|i. Title: The enigma of drug resistant hypertension: is renal nerve ablation a remedy
Supervisors: Dr. Andreas Baumbach (UHBristol) and Professor Julian Paton (University of Bristol).
This project will be registered at the University of Bristol.
Hypertension has been identified as the leading factor for mortality worldwide. Remarkably, blood pressure (BP) remains uncontrolled in approximately 25% of patients treated with anti-hypertensive medication suggesting that current therapeutic interventions are ineffective in a significant proportion of patients.
Recently, a novel treatment for hypertension in patients resistant to drug treatment has been developed. A proof of principle study based in Australia indicated that bilateral renal nerve denervation (via renal artery intra-luminal radio-frequency ablation) decreased BP by ~20 mmHg that persisted for 24 months post-operatively. However, all patients remained on anti-hypertensive medication and an additional 13% (6/45 patients) did not respond. At the Bristol Heart Institute, we are running a UK based trial to understand how renal nerve ablation lowers BP and establish selection criteria for patients to ensure a maximal anti-hypertensive effect. The proposed study will equate the BP lowering effect after renal nerve ablation with the extent to which there have been improvements in baroreceptor reflex function (using microneurography recording of sympathetic nerve activity) and renal perfusion (Doppler; fMRI) thereby yielding novel mechanistic insight. Longitudinal studies on renal blood flow will determine the efficacy of renal nerve ablation and establish if nerve re-growth occurs.
Background: Hypertension is one of the leading causes of mortality worldwide. Blood pressure (BP) remains uncontrolled in approximately 25% of patients treated with anti-hypertensive medications. Recently, a non-pharmacological method for treating hypertension has been developed. In a proof of principle study bilateral renal nerve denervation (achieved by renal artery intra-luminal radio-frequency lesions) caused a reduction in BP, which persisted 24 months post-operatively. Interestingly, all patients remained on anti-hypertensive medications and 6 of 45 patients tested did not respond to the procedure. A failure to reduce BP may be due to incomplete renal nerve denervation. Studies to assess completeness of renal nerve denervation have not been performed routinely making it unclear whether a failure to reduce BP reflects either incomplete nerve ablation or non-responsive to treatment. Since changes in renal blood flow are partly under sympathetic control, renal blood flow responses to sympatho-excitatory stimuli may be a non-invasive approach for assessing completeness of the nerve denervation procedure. However, this approach awaits validation and forms the core of the PhD proposal.
Aim: Develop a technique to assess the completeness of renal denervation in patients being treated for drug-resistant hypertension. To test whether poor BP responses or a failure to respond to renal nerve denervation is due to sub-optimal procedural success. Follow up assessment will determine whether sympathetic efferents re-grow.
Methods: We have initiated a UK based trial at the Bristol Heart Institute to examine whether bilateral renal nerve denervation is an effective treatment in patients who have drug-resistant hypertension (defined as uncontrolled BP despite 3 or more anti-hypertensive medications). As a contributing mechanism, we are examining whether bilateral renal nerve denervation changes peripheral chemoreflex and baroreflex sensitivity immediately after renal nerve ablation and 1, 3, 6 and 12 months post-operatively. Presently, this on-going mechanistic study does not include measures of procedural success. Whilst the student would play a supportive role with this study, the specific aim of the PhD project would be to test whether renal nerve ablation is successful by measuring changes in renal artery blood flow using Doppler ultrasound and fMRI-arterial spin labeling in response to sympatho-excitatory stimuli before and after renal nerve ablation. Markers of a successful intervention include lowering of both BP and muscle sympathetic nerve activity (using microneurography), improved renal function (glomelular filtration index; urinary and plasma electrolyte osmolality) and reduced urinary catecholamines as an indirect index of sympathetic activity levels specifically to the kidney. We will assess renal artery structure using magnetic resonance angiography and equate any changes with renal blood flow/vascular resistance measures obtained in response to stimuli that increase sympathetic activity. This will be assessed before and at multiple time points after renal nerve ablation to identify possible re-innervation by sympathetic nerves.
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