Integrative Blood Pressure Response to Upright Tilt Post Renal Denervation

Abstract

Background: Whether renal denervation (RDN) in patients with resistant hypertension normalizes blood pressure (BP) regulation in response to routine cardiovascular stimuli such as upright posture is unknown. We conducted an integrative study of BP regulation in patients with resistant hypertension who had received RDN to characterize autonomic circulatory control.

Methods: Twelve patients (60 ± 9 [SD] years, n = 10 males) who participated in the Symplicity HTN-3 trial were studied and compared to 2 age-matched normotensive (Norm) and hypertensive (unmedicated, HTN) control groups. BP, heart rate (HR), cardiac output (Qc), muscle sympathetic nerve activity (MSNA), and neurohormonal variables were measured supine, and 30° (5 minutes) and 60° (20 minutes) head-up-tilt (HUT). Total peripheral resistance (TPR) was calculated from mean arterial pressure and Qc.

Results: Despite treatment with RDN and 4.8 (range, 3-7) antihypertensive medications, the RDN had significantly higher supine systolic BP compared to Norm and HTN (149 ± 15 vs. 118 ± 6, 108 ± 8 mm Hg, P < 0.001). When supine, RDN had higher HR, TPR, MSNA, plasma norepinephrine, and effective arterial elastance compared to Norm. Plasma norepinephrine, Qc, and HR were also higher in the RDN vs. HTN. During HUT, BP remained higher in the RDN, due to increases in Qc, plasma norepinephrine, and aldosterone.

Conclusion: We provide evidence of a possible mechanism by which BP remains elevated post RDN, with the observation of increased Qc and arterial stiffness, as well as plasma norepinephrine and aldosterone levels at approximately 2 years post treatment. These findings may be the consequence of incomplete ablation of sympathetic renal nerves or be related to other factors.

Keywords: ablation; autonomic nervous system; blood pressure; human; hypertension; physiology; sympathetic activity.

Figure 1.

Overview of the integrative regulation of blood pressure. Blood pressure is a function of cardiac output (stroke volume and heart rate) as well as total peripheral resistance. In the case of enhanced renal sympathetic activity, the renin–angiotensin–aldosterone system is activated and renal blood flow is reduced, causing volume retention, sodium reabsorption, and ultimately elevating BP. (1) Denervation of the renal arteries is proposed to alter BP via a decrease in renal afferent and efferent nerve activity, (2) causing a reduction in both centrally mediated sympathetic outflow, thus reducing (3) muscle sympathetic nerve activity, (4) norepinephrine spillover and (5) vascular resistance and (6) in total peripheral resistance, thereby lowering blood pressure. In addition, reduced sympathetic activity to the heart (7) should reduce heart rate and thereby reduce cardiac output (8) and lower blood pressure. The decrease in renin, could lower blood pressure via reduction in aldosterone levels, blood volume and cardiac output, or alternatively a decrease in angiotensin II reducing peripheral vascular resistance. Abbreviations: BP, blood pressure; MSNA, muscle sympathetic nerve activity; CVLM, caudal ventrolateral medulla; NA, nucleus ambiguus; NE, norepinephrine; NTS, nucleus tractus solitraius; PAG, periaqueductal grey; PVN, paraventricular nucleus; RVLM, rostral ventrolateral medulla.

Figure 2.

Representative tracing of integrative MSNA signal in the supine position and at 20 minutes HUT 60° posture in normotensive (a), hypertensive (b), and renal denervation subject (c). Note that the upward shift in the baseline during head up tilt does not influence total MSNA. Abbreviations: HUT, head up tilt; MSNA, muscle sympathetic nerve activity.

Figure 3.

Comparison of supine resting blood pressure (a), heart rate (b), MSNA (c) and plasma norepinephrine (d) in RDN subjects, unmedicated mild HTN and Norm subjects. Mean BP, heart rate and plasma norepinephrine levels were significantly higher in the RDN subjects than both other groups, while MSNA was significantly higher in the RDN vs. Norm group only. *P ≤ 0.05. Abbreviations: HTN, hypertensive; MSNA, muscle sympathetic nerve activity; Norm, normotensive; RDN, renal denervation.

Figure 4.

Comparison of the hemodynamic and neural response to head up tilt in RDN subjects, with HTN and Norm control subjects. Mean blood pressure (a) was higher in the RDN subjects; however, the response to HUT was similar between groups. The heart rate (b) and (c) total peripheral resistance was similar between groups, while Qc remained higher in the RDN group (d). The neural response, as assessed by the change in burst frequency (e) and change from baseline in total activity (f) was also similar among the groups. Total activity was analyzable in n = 9 subjects in the RDN group and n = 11 subjects in the NORM group. *P ≤0.05 compared to Norm under the same condition, ^†P ≤0.05 compared to HTN under the same condition. Abbreviations: HR, heart rate; HUT, head up tilt; MAP, mean arterial pressure; MSNA, muscle sympathetic nerve activity; Norm, normotensive; Qc, cardiac output; RDN, renal denervation; HTN, hypertensive; TPR, total peripheral resistance.