Catheter-Based Renal Nerve Ablation as a Novel Hypertension Therapy

Abstract

randomized controlled trial with blinded end point evaluation was conducted in 15 French centers in patients with resistant hypertension. To verify that patients were drug resistant, a combination of 1.5 mg indapamide, 10 mg ramipril (or 300 mg of irbesartan), and 10 mg of amlodipine was administered for 4 weeks during which time ambulatory blood pressure was measured. Patients were then randomized 1:1 and assigned to receive either standardized stepped-care antihypertensive treatment alone or standardized stepped-care antihyperten-sive treatment and renal denervation. Standardized stepped-care antihypertensive treatment involved the addition of 25 mg spironolactone, 10 mg bisoprolol, 5 mg prazosin, and 1 mg rilmenidine for 3 months if home and ambulatory blood pressure were >135/85 mm Hg. Ambulatory systolic pressure decreased 9.9 mm Hg in the control (SSHAT) group and 15.8 mm Hg in the renal denervation+SSHAT group. More importantly, it was reported that the number of antihyper-tensive drugs and drug adherence at 6 months was similar in both groups. These investigators concluded that, in patients with well-defined resistant hypertension, renal denervation decreases blood pressure more than optimization of drug therapy alone and that this additional blood pressure-lowering effect may contribute to a reduction in cardiovascular morbidity if maintained in long term after renal denervation. 12 These findings, as well as the issues raised in the Symplicity HTN trials, raised several questions on CBRNA as a therapy for hypertension. We attempt to address some of these questions in the following sections. It has been reported that CBRNA had no effect on plasma renin and aldosterone. 13 However, the expected decrease in renin release caused by CBRNA may be offset by the direct effect of reduced renal perfusion pressure to stimulate renin release. 1 These investigators also reported that CBRNA decreased total peripheral resistance, whereas cardiac output did not change. 13 It is not known whether the decrease in peripheral resistance was because of reduced renal vascular resistance specifically, or whether vasodilation occurred in other vascular beds. CBRNA reportedly reduces renal resis-tive index with no change in glomerular filtration rate. 14 The hypothesis that afferent renal nerves contribute to the effects of CBRNA was sparked by clinical studies showing that CBRNA had off-target effects, including reduced fasting plasma glucose, decreased muscle sympathetic nerve activity (MSNA), lower sleep apneic frequency, and less cardiac arrhythmias. 15-17 These findings are consistent with preclinical studies demonstrating that sensory neural signals from kidneys modulate sympathetic activity not only to the kidney but other organs. 1 Techniques to ablate afferent renal nerves, independent of efferent nerves, have been used to study experimental hypertension. The first method was bilateral sectioning of the spinal dorsal roots from T9 to L1, or dorsal rhizotomy. This method interrupts renal sensory input to the spinal cord and has been reported to attenuate several models of experimental hypertension. 1 However, dorsal rhizotomy is not specific for renal afferent nerves because cutaneous, somatic, and all other visceral afferent inputs between T9 and L1 are also sectioned by this method. This is a confounding factor, particularly in salt-sensitive models of hyperten-sion, because animal and human studies have shown that the skin and skeletal muscle store sodium and may be important in sodium homeostasis. 18 We recently developed a chemical ablation method that targets renal afferent nerves while leaving renal effer-ent nerves and other sensory afferent nerves intact. 19 This method attenuates the development of deoxycorticosterone acetate-salt hypertension in the rat just as effectively as total (efferent+afferent) surgical renal denervation (RDN). 19,20 This finding combined with the observation that basal affer-ent renal nerve activity was 2.5-fold higher in deoxycorti-costerone acetate-salt compared with normotensive control rats 20 suggests that this model is driven by afferent, not effer-ent, renal nerves. However, it is important to note that this method of targeted afferent renal nerve ablation has no effect on another model of hypertension, the Dahl salt-sensitive rat, despite the fact that complete RDN lowered arterial pressure. 21 These data suggest that the response to RDN in this model is mediated by ablation of efferent, not afferent, renal nerves. The same is true for the angiotensin II-induced mouse model in that RDN attenuates hypertension, but affer-ent renal nerve ablation does not. 22 When combined, these studies indicate the role of efferent and afferent nerves to the pathogenesis of hypertension are model dependent.