Petra Marusic

Substantial reduction in single sympathetic nerve firing after renal denervation in patients with resistant hypertension.

Renal denervation (RDN) has been shown to reduce blood pressure (BP) and muscle sympathetic nerve activity (MSNA) in patients with resistant hypertension. The mechanisms underlying sympathetic neural inhibition are unknown. We examined whether RDN differentially influences the sympathetic discharge pattern of vasoconstrictor neurons in patients with resistant hypertension. Standardized office BP, single-unit MSNA, and multi-unit MSNA were obtained at baseline and at 3-month follow-up in 35 patients with resistant hypertension. Twenty-five patients underwent RDN, and 10 patients underwent repeated measurements without RDN (non-RDN). Baseline BP averaged 164/93 mm Hg (RDN) and 164/87 mm Hg (non-RDN) despite use of an average of 4.8±0.4 and 4.4±0.5 antihypertensive drugs, respectively. Mean office BP decreased significantly by −13/−6 mm Hg for systolic BP (P<0.001) and diastolic BP (P<0.05) with RDN but not in non-RDN at 3-month follow-up. RDN moderately decreased multi-unit MSNA (79±3 versus 73±4 bursts/100 heartbeats; P<0.05), whereas all properties of single-unit MSNA including firing rates of individual vasoconstrictor fibers (43±5 versus 27±3 spikes/100 heartbeats; P<0.01), firing probability (30±2 versus 22±2% per heartbeat; P<0.02), and multiple firing incidence of single units within a cardiac cycle (8±1 versus 4±1% per heartbeat; P<0.05) were substantially reduced at follow-up. BP, single-unit MSNA, and multi-unit MSNA remained unaltered in the non-RDN cohort at follow-up. RDN results in the substantial and rapid reduction in firing properties of single sympathetic vasoconstrictor fibers, this being more pronounced than multi-unit MSNA inhibition. Whether the earlier changes in single-unit firing patterns may predict long-term BP response to RDN warrants further exploration.

Feasibility of catheter-based renal nerve ablation and effects on sympathetic nerve activity and blood pressure in patients with end-stage renal disease.

BACKGROUND AND OBJECTIVES Sympathetic activation is a hallmark of ESRD and adversely affects cardiovascular prognosis. Efferent sympathetic outflow and afferent neural signalling from the failing native kidneys are key mediators and can be targeted by renal denervation (RDN). Whether this is feasible and effective in ESRD is not known. DESIGN, SETTING, PARTICIPANTS AND MEASUREMENTS In an initial safety and proof-of-concept study we attempted to perform RDN in 12 patients with ESRD and uncontrolled blood pressure (BP). Standardized BP measurements were obtained in all patients on dialysis free days at baseline and follow up. Measures of renal noradrenaline spillover and muscle sympathetic nerve activity were available from 5 patients at baseline and from 2 patients at 12 month follow up and beyond. RESULTS Average office BP was 170.8 ± 16.9/89.2 ± 12.1 mmHg despite the use of 3.8 ± 1.4 antihypertensive drugs. All 5 patients in whom muscle sympathetic nerve activity and noradrenaline spillover was assessed at baseline displayed substantially elevated levels. Three out of 12 patients could not undergo RDN due to atrophic renal arteries. Compared to baseline, office systolic BP was significantly reduced at 3, 6, and 12 months after RDN (from 166 ± 16.0 to 148 ± 11, 150 ± 14, and 138 ± 17 mmHg, respectively), whereas no change was evident in the 3 non-treated patients. Sympathetic nerve activity was substantially reduced in 2 patients who underwent repeat assessment. CONCLUSIONS RDN is feasible in patients with ESRD and associated with a sustained reduction in systolic office BP. Atrophic renal arteries may pose a problem for application of this technology in some patients with ESRD.

Sustained Sympathetic and Blood Pressure Reduction 1 Year After Renal Denervation in Patients With Resistant Hypertension

Renal denervation (RDN) reduces muscle sympathetic nerve activity (MSNA) and blood pressure (BP) in resistant hypertension. Although a persistent BP-lowering effect has been demonstrated, the long-term effect on MSNA remains elusive. We investigated whether RDN influences MSNA over time. Office BP and MSNA were obtained at baseline, 3, 6, and 12 months after RDN in 35 patients with resistant hypertension. Office BP averaged 166±22/88±19 mm Hg, despite the use of an average of 4.8±2.1 antihypertensive drugs. Baseline MSNA was 51±11 bursts/min ≈2- to 3-fold higher than the level observed in healthy controls. Mean office systolic and diastolic BP significantly decreased by –12.6±18.3/–6.5±9.2, –16.1±25.6/–8.6±12.9, and –21.2±29.1/–11.1±12.9 mm Hg (P<0.001 for both systolic BP and diastolic BP) with RDN at 3-, 6-, and 12-month follow-up, respectively. MSNA was reduced by –8±12, –6±12, and –6±11 bursts/min (P<0.01) at 3-, 6-, and 12-month follow-up. The reduction in MSNA was maintained, despite a progressive fall in BP over time. No such changes were observed in 7 control subjects at 6-month follow-up. These findings confirm previous reports on the favorable effects of RDN on elevated BP and demonstrate sustained reduction of central sympathetic outflow ⩽1-year follow-up in patients with resistant hypertension and high baseline MSNA. These observations are compatible with the hypothesis of a substantial contribution of afferent renal nerve signaling to increased BP in resistant hypertension and argue against a relevant reinnervation at 1 year after procedure.

Health-Related Quality of Life After Renal Denervation in Patients With Treatment-Resistant Hypertension

Recent studies have demonstrated the effectiveness of radiofrequency ablation of the renal sympathetic nerves in reducing blood pressure (BP) in patients with resistant hypertension. The effect of renal denervation on health-related quality of life (QoL) has not been evaluated. Using the Medical Outcomes Study 36-Item Short-Form Health Survey and Beck Depression Inventory-II, we examined QoL before and 3 months after renal denervation in patients with uncontrolled BP. For baseline comparisons, matched data were extracted from the Australian Diabetes, Obesity, and Lifestyle database. Before renal denervation, patients with resistant hypertension (n=62) scored significantly worse in 5 of the eight 36-Item Short-Form Health Survey domains and the Mental Component Summary score. Three months after denervation (n=40), clinic BP was reduced (change in systolic and diastolic BP, −16±4 and −6±2 mm Hg, respectively; P<0.01). The Mental Component Summary score improved (47.6±1.1 versus 52±1; P=0.001) as a result of increases in the vitality, social function, role emotion, and mental health domains. Beck Depression Inventory scores were also improved, particularly with regard to symptoms of sadness (P=0.01), tiredness (P<0.001), and libido (P<0.01). The magnitude of BP reduction or BP level achieved at 3 months bore no association to the change in QoL. Renal denervation was without a detrimental effect on any elements of the 36-Item Short-Form Health Survey. These results indicate that patients with severe hypertension resistant to therapy present with a marked reduction in subjective QoL. In this pre- and post-hypothesis generating study, several aspects of QoL were improved after renal denervation; however, this was not directly associated with the magnitude of BP reduction.

Renal nerve ablation reduces augmentation index in patients with resistant hypertension.

Objective: Renal denervation (RDN) has been demonstrated to reduce muscle sympathetic nerve activity (MSNA) and blood pressure (BP) in patients with resistant hypertension. Whether alterations of arterial stiffness may contribute to BP-lowering effects of RDN is unknown. Methods: We measured office BP and arterial stiffness using fingertip tonometry-derived augmentation index (EndoPAT2000) at baseline and at 3-month follow-up in 50 consecutive patients with resistant hypertension. Forty patients received RDN and 10 patients served as controls. MSNA was obtained in 20 RDN and 10 non-RDN patients. Results: Baseline BP averaged 170/92 ± 19/15 mmHg (RDN) and 171/93 ± 14/8 mmHg (non-RDN) despite the use of 4.9 ± 1.9 and 4.4 ± 2.0 antihypertensive drugs, respectively. RDN significantly reduced SBP (170 ± 19 vs. 154 ± 25 mmHg; P < 0.001) and DBP (92 ± 15 vs. 84 ± 16 mmHg; P < 0.001), augmentation index (30.6 ± 23.8 vs. 22.7 ± 22.4%; P = 0.002), AI@75 corrected for heart rate (22.4 ± 21.6 vs. 14.4 ± 20.7; P = 0.002) and MSNA (80 ± 15 vs. 71 ± 18 bursts/100 heartbeats; P < 0.01). Changes in AI@75 with RDN were unrelated to SBP (r = 0.043; P = 0.79), and DBP (r = 0.092; P = 0.57) and MSNA changes (r = −0.17; P = 0.49). No changes in BP, augmentation index, AI@75 or MSNA were observed in the non-RDN group. Conclusion: RDN results in a substantial and rapid reduction in augmentation index, which appears to be independent of BP and MSNA changes. These findings are indicative of a beneficial effect of RDN on arterial stiffness in patients with resistant hypertension and may contribute to the sustained BP-lowering effect of RDN.

Reverse cardiac remodeling after renal denervation: Atrial electrophysiologic and structural changes associated with blood pressure lowering

BACKGROUND Hypertension is the most common modifiable risk factor associated with atrial fibrillation. OBJECTIVE The purpose of this study was to determine the effects of blood pressure (BP) lowering after renal denervation on atrial electrophysiologic and structural remodeling in humans. METHODS Fourteen patients (mean age 64 ± 9 years, duration of hypertension 16 ± 11 years, on 5 ± 2 antihypertensive medications) with treatment-resistant hypertension underwent baseline 24-hour ambulatory BP monitoring, echocardiography, cardiac magnetic resonance imaging, and electrophysiologic study. Electrophysiologic study included measurements of P-wave duration, effective refractory periods, and conduction times. Electroanatomic mapping of the right atrium was completed using CARTO3 to determine local and regional conduction velocity and tissue voltage. Bilateral renal denervation was performed, and all measurements repeated after 6 months. RESULTS After renal denervation, mean 24-hour BP reduced from 152/84 mm Hg to 141/80 mm Hg at 6-month follow-up (P < .01). Global conduction velocity increased significantly (0.98 ± 0.13 m/s to 1.2 ± 0.16 m/s at 6 months, P < .01), conduction time shortened (32 ± 5 ms to 27 ± 6 ms, P < .01), and complex fractionated activity was reduced (37% ± 14% to 19% ± 12%, P = .02). Changes in conduction velocity correlated positively with changes in 24-hour mean systolic BP (R(2) = 0.55, P = .01). There was a significant reduction in left ventricular mass (139 ± 37 g to 120 ± 29 g, P < .01) and diffuse ventricular fibrosis (T1 partition coefficient 0.39 ± 0.07 to 0.31 ± 0.09, P = .01) on cardiac magnetic resonance imaging. CONCLUSION BP reduction after renal denervation is associated with improvements in regional and global atrial conduction and reductions in ventricular mass and fibrosis. Whether changes in electrical and structural remodeling are solely due to BP lowering or are due in part to intrinsic effects of renal denervation remains to be determined.

A Randomized Controlled Trial of the Effects of Pioglitazone Treatment on Sympathetic Nervous System Activity and Cardiovascular Function in Obese Subjects With Metabolic Syndrome

CONTEXT Insulin resistance and sympathetic nervous system overactivity are closely associated and contribute to cardiovascular risk. OBJECTIVE The objective of the study was to test the hypotheses that pharmacological improvement in insulin sensitivity would (1) attenuate sympathetic neural drive and (2) enhance neuronal norepinephrine uptake. PARTICIPANTS AND METHODS A randomized, double-blind trial was conducted in 42 obese, unmedicated individuals with metabolic syndrome (mean age 56 ± 1 y, body mass index 34 ± 0.6 kg/m(2)) who received 12 weeks of pioglitazone (PIO; 15 mg for 6 wk, then 30 mg daily) or matched placebo. Clinical measurements included whole-body norepinephrine kinetics [spillover rate, plasma clearance, and the steady state ratio of tritiated 3,4-dihydroxyphenylglycol to tritiated norepinephrine ([(3)H]-DHPG to [(3)H]-NE) as an index of neuronal uptake-1], muscle sympathetic nerve activity, spontaneous baroreflex sensitivity, euglycemic hyperinsulinemic clamp, oral glucose tolerance test, ambulatory blood pressure, and Doppler echocardiography. RESULTS PIO treatment increased glucose uptake by 35% and was accompanied by significant reductions in diastolic blood pressure and improved left ventricular diastolic and endothelial function. Resting muscle sympathetic nerve activity burst frequency decreased by -6 ± 3 burst/min compared with baseline (P = .03), but the magnitude of change was not different from placebo (P = .89). Norepinephrine spillover and clearance rates and baroreflex sensitivity were unchanged. Post hoc subgroup analyses revealed an 83% increase in [(3)H]-DHPG to [(3)H]-NE ratio in hyperinsulinemic (P = .04) but not normoinsulinemic subjects (time × group interaction, P = .045). Change in [(3)H]-DHPG to [(3)H]-NE ratio correlated with improvements in diastolic blood pressure (r = -0.67, P = .002), the ratio of early (E) to late (A) peak transmitral diastolic inflow velocity (r = 0.62, P = .008), E wave deceleration time (r = -0.48, P = .05), and Δinsulin area under the curve0-120 during the oral glucose tolerance test (r = -0.42, P = .08). CONCLUSIONS Compared with placebo, PIO does not affect resting sympathetic drive or norepinephrine disposition in obese subjects with metabolic syndrome. Treatment induced changes in the [(3)H]-DHPG to [(3)H]-NE ratio related to reduction in hyperinsulinemia and improvements in diastolic function.

Renal artery anatomy affects the blood pressure response to renal denervation in patients with resistant hypertension

BACKGROUND Renal denervation (RDN) has been shown to reduce blood pressure (BP), muscle sympathetic nerve activity (MSNA) and target organ damage in patients with resistant hypertension (RH) and bilateral single renal arteries. The safety and efficacy of RDN in patients with multiple renal arteries remains unclear. METHODS We measured office and 24-hour BP at baseline, 3 and 6 months following RDN in 91 patients with RH, including 65 patients with single renal arteries bilaterally (group 1), 16 patients with dual renal arteries on either one or both sides (group 2) and 10 patients with other anatomical constellations or structural abnormalities (group 3). Thirty nine out of 91 patients completed MSNA at baseline and follow-up. RESULTS RDN significantly reduced office and daytime SBP in group 1 at both 3 and 6 months follow-up (P<0.001) but not in groups 2 and 3. Similarly, a significant reduction in resting baseline MSNA was only observed in group 1 (P<0.05). There was no deterioration in kidney function in any group. CONCLUSION While RDN can be performed safely irrespective of the underlying renal anatomy, the presence of single renal arteries with or without structural abnormalities is associated with a more pronounced BP and MSNA lowering effect than the presence of dual renal arteries in patients with RH. However, when patients with dual renal arteries received renal nerve ablation in all arteries there was trend towards a greater BP reduction. Insufficient renal sympathetic nerve ablation may account for these differences.

Effect of renal denervation on kidney function in patients with chronic kidney disease

AIMS Renal denervation (RDN) can reduce blood pressure (BP) and slow the decline of renal function in chronic kidney disease (CKD) up to one year. Whether this effect is maintained beyond 12months and whether the magnitude of BP reduction affects estimated glomerular filtration rate (eGFR) is unknown. METHODS AND RESULTS We examined eGFR in 46 CKD patients (baseline eGFR ≤60mL/min/1.73m2) on a yearly basis from 60months before to 3, 6, 12 and 24months after RDN. Ambulatory BP was measured before and after RDN. Linear mixed models analysis demonstrated a significant progressive decline in eGFR from months 60 to 12months (-15.47±1.98mL/min/1.73m2, P<0.0001) and from 12months to baseline prior to RDN (-3.41±1.64mL/min/1.73m2, P=0.038). Compared to baseline, RDN was associated with improved eGFR at 3months (+3.73±1.64mL/min/1.73m2, P=0.02) and no significant changes at 6 (+2.54±1.66mL/min/1.73m2, P=0.13), 12 (+1.78±1.64mL/min/1.73m2, P=0.28), and 24 (-0.24±2.24mL/min/1.73m2, P=0.91) months post procedure were observed. RDN significantly reduced daytime SBP from baseline to 24months post procedure (148±19 vs 136±17mmHg, P=0.03) for the entire cohort. Changes in SBP were unrelated to the eGFR changes at 6 (r=0.033, P=0.84), 12 (r=0.01, P=0.93) and 24months (r=-0.42, P=0.17) follow-up. CONCLUSION RDN can slow further deterioration of renal function irrespective of BP lowering effects in CKD. RDN-induced inhibition of sympathetic outflow to the renal vascular bed may account for improved eGFR via alterations of intrarenal and glomerular hemodynamics.

Renal Denervation Reduces Monocyte Activation and Monocyte-Platelet Aggregate Formation: An Anti-Inflammatory Effect Relevant for Cardiovascular Risk

Overactivation of renal sympathetic nervous system and low-grade systemic inflammation are common features of hypertension. Renal denervation (RDN) reduces sympathetic activity in patients with resistant hypertension. However, its effect on systemic inflammation has not been examined. We prospectively investigated the effect of RDN on monocyte activation and inflammation in patients with uncontrolled hypertension scheduled for RDN. Ambulatory blood pressure, monocyte, and monocyte subset activation and inflammatory markers were assessed at baseline, 3 months, and 6 months after procedure in 42 patients. RDN significantly lowered blood pressure at 3 months (150.5±11.2/81.0±11.2 mm Hg to 144.7±11.8/77.9±11.0 mm Hg), which was sustained at 6 months (144.7±13.8/78.6±11.0 mm Hg). Activation status of monocytes significantly decreased at 3 months (P<0.01) and 6 months (P<0.01) after the procedure. In particular, classical monocyte activation was reduced at 6 months (P<0.05). Similarly, we observed a reduction of several inflammatory markers, including monocyte–platelet aggregates (3 months, P<0.01), plasma monocyte chemoattractant protein-1 levels (3 months, P<0.0001; 6 months, P<0.05), interleukin-1&bgr; (3 months, P<0.05; 6 months, P<0.05), tumor necrosis factor-&agr; (3 months, P<0.01; 6 months, P<0.05), and interleukin-12 (3 months, P<0.01; 6 months, P<0.05). A positive correlation was observed between muscle sympathetic nerve activity and monocyte activation before and after the procedure. These results indicate that inhibition of sympathetic activity via RDN is associated with a reduction of monocyte activation and other inflammatory markers in hypertensive patients. These findings point to a direct interaction between the inflammatory and sympathetic nervous system, which is of central relevance for the understanding of beneficial cardiovascular effects of RDN.