K.M. Akkerhuis

A pharmacogenetic analysis of determinants of hypertension and blood pressure response to angiotensin-converting enzyme inhibitor therapy in patients with vascular disease and healthy individuals

Aims To investigate whether genetic variation in the renin–angiotensin–aldosterone system (RAAS) and kallikrein-bradykinin pathways is related to hypertension and blood pressure (BP) response to angiotensin-converting enzyme (ACE) inhibitor therapy in stable coronary artery disease (CAD) patients. Methods and results In 8907 stable CAD patients from the EUROPA trial, 52 haplotype-tagging single-nucleotide polymorphisms (SNPs) in 12 candidate genes within the RAAS and kallikrein-bradykinin pathways were investigated for association with hypertension (defined as BP ≥160/95 mmHg or use of antihypertensives) and BP response to ACE inhibitors, during a 4-week run-in period. All analyses were adjusted for age, sex, body mass index and creatinine clearance and corrected for multiple testing. Results Hypertension was present in 28.3% of the patients (n = 2526); median BP reduction after perindopril was 10/4 mmHg. Four polymorphisms, located in the ACE (rs4291), angiotensinogen (rs5049) and (pro)renin receptor (rs2968915; rs5981008) genes were significantly associated with hypertension in two vascular disease populations of CAD (EUROPA) and cerebrovascular disease (PROGRESS; n = 3571). A cumulative profile demonstrated a stepwise increase in the prevalence of hypertension, mounting to a 2–3-fold increase (P for trend <0.001). Similar associations on hypertension were observed for angiotensinogen in a healthy population (n = 2197). In addition, genetic polymorphisms were identified that significantly modified the BP reduction by ACE inhibitor therapy; however, the observed BP differences were small and did not remain significant after permutation analysis. Conclusion This large genetic association study identified genetic determinants of hypertension in three cohorts of patients with vascular disease and healthy individuals.

Von Willebrand factor in relation to coronary plaque characteristics and cardiovascular outcome. Results of the ATHEROREMO-IVUS study.

High von Willebrand factor (VWF) plasma levels are associated with an increased risk of coronary artery disease. It has been suggested that the increase of VWF levels is partly due to endothelial dysfunction and atherosclerosis. Our aim was to investigate the association between coronary plaque burden, the presence of high-risk coronary lesions as measured by intravascular ultrasound virtual histology (IVUS-VH) and VWF levels. In addition, we studied the association between VWF levels and one-year cardiovascular outcome. Between 2008 and 2011, IVUS-VH imaging of a non-culprit coronary artery was performed in 581 patients undergoing coronary angiography for acute coronary syndrome (ACS) (n= 318) or stable angina pectoris (SAP) (n= 263). Arterial blood was sampled prior to the coronary angiography. VWF antigen (VWF:Ag) levels were measured using ELISA (n= 577). Patients with ACS had significantly higher VWF:Ag levels than SAP patients (median 1.73 IU/ml [IQR 1.27-2.31] vs 1.26 IU/ml [0.93-1.63], p< 0.001). High coronary plaque burden was associated with higher VWF:Ag levels (β= 0.12, p=0.027) in SAP patients, but not in ACS patients. In ACS patients, VWF:Ag levels were associated with 1-year MACE (HR 4.14 per SD increase of lnVWF:Ag, 95 % CI 1.47-11.6), whereas in SAP patients VWF:Ag levels predicted 1-year all-cause death and hospitalisation for ACS (HR 7.07 95 % CI 1.40-35.6). In conclusion, coronary plaque burden was associated with VWF:Ag levels in SAP patients undergoing coronary angiography. In ACS and SAP patients, high VWF levels are predictive of adverse cardiovascular outcome and death during one-year follow-up.