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Current heart failure (HF) guidelines place special emphasis on the early detection of people with subclinical left ventricular (LV) remodeling and dysfunction. To better understand the mechanism of LV remodeling related to cardiovascular risk factors such as hypertension and diabetes, it is important to evaluate LV function in relation to changes in loading, i.e. preload and afterload. For instance, arterial stiffening increases the vascular loading on the heart, triggering a cardiac response of hypertrophy and LV stiffening to cope with the increased systolic afterload. However, this matched increase in cardiac and arterial stiffness likely contributes to systolic and diastolic LV dysfunction as it impairs the hemodynamic stability and cardiac reserve. To date, the early signs of such ventricular-arterial coupling (VAC) mismatching and indexes of myocardial performance (work) remain insufficiently investigated in a general population. Within an epidemiological framework, this PhD dissertation addresses the contribution of increased central haemodynamics and arterial stiffening to early remodelling and dysfunction of the heart. We first explored in both cross-sectional and longitudinal analyses the relationship between subclinical LV remodelling and dysfunction and arterial stiffening in a general population. Then, we studied the clinical correlates of the area of the LV pressure-strain loop during ejection (EWD) as VAC index and explored its relation with conventional echocardiographic and central blood pressure indexes. In addition, we aimed to identify circulating biomarkers that predict changes in LV geometry and function in the community. We addressed our research objectives by analysing cardiovascular and biochemical profiles retrieved from European general population cohorts. In short, we observed from an epidemiological perspective that: i) aortic stiffening plays an important role in LV concentric remodelling; (ii) increased pulsatile load might mediate LV diastolic dysfunction, particularly in women; iii) the LV pressure-strain loop area is a promising index to evaluate the sex-dependent interplay between preload, afterload and LV performance; and that iv) a set of circulating biomarkers reflecting insulin resistance, vascular calcification and LV fibrosis and injury predicted adverse changes in LV geometry and function. Our findings justify further research to unravel the pathophysiological mechanisms mediated by systemic hypertension, arterial stiffening and insulin resistance that precede LV maladaptation. Interventions targeting these risk factors might timely prevent or delay the progression of LV maladaptation and, on the long run, clinically overt HF. The imaging and molecular biomarkers highlighted in our studies merit further validation in patient and community-based cohorts for risk stratification of HF. status: published

IMPORTANCE: Blood pressure (BP) is a known risk factor for overall mortality and cardiovascular (CV)-specific fatal and nonfatal outcomes. It is uncertain which BP index is most strongly associated with these outcomes. OBJECTIVE: To evaluate the association of BP indexes with death and a composite CV event. DESIGN, SETTING, AND PARTICIPANTS: Longitudinal population-based cohort study of 11 135 adults from Europe, Asia, and South America with baseline observations collected from May 1988 to May 2010 (last follow-ups, August 2006-October 2016). EXPOSURES: Blood pressure measured by an observer or an automated office machine; measured for 24 hours, during the day or the night; and the dipping ratio (nighttime divided by daytime readings). MAIN OUTCOMES AND MEASURES: Multivariable-adjusted hazard ratios (HRs) expressed the risk of death or a CV event associated with BP increments of 20/10 mm Hg. Cardiovascular events included CV mortality combined with nonfatal coronary events, heart failure, and stroke. Improvement in model performance was assessed by the change in the area under the curve (AUC). RESULTS: Among 11 135 participants (median age, 54.7 years, 49.3% women), 2836 participants died (18.5 per 1000 person-years) and 2049 (13.4 per 1000 person-years) experienced a CV event over a median of 13.8 years of follow-up. Both end points were significantly associated with all single systolic BP indexes (P

Background In mice MEOX2/TCF15 heterodimers are highly expressed in heart endothelial cells and are involved in the transcriptional regulation of lipid transport. In a general population, we investigated whether genetic variation in these genes predicted coronary heart disease (CHD). Results In 2027 participants randomly recruited from a Flemish population (51.0 % women; mean age 43.6 years), we genotyped six SNPs in MEOX2 and four in TCF15. Over 15.2 years (median), CHD, myocardial infarction, coronary revascularisation and ischaemic cardiomyopathy occurred in 106, 53, 78 and 22 participants. For SNPs, we contrasted CHD risk in minor-allele heterozygotes and homozygotes (variant) vs. major-allele homozygotes (reference) and for haplotypes carriers (variant) vs. non-carriers. In multivariable-adjusted analyses with correction for multiple testing, CHD risk was associated with MEOX2 SNPs (P ≤ 0.049), but not with TCF15 SNPs (P ≥ 0.29). The MEOX2 GTCCGC haplotype (frequency 16.5 %) was associated with the sex- and age-standardised CHD incidence (5.26 vs. 3.03 events per 1000 person-years; P = 0.036); the multivariable-adjusted hazard ratio [HR] of CHD was 1.78 (95 % confidence interval, 1.25–2.56; P = 0.0054). For myocardial infarction, coronary revascularisation, and ischaemic cardiomyopathy, the corresponding HRs were 1.96 (1.16–3.31), 1.87 (1.20–2.91) and 3.16 (1.41–7.09), respectively. The MEOX2 GTCCGC haplotype significantly improved the prediction of CHD over and beyond traditional risk factors and was associated with similar population-attributable risk as smoking (18.7 % vs. 16.2 %). Conclusions Genetic variation in MEOX2, but not TCF15, is a strong predictor of CHD. Further experimental studies should elucidate the underlying molecular mechanisms. Electronic supplementary material The online version of this article (doi:10.1186/s12863-015-0272-2) contains supplementary material, which is available to authorized users.