Obesity increases heart failure incidence and mortality: observational and Mendelian randomization studies totalling over 1 million individuals.

AIMS: Whether high body mass index (BMI) causally influences development and prognosis of heart failure has implications for clinical practice. We tested the hypotheses that high BMI causally influences heart failure incidence and mortality. METHODS AND RESULTS: Using observational and Mendelian randomization causal, genetic analyses, we studied 106 121 individuals from the Copenhagen General Population Study, 18 407 from the Copenhagen City Heart Study, and 977 323 from publicly available databases. In observational analyses in the Copenhagen studies with 10 years of median follow-up, multivariable adjusted hazard ratios per 1 kg/m2 increment of BMI were 1.06 (95% confidence interval: 1.05-1.07; P < 0.001; n = 124 528; events = 6589) for heart failure incidence, 1.04 (1.03-1.06; P < 0.001; n = 124 528; events = 1237) for heart failure mortality, and 1.01 (1.00-1.01; P < 0.001; n = 124 528; events = 24 144) for all-cause mortality. In genetic analyses in the Copenhagen studies, the age and sex adjusted causal risk ratios per 1 kg/m2 increment of BMI were 1.19 (1.05-1.36; P = 0.008; n = 118 200; events = 6541) for heart failure incidence, 1.27 (0.82-1.98; P = 0.28; n = 118 200; events = 889) for heart failure mortality, and 1.11 (1.02-1.22; P = 0.022; n = 118 200; events = 16 814) for all-cause mortality. Finally, combining genetic data from the Copenhagen studies, the Genetic Investigation of ANthropometric Traits, the Heart Failure Molecular Epidemiology for Therapeutic Targets, and the UK Biobank, the unadjusted causal risk ratios per 1 kg/m2 increment of BMI were 1.39 (1.27-1.52; P < 0.001; n = 1 095 523; events = 53 850) for heart failure incidence, 1.18 (1.00-1.38; P = 0.05; n = 576 853; events = 2373) for heart failure mortality, and 1.02 (1.00-1.04; P = 0.03; n = 576 853; events = 44 734) for all-cause mortality. CONCLUSION: High BMI causally increases the risk of both heart failure incidence and mortality.

Impact of Glucose Level on Micro- and Macrovascular Disease in the General Population: A Mendelian Randomization Study.

OBJECTIVE: To evaluate whether high glucose levels in the normoglycemic range and higher have a causal genetic effect on risk of retinopathy, neuropathy, nephropathy, chronic kidney disease (CKD), peripheral arterial disease (PAD), and myocardial infarction (MI; positive control) in the general population. RESEARCH DESIGN AND METHODS: This study applied observational and one-sample Mendelian randomization (MR) analyses to individual-level data from 117,193 Danish individuals, and validation by two-sample MR analyses on summary-level data from 133,010 individuals from the Meta-Analyses of Glucose and Insulin-Related Traits Consortium (MAGIC), 117,165 from the CKDGen Consortium, and 452,264 from the UK Biobank. RESULTS: Observationally, glucose levels in the normoglycemic range and higher were associated with high risks of retinopathy, neuropathy, diabetic nephropathy, PAD, and MI (all P for trend <0.001). In genetic causal analyses, the risk ratio for a 1 mmol/L higher glucose level was 2.01 (95% CI 1.18-3.41) for retinopathy, 2.15 (1.38-3.35) for neuropathy, 1.58 (1.04-2.40) for diabetic nephropathy, 0.97 (0.84-1.12) for estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2, 1.19 (0.90-1.58) for PAD, and 1.49 (1.02-2.17) for MI. Summary-level data from the MAGIC, the CKDGen Consortium, and the UK Biobank gave a genetic risk ratio of 4.55 (95% CI 2.26-9.15) for retinopathy, 1.48 (0.83-2.66) for peripheral neuropathy, 0.98 (0.94-1.01) for eGFR <60 mL/min/1.73 m2, and 1.23 (0.57-2.67) for PAD per 1 mmol/L higher glucose level. CONCLUSIONS: Glucose levels in the normoglycemic range and higher were prospectively associated with a high risk of retinopathy, neuropathy, diabetic nephropathy, eGFR <60 mL/min/1.73 m2, PAD, and MI. These associations were confirmed in genetic causal analyses for retinopathy, neuropathy, diabetic nephropathy, and MI, but they could not be confirmed for PAD and seemed to be refuted for eGFR <60 mL/min/1.73 m2.

Causal Associations in Type 2 Diabetes Development.

CONTEXT: Obesity, glucose, insulin resistance [homeostatic model assessment, version 2, for insulin resistance (HOMA2-IR)], and insulin secretion (HOMA2-ß) have been associated with type 2 diabetes (T2D) observationally. However, the causal, genetic contribution of each parameter to this risk is largely unknown and important to study because observational data are prone to confounding but genetic, causal data are free of confounding and reverse causation. OBJECTIVE: We examined the causal, genetic contribution of body mass index (BMI), glucose level, C-peptide level, HOMA2-IR, and HOMA2-ß to the risk of T2D in 95,540 individuals from the Copenhagen General Population Study and estimated the absolute 10-year risks. METHODS: Cox regression analysis, instrumental variable analysis, and Poisson regression analysis were performed to estimate the observational hazard ratios, causal, genetic ORs, and absolute 10-year risks of T2D. RESULTS: For 1-SD greater level, BMI was associated with an observational 66% (95% CI, 62% to 72%) and causal, genetic 121% (95% CI, 25% to 291%) greater risk of T2D; glucose with an observational 44% (95% CI, 41% to 46%) and causal, genetic 183% (95% CI, 56% to 416%) greater risk of T2D; and HOMA2-IR with an observational 30% (95% CI, 18% to 44%) and causal, genetic 12% (95% CI, 2% to 22%) greater risk of T2D. In contrast, for 1-SD greater level, HOMA2-ß was associated with an observational 14% (95% CI, 11% to 16%) and causal, genetic 21% (95% CI, 8% to 32%) lower risk of T2D. The upper tertiles of HOMA2-IR were associated with absolute 10-year diabetes risks of 31% and 37% in obese women and men, age >60 years, and a glucose level of 6.1 to 11.0 mmol/L. CONCLUSIONS: BMI, glucose level, HOMA2-IR, and HOMA2-ß are causally associated with T2D.

Components of the Metabolic Syndrome and Risk of Type 2 Diabetes.

CONTEXT: The metabolic syndrome (MetS) is associated with type 2 diabetes (T2D). However, whether each of the 5 components of the MetS individually is causally associated with T2D is unknown. OBJECTIVE: We tested the hypothesis that each component is causally associated with T2D. DESIGN: Mendelian randomization using genetic variations that alter levels of the MetS components are randomly assorted at gamete formation and free of confounding and reverse causation, which allows us to infer causality. SETTING: General community. STUDY PARTICIPANTS: A total of 95 756 individuals from the prospective Copenhagen General Population Study. MAIN OUTCOME MEASURE: Type 2 diabetes. RESULTS: A 1-cm larger waist circumference was associated with an observational 5% (95% confidence interval, 4%-5%) and a causal genetic 5% (1%-10%) higher risk of T2D. In contrast, although a 1-unit higher level of triglycerides and blood pressure and a 1-unit lower level of high-density lipoprotein cholesterol were associated with higher observational T2D risk, the corresponding causal genetic risks were not. As expected, a 1 mmol/L higher glucose level was associated with an observational 32% (30%-34%) and a causal genetic 82% (21%-173%) higher T2D risk. CONCLUSIONS: In conclusion, larger waist circumference and higher glucose levels were each causally associated with higher risk of T2D. Findings like these may change clinical thinking so that waist circumference control will be prioritized to the same extend as control of blood pressure, lipids, and glucose levels in T2D prevention.

Antihypertensive treatment and risk of atrial fibrillation: a nationwide study.

AIMS: To examine the associations between antihypertensive treatment with angiotensin-converting enzyme inhibitors (ACEis) or angiotensin receptor blockers (ARBs), ß-blockers, diuretics, or calcium-antagonists, and risk of atrial fibrillation. We examined these associations using the entire Danish population from 1995 through 2010. METHODS AND RESULTS: Excluding medication used in atrial fibrillation, we matched individuals on ACEi monotherapy 1:1 with individuals on ß-blocker (n = 48 658), diuretic (n = 69 630), calcium-antagonist (n = 57 646), and ARB monotherapy (n = 20 158). Likewise, individuals on ARB monotherapy were matched 1:1 with individuals on ß-blocker (n = 20 566), diuretic (n = 20 832), calcium-antagonist (n = 20 232), and ACEi monotherapy (n = 20 158). All were free of atrial fibrillation and of predisposing diseases like heart failure, ischaemic heart disease, diabetes mellitus, and hyperthyroidism at baseline and none received any other antihypertensive medication. We studied risk of atrial fibrillation, and used risk of stroke, influenced by lowering blood pressure rather than renin-angiotensin system blockade per se, as an indicator of the importance of blood pressure lowering per se. Hazard ratios of atrial fibrillation for ACEi and ARB monotherapy were 0.12 (95% CI: 0.10-0.15) and 0.10 (0.07-0.14) compared with ß-blocker, 0.51 (0.44-0.59) and 0.43 (0.32-0.58) compared with diuretic, and 0.97 (0.81-1.16) and 0.78 (0.56-1.08) compared with calcium-antagonist monotherapy. Risk of stroke did not differ among the five antihypertensive medications. CONCLUSION: Use of ACEis and ARBs compared with ß-blockers and diuretics associates with a reduced risk of atrial fibrillation, but not stroke, within the limitations of a retrospective study reporting associations. This suggests that controlling activation of the renin-angiotensin system in addition to controlling blood pressure is associated with a reduced risk of atrial fibrillation.

YKL-40 levels and atrial fibrillation in the general population.

BACKGROUND: Atrial fibrillation is associated with inflammation. In contrast to inflammatory markers like C-reactive protein (CRP) and fibrinogen produced in the liver, YKL-40 is produced at the site of inflammation including in the myocardium. We hypothesized that elevated plasma YKL-40 levels associate with increased risk of atrial fibrillation. METHOD AND RESULTS: We measured plasma YKL-40 in 8731 participants from the prospective Copenhagen City Heart Study including 896 individuals who developed atrial fibrillation during up to 18 years of follow-up. Additionally, we measured YKL-40 in 6621 individuals from the cross-sectional Copenhagen General Population Study including 337 cases with atrial fibrillation. A YKL-40 level >95% percentile (>204 µg/L) versus <25% percentile (<36 µg/L) associated prospectively with a 2.10-fold (95%CI:1.43-3.09) increased risk of atrial fibrillation. Hazard ratios attenuated slightly after multifactorial adjustment to 2.01 (1.35-2.98), and further after additional adjustment for heart failure to 1.89 (1.27-2.80), for plasma CRP to 1.79 (1.20-2.67), and for fibrinogen levels to 1.89 (1.27-2.81). Adjusting multifactorially including both heart failure, CRP, and fibrinogen attenuated the risk of atrial fibrillation to 1.79 (1.20-2.67). These findings were supported in the cross-sectional study with an odds ratio of 2.73 (1.46-5.11) for a YKL-40 level >95% percentile versus <25% percentile, attenuating to an odds ratio of 2.13 (1.09-4.18) when adjusting multifactorially including heart failure, CRP, and fibrinogen. CONCLUSIONS: Elevated plasma YKL-40 levels robustly associated with increased risk of atrial fibrillation originating from hospital admissions or visits to the emergency department, independent of heart failure, and CRP and fibrinogen levels. These findings need to be confirmed in other independent studies.

AT1 mutations and risk of atrial fibrillation based on genotypes from 71,000 individuals from the general population.

AIMS: Activation of the angiotensin II type 1 (AT1 ) receptor has been shown to mediate the structural and electrical remodelling of the atrial myocardium associated with atrial fibrillation. We hypothesized that AT1 genotypic variation is associated with atrial fibrillation or diseases predisposing to atrial fibrillation, such as hypertension, heart failure, ischaemic heart disease and myocardial infarction, in the general population. METHODS: We resequenced the AT1 gene in 760 individuals with atrial fibrillation and identified two nonsynonymous variants (I103T and A244S), which were subsequently genotyped in the prospective Copenhagen City Heart Study (n = 10 603) and the prospective Copenhagen General Population Study (n = 60 647). RESULTS: Risk of atrial fibrillation for heterozygotes for AT1 genetic variants A244S and I103T/A244S vs. noncarriers was increased by 2.7-fold (95% confidence interval 1.5- to 5.1-fold) and 2.6-fold (95% confidence interval 1.6- to 4.2-fold), respectively, for men. CONCLUSIONS: Heterozygosity for the nonsynonymous AT1 genetic variants A244S and I103T/A244S was associated with increased risk of atrial fibrillation in men. The AT1 recptor might be a target for the pharmaceutical industry. This finding needs to be validated in independent studies.

Does elevated C-reactive protein increase atrial fibrillation risk? A Mendelian randomization of 47,000 individuals from the general population.

OBJECTIVES: The purpose of this study was to test whether the association of C-reactive protein (CRP) with increased risk of atrial fibrillation is a robust and perhaps even causal association. BACKGROUND: Elevated levels of CRP previously have been associated with increased risk of atrial fibrillation. METHODS: We studied 10,276 individuals from the prospective Copenhagen City Heart Study, including 771 individuals who had atrial fibrillation during follow-up, and another 36,600 persons from the cross-sectional Copenhagen General Population Study, including 1,340 cases with atrial fibrillation. Individuals were genotyped for 4 CRP gene polymorphisms and had high-sensitivity CRP levels measured. RESULTS: A CRP level in the upper versus lower quintile associated with a 2.19-fold (95% confidence interval [CI]: 1.54- to 3.10-fold) increased risk of atrial fibrillation. Risk estimates attenuated slightly after multifactorial adjustment to 1.77 (95% CI: 1.22 to 2.55), and after additional adjustment for heart failure and plasma fibrinogen level to 1.47 (95% CI: 1.02 to 2.13) and 1.63 (95% CI: 1.21 to 2.20), respectively. Genotype combinations of the 4 CRP polymorphisms associated with up to a 63% increase in plasma CRP levels (p < 0.001), but not with increased risk of atrial fibrillation. The estimated causal odds ratio for atrial fibrillation by instrumental variable analysis for a doubling in genetically elevated CRP levels was lower than the odds ratio for atrial fibrillation observed for a doubling in plasma CRP on logistic regression (0.94 [95% CI: 0.70 to 1.27] vs. 1.36 [95% CI: 1.30 to 1.44]; p < 0.001). CONCLUSIONS: Elevated plasma CRP robustly associated with increased risk of atrial fibrillation; however, genetically elevated CRP levels did not. This suggests that elevated plasma CRP per se does not increase atrial fibrillation risk.