Successful renal denervation decreases the platelet activation status in hypertensive patients.

AIMS: To determine whether renal denervation (RDN) in hypertensive patients affects the platelet activation status. METHODS AND RESULTS: We investigated the effect of RDN on the platelet activation status in 41 hypertensive patients undergoing RDN. Ambulatory blood pressure (BP), plasma sympathetic neurotransmitter Neuropeptide Y, and platelet activation markers were measured at baseline, at 3 months, and 6 months after RDN. RDN significantly decreased BP at 3 months (150.6 ± 11.3/80.9 ± 11.4 mmHg to 144.7 ± 12.0/77.1 ± 11.1 mmHg; P < 0.01) and at 6 months (144.3 ± 13.8/78.3 ± 11.1 mmHg; P < 0.01). Plasma levels of the sympathetic neurotransmitter Neuropeptide Y, an indicator of sympathetic nerve activity, were significantly decreased at 3 months (0.29 ± 0.11 ng/mL to 0.23 ± 0.11 ng/mL; P < 0.0001) and at 6 months (0.22 ± 0.12 ng/mL; P < 0.001) after RDN. This was associated with a reduction in platelet membrane P-selectin expression (3 months, P < 0.05; 6 months, P < 0.05), soluble P-selectin (6 months, P < 0.05), circulating numbers of platelet-derived extracellular vesicles (EVs) (3 months, P < 0.001; 6 months, P < 0.01), and phosphatidylserine expressing EVs (3 months, P < 0.001; 6 months, P < 0.0001), indicative of a reduction in platelet activation status and procoagulant activity. Only patients who responded to RDN with a BP reduction showed inhibition of P-selectin expression at 3 months (P < 0.05) and 6 months (P < 0.05) as well as reduction of glycoprotein IIb/IIIa activation at 3 months (P < 0.05). Notably, 13 patients who took aspirin did not show significant reduction in platelet P-selectin expression following RDN. CONCLUSION: Our results imply a connection between the sympathetic nervous system and the platelet activation status and provide a potential mechanistic explanation by which RDN can have favourable effects towards reducing cardiovascular complications.

The Effect of Renal Denervation on Plasma Adipokine Profile in Patients with Treatment Resistant Hypertension.

Background: We previously demonstrated the effectiveness of renal denervation (RDN) to lower blood pressure (BP) at least partially via the reduction of sympathetic stimulation to the kidney. A number of adipocyte-derived factors are implicated in BP control in obesity. Aim: The aim of this study was to examine whether RDN may have salutary effects on the adipokine profile in patients with resistant hypertension (RH). Methods: Fifty seven patients with RH undergoing RDN program have been included in this study (65% males, age 60.8 ± 1.5 years, BMI 32.6 ± 0.7 kg/m2, mean ± SEM). Throughout the study, the patients were on an average of 4.5 ± 2.7 antihypertensive drugs. Automated seated office BP measurements and plasma concentrations of leptin, insulin, non-esterified fatty acids (NEFA), adiponectin and resistin were assessed at baseline and the 3 months after RDN. Results: There was a significant reduction in mean office systolic (168.75 ± 2.57 vs. 155.23 ± 3.17 mmHg, p < 0.001) and diastolic (90.68 ± 2.31 vs. 83.74 ± 2.36 mmHg, p < 0.001) BP 3 months after RDN. Body weight, plasma leptin and resistin levels and heart rate remained unchanged. Fasting insulin concentration significantly increased 3 months after the procedure (20.05 ± 1.46 vs. 29.70 ± 2.51 uU/ml, p = 0.002). There was a significant drop in circulating NEFA at follow up (1.01 ± 0.07 vs. 0.47 ± 0.04 mEq/l, p < 0.001). Adiponectin concentration was significantly higher after RDN (5,654 ± 800 vs. 6,644 ± 967 ng/ml, p = 0.024). Conclusions: This is the first study to demonstrate that RDN is associated with potentially beneficial effects on aspects of the adipokine profile. Increased adiponectin and reduced NEFA production may contribute to BP reduction via an effect on metabolic pathways. Clinical Trial Registration Number: NCT00483808, NCT00888433.

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-1ß (3 months, P<0.05; 6 months, P<0.05), tumor necrosis factor-α (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.

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.

Health-related quality of life and blood pressure 12 months after renal denervation.

AIM: To examine the effect of renal denervation (RDN) on blood pressure (BP) and health-related quality of life (QoL) in patients with resistant hypertension, pseudoresistant hypertension due to a white-coat effect and in patients with uncontrolled masked hypertension. METHODS: Using the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36), Beck Depression Inventory (BDI) and Spielberger's state and trait anxiety questionnaires, we examined QoL, symptoms of depression and anxiety prior to and 12 months following RDN. BP was assessed from clinic and ambulatory blood pressure monitoring (ABPM) recordings. RESULTS: Patients with uncontrolled masked hypertension had the highest BDI and anxiety scores among all groups at baseline. Twelve months following RDN clinic and ambulatory BP were reduced only in those patients with resistant hypertension (delta SBP: clinic -16 ±â€Š3 mmHg, ABPMday -8 ±â€Š2 mmHg, ABPMnight -8 ±â€Š2 mmHg, all P < 0.01). Clinic BP was reduced in the pseudoresistant group (-17 ±â€Š6 mmHg, P < 0.01) but was elevated in the uncontrolled masked group (+13 ±â€Š6 mmHg, P = 0.02). In all patients, trait anxiety (P < 0.05), BDI scores (P < 0.05) and the SF-36 mental component summary (MCS) score (P < 0.001) were improved. The improvement in the SF-36 MCS was confined to those patients with resistant hypertension (+4.0 ±â€Š1.1, P < 0.01). The change in clinic BP after RDN was related to the baseline clinic BP (systolic: r = 0.54, P < 0.001; diastolic r = 0.43, P < 0.001), the number of ablations delivered (both clinic and mean day ABPM systolic r = 0.24, P < 0.05) and to the change in SF-36 MCS score (systolic: r = 0.25, P = 0.01; diastolic r = 0.24, P = 0.02). CONCLUSION: These results indicate that in patients with confirmed resistant hypertension, RDN is associated with a reduction in BP and a sustained improvement in mental health-related aspects of QoL.

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.