Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk.

Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or  ≥90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention

Genetic Markers Enhance Coronary Risk Prediction in Men: The MORGAM Prospective Cohorts

WOS:000306806600029Peer reviewe

Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function.

Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways

Abstract 3634: Association of Weight Loss and Changes in Left Ventricular Geometry and Function - Results of the longitudinal population based MONICA/KORA-Survey

Background: Obesity is related to left ventricular (LV) hypertrophy and diastolic dysfunction. However it remains unclear if changes in life style resulting in loss of body weight also have beneficial effects on left ventricular remodeling. In this study we evaluated the effects of weight loss on left ventricular geometry and function during ten years of follow-up. Methods: Subjects (n=1005, aged 25 to 74 years) who originated from a gender and age stratified random sample of German residents of the Augsburg area were examined by standardized echocardiography at baseline and again after ten years. The associations between weight loss and long-term changes of left ventricular end-diastolic diameter (LVEDD), wall thickness (WT), left ventricular mass (LVM), and left atrial diameter (LA) were assessed. Mean relative changes and odds ratios were computed by statistical models adjusting for gender, age, body height, systolic blood pressure and body weight at baseline. Results: After ten years of follow-up 305 individuals presented with a loss of body weight (−3.5+/−3.4kg on average). Whereas 700 subjects presented with an increase of body weight (+5.4+/−4.7kg). Ageing related changes in LV geometry were significantly different in the two groups. Specifically, individuals with weight loss displayed a favorable geometry with relative changes of WT (+5.9% [CI-95% 4.3, 7.5] vs. + 8.1% [7.0, 9.2], p=0.024), LVEDD (−0.6% [−1.5, 0.2] vs. 30.8% [0.2, 1.4], p=0.008), LVM (+6.5% [4.3, 8.8] vs. +11.9% [10.4, 13.5], p&lt;0.001) and LA (−0.9% [−2.1, 0.2] vs. +2.5% [1.7, 3.3], p&lt;0.001), as compared to individuals with weight gain. Moreover, the risk for incident left ventricular hypertrophy (OR 2.5 [1.5– 4.3], p=0.001) and incident diastolic dysfunction (OR 1.9 [1.1–3.4], p=0.023) was significantly higher in individuals presenting with an increase in body weight. Conclusions: As compared to weight gain, weight loss is associated with a significant deceleration of left ventricular remodeling during ageing of the heart. Nevertheless, even in the weight loss group there was no regression in left ventricular mass detectable. Consequently, early interventions especially in young obese individuals are essential for prevention of premature onset of cardiac remodeling.</jats:p

Abstract 3782: Persistent Prehypertension is a Risk Factor for Left Ventricular Hypertrophy

BACKGROUND: We aimed to study whether persistent prehypertension has detrimental effects on left ventricular (LV) geometry and function and increases cardiovascular risk. METHODS: Subjects (n=1005, aged 25 to 74 years) from a gender and age stratified random sample of residents of the Augsburg (D) area, were examined by standardized echocardiography at baseline and a second time, at a ten year follow-up. We defined two groups of individuals who persistently had either normal systolic and diastolic blood pressures (nBP, i.e., &lt;120 mm Hg and &lt;80 mm Hg; n=142) or prehypertensive blood pressures (preBP, 120 – 139 mm Hg or 80 – 89 mm Hg; n=119) at both examinations. We prospectively evaluated temporal changes in geometry, mass and function occurring with either persistent normotension or prehypertension using linear regression models adjusting for relevant confounders. Subjects taking antihypertensive medications or having hypertensive blood pressures (≥ 140 mm Hg or ≥ 90 mm Hg) were excluded from this analysis. RESULTS: After ten years of follow-up, individuals with preBP , as compared to nBP, showed larger relative increases in LV wall thickness (WT, 11.9% [95% CI: 9.3 to 14.5] versus 4.7% [2.4 to 7.1]; p&lt;0.001), relative wall thickness (RWT, 12.9% [9.3 to 16.5] versus 4.3% [1 to 7.5]; p=0.001) and LVM indexed to height 2.7 (LVM/height 2.7 , 15.8% [12.4 to 19.3] versus 8.5% [5.4 to 11.6]; p=0.004) and decrease in E/A (early/late diastolic peak transmitral flow velocity, 15.7% [12 to 19.3] versus 7.7% [4.4 to 11]; p=0.003), respectively. Persistent prehypertension was also associated with a markedly elevated incidence of concentric remodeling of the left ventricle (RWT &gt;0.43) with an odds ratio OR =9.38 [2.94 to 29.9] (p&lt;0.001), of LV hypertrophy (LVM/height 2.7 &gt;44 g/m 2.7 in women and &gt;48 g/m 2.7 in men) with OR =5.59 [1.69 to 18.4] (p=0.009) and of diastolic dysfunction (E/A &lt;1 or E/A ≥ 1 and left atrial end-systolic diameter larger than 40 mm for males or 38 mm for females) with OR=2.52 [1.01 to 6.31] (p=0.048). CONCLUSIONS: Persistent prehypertension is associated with an increased risk of concentric remodelling and hypertrophy of the left ventricle and a worse diastolic function suggesting that prehypertension is related to detrimental alterations of the left ventricle. </jats:p

Ticagrelor-based antiplatelet regimens in patients treated with coronary artery bypass grafting: a meta-analysis of randomized controlled trials

Abstract OBJECTIVES The optimal antiplatelet strategy in patients undergoing CABG remains unclear. This is the first meta-analysis investigating the clinical outcomes associated with ticagrelor-based antiplatelet regimens in patients receiving CABG. METHODS Relevant scientific databases were searched for studies investigating antiplatelet regimens after CABG from inception until April 1, 2019. Studies which randomly assigned CABG patients to either ticagrelor-based or control antiplatelet regimens were eligible. The primary outcome of this analysis was all-cause death. The main secondary outcome was MI. Other outcomes of interest were cardiac death, major adverse cardiac events, stroke and bleeding. This study is registered with PROSPERO, number CRD42019122192. RESULTS Five trials comprising 3996 patients (2002 assigned to ticagrelor-based and 1994 to control antiplatelet regimens) were eligible for quantitative synthesis. The median follow-up was 12 months. Control antiplatelet regimens consisted of either aspirin or clopidogrel or both. As compared to control, ticagrelor-based regimens reduced the risk of all-cause death [0.61 (0.43–0.87); P = 0.007], cardiac death [0.58 (0.39–0.86); P = 0.007] and major adverse cardiac events [0.79 (0.63–0.98); P = 0.03], without difference in the risk of MI [0.76 (0.50–1.18); P = 0.22], stroke [0.99 (0.56–1.78); P = 0.98] or bleeding [1.04 (0.95–1.14); P = 0.41]. There was a treatment effect modification for the primary outcome associated with trials enrolling predominantly patients with acute coronary syndrome (P for interaction = 0.038). CONCLUSIONS In patients receiving CABG, ticagrelor-based regimens reduce mortality and major adverse cardiac events without excess bleeding risk as compared with aspirin monotherapy or the combination of aspirin and clopidogrel. The benefit of ticagrelor-based regimens is more relevant in those studies enrolling predominantly patients with acute coronary syndrome. These findings require further confirmation in randomized trials focused on this subset of patients and powered for clinical outcomes. </jats:sec