Hypertension Clinical Trial
Official title:
Physiological Study of the Efficacy and Mechanistic Effects of Alcohol Renal Denervation
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).
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).
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