Hypertension and Cardiovascular Epidemiology

The Research Unit Hypertension and Cardiovascular Epidemiology (HCVE) coordinated influential clinical trials, published in top-ranking journals, such as the Systolic Hypertension in Europe Trial (Syst-Eur), the Ambulatory blood Pressure monitoring and Treatment of Hypertension trial (APTH) and the Treatment of hypertension based on Home or Office blood Pressure trial (THOP).  HCVE led the Data Safety and Monitoring Board of large clinical trials, including the Systolic Hypertension in China trial (Syst-China), the Randomised Olmesartan and Diabetes Microalbuminuria Prevention Study (ROADMAP) and the Hypertension in the very Elderly trial (HYVET).  HCVE organised the Ouabain and Adducin for Specific Intervention on Sodium in HyperTension trial (OASIS-HT) and the Newer vs. Older Antihypertensive Agents in African Hypertensive patients (NOAAH) trial, which was running at six clinical sites in sub-Saharan Africa.  HCVE played a pivotal role in delineating the deleterious adverse health effects of environmental exposure of the Flemish population to heavy metals, such as lead and cadmium, and more recently to air pollutants (fine particulate).

The current research interests of HCVE focus on the clinical application of omics (genomics, epigenomics, proteomics and metabolomics), population science, and the treatment of cardiovascular disease, in particular hypertension.  In 1985, HCVE initiated the still ongoing FLEmish Study on ENvironment Genes and Health Outcomes (FLEMENGHO), which served as a template for other population studies across Europe, including the European Project on Genes in Hypertension (EPOGH) and the Swiss Kidney Project on Genes in Hypertension (SKIPOGH), in China (Jingning County), and more recently in Montevideo, Uruguay and Lugbe (Abuja), Nigeria.  In 1998, HCVE participated in several FP7 projects, including INGENIOUS HYPERCARE, HYPERGENES, EU-MASCARA and HOMAGE.  Within H2020, HCVE is the coordinator of the ERA-CVD project PROACT (2018) on the prediction and pathophysiology of acute coronary syndrome, using omics technologies. 

HCVE set up several international research consortia.  IDACO (International Database on Ambulatory blood pressure monitoring in relation to Cardiovascular Outcome) and IDHOCO (International Database of HOme blood pressure in relation to Cardiovascular Outcome) focus on the clinical applicability of ambulatory blood pressure monitoring or the self-measured blood pressure at home in risk stratification, using data from prospective population studies.  HCVE started the European Network coordinating research on REnal denervation (ENCOReD) and in 2017 published the pilot phase of the INSPiRED (Investigator-Steered Project on intravascular Renal Denervation for Management of Drug-Resistant Hypertension) trial.

The European Research Council Advanced Researcher project EPLORE (Epidemiological Left ventricular Outcomes Research in Europe) focused on left ventricular diastolic dysfunction in the general population and was followed-up by a Proof-of-Concept project granted by the European Research Council on the use of urinary proteomics for the prediction of heart transplantation outcomes (uPROPHET – Urinary PROteomics in Predicting HEart Transplantation outcomes). 

HCVE coordinated PREMATCH (PREMATurity as predictor of children's Cardiovascular-renal Health), which was a case-control study comparing the health of children at 11 years, between those born with extremely low birth weight (<1000 g) and those born at term.  HCVE is currently running a study in workers at a battery recycling plant in the United Staes with the goal to describe the health effects associated with a 4-5 fold increase in the blood lead concentration (SPHERL – Study for Promotion of HEalth in Recycling Lead) when unexposed workers are hired and start working in the plant.

EPLORE

Heart failure affects 15 million Europeans.  EPLORE documented the longitudinal changes in diastolic left ventricular function over 5-year time span in a randomly selected cohort representative for the Flemish population.  We showed that subclinical (asymptomatic) diastolic left ventricular dysfunction affects 25% of the population and is a predictor of cardiac and cardiovascular complications.  We implemented novel and completely non-invasive methods to describe coupling of the left ventricle with the large arteries, in which the heart ejects the blood.  A major achievement of EPLORE was the discovery and validation of urinary biomarkers,  which predict deterioration of the performance of the heart, decline in renal function and the incidence of cardiovascular and cardiac complications.  These urinary biomarkers consist of small molecules (so-called peptides derived from protein) that also shed light on the pathophysiology of heart failure and chronic kidney disease.   We also identified in blood circulating biomarkers associated with cardiomyocyte micro-injury and with calcification of the conduit arteries.  Other metabolic biomarkers in the blood were consistently associated with the function of the heart.  They mainly reflected how the heart uses glucose as opposed to fatty acids as source of energy, and additionally included essential amino-acids with a branched structure that humans need to take up with food and act a metabolic signal throughout the whole body.  The cardiorenal syndrome refers to the observation that decline in cardiac and renal function often go hand in hand.  Along these lines, we found evidence that both the heart and the kidney need a protein (matrix Gla protein) protecting against calcification, calcium deposition in tissues and that helps maintaining the integrity of the microcirculation, i.e., the smallest vessels in the human body that transport oxygen and nutrients to all organs.  Matrix Gla protein needs vitamin K for becoming active.  

uPROPHET

uPROPHET rests on EPLORE findings showing that capillary electrophoresis coupled with mass spectroscopy identifies urinary proteomic (UP) profiles associated with left ventricular and renal dysfunction. The uPROPHET database already includes ~400 patients who received a heart transplant (HTx) and were followed up (3 UP samples/patient) at the University Hospitals Leuven. uPROPHET proved the feasibility of generating IPR related to UP signatures diagnostic in HTx patients and to the identification of new drug targets. Notwithstanding this success, uPROPHET remains underpowered in terms of critical 1st-year post HTx data, when graft failure most often occurs. uPROPHET-CS (consolidator) aims to enrol ~60 patients within the 1st year of HTx with frequent UP assessment simultaneously performed with endomyocardial biopsy and haemodynamic assessment. The scientific goals are: (i) identification of specific multidimensional UP markers, which in the 1st post HTxyear help in detecting graft vasculopathy, monitoring immune system activity and graft performance and adjusting immunosuppression ; (ii) to sequence UP peptide fragments and to identify key proteins mediating early HTx-related complications; (iii) to establish the value of UP markers in predicting adverse outcomes of HTx, including cancer; and (iv) to bridge the gap between idea and preclinical research and premarket exploration. uPROPHET‑CS will show case the translation of proteomics into “innovative services”, broaden the indications for UP, and have a major impact on the development of the SME business partner measuring the UP profiles. The evident benefit for the customer (patient) is the early and non-invasive risk stratification after HTx, hence allowing a personalised and targeted approach. uPROPHET findings will bring European research to the forefront in the highly competitive field of biomarker research and impact on transplantation medicine over and beyond HTx. 

INSPiRED

The SYMPLICITY studies showed that renal denervation (RDN) is feasible as novel treatment for resistant hypertension. However, RDN is a costly and invasive procedure, the long-term effi cacy and safety of which has not yet been proven. Therefore, we designed the INSPiRED trial to compare the blood pressure lowering effi cacy and safety of RDN vs usual medical therapy. INSPiRED is a randomized controlled trial enrolling 240 treatment-resistant hypertensive patients at 16 expert hypertension centres in Belgium. Eligible patients, aged 20 – 69 years old, have a 24-h ambulatory blood pressure of 130 mmHg systolic or 80 mmHg diastolic or more, while taking at least three antihypertensive drugs. They are randomized to RDN (EnligHTN TM , SJM system) plus usual care (intervention group) or usual care alone (control group) in a ratio of 1:1. The primary endpoints for efficacy and safety, measured after 6 months, are the baseline-adjusted between-group differences in 24h systolic blood pressure and in glomerular fi ltration rate as estimated by the Chronic Kidney Disease Epidemiology Collaboration equation. Follow-up will continue up to 36 months after randomization. INSPiRED is powered to demonstrate a 10-mmHg difference in systolic blood pressure between randomized groups with a two-sided p -value of 0.01 and 90% power. It will generate long-term effi cacy and safety data, identify the subset of treatment-resistant hypertensive patients responsive to RDN, provide information on costeffectiveness, and by doing so INSPiRED will inform guideline committees and health policy makers.

PREMATCH

The microvasculature and macrovasculature undergo extensive, organ-specifi c perinatal maturation. Multiple studies show associations between low birth weight and subsequent cardiovascular dysfunction in adulthood, suggesting that extreme preterm birth interferes with this maturation process. Therefore, we designed PREMATCH (PREMATurity as predictor of Cardiovascular – renal Health) to phenotype the microcirculation and macrocirculation during childhood in former preterm infants. A well-characterized cohort of former extreme preterm birth survivors and gender- and age-matched controls (aged 8 – 13 years) will be investigated for microvascular and macrovascular structure and function. In addition to cognitive performance and anthropometrics, we will investigate (i) the microvascular structure and function by endothelial function (photoplethysmography), sublingual capillary glycocalyx function (sidestream dark fi eld imaging) and retinal structure (diameters of arterioles and venules); and (ii) the macrovascular phenotype by cardiac and renal ultrasound, repeated blood pressure measurements and arterial pulse-wave recordings. The PREMATCH study is unique in its design, and ongoing recruitment demonstrates excellent feasibility. The expectation is that the results of this study will id entify risk factors during childhood for subsequent cardiovascular – renal disease in the adult life of former preterm infants, while further analysis on mediators in neonatal life of this cardiovascular – renal outcome may provide new information on perinatal risk factors.

SPHERL

Background. The level at which low-level lead exposure produces subclinical adverse health effects in adults remains to be established. Methods. The Study for Promotion of Health in Recycling Lead (SPHERL) will enroll 500 newly hired workers, whose blood lead during 2 years of follow-up is expected to increase from levels less than 2 µg/dl, as currently observed in the US population, to 20–30 µg/dl. The main outcome variables to be studied are (i) blood pressure (BP) analyzed as a continuous or categorical variable, both cross-sectionally and longitudinally, and using conventional and ambulatory BP measurement; (ii) indexes of glomerular and tubular renal function, (iii) heart rate variability analyzed in the frequency domain as measure of autonomous sympathetic modulation, (iv) peripheral nerve conductivity velocity, (v) neurocognitive performance, and (vi) quality of life. Expected outcomes. Assuming a 10-fold increase in blood lead, SPHERL will have sufficient statistical power to detect over 2 years a steepening of the age-related rise in systolic BP from 1 to 5 mmHg and a doubling of the age-related decline in the estimated glomerular filtration rate from 3.5 to 7.0 ml/min/1.73 m2. The longitudinal design of our study complies with the temporality principle of the Bradford–Hill criteria for assessing possible causality between outcomes and exposure. SPHERL will attempt to resolve the apparent contradiction between general population studies showing associations between adverse health effects and low lead exposure with blood lead levels below 5 µg/dl and studies conducted in occupational cohorts indicating that adverse effects of lead exposure occur at much higher blood lead levels.