Comparison of medical therapy with renal denervation in patients with resistant hypertension

Introduction: Catheter-based renal denervation selectively reduces renal sympathetic efferent activity and is accompanied by an increase in renal blood flow and reduction in plasma renin activity. Thus, ablation of afferent and efferent renal nerves in patients with treatment-resistant hypertension probably leads to reductions in blood pressure. Material and methods: The present study conducted a non-randomized case-control study and enrolled 15 patients who underwent renal denervation therapy for resistant hypertension as cases and 16 patients who were on medical management for resistant hypertension served as controls. Results: It was found that catheter based renal denervation is safe, significantly reduces blood pressure at 1 month, 3 months and 6 months of follow-up without any major adverse events. It was observed that a significant BP reduction when compared to patients only on medical therapy. The mean number of drugs decreased significantly in the denervation group in follow-up. Conclusions: Though the present study showed a significant BP reduction in patients with renal denervation, a significant effect on BP was not observed in a large randomized trial simplicity HTN-3 and major criticism was on the trials design and neuroscience failings. Even today the clinical dilemma is still continuing and further evaluation in rigorously designed clinical trials are necessary to validate alternative methods of renal denervation or to confirm previously reported benefits of renal denervation. The current study anticipate that future trials will also address the effectiveness of renal denervation in disease states other than hypertension.

Renal sympathetic denervation for treatment of resistant hypertension using a 5 F microtube-irrigated ablation catheter / 第二军医大学学报

Objective: To observe the effectiveness of catheter-based renal sympathetic denervation (RDN) for reducing blood pressure in patients with resistant hypertension using a 5 F microtube-irrigated ablation catheter. Methods: Thirty patients with resistant hypertension received RDN between January 2013 and December 2015. They were randomly divided into two groups: general ablation catheter group and microtube-irrigated ablation catheter group, with 15 cases in each group. 5 F temperature-controlled catheter was used in the general ablation catheter group. 5 F microtube-irrigated ablation catheter (microtubes at the head) was used in the microtube-irrigated ablation catheter group. Cold saline was irrigated for mapping and ablation. All patients were followed up for 9 months. Clinic blood pressure, 24 h ambulatory blood pressure, biochemical tests and cardiac function were measured at baseline and during follow-up. Results: RDN was successfully performed in all patients. At the 9-month follow-up, the decrease of 24 h ambulatory systolic blood pressure (SBP) in the microtube-irrigated ablation catheter group was more obvious than that in the general ablation catheter group ([34.67±13.02] mmHg vs [17.00 ± 16.74] mmHg, P<0.01; 1 mmHg=0.133 kPa). The 24 h ambulatory diastolic blood pressure (DBP) in the microtube-irrigated ablation catheter group was significantly lower than that in the general ablation catheter group ([81.20 ± 7.15] mmHg vs (87.60 ± 8.17) mmHg, P<0.05). There was a decreased trend in the use of antihypertensive drugs in the microtube-irrigated ablation catheter group as compared with the general ablation catheter group, particularly in the use of diuretics (P<0.05). During the operation, the microtube-irrigated ablation catheter group had a significantly lower catheter temperature (P<0.001), greater energy (P<0.05), and greater decrease in impedance than the general ablation catheter group (P<0.05). No syncope or amaurosis caused by hypotension, or deterioration of renal function occurred in either group. Conclusion: 5 F microtube-irrigated ablation catheter is a safe and effective device during renal artery ablation. It has more advantages than general ablation catheter in reducing SBP and diuretic use in the treatment of resistant hypertension.

Efficiency and safety of catheter-based renal denervation for chronic heart failure: Meta-analysis / 中国介入影像与治疗学

Objective: To evaluate the efficacy and safety of catheter-based renal denervation (RDN) for chronic heart failure using Meta-analysis. Methods: Literature about catheter-based RDN for chronic heart failure were searched in Cochrane Library, PubMed, EMBASE, CNKI and Wanfang databases from the establishment of databases to Dec. 2018 for Meta-analysis after screening. The primary outcome indexes included left ventricular ejection fraction (LVEF), left ventricular end systolic diameter (LVDD) and brain natriuretic peptide (BNP), and the secondary outcome indexes included heart rate, systolic and diastolic blood pressures as well as the results of 6 min walk test. Data processing were performed using Rev Man 5. 3 software. The effect size was expressed as weighted mean difference (WMD) or standardized mean difference (SMD) and the 95% confidence interval (CI). For randomized controlled trials (RCT) and cohort studies (CS), the changes of outcomes were analyzed based on RDN group and drug-treated group, while for self-controlled trials were analyzed based on pre-treatment and post-treatment outcomes. Results: A total of 8 studies involved 230 patients were finally included. In RCT/CS, LVEF of RDN group significantly increased than that of drug-treated group (weighted mean difference WMD=7.17, 95%CI [3.77, 10.56], P0.05). In self-controlled trials, BNP significantly increased (SMD=-0.47, 95%CI [-0.83, 0.11], P=0.01), while the heart rate significantly decreased (WMD=-2.57, 95%CI [-4.75, -0.39], P=0.02) after RDN. No statistic difference of another outcome indexes was found before and after RDN treatment (all P>0.05). Conclusion: Catheter-based RDN can significantly improve cardiac function in patients with chronic heart failure.

Effects of renal denervation on blood-pressure response to hemorrhagic shock in spontaneously hypertensive rats / 中华创伤杂志(英文版)

<p><b>PURPOSE</b>Renal denervation (RD) has been demonstrated to be an effective approach to reduce blood pressure for those with resistant hypertension. Yet, we aimed to explore the effect and possible mechanism of RD on blood-pressure response to hemorrhagic shock in spontaneously hypertensive rats.</p><p><b>METHODS</b>A total of 48 male spontaneously hypertensive rats were randomized to three groups: study group, sham-operation group and control group. RD was achieved by cutting off renal nerves and swabbing phenol on it. Ten weeks after RD, 8 rats in each group were sacrificed to collect the kidney and heart tissues. The remaining rats were subjected to an operation to induce hemorrhagic shock which would lead to 40% loss of total blood volume, and observed for 120 min. The serum concentration of norepinephrine was measured before and three weeks after RD.</p><p><b>RESULTS</b>The blood-pressure and norepinephrine levels were reduced significantly after RD (p < 0.05). Systolic blood pressure and diastolic blood pressure of the surgery group were higher than those in the sham and control groups at 15, 30 and 45 min after hemorrhagic shock (p < 0.05), while no significant difference was observed at 60, 90 and 120 min (p > 0.05). Additionally, the beta-1 adrenergic receptor (β1-AR) in the study group was significantly higher than those in the other two groups (p < 0.05) after hemorrhagic shock.</p><p><b>CONCLUSION</b>This study demonstrated that RD could to some extent improve blood-pressure response to hemorrhagic shock in an established model of severe hemorrhagic shock in spontaneously hypertensive rats. The mechanism might be associated with up-regulation of β1-AR.</p>

The effects of renal denervation on hypothalamus angiotensinⅡand oxidative stress in myocardial infarction dogs / 天津医药

Objective To explore the effects of renal denervation (RDN) on hypothalamus angiotensinⅡ(AngⅡ) and oxidative stress in myocardial infarction (MI) dogs. Methods Eighteen mongrel dogs were randomly divided into MI group (n=6), RDN group (n=6) and sham operation group (n=6). Myocardial infarction model was made in the former two groups by gelatin sponge embolization of the left anterior descending artery. One week after MI, RDN was given to dogs in RDN group. Levels of AngⅡ, malondialdehyde (MDA), superoxide dismutase (SOD) and expression of gp91phox protein were detected four weeks after MI. Results Compared with control group, hypothalamus AngⅡ, MDA and expression of gp91phox protein were increased in MI group (P<0.01), but SOD was decreased (P<0.01). There was a negative correlation between AngⅡand SOD activity in MI group (r=-0.849, P < 0.01). There was a positive correlation between AngⅡ and expression of gp91phox protein in MI group (r=0.950, P<0.01). Compared with MI group, hypothalamus AngⅡ, MDA and expression of gp91phox protein were decreased in RDN group (P<0.01), but SOD was increased (P<0.01). Conclusion RDN can de?crease the level of hypothalamus AngⅡand the level of hypothalamus oxidative stress, and improve heart function of MI dogs.

The effect and mechanism of renal denervation combined with Losartan on cardiac hypertrophy induced by Spontaneous hypertensive rats / 实用医学杂志

Objective To explore the effect and mechanism of renal denervation combined with Losartan on cardiac hypertrophy in spontaneous hypertensive rats. Methods Spontaneous hypertensive rats with cardiac hypertrophy underwent renal denervation combined with following 4 weeks drug treatments. Transthoracic two-dimensional guided M-mode echocardiography was performed. The expression of hypertrophy-related gene was detected. Left ventricularmass index was calculated and histological sectionsstained with hematoxylin and eosin (HE). Results The characteristics of cardiac hypertrophy was observed in left ventricular tissues with HE staining in12 weeks old spontaneous hypertensive rats.The thickness was increased in those ventricular (IVSs, IVSd, LVPWs and LVPWd). After4 weeks after treatment, histological improvements were observed in both RDN and R+L groups compared with sham group. The improvement was more obvious in R+L group. Similar results were observed in histological sections, ventricular thicknesses (IVSs, IVSd, LVPWs and LVPWd), related-hypertrophy genes (ANP and β-MHC) expression, left ventricular mass idex (LVMI) and the protein expression of inflammatory cytokines (TNF-α and IL-6). Conculsion Renal denervation therapy can improve hypertensive-induced cardiac hypertrophy in spontaneous hypertensive rats. The effect was more significant when combined with Losartan. The mechanism might be involved in inhibiting inflammatory cytokines.

Declaración ante los resultados del ensayo clínico Symplicity HTN 3. Grupo de estudio de la hipertensión arterial resistente / Position paper on the results of Symplicity HTN-3 trial. Grupo de estudio de la hipertensión arterial resistente

La denervación de las arterias renales ha sido una alternativa para el tratamiento de la hipertensión arterial resistente. Los estudios Symplicity HTN 1 y 2 mostraron en grupos pequeños y no controlados disminuciones de la presión sistólica hasta de 30 mm Hg. Este entusiasmo ha sido opacado por el estudio Symplicity HTN 3, ensayo clínico aleatorizado y controlado con un procedimiento placebo. Sorprendentemente, los resultados sugirieron que la denervación renal tuvo un efecto similar al del placebo, aunque en el análisis de subgrupos preespecificados los pacientes que no eran de raza negra, los menores de 65 años y los que tenían función renal normal tuvieron una reducción de la presión arterial sistólica estadísticamente significativa. Esta es una evaluación crítica de los resultados del Symplicity HTN 3 y propone posibles explicaciones para estos. Además, declara la postura de nuestro grupo y las acciones futuras.

Renal artery denervation has shown to be an effective treatment for resistant hypertension. Symplicity HTN 1 and 2 trials showed in small and uncontrolled groups, significant systolic blood pressure reductions down to 30 mm Hg. Symplicity HTN-3, a double blind, randomized, placebo controlled clinical trial shaded this initial enthusiasm. Surprisingly, their results showed that renal denervation has a similar effect to placebo. Pre-specified subgroup analysis showed that non-black race individuals, younger than 65 years and with normal renal function, had a statistically significant systolic blood pressure decrease. This manuscript critically appraises the Symplicity HTN-3 trial, proposing possible explanations for the results. Also declares our group position and future actions regarding renal denervation.

Effect of renal denervation on cardiac oxidative stress and sympathetic nerve remodeling after myocardial infarction in canine / 天津医药

Objective To observe the effect of renal denervation (RDN) on the cardiac oxidative stress and sympathetic nerve remodeling after myocardial infarction (MI) in canine. Methods Canine (n=18) were randomly divided into three groups: Sham operation group (SHAM group, n=6), MI group (n=6), MI+RDN group (n=6). Anterior myocardial infarction was gained by gelatin sponge embolization of the left anterior descending artery. At four weeks post-MI, left ventricular end-diastolic volume (LVEDV), left ventricular end-systolic volume (LVESV) and left ventricular ejection fraction (LVEF) were examined using echocardiography. Immunohistochemical assay was used to analyze the distribution and density of tyrosine hydroxylase (TH) stained nerve fibers at peri-infarct zone. Myocardial superoxide dismutase (SOD) activity and malondialde?hyde (MDA) were also assessed. Results Compared with dogs in SHAM group, LVEF and SOD expression were decreased in MI group and MI+RDN group (P<0.05), but Left ventricular end diastolic pressure (LVEDP), LVEDV, LVESV, MDA and rate of TH positive staining nerve fibers were increased (P<0.05). There was a negative correlation between the rate of TH positive staining nerve fibers and SOD level (rs=-0.818,P<0.05) and a positive correlation between rate of TH positive stain?ing nerve fibers with MDA level (rs=0.900,P<0.05). By contract, compared with MI group, LVEF and SOD in MI +RDN group were increased (P<0.05), while LVEDV, LVESV, MDA and rate of TH positive staining nerve fibers were significant?ly lowered (P<0.05). Conclusion RDN is effective to decrease the level of cardiac oxidative stress and improve cardiac sympathetic nerve remodeling and heart function after myocardial infarction in canine.

Hipertensión arterial resistenteEstrategias de tratamiento y papel de la terapia de denervación simpática renal / Resistant hypertension Treatment strategies and role of renal sympathetic denervation therapy

Resumen Introducción: la hipertensión arterial (HTA) es una de las enfermedades crónicas de mayor prevalencia en el mundo, es así como se estima que afecta a 77.9 millones de americanos mayores de 20 años, de los cuales 78% eran conscientes de su diagnóstico, 68% usaron medicación antihipertensiva, pero tan solo 64% de los pacientes tratados estaban controlados. Métodos: se realizó una búsqueda sistemática de la literatura científica en las bases de datos PUBMED, SCIELO y EMBASE, de artículos primarios y secundarios con una estrategia definida, limitados a idioma español e inglés, utilizando diversas combinaciones de términos libres y tipo Mesh que incluyeron: hipertensión arterial resistente, hipertensión arterial secundaria, pseudorresistencia y denervación simpática renal Resultados: la HTA resistente se define como aquella que permanece fuera de metas, >140/90 mmHg en población general, luego del uso de tres agentes antihipertensivos de diferentes clases, en dosis óptimas y donde uno de ellos es un diurético. También se incluyen pacientes que a pesar de estar controlados, requieren del uso de cuatro medicamentos o más. La tasa de HTA resistente se ha incrementado en los últimos años, de la mano de la obesidad y la diabetes. El fenómeno está relacionado con causas secundarias, pseudorresistencia e hiperactividad simpática. La búsqueda y control de estos factores en conjunto con la optimización del manejo médico, constituyen el pilar fundamental del tratamiento. En pacientes que no se controlan adecuadamente a pesar de estas medidas, la terapia de denervación simpática renal se convierte en un arma terapéutica efectiva. Conclusión: la prevalencia de la HTA resistente ha aumentado en forma significativa en la última década. El manejo médico óptimo y la consideración de la terapia de denervación simpática renal se convierte en la piedra angular del tratamiento. (Acta Med Colomb 2014; 39: 57-63).

Abstract Introduction: hypertension ( HT) is one of the most prevalent chronic diseases in the world, and affects an estimated 77.9 million Americans over 20 years old, of which 78% were aware of their diagnosis, 68 % used antihypertensive medication , but only 64% of the treated patients were controlled. Methods: a systematic search of the scientific literature on the basis of PUBMED , SCIELO and EMBASE data of primary and secondary items with a defined strategy limited to Spanish and English was performed using various combinations of free terms and Mesh type that included: resistant hypertension, secondary high blood pressure, pseudo-resistance and renal sympathetic denervation. Results: resistant hypertension is defined as that which remains outside goals, > 140/90 mmHg in the general population after the use of three antihypertensive agents of different classes at optimal doses being one of them a diuretic. Patients who despite being controlled required the use of four or more drugs were also included. The rate of resistant hypertension has increased in recent years along with obesity and diabetes. The phenomenon is related to secondary causes, pseudo-resistance and sympathetic hyperactivity. Search and control of these factors together with the optimization of medical management are the mainstay of treatment. In patients not adequately controlled despite these measures, the renal sympathetic denervation therapy becomes an effective therapeutic tool. Conclusion: the prevalence of resistant hypertension has increased significantly in the last decade. Optimal medical management and consideration of renal sympathetic denervation therapy becomes the mainstay of treatment. (Acta Med Colomb 2014; 39: 57-63).

Heart rate variability in a patient after percutaneous renal denervation: a case report.

The overactivity of sympathetic component of autonomic nervous system is implicated in the genesis and progression of hypertension. We report the heart rate variability (HRV) of a patient after renal denervation for treatment of medically resistant hypertension. Catheter based renal denervation done for treatment of resistant hypertension reduces blood pressure by reducing the central sympathetic drive. In the present study we found a significant decrease in low frequency component of HRV in one month follow-up period after the procedure. We propose a simple, non-invasive 5-minute HRV could be a predictor of effective renal sympathetic denervation.

New Hope for Resistant Hypertention.

Hypertension is a major public health problem. Despite the increasing awareness of hypertension and its implications among patients and treating physicians, the prevalence of resistant hypertension remains high. Resistant hypertension define as blood pressure that remains elevated above treatment goals despite administration of an optimal three drug regimen that include a diuretic1 The prevalence of resistant hypertension is projected to increase, owing to the aging population and increasing trends in obesity, sleep apnea, and chronic kidney disease. It is estimated that at least 10% of all patients with hypertension are resistant to existing drugs. Management of resistant hypertension must begin with a careful evaluation of the patient to confirm the diagnosis and exclude factors associated with “pseudo-resistance,” such as improper BP measurement technique, the white-coat effect, and poor patient adherence to life-style and/or antihypertensive medications. Despite the use of the appropriate dose and type of diuretic to overcome the management of resistant hypertension, we can’t achieve our goal. But there is at least two devices namely Baroreflex Activation Therapy and Catheter-based renal sympathetic denervation make the new hope for the patient with resistant hypertension.

Role of norepinephrine & angiotensin II in the neural control of renal sodium & water handling in spontaneously hypertensive rats.

Background & objectives: A wealth of information concerning the essential role of renal sympathetic nerve activity (RSNA) in the regulation of renal function and mean arterial blood pressure homeostasis has been established. However, many important parameters with which RSNA interacts are yet to be explicitly characterized. Therefore, the present study aimed to investigate the impact of acute renal denervation (ARD) on sodium and water excretory responses to intravenous (iv) infusions of either norepinephrine (NE) or angiotensin II (Ang II) in anaesthetized spontaneously hypertensive rats (SHR). Methods: Anaesthetized SHR were acutely denervated and a continuous iv infusion of NE (200 ng/min/kg) or Ang II (50 ng/min/kg) was instigated for 1 h. Three 20-min urine clearances were subsequently collected to measure urine flow rate (UV) and absolute sodium excretion (UNaV). Results: Higher UV and UNaV (P<0.05) were observed in denervated control SHR as compared to innervated counterparts. The administration of NE or Ang II to innervated SHR produced lower UV and UNaV (P<0.05 vs. innervated control SHR). Lower diuresis/natriuresis response to ARD was observed in NE-treated SHR compared to denervated control SHR (P<0.05). Salt and water excretions in denervated NE-treated SHR, however, were significantly higher (P<0.05) relative to the excretion levels in control denervated SHR. Conversely, there was a higher (all P<0.05) diuresis/natriuresis response to ARD when Ang II was administered to SHR compared to denervated control or innervated Ang II-treated SHR. Interpretation & conclusions: NE retains its characteristic antidiuretic/antinatriuretic action following ARD in SHR. Typical action of Ang II on salt and water excretions necessitates the presence of an intact renal innervation. Ang II is likely to facilitate the release of NE from renal sympathetic nerve terminals through a presynaptic site of action. Moreover, there is a lack of an immediate enhancement in the renal sensitivity to the actions of NE and Ang II following ARD in a rat model of essential hypertension.

Renal functional & haemodynamic changes following acute unilateral renal denervation in Sprague Dawley rats.

Background & objectives: Regulation of renal function and haemodynamics are under a direct control from the renal sympathetic nerves and renal denervation produces overt diuresis and natriuresis in several mammalian species. However, the inter-related series of changes in renal function and haemodynamics following acute renal denervation (ARD) is not fully understood. Thus, we aimed to investigate and relate the changes in renal function and haemodynamics following acute unilateral renal denervation in anaesthetized Sprague Dawley (SD) rats. Methods: Male SD rats were fasted overnight, anaesthetized with sodium pentobarbitone (60 mg/kg ip), denervated by application of phenol to the left renal artery and maintained on an intravenous (iv) infusion of isotonic saline for 2 h. Throughout this period, six urine and plasma samples were taken at 20-min intervals to study kidney function parameters. In a different set of experiments, renal nerve stimulation (RNS) was carried out to characterize the changes in renal vasoconstrictor responses following ARD. Results: Denervated animals showed significantly (P<0.05 vs. control innervated rats) higher urine flow rate (UFR), absolute sodium excretion (UNaV), fractional sodium excretion (FENa) and glomerular filtration rate (GFR). The renal vasoconstrictor responses to RNS were significantly (P<0.05) lower in denervated rats as compared to the innervated counterparts. However, no appreciable differences were seen in the mean arterial pressure (MAP), plasma sodium (PNa), basal renal blood flow (RBF) and basal renal vascular resistance (RVR) in both innervated and denervated SD rats. Interpretation & conclusions: Natriuresis, diuresis, enhanced GFR and impaired vasoconstriction in response to RNS are typical and instant responses to ARD in SD rats. Renal sympathetic nerves serve more important role in salt and water conservation than in dynamic autoregulation of RBF under normal sympathetic tone; yet, their effects on renal haemodynamics become more evident in the presence of augmented renal sympathetic nerve activity (RSNA).