Physiological Study of the Efficacy and Mechanistic Effects of Alcohol Renal Denervation
Condition: Hypertension
MeSH terms: Hypertension
Study type: Interventional
Phase: Early Phase 1

Summary: 
      Hypertension is a major risk factor for heart disease and stroke, two of the leading causes
      of death in the United States. Hypertension is a common and widespread problem;
      unfortunately, current treatment strategies fail to adequately control blood pressure in up
      to 50% of patients either because of failure to take prescribed medications (because of cost,
      side effects, inconvenience etc.) or lack of therapeutic response. Indeed, it is estimated
      that 50% of patients stop taking antihypertensive medication within 6-12 months after the
      initiation of drug therapy.

      Despite enthusiasm for a novel approach called renal denercation, presently there are no
      integrative studies of the antihypertensive effect of renal denervation on the multiple
      regulatory pathways it may consequentially affect. Experimental evidence from pre-clinical
      models suggests the effects are due to reducing efferent sympathetic activity and thus
      lowering blood pressure by altering the renin-angiotensin system. Uncontrolled clinical
      studies in humans suggest that when effective, this procedure may also lower renal
      sympathetic nerve activity. However the sympathetic response to monopolar radiofrequency
      therapy has been highly variable. Moreover, there have been no assessments of procedural
      efficacy performed in humans. Thus the actual mechanism by which this type of procedure
      reduces BP in humans is largely unknown, making it extremely difficult to identify the
      appropriate patients for this invasive procedure.

      Recently, chemical renal denervation using ethanol (EtOH), was demonstrated to markedly lower
      blood pressure in small numbers of patients with resistant hypertension. However the
      mechanisms by which blood pressure is altered using this novel technique in humans is
      entirely unknown, and procedural efficacy has also not been assessed. Therefore it is
      unclear, whether in humans renal sympathetic nerve activity is lowered following renal
      denervation using this new approach. The Investigators propose to use high resolution
      physiological testing to determine the effects of chemical renal artery denervation on
      sympathetic activity.

      Therefore the global objective of this physiological study is to provide the first detailed
      assessment of the integrated mechanistic effects of chemical renal nerve denervation in
      humans with hypertension that is uncontrolled by conventional treatment (because of lack of
      adherence or response to therapy).
    

Detailed description: 
      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).
    

Intervention name(s): Renal Denervation
Intervention type(s): Combination Product
Intervention description(s): Bilateral denervation of the renal arteries using extravascular administration of neurolytic alcohol
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Basic Science