Renal Denervation Group Research Articles

Renal Denervation Suppresses Coronary Hyperconstricting Responses After Drug-Eluting Stent Implantation in Pigs In Vivo Through the Kidney-Brain-Heart Axis.

Drug-eluting stent-induced coronary hyperconstricting responses remain an important issue. The adventitia harbors a variety of components that potently modulate vascular tone, including sympathetic nerve fibers (SNF) and vasa vasorum. Catheter-based renal denervation (RDN) inhibits sympathetic nerve activity. We, thus, examined whether RDN suppresses drug-eluting stent-induced coronary hyperconstricting responses, and if so, what mechanisms are involved. Protocol 1: pigs implanted with everolimus-eluting stents into the left coronary arteries underwent coronary angiography at 1 month after implantation for assessment of coronary vasomotion and adventitial SNF formation. Drug-eluting stent-induced coronary hyperconstricting responses were significantly enhanced associated with enhanced coronary adventitial SNF and vasa vasorum formation. Protocol 2: pigs implanted with everolimus-eluting stents were randomly assigned to the RDN or sham group. The RDN group underwent renal ablation. At 1 month, RDN significantly caused marked damage of the SNF at the renal arteries without any stenosis, thrombus, or dissections. Notably, RDN significantly upregulated the expression of α2-adrenergic receptor-binding sites in the nucleus tractus solitarius, attenuated muscle sympathetic nerve activity, and decreased systolic blood pressure and plasma renin activity. In addition, RDN attenuated coronary hyperconstricting responses to intracoronary serotonin at the proximal and distal stent edges associated with decreases in SNF and vasa vasorum formation, inflammatory cell infiltration, and Rho-kinase expression/activation. Furthermore, there were significant positive correlations between SNF and vasa vasorum and between SNF and coronary vasoconstricting responses. These results provide the first evidence that RDN ameliorates drug-eluting stent-induced coronary hyperconstricting responses in pigs in vivo through the kidney-brain-heart axis.

Account for Clinical Heterogeneity in Assessment of Catheter-based Renal Denervation among Resistant Hypertension Patients: Subgroup Meta-analysis.

Background:Catheter-based renal denervation (RDN) is a novel treatment for resistant hypertension (RH). A recent meta-analysis reported that RDN did not significantly reduce blood pressure (BP) based on the pooled effects with mild to severe heterogeneity. The aim of the present study was to identify and reduce clinical sources of heterogeneity and reassess the safety and efficacy of RDN within the identified homogeneous subpopulations.Methods:This was a meta-analysis of 9 randomized clinical trials (RCTs) among patients with RH up to June 2016. Sensitivity analyses and subgroup analyses were extensively conducted by baseline systolic blood pressure (SBP) level, antihypertensive medication change rates, and coronary heart disease (CHD).Results:In all patients with RH, no statistical differences were found in mortality, severe cardiovascular events rate, and changes in 24-h SBP and office SBP at 6 and 12 months. However, subgroup analyses showed significant differences between the RDN and control groups. In the subpopulations with baseline 24-h SBP ≥155 mmHg (1 mmHg = 0.133 kPa) and the infrequently changed medication, the use of RDN resulted in a significant reduction in 24-h SBP level at 6 months (P = 0.100 and P = 0.009, respectively). Subgrouping RCTs with a higher prevalent CHD in control showed that the control treatment was significantly better than RDN in office SBP reduction at 6 months (P < 0.001).Conclusions:In all patients with RH, the catheter-based RDN is not more effective in lowering ambulatory or office BP than an optimized antihypertensive drug treatment at 6 and 12 months. However, among RH patients with higher baseline SBP, RDN might be more effective in reducing SBP.

Effects of catheter-based renal denervation on heart failure with reduced ejection fraction: a systematic review and meta-analysis.

Despite the recent advances in the management of heart failure, the mortality of heart failure patients remains high. It is of urgent need to develop new therapy for heart failure. Heart failure is characterized by increased sympathetic activity, and chronic sympathetic activation is involved in the maintenance of the pathological state. Catheter-based renal denervation (RDN) has emerged as an invasive but safe approach that can reduce sympathetic activation. Studies have reported inconsistent results regarding the effect of RDN in heart failure patients due to limited power with small sample sizes. We aimed to conduct a meta-analysis of the effect of RDN on heart failure patients with reduced left ventricular (LV) ejection fraction (EF). An electronic search for studies examining the effect of RDN on LV function in heart failure patients with reduced EF was conducted. Two controlled (80 patients) and 2 uncontrolled studies (21 patients) were included in this meta-analysis. In the pooled analysis, 6months after RDN, there was a greater increase in EF (weighted mean difference [95% CI]=8.63 [6.02, 11.24] %) and a greater decrease in LV end-diastolic diameter (-0.58 [-0.83, -0.34] cm) in RDN group than in control group. No serious adverse events such as acute renal artery stenosis and dissection occurred. Our meta-analysis of feasibility studies suggests that RDN may improve LV function in heart failure patients with reduced EF, providing the rationale to conduct next phase trials to confirm the observed potential benefits of RDN.

Effects of multielectrode renal denervation on elevated sympathetic nerve activity and insulin resistance in metabolic syndrome.

This study aimed to investigate the effects of renal denervation (RDN) on sympathetic nerve activity and insulin resistance in patients with metabolic syndrome. Seventeen patients fulfilled at least four of five criteria for metabolic syndrome and under stable use of at least two antihypertensive drugs were randomized in 3 : 1 ratio to RDN (n = 13, 12 men, age: 58 ± 7 years) and control groups (n = 4, three men, age: 60 ± 5 years) and followed up for 3 months. Muscle sympathetic nerve activity (MSNA) at rest and during standard 75 g oral glucose tolerance test (OGTT) was assessed. In the RDN group, office and average 24-h blood pressures reduced by 16 ± 21/10 ± 11 mmHg (P = 0.01/0.007) and 14 ± 16/5 ± 8 mmHg (P = 0.008/0.03) respectively; waist circumference reduced by 3.1 ± 3.6 cm (P = 0.008); and resting MSNA reduced from 55 ± 9 bursts per minute to 46 ± 8 bursts per minute (P = 0.0008) at month 3 post-RDN. During OGTT, although blunted MSNA responses were noted at baseline throughout the 120-min test, improved MSNA responses with burst frequency increased to 52 ± 8 bursts per minute (P < 0.001 vs. the resting MSNA, n = 13) at 30 min and to 54 ± 8 bursts per minute (P = 0.004 vs. the resting MSNA, n = 10) at 120 min and were observed at month 3 post-RDN. No such improvements were observed in the controls. No significant change was observed in the HOMA-IR in both groups at month 3. In this pilot study of patients with metabolic syndrome and associated hypertension, RDN reduced elevated sympathetic nerve activity and restored the normal neural response to oral glucose loading.

Feasibility of catheter ablation renal denervation in "mild" resistant hypertension.

Renal denervation (RDN) has been proposed as a novel interventional antihypertensive technique. However, existing evidence was mainly from patients with severe resistant hypertension. The authors aimed to evaluate the efficacy of RDN in patients with resistant hypertension with mildly elevated blood pressure (BP). Studies of RDN in patients with mild resistant hypertension (systolic office BP 140-160mm Hg despite treatment with three antihypertensive drugs including one diuretic, or mean systolic BP by 24-hour ambulatory BP measurement [ABPM] 135-150mm Hg) were included. Two observational and one randomized cohort were identified (109 patients in the RDN group and 36 patients in the control group). Overall, the mean age of patients was 62±10years, and 69.7% were male. Before-after comparison showed that RDN significantly reduced ABPM as compared with the baseline systolic ABPM, from 146.3±13mm Hg at baseline to 134.6±14.7mm Hg at 6-month follow-up and diastolic ABPM from 80.8±9.4mm Hg at baseline to 75.5±9.8mm Hg at 6-month follow up (both P<.001). This significant effect was not observed in the control group. Between-group comparison showed a greater change in ABPM in the RDN group as compared with that in the control group (change in systolic ABPM: -11.7±9.9mm Hg in RDN vs -3.5±9.6mm Hg in controls [P<.001]; change in diastolic ABPM: -5.3±6.3mm Hg in RDN vs -2.1±5.5mm Hg in control [P=.007]). RDN was also associated with a significantly decreased office systolic/diastolic BP and reduced number of antihypertensive medications. No severe adverse events were found during follow-up. RDN seems feasible to treat patients with mild resistant hypertension.

Effects of Renal Artery Denervation on Ventricular Arrhythmias in a Postinfarct Model

The therapeutic potential of renal denervation (RDN) for arrhythmias has not been fully explored. Detailed mechanistic evaluation is in order. The objective of the present study was to determine the antiarrhythmic potential of RDN in a postinfarct animal model and to determine whether any benefits relate to RDN-induced reduction of sympathetic effectors on the myocardium. Pigs implanted with single-chamber implantable cardioverter defibrillators to record ventricular arrhythmias (VAs) were subjected to percutaneous coronary occlusion to induce myocardial infarction. Two weeks later, a sham or real RDN treatment was performed bilaterally using the St Jude EnligHTN basket catheter. Parameters of ventricular remodeling and modulation of cardio-renal sympathetic axis were monitored for 3 weeks after myocardial infarction. Histological analysis of renal arteries yielded a mean neurofilament score of healthy nerves that was significantly lower in the real RDN group than in sham controls; damaged nerves were found only in the real RDN group. There was a 100% reduction in the rate of spontaneous VAs after real RDN and a 75% increase in the rate of spontaneous VAs after sham RDN (P=0.03). In the infarcted myocardium, presence of sympathetic nerves and tissue abundance of neuropeptide-Y, an indicator of sympathetic nerve activities, were significantly lower in the RDN group. Peak and mean sinus tachycardia rates were significantly reduced after RDN. RDN in the infarcted pig model leads to reduction of postinfarction VAs and myocardial sympathetic effectors. This may form the basis for a potential therapeutic role of RDN in postinfarct VAs.

Predictive Factors for Efficacy of Catheterbased Renal Denervation with Standard Ablation Catheter in Refractory Hypertension

Objective: Renal denervation (RDN) has been demonstrated to reduce blood pressure durably, but its efficacy and safety is still unclear with standard radiofrequency ablation catheters, and related predictive factors remain unknown for its efficacy. Methods: Sixty patients with refractory hypertension were enrolled to undergo RDN procedure or drug therapy. Blood pressure was measured at baseline and 3-month follow-up. Eight of them excluded, forty-two patients underwent RDN treatment while the other ten served as controls. Results: The patients in RDN group and controls both had a high blood pressure (166.5/99.8 ± 12.6/12.2 vs. 170.4/102.5 ± 17.8/16.2 mmHg, Pi¼ž0.05) in spite of the use of 3.8 ± 1.0 or 4.3 ± 1.2 types of anti-hypertensive drugs. Mean blood pressure was significantly decreased after RDN (153.0/99.8 ± 16.8/12.2 vs. 166.5/90.5 ± 12.6/11.5 mmHg, Pi¼œ0.001), while no significant reduction of blood pressure was observed in controls. There were no severe adverse cardiovascular events in RDN group. Multiple linear regression analysis showed that impedance reduction, sex was related to the decrease of SBP (Pi¼œ0.05), while impedance reduction, BMI and eGFR were correlated to the decrease of DBP (Pi¼œ0.05). Conclusion: RDN with standard ablation catheters could safely reduce blood pressure in Chinese patients with refractory hypertension. The effectiveness of RDN appears to be associated with impedance change, sex, BMI and eGFR.

Effects of renal denervation on left ventricular remodeling and cardiac oxidative stress after myocardial infarction in canine

Objective To investigate the effects of renal denervation (RDN) on left ventricular remodeling and cardiac oxidative stress due to myocardial infarction (MI) in canine. Methods Anterior myocardial infarction was produced by gelatin sponge embolization of the left anterior descending artery. Eighteen canines were randomly divided into three groups. Sham group (renal arteriography performed a week after coronary angiograph, n=6), MI group (renal arteriography performed a week after MI, n=6), and RDN group (RDN performed a week after MI, n=6). Four weeks post-MI, left ventricular function was measured by hemodynamics. Echocardiography examination was administered to identify left ventricular end-diastolic dimension (LVEDD), left ventricular end systolic diameter (LVESD), fraction shortening (FS), and left ventricular ejection fraction (LVEF). Anti-superoxide anion free radical (ASAFR) activity was detected by colorimetry. Thiobarbituric acid method was used to measure the concentration of malonaldehyde (MDA). Results Compared to Sham group, the LVEF, FS and left ventricular systolic pressure (LVSP) in MI group and RDN group were decreased obviously (all P 0.05). There were no significant difference in heart rate (HR) among three groups (P>0.05). Although the levels of MDA, ASAFR, and p47phox mRNA were higher in MI group and RDN group, compared to the Sham group (all P<0.05), they were all significantly decreased in RDN group compared to the MI group (all P<0.05). Conclusions RDN was able to improve heart function and myocardial remodeling and inhibit cardiac oxidative stress. Key words: Sympathectomy; Kidney/IR; Myocardial infarction/CO/SU; Ventricular remodeling; Oxidative stress; Myocardium/PA

Beneficial effects of renal denervation on cardiac angiogenesis in rats with prolonged pressure overload.

Renal denervation (RDN) has beneficial effects on cardiac remodelling and function in resistant hypertension. We aimed to investigate the impact of RDN on cardiac angiogenesis during prolonged pressure overload. Cardiac pressure overload was reproduced by transverse aorta constriction (TAC) procedure in adult Sprague Dawley male rats (n=35). RDN/sham-RDN procedure was performed in surviving rats at 5weeks after TAC. Five weeks post-TAC, transthoracic echocardiography revealed that myocardial hypertrophy occurred in TAC rats, with ejection fraction and fractional shortening not significantly changed. At the end of 10weeks, cardiac systolic function was preserved in RDN group, but not in sham group. CD31 immunohistochemical staining showed that RDN-treated rats had higher cardiac capillary density than sham rats. However, no significant between-group difference was observed in the kidneys. A decreased protein expression of left ventricle vascular endothelial growth factor (VEGF) was observed in sham group, while RDN attenuated this decrease. Compared with sham, RDN resulted in a higher protein expression of VEGF receptor 2 (VEGFR2) and phosphorylated endothelial nitric oxide synthase (p-eNOS) in the heart. Renal denervation benefits cardiac angiogenesis during sustained pressure overload, involving regulation of VEGF and VEGFR2 expression as well as activation of eNOS.

OP.4C.03] 24H BLOOD PRESSURE MONITORING TO PREDICT AND ASSESS IMPACT OF RENAL DENERVATION

Objective: The Renal Denervation for Hypertension (DENERHTN) trial showed that renal denervation (RD) with the Symplicity™ catheter added to a standardized stepped-care antihypertensive treatment (SSAHT) significantly reduced daytime ambulatory SBP by ∼6 mmHg more than the SSAHT alone after 6 months in patients with resistant hypertension. The aim of this analysis is to report in details the ABPM results, and to look for predictors of the BP response to RD. Design and method: 24 h ABPM were performed at baseline and 6 months. For each recording, we calculated the average and standard deviation (SD) of 24 h, daytime and nighttime SBP, DBP and HR, and the smoothness index (SI). Analyses were performed on the per-protocol population to compare the RD group (RDG) to the control group (CG) and responders (daytime SBP reduction > = 20 mmHg) to non-responders. Results: 44/ 53 patients of the RDG and 53/53 of the CG were included. The average number of measurements for each ABPM was 73. The significantly greater ambulatory SBP reduction in the RDG was homogeneous over 24 h with a higher SI (1.4 ± 1.2) than in the CG (0.9 ± 0.6; P = 0.02). SD of 24 h, daytime and nighttime SBP/DBP and HR were not significantly influenced by RD. In a stepwise discriminant analysis, baseline average nighttime SBP, nighttime SDSBP and treatment group were significant predictors of the daytime ambulatory SBP response at 6 months. The first two remained significantly associated to responders (P = 0.005) in the RDG but not in CG. The ROC curves to predict responders in the RDG had an area under the curve of 0.65 (95%CI: 0.488–0.815, P = 0.08) for nighttime SBP and 0.72 (95%CI: 0.566- 0.874, P = 0.01) for nighttime SDSBP. The cut-offs offering best sensitivity+specificity to predict responders were136 mmHg for nighttime SBP and 12 mmHg for nighttime SDSBP. Together, these cut-offs allow adequate classification of 70% of responder patients. Conclusions: This analysis of ABPM data in DENER-HTN confirms the efficacy of RD in lowering BP in patients with resistant hypertension, with an homogenous effect along the 24 h. Baseline nighttime SBP and SDSBP appear as good candidates to predict responders to RD.

OS 32-04 ACUTE BLOOD PRESSURE CONTROL BY RENAL DENERVATION IMPROVED PROGNOSIS AFTER CEREBRAL INFARCTION THROUGH REDUCTION OF OXIDATIVE STRESS IN SHRSP RATS

Although hypertensive patients show significant elevation of blood pressure (BP) in acute phase after cerebral infarction, it is still unknown how it should be managed to carry the best prognosis. To address this issue, we investigated the effect of acute control of elevated BP by bilateral renal denervation (RD) against ischemic stroke in SHRSP rats with 90 minutes transient middle cerebral arterial occlusion (MCAO). Seventy-five male SHRSP rats of 15 weeks of age were assigned to sham-operated (control, n = 15) and MCAO + sham (sham, n = 30), and MCAO + RD (RD, n = 30). Bilateral RD was done approximately 30 minutes after ischemia induction. In experiment 1, we evaluated the acute effects of RD by measurement of continuous BP, cerebral blood flow (CBF), cerebral vascular resistance (CVR), vasoreactivity by acetazolamide, neurological function, and infarct volume. In addition, phosphorylated Akt and e-NOS, and oxidative stress using gp91phox and dihydroethidium in ischemic brain were also evaluated at 24 hours after ischemia induction. In experiment 2, temporal changes of body weight of the rats were measured in every week and also rotarod test were assessed around 4 weeks after ischemia induction. Although the ischemic rats in sham group showed severe hypertension, RD significantly reduced BP through 24 hours after ischemia induction. The value of CBF after reprefusion was significantly lower in RD group compared to sham group, while CVR and vasoreactivity was not changed by RD. RD significantly ameliorated neurological deficit and infarct volume. Moreover, RD reduced not only the level of phosphorylated Akt and e-NOS but also oxidative stress. In experiment 2, body weight and rotarod test showed significant increasing in RD group compared to sham group. Our results suggest that acute blood pressure control by RD is promising therapeutic strategy to improve prognosis after ischemic stroke in hypertensive patients.

OP.LB.02.03] EFFECTS OF MULTIELECTRODE RENAL DENERVATION ON SYMPATHETIC NERVE ACTIVITY AND INSULIN RESISTANCE IN METABOLIC SYNDROME

Objective: This study aimed to investigate the effects of renal denervation (RDN) on sympathetic nerve activity and insulin resistance in patients with metabolic syndrome at 3 months post-RDN. Design and method: Seventeen patients fulfilled 4/5 criteria for metabolic syndrome and under stable use of at least two anti-hypertensive drugs at maximum tolerated doses for at least 4 weeks were enrolled and randomized in 3:1 ratio to RDN [n = 13, 12 males, age: 58 ± 7 years] and Control groups [n = 4, 3 males, age: 60 ± 5 years]. Both groups were followed up for 3 months. Muscle sympathetic nerve activity (MSNA) measurements were performed to assess sympathetic nerve activity at fasting state and during standard 75 g oral glucose tolerance test (OGTT). Blood sampling was also performed to assess insulin resistance (HOMA-IR). Results: In the RDN group, office BP reduced by 16 ± 21/10 ± 11 mmHg (P = 0.01/0.007); average 24-hour BP reduced by 14 ± 16/5 ± 8 mmHg (P = 0.008/0.03); waist circumference reduced by 3.1 ± 3.6 cm (P = 0.008); and MSNA at fasting state reduced from 55 ± 10 bursts per minute/82 ± 15 bursts per 100 heart beats to 46 ± 8 bursts per minute/71 ± 15 bursts per 100 heart beats (P = 0.0008/0.006) at 3 months post-RDN. During OGTT, while blunted MSNA responses were noted at baseline throughout the 120-minute test (P > 0.05/0.05 vs. MSNA at fasting state), improved MSNA responses with burst frequency/burst incidence increased to 52 ± 8 bursts per minute/76 ± 12 bursts per 100 heart beats (P < 0.001/0.04 vs. the MSNA at fasting state, n = 13) at 30 minutes and to 58 ± 16 bursts per minute/80 ± 14 bursts per 100 heart beats (P = 0.04/0.008 vs. the MSNA at fasting state, n = 10) at 120 minutes were observed at 3 months post- RDN. No such improvements were observed in the 4 control group subjects at 3 months follow-up. No statistical significant change was observed in the HOMA-IR in both groups at 3 months. Conclusions: Strategies to target specifically the elevated sympathetic nerve activity may provide substantial clinical benefits to patients with metabolic syndrome and associated hypertension.

Adherence to Antihypertensive Treatment and the Blood Pressure-Lowering Effects of Renal Denervation in the Renal Denervation for Hypertension (DENERHTN) Trial.

The DENERHTN trial (Renal Denervation for Hypertension) confirmed the blood pressure-lowering efficacy of renal denervation added to a standardized stepped-care antihypertensive treatment for resistant hypertension at 6 months. We report the influence of adherence to antihypertensive treatment on blood pressure control. One hundred six patients with hypertension resistant to 4 weeks of treatment with indapamide 1.5 mg/d, ramipril 10 mg/d (or irbesartan 300 mg/d), and amlodipine 10 mg/d were randomly assigned to renal denervation plus standardized stepped-care antihypertensive treatment, or the same antihypertensive treatment alone. For standardized stepped-care antihypertensive treatment, spironolactone 25 mg/d, bisoprolol 10 mg/d, prazosin 5 mg/d, and rilmenidine 1 mg/d were sequentially added at monthly visits if home blood pressure was ≥135/85 mm Hg after randomization. We assessed adherence to antihypertensive treatment at 6 months by drug screening in urine/plasma samples from 85 patients. The numbers of fully adherent (20/40 versus 21/45), partially nonadherent (13/40 versus 20/45), or completely nonadherent patients (7/40 versus 4/45) to antihypertensive treatment were not different in the renal denervation and the control groups, respectively (P=0.3605). The difference in the change in daytime ambulatory systolic blood pressure from baseline to 6 months between the 2 groups was -6.7 mm Hg (P=0.0461) in fully adherent and -7.8 mm Hg (P=0.0996) in nonadherent (partially nonadherent plus completely nonadherent) patients. The between-patient variability of daytime ambulatory systolic blood pressure was greater for nonadherent than for fully adherent patients. In the DENERHTN trial, the prevalence of nonadherence to antihypertensive drugs at 6 months was high (≈50%) but not different in the renal denervation and control groups. Regardless of adherence to treatment, renal denervation plus standardized stepped-care antihypertensive treatment resulted in a greater decrease in blood pressure than standardized stepped-care antihypertensive treatment alone. URL: http://www.clinicaltrials.gov. Unique identifier: NCT01570777.

Renal Denervation Suppresses the Inducibility of Atrial Fibrillation in a Rabbit Model for Atrial Fibrosis.

Renal denervation (RD) was reported to reduce the susceptibility of atrial fibrillation (AF), but the underlying mechanism has not been well understood. This study was performed to investigate the effect of RD on the inducibility of AF in a rabbit model for atrial fibrosis and to explore the potential mechanisms. Thirty-five rabbits were randomly assigned into sham-operated group (n = 12), abdominal aortic constriction (AAC) group (n = 12) and AAC with RD (AAC-RD) group (n = 11). The incidence of AF induced by burst pacing in atriums was determined. Blood was collected to measure the levels of rennin, angiotensin II and aldosterone. Atrial samples were preserved to evaluate protein and gene expression of collagen, connective tissue growth factor (CTGF) and transforming growth factor-β1 (TGF-β1). Our data suggested cardiac structure remodeling and atrial fibrosis were successfully induced by AAC. Compared with the AAC group, the AAC-RD rabbits had smaller ascending aortic diameter and left ventricular end-systolic diameter. For burst pacing at the left atrium (LA), AF was induced in two of the 12 rabbits in the sham-operated group, 10 of the 12 rabbits in the AAC group, and 2 of the 11 rabbits in the AAC-RD group, with great difference among the three groups (P = 0.001). The percentage of LA burst stimulations with induced AF achieved 47.2% in the AAC group, which was higher than those in both the AAC-RD (12.1%) and the Sham-operated (5.6%) groups. Significantly increasing intercellular space in the AAC group (P<0.001) compared with the sham-operated rabbits. RD clearly decreased the volume fraction of collagen in LA and right atrium compared with that of the AAC group (P< 0.01). AAC-induced elevation of collagen I, CTGF and TGF-β1 was suppressed by RD. In conclusion, RD suppressed the inducibility of AF in a rabbit model for pressure associated atrial fibrosis, potentially by modulating renin-angiotensin-aldosterone system and decreasing pro-fibrotic factors.

Renal denervation significantly attenuates cardiorenal fibrosis in rats with sustained pressure overload

To investigate the effects of renal denervation (RDN) on comprehensive cardiac and renal fibrosis in cardiomyopathy. Five weeks after successful transverse aortic constriction (TAC)–induced cardiomyopathy model building, Sprague-Dawley rats were randomly assigned to three groups: (1) RDN, (2) sham, and (3) losartan. Sham TAC rats served as control group. Compared with control, TAC groups showed a significant decrease in left ventricle ejection fraction and increase in ventricular septum thickness and left atrium diameter on echocardiography after 5 weeks. At 10 weeks post-TAC, venous blood samples were collected for fibrosis biochemical assay. Heart and kidney samples were also harvested for fibrosis pathophysiological detection. Cardiac and renal fibrosis quantity results showed that, compared with sham group, collagen volume fraction was significantly decreased in RDN group more than in losartan group. Biochemical parameters such as tumor necrosis factor α, aldosterone, and B-type natriuretic peptide levels as well as biomarkers for fibrosis such as procollagen type I N-terminal propeptide and procollagen type III N-terminal propeptide concentrations were significantly decreased in RDN group in comparison with sham. In addition, compared with sham group, left ventricle tissue protein expression of transforming growth factor-β1 and angiotensin II type I receptor was downregulated, and angiotensin-converting enzyme 2 was upregulated in RDN but not in losartan group. RDN significantly attenuates cardiac and renal fibrosis in cardiomyopathy. Differing from losartan, which only has angiotensin II type I receptor inhibition effects, RDN comprehensively suppresses cardiac and renal fibrogenesis through multiple pathways.

Preliminary effects of renal denervation with saline irrigated catheter on cardiac systolic function in patients with heart failure: A Prospective, Randomized, Controlled, Pilot Study.

To assess efficacy and safety of renal denervation (RDN) for heart failure (HF). RDN has been demonstrated to be an effective method in lowing overactive sympathetic nerve. However, it's feasibility and efficacy for HF is unclear. In this randomized, controlled pilot study, patients with HF were randomly assigned in 1:1 ratio to undergo RDN plus optimal medical therapy (RDN group) or only optimal medical therapy (control group). Before randomization, patients received optimal medical therapy at least half a year. Primary efficacy end point was the change in LVEF over six months; secondary efficacy end points were the change in six-minute walk distance and SF-36 Health Survey scores over six months. Up to Apr 2015, sixty symptomatic HF patients were successfully enrolled into study. Thirty patients were randomly assigned to RDN group and 30 patients were randomly assigned to control group. All patients completed six months follow up. During follow up, no severe adverse events were observed. Blood pressure was stable in both groups. Patients in RDN group had shown a significant improvement in LVEF (P < 0.001), SMWD (P = 0.043), NYHA class (P < 0.001), NT-proBNP (P < 0.001) and office heart rate (P = 0.008). Compared with control group, RDN patients were associated with significant improvement in all domains of SF-36 but bodily pain (P = 0.74). No significant change in estimate glomerular filtration nor complication of renal artery stenosis were observed. Results imply that RDN could be safely applied to treatment of HF and probably improve cardiac systolic function and patients' quality of life. © 2016 Wiley Periodicals, Inc.

Renal Denervation Attenuates Multi-Organ Fibrosis and Improves Vascular Remodeling in Rats with Transverse Aortic Constriction Induced Cardiomyopathy

Background/Aims: To investigate the effects of renal denervation (RDN) on multi-organ fibrosis and vascular remodeling in cardiomyopathy. Methods: Thirty-six male Sprague-Dawley rats underwent transverse aortic constriction (TAC). Five weeks later, 28 surviving TAC rats were randomly assigned to three groups: (1) RDN, (2) Sham, (3) Carvedilol. Six male Sham TAC rats served as the Control. Ten weeks after TAC, samples were collected. Results: TAC rats showed an increased diastolic interventricular septal thickness at week 5. At 10 weeks, Masson staining showed that left ventricular and renal glomerular fibrosis were significantly reduced in RDN compared with Sham group. In comparison to Sham group, hepatic perivascular fibrosis was attenuated in both RDN and Carvedilol group, so were the media thickness and the media/lumen of aorta. The plasma levels of B-type natriuretic peptide (BNP), Cystatin C (Cys-C), Alanine Transaminase, angiotensin II (Ang II), transforming growth factor beta 1 (TGF-β1), and malondialdehyde increased, and total superoxide dismutase (T-SOD) decreased in Sham but not in RDN group, compared with Control group. Both RDN and Carvedilol reduced the Cys-C and TGF-β1 levels, and restored T-SOD concentration, compared with Sham group. While only RDN lowered the plasma levels of BNP and Ang II. No significant effects of RDN on blood pressure (BP) and heart rate (HR) were oberved. Conclusions: RDN can attenuate multi-organ fibrosis and improve vascular remodeling independent of BP and HR change in TAC-induced cardiomyopathy. These effects of RDN may be associated with the direct inhibition of renin-angiotensin-aldosterone system and oxidative stress.

Renal Denervation Findings on Cardiac and Renal Fibrosis in Rats with Isoproterenol Induced Cardiomyopathy.

Cardio-renal fibrosis plays key roles in heart failure and chronic kidney disease. We sought to determine the effects of renal denervation (RDN) on cardiac and renal fibrosis in rats with isoproterenol induced cardiomyopathy. Sixty male Sprague Dawley rats were randomly assigned to Control (n = 10) and isoproterenol (ISO)-induced cardiomyopathy group (n = 50). At week 5, 31 survival ISO-induced cardiomyopathy rats were randomized to RDN (n = 15) and Sham group (n = 16). Compared with Control group, ejection fraction was decreased, diastolic interventricular septal thickness and left atrial dimension were increased in ISO-induced cardiomyopathy group at 5 week. After 10 weeks, cardio-renal pathophysiologic results demonstrated that the collagen volume fraction of left atrio-ventricular and kidney tissues reduced significantly in RDN group compared with Sham group. Moreover the pro-fibrosis factors (TGF-β1, MMP2 and Collagen I), inflammatory cytokines (CRP and TNF-α), and collagen synthesis biomarkers (PICP, PINP and PIIINP) concentration significantly decreased in RDN group. Compared with Sham group, RDN group showed that release of noradrenaline and aldosterone were reduced, angiotensin-converting enzyme (ACE)/angiotensin II (Ang II)/angiotensin II type-1 receptor (AT1R) axis was downregulated. Meanwhile, angiotensin-converting enzyme 2 (ACE2)/angiotensin-1-7 (Ang-(1-7))/mas receptor (Mas-R) axis was upregulated. RDN inhibits cardio-renal fibrogenesis through multiple pathways, including reducing SNS over-activity, rebalancing RAAS axis.

Sympathetic denervation of heart and kidney induces similar effects on ventricular electrophysiological properties.

We aimed to investigate whether sympathetic denervation of the heart and kidney had similar effects on ventricular effective refractory period (ERP) and action potential duration (APD) restitution properties in a canine model. Twenty-four anaesthetised open-chest dogs (17-20 kg) were assigned to a sham operation group (n=8), a cardiac sympathetic denervation group (CSD, n=8) or a renal sympathetic denervation group (RSD, n=8). CSD was performed by ablating the caudal half of the LSG and T2-T4 thoracic sympathetic ganglia, while RSD was performed by ablating four sites on the adventitial surface of each renal artery. The ventricular electrophysiological properties were determined at four time points: baseline, 0 min, 30 min, and 60 min after interventions. The results showed that, when compared to the control group at the time point of 60 min after interventions, both CSD and RSD significantly reduced heart rate, prolonged the QT interval and ventricular ERP and APD, decreased the ERP dispersion and the slopes of APD restitution curves, and suppressed the APD alternans without affecting blood pressure and corrected QT interval. However, there were no significant differences in these parameters between CSD and RSD groups at the same time point. This study showed that sympathetic denervation of the heart and kidney induced similar electrophysiological effects in ventricles.

An analysis of the blood pressure and safety outcomes to renal denervation in African Americans and Non-African Americans in the SYMPLICITY HTN-3 trial

SYMPLICITY HTN-3, the first trial of renal denervation (RDN) versus sham, enrolled 26% African Americans, a prospectively stratified cohort. Although the 6-month systolic blood pressure (SBP) reduction in African Americans (AAs) was similar in the RDN group (−15.5 ± 25.4 mm Hg, n = 85 vs. −17.8 ± 29.2, n = 49, P = .641), the sham SBP response was 9.2 mm Hg greater (P = .057) in AAs than non-AAs. In multivariate analyses, sham SBP response was predicted by an interaction between AA and a complex antihypertensive regimen (at least one antihypertensive medication prescribed ≥3 times daily), while in the RDN group, SBP response was predicted by an interaction between AA race and baseline BP ≥ 180 mm Hg. AA race did not independently predict SBP response in either sham or RDN. There appears to be effect modification by race with individual-level patient characteristics in both treatment arms that affect the observed pattern of SBP responses.