Effect of Alcohol-Mediated Renal Denervation on Blood Pressure in the Presence of Antihypertensive Medications: Primary Results From the TARGET BP I Randomized Clinical Trial.

BACKGROUND: Renal denervation (RDN) has demonstrated clinically relevant reductions in blood pressure (BP) among individuals with uncontrolled hypertension despite lifestyle intervention and medications. The safety and effectiveness of alcohol-mediated RDN have not been formally studied in this indication. METHODS: TARGET BP I is a prospective, international, sham-controlled, randomized, patient- and assessor-blinded trial investigating the safety and efficacy of alcohol-mediated RDN. Patients with office systolic BP (SBP) ≥150 and ≤180 mm Hg, office diastolic BP ≥90 mm Hg, and mean 24-hour ambulatory SBP ≥135 and ≤170 mm Hg despite prescription of 2 to 5 antihypertensive medications were enrolled. The primary end point was the baseline-adjusted change in mean 24-hour ambulatory SBP 3 months after the procedure. Secondary end points included mean between-group differences in office and ambulatory BP at additional time points. RESULTS: Among 301 patients randomized 1:1 to RDN or sham control, RDN was associated with a significant reduction in 24-hour ambulatory SBP at 3 months (mean±SD, -10.0±14.2 mm Hg versus -6.8±12.1 mm Hg; treatment difference, -3.2 mm Hg [95% CI, -6.3 to 0.0]; P=0.0487). Subgroup analysis of the primary end point revealed no significant interaction across predefined subgroups. At 3 months, the mean change in office SBP was -12.7±18.3 and -9.7±17.3 mm Hg (difference, -3.0 [95% CI, -7.0 to 1.0]; P=0.173) for RDN and sham, respectively. No significant differences in ambulatory or office diastolic BP were observed. Adverse safety events through 6 months were uncommon, with one instance of accessory renal artery dissection in the RDN group (0.7%). No significant between-group differences in medication changes or patient adherence were identified. CONCLUSIONS: Alcohol-mediated RDN was associated with a modest but statistically significant reduction in 24-hour ambulatory SBP compared with sham control. No significant differences between groups in office BP or 6-month major adverse events were observed. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02910414.

Controversies related to renal artery denervation and devices.

PURPOSE OF REVIEW: This review article discusses the controversies, strengths, and limitations of the current literature on renal artery denervation in the management of resistant hypertension, as well as the future directions of this intervention. RECENT FINDINGS: There have been conflicting data from the different randomized control trials assessing the efficacy of renal artery denervation in the management of resistant hypertension. SUMMARY: Renal artery denervation is achieved by ablating the sympathetic nerves surrounding the renal arteries using endovascular ultrasound, radiofrequency, or alcohol. Our review article highlights that renal artery denervation is generally effective in improving blood pressure in patients with resistant hypertension. The Food and Drug Administration (FDA) has recently approved the ReCor Medical Paradise system, and the Symplicity Spyral RDN systems for renal artery denervation.

Renal nerve stimulation identifies renal innervation and optimizes the strategy for renal denervation in canine.

BACKGROUND: Renal denervation (RDN) was still performed without any intra-procedural method for nerve mapping. Whether renal nerve stimulation (RNS) is an efficient way to identify renal autonomic innervation and optimize the strategy for RDN remain to be worthy for further exploration. METHODS: The characteristics of renal autonomic innervation at the sites with different blood pressure (BP) responses to RNS were explored. Then, dogs anatomically eligible for RDN were randomly assigned into elevated BP response ablation group, reduced BP response ablation group, and RNS-control group. The postoperative outcomes were measured at baseline and after 4 weeks follow-up. RESULTS: The proportion of afferent sensory nerve was higher at elevated BP response sites (ERS) than reduced BP response sites (RRS) and non-response sites (NRS) (P = 0.012 and P = 0.004). Conversely, the proportion of parasympathetic nerve at RRS was the highest (RRS vs. ERS, P = 0.017; RRS vs. NRS, P = 0.023). More importantly, there was a significant correlation between systolic blood pressure changes and the area ratios of afferent sensory and parasympathetic nerve (R = 0.859; P < 0.001). In addition, ablation at BP-elevation sites can result in a significant decrease in BP and plasma norepinephrine (NE) after 4 weeks (P = 0.002; P = 0.008), while ablation at BP-reduction sites can lead to significant increases in BP and plasma NE (P = 0.016; P = 0.033). CONCLUSIONS: RNS is an effective method to identify renal autonomic innervation. It could not only help to identify optimal target sites, but also avoid ablation of sympathetic-inhibitory areas during RDN.

Ultrasound renal denervation for hypertension resistant to a triple medication pill (RADIANCE-HTN TRIO): a randomised, multicentre, single-blind, sham-controlled trial.

BACKGROUND: Endovascular renal denervation reduces blood pressure in patients with mild-to-moderate hypertension, but its efficacy in patients with true resistant hypertension has not been shown. We aimed to assess the efficacy and safety of endovascular ultrasound renal denervation in patients with hypertension resistant to three or more antihypertensive medications. METHODS: In a randomised, international, multicentre, single-blind, sham-controlled trial done at 28 tertiary centres in the USA and 25 in Europe, we included patients aged 18-75 years with office blood pressure of at least 140/90 mm Hg despite three or more antihypertensive medications including a diuretic. Eligible patients were switched to a once daily, fixed-dose, single-pill combination of a calcium channel blocker, an angiotensin receptor blocker, and a thiazide diuretic. After 4 weeks of standardised therapy, patients with daytime ambulatory blood pressure of at least 135/85 mm Hg were randomly assigned (1:1) by computer (stratified by centres) to ultrasound renal denervation or a sham procedure. Patients and outcome assessors were masked to randomisation. Addition of antihypertensive medications was allowed if specified blood pressure thresholds were exceeded. The primary endpoint was the change in daytime ambulatory systolic blood pressure at 2 months in the intention-to-treat population. Safety was also assessed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT02649426. FINDINGS: Between March 11, 2016, and March 13, 2020, 989 participants were enrolled and 136 were randomly assigned to renal denervation (n=69) or a sham procedure (n=67). Full adherence to the combination medications at 2 months among patients with urine samples was similar in both groups (42 [82%] of 51 in the renal denervation group vs 47 [82%] of 57 in the sham procedure group; p=0·99). Renal denervation reduced daytime ambulatory systolic blood pressure more than the sham procedure (-8·0 mm Hg [IQR -16·4 to 0·0] vs -3·0 mm Hg [-10·3 to 1·8]; median between-group difference -4·5 mm Hg [95% CI -8·5 to -0·3]; adjusted p=0·022); the median between-group difference was -5·8 mm Hg (95% CI -9·7 to -1·6; adjusted p=0·0051) among patients with complete ambulatory blood pressure data. There were no differences in safety outcomes between the two groups. INTERPRETATION: Compared with a sham procedure, ultrasound renal denervation reduced blood pressure at 2 months in patients with hypertension resistant to a standardised triple combination pill. If the blood pressure lowering effect and safety of renal denervation are maintained in the long term, renal denervation might be an alternative to the addition of further antihypertensive medications in patients with resistant hypertension. FUNDING: ReCor Medical.

Effect of renal denervation on long-term outcomes in patients with resistant hypertension.

Increasing studies strongly prove that renal denervation, a minimally invasive surgery, is a promising new non-drug treatment method that can effectively control blood pressure in patients with resistant hypertension, but the evaluation of the long-term blood pressure control effect of renal denervation for resistant hypertension is still lacking. Here, we critically review current long-term follow-up data about the use of renal denervation for RH to comprehensively evaluate the effectiveness of renal denervation for RH, and to provide practical guidance for practitioners who are establishing a renal denervation service. Limited by the current research, many problems need to be solved before renal denervation is applied to RH. In addition, ambulatory blood pressure should be the first choice for the evaluation of blood pressure. Finally, the continuous antihypertensive effect of renal denervation in different renal denervation systems also needs to be strictly compared.

Impact of Renal Pelvic Denervation on Systemic Hemodynamics and Neurohumoral Changes in a Porcine Model.

INTRODUCTION: The blood pressure (BP) response to arterial renal denervation (RDN) is variable. METHODS: This study examined the effectiveness of renal pelvic denervation (RPD) on BP, heart rate (HR), norepinephrine (NE), and histopathology in 42 swine. NE levels were measured immediately, 7, 14, 30, and 90 days after RPD. Intra-arterial BP and HR were measured throughout RPD and after 14 days in 5 swine. RESULTS: During the procedure, RPD immediately reduced systolic BP (-20.6 ± 18.3 mm Hg), diastolic BP (-6.0 ± 8.3 mm Hg), and HR (-5.4 ± 5.6 bpm), which remained decreased at follow-up. The porcine kidneys had a mean NE reduction of 76% directly post procedure and 60% after 7 days, 64% after 14 days, 57% after 30 days, and 65% after 90 days. Histopathological examination confirmed nerve ablation. CONCLUSIONS: These preliminary findings suggest that the renal pelvis nerve ablation is an encouraging target for RDN. Clinical trials are required to test the feasibility of RPD in human hypertension.

A Systematic Review of Randomized Controlled Trials Comparing Renal Sympathetic Denervation Versus Sham Procedure for the Management of Uncontrolled Hypertension.

ABSTRACT: The efficacy of renal sympathetic denervation (RSD) in the treatment of uncontrolled hypertension (HTN) remains uncertain. A systematic review of randomized controlled trials was performed to evaluate the efficacy and safety of RSD for resistant HTN. PubMed, EMBASE, MEDLINE, Cochrane, Directory of Open Access Journals, CINAHL, and Google Scholar were searched from January 01, 2001, through July 30, 2020. Randomized controlled trials comparing RSD with the sham procedure for uncontrolled HTN were selected. The primary efficacy outcome was the reduction in ambulatory systolic blood pressure. We used random-effects models. Nine prospective clinical trials met the inclusion criteria. The ReSet and Symplicity HTN-3 Trial showed no significant changes because of discrepancies in complete circumferential ablation during RSD. The Relief study, The Radiance HTN solo, and the SPYRAL HTN OFF medical trials showed a significant reduction in systolic blood pressure in the group that had undergone the intervention compared with the sham group attributed to rigorous trial design. In conclusion, our systematic review suggests that efficacy of RSD seems to be superior to sham-controlled interventions provided circumferential denervation is performed. However, difference in efficacy is marginal.

Technical advance in silico and in vitro development of a new bipolar radiofrequency ablation device for renal denervation.

BACKGROUND: Renal denervation with radiofrequency ablation has become an accepted treatment for drug-resistant hypertension. However, there is a continuing need to develop new catheters for high-accuracy, targeted ablation. We therefore developed a radiofrequency bipolar electrode for controlled, targeted ablation through Joule heating induction between 60 and 100 °C. The bipolar design can easily be assembled into a basket catheter for deployment inside the renal artery. METHODS: Finite element modeling was used to determine the optimum catheter design to deliver a minimum ablation zone of 4 mm (W) × 10 mm (L) × 4 mm (H) within 60 s with a 500 kHz, 60 Vp-p signal, and 3 W maximum. The in silico model was validated with in vitro experiments using a thermochromic phantom tissue prepared with polyacrylamide gel and a thermochromic ink additive that permanently changes from pink to magenta when heated over 60 °C. RESULTS: The in vitro ablation zone closely matched the size and shape of the simulated area. The new electrode design directs the current density towards the artery walls and tissue, reducing unwanted blood temperature increases by focusing energy on the ablation zone. In contrast, the basket catheter design does not block renal flow during renal denervation. CONCLUSIONS: This computational model of radiofrequency ablation can be used to estimate renal artery ablation zones for highly targeted renal denervation in patients with resistant hypertension. Furthermore, this innovative catheter has short ablation times and is one of the lowest power requirements of existing designs to perform the ablation.

Renal denervation in a patient with a highly tortuous renal artery using a guide extension catheter: a case report.

BACKGROUND: Catheter-based renal denervation (RDN) has been introduced to treat resistant hypertension. Although the technology of RDN has been largely improved, denervation of tortuous renal arteries remains challenging. CASE PRESENTATION: This is a case report of a 49-year-old man with drug resistant hypertension. The patient was selected for RDN after ruling out possible causes of secondary hypertension. Computed tomography angiography showed a highly tortuous left renal artery. An Iberis multielectrode ablation catheter failed to reach the target vessel with a regular guiding catheter. A 5-French extension catheter was introduced into the proximal segment of the main left renal artery to provide extra support force, which enabled successful ablation of the highly tortuous left renal artery. His ambulatory blood pressure was significantly decreased at 1 month follow-up. CONCLUSIONS: It is feasible and effective to use a guide extension catheter for denervation of highly tortuous renal arteries. The present study provides a useful method to ablate tortuous and angled renal arteries and branches.

A Three-Arm Randomized Trial of Different Renal Denervation Devices and Techniques in Patients With Resistant Hypertension (RADIOSOUND-HTN).

BACKGROUND: Both radiofrequency and ultrasound endovascular renal sympathetic denervation (RDN) have proven clinical efficacy for the treatment of hypertension. We performed a head-to-head comparison of these technologies. METHODS: Patients with resistant hypertension were randomly assigned in a 1:1:1 manner to receive either treatment with (1) radiofrequency RDN of the main renal arteries; (2) radiofrequency RDN of the main renal arteries, side branches, and accessories; or (3) an endovascular ultrasound-based RDN of the main renal artery. The primary end point was change in systolic daytime ambulatory blood pressure at 3 months. RESULTS: Between June 2015 and June 2018, 120 patients were enrolled (mean age, 64±9 years±SD; mean daytime blood pressure, 153/86±12/13 mm Hg). Of these, 39 were randomly assigned to radiofrequency main renal artery ablation, 39 to combined radiofrequency ablation of the main artery and branches, and 42 to ultrasound-based treatment. Baseline daytime blood pressure, clinical characteristics, and treatment were well balanced between the groups. At 3 months, systolic daytime ambulatory blood pressure decreased by 9.5±12.3 mm Hg ( P<0.001) in the whole cohort. Although blood pressure was significantly more reduced in the ultrasound ablation group than in the radiofrequency ablation group of the main renal artery (-13.2±13.7 versus -6.5±10.3 mm Hg; mean difference, -6.7 mm Hg; global P=0.038 by ANOVA, adjusted P=0.043), no significant difference was found between the radiofrequency ablation groups (-8.3±11.7 mm Hg for additional side branch ablation; mean difference, -1.8 mm Hg; adjusted P>0.99). Similarly, the blood pressure reduction was not found to be significantly different between the ultrasound and the side branch ablation groups. Frequencies of blood pressure response ≥5 mm Hg were not significantly different (global P=0.77). CONCLUSIONS: In patients with resistant hypertension, endovascular ultrasound-based RDN was found to be superior to radiofrequency ablation of the main renal arteries only, whereas a combined approach of radiofrequency ablation of the main arteries, accessories, and side branches was not. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02920034.

Sex-specific computational models for blood pressure regulation in the rat.

In the past decades, substantial effort has been devoted to the development of computational models of the cardiovascular system. Some of these models simulate blood pressure regulation in humans and include components of the circulatory, renal, and neurohormonal systems. Although such human models are intended to have clinical value in that they can be used to assess the effects and reveal mechanisms of hypertensive therapeutic treatments, rodent models would be more useful in assisting the interpretation of animal experiments. Also, despite well-known sexual dimorphism in blood pressure regulation, almost all published models are gender neutral. Given these observations, the goal of this project is to develop the first computational models of blood pressure regulation for male and female rats. The resulting sex-specific models represent the interplay among cardiovascular function, renal hemodynamics, and kidney function in the rat; they also include the actions of the renal sympathetic nerve activity and the renin-angiotensin-aldosterone system as well as physiological sex differences. We explore mechanisms responsible for blood pressure and renal autoregulation and notable sexual dimorphism. Model simulations suggest that fluid and sodium handling in the kidney of female rats, which differs significantly from males, may contribute to their observed lower salt sensitivity as compared with males. Additionally, model simulations highlight sodium handling in the kidney and renal sympathetic nerve activity sensitivity as key players in the increased resistance of females to angiotensin II-induced hypertension as compared with males.

High-fructose corn syrup-sweetened soft drink consumption increases vascular resistance in the kidneys at rest and during sympathetic activation.

We first tested the hypothesis that consuming a high-fructose corn syrup (HFCS)-sweetened soft drink augments kidney vasoconstriction to sympathetic stimulation compared with water (study 1). In a second study, we examined the mechanisms underlying these observations (study 2). In study 1, 13 healthy adults completed a cold pressor test, a sympathoexcitatory maneuver, before (preconsumption) and 30 min after drinking 500 mL of decarbonated HFCS-sweetened soft drink or water (postconsumption). In study 2, venous blood samples were obtained in 12 healthy adults before and 30 min after consumption of 500 mL water or soft drinks matched for caffeine content and taste, which were either artificially sweetened (Diet trial), sucrose-sweetened (Sucrose trial), or sweetened with HFCS (HFCS trial). In both study 1 and study 2, vascular resistance was calculated as mean arterial pressure divided by blood velocity, which was measured via Doppler ultrasound in renal and segmental arteries. In study 1, HFCS consumption increased vascular resistance in the segmental artery at rest (by 0.5 ± 0.6 mmHg·cm-1·s-1, P = 0.01) and during the cold pressor test (average change: 0.5 ± 1.0 mmHg·cm-1·s-1, main effect: P = 0.05). In study 2, segmental artery vascular resistance increased in the HFCS trial (by 0.8 ± 0.7 mmHg·cm-1·s-1, P = 0.02) but not in the other trials. Increases in serum uric acid were greater in the HFCS trial (0.3 ± 0.4 mg/dL, P ≤ 0.04) compared with the Water and Diet trials, and serum copeptin increased in the HFCS trial (by 0.8 ± 1.0 pmol/L, P = 0.06). These findings indicate that HFCS acutely increases vascular resistance in the kidneys, independent of caffeine content and beverage osmolality, which likely occurs via simultaneous elevations in circulating uric acid and vasopressin.

Renal denervation restrains the inflammatory response in myocardial ischemia-reperfusion injury.

Myocardial ischemia-reperfusion (I/R) injury leads to intensive sympathetic nervous system (SNS) activation and inflammatory reactions. Whether renal sympathetic denervation (RDN) could be a new therapeutic strategy to modulate I/R inflammation and reduce infarct size after myocardial I/R injury needs to be explored. First, we investigated the correlation between plasma norepinephrine concentrations and circulating myeloid cell numbers in patients with acute myocardial infarction. And then, C57BL/6 mice underwent a "two-hit" operation, with 10% phenol applied to bilateral renal nerves to abrogate sympathoexcitation, and a 45-min ligation of the left coronary artery to induce myocardial I/R injury. The effects of RDN on the mobilization of immune cells in mice following myocardial I/R injury were explored. We observed a strong association between SNS overactivation and myeloid cell excessive accumulation in patients. In animal experiments, there was a significant reduction in infarct size per area at risk in the denervated-I/R group when compared to that of the innervated-I/R group (39.2% versus 49.8%; p < 0.005), and RDN also improved the left ventricular ejection fraction by 20% after 1 week. Furthermore, the denervated-I/R group showed a decrease in the number of neutrophils and macrophages in the blood and the myocardium as reflected by immunohistochemical staining and flow cytometry analysis (p < 0.05); the decrease was associated with a significant reduction in the circulating production of IL-1, IL-6 and TNF-α (p < 0.05). In summary, our study reveals a novel link between the SNS activity and inflammatory response undergoing myocardium I/R injury and identifies RDN as a potential therapeutic strategy against myocardium I/R injury via preserving the spleen immune cells mobilization.

Effect of Renal Denervation on Cardiac Function and Inflammatory Factors in Heart Failure After Myocardial Infarction.

Heart failure (HF) affects around 100 million people and is a staggering burden for health care system worldwide. Rapid and sustained activation of inflammatory response is an important feature of HF after myocardial infarction. Sympathetic overactivation is also an important factor in the occurrence and progression of HF. The beneficial effect of renal denervation (RDN) has been demonstrated in HF. In the current study, we hypothesized that RDN improves cardiac function in HF canine models due to acute myocardial infarction (AMI) and reduced inflammation might be involved. Twenty-four beagles were randomized into the control (n = 8), HF (n = 8), and HF + RDN group (n = 8). The HF model after AMI was established by embolization the anterior descending distal artery with anhydrous ethanol in the HF and HF + RDN group. Bilateral renal artery ablation was performed in the HF + RDN group. Cardiac function, serum creatine kinase, creatine kinase-MB and NT-Pro BNP level, and expression of inflammation-related proteins in myocardial were examined. Because the paraventricular nucleus of the hypothalamus might be involved in inflammation-induced central neural excitation in HF and plays an important role in regulating extracellular fluid volume and sympathetic activity, expression of inflammation-related proteins in hypothalamus was also examined. AMI and post-AMI HF model was created successfully. Compared with the HF group, dogs in the HF + RDN group showed better cardiac function 4 weeks after AMI: lower left ventricular end-diastolic pressure, left ventricular end-diastolic dimension, and left ventricular end-systolic dimension and higher LEVF and left ventricular systolic pressure (P < 0.05 for all) were observed in the HF + RDN group. In addition, dogs in the HF + RDN group had slightly less ventricular fibrosis. Interestingly, RDN had lower expression of inflammation-related proteins including interleukin-6, tumor necrosis factors-α, nuclear factor κB, and monocyte chemotactic protein 1 (P < 0.05 for all) in both myocardial tissue and hypothalamus. RDN can improve cardiac function in dogs with HF after myocardial infarction. Our results suggested that RDN might affect cytokine-induced central neural excitation in HF and later affect sympathetic activity. Our results suggested a potential beneficial mechanism of RDN independent of mechanism involving renal afferent and efferent sympathetic nerves.

Laparoscopic based renal denervation in a canine neurogenic hypertension model.

BACKGROUND: Previous renal denervation (RDN) studies showed controversial results in reducing blood pressure. The aim of this study was to provide evidence supporting the effectiveness of laparoscopic-based renal denervation (L-RDN) in treating hypertension. METHODS: Sixteen Beagle dogs were randomly divided into RDN group (n = 12) and sham group (n = 4). Neurogenic hypertension was generated in all dogs via carotid artery route. L-RDN was performed in the RDN group, with sham operation performed as a control. Blood pressure (BP) changes were recorded at 2, 4, 6, and 8 weeks after the procedure. Changes in serum creatinine (sCr), blood urea nitrogen (BUN) and level of norepinephrine (NE) were analyzed. Histological changes of kidney and renal arteries were also evaluated. RESULTS: BP and NE levels were significantly elevated after hypertension induction (p < 0.01). Systolic and diastolic BP of RDN group were decreased by 15.5 mmHg and 7.3 mmHg (p < 0.0001 and p = 0.0021, respectively) at the eighth week after L-RDN. Invasive systolic and diastolic BP of RDN group were significantly decreased by 14.5 mmHg and 15.3 mmHg (p < 0.0001). In contrast, there was no significant decrease in blood pressure in the sham group. In addition, RDN group but not the sham group showed a significant decrease in NE levels (p < 0.001), while no significant changes in sCr and BUN were observed in both groups. Pathological examinations showed no discernible damage, tear, or dissection to the renal arteries in RND group. CONCLUSIONS: L-RDN lowered BP and NE levels in hypertensive dogs without affecting renal artery morphology and kidney function.

Aggravated endothelial endocrine dysfunction and intimal thickening of renal artery in high-fat diet-induced obese pigs following renal denervation.

BACKGROUND: Renal denervation (RDN) targeting the sympathetic nerves in the renal arterial adventitia as a treatment of resistant hypertension can cause endothelial injury and vascular wall injury. This study aims to evaluate the risk of atherosclerosis induced by RDN in renal arteries. METHODS: A total of 15 minipigs were randomly assigned to 3 groups: (1) control group, (2) sham group, and (3) RDN group (n = 5 per group). All pigs were fed a high-fat diet (HFD) for 6 months after appropriate treatment. The degree of intimal thickening of renal artery and the conversion of endothelin 1 (ET-1) receptors were evaluated by histological staining. Western blot was used to assess the expression of nitric oxide (NO) synthesis signaling pathway, ET-1 and its receptors, NADPH oxidase 2 (NOX2) and 4-hydroxynonenal (4-HNE) proteins, and the activation of NF-kappa B (NF-κB). RESULTS: The histological staining results suggested that compared to the sham treatment, RDN led to significant intimal thickening and significantly promoted the production of endothelin B receptor (ETBR) in vascular smooth muscle cells (VSMCs). Western blotting analysis indicated that RDN significantly suppressed the expression of AMPK/Akt/eNOS signaling pathway proteins, and decreased the production of NO, and increased the expression of endothelin system proteins including endothelin-1 (ET-1), endothelin converting enzyme 1 (ECE1), endothelin A receptor (ETAR) and ETBR; and upregulated the expression of NOX2 and 4-HNE proteins and enhanced the activation of NF-kappa B (NF-κB) when compared with the sham treatment (all p < 0.05). There were no significant differences between the control and sham groups (all p > 0.05). CONCLUSIONS: RDN aggravated endothelial endocrine dysfunction and intimal thickening, and increased the risk of atherosclerosis in renal arteries of HFD-fed pigs.

Chemical renal denervation-induced upregulation of the ACE2/Ang (1-7)/Mas axis attenuates blood pressure elevation in spontaneously hypertensive rats.

OBJECTIVE: Evidence has shown that the ACE2/Ang (1-7)/Mas axis plays an important role in the control of hypertension. Thus, we hypothesized that chemical renal denervation (RDN) could reduce blood pressure by regulating the ACE2/Ang (1-7)/Mas axis in spontaneously hypertensive rats. METHODS: Twelve rats were randomly divided into sham group and chemical RDN group. All the rats were sacrificed 4 weeks later. Plasma samples were collected to measure the renin-angiotensin system (RAS) activities and reactive oxygen species levels by radioimmunoassay, chromatometry and ELISA. Paraventricular nucleus (PVN) tissues were collected to examine the expression of the components of the ACE2/Ang (1-7)/Mas axis by western bolt and immunofluorescence. RESULTS: The systolic blood pressure (169.33 ± 7.50 vs 182.67 ± 7.00 mmHg, p < .05) and the diastolic blood pressure (97.50 ± 4.68 vs 109.33 ± 4.41 mmHg, p < .05) in the RDN group were obviously lower than the baseline levels, whereas the opposite results were observed in the sham group. The RDN group exhibited a significant reduction in the plasma ROS (91.59 ± 13.12 vs 72.34 ± 11.76 U/ml, p < .05) and NADPH oxidase (171.86 ± 1.14 vs 175.75 ± 1.74 nmol/ml, p < .001) compared with the sham group, while the plasma eNOS (3.47 ± 0.42 vs 2.49 ± 0.51 U/ml, p < .05) and NO (55.92 ± 8.10 vs 43.53 ± 4.58 µmol/L, p < .05) were increased. The expression of the components of the ACE2/Ang (1-7)/Mas axis was upregulated while the expression of the components of the ACE/Ang II/AT1 R axis was downregulated in the plasma and PVN in the RDN group. CONCLUSION: Our findings suggested that the reduction in blood pressure was regulated by chemical RDN-induced upregulation of the components of the ACE2/Ang (1-7)/Mas axis.

Ambulatory heart rate reduction after catheter-based renal denervation in hypertensive patients not receiving anti-hypertensive medications: data from SPYRAL HTN-OFF MED, a randomized, sham-controlled, proof-of-concept trial.

AIMS: The randomized sham-controlled SPYRAL HTN-OFF MED trial demonstrated that renal denervation (RDN) using a multi-electrode catheter lowers ambulatory blood pressure (BP) in non-medicated hypertensive patients. The current report describes the effects of RDN on heart rate (HR) in this population. METHODS AND RESULTS: Patients were enrolled with an office systolic BP (SBP) of ≥150 mmHg and <180 mmHg, office diastolic BP (DBP) of ≥90 mmHg, and a mean ambulatory SBP of ≥140 mmHg and <170 mmHg. Patients were drug naïve or removed from their anti-hypertensive medications. Eighty patients were randomized 1:1 to RDN or sham procedure. This post hoc analysis examines the effect at 3 months of RDN on HR and of high baseline 24-h HR on BP and HR changes. There was a significant reduction in 24-h HR at 3 months for the RDN group (-2.5 b.p.m.) compared with sham (-0.2 b.p.m.), P = 0.003 (analysis of covariance). Mean baseline-adjusted treatment differences were significantly different between groups at 3 months for average morning HR (-4.4 b.p.m., P = 0.046) and minimum morning HR (-3.0 b.p.m., P = 0.026). RDN patients with baseline 24-h HR above the median (73.5 b.p.m.) had significant reductions in average ambulatory SBP (-10.7 mmHg difference, P = 0.001) and DBP (-7.5 mmHg, P < 0.001), whereas BP changes in RDN patients with below-median HRs were not significant. CONCLUSION: Average and minimum morning HR were significantly reduced at 3 months for RDN compared with sham patients. A baseline 24-h HR above the median predicted greater BP reductions and may allow physicians to select patients likely to respond to the procedure.

Numerical simulation of electromagnetic heating process of biological tissue via time-fractional Cattaneo transfer equation.

In order to simulate the heat transfer in the process of hyperthermia, one-dimensional time-fractional Cattaneo heat transfer equation (TFHE) is established. Based on TFHE, the heat transfer model is solved by using finite difference method, because a single layer of biological tissue in vitro is irradiated by electromagnetic energy. The effect of power parameters (energy flux density P0, tissue attenuation coefficient h) and equation parameters (relaxation time τq and fractional order ß) on the prediction of temperature simulated by TFHE were studied. Furthermore, comparative studies on TFHE, Pennes and CV are performed and evaluated. In the heating process, because of the existence of relaxation time τq, the temperature response of TFHE and CV are later than Pennes, leading to the lower temperature prediction of TFHE and CV than that of Pennes. The shorter the time is, the higher the energy is, and the more obvious the difference is.

Renal Artery Denervation in Resistant Hypertension: The Good, The Bad and The Future.

Early studies of renal artery denervation (RAD) demonstrated efficacy in treating resistant hypertension patients with significant reduction in office blood pressure (BP). This resulted in a growing enthusiasm in the field and a rapid evolution of technology with expanding procedural indications. However, the first randomised sham-controlled trial, Symplicity HTN-3, failed to demonstrate a significant difference in BP reduction between the RAD and the sham control arm, which subsequently led to a major reduction in the clinical application of this procedure. Additionally, the results generated further interest into understanding the mechanism and factors affecting procedural success and identifying the limitations within the field. Many lessons were learned from Symplicity HTN-3 trial, and with recent evidence emerging for RAD in hypertension treatment, the field continues to be refined.