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Renal sympathetic activation plays a key role in the pathogenesis of hypertension, as demonstrated by high renal norepinephrine spillover into plasma of patients with essential hypertension. Renal denervation has demonstrated a significant reduction in blood pressure in unblinded studies of hypertensive patients. The SYMPLICITY HTN-3 trial, the first prospective, masked, randomized study of renal denervation versus sham control, failed its primary efficacy end point and raised important questions around potentially confounding factors, such as drug changes and adherence, study population, and procedural methods. The SPYRAL HTN Global Clinical Trial Program is designed to address limitations associated with predicate studies and provide insight into the impact of pharmacotherapy on renal denervation efficacy. The 2 initial trials of the program focus on the effect of renal denervation using the Symplicity Spyral multielectrode renal denervation catheter in hypertensive patients in the absence (SPYRAL HTN OFF-MED) and presence (SPYRAL HTN ON-MED) of antihypertensive medications. The SPYRAL HTN ON-MED study requires patients to be treated with a consistent triple therapy antihypertensive regimen, whereas the SPYRAL HTN OFF-MED study includes a 3- to 4-week drug washout period followed by a 3-month efficacy and safety end point in the absence of antihypertensive medications. The studies will randomize patients with combined systolic-diastolic hypertension to renal denervation or sham procedure. Both studies allow renal denervation treatments in renal artery branches and accessories. These studies will inform the design of the second pivotal phase of the program, which will more definitively analyze the antihypertensive effect of renal denervation.

BackgroundHypertension is poorly controlled in numerous patients despite effective medication being available. Catheter-based renal denervation (RDN) has emerged as an alternative treatment option. We aimed to assess how likely patients with elevated blood pressure (BP) are to accept RDN as treatment option.MethodsA questionnaire-based cross-sectional survey was performed in patients with elevated BP in Germany. Data on patient demographics, clinical characteristics and treatment preferences were collected, anonymized and analyzed.ResultsOne thousand and eleven patients completed the survey. Mean age was 66 years (55% male). If not already on medication (n = 172), 38.2% of patients would prefer RDN. Of those already on drug therapy (n = 839), 28.2% would opt for RDN. Patients who were pro-RDN were younger (p < 0.0001) and more often male (p < 0.0001). Nineteen percent would choose RDN if it lowered systolic BP by at least 20 mmHg, more than 40% if they did not have to take any more pills thereafter, and 30% if it would lower BP by at least 10 mmHg. Experiences of side effects and drug adherence were identified as determinants of patient preference. Physicians were the main source of information regarding medical problems (95.5%) and influence patients’ decision regarding therapies (98%).ConclusionsThis survey found that a significant proportion of patients would choose catheter-based RDN over lifelong pharmacotherapy. These patients were younger and more likely to be male but their expectation of the extent of BP decrease with RDN was high. Physicians are key mediators for treatment selection. They need to incorporate patient preferences into shared decision making.

To assess the efficacy and safety of catheter-based renal denervation (RDN) for the treatment of uncontrolled hypertension by conducting a systematic review and a meta-analysis. The Medline, Cochrane Library, and Embase databases were searched for clinical studies between January 1, 2009, and July 16, 2018. Studies that evaluated the effect of RDN on uncontrolled hypertension were identified. The primary endpoints were changes in 24-hour ambulatory systolic blood pressure (BP) and office systolic BP. The secondary endpoints included changes in 24-hour ambulatory diastolic BP, office diastolic BP, and major adverse events. After a literature search and detailed evaluation, 12 randomized controlled trials with a total of 1539 individuals were included in the quantitative analysis. Pooled analyses indicated that RDN was associated with a significantly greater reduction of 24-hour systolic BP (mean difference [MD], −4.02 mm Hg; 95% CI, −5.49 to −2.56; P<.001) and office systolic BP (MD, −8.93 mm Hg; 95% CI, −14.03 to −3.83; P<.001) than controls. Similarly, RDN significantly reduced 24-hour diastolic BP (MD, −2.05 mm Hg; 95% CI, −3.05 to −1.05; P<.001) and office diastolic BP (MD, −4.49 mm Hg; 95% CI, −6.46 to −2.52; P<.001). RDN was not associated with an increased risk of major adverse events (relative risk, 1.06; 95% CI, 0.72 to 1.57; P=.76). Catheter-based RDN was associated with a significant BP-lowering benefit without increasing major adverse events.

Because of uncertainty around the blood-pressure-lowering effect of renal denervation and the safety of the procedure in this specific population of patients with hypertension at very low cardiovascular risk, follow-up was short after randomisation (3 months).In the third interim analysis of 80 patients (n=38 in the intervention group and n=42 in the sham-control group), significant differences in favour of renal denervation were reported between the groups in the 3-month change in 24-h ambulatory and office blood pressures from baseline: 24-h SBP −5·0 mm Hg (95% CI −9·9 to −0·2; p=0·0414), 24-h diastolic blood pressure (DBP) −4·4 mm Hg (−7·2 to −1·6; p=0·0024), office SBP −7·7 mm Hg (−14·0 to −1·5; p=0·0155), and office DBP −4·9 mm Hg (−8·5 to −1·4; p=0·0077).8

Enthusiasm for cell therapy for myocardial injury has waned due to equivocal benefits in clinical trials. In an attempt to improve efficacy, we investigated repeated cell therapy and adjunct renal denervation (RDN) as strategies for augmenting cardioprotection with cardiosphere-derived cells (CDCs). We hypothesized that combining CDC post-conditioning with repeated CDC doses or delayed RDN therapy would result in superior function and remodeling. Wistar–Kyoto (WKY) rats or spontaneously hypertensive rats (SHR) were subjected to 45 min of coronary artery ligation followed by reperfusion for 12–14 weeks. In the first study arm, SHR were treated with CDCs (0.5 × 106 i.c.) or PBS 20 min following reperfusion, or additionally treated with CDCs (1.0 × 106 i.v.) at 2, 4, and 8 weeks. In the second arm, at 4 weeks following myocardial infarction (MI), SHR received CDCs (0.5 × 106 i.c.) or CDCs + RDN. In the third arm, WKY rats were treated with i.c. CDCs administered 20 min following reperfusion and RDN or a sham at 4 weeks. Early i.c. + multiple i.v. dosing, but not single i.c. dosing, of CDCs improved long-term left ventricular (LV) function, but not remodeling. Delayed CDC + RDN therapy was not superior to single-dose delayed CDC therapy. Early CDC + delayed RDN therapy improved LV ejection fraction and remodeling compared to both CDCs alone and RDN alone. Given that both RDN and CDCs are currently in the clinic, our findings motivate further translation targeting a heart failure indication with combined approaches.

Purpose Multiple lead and generator replacement and related complications often complicate the decision of pacemaker implantation in non-elderly patients with symptomatic bradycardia. This study sought to investigate the efficacy and safety of atrial autonomic denervation for treating the symptomatic long-standing sinus bradycardia (SB) in non-elderly patients. Methods and results Eleven non-elderly patients (mean age, 45.9 ± 10.9 years; eight men) with a long history of SB (106.2 ± 43.7 months; range, 60–189) were enrolled. Five atrial ganglionated plexies (GPs), identified by anatomic distribution and high-frequency stimulation, were targeted and ablated. The end point was elimination of the vagal response at ablation sites. The symptoms of SB and Holter were followed up at 3 days, 6, and 12 months and, thereafter, over a period of 18 months. Six patients were under 50 years old (group I) and 5 patients were between 50 and 60 years old (group II). There were 3.1 ± 0.7 GPs with positive vagal response and 11.3 ± 2.7 ablation sites in each patient. During the 18.4 ± 6.2 (range, 12–25) months of follow-up, all patients reported significant symptom improvement with a significant decrease of the SB-related symptoms score. The total heartbeats, mean, and minimum heart rate significantly increased that persisted for 12 months. Compared with patients in group II, those in group I had more increases in total heartbeats and mean heart rate (HR). Conclusion Atrial autonomic denervation increases sinus rate and improves symptoms in non-elderly patients with symptomatic long-standing SB, thus, potentially serving as an alternative to pacemaker implantation.

A close association exists between renal impairment (RI) and atrial fibrillation (AF) occurrence. Increased activity of the sympathetic nervous system (SNS) may contribute to the development of AF associated with RI. Renal denervation (RDN) decreases central sympathetic activity. The main objective of the study was to explore the effects of RDN on AF occurrence and its possible mechanisms in beagles with RI. Unilateral RI was induced in beagles by embolization of small branches of the renal artery in the right kidney using gelatin sponge granules in Model (n = 6) and RDN group (n = 6). The Sham group (n = 6) underwent the same procedure, except for embolization. Then animals in RDN group underwent radiofrequency ablation of the renal sympathetic nerve. Cardiac electrophysiological parameters, blood pressure, left ventricular end-diastolic pressure, and AF inducibility were investigated. The activity of the SNS, renin-angiotensin-aldosterone system (RAAS), inflammation and atrial interstitial fibrosis were measured. Embolization of small branches of the renal artery in the right kidney led to ischemic RI. Heart rate, P wave duration and BP were increased by RI, which were prevented or attenuated by RDN. Atrial effective refractory period was shortened and AF inducibility was increased by RI, which were prevented by RDN. Antegrade Wenckebach point was shortened, atrial and ventricular rates during AF were increased by RI, which were attenuated or prevented by RDN. Levels of norepinephrine, renin and aldosterone in plasma, norepinephrine, angiotensin II, aldosterone, interleukin-6 and high sensitivity C-reactive protein in atrial tissue were elevated, and atrial interstitial fibrosis was enhanced by RI, which were attenuated by RDN. RDN significantly reduced AF inducibility, prevented the atrial electrophysiological changes in a model of RI by combined reduction of sympathetic drive and RAAS activity, and inhibition of inflammation activity and fibrotic pathway in atrial tissue.

Catheter-based renal denervation (RD) has been introduced recently as a potentially effective invasive treatment of refractory hypertension. The proportion of patients with severe hypertension suitable for RD is not clear. The aim of this study was to identify what percentage of patients has truly resistant essential hypertension and are thus potentially eligible for RD. We investigated 205 consecutive patients referred to a university hypertension center for severe hypertension within 12 months. Ambulatory 24-h blood pressure (BP) monitoring (24 h ABPM), secondary hypertension screening and compliance to treatment testing (by use of plasma drug level measurements) were performed in all patients. Fifty-seven patients (27.8%) did not have truly resistant hypertension (RH) based on clinical BP. Among the remaining 122 patients (59.5%) with RH confirmed by 24 h ABPM, 50 patients (24.4% of the original cohort) had a secondary cause of hypertension and in 27 (13.2%) non-compliance to treatment was confirmed. Thus, only 45 patients (22%) had truly resistant essential hypertension and were considered for RD. Only one-third ( n =15, 7.3% of the original cohort) was, however, finally referred for RD (14 were excluded due to contraindications for RD and 16 refused the invasive treatment). In conclusion, thorough examination of severe hypertension including 24 h ABPM, secondary hypertension exclusion and drug compliance testing before considering RD reveals that majority of these patients are not suitable for RD. Specifically, compliance to treatment testing should be mandatory in order to identify eligible candidates for RD.

Background Myocardial apoptosis is important in the pathogenesis and progression of myocardial infarction-induced heart failure (MI-HF). Renal sympathetic denervation (RDN) has become a promising therapeutic strategy for the treatment of HF. Previous studies have shown that RDN could improve heart function Yao et al. (Exp Ther Med 14:4104-4110, 2017). However, whether and how RDN regulates myocardial apoptosis in MI-HF is unclear. This study sought to evaluate the effects of RDN on cardiac function and apoptosis-related gene expression in MI-HF dogs. Methods Eighteen healthy mongrel dogs were randomly divided into control group( n  = 6), model group( n  = 6) and treatment group( n  = 6). MI-HF was established in model group and treatment group by anhydrous alcohol embolization, after heart failure dogs in the treatment group and model group proceeded bilateral renal artery ablation and bilateral renal arteriography, respectively. The cardiac function parameters were evaluated by echocardiographic; the serum NT-BNP level was detected by ELISA; the degree of myocardial fibrosis was observed through masson staining; the expression of MMP-2, MMP-9 in the cardiac were got by immunohistochemistry. TUNEL method was used to observe cardiomyocyte apoptotsis and calculate the apoptosis index (AI). Relative expression of Bcl-2 and Bax, Caspase3 and GRP78 were detected using RT-PCR and Western Blot. Renal artery H&E staining and serum creatinine were conducted to access the efficacy and safety of RDN. Results Four weeks after RDN, the LVEDD, LVESD and LVEDP decreased, and the LVEF and LVSP increased in the treatment group compared with those in the control group (all P  < 0.05). Moreover, NT-BNP, an indicator of cardiac function was decreased. Additionally, MMP-2 and MMP-9 levels in the myocardium decreased significantly in the treatment group. Furthermore, the levels of Bax, and caspase 3 decreased, while the level of Bcl-2 increased. Thus, myocardial apoptosis was attenuated in RDN treated dogs. We also found that the level of GRP78 which is activated in response to endoplasmic reticulum (ER) stress, was decreased. However, serum creatinine levels were not significantly different between the RND-treated dogs and the control dogs. Conclusion Cardiac function was improved by RDN treatment through regulating apoptosis and ER stress in cardiomyocytes in dogs after MI.

Agrin signals through the muscle-specific receptor tyrosine kinase (MuSK) to cluster acetylcholine receptors (AChRs) on the postsynaptic membrane of the neuromuscular junction (NMJ). This stands as the prevailing model of synapse induction by a presynaptic factor, yet the agrin-dependent MuSK signaling cascade is largely undefined. Abl1 (previously known as Abl) and the Abl1-related gene product Abl2 (previously known as Arg) define a family of tyrosine kinases that regulate actin structure and presynaptic axon guidance. Here we show that the Abl kinases are critical mediators of postsynaptic assembly downstream of agrin and MuSK. In mouse muscle, Abl kinases were localized to the postsynaptic membrane of the developing NMJ. In cultured myotubes, Abl kinase activity was required for agrin-induced AChR clustering and enhancement of MuSK tyrosine phosphorylation. Moreover, MuSK and Abl kinases effected reciprocal tyrosine phosphorylation and formed a complex after agrin engagement. Our findings suggest that Abl kinases provide the developing synapse with the kinase activity required for signal amplification and the intrinsic cytoskeletal regulatory capacity required for assembly and remodeling.