Physiological Study of the Efficacy and Mechanistic Effects of Alcohol Renal Denervation

AIM1: The first aim of the study will be to determine the efficacy of chemical renal denervation in altering renal sympathetic nerve activity. This objective will be assessed by change in urinary catecholamines and sympathetic activity in the kidney 8 weeks post renal denervation (+/- 7 days). Specifically the investigators will compare the change in peak concentrations of 6-18F-fluorodopamine radioactivity in the renal cortex after renal denervation. A finding of a reduction in 6-18F-fluorodopamine radioactivity in the renal cortex will suggest that the chemical denervation has reduced sympathetic innervation in the kidney. The secondary assessment of efficacy will be via change in excretion of urinary norepinephrine, assessed by 24 hour urine collection. In addition, the investigators will measure plasma norepinephrine and metanephrine concentrations to isolate the systemic contribution from the kidney. Again a reduction in sympathetic innervation of the kidney by renal denervation will reduce norepinephrine excretion. AIM 2: The second aim of the study will be to utilize high resolution physiological testing to identify how chemical renal denervation alters the integrative regulation of blood pressure. The proposal entails using classic physiological techniques to examine blood pressure regulation, which are well established in this laboratory. Briefly the testing will include a detailed assessment of hemodynamics, autonomic function, neurohormonal volume control, renal blood flow, endothelial function and vascular compliance. While mean blood pressure is the product of cardiac output × total peripheral resistance, reductions in blood pressure may be via a number of divergent mechanisms following renal denervation. Following this study, the investigators will be able to characterize how blood pressure is reduced, and whether there is individual variability in the response. Experimental protocol. All patients will be required to undergo a battery of testing at baseline, and at 8 weeks post renal denervation. At the 8 week appointment patients will be followed up again at 6 and 12 months with an office blood pressure measurement, ambulatory blood pressure monitoring, vital signs, adverse events, assessment of renal anatomy (at 6 months and assessment of renal function. Autonomic function testing and blood volume (Baseline, week 8): Prior to testing all patients will consume a standardized isocaloric diet provided to them for 3 days. The diet will follow the principles of the DASH diet (Dietary Approaches to Stop Hypertension). In addition, patients will avoid caffeine and alcoholic beverages for ≥24 h prior to testing, other fluid intake will be ad libitum. All studies will take place in the morning after a \>12h fast. A fasting resting blood sample will be taken for measurement of FGF-23, electrolytes, hemoglobin, hematocrit, insulin and glucose. Patients will be instructed to withhold medication on the morning of this visit and a urine sample will be collected to confirm medication compliance. Autonomic function tests including spontaneous and controlled breathing, Valsalva, cold pressor test, submaximal handgrip to fatigue with post-exercise circulatory arrest, 30º and 60º head-up tilt will be performed. Measurements will include: MSNA recorded from the peroneal nerve by microneurography, beat-to-beat arterial pressure (Nexfin, BMEYE), brachial blood pressure will be measured by electrosphygmomanometry (Suntech), heart rate (HR, lead II of the ECG), cardiac output (Qc, modified acetylene rebreathing method), stroke volume (SV=Qc/HR), renal artery blood flow from doppler and total peripheral resistance (TPR=mean BP/Qc). Neurohumoral measurements include: catecholamines, plasma renin activity, aldosterone, and vasopressin will be performed at baseline and after 20 minutes of 60º head-up tilt. Sympathetic vascular transduction will be determined by the simultaneous measurement of forearm blood flow and vascular conductance (Doppler ultrasound) and MSNA at baseline. Blood volume will be measured in the sitting position by the modified carbon monoxide rebreathing technique. Vascular, ventricular and endothelial function testing (Baseline, 8 weeks, 6 months): As systolic blood pressure is largely determined by arterial stiffness and afterload the investigators will measure the effect of renal denervation in a number of ways. Arterial stiffness will be measured using the SphygmoCor device from which the measurement of peripheral and central pulse wave velocity, augmentation index and central blood pressures will determined. In addition, based on the Windkessel model, total arterial compliance will be calculated from stroke volume/pulse pressure, effective arterial stance will be calculated from end systolic pressure/stroke volume. Aortic age, will be derived using the Modelflow method and vascular compliance as beta stiffness. Two- and three-dimensional echo for left ventricular volumes and pulse wave Doppler, Tissue Doppler parameters, and color M-Mode Doppler for assessment of diastolic function will also be performed, using a standard echo machine (Phillips, iE33). Offline analysis for torsion and strain will be performed using commercially available software (Qlab). Finally, brachial artery flow-mediated (endothelium-dependent) and nitroglycerin-induced (endothelium-independent) vasodilatation will be measured using a high-resolution Doppler ultrasound machine in the supine position. Positron emission tomography (PET) imaging (Baseline, 8 weeks): Subjects who agree to participate in our study will travel to the National Institute of Neurological Disorders and Stroke, Bethesda Maryland, and undergo PET imaging of sympathetic activity in the kidney using PET/CT scanner (Siemens).