Challenges in the management of hypertension and heart failure

Abstract

The research described in this thesis addresses several challenges in the management of hypertension and heart failure with preserved ejection fraction (HFpEF). It mainly focusses on the influence of antihypertensive medication on the diagnostic work-up strategy of hypertension, the shortcomings of renal denervation as a treatment option for hypertension and explores the role of the sympathetic nervous system in HFpEF and the potential of renal denervation as a therapeutic option for patients with HFpEF. We demonstrated that temporary discontinuation, which can improve the performance of diagnostic strategies for identifying secondary causes for hypertension, does not increase short-term cardiovascular risk. We also demonstrated that discontinuation of medication has unpredictable effects on blood pressure, as blood pressure remained the same or even decreased in 40% of patients. We used frequent home blood pressure measurement to investigate blood pressure changes following renal denervation and found that blood pressure decreases in a gradual fashion throughout the first year rather than an acute drop shortly after treatment. Further evaluation of the renal denevation procedure was performed by analyzing the effect of spatial distribution of ablation placement on the achieved blood pressure reduction to test the hypothesis that renal denervation is more effective when performed distal to the renal artery bifurcation because of the smaller distance between the renal artery lumen and the sympathetic nerves. Although we did not find any safety issues, we also did not observe a significant difference in blood pressure reduction between patients treated proximal or distal in the renal artery. The second part of the thesis focusses on HFpEF. A systematic review was performed to explore a possible relationship between the sympathetic nervous system and HFpEF, which indicated that sympathetic hypertactivity indeed seems to play a role in this syndrome. This led to the design of the DIASTOLE trial, a multicenter randomized controlled trial to investigate the effect of renal denervation on top of medical care, compared to medical care alone. Unfortunately, the study was hindered by enrolment issues and was forced to terminate prematurely. The heterogeneity of the disease, unfamiliarity with the diagnostic criteria, reluctance to participate in a trial due to high age and comorbidities and a low prevalence of the disease in the academic setting likely have contributed to the difficult enrolment. The limited data did not show any safety issues regarding this novel application, but was insufficient to make any statements regarding efficacy.