Ruben N. Eppinga

Identification of genomic loci associated with resting heart rate and shared genetic predictors with all-cause mortality

Resting heart rate is a heritable trait correlated with life span. Little is known about the genetic contribution to resting heart rate and its relationship with mortality. We performed a genome-wide association discovery and replication analysis starting with 19.9 million genetic variants and studying up to 265,046 individuals to identify 64 loci associated with resting heart rate (P < 5 × 10−8); 46 of these were novel. We then used the genetic variants identified to study the association between resting heart rate and all-cause mortality. We observed that a genetically predicted resting heart rate increase of 5 beats per minute was associated with a 20% increase in mortality risk (hazard ratio 1.20, 95% confidence interval 1.11–1.28, P = 8.20 × 10−7) translating to a reduction in life expectancy of 2.9 years for males and 2.6 years for females. Our findings provide evidence for shared genetic predictors of resting heart rate and all-cause mortality.

Identification of 15 novel risk loci for coronary artery disease and genetic risk of recurrent events, atrial fibrillation and heart failure

Coronary artery disease (CAD) is the major cause of morbidity and mortality in the world. Identification of novel genetic determinants may provide new opportunities for developing innovative strategies to predict, prevent and treat CAD. Therefore, we meta-analyzed independent genetic variants passing P <× 10−5 in CARDIoGRAMplusC4D with novel data made available by UK Biobank. Of the 161 genetic variants studied, 71 reached genome wide significance (p < 5 × 10−8) including 15 novel loci. These novel loci include multiple genes that are involved in angiogenesis (TGFB1, ITGB5, CDH13 and RHOA) and 2 independent variants in the TGFB1 locus. We also identified SGEF as a candidate gene in one of the novel CAD loci. SGEF was previously suggested as a therapeutic target based on mouse studies. The genetic risk score of CAD predicted recurrent CAD events and cardiovascular mortality. We also identified significant genetic correlations between CAD and other cardiovascular conditions, including heart failure and atrial fibrillation. In conclusion, we substantially increased the number of loci convincingly associated with CAD and provide additional biological and clinical insights.

Effect of Metformin Treatment on Lipoprotein Subfractions in Non-Diabetic Patients with Acute Myocardial Infarction: A Glycometabolic Intervention as Adjunct to Primary Coronary Intervention in ST Elevation Myocardial Infarction (GIPS-III) Trial

Objective Metformin affects low density lipoprotein (LDL) and high density (HDL) subfractions in the context of impaired glucose tolerance, but its effects in the setting of acute myocardial infarction (MI) are unknown. We determined whether metformin administration affects lipoprotein subfractions 4 months after ST-segment elevation MI (STEMI). Second, we assessed associations of lipoprotein subfractions with left ventricular ejection fraction (LVEF) and infarct size 4 months after STEMI. Methods 371 participants without known diabetes participating in the GIPS-III trial, a placebo controlled, double-blind randomized trial studying the effect of metformin (500 mg bid) during 4 months after primary percutaneous coronary intervention for STEMI were included of whom 317 completed follow-up (clinicaltrial.gov Identifier: NCT01217307). Lipoprotein subfractions were measured using nuclear magnetic resonance spectroscopy at presentation, 24 hours and 4 months after STEMI. (Apo)lipoprotein measures were obtained during acute STEMI and 4 months post-STEMI. LVEF and infarct size were measured by cardiac magnetic resonance imaging. Results Metformin treatment slightly decreased LDL cholesterol levels (adjusted P = 0.01), whereas apoB remained unchanged. Large LDL particles and LDL size were also decreased after metformin treatment (adjusted P<0.001). After adjustment for covariates, increased small HDL particles at 24 hours after STEMI predicted higher LVEF (P = 0.005). In addition, increased medium-sized VLDL particles at the same time point predicted a smaller infarct size (P<0.001). Conclusion LDL cholesterol and large LDL particles were decreased during 4 months treatment with metformin started early after MI. Higher small HDL and medium VLDL particle concentrations are associated with favorable LVEF and infarct size.

Telomere Length and Risk of Cardiovascular Disease and Cancer

Telomeres are DNA repeat structures with protein complexes capping the ends of chromosomes important for chromosomal stability and cellular integrity [(1)][1]. Telomeres shorten with each cell division and under environmental conditions such as oxidative stress. Therefore, telomere length (TL) has

Effect of Metformin on Metabolites and Relation With Myocardial Infarct Size and Left Ventricular Ejection Fraction After Myocardial Infarction

Background— Left ventricular ejection fraction (LVEF) and infarct size (ISZ) are key predictors of long-term survival after myocardial infarction (MI). However, little is known about the biochemical pathways driving LV dysfunction after MI. To identify novel biomarkers predicting post-MI LVEF and ISZ, we performed metabolic profiling in the GIPS-III randomized clinical trial (Glycometabolic Intervention as Adjunct to Primary Percutaneous Intervention in ST Elevation Myocardial Infarction). We also investigated the metabolic footprint of metformin, a drug associated with improved post-MI LV function in experimental studies. Methods and Results— Participants were patients with ST-segment–elevated MI who were randomly assigned to receive metformin or placebo for 4 months. Blood samples were obtained on admission, 24 hours post-MI, and 4 months post-MI. A total of 233 metabolite measures were quantified using nuclear magnetic resonance spectrometry. LVEF and ISZ were assessed 4 months post-MI. Twenty-four hours post-MI measurements of high-density lipoprotein (HDL) triglycerides (HDL-TG) predicted LVEF (&bgr;=1.90 [95% confidence interval (CI), 0.82 to 2.98]; P=6.4×10−4) and ISZ (&bgr;=−0.41 [95% CI, −0.60 to −0.21]; P=3.2×10−5). In addition, 24 hours post-MI measurements of medium HDL-TG (&bgr;=−0.40 [95% CI, −0.60 to −0.20]; P=6.4×2×10−5), small HDL-TG (&bgr;=−0.34 [95% CI, −0.53 to −0.14]; P=7.3×10−4), and the triglyceride content of very large HDL (&bgr;=−0.38 [95% CI, −0.58 to −0.18]; P=2.7×10−4) were associated with ISZ. After the 4-month treatment, the phospholipid content of very large HDL was lower in metformin than in placebo-treated patients (28.89% versus 38.79%; P=7.5×10−5); alanine levels were higher in the metformin group (0.46 versus 0.44 mmol/L; P=2.4×10−4). Conclusions— HDL triglyceride concentrations predict post-MI LVEF and ISZ. Metformin increases alanine levels and reduces the phospholipid content in very large HDL particles. Clinical Trial Registration— URL: https://clinicaltrials.gov/ct2/show/NCT01217307. Unique Identifier: NCT01217307.

Relationship of Arterial Stiffness Index and Pulse Pressure With Cardiovascular Disease and Mortality

Background Vascular aging results in stiffer arteries and may have a role in the development of cardiovascular disease (CVD). Arterial stiffness index (ASI), measured by finger photoplethysmography, and pulse pressure (PP) are 2 independent vascular aging indices. We investigated whether ASI or PP predict new‐onset CVD and mortality in a large community‐based population. Methods and Results We studied 169 613 UK Biobank participants (mean age 56.8 years; 45.8% males) who underwent ASI measurement and blood pressure measurement for PP calculation. Mean±SD ASI was 9.30±3.1 m/s and mean±SD PP was 50.98±13.2 mm Hg. During a median disease follow‐up of 2.8 years (interquartile range 1.4–4.0), 18 190 participants developed CVD, of which 1587 myocardial infarction (MI), 4326 coronary heart disease, 1192 heart failure, and 1319 stroke. During a median mortality follow‐up of 6.1 years (interquartile range 5.8–6.3), 3678 participants died, of which 1180 of CVD. Higher ASI was associated with increased risk of overall CVD (unadjusted hazard ratio 1.27; 95% confidence interval [CI], 1.25–1.28), myocardial infarction (1.38; 95% CI, 1.32–1.44), coronary heart disease (1.31; 95% CI, 1.27–1.34), and heart failure (1.31; 95% CI 1.24–1.37). ASI also predicted mortality (all‐cause, CVD, other). Higher PP was associated with overall CVD (1.57; 95% CI, 1.55–1.59), myocardial infarction (1.48; 95% CI, 1.42–1.54), coronary heart disease (1.47; 95% CI, 1.43–1.50), heart failure (1.47; 95% CI, 1.40–1.55), and CVD mortality (1.47; 95% CI, 1.40–1.55). PP improved risk reclassification of CVD in a non–laboratory‐based Framingham Risk Score by 5.4%, ASI by 2.3%. Conclusions ASI and PP are independent predictors of CVD and mortality outcomes. Although both improved risk prediction for new‐onset disease, PP appears to have a larger clinical value than ASI.

The contemporary value of peak creatine kinase-MB after ST-segment elevation myocardial infarction above other clinical and angiographic characteristics in predicting infarct size, left ventricular ejection fraction, and mortality

Complex multimarker approaches to predict outcome after ST‐elevation myocardial infarction (STEMI) have only considered a single baseline sample, while neglecting easily obtainable peak creatine kinase and creatine kinase‐MB (CK‐MB) values during hospitalization.

Statin Effects on Metabolic Profiles: Data From the PREVEND IT (Prevention of Renal and Vascular End-stage Disease Intervention Trial)

Background— Statins lower cholesterol by inhibiting HMG-CoA reductase, the rate-limiting enzyme of the metabolic pathway that produces cholesterol and other isoprenoids. Little is known about their effects on metabolite and lipoprotein subclass profiles. We, therefore, investigated the molecular changes associated with pravastatin treatment compared with placebo administration using a nuclear magnetic resonance–based metabolomics platform. Methods and Results— We performed metabolic profiling of 231 lipoprotein and metabolite measures in the PREVEND IT (Prevention of Renal and Vascular End-stage Disease Intervention Trial) study, a placebo-controlled randomized clinical trial designed to test the effects of pravastatin (40 mg once daily) on cardiovascular risk. Metabolic profiles were assessed at baseline and after 3 months of treatment. Pravastatin lowered low-density lipoprotein cholesterol (change in SD units [95% confidence interval]: −1.01 [−1.14, −0.88]), remnant cholesterol (change in SD units [95% confidence interval]: −1.03 [−1.17, −0.89]), and apolipoprotein B (change in SD units [95% confidence interval]: −0.98 [−1.11, −0.86]) with similar effect magnitudes. In addition, pravastatin globally lowered levels of lipoprotein subclasses, with the exception of high-density lipoprotein subclasses, which displayed a more heterogeneous response pattern. The lipid-lowering effect of pravastatin was accompanied by selective changes in lipid composition, particularly in the cholesterol content of very-low-density lipoproteinparticles. In addition, pravastatin reduced levels of several fatty acids but had limited effects on fatty acid ratios. Conclusions— These randomized clinical trial data demonstrate the widespread effects of pravastatin treatment on lipoprotein subclass profiles and fatty acids. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT03073018.

Novel genetic associations for blood pressure identified via gene-alcohol interaction in up to 570K individuals across multiple ancestries

Heavy alcohol consumption is an established risk factor for hypertension; the mechanism by which alcohol consumption impact blood pressure (BP) regulation remains unknown. We hypothesized that a genome-wide association study accounting for gene-alcohol consumption interaction for BP might identify additional BP loci and contribute to the understanding of alcohol-related BP regulation. We conducted a large two-stage investigation incorporating joint testing of main genetic effects and single nucleotide variant (SNV)-alcohol consumption interactions. In Stage 1, genome-wide discovery meta-analyses in ≈131K individuals across several ancestry groups yielded 3,514 SNVs (245 loci) with suggestive evidence of association (P < 1.0 x 10−5). In Stage 2, these SNVs were tested for independent external replication in ≈440K individuals across multiple ancestries. We identified and replicated (at Bonferroni correction threshold) five novel BP loci (380 SNVs in 21 genes) and 49 previously reported BP loci (2,159 SNVs in 109 genes) in European ancestry, and in multi-ancestry meta-analyses (P < 5.0 x 10−8). For African ancestry samples, we detected 18 potentially novel BP loci (P < 5.0 x 10−8) in Stage 1 that warrant further replication. Additionally, correlated meta-analysis identified eight novel BP loci (11 genes). Several genes in these loci (e.g., PINX1, GATA4, BLK, FTO and GABBR2) have been previously reported to be associated with alcohol consumption. These findings provide insights into the role of alcohol consumption in the genetic architecture of hypertension.

Refining Thromboembolic Risk in the General Population

The most widely adapted algorithm to estimate stroke risk is the easily applicable congestive heart failure, hypertension, age >75, diabetes mellitus, prior stroke, vascular disease, age 65 to 74, and sex (CHA2DS2-VASc) score. This score has been developed in patients with atrial fibrillation (AF),