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Background and Aims: Anti-inflammatory trials have shown considerable benefits for cardiovascular disease. High neutrophil counts, an easily accessible inflammation biomarker, are associated with atherosclerosis in experimental studies. This study aimed to investigate the associations between neutrophil counts and risk of nine cardiovascular endpoints using observational and genetic approaches., Methods: Observational studies were conducted in the Copenhagen General Population Study (n = 101 730). Genetic studies were firstly performed using one-sample Mendelian randomization (MR) with individual-level data from the UK Biobank (n = 365 913); secondly, two-sample MR analyses were performed using summary-level data from the Blood Cell Consortium (n = 563 085). Outcomes included ischaemic heart disease, myocardial infarction, peripheral arterial disease, ischaemic cerebrovascular disease, ischaemic stroke, vascular-related dementia, vascular dementia, heart failure, and atrial fibrillation., Results: Observational analyses showed associations between high neutrophil counts with high risks of all outcomes. In the UK Biobank, odds ratios (95% confidence intervals) per 1-SD higher genetically predicted neutrophil counts were 1.15 (1.08, 1.21) for ischaemic heart disease, 1.22 (1.12, 1.34) for myocardial infarction, and 1.19 (1.04, 1.36) for peripheral arterial disease; similar results were observed in men and women separately. In two-sample MR, corresponding estimates were 1.14 (1.05, 1.23) for ischaemic heart disease and 1.11 (1.02, 1.20) for myocardial infarction; multiple sensitivity analyses showed consistent results. No robust associations in two-sample MR analyses were found for other types of leucocytes., Conclusions: Observational and genetically determined high neutrophil counts were associated with atherosclerotic cardiovascular disease, supporting that high blood neutrophil counts is a causal risk factor for atherosclerotic cardiovascular disease., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims/hypothesis: Elevated remnant cholesterol is observationally and causally associated with increased risk of atherosclerotic cardiovascular disease (ASCVD) in the general population. This association is not well studied in individuals with diabetes, who are often included in clinical trials of remnant cholesterol-lowering therapy. We tested the hypothesis that elevated remnant cholesterol is associated with increased risk of ASCVD in individuals with diabetes. We also explored the fraction of excess risk conferred by diabetes which can be explained by elevated remnant cholesterol., Methods: We included 4569 white Danish individuals with diabetes (58% statin users) nested within the Copenhagen General Population Study (2003-2015). The ASCVDs peripheral artery disease, myocardial infarction and ischaemic stroke were extracted from national Danish health registries without losses to follow-up. Remnant cholesterol was calculated from a standard lipid profile., Results: During up to 15 years of follow-up, 236 individuals were diagnosed with peripheral artery disease, 234 with myocardial infarction, 226 with ischaemic stroke and 498 with any ASCVD. Multivariable adjusted HR (95% CI) per doubling of remnant cholesterol was 1.6 (1.1, 2.3; p=0.01) for peripheral artery disease, 1.8 (1.2, 2.5; p=0.002) for myocardial infarction, 1.5 (1.0, 2.1; p=0.04) for ischaemic stroke, and 1.6 (1.2, 2.0; p=0.0003) for any ASCVD. Excess risk conferred by diabetes was 2.5-fold for peripheral artery disease, 1.6-fold for myocardial infarction, 1.4-fold for ischaemic stroke and 1.6-fold for any ASCVD. Excess risk explained by elevated remnant cholesterol and low-grade inflammation was 14% and 8% for peripheral artery disease, 26% and 16% for myocardial infarction, 34% and 34% for ischaemic stroke, and 24% and 18% for any ASCVD, respectively. LDL-cholesterol did not explain excess risk, as it was not higher in individuals with diabetes. We also explored the fraction of excess risk conferred by diabetes which can be explained by elevated remnant cholesterol., Conclusions/interpretation: Elevated remnant cholesterol was associated with increased risk of ASCVD in individuals with diabetes. Remnant cholesterol and low-grade inflammation explained substantial excess risk of ASCVD conferred by diabetes. Whether remnant cholesterol should be used as a treatment target remains to be determined in randomised controlled trials., (© 2023. The Author(s).)

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., Competing Interests: Conflicts of interest: Børge Nordestgaard reports consultancies with Novo Nordisk. The other authors have no disclosures., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background and Aims: Elevated remnant cholesterol and low-grade inflammation each cause atherosclerotic cardiovascular disease (ASCVD); however, it is unknown whether joint elevation of both factors confers the highest risk. We tested the hypothesis that dual elevated remnant cholesterol and low-grade inflammation marked by elevated C-reactive protein is associated with the highest risk of myocardial infarction, ASCVD, and all-cause mortality., Methods: The Copenhagen General Population Study randomly recruited white Danish individuals aged 20-100 years in 2003-2015 and followed them for a median 9.5 years. ASCVD was cardiovascular mortality, myocardial infarction, stroke, and coronary revascularization., Results: In 103,221 individuals, we observed 2,454 (2.4%) myocardial infarctions, 5,437 (5.3%) ASCVD events, and 10,521 (10.2%) deaths. The hazard ratios increased with each of stepwise higher remnant cholesterol and stepwise higher C-reactive protein. In individuals with the highest tertile of both remnant cholesterol and C-reactive protein compared to individuals with the lowest tertile of both, the multivariable adjusted hazard ratios were 2.2 (95%CI:1.9-2.7) for myocardial infarction, 1.9 (1.7-2.2) for ASCVD, and 1.4 (1.3-1.5) for all-cause mortality. Corresponding values for only the highest tertile of remnant cholesterol were 1.6 (1.5-1.8), 1.4 (1.3-1.5), and 1.1 (1.0-1.1), and those for only the highest tertile of C-reactive protein were 1.7 (1.5-1.8), 1.6 (1.5-1.7), and 1.3 (1.3-1.4), respectively. There was no statistical evidence for interaction between elevated remnant cholesterol and elevated C-reactive protein on risk of myocardial infarction (p = 0.10), ASCVD (p = 0.40), or all-cause mortality (p = 0.74)., Conclusions: Dual elevated remnant cholesterol and C-reactive protein confers the highest risk of myocardial infarction, ASCVD, and all-cause mortality, that is, compared to either of these two factors individually., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Børge G. Nordestgaard reports consultancies or talks sponsored by AstraZeneca, Sanofi, Regeneron, Akcea, Amgen, Amarin, Kowa, Denka, Novartis, Novo Nordisk, Esperion, Abbott, and Silence Therapeutics. Takahito Doi and Anne Langsted declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Aims: The association between thyroid stimulating hormone (TSH) and cardiovascular disease has mainly been determined using clinical categories of disease. We tested the hypothesis that TSH on a continuous scale is associated with risk of atrial fibrillation (AF), myocardial infarction (MI), stroke, heart failure (HF), aortic valve stenosis (AVS), and major adverse cardiovascular events (MACE) and whether these associations are likely to be causal., Methods: We first tested whether plasma TSH on a continuous scale was observationally associated with incident cardiovascular events in a prospective cohort study of 105,224 individuals from the Copenhagen General Population Study followed for a median 7 years. Next, we tested whether a genetic risk score weighted on TSH was associated with cardiovascular endpoints. Finally, using Mendelian randomization, we tested whether the observed associations were likely to be causal., Results: Using restricted cubic splines, lower concentrations of TSH relative to the population median (=1.53 mIU/L) were associated with higher risk of AF, MI, stroke, HF, AVS, and MACE. Comparing individuals with TSH ≤5th percentile (≤0.54 mIU/L) versus >50th percentile (>1.53 mIU/L), hazard ratios (HRs) ranged from 1.12 (1.00-1.26) for stroke to 1.27 (1.11-1.46) for HF. Genetic risk estimates per standard deviation decrease in TSH were 1.28 (1.08-1.52) for AF, 1.35 (1.06-1.71) for MI, 1.06 (0.89-1.26) for stroke, 1.19 (0.94-1.52) for HF, 1.53 (1.03-2.26) for AVS, and 1.09 (0.97-1.23) for MACE., Conclusions: In 105,224 individuals from the general population low plasma TSH was observationally and genetically associated with increased risk of AF, MI, and AVS suggesting that these observations may reflect causal pathways., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. AT-H reports consultancies or talks sponsored by Akcea, Amgen, AstraZeneca, Draupnir Bio, Novartis, Regeneron, Sanofi, and Silence Therapeutics. BGN reports consultancies or talks sponsored by AstraZeneca, Sanofi, Regeneron, Akcea, Amgen, Kowa, Denka Seiken, Amarin, Novartis, Novo Nordisk, and Silence Therapeutics. RF-S reports consultancy sponsored by Novo Nordisk. ND had no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

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., Competing Interests: Conflicts of interest: B.G.N. reports consultancies with Akcea, Amarin, Amgen, AstraZeneca, Denka, Kowa, Novartis, Novo Nordisk, Sanofi, Regeneron, Esperion, and Silence Therapeutics. P.R.K. reports lecture honoraria or consultancies from Physicians’ Academy for Cardiovascular Education, Silence Therapeutics, and Novartis. P.E.T. and S.V.-K. declare no conflicts of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose of Review: To summarize recent studies analyzing reclassification of estimated risk of myocardial infarction (MI) and ischemic heart disease (IHD) by inclusion of remnant cholesterol (= cholesterol content in triglyceride-rich lipoproteins) in primary and secondary prevention settings., Recent Findings: For individuals in a primary prevention setting with remnant cholesterol levels at least 95th percentile (≥1.6 mmol/l, 61 mg/dl), 23% of MI and 21% of IHD events developed later were reclassified correctly from below to above 5% for 10-year occurrence when remnant cholesterol levels were added to models based on conventional risk factors, whereas no events were reclassified incorrectly. Overall improved reclassification of MI was also observed for remnant cholesterol levels as low as at least 50th percentile (≥0.6 mmol/l, 25 mg/dl); however, the addition of remnant cholesterol over the entire concentration range yielded insignificant improvements of NRI for MI but slightly improved reclassification of NRI for IHD. In a secondary prevention setting, addition of remnant cholesterol over the entire concentration range to a conventional risk model improved reclassification., Summary: Elevated remnant cholesterol levels considerably improves reclassification of individuals who later develop MI and IHD, in primary as well as in secondary prevention settings., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Elevated remnant cholesterol causes ischemic heart disease., Objectives: We tested the hypothesis that the inclusion of elevated remnant cholesterol will lead to appropriate reclassification of individuals who later experience myocardial infarction and ischemic heart disease., Methods: For >10 years we followed up 41,928 white Danish individuals from the Copenhagen General Population Study without a history of ischemic cardiovascular disease, diabetes, and statin use. Using predefined cut points for elevated remnant cholesterol, we calculated net reclassification index (NRI) from below to above 5%, 7.5%, and/or 10% 10-year occurrence of myocardial infarction and ischemic heart disease defined as a composite of death from ischemic heart disease, myocardial infarction, and coronary revascularization., Results: For individuals with remnant cholesterol levels ≥95th percentile (≥1.6 mmol/L, 61 mg/dL), 23% (P < 0.001) of myocardial infarction and 21% (P < 0.001) of ischemic heart disease were reclassified correctly from below to above 5% for 10-year occurrence when remnant cholesterol levels were added to models based on conventional risk factors, whereas no events were reclassified incorrectly. Consequently, the addition of remnant cholesterol levels yielded NRI of 10% (95% CI: 1%-20%) for myocardial infarction and 5% (95% CI: -3% to 13%) for ischemic heart disease. Correspondingly, when reclassifications were combined from below to above 5%, 7.5%, and 10% risk of events, 42% (P < 0.001) of individuals with myocardial infarction and 41% (P < 0.001) with ischemic heart disease were reclassified appropriately, leading to NRI of respectively 20% (95% CI: 9%-31%) and 11% (95% CI: 2%-21%)., Conclusions: Elevated remnant cholesterol levels considerably improve myocardial infarction and ischemic heart disease risk prediction., Competing Interests: Funding Support and Author Disclosures This work was supported by the Global Excellence Programme (to Dr Nordestgaard) and by the Research Fund for the Capital Region of Denmark (to Drs Doi and Langsted), by the Japanese College of Cardiology Overseas Research Fellowship (to Dr Doi) and by Scandinavia-Japan Sasakawa Foundation (to Dr Doi). Dr Nordestgaard has reported consultancies or talks sponsored by AstraZeneca, Sanofi, Regeneron, Akcea, Amgen, Amarin, Kowa, Denka, Novartis, Novo Nordisk, Esperion, and Silence Therapeutics. Dr Doi has reported talks sponsored by MSD. Dr Langsted has reported that she has no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Purpose of Review: Individuals with familial hypercholesterolemia have very high risk of cardiovascular disease due to lifelong elevations in LDL cholesterol. Elevated lipoprotein(a) is a risk factor for cardiovascular diseases such as myocardial infarction and aortic valve stenosis. It has been proposed to include elevated lipoprotein(a) in the diagnosis of clinical familial hypercholesterolemia., Recent Findings: Lipoprotein(a) is co-measured in LDL cholesterol, and up to one-quarter of all diagnoses of clinical familial hypercholesterolemia are due to high levels of lipoprotein(a). Further, individuals with both familial hypercholesterolemia and elevated lipoprotein(a) have an extremely high risk of myocardial infarction. We discuss the background for familial hypercholesterolemia and elevated lipoprotein(a) as risk factors for cardiovascular disease and the consequences of the fact that LDL cholesterol measurements/calculations include the cholesterol present in lipoprotein(a). Finally, we discuss the potential of including lipoprotein(a) as part of the diagnosis of familial hypercholesterolemia and in consequence possible treatments., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: DNA hypomethylation at the F2RL3 (F2R like thrombin or trypsin receptor 3) locus has been associated with both smoking and atherosclerotic cardiovascular disease; whether these smoking-related associations form a pathway to disease is unknown. F2RL3 encodes protease-activated receptor 4, a potent thrombin receptor expressed on platelets. Given the role of thrombin in platelet activation and the role of thrombus formation in myocardial infarction, alterations to this biological pathway could be important for ischemic cardiovascular disease., Methods: We conducted multiple independent experiments to assess whether DNA hypomethylation at F2RL3 in response to smoking is associated with risk of myocardial infarction via changes to platelet reactivity. Using cohort data (N=3205), we explored the relationship between smoking, DNA hypomethylation at F2RL3 , and myocardial infarction. We compared platelet reactivity in individuals with low versus high DNA methylation at F2RL3 (N=41). We used an in vitro model to explore the biological response of F2RL3 to cigarette smoke extract. Finally, a series of reporter constructs were used to investigate how differential methylation could impact F2RL3 gene expression., Results: Observationally, DNA methylation at F2RL3 mediated an estimated 34% of the smoking effect on increased risk of myocardial infarction. An association between methylation group (low/high) and platelet reactivity was observed in response to PAR4 (protease-activated receptor 4) stimulation. In cells, cigarette smoke extract exposure was associated with a 4.9% to 9.3% reduction in DNA methylation at F2RL3 and a corresponding 1.7-(95% CI, 1.2-2.4, P =0.04) fold increase in F2RL3 mRNA. Results from reporter assays suggest the exon 2 region of F2RL3 may help control gene expression., Conclusions: Smoking-induced epigenetic DNA hypomethylation at F2RL3 appears to increase PAR4 expression with potential downstream consequences for platelet reactivity. Combined evidence here not only identifies F2RL3 DNA methylation as a possible contributory pathway from smoking to cardiovascular disease risk but from any feature potentially influencing F2RL3 regulation in a similar manner.

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., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

[Figure: see text].

Background: Circulating total calcium or albumin-adjusted calcium is a risk factor for cardiovascular disease. As the biologically active ionized calcium is a physiologically more relevant measure and its association with cardiovascular disease is poorly understood, we tested the hypothesis that high plasma ionized calcium is associated with higher risk of myocardial infarction and ischemic stroke in individuals in the general population., Methods: We included 106 774 individuals from the Copenhagen General Population Study, and defined hypocalcemia and hypercalcemia by the lowest and highest 2.5 percentiles, respectively, using the central 95% reference interval. Information on myocardial infarction and ischemic stroke was from registries and risks calculated using Cox regression and Fine and Gray competing-risks regression., Results: During a median follow-up of 9.2 years, 4932 individuals received a diagnosis of either myocardial infarction or ischemic stroke. Hypercalcemia was associated with subdistribution hazard ratios of 1.67 (95%CI: 1.05-2.67) for myocardial infarction, 1.28 (0.81-2.02) for ischemic stroke, and of 1.54 (1.10-2.15) for the combined endpoint compared to individuals with plasma ionized calcium within the reference interval; hypocalcemia was not associated with cardiovascular disease. In models using plasma ionized calcium as a continuous variable, the associations were nonlinear; above the median, each 0.1 mmol/L higher plasma ionized calcium was associated with a hazard ratio of 1.31(1.02-1.68) for myocardial infarction, 1.21 (0.95-1.54) for ischemic stroke, and of 1.28 (1.08-1.53) for the combined endpoint., Conclusions: High plasma ionized calcium is associated with higher risk of myocardial infarction and ischemic stroke compared to plasma ionized calcium within the reference interval., (© American Association for Clinical Chemistry 2020. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Individuals with obesity have higher concentrations of very low-density lipoprotein (VLDL) cholesterol and increased risk of myocardial infarction. We hypothesized that VLDL cholesterol explains a fraction of the excess myocardial infarction risk in individuals with obesity., Methods: We included 29 010 individuals free of myocardial infarction at baseline, nested within 109 751 individuals from the Copenhagen General Population Study. During 10 years of follow-up, 2306 individuals developed myocardial infarction. Cholesterol content in large and small VLDLs, in intermediate-density lipoprotein (IDL), and in LDL was measured directly with nuclear magnetic resonance spectroscopy., Results: Median concentrations of cholesterol in large and small VLDLs were 0.12 mmol/L (interquartile range [IQR], 0.07-0.20 mmol/L; 4.5 mg/dL [IQR, 2.6-6.9 mg/dL]) and 0.6 mmol/L (IQR, 0.5-0.8 mmol/L; 25 mg/dL [IQR, 20-30 mg/dL]) in individuals with obesity vs 0.06 mmol/L (IQR, 0.03-0.1 mmol/L; 2.2 mg/dL [IQR, 1.1-3.8 mg/dL]), and 0.5 mmol/L (IQR, 0.4-0.6 mmol/L; 20 mg/dL (IQR, 16-25 mg/dL]) in individuals with normal weight; in contrast, concentrations of IDL and LDL cholesterol were similar across body mass index (BMI) categories. Cholesterol in large and small VLDLs combined explained 40% (95% CI, 27%-53%) of the excess risk of myocardial infarction associated with higher BMI. In contrast, IDL and LDL cholesterol did not explain excess risk of myocardial infarction, whereas systolic blood pressure explained 17% (11%-23%) and diabetes mellitus explained 8.6% (3.2%-14%)., Conclusions: VLDL cholesterol explains a large fraction of excess myocardial infarction risk in individuals with obesity. These novel findings support a focus on cholesterol in VLDL for prevention of myocardial infarction and atherosclerotic cardiovascular disease in individuals with obesity., (© American Association for Clinical Chemistry 2021. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Aims: Left ventricular (LV) myocardial crypts are considered a subtle marker of hypertrophic cardiomyopathy. However, crypts have also been observed in seemingly healthy individuals and it is unknown whether myocardial crypts are associated with adverse outcome., Methods and Results: Myocardial crypts were defined as invaginations traversing >50% of the myocardial wall and assessed using contrast-enhanced cardiac computed tomography in 10 097 individuals from the Copenhagen General Population Study. Number of crypts, location, shape, penetrance, and volume were assessed. The endpoint was a composite of major adverse cardiovascular events and defined as death, myocardial infarction, heart failure, or stroke. Cox regression models were adjusted for clinical variables, medical history, electrocardiographic parameters, and cardiac chamber sizes. A total of 1199 LV myocardial crypts were identified in 915 (9.1%) individuals. Seven hundred (6.9%) had one crypt and 215 (2.1%) had multiple crypts. During a median follow-up of 4.0 years (interquartile range 1.5-6.7), major adverse cardiovascular events occurred in 619 individuals. Individuals with one or multiple crypts had a hazard ratio for major adverse cardiovascular events of 1.00 [95% confidence interval (CI): 0.72-1.40; P = 0.98] and 0.90 (95% CI: 0.47-1.75; P = 0.76), respectively, compared with those with no crypts. No specific pattern of crypt location, shape, penetrance, or volume was associated to an increased hazard ratio for major adverse cardiovascular events., Conclusion: LV myocardial crypts are frequent in the general population and are not associated with intermediate-term major adverse cardiovascular events., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

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., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Background and Aims: Smoking causes cardiovascular disease. AHRR hypomethylation at the cg05575921 site is associated with active and former smoking status at baseline, and cumulative amount of tobacco smoked. We tested the hypothesis that AHRR cg05575921 hypomethylation as an epigenetic marker of smoking history predicts the risk of myocardial infarction in former smokers., Methods: We included 10,510 individuals with methylation extent measurements and information on smoking status from the Copenhagen City Heart Study (CCHS), a prospective, cohort study of the general population carried out from 1991 to 2003. The endpoint myocardial infarction was retrieved from the national Danish Patient Registry and the national Danish Causes of Death Registry., Results: For individuals in the 1st (lowest) quartile of AHRR cg05575921 methylation (≤49% methylation extent), 99% were ever smokers at baseline (active and former smokers combined) compared to 42% in the 4th (highest) quartile (>62% methylation extent). For former smokers, the cumulative incidence of myocardial infarction was higher in the lowest methylation extent (1st-50th percentile) compared to the highest methylation extent (51st-100th percentile). Compared to never smokers, the multivariable adjusted subhazard ratio for myocardial infarction was 1.09 (95%CI:0.88-1.35) for former smokers with the highest methylation degree, 1.38 (1.06-1.80) for active smokers with the highest methylation extent, 1.39 (1.08-1.78) for former smokers with the lowest methylation extent, and 1.61 (1.35-1.92) for active smokers with the lowest methylation extent., Conclusions: AHRR cg05575921 hypomethylation as an epigenetic marker of smoking history predicts risk of myocardial infarction, particularly in former smokers. Further, AHRR hypomethylation, regardless of smoking status, was associated with increased risk of myocardial infarction., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Purpose of Review: To summarize the recent studies directly comparing LDL and lipoprotein(a) as causal factors for cardiovascular disease and mortality., Recent Findings: In approximately 100,000 individuals from the Copenhagen General Population Study for risk of myocardial infarction, in observational analyses per 39 mg/dl (1 mmol/l) cholesterol increase, the hazard ratio was 1.3 (95% confidence interval: 1.2-1.3) for LDL cholesterol and 1.6 (1.4-1.9) for lipoprotein(a) cholesterol. In corresponding genetic analyses, the causal risk ratio was 2.1 (1.3-3.4) for LDL and 2.0 (1.6-2.6) for lipoprotein(a). Also, a 15 mg/dl (0.39 mmol/l) cholesterol increase was associated with a hazard ratio for cardiovascular mortality of 1.05 (1.04-1.07) for LDL cholesterol and 1.18 (1.12-1.25) for lipoprotein(a) cholesterol. Corresponding values for all-cause mortality were 1.01 (1.00-1.01) for LDL cholesterol and 1.07 (1.04-1.10) for lipoprotein(a) cholesterol. In genetic, causal analyses, the mortality increases for elevated lipoprotein(a) appeared to be through apolipoprotein(a) kringle IV-2 rather than through lipoprotein(a) levels per se., Summary: On cholesterol scales, lipoprotein(a) and LDL appeared equal as causal factors for myocardial infarction; however, lipoprotein(a) was most important for mortality. Lipoprotein(a) effects may not only be due to cholesterol content but could also be due to the structure of lipoprotein(a) resembling plasminogen.

Context: How best to identify families with premature myocardial infarction is unclear., Objective: We compared approaches to identify familial premature myocardial infarction in the general population using different familial hypercholesterolemia (FH) criteria and low-density lipoprotein (LDL) cholesterol cut-points., Design and Setting: Clinical and mutation criteria for FH and LDL cholesterol cut-points were applied for identification of familial premature myocardial infarction in 106,732 individuals from the Copenhagen General Population Study., Results: FH criteria identified 898 (13%) cases with familial premature myocardial infarction, leaving 5856 (87%) cases undetected. The ORs for familial premature myocardial infarction, compared with the respective remainder groups, were 4.7 (95% CI, 3.7 to 6.0) for clinical FH by Dutch Lipid Clinic Network criteria, 4.4 (4.0 to 4.7) for Simon Broome criteria, 2.1 (95% CI, 1.7 to 3.6) for Make Early Diagnosis to Prevent Early Death criteria, 2.1 (95% CI, 1.4 to 3.3) for FH mutation, and 1.4 (95% CI, 1.3 to1.6) for LDL cholesterol ≥5 mmol/L (193 mg/dL). For these risk groups, the sensitivity (true positive rate) for identification of familial premature myocardial infarction were 1.3%, 13%, 1.6%, 0.9%, and 7.1%, respectively. Compared with universal screening of a similar fraction of the population, the relative increase in sensitivity for these risk groups was 3.8-fold [fraction of population examined: 0.3%, 3.3-fold (4%), 2.0-fold (0.8%), 2.0-fold (0.4%), and 1.4-fold (5.3%), respectively]., Conclusion: Criteria for FH identify a small fraction of individuals with familial premature myocardial infarction in the general population. Actively identifying families with premature myocardial infarction would be of potential preventive importance, and this study provides data that could be used to choose the best method for such family identification., (Copyright © 2019 Endocrine Society.)

Context: Individuals with familial hypercholesterolemia (FH) have a high risk of coronary artery disease, but their risk of peripheral arterial disease (PAD) and chronic kidney disease (CKD) is unknown., Objective: In individuals with clinical FH, we tested the hypotheses (1) that the risks of PAD and CKD are elevated and (2) that low ankle-brachial index (ABI) and estimated glomerular filtration rate (eGFR) are associated with a high risk of myocardial infarction., Design and Setting: Prospective cohort study of the general population., Participants: A total of 106,172 individuals, of whom 7109 were diagnosed with FH., Main Outcome Measures: PAD, CKD, and myocardial infarction., Results: Compared with individuals with unlikely FH, multivariable adjusted ORs (95% CIs) of PAD were 1.84 (1.70 to 2.00) in those with possible FH and 1.36 (1.00 to 1.84) in individuals with probable/definite FH. For CKD, the corresponding ORs (95% CIs) were 1.92 (1.78 to 2.07) and 2.42 (1.86 to 3.26). Compared with individuals with unlikely FH and ABI >0.9, the multivariable adjusted hazard ratio (95% CI) of myocardial infarction was 4.60 (2.36 to 8.97) in those with possible/probable/definite FH and ABI ≤0.9. Compared with individuals with unlikely FH and eGFR ≥60 mL/min/1.73 m2, the corresponding value was 2.19 (1.71 to 2.82) in those with possible/probable/definite FH and eGFR <60 mL/min/1.73 m2., Conclusions: Individuals with clinical FH have increased risks of PAD and CKD, and low ABI and eGFR are associated with high risk of myocardial infarction. Consequently, individuals with FH should be screened for PAD and CKD, and ABI and eGFR may be used as prognostic tools in the management and treatment of FH to identify those at very high risk of myocardial infarction.

Aims: Myocardial infarction (MI) and gallstone disease (GSD) are intrinsically linked via cholesterol metabolism. We tested the hypothesis that genetic variants in the gene encoding cholesterol 7 alpha-hydroxylase (CYP7A1), the rate-limiting enzyme in the conversion of cholesterol to bile acids in the liver, are associated with risk of MI and GSD in the general population., Methods and Results: We performed tests of association between lipid levels and eight rare non-synonymous mutations and two common variants, rs2081687 and rs3808607, in CYP7A1 in 100 149 individuals from the general population. We further tested whether weighted allele scores for rs2081687 and rs3808607, which were associated with increased plasma levels of low-density lipoprotein (LDL) cholesterol, were associated with an increased risk of both MI and symptomatic GSD. During a mean follow-up of 7 years (0-23 years), MI developed in 2326 individuals and GSD in 2007. For rare mutations, CYP7A1 allele count was associated with an increase in LDL cholesterol of 12% (0.4 mmol/L) for individuals with the highest vs. the lowest allele count (P for trend = 3 × 10-4). For common variants, CYP7A1 weighted allele scores in individuals with a score >0.04 vs. ≤0 were associated with stepwise increases in LDL cholesterol of up to 2.4% (0.08 mmol/L), and with corresponding multifactorially adjusted hazard ratios of 1.25 [95% confidence interval (CI) 1.10-1.41] for MI and 1.39 (95% CI 1.22-1.59) for GSD (P for trend = 5 × 10-4 and 2 × 10-7, respectively). Results were similar in meta-analyses including publicly available data from large consortia., Conclusion: Genetic variants in CYP7A1 which are associated with increased levels of LDL cholesterol, are associated with an increased risk of both MI and GSD.

Background: We tested whether high remnant cholesterol is associated with high myocardial infarction risk, independent of whether an individual is normal weight, overweight, or obese., Methods: A total of 106216 individuals from the Copenhagen General Population Study were followed for up to 11 years, during which 1565 experienced a myocardial infarction. Individuals were grouped by clinically meaningful remnant cholesterol concentrations of <0.5 mmol/L (19 mg/dL), 0.5 to 0.99 mmol/L (19-38 mg/dL), 1.0 to 1.49 mmol/L (39-58 mg/dL), and ≥1.5 mmol/L (58 mg/dL), and by body mass index (BMI) of <18.5 kg/m 2 (underweight), 18.5 to 24.9 kg/m 2 (normal weight), 25 to 29.9 kg/m 2 (overweight), and ≥30 kg/m 2 (obese)., Results: Median calculated remnant cholesterol was 0.40 mmol/L [interquartile range (IQR), 0.30-0.55 mmol/L] [15 mg/dL (12-21 mg/dL)] for underweight, 0.50 mmol/L (IQR, 0.37-0.71 mmol/L) [19 mg/dL (14-27 mg/dL)] for normal weight, 0.70 mmol/L (IQR, 0.49-1.00 mmol/L) [27 mg/dL (19-39 mg/dL)] for overweight, and 0.85 mmol/L (IQR, 0.61-1.20 mmol/L) [(33 mg/dL (24-46 mg/dL)] for obese individuals. On continuous scales, remnant cholesterol was positively correlated with BMI until reaching a plateau of approximately 1 mmol/L (39 mg/dL) at BMI >35 kg/m 2 . R from an unadjusted linear regression for the correlation between calculated remnant cholesterol and BMI was 12%. Stepwise higher remnant cholesterol was associated with stepwise higher myocardial infarction risk in a similar pattern for normal weight, overweight, and obese individuals. When compared with individuals with remnant cholesterol <0.5 mmol/L (19 mg/dL), individuals with remnant cholesterol ≥1.5 mmol/L (58 mg/dL) had hazard ratios for myocardial infarction of 2.0 (95% CI, 1.3-3.2) for normal weight, 1.9 (95% CI, 1.4-2.6) for overweight, and 2.3 (95% CI, 1.4-3.5) for obese individuals. Directly measured remnant cholesterol increased 0.91 mmol/L (95% CI, 0.89-0.94 mmol/L) [35 mg/dL (34-36 mg/dL)] per 1 mmol/L (39 mg/dL) increase in calculated remnant cholesterol.2 from an unadjusted linear regression for the correlation between calculated remnant cholesterol and BMI was 12%. Stepwise higher remnant cholesterol was associated with stepwise higher myocardial infarction risk in a similar pattern for normal weight, overweight, and obese individuals. When compared with individuals with remnant cholesterol <0.5 mmol/L (19 mg/dL), individuals with remnant cholesterol ≥1.5 mmol/L (58 mg/dL) had hazard ratios for myocardial infarction of 2.0 (95% CI, 1.3-3.2) for normal weight, 1.9 (95% CI, 1.4-2.6) for overweight, and 2.3 (95% CI, 1.4-3.5) for obese individuals. Directly measured remnant cholesterol increased 0.91 mmol/L (95% CI, 0.89-0.94 mmol/L) [35 mg/dL (34-36 mg/dL)] per 1 mmol/L (39 mg/dL) increase in calculated remnant cholesterol., Conclusions: Remnant cholesterol and BMI were positively correlated; however, high remnant cholesterol was associated with higher myocardial infarction risk across the examined BMI subcategories, indicating that remnant cholesterol is a risk factor for myocardial infarction independent of overweight and obesity., (© 2017 American Association for Clinical Chemistry.)

Context: APOEε2/3/4 genotypes affect plasma lipoprotein(a); however, the effects of APOE genotypes on the prediction of myocardial infarction and aortic valve stenosis by lipoprotein(a) are unknown., Objective: We tested the hypothesis that APOEε2/3/4 genotype affects plasma lipoprotein(a), the contribution of plasma apoE levels to this association as well as the associated risk of myocardial infarction and aortic valve stenosis., Design and Outcome Measures: In 46,615 individuals from the general population, we examined plasma lipoprotein(a), APOE ε2/3/4, and incidence of myocardial infarction (n = 1807) and aortic valve stenosis (n = 345) over 37 years of follow-up (range: 0.3 to 38 years)., Results: Compared with ε33, age- and sex-adjusted lipoprotein(a) concentrations were lower by 15% in ε23, by 24% in ε24, and by 36% in ε22; adjusted for plasma apolipoprotein E, corresponding values were 22%, 28%, and 62%. These reductions were independent of LPA genotypes. Compared with ε2 carriers with lipoprotein(a) ≤50 mg/dL, the hazard ratio for myocardial infarction was 1.26 (95% confidence interval: 1.06 to 1.49) for ε2 noncarriers with lipoprotein(a) ≤50 mg/dL, 1.68 (1.21 to 2.32) for ε2 carriers with lipoprotein(a) >50 mg/dL, and 1.92 (1.59 to 2.32) for ε2 noncarriers with lipoprotein(a) >50 mg/dL (interaction, P = 0.57); corresponding values for aortic valve stenosis were 1.05 (0.74 to 1.51), 1.49 (0.72 to 3.08), and 2.04 (1.46 to 2.26) (interaction, P = 0.50). Further adjustment for APOE ε2/3/4 genotype had minimal influence on these risk estimates., Conclusions: APOE ε2 is a strong genetic determinant of low lipoprotein(a) concentrations but does not modify the causal association of lipoprotein(a) with myocardial infarction or aortic valve stenosis., (Copyright © 2017 Endocrine Society)

Objective: High lipoprotein(a) (Lp[a]) is the most common genetic dyslipidemia and is a causal factor for myocardial infarction (MI) and aortic stenosis (AS). We sought to estimate the population impact of Lp(a) lowering that could be achieved in primary prevention using the therapies in development., Approach and Results: We used published data from 2 prospective cohorts. High Lp(a) was defined as ≥50 mg/dL (≈20th percentile). Relative risk, attributable risk, the attributable risk percentage, population attributable risk, and the population attributable risk percentage were calculated as measures of the population impact. For MI, the event rate was 4.0% versus 2.8% for high versus low Lp(a) (relative risk, 1.46; 95% confidence interval [CI], 1.45-1.46). The attributable risk was 1.26% (95% CI, 1.24-1.27), corresponding to 31.3% (95% CI, 31.0-31.7) of the excess MI risk in those with high Lp(a). The population attributable risk was 0.21%, representing a population attributable risk percentage of 7.13%. For AS, the event rate was 1.51% versus 0.78% for high versus low Lp(a) (relative risk, 1.95; 95% CI, 1.94-1.97). The attributable risk was 0.74% (95% CI, 0.73-0.75), corresponding to 48.8% (95% CI, 48.3-49.3) of the excess AS risk in those with high Lp(a). The population attributable risk was 0.13%, representing a population attributable risk percentage of 13.9%. In sensitivity analyses targeting the top 10% of Lp(a), the population attributable risk percentage was 5.2% for MI and 7.8% for AS., Conclusions: Lp(a) lowering among the top 20% of the population distribution for Lp(a) could prevent 1 in 14 cases of MI and 1 in 7 cases of AS, suggesting a major impact on reducing the burden of cardiovascular disease. Targeting the top 10% could prevent 1 in 20 MI cases and 1 in 12 AS cases., (© 2016 American Heart Association, Inc.)

Human epidemiologic and genetic evidence using the Mendelian randomization approach in large-scale studies now strongly supports that elevated lipoprotein (a) [Lp(a)] is a causal risk factor for cardiovascular disease, that is, for myocardial infarction, atherosclerotic stenosis, and aortic valve stenosis. The Mendelian randomization approach used to infer causality is generally not affected by confounding and reverse causation, the major problems of observational epidemiology. This approach is particularly valuable to study causality of Lp(a), as single genetic variants exist that explain 27-28% of all variation in plasma Lp(a). The most important genetic variant likely is the kringle IV type 2 (KIV-2) copy number variant, as the apo(a) product of this variant influences fibrinolysis and thereby thrombosis, as opposed to the Lp(a) particle per se. We speculate that the physiological role of KIV-2 in Lp(a) could be through wound healing during childbirth, infections, and injury, a role that, in addition, could lead to more blood clots promoting stenosis of arteries and the aortic valve, and myocardial infarction. Randomized placebo-controlled trials of Lp(a) reduction in individuals with very high concentrations to reduce cardiovascular disease are awaited. Recent genetic evidence documents elevated Lp(a) as a cause of myocardial infarction, atherosclerotic stenosis, and aortic valve stenosis., (Copyright © 2016 by the American Society for Biochemistry and Molecular Biology, Inc.)

Context: Novel, low-density lipoprotein (LDL) cholesterol-lowering proprotein convertase subtilisin/kexin type-9 (PCSK9) inhibitors also lower lipoprotein(a) levels, but the effect on aortic valve stenosis and myocardial infarction is unknown., Objective: We tested the hypothesis that the PCSK9 R46L loss-of-function mutation is associated with lower levels of lipoprotein(a) and with reduced risk of aortic valve stenosis and myocardial infarction., Design: We used two prospective cohort studies of the general population and one patient-based cohort., Setting: Cohort studies selected at random individuals of Danish descent., Participants: We studied 103 083 individuals from the Copenhagen General Population Study, the Copenhagen City Heart Study, and the Copenhagen Ischemic Heart Disease Study., Main Outcome Measures: Lipoprotein(a), LDL cholesterol, and PCSK9 R46L genotype and diagnoses of aortic valve stenosis and myocardial infarction from national registries; lipoprotein(a) was measured from 49,617 individuals., Results: Median (interquartile range) lipoprotein(a) levels were 10 (5-30) mg/dl for PCSK9 R46L noncarriers, 9 (4-32) mg/dl for heterozygotes, and 8 (4-42) mg/dl for homozygotes (trend P = .02). The corresponding values for LDL cholesterol levels were 124 (101-147) mg/dl, 104 (85-132) mg/dl, and 97 (85-128) mg/dl, respectively (trend P = 2 × 10(-52)). PCSK9 R46L carriers vs noncarriers had an age- and sex-adjusted odds ratio of 0.64 (95% confidence interval, 0.44-0.95) for aortic valve stenosis, 0.77 (0.65-0.92) for myocardial infarction, and 0.76 (0.64-0.89) for aortic valve stenosis or myocardial infarction., Conclusions: PCSK9 R46L carriers have lower levels of lipoprotein(a) and LDL cholesterol as well as reduced risk of aortic valve stenosis and myocardial infarction. This indirectly suggests that PCSK9 inhibitors may have a role in patients with aortic valve stenosis.

Importance: The prevalence of cardiometabolic multimorbidity is increasing., Objective: To estimate reductions in life expectancy associated with cardiometabolic multimorbidity., Design, Setting, and Participants: Age- and sex-adjusted mortality rates and hazard ratios (HRs) were calculated using individual participant data from the Emerging Risk Factors Collaboration (689,300 participants; 91 cohorts; years of baseline surveys: 1960-2007; latest mortality follow-up: April 2013; 128,843 deaths). The HRs from the Emerging Risk Factors Collaboration were compared with those from the UK Biobank (499,808 participants; years of baseline surveys: 2006-2010; latest mortality follow-up: November 2013; 7995 deaths). Cumulative survival was estimated by applying calculated age-specific HRs for mortality to contemporary US age-specific death rates., Exposures: A history of 2 or more of the following: diabetes mellitus, stroke, myocardial infarction (MI)., Main Outcomes and Measures: All-cause mortality and estimated reductions in life expectancy., Results: In participants in the Emerging Risk Factors Collaboration without a history of diabetes, stroke, or MI at baseline (reference group), the all-cause mortality rate adjusted to the age of 60 years was 6.8 per 1000 person-years. Mortality rates per 1000 person-years were 15.6 in participants with a history of diabetes, 16.1 in those with stroke, 16.8 in those with MI, 32.0 in those with both diabetes and MI, 32.5 in those with both diabetes and stroke, 32.8 in those with both stroke and MI, and 59.5 in those with diabetes, stroke, and MI. Compared with the reference group, the HRs for all-cause mortality were 1.9 (95% CI, 1.8-2.0) in participants with a history of diabetes, 2.1 (95% CI, 2.0-2.2) in those with stroke, 2.0 (95% CI, 1.9-2.2) in those with MI, 3.7 (95% CI, 3.3-4.1) in those with both diabetes and MI, 3.8 (95% CI, 3.5-4.2) in those with both diabetes and stroke, 3.5 (95% CI, 3.1-4.0) in those with both stroke and MI, and 6.9 (95% CI, 5.7-8.3) in those with diabetes, stroke, and MI. The HRs from the Emerging Risk Factors Collaboration were similar to those from the more recently recruited UK Biobank. The HRs were little changed after further adjustment for markers of established intermediate pathways (eg, levels of lipids and blood pressure) and lifestyle factors (eg, smoking, diet). At the age of 60 years, a history of any 2 of these conditions was associated with 12 years of reduced life expectancy and a history of all 3 of these conditions was associated with 15 years of reduced life expectancy., Conclusions and Relevance: Mortality associated with a history of diabetes, stroke, or MI was similar for each condition. Because any combination of these conditions was associated with multiplicative mortality risk, life expectancy was substantially lower in people with multimorbidity.

Context: It is unknown whether elevated lipoprotein(a) is causally associated with low-grade inflammation., Objective: We tested the hypothesis that elevated lipoprotein(a) is observationally and causally associated with low-grade inflammation together with aortic valve stenosis and myocardial infarction., Design and Setting: Using a multidirectional Mendelian randomization approach, we studied 100,578 individuals from the Danish general population with plasma levels of and/or genotypes known to affect levels of lipoprotein(a) and C-reactive protein (CRP), and using information regarding diagnosis of aortic valve stenosis and of myocardial infarction (MI) from registries., Results: Observationally, CRP increased by 29% (95% confidence interval [CI], 23-34) per 50-mg/dL increase in lipoprotein(a). However, two LPA single nucleotide polymorphisms (SNPs) and the kringle IV type 2 (KIV-2) genotype that were associated with 98, 95, and 68 mg/dL higher lipoprotein(a) levels were not causally associated with increased CRP levels. For aortic valve stenosis, a 1-SD increase in lipoprotein(a) levels was associated observationally with a multifactorially adjusted hazard ratio of 1.23 (95% CI, 1.06-1.41), with corresponding causal risk ratios of 1.38 (1.23-1.55) based on LPA SNPs and of 1.21 (1.06-1.40) based on LPA KIV-2 genotype. For myocardial infarction, corresponding values were 1.20 (1.10;1.31) observationally, and 1.18 (1.11;1.26) and 1.31 (1.22;1.42) causally, respectively. Observational hazard ratios for aortic valve stenosis and MI were similar after further adjustment for CRP levels., Conclusions: Elevated levels of lipoprotein(a) were not causally associated with increased low-grade inflammation as measured through CRP despite a causal association with increased risk of aortic valve stenosis and MI.

Background: Human immunodeficiency virus-infected individuals have increased risk of myocardial infarction (MI); however, the contribution from smoking and potentiating effects of HIV are controversial., Methods: From the Danish HIV Cohort Study and the Copenhagen General Population Study, we identified 3251 HIV-infected individuals and 13 004 population controls matched on age and gender. Data on MI were obtained from the National Hospital Registry and the National Registry of Causes of Death. We calculated adjusted incidence rate ratios (aIRR) for risk of MI and population-attributable fractions (PAF) of MI associated with smoking., Results: In never smokers, HIV was not associated with an increased risk of MI (aIRR, 1.01; 95% confidence interval [CI], .41-2.54). In previous and current smokers, HIV was associated with a substantially increased risk of MI (aIRR, 1.78; 95% CI, .75-4.24 and aIRR, 2.83; 95% CI, 1.71-4.70). The PAF associated with ever smoking (previous or current) was 72% (95% CI, 55%-82%) for HIV-infected individuals and 24% (95% CI, 3%-40%) for population controls. If all current smokers stopped smoking, 42% (95% CI, 21%-57%) and 21% (95% CI, 12%-28%) of all MIs could potentially be avoided in these 2 populations., Conclusions: Smoking is associated with a higher risk of MI in the HIV-infected population than in the general population. Approximately 3 of 4 MIs among HIV-infected individuals are associated with ever smoking compared with only 1 of 4 MIs among population controls. Smoking cessation could potentially prevent more than 40% of MIs among HIV-infected individuals, and smoking cessation should be a primary focus in modern HIV care., (© The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Objective: We tested the hypothesis that moderately elevated plasma creatinine levels and decreased levels of estimated glomerular filtration rate (eGFR) are associated with increased risk of myocardial infarction, ischemic heart disease, and early death in the general population., Methods: We studied 10,489 individuals with a plasma creatinine measurement and calculated eGFR from the Danish general population, of which 1498 developed myocardial infarction, 3001 ischemic heart disease, and 7573 died during 32 years follow-up., Results: Cumulative incidences of myocardial infarction and ischemic heart disease as a function of age increased with increasing levels of creatinine, and survival decreased (log-rank trends: <0.001). The median survival age was 78.7 (95%CI: 78.0-79.2) years for persons with creatinine levels <90th percentile, 78.1 (76.3-79.5) years for 90th-94th percentiles, and 74.8 (72.8-76.7) years for ≥95th percentile. Hazard ratios for myocardial infarction and plasma creatinine levels of 90th-94th percentiles and ≥95th percentile versus <50th percentile were 2.06 (95%CI: 1.67-2.56) and 1.90 (1.56-2.31) adjusted for gender and age, and 1.35 (1.09-1.68) and 1.11 (0.90-1.36) adjusted multifactorially, respectively. Corresponding estimates for creatinine and ischemic heart disease were 1.57 (1.33-1.85) and 1.64 (1.42-1.89) adjusted for gender and age, and 1.16 (0.98-1.37) and 1.11 (0.95-1.29) adjusted multifactorially. Finally, corresponding values for early death were 1.18 (1.06-1.32) and 1.43 (1.30-1.57), and 0.97 (0.87-1.09) and 1.13 (1.02-1.24), respectively. Low eGFR did not associate consistently with increased risk of these endpoints., Conclusion: In the general population, moderately elevated plasma creatinine was associated with increased risk of myocardial infarction, ischemic heart disease, and early death, while low eGFR was not., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Objectives: The study sought to test the hypothesis that genetic variation in ABCG5/8, the transporter responsible for intestinal and hepatobiliary cholesterol efflux, may simultaneously influence plasma and biliary cholesterol levels, and hence risk of myocardial infarction (MI) and gallstone disease in opposite directions., Background: High plasma levels of low-density lipoprotein (LDL) cholesterol are a causal risk factor for MI, whereas high levels of biliary cholesterol promote gallstone formation., Methods: A total of 60,239 subjects from Copenhagen were included, including 5,647 with MI and 3,174 with symptomatic gallstone disease. Subjects were genotyped for 6 common, nonsynonymous and functional variants in ABCG5/8, and a combined weighted genotype score was calculated., Results: Combined, weighted genotype scores were associated with stepwise decreases in LDL cholesterol of up to 5.9% (0.20 mmol/l) for individuals with a score ≥8.0 (prevalence = 11%) versus <2.0 (prevalence = 9%; p for trend across 5 groups = 2 × 10E-35). The cumulative incidences of MI and gallstone disease as a function of age and increasing genotype score were decreased and increased (log-rank ps for trend: 6 × 10E-4 and 9 × 10E-45), respectively. The multifactorially adjusted odds ratios were 0.83 (95% confidence interval: 0.73 to 0.94) for MI and 2.85 (95% confidence interval: 2.39 to 3.39) for symptomatic gallstone disease for individuals with a genotype score ≥8.0 versus <2.0., Conclusions: Genetic variation in ABCG5/8, which associates with decreased levels of plasma LDL cholesterol protects against MI, but increases the risk of symptomatic gallstone disease. These results suggest that MI and gallstones, 2 seemingly unrelated diseases, are intrinsically linked via the function of the ABCG5/8 cholesterol transporter., (Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Cardiovascular disease is 1 of the most common age-related diseases, and also 1 of the most common causes of death in the general population. We tested the hypothesis that visible age-related signs associate with risk of ischemic heart disease (IHD), myocardial infarction (MI), and death in the general population, independent of chronological age., Methods and Results: 10,885 individuals aged 20 to 93 years free of IHD were followed from 1976 through 1978 until June 2011 with 100% complete follow-up. During these 35 years of follow-up, 3401 participants developed IHD and 1708 developed MI. Presence of frontoparietal baldness, crown top baldness, earlobe crease, and xanthelasmata was associated with increased risk of IHD or MI after multifactorial adjustment for chronological age and well-known cardiovascular risk factors. The risk of IHD and MI increased stepwise with increasing number of age-related signs with multifactorially adjusted hazard ratios up to 1.40 (95% confidence interval, 1.20-1.62) for IHD and 1.57 (1.28-1.93) for MI, in individuals with 3 to 4 versus no age-related signs at baseline (P for trend <0.001). In all age groups in both women and men, absolute 10-year risk of IHD and MI increased with increasing number of visible age-related signs., Conclusions: Male pattern baldness, earlobe crease, and xanthelasmata-alone or in combination-associate with increased risk of ischemic heart disease and myocardial infarction independent of chronological age and other well-known cardiovascular risk factors. This is the first prospective study to show that looking old for your age is a marker of poor cardiovascular health.

Importance: Overweight and obesity likely cause myocardial infarction (MI) and ischemic heart disease (IHD); however, whether coexisting metabolic syndrome is a necessary condition is unknown., Objective: To test the hypothesis that overweight and obesity with and without metabolic syndrome are associated with increased risk of MI and IHD., Design, Setting, and Participants: We examined 71,527 individuals from the Copenhagen General Population Study and categorized them according to body mass index (BMI) as normal weight, overweight, or obese and according to absence or presence of metabolic syndrome., Main Outcomes and Measures: Hazard ratios for incident MI and IHD according to combinations of BMI category and absence or presence of metabolic syndrome., Results: During a median of 3.6 years' follow-up, we recorded 634 incident MI and 1781 incident IHD events. For MI, multivariable adjusted hazard ratios vs normal weight individuals without metabolic syndrome were 1.26 (95% CI, 1.00-1.61) in overweight and 1.88 (95% CI, 1.34-2.63) in obese individuals without metabolic syndrome and 1.39 (95% CI, 0.96-2.02) in normal weight, 1.70 (95% CI, 1.35-2.15) in overweight, and 2.33 (95% CI, 1.81-3.00) in obese individuals with metabolic syndrome. For IHD, results were similar but attenuated. Normal weight vs overweight vs obesity and presence vs absence of metabolic syndrome did not interact on risk of MI or IHD (P = .90 and P = .44). Among individuals both with and without metabolic syndrome there were increasing cumulative incidences of MI and IHD from normal weight through overweight to obese individuals (log-rank trend P = .006 to P < .001). Although the multivariable adjusted hazard ratio for MI in individuals with vs without metabolic syndrome was 1.54 (95% CI, 1.32-1.81) across all BMI categories, addition of metabolic syndrome to a multivariable model including BMI and other clinical characteristics improved the Harell C-statistic only slightly for risk of MI (comparison P = .03) but not for IHD (P = .41)., Conclusions and Relevance: These findings suggest that overweight and obesity are risk factors for MI and IHD regardless of the presence or absence of metabolic syndrome and that metabolic syndrome is no more valuable than BMI in identifying individuals at risk.

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=22,107), 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.

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.

Background: ABO blood type locus has been reported to be an important genetic determinant of venous and arterial thrombosis in genome-wide association studies. We tested the hypothesis that ABO blood type alone and in combination with mutations in factor V Leiden R506Q and prothrombin G20210A is associated with the risk of venous thromboembolism and myocardial infarction in the general population., Methods: We used data from 2 Danish studies that followed members of the general public from 1977 through 2010. We obtained the genotype of 66 001 white participants for ABO blood type, factor V Leiden R506Q and prothrombin G20210A. We calculated hazard ratios (HRs) and population attributable risk. Our main outcome measures were venous thromboembolism and myocardial infarction., Results: The multivariable adjusted HR for venous thromboembolism was 1.4 (95% confidence interval [CI] 1.3-1.5) for non-O blood type (v. O blood type). For the factor V Leiden R506Q mutation, the adjusted HR was 2.2 (95% CI 2.0-2.5) for heterozygous participants and 7.0 (95%CI 4.8-10) for homozygous participants (v. participants without the mutation). For prothrombin G20210A, the adjusted HR was 1.5 (95%CI 1.2-1.9) for heterozygous participants and 11 (95% CI 2.8-44) for homozygous participants (v. participants without the mutation). When we combined ABO blood type and factor V Leiden R506Q or prothrombin G20210A genotype, there was a stepwise increase in the risk of venous thromboembolism (trend, p<0.001). The population attributable risk of venous thromboembolism was 20% for ABO blood type, 10% for factor V Leiden R506Q and 1% for prothrombin G20210A. Multivariable adjusted HRs for myocardial infarction by genotypes did not differ from 1.0., Interpretation: ABO blood type had an additive effect on the risk of venous thromboembolism when combined with factor V Leiden R506Q and prothrombin G20210A mutations; blood type was the most important risk factor for venous thromboembolism in the general population.

Objectives: The study tested whether extreme lipoprotein(a) levels and/or corresponding LPA risk genotypes improve myocardial infarction (MI) and coronary heart disease (CHD) risk prediction beyond conventional risk factors., Background: Elevated lipoprotein(a) levels cause MI and CHD. Levels are primarily determined by variation in the LPA gene., Methods: We followed 8,720 Danish participants in a general population study from 1991 to 1994 through 2011 without losses to follow-up. During this period, 730 and 1,683 first-time MI and CHD events occurred. Using predefined cutpoints for extreme lipoprotein(a) levels and/or corresponding LPA risk genotypes (kringle IV type 2 [KIV-2]) repeat polymorphism, rs3798220, and rs10455872 single nucleotide polymorphisms), we calculated net reclassification indices from <10% to 10% to 19.9% to ≥20% absolute 10-year MI and CHD risk., Results: For individuals with lipoprotein(a) levels ≥80th percentile (≥47 mg/dl), 23% (p < 0.001) of MI events and 12% (p < 0.001) of CHD events were reclassified correctly, while no events were reclassified incorrectly for either endpoint. As some incorrect reclassification of individuals with no events occurred, addition of lipoprotein(a) levels ≥80th percentile overall yielded net reclassification indices of +16% (95% confidence interval: 8% to 24%) and +3% (-1% to 8%) for MI and CHD, respectively. Corresponding net reclassification indices for number of KIV-2 repeats ≤21st percentile were +12% (5% to 19%) and +4% (0% to 8%), for rs3798220 carrier status +15% (-14% to 44%) and +10% (-10% to 30%), and for rs10455872 carrier status +16% (6% to 26%) and +2% (-1% to 6%). Considering only individuals at 10% to 19.9% absolute 10-year MI and CHD risk, addition of extreme lipoprotein(a) levels or corresponding LPA risk genotypes improved risk prediction even further., Conclusions: Extreme lipoprotein(a) levels or corresponding LPA KIV-2/rs10455872 risk genotypes substantially improved MI and CHD risk prediction., (Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objective: We tested the hypothesis that reduced plasma 25-hydroxyvitamin D associates with increased risk of ischemic heart disease, myocardial infarction, and early death., Methods and Results: We measured baseline plasma 25-hydroxyvitamin D in 10 170 women and men from the Danish general population without vitamin D-fortified food. During 29 years of follow-up, 3100 persons developed ischemic heart disease, 1625 myocardial infarction, and 6747 died. Decreasing plasma 25-hydroxyvitamin D levels were associated with increasing risk of ischemic heart disease, myocardial infarction, and early death as a function of seasonally adjusted percentile categories (P for trend, 2×10(-4)-3×10(-53)). Comparing individuals with plasma 25-hydroxyvitamin D levels at the 1st to 4th percentile with individuals with levels at the 50th to 100th percentile, the multivariable adjusted risk was increased by 40% (95% CI, 14%-72%) for ischemic heart disease, by 64% (25%-114%) for myocardial infarction, by 57% (38%-78%) for early death, and by 81% (40%-135%) for fatal ischemic heart disease/myocardial infarction. In the meta-analyses of 18 and 17 studies, risk of ischemic heart disease and early death were increased by 39% (25%-54%) and 46% (31%-64%) for lowest versus highest quartile of 25-hydroxyvitamin D level., Conclusions: We observed increasing risk of ischemic heart disease, myocardial infarction, and early death with decreasing plasma 25-hydroxyvitamin D levels. These findings were substantiated in meta-analyses.

Objective: We tested the hypothesis that short telomere length is associated with increased risk of myocardial infarction, ischemic heart disease, and early death., Methods and Results: We measured leukocyte telomere length in 2 prospective studies of 19 838 Danish general population participants from the Copenhagen City Heart Study and the Copenhagen General Population Study. Participants were followed for up to 19 years for incident myocardial infarction (n=929), ischemic heart disease (n=2038), and death (n=4342). Follow-up was 100% complete. Telomere length decreased linearly with increasing age in women and men in both studies (P=7×10(-74) to P=3×10(-125)). Multifactorially adjusted hazard ratios were 1.10 (95% CI 1.01-1.19) for myocardial infarction, 1.06 (1.00-1.11) for ischemic heart disease, and 1.09 (1.05-1.13) for early death per 1000-base pair decrease in telomere length. The multifactorially adjusted hazard ratios for the shortest versus the longest decile of telomere length were 1.49 (1.07-2.07) for myocardial infarction, 1.24 (1.01-1.53) for ischemic heart disease, and 1.25 (1.07-1.46) for early death., Conclusion: Short telomere length is associated with only modestly increased risk of myocardial infarction, ischemic heart disease, and early death.

Objective: ATP binding cassette transporter G1 (ABCG1) facilitates cholesterol efflux from macrophages to mature high-density lipoprotein particles. Whether genetic variation in ABCG1 affects risk of atherosclerosis in humans remains to be determined., Methods and Results: We resequenced the core promoter and coding regions of ABCG1 in 380 individuals from the general population. Next, we genotyped 10 237 individuals from the Copenhagen City Heart Study for the identified variants and determined the effect on lipid and lipoprotein levels and on risk of myocardial infarction (MI) and ischemic heart disease (IHD). g.-376C>T, g.-311T>A, and Ser630Leu predicted risk of MI in the Copenhagen City Heart Study, with hazard ratios of 2.2 (95% confidence interval: 1.2-4.3), 1.7 (1.0-2.9), and 7.5 (1.9-30), respectively. These results were confirmed for g.-376C>T in a case-control study comprising 4983 independently ascertained IHD cases and 7489 controls. Expression levels of ABCG1 mRNA were decreased by approximately 40% in g.-376C>T heterozygotes versus noncarriers (probability values: 0.005-0.009). Finally, in vitro specificity protein 1 (Sp1) bound specifically to a putative Sp1 binding site at position -382 to -373 in the ABCG1 promoter, and the presence of the -376 T allele reduced binding and transactivation of the promoter by Sp1., Conclusions: This is the first report of a functional variant in ABCG1 that associates with increased risk of MI and IHD in the general population.

Rare genetic variants, identified by in-detail resequencing of loci, may contribute to complex traits. We used the apolipoprotein A-I gene (APOA1), a major high-density lipoprotein (HDL) gene, and population-based resequencing to determine the spectrum of genetic variants, the phenotypic characteristics of these variants, and how these results compared with results based on resequencing only the extremes of the apolipoprotein A-I (apoA-I) distribution. First, we resequenced APOA1 in 10,330 population-based participants in the Copenhagen City Heart Study. The spectrum and distribution of genetic variants was determined as a function of the number of individuals resequenced. Second, apoA-I and HDL cholesterol phenotypes were determined for nonsynonymous (NS) and synonymous (S) variants and were validated in the Copenhagen General Population Study (n = 45,239). Third, observed phenotypes were compared with those predicted using an extreme phenotype approach based on the apoA-I distribution. Our results are as follows: First, population-based resequencing of APOA1 identified 40 variants of which only 7 (18%) had minor allele frequencies >1%, and most were exceedingly rare. Second, 0.27% of individuals in the general population were heterozygous for NS variants which were associated with substantial reductions in apoA-I (up to 39 mg/dL) and/or HDL cholesterol (up to 0.9 mmol/L) and, surprisingly, 0.41% were heterozygous for variants predisposing to amyloidosis. NS variants associated with a hazard ratio of 1.72 (1.09-2.70) for myocardial infarction (MI), largely driven by A164S, a variant not associated with apoA-I or HDL cholesterol levels. Third, using the extreme apoA-I phenotype approach, NS variants correctly predicted the apoA-I phenotype observed in the population-based resequencing. However, using the extreme approach, between 79% (screening 0-1(st) percentile) and 21% (screening 0-20(th) percentile) of all variants were not identified; among these were variants previously associated with amyloidosis. Population-based resequencing of APOA1 identified a majority of rare NS variants associated with reduced apoA-1 and HDL cholesterol levels and/or predisposing to amyloidosis. In addition, NS variants associated with increased risk of MI., Competing Interests: The authors have declared that no competing interests exist.

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.

Elevated levels of lipoprotein(a) are associated with an increased risk of myocardial infarction. Our study aimed to test whether genetic data are consistent with this association being causal. Accordingly, we developed a high-throughput realtime PCR assay to genotype for the lipoprotein(a) kringle IV type 2 (KIV-2) repeat polymorphism in the LPA gene in > 40,000 individuals. The LPA KIV-2 genotype associated with plasma levels of lipoprotein(a) (trend p < 0.001), and the LPA KIV-2 genotype associated with risk of myocardial infarction (trend p < 0.001 to 0.03) in a manner consistent with its effect on plasma levels of lipoprotein(a). The association of LPA KIV-2 genotypes raising plasma levels of lipoprotein(a) with increased risk of myocardial infarction strongly supports a causal association of lipoprotein(a) with risk of myocardial infarction.

Background: HDL-cholesterol concentrations are inversely associated with occurrence of cardiovascular events. We addressed, using the JUPITER trial cohort, whether this association remains when LDL-cholesterol concentrations are reduced to the very low ranges with high-dose statin treatment., Methods: Participants in the randomised placebo-controlled JUPITER trial were adults without diabetes or previous cardiovascular disease, and had baseline concentrations of LDL cholesterol of less than 3.37 mmol/L and high-sensitivity C-reactive protein of 2 mg/L or more. Participants were randomly allocated by a computer-generated sequence to receive rosuvastatin 20 mg per day or placebo, with participants and adjudicators masked to treatment assignment. In the present analysis, we divided the participants into quartiles of HDL-cholesterol or apolipoprotein A1 and sought evidence of association between these quartiles and the JUPITER primary endpoint of first non-fatal myocardial infarction or stroke, hospitalisation for unstable angina, arterial revascularisation, or cardiovascular death. This trial is registered with ClinicalTrials.gov, number NCT00239681., Findings: For 17,802 patients in the JUPITER trial, rosuvastatin 20 mg per day reduced the incidence of the primary endpoint by 44% (p<0.0001). In 8901 (50%) patients given placebo (who had a median on-treatment LDL-cholesterol concentration of 2.80 mmol/L [IQR 2.43-3.24]), HDL-cholesterol concentrations were inversely related to vascular risk both at baseline (top quartile vs bottom quartile hazard ratio [HR] 0.54, 95% CI 0.35-0.83, p=0.0039) and on-treatment (0.55, 0.35-0.87, p=0.0047). By contrast, among the 8900 (50%) patients given rosuvastatin 20 mg (who had a median on-treatment LDL-cholesterol concentration of 1.42 mmol/L [IQR 1.14-1.86]), no significant relationships were noted between quartiles of HDL-cholesterol concentration and vascular risk either at baseline (1.12, 0.62-2.03, p=0.82) or on-treatment (1.03, 0.57-1.87, p=0.97). Our analyses for apolipoprotein A1 showed an equivalent strong relation to frequency of primary outcomes in the placebo group but little association in the rosuvastatin group., Interpretation: Although measurement of HDL-cholesterol concentration is useful as part of initial cardiovascular risk assessment, HDL-cholesterol concentrations are not predictive of residual vascular risk among patients treated with potent statin therapy who attain very low concentrations of LDL cholesterol., Funding: AstraZeneca., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Background: Limited information is available regarding risk factors for the near-term (4 years) onset of myocardial infarction (MI). We evaluated established cardiovascular risk factors and putative circulating biomarkers as predictors for MI within 4 years of measurement., Methods: We conducted a matched, nested case-control study (252 cases and 499 controls) drawing on 45 735 men and women participating in the Copenhagen City Heart Study and the Copenhagen General Population Study. Established risk factors and 17 putative biomarkers, including inflammation-sensitive plasma proteins (C-reactive protein, fibrinogen, alpha(l)-antitrypsin, complement 3), apolipoproteins (A1, B, E, B/A1 ratio), markers of iron overload (iron, transferrin, transferrin saturation), creatinine, alkaline phosphatase, gamma-glutamyl transpeptidase, and leukocytes (lymphocyte count, neutrophil count, neutrophil/lymphocyte ratio) were assessed., Results: Among women and men, only 13% and 50%, respectively, of those with near-term MI were classified as high risk by Framingham risk score at baseline. After adjustment for established risk factors, odds ratios for near-term MI, which compared highest to lowest quintiles, were 2.87(95% CI 1.51-5.48; P = 0.001) for alpha(l)-antitrypsin, 2.84(1.42-5.67; P = 0.003) for C-reactive protein, 1.97(1.09-3.57; P = 0.03) for creatinine, 1.99(1.09-3.65; P = 0.03) for fibrinogen, and 0.37(0.19-0.73; P = 0.004) for iron. The corresponding odds ratio for all biomarkers combined was 7.24 (3.28-16.0; P < 0.001)., Conclusions: We identified 5 biomarkers associated with increased near-term risk of MI independently of established risk factors. All putative biomarkers combined explained a 7-fold increase in the odds of near-term MI.

Background: As recently demonstrated, random allocation to rosuvastatin results in large relative risk reductions for first cardiovascular events among apparently healthy men and women with low levels of low-density lipoprotein cholesterol but elevated levels of high-sensitivity C-reactive protein. However, whether the absolute risk reduction among such individuals justifies wide application of statin therapy in primary prevention is a controversial issue with broad policy and public health implications., Methods and Results: Absolute risk reductions and consequent number needed to treat (NNT) values were calculated across a range of end points, timeframes, and subgroups using data from Justification for the Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER), a randomized evaluation of rosuvastatin 20 mg versus placebo conducted among 17 802 apparently healthy men and women with low-density lipoprotein cholesterol <130 mg/dL and high-sensitivity C-reactive protein >or=2 mg/L. Sensitivity analyses were also performed to address the potential impact that alternative statin regimens might have on a similar primary prevention population. For the end point of myocardial infarction, stroke, revascularization, or death, the 5-year NNT within JUPITER was 20 (95% CI, 14 to 34). All subgroups had 5-year NNT values for this end point below 50; as examples, 5-year NNT values were 17 for men and 31 for women, 21 for whites and 19 for nonwhites, 18 for those with body mass index 300)., Conclusions: Absolute risk reductions and consequent NNT values associated with statin therapy among those with elevated high-sensitivity C-reactive protein and low low-density lipoprotein cholesterol are comparable if not superior to published NNT values for several widely accepted interventions for primary cardiovascular prevention, including the use of statin therapy among those with overt hyperlipidemia., Clinical Trial Registration: clinicaltrials.gov. Identifier NCT00239681.

Background: The risk of myocardial infarction is lower among light-to-moderate alcohol drinkers compared with abstainers. We tested associations between alcohol intake and risk of myocardial infarction and risk factors and whether these associations are modified by variations in alcohol dehydrogenases., Methods and Results: We used information on 9584 men and women from the Danish general population in the Copenhagen City Heart Study. During follow-up, from 1991 to 2007, 663 incident cases of myocardial infarction occurred. We observed that increasing alcohol intake was associated with decreasing risk of myocardial infarction, decreasing low-density lipoprotein cholesterol and fibrinogen, increasing diastolic and systolic blood pressure and high-density lipoprotein cholesterol, and with U-shaped nonfasting triglycerides. In contrast, ADH1B and ADH1C genotypes were not associated with risk of myocardial infarction or with any of the cardiovascular biochemical risk factors, and there was no indication that associations between alcohol intake and myocardial infarction and between alcohol intake and risk factors were modified by genotypes., Conclusions: Increasing alcohol intake is associated with decreasing risk of myocardial infarction, decreasing low-density lipoprotein cholesterol and fibrinogen, increasing diastolic and systolic blood pressure and high-density lipoprotein cholesterol, and U-shaped nonfasting triglycerides. These associations were not modified by ADH1B and ADH1C are genotypes.

Context: High levels of lipoprotein(a) are associated with increased risk of myocardial infarction (MI)., Objective: To assess whether genetic data are consistent with this association being causal., Design, Setting, and Participants: Three studies of white individuals from Copenhagen, Denmark, were used: the Copenhagen City Heart Study (CCHS), a prospective general population study with 16 years of follow-up (1991-2007, n = 8637, 599 MI events); the Copenhagen General Population Study (CGPS), a cross-sectional general population study (2003-2006, n = 29 388, 994 MI events); and the Copenhagen Ischemic Heart Disease Study (CIHDS), a case-control study (1991-2004, n = 2461, 1231 MI events)., Main Outcome Measures: Plasma lipoprotein(a) levels, lipoprotein(a) kringle IV type 2 (KIV-2) size polymorphism genotype, and MIs recorded from 1976 through July 2007 for all participants., Results: In the CCHS, multivariable-adjusted hazard ratios (HRs) for MI for elevated lipoprotein(a) levels were 1.2 (95% confidence interval [CI], 0.9-1.6; events/10,000 person-years, 59) for levels between the 22nd and 66th percentile, 1.6 (95% CI, 1.1-2.2; events/10,000 person-years, 75) for the 67th to 89th percentile, 1.9 (95% CI, 1.2-3.0; events/10,000 person-years, 84) for the 90th to 95th percentile, and 2.6 (95% CI, 1.6-4.1; events/10,000 person-years, 108) for levels greater than the 95th percentile, respectively, vs levels less than the 22nd percentile (events/10,000 person-years, 55) (trend P < .001). Numbers of KIV-2 repeats (sum of repeats on both alleles) ranged from 6 to 99 and on analysis of variance explained 21% and 27% of all variation in plasma lipoprotein(a) levels in the CCHS and CGPS, respectively. Mean lipoprotein(a) levels were 56, 31, 20, and 15 mg/dL for the first, second, third, and fourth quartiles of KIV-2 repeats in the CCHS, respectively (trend P < .001); corresponding values in the CGPS were 60, 34, 22, and 19 mg/dL (trend P < .001). In the CCHS, multivariable-adjusted HRs for MI were 1.5 (95% CI, 1.2-1.9; events/10,000 person-years, 75), 1.3 (95% CI, 1.0-1.6; events/10,000 person-years, 66), and 1.1 (95% CI, 0.9-1.4; events/10,000 person-years, 57) for individuals in the first, second, and third quartiles, respectively, as compared with individuals in the fourth quartile of KIV-2 repeats (events/10,000 person-years, 51) (trend P < .001). Corresponding odds ratios were 1.3 (95% CI, 1.1-1.5), 1.1 (95% CI, 0.9-1.3), and 0.9 (95% CI, 0.8-1.1) in the CGPS (trend P = .005), and 1.4 (95% CI, 1.1-1.7), 1.2 (95% CI, 1.0-1.6), and 1.3 (95% CI, 1.0-1.6) in the CIHDS (trend P = .01). Genetically elevated lipoprotein(a) was associated with an HR of 1.22 (95% CI, 1.09-1.37) per doubling of lipoprotein(a) level on instrumental variable analysis, while the corresponding value for plasma lipoprotein(a) levels on Cox regression was 1.08 (95% CI, 1.03-1.12)., Conclusion: These data are consistent with a causal association between elevated lipoprotein(a) levels and increased risk of MI.