measured and calculated remnant cholesterol, both representing cholesterol content in triglyceride-rich lipoproteins, were followed up for 14 years to analyse the risk for IHD and MI. For directly measured and calculated remnant cholesterol, hazard ratios for individuals with concentrations ≥95th percentile vs. <40th percentile were 1.75 (95% confidence interval 1.42–2.15) and 1.76 (1.42–2.17) for IHD and 2.05 (1.50–2.80) and 1.93 (1.40–2.66) for MI. Compared to individuals with both directly measured and calculated remnant cholesterol <80th percentile (75% of the whole population), those with only directly measured remnant cholesterol ≥80th percentile (5%) had hazard ratios of 1.42 (1.15–1.75) for IHD and 1.83 (1.35–2.47) for MI. Corresponding hazard ratios for individuals with only calculated remnant cholesterol ≥80th percentile (5%) were 1.14 (0.91–1.44) and 1.14 (0.80–1.62), respectively, and corresponding hazard ratios for individuals with both directly measured and calculated remnant cholesterol ≥80th percentiles (15%) were 1.48 (1.30–1.68) and 1.67 (1.38–2.01), respectively. In individuals with high directly measured or high calculated remnant cholesterol, the median directly measured remnant cholesterol was 1.9 and 1.5 mmol/L, the median plasma triglycerides were 2.0 and 2.7 mmol/L, and the median plasma apolipoprotein B was 132 and 142 mg/dL, respectively. Conclusions  Directly measured vs. calculated remnant cholesterol identifies 5% overlooked individuals in the general population with cholesterol-rich, triglyceride-poor remnants and 1.8-fold increased risk of MI. [ABSTRACT FROM AUTHOR]

Aims  Prominent left ventricular trabeculations is a phenotypic trait observed in cardiovascular diseases. In the general population, the extent of left ventricular trabeculations is highly variable, yet it is unknown whether increased trabeculation is associated with adverse outcome. Methods and results  Left ventricular trabeculated mass (g/m2) was measured with contrast-enhanced cardiac computed tomography in 10 097 individuals from the Copenhagen General Population Study. The primary endpoint was a composite of major adverse cardiovascular events and defined as death, heart failure, myocardial infarction, or stroke. The secondary endpoints were the individual components of the primary endpoint. Cox regression models were adjusted for clinical parameters, medical history, electrocardiographic parameters, and cardiac chamber sizes. The mean trabeculated mass was 19.1 g/m2 (standard deviation 4.9 g/m2). During a median follow-up of 4.0 years (interquartile range 1.5–6.7), 710 major adverse cardiovascular events occurred in 619 individuals. Individuals with a left ventricular trabeculated mass in the highest quartile had a hazard ratio for major adverse cardiovascular events of 1.64 [95% confidence interval (CI) 1.30–2.08; P  < 0.001] compared to those in the lowest quartile. Corresponding hazard ratios were 2.08 (95% CI 1.38–3.14; P  < 0.001) for death, 2.63 (95% CI 1.61–4.31; P  < 0.001) for heart failure, 1.08 (95% CI 0.56–2.08; P  = 0.82) for myocardial infarction, and 1.07 (95% CI 0.72–1.57; P  = 0.74) for stroke. Conclusion  Increased left ventricular trabeculation is independently associated with an increased rate of major adverse cardiovascular events in the general population. [ABSTRACT FROM AUTHOR]

Aim We compared the 2013 American College of Cardiology/American Heart Association (ACC/AHA) and the 2016 European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) guidelines on prevention of atherosclerotic cardiovascular disease (ASCVD) using different risk prediction models [US Pooled Cohort Equations (US-PCE for any ASCVD) and European Systematic COronary Risk Evaluation system (European-SCORE for fatal ASCVD)] and different statin eligibility criteria. Methods and results We examined 44 889 individuals aged 40–75 recruited in 2003–09 in the Copenhagen General Population Study, all free of ASCVD, diabetes, and statin use at baseline. We detected 2217 any ASCVD events and 199 fatal ASCVD events through 2014. The predicted-to-observed event ratio was 1.2 using US-PCE for any ASCVD and 5.0 using European-SCORE for fatal ASCVD. The US-PCE, but not the European-SCORE, was well-calibrated around decision thresholds for statin therapy. For a Class I recommendation, 42% of individuals qualified for statins using the ACC/AHA guidelines vs. 6% with the ESC/EAS guidelines. Using ACC/AHA- vs. ESC/EAS-defined statin eligibility led to a substantial gain in sensitivity (+62% for any ASCVD and +76% for fatal ASCVD) with a smaller loss in specificity (−35% for any ASCVD and −36% for fatal ASCVD). Similar differences between the ACC/AHA and ESC/EAS guidelines were found for men and women separately, and for Class IIa recommendations. The sensitivity and specificity of a US-PCE risk of 5% were similar to those of a European-SCORE risk of 1.4%, whereas a US-PCE risk of 7.5% was similar to a European-SCORE risk of 2.4%. Conclusions The ACC/AHA guidelines were superior to the ESC/EAS guidelines for primary prevention of ASCVD, that is, for accurately assigning statin therapy to those who would benefit. [ABSTRACT FROM AUTHOR]

Background: Observationally, reports on the association between milk intake and risk of ischaemic heart disease (IHD) and myocardial infarction (MI) have produced conflicting results; and no previous large-scale study using the lactase persistent/non-persistent LCT-13910 C/T genotype as a largely unconfounded proxy for milk intake free of reverse causation has been conducted. We tested the hypothesis that milk intake observationally and genetically through the LCT-13910 C/T genotype is associated with risk of IHD and MI in a Mendelian randomization design. Methods: We included 98 529 White individuals of Danish descent, aged 20-100 years, from three studies of the general population. Information on IHD (N=10 372) and MI (N=4188) were obtained from national Danish registries. First, we investigated observational associations between milk intake and incident IHD and MI. Second, we confirmed the association between the rs4988235 genetic variant LCT-13910 C/T, associated with lactase persistence/non-persistence, and milk intake. Finally, we tested whether LCT-13910 C/T genotype was associated with risk of IHD and MI as well as with cardiovascular risk factors. Results: During a mean follow-up time of 5.4 years, the observational hazard ratio for a 1 glass/week higher milk intake was 1.00 [95% confidence interval (CI): 1.00,1.01] for both IHD and MI. Median milk intake was 3 glasses/week (interquartile range: 0-7) in lactase CC non-persistent individuals compared with 5 glasses/week (0-10) in lactase TC/TT persistent individuals (P=3*10-60). In the dominant genetic model comparing lactase TC/TT persistent individuals with lactase CC non-persistent individuals, the odds ratio was 1.00 (0.92,1.09) for IHD and 0.96 (0.84,1.09) for MI. Finally, in the dominant genetic model genotype was not associated convincingly with plasma levels of total cholesterol, low density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides or glucose, nor with blood pressure. Conclusion: Milk intake was not associated with risk of IHD or MI, observationally orgenetically [ABSTRACT FROM AUTHOR]

Background Sun exposure is the single most important risk factor for skin cancer, but sun exposure may also have beneficial effects on health. We tested the hypothesis that individuals with skin cancer (non-melanoma skin cancer and cutaneous malignant melanoma) have less myocardial infarction, hip fracture and death from any cause, compared with general population controls.Methods We examined the entire Danish population above age 40 years from 1980 through 2006, comprising 4.4 million individuals. Diagnoses of non-melanoma skin cancer (n = 129 206), cutaneous malignant melanoma (n = 22107), myocardial infarction (n = 327 856), hip fracture (n = 129 419), and deaths from any cause (n = 1 629 519) were drawn from national registries.Results In individuals with vs without non-melanoma skin cancer, multifactorially adjusted odds ratios were 0.96 (95% confidence interval: 0.94–0.98) for myocardial infarction and 1.15 (1.12–1.18) for hip fracture, and the multifactorially adjusted hazard ratio was 0.52 (0.52–0.53) for death from any cause. Risk of hip fracture was reduced (odds ratios were below 1.0) in individuals below age 90 years. In individuals with vs without cutaneous malignant melanoma, corresponding odds ratios were 0.79 (0.74–0.84) for myocardial infarction and 0.84 (0.76–0.93) for hip fracture, and the corresponding hazard ratio for death from any cause was 0.89 (0.87–0.91); however, cutaneous malignant melanoma was associated positively with death from any cause in some individuals.Conclusions In this nationwide study, having a diagnosis of skin cancer was associated with less myocardial infarction, less hip fracture in those below age 90 years and less death from any cause. Causal conclusions cannot be made from our data. A beneficial effect of sun exposure per se needs to be examined in other studies. [ABSTRACT FROM AUTHOR]

Aims Elevated non-fasting triglycerides mark elevated levels of remnant cholesterol. Using a Mendelian randomization approach, we tested whether genetically increased remnant cholesterol in hypertriglyceridaemia due to genetic variation in the apolipoprotein A5 gene (APOA5) associates with an increased risk of myocardial infarction (MI). Methods and results We resequenced the core promoter and coding regions of APOA5 in individuals with the lowest 1% (n = 95) and highest 2% (n = 190) triglyceride levels in the Copenhagen City Heart Study (CCHS, n = 10 391). Genetic variants which differed in frequency between the two extreme triglyceride groups (c.-1131T > C, S19W, and c.*31C > T; P-value: 0.06 to <0.001), thus suggesting an effect on triglyceride levels, were genotyped in the Copenhagen General Population Study (CGPS), the CCHS, and the Copenhagen Ischemic Heart Disease Study (CIHDS), comprising a total of 5705 MI cases and 54 408 controls. Genotype combinations of these common variants associated with increases in non-fasting triglycerides and calculated remnant cholesterol of, respectively, up to 68% (1.10 mmol/L) and 56% (0.40 mmol/L) (P < 0.001), and with a corresponding odds ratio for MI of 1.87 (95% confidence interval: 1.25–2.81). Using APOA5 genotypes in instrumental variable analysis, the observational hazard ratio for a doubling in non-fasting triglycerides was 1.57 (1.32–2.68) compared with a causal genetic odds ratio of 1.94 (1.40–1.85) (P for comparison = 0.28). For calculated remnant cholesterol, the corresponding values were 1.67(1.38–2.02) observational and 2.23(1.48–3.35) causal (P for comparison = 0.21). Conclusion These data are consistent with a causal association between elevated levels of remnant cholesterol in hypertriglyceridaemia and an increased risk of MI. Limitations include that remnants were not measured directly, and that APOA5 genetic variants may influence other lipoprotein parameters. [ABSTRACT FROM PUBLISHER]

Aims Myocardial infarction is nominally the most important co-morbidity in patients with chronic obstructive pulmonary disease, and the one with the greatest potential for treatment and prevention to improve the overall prognosis of chronic obstructive pulmonary disease patients. We assessed the extent of myocardial infarction and other co-morbidities in individuals with chronic obstructive pulmonary disease in the general population. Methods and results We used individual participant data for the entire Danish population from 1980 through 2006, comprising 140 million person-years of follow-up. We used information from four national Danish registries with 100% follow-up and detected ever-diagnosed chronic obstructive pulmonary disease (n = 313 958) and incident cases of a first myocardial infarction (n = 422 344), lung cancer (n = 116 629), hip fracture (n = 53 756), depression (n = 93 038), and diabetes mellitus (n = 292 228). Multivariate adjusted hazard ratios for life-time association with ever-diagnosed chronic obstructive pulmonary disease were 1.26 (95% CI 1.25–1.27) for myocardial infarction, 2.05 (2.03–2.08) for lung cancer, 2.12 (2.07–2.17) for hip fracture, 1.74 (1.70–1.77) for depression, and 1.21 (1.20–1.23) for diabetes mellitus, compared with controls; these risk estimates were highest in women and the youngest age groups. Before the first hospitalization with chronic obstructive pulmonary disease, multivariate adjusted odds ratios were 1.47 (1.44–1.49) for myocardial infarction, 3.68 (3.52–3.84) for lung cancer, 1.16 (1.13–1.18) for hip fracture, 1.88 (1.80–1.96) for depression, and 1.16 (1.13–1.18) for diabetes mellitus, compared with matched controls. Corresponding values after a chronic obstructive pulmonary disease hospitalization were 0.74 (0.73–0.76), 1.48 (1.45–1.51), 1.23 (1.20–1.27), 1.21 (1.18–1.24), and 0.83 (0.81–0.85), respectively. Conclusion Chronic obstructive pulmonary disease was associated with higher rates of myocardial infarction, lung cancer, diabetes, hip fracture, and depression, but the strength of these associations was modified after a first admission for chronic obstructive pulmonary disease. These associations may be related to common genetic and/or lifestyle/environmental risk factors, and therefore these factors are likely to have an adverse health impact rather than chronic obstructive pulmonary disease per se. [ABSTRACT FROM PUBLISHER]

Aims The aims of the study were, first, to critically evaluate lipoprotein(a) [Lp(a)] as a cardiovascular risk factor and, second, to advise on screening for elevated plasma Lp(a), on desirable levels, and on therapeutic strategies. Methods and results The robust and specific association between elevated Lp(a) levels and increased cardiovascular disease (CVD)/coronary heart disease (CHD) risk, together with recent genetic findings, indicates that elevated Lp(a), like elevated LDL-cholesterol, is causally related to premature CVD/CHD. The association is continuous without a threshold or dependence on LDL- or non-HDL-cholesterol levels. Mechanistically, elevated Lp(a) levels may either induce a prothrombotic/anti-fibrinolytic effect as apolipoprotein(a) resembles both plasminogen and plasmin but has no fibrinolytic activity, or may accelerate atherosclerosis because, like LDL, the Lp(a) particle is cholesterol-rich, or both. We advise that Lp(a) be measured once, using an isoform-insensitive assay, in subjects at intermediate or high CVD/CHD risk with premature CVD, familial hypercholesterolaemia, a family history of premature CVD and/or elevated Lp(a), recurrent CVD despite statin treatment, ≥3% 10-year risk of fatal CVD according to European guidelines, and/or ≥10% 10-year risk of fatal + non-fatal CHD according to US guidelines. As a secondary priority after LDL-cholesterol reduction, we recommend a desirable level for Lp(a) <80th percentile (less than ∼50 mg/dL). Treatment should primarily be niacin 1–3 g/day, as a meta-analysis of randomized, controlled intervention trials demonstrates reduced CVD by niacin treatment. In extreme cases, LDL-apheresis is efficacious in removing Lp(a). Conclusion We recommend screening for elevated Lp(a) in those at intermediate or high CVD/CHD risk, a desirable level <50 mg/dL as a function of global cardiovascular risk, and use of niacin for Lp(a) and CVD/CHD risk reduction. [ABSTRACT FROM PUBLISHER]