Hypertension and Device-Based Therapies for Resistant Hypertension: An Up-to-Date Review.

Hypertension is the most prevalent modifiable risk factor associated with cardiovascular mortality. The World Health Organization (WHO) estimates that hypertension directly or indirectly causes the death of at least nine million people globally every year. The number of people living with hypertension (blood pressure (BP) of ≥140 mmHg systolic or ≥90 mmHg diastolic or on medication) doubled between 1990 and 2019, from 650 million to 1.3 billion. Despite a plethora of antihypertensive drugs widely available, a sizable part of the antihypertensive population stays uncontrolled. The unmet need of controlling BP in this population may be addressed, in part, by developing new drugs and devices/procedures to treat hypertension and its comorbidities. Several device-based approaches have been introduced to lower BP, and most of these strategies aim to modulate autonomic nervous system activity. Importantly, when considering a device-based treatment, each patient's underlying pathophysiology is considered, and the procedural risks are weighed against the cardiovascular risk attributed to the elevated BP. In November 2023, the FDA approved two renal denervation (RDN) devices. This manuscript discusses current interventional devices and procedures recently approved (RDN) and others in the clinical testing stage for arterial hypertension intervention or management. As we list below, all others have shown promising results and are being evaluated on a larger clinical trial. The new device-based classes are as follows: catheter-based RDN, baroreflex amplification, arteriovenous (AV) malformation, carotid body (CB) ablation, pacemaker-based cardiac neuromodulation, electro-acupuncture, and deep brain stimulation. Baroreflex amplification uses peripheral neuromodulation, while AV malformation leverages AV anastomosis. CB ablation modulates chemoreceptors, and pacemaker-based neuromodulation adjusts atrioventricular intervals. Electro-acupuncture proves potential, and deep brain stimulation offers central nervous system intervention.

Impacts of renal denervation on blood pressure in patients with obstructive sleep apnea.

BACKGROUND: Sympathetic nerve activation followed by obstructive sleep apnea (OSA) accounts for blood pressure elevation. The effectiveness of renal denervation (RDN) in controlling blood pressure in patients with OSA remains controversial. In this systematic review, we tried to pool currently available data to assess the effects of RDN therapy on blood pressure in OSA patients. METHODS: We retrieved Pubmed, EMbase and Cochrane Library through 17 May 2023, using the following key words: "renal denervation" and"obstructive sleep apnea". Full articles reporting the change of blood pressure after RDN procedure were included. RESULTS: A total of five studies were included in the meta-analysis. Pooled analysis showed that RDN markedly reduced both 24-h ambulatory systolic blood pressure (24 h-SBP) (Mean difference (MD): -7.54mmHg; 95%Cl: -10.16 to -4.91mmHg; I2 = 0%) and 24-h ambulatory diastolic blood pressure (24 h-DBP) (MD: -5.28mmHg; 95%Cl: -7.35 to -3.22mmHg; I2=0%). Daytime systolic blood pressure (dSBP) was reduced after RDN (MD: -7.54mmHg; 95%Cl: -10.82 to -4.57mmHg; I2 = 54%). With regards to nocturnal blood pressure, we found that RDN resulted in a significant reduction in nighttime systolic blood pressure (nSBP) (MD: -6.91mmHg; 95%Cl: -10.69 to -2.85mmHg; I2=0%). Subgroup analysis showed that dSBP was reduced by 12.00 mmHg, 12.00 mmHg, and 7.25 mmHg at 1 month, 3 months and 6 months, respectively. Our pooled analysis showed that AHI was not significantly changed by RDN. No major compilations were associated with RDN. CONCLUSIONS: RDN exerts a considerable blood pressure-lowering effect in hypertensive patients with OSA, which was sustained at least 6 months.

Efficacy of renal denervation as an adjunct to pulmonary vein isolation for atrial fibrillation treatment: a systematic review and meta-analysis.

Aims: Catheter ablation, consisting of pulmonary vein isolation (PVI), is the most effective treatment modality for the management of symptomatic patients with atrial fibrillation (AF). Unfortunately, this procedure has a considerable relapse rate, ranging from 15 to 50% depending on AF type and other patient factors. Hypertension (HTN) is associated with a higher risk of developing AF and can also be managed with a catheter-based procedure-renal denervation (RDN). This meta-analysis aimed to compare the effect of PVI with and without RDN in hypertensive patients with AF. Methods and results: OVID MEDLINE and Embase were searched on 1 February 2023 and trials that reported the effects of RDN on AF recurrence in hypertensive patients were included. A total of 637 patients across 8 randomised controlled trials were included. The results from the pooled analysis showed that when compared with PVI alone, RDN added to PVI: (1) Lowered AF recurrence [RR 0.67 (0.53, 0.85), P = 0.001, I 2 = 23%, NNT = 5.9 patients]; (2) Reduced both systolic blood pressure and diastolic blood pressure, with medium effect size, as reflected by standardised mean differences of 0.5 (P = 0.02, I 2 = 80%) and 0.43 (P = 0.006, I 2 = 60%), respectively; and (3) was not associated with a decrease in estimated glomerular filtration rate (+7.19 mL/min/1.73 m2, P = 0.15, I 2 = 89%). Conclusion: Adding RDN to PVI in patients with AF and resistant HTN was associated with a reduction of blood pressure levels and AF recurrence. Consideration to RDN should be given as an adjunctive treatment for patients with AF and resistant HTN.

Renal denervation improves mitochondrial oxidative stress and cardiac hypertrophy through inactivating SP1/BACH1-PACS2 signaling.

BACKGROUND: Renal denervation (RDN) has been proved to relieve cardiac hypertrophy; however, its detailed mechanisms remain obscure. This study investigated the detailed protective mechanisms of RDN against cardiac hypertrophy during hypertensive heart failure (HF). METHODS: Male 5-month-old spontaneously hypertension (SHR) rats were used in a HF rat model, and male Wistar-Kyoto (WKY) rats of the same age were used as the baseline control. Myocardial hypertrophy and fibrosis were evaluated by hematoxylin-eosin (HE) staining and Masson staining. The expression of target molecule was analyzed by reverse transcription-quantitative polymerase chain reaction (RT-qPCR), Western blot, immunohistochemical and immunofluorescence, respectively. Cardiomyocyte hypertrophy was induced by norepinephrine (NE) in H9c2 cells in vitro and evaluated by brain natriuretic peptide (BNP), atrial natriuretic peptide (ANP), ß-myosin heavy chain (ß-MHC), and α-myosin heavy chain (α-MHC) levels. Oxidative stress was determined by malondialdehyde (MDA) level, superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) enzyme activities. Mitochondrial function was measured by mitochondrial membrane potential, adenosine triphosphate (ATP) production, mitochondrial DNA (mtDNA) number, and mitochondrial complex I-IV activities. Molecular mechanism was assessed by dual luciferase reporter and chromatin immunoprecipitation (ChIP) assays. RESULTS: RDN decreased sympathetic nerve activity, attenuated myocardial hypertrophy and fibrosis, and improved cardiac function in the rat model of HF. In addition, RDN ameliorated mitochondrial oxidative stress in myocardial tissues as evidenced by reducing MDA and mitochondrial reactive oxygen species (ROS) levels, and enhancing SOD and GSH-Px activities. Moreover, phosphofurin acid cluster sorting protein 2 (PACS-2) and broad-complex, tramtrak and bric à brac (BTB) domain and cap'n'collar (CNC) homolog 1 (BACH1) were down-regulated by RDN. In NE-stimulated H9c2 cells, PACS-2 and BACH1 levels were markedly elevated, and knockdown of them could suppress NE-induced oxidative stress, cardiomyocyte hypertrophy, fibrosis, as well as mitochondrial dysfunction. Transforming growth factor beta1(TGFß1)/SMADs signaling pathway was inactivated by RDN in the HF rats, which sequentially inhibited specificity protein 1 (SP1)-mediated transcription of PACS2 and BACH1. CONCLUSION: Collectively, these data demonstrated that RDN improved cardiac hypertrophy and sympathetic nerve activity of HF rats via repressing BACH1 and PACS-2-mediated mitochondrial oxidative stress by inactivating TGF-ß1/SMADs/SP1 pathway, which shed lights on the cardioprotective mechanism of RDN in HF.

Aspects of renal function and renal artery anatomy as indications for renal denervation.

Renal denervation (RDN) is a minimally invasive, endovascular catheter-based procedure using radiofrequency, ultrasound, or alcohol-mediated ablation to treat resistant hypertension. As more attention is focused on the renal sympathetic nerve as a cause and treatment target of hypertension, understanding the anatomy of the renal artery may have important implications for determining endovascular treatment strategies as well as for future selection of devices and appropriate candidates for RDN treatment. However, the anatomical structure of the renal artery (RA) is complex, and standardized morphological evaluations of the RA structure are lacking. Computed tomography angiography or magnetic resonance angiography imaging is useful for assessing RA anatomy before conducting RDN. RA echocardiography is an established noninvasive screening method for significant stenosis. Major randomized controlled trials have limited enrollment to patients with preserved renal function, usually defined as an estimated glomerular filtration rate (eGFR) ≥ 45 mL/min/1.73 m2. Therefore, the level of renal function at which RDN is indicated has not yet been determined. This mini-review summarizes the characteristics of renal artery anatomy and renal function that constitute indications for renal denervation. (Role of Clinical Trials: K. Kario is an Executive Committee Principal Investigator for the Spyral OFF MED, the Spyral ON MED, the DUO and the REQUIRE; a Coordinating investigator for the TCD-16164 study; a Site Principal Investigator for the HTN-J, the Spyral OFF MED, the Spyral ON MED, the DUO, the REQUIRE and the TCD-16164 study). Evaluation of renal arteries for radiofrequency renal denervation. A Simultaneous quadrantal ablations at four sites in the main renal artery or the equivalent renal artery to the main renal artery. B If there is a renal artery branch with a diameter >3 mm in the middle of the main renal artery, this branch is the distal end of the main renal artery. In this case, four simultaneous and quadrantal ablations can be performed on the equivalent renal arteries. C Four simultaneous and quadrantal ablations can be performed in the branch renal artery. D Sonication should be spaced at least 5 mm (one transducer*) apart. Perform 2 to 3 mm proximal to the arterial bifurcation. Perform 2 to 3 mm distal to the abdominal aortic inlet.

Effects of renal denervation on the incidence and severity of cardiovascular diseases.

Renal denervation (RDN) is a neuromodulation therapy performed in patients with hypertension using an intraarterial catheter. Recent randomized sham-controlled trials have shown that RDN has significant antihypertensive effects that last for more than 3 years. Based on this evidence, the US Food and Drug Administration has approved two devices, the ultrasound-based ReCor ParadiseTM RDN system and the radiofrequency-based Medtronic Symplicity SpyralTM RDN system, as adjunctive therapy for patients with refractory and uncontrolled hypertension. On the other hand, there have been no randomized sham-controlled prospective outcome trials on RDN, and the effects of RDN on cardiovascular events such as myocardial infarction, heart failure, and stroke have not been elucidated. This mini-review summarizes the latest findings focusing on the effects of RDN on organ protection and physiological function and symptoms in both preclinical and clinical studies. Furthermore, the feasibility of using blood pressure as surrogate marker for cardiovascular outcomes is discussed in the context of relevant clinical studies on RDN. A comprehensive understanding of the beneficial effects of RDN on the incidence and severity of cardiovascular diseases with their underlying mechanisms will enhance physicians' ability to incorporate RDN into clinical strategies to prevent cardiovascular events including myocardial infarction, heart failure, and stroke. This mini-review focuses on the effects of RDN on organ protection and physiological function and symptoms in preclinical and clinical studies. RDN is expected to reduce the onset and progression of cardiovascular diseases including myocardial infarction, heart failure, and stroke in clinical practice. LV left ventricular, LVEF left ventricular ejection fraction, VO2max maximal oxygen uptake, VT ventricular tachycardia, VF ventricular fibrillation, 6MWD 6-min walk distance, NT-proBNP N-terminal pro-B-type natriuretic peptide, NYHA New York Heart Association, BBB blood-brain barrier, BP blood pressure.

What are the ideal metrics for assessing the quality of long-term stabilized "perfect" 24-h BP control after renal denervation?

A significant number of individuals being treated for hypertension still have uncontrolled blood pressure (BP). In Japan, renal denervation (RDN) is being introduced into clinical practice as an adjunctive treatment for hypertension that is uncontrolled despite adequate lifestyle changes and maximal antihypertensive drug therapy. The pivotal SPYRAL ON-MED trial showed that there was a significant reduction in trough office and nighttime ambulatory BP values in the RDN group compared with sham control group, although 24-h and daytime BP values were not significantly different between the two groups. The trough office BP measurement (taken before morning antihypertensive dosing) is similar to guideline recommendations for taking morning home BP before taking the morning antihypertensive drug dose. Recent guidelines recommend the measurement of nighttime BP because nighttime BP is a stronger predictor of cardiovascular event risk than daytime BP. It is particularly important to assess nighttime BP in medicated individuals with hypertension because the up- or down-titration of antihypertensive drug dosing is primarily based on office and daytime BPs in clinical practice. This means that there may be significant risk relating to nocturnal hypertension during longer follow-up. Because RDN results in persistent, "always-on" 24-h BP-lowering effects, the best BP metrics to assess the potential benefit of RDN are nighttime BP (determined using home or ambulatory BP monitoring) and morning BP (determined using home BP monitoring or morning trough office BP measurement). The variability of office, home, and ambulatory BP values is another important metric to assess the quality of RDN-related BP lowering.

Indications for renal denervation in the treatment of hypertension.

Renal denervation (RDN) is a neuromodulation therapy performed using an intraarterial catheter in patients with hypertension. Recent randomized sham-operated controlled trials have shown that RDN has significant antihypertensive effects in patients with resistant, uncontrolled, and/or drug-naïve hypertension. Based on available evidence, the European Society of Hypertension 2023 guidelines include a Class II recommendation for the use of RDN in individuals with resistant and uncontrolled hypertension. The US Food and Drug Administration approved two devices, the ultrasound-based ReCor ParadiseTM RDN system and the radiofrequency-based Medtronic Symplicity SpyralTM RDN system, as adjunctive therapy for patients with resistant and uncontrolled hypertension. The indications for RDN and incorporation of RDN into clinical practice will grow as clinical evidence accumulates. This mini review summarizes latest findings focusing on the safety and effectiveness of RDN for treating hypertension in the absence and presence of antihypertensive drugs, and discusses the indications for RDN. This mini review focuses on the safety and effectiveness of RDN for treating hypertension in the absence and presence of antihypertensive drugs. The indications for RDN and incorporation of RDN into clinical practice will grow as clinical evidence accumulates and should be reviewed and updated.

Autonomic Nervous System: A Therapeutic Target for Cardiac End-Organ Damage in Hypertension.

More than 1.5 billion people worldwide have arterial hypertension. Hypertension increases the risks of death and cardiovascular disease, such as atrial fibrillation and heart failure. The autonomic nervous system plays an essential role in hypertension development and disease progression. While lifestyle factors, such as obesity and obstructive sleep apnea, predispose to hypertension by increasing sympathetic activity, hypertension itself maintains the autonomic nervous imbalance, providing the substrate for atrial fibrillation and heart failure. Therefore, autonomic nervous system modulation either by direct targeting or indirect treatment of comorbidities has the potential to treat both hypertension and related atrial and ventricular end-organ damage. We discuss interventions for the modulation of the autonomic nervous system for hypertension and related cardiac end-organ damage, including pharmacological adrenergic beta-receptor blockade, renal denervation, carotid baroreceptor stimulation, low-level vagal stimulation, and ablation of ganglionated plexuses. In summary, the literature suggests that targeting the autonomic nervous system potentially represents a therapeutic approach to prevent atrial and ventricular end-organ damage in patients with hypertension. However, clinical trials specifically designed to test the effect of autonomic modulation on hypertension-mediated cardiac end-organ damage are scarce.

Randomized Trials of Renal Denervation for Uncontrolled Hypertension: An Updated Meta-Analysis.

BACKGROUND: Despite optimal medical therapy, a significant proportion of patients' blood pressure remains uncontrolled. Catheter-based renal denervation (RDN) has been proposed as a potential intervention for uncontrolled hypertension. We conducted an updated meta-analysis to assess the efficacy and safety of RDN in patients with uncontrolled hypertension, with emphasis on the differential effect of RDN in patients on and off antihypertensive medications. METHODS AND RESULTS: Online databases were searched to identify randomized clinical trials comparing efficacy and safety of RDN versus control in patients with uncontrolled hypertension. Subgroup analyses were conducted for sham-controlled trials and studies that used RDN devices that have gained or are currently seeking US Food and Drug Administration approval. Fifteen trials with 2581 patients (RDN, 1723; sham, 858) were included. In patients off antihypertensive medications undergoing RDN, a significant reduction in 24-hour ambulatory (-3.70 [95% CI, -5.41 to -2.00] mm Hg), office (-4.76 [95% CI, -7.57 to -1.94] mm Hg), and home (-3.28 [95% CI, -5.96 to -0.61] mm Hg) systolic blood pressures was noted. In patients on antihypertensive medications, a significant reduction was observed in 24-hour ambulatory (-2.23 [95% CI, -3.56 to -0.90] mm Hg), office (-6.39 [95% CI, -11.49 to -1.30]), home (-6.08 [95% CI, -11.54 to -0.61] mm Hg), daytime (-2.62 [95% CI, -4.14 to -1.11]), and nighttime (-2.70 [95% CI, -5.13 to -0.27]) systolic blood pressures, as well as 24-hour ambulatory (-1.16 [95% CI, -1.96 to -0.35]), office (-3.17 [95% CI, -5.54 to -0.80]), and daytime (-1.47 [95% CI, -2.50 to -0.27]) diastolic blood pressures. CONCLUSIONS: RDN significantly lowers blood pressure in patients with uncontrolled hypertension, in patients off and on antihypertensive medications, with a favorable safety profile. The efficacy of RDN was consistent in sham-controlled trials and contemporary trials using US Food and Drug Administration-approved devices.

The Global Burden of Resistant Hypertension and Potential Treatment Options.

Resistant hypertension (RH) is defined as systolic blood pressure (SBP) or diastolic blood pressure (DBP) that remains .140 mmHg or .90 mmHg, respectively, despite an appropriate lifestyle and the use of optimal or maximally tolerated doses of a three-drug combination, including a diuretic. This definition encompasses the category of controlled RH, defined as the presence of blood pressure (BP) effectively controlled by four or more antihypertensive agents, as well as refractory hypertension, referred to as uncontrolled BP despite five or more drugs of different classes, including a diuretic. To confirm RH presence, various causes of pseudo-resistant hypertension (such as improper BP measurement techniques and poor medication adherence) and secondary hypertension must be ruled out. Inadequate BP control should be confirmed by out-of-office BP measurement. RH affects about 5% of the hypertensive population and is associated with increased cardiovascular morbidity and mortality. Once RH presence is confirmed, patient evaluation includes identification of contributing factors such as lifestyle issues or interfering drugs/substances and assessment of hypertension-mediated organ damage. Management of RH comprises lifestyle interventions and optimisation of current medication therapy. Additional drugs should be introduced sequentially if BP remains uncontrolled and renal denervation can be considered as an additional treatment option. However, achieving optimal BP control remains challenging in this setting. This review aims to provide an overview of RH, including its epidemiology, pathophysiology, diagnostic work-up, as well as the latest therapeutic developments.

Renal Denervation for Hypertension: The Current Landscape and Future Directions.

Hypertension (HTN) is one of the largest contributors to cardiovascular (CV) morbidity and mortality in the USA and is estimated to affect 47% of the US population; however, recent estimates suggest that over 40% continue to have uncontrolled HTN. In the past decade, multiple placebo-controlled randomized studies have shown the safety and efficacy of renal denervation as an adjunctive therapy, culminating in the recent approval of two devices by the US Food and Drug Administration (FDA). These devices use either radiofrequency or ultrasound energies to ablate the perivascular sympathetic nerves in the renal arteries and have been shown to reduce blood pressure. In this immediate post-FDA approval era, there are still multiple issues regarding the future of the technology in its applications and reimbursement landscapes.

Patient Preference for Catheter-Based Hypertension Therapy and Subgroup Analysis: A Pilot Study Based on Taiwan Consensus on Renal Denervation.

Ojective: To understand hypertensive patients' preference for catheter-based therapy to manage hypertension. Methods: Survey data regarding catheter-based therapies performed at MacKay Memorial Hospital in Taipei, Taiwan, between 2019-2020 were analyzed. The questionnaire was circulated either in the clinics or during admission. A total of 46 patients completed the questionnaire. Results: A total of 46 patients (mean age 53.4 ± 13.5 years, 78.3% male) completed the questionnaire. In subgroup analysis according to Taiwan renal denervation (RDN) consensus, patients with drug intolerance (61.8% vs. 31.3%, p = 0.02) were more likely to choose RDN. Moreover, although lacking statistical significance, it is noteworthy that numerically more of the resistant hypertension group (55.6% vs. 28.0%, p = 0.09) and non-adherence group (38.5% vs. 30.0%, p = 0.20) were willing to undergo RDN. Conversely, numerically fewer patients with hypertension-mediated organ damage accepted RDN compared to those who did not have hypertension-mediated organ damage (26.1% vs. 43.5%, p = 0.21), although this disparity did not reach statistical significance. Conclusions: Approximately one-third of the patients expressed interest in considering RDN in this study. The most influential factor in patients' preference for RDN was drug intolerance due to medication-related side effects.

Differences in the effectiveness and safety of different renal denervation devices.

Renal denervation (RDN) is a minimally invasive, endovascular catheter-based procedure using radiofrequency, ultrasound, or alcohol-mediated ablation to treat resistant hypertension. RDN gained popularity in 2009 when it was shown to have an antihypertensive effect. However, concerns about the efficacy of RDN were raised in the HTN-3 trial published in 2014, and the development of several RDN devices was then discontinued. In the process, new randomized controlled trials were conducted after the development of some of the RDN devices, the quality assurance of the procedure, changes in ablation points, and improvements in study design. In November 2023, the U.S. Food and Drug Administration approved a radiofrequency RDN device and an ultrasound RDN device. The results of a randomized controlled trial of an alcohol-mediated RDN device have been published, and future trends are being watched closely. In this mini-review, we summarize the differences in the antihypertensive effect and safety of the different RDN devices and the endpoints of the procedure in order to contribute to the further development of RDN devices Currently available renal denervation device. A multielectrode radiofrequency ablation (Spyral), (B) ultrasound denervation (Paraise), and (C) alcohol-mediated perivascular denervation (Peregrine). ASBP ambulatory systolic blood pressure, ADBP ambulatory diastolic blood pressure, OSBP office systolic blood pressure, ODBP office diastolic blood pressure. Analysis according to types of renal denervation device (radiofrequency, ultrasound, or alcohol-mediated device). P values for interaction were 0.578 (ambulatory SBP), 0.499 (ambulatory diastolic BP), 0.853 (office SBP), and 0.870 (office diastolic BP).

Advances on the Experimental Research in Resistant Hypertension.

PURPOSE OF REVIEW: Resistant Hypertension (RH) poses a significant public health challenge, contributing to increased mortality, cardiovascular events and organ damage. Both clinical and experimental research are striving for higher standards in a translational manner to integrate new findings and confirm hypotheses. Considering that many are the aspects of RH that are still under investigation, this review aims to shed light on the advances made in experimental research concerning RH. It seeks to underscore the pivotal role of experimental studies in shaping clinical practices and also explore future perspectives. RECENT FINDINGS: It is important to emphasize the significance of experimental models, primarily for advancing our understanding: experimental models have greatly contributed to our comprehension of the underlying mechanisms in RH, including factors like sympathetic activation, endothelial dysfunction and structural vessel abnormalities. Secondly, for assessing treatment approaches: animal models have also played a crucial role in evaluating the potential effectiveness of diverse treatment approaches for RH. These encompass both pharmacological options, involving combinations of established drugs or novel pharmaceuticals, and non-pharmacological alternatives, which include surgical procedures like renal denervation, medical devices like baroreceptor stimulators, and lifestyle modifications. The most lacking component in translational research is the fact that there is no well-established animal model that perfectly replicates RH. Consequently, alternative strategies, including the combination of models, must be considered. What remains clear is that the development of animal models closely mimicking RH holds the promise of providing valuable insights into the essential mechanisms and responses necessary to combat or slow the global progression of RH.

Is Renal Denervation Effective in Treating Resistant Hypertension?

Resistant hypertension is diagnosed in patients whose blood pressure target is unmet despite the use of three or more antihypertensive medications. Systemic sympathetic hyperactivation is associated with the development of resistant hypertension. As the kidney is largely pervasive of the sympathetic nervous system renal denervation procedure was developed to control blood pressure by attenuating the renal and systemic sympathetic hyperactivity. Renal denervation is a minimally invasive procedure that uses radiofrequency or ultrasound energy waves to reduce the activity of the renal artery nerves. Previous clinical trials have shown conflicting results regarding the efficacy of the procedure. Symplicity HTN-1 and -2 trials showed effective blood pressure lowering results in the renal denervation group with a good safety profile. However, the Symplicity HTN-3 trial showed no difference in blood pressure lowering effect between the renal denervation and control Sham procedure groups. Notwithstanding, some recent clinical trials with Sham control and meta-analysis showed clinical benefits of renal denervation. Other clinical benefits of renal denervation include glucose control, cardiovascular protective effect, reduction of obstructive sleep apnea, and neuralgia control. A subset of patients with satisfactory blood pressure control response to the procedure may experience improved glucose control due to the overall reduced sympathetic activity and insulin resistance. Sympathetic activity control after renal denervation has cardioprotective effects, especially for those with arrhythmia and left ventricular hypertrophy. Also, renal denervation could be helpful in renalorigin pain control. Renal denervation is an effective, safe, non-invasive procedure with many clinical benefits beyond blood pressure control. Further development in the procedure technique and selection of target patients are needed for wider clinical use of renal denervation in resistant hypertension.

Renal denervation: a key approach to hypertension and cardiovascular disease.

Sympathetic activation plays a critical role in the development of hypertension and cardiovascular disease, including heart failure and arrhythmias. Renal nerves contribute to the regulation of blood pressure and fluid volume through renal sympathetic efferent nerves, and to the modulation of sympathetic outflow through renal sensory afferent nerves. Previous studies including ours suggest that selective afferent renal denervation with preservation of efferent renal nerves can significantly decrease central sympathetic outflow in animal models of hypertension with renal damage. In Dahl salt-sensitive rats fed high salt diet from an early age, a model of hypertensive heart failure, this central sympathoinhibition by afferent renal denervation may attenuate the development of heart failure without significant blood pressure reduction. Accumulating clinical evidence supports the efficacy of renal denervation as an antihypertensive treatment. However, it remains important to clarify the appropriate indications and predictors of responders to renal denervation in the treatment of hypertension. Several clinical studies suggest beneficial effects of renal denervation in patients with heart disease, with or without hypertension, although most were not sham-controlled. In particular, some clinical studies have demonstrated that renal denervation reduces the incidence of atrial fibrillation or cardiovascular events even without a significant antihypertensive effect. It is essential to accumulate more insightful data in patients undergoing renal denervation, to establish the efficacy of renal denervation in patients with cardiovascular disease in the clinical setting, and to elucidate the therapeutic mechanisms of renal denervation and the renal nerves-linked pathophysiology of cardiovascular disease in basic research. This review outlines the effects of renal denervation on sympathetic activity and organ damage in animal models of hypertension and hypertensive heart failure, including our own data. Beyond the antihypertensive effects, the beneficial effects of renal denervation on cardiovascular disease are also discussed based on clinical studies. Several animal and clinical studies suggest the cardioprotective effects of renal denervation even in the absence of significant blood pressure reduction, probably due to its sympathoinhibitory effects.

Consensus Statement on Renal Denervation by the Joint Committee of Japanese Society of Hypertension (JSH), Japanese Association of Cardiovascular Intervention and Therapeutics (CVIT), and the Japanese Circulation Society (JCS).

This is the first consensus statement of the Joint Committee on Renal Denervation of the Japanese Society of Hypertension (JSH)/Japanese Association of Cardiovascular Intervention and Therapeutics (CVIT)/Japanese Circulation Society (JCS). The consensus is that the indication for renal denervation (RDN) is resistant hypertension or "conditioned" uncontrolled hypertension, with high office and out-of-office blood pressure (BP) readings despite appropriate lifestyle modification and antihypertensive drug therapy. "Conditioned" uncontrolled hypertension is defined as having one of the following: 1) inability to up-titrate antihypertensive medication due to side effects, the presence of complications, or reduced quality of life. This includes patients who are intolerant of antihypertensive drugs; or 2) comorbidity at high cardiovascular risk due to increased sympathetic nerve activity, such as orthostatic hypertension, morning hypertension, nocturnal hypertension, or sleep apnea (unable to use continuous positive airway pressure), atrial fibrillation, ventricular arrythmia, or heart failure. RDN should be performed by the multidisciplinary Hypertension Renal Denervation Treatment (HRT) team, led by specialists in hypertension, cardiovascular intervention and cardiology, in specialized centers validated by JSH, CVIT, and JCS. The HRT team reviews lifestyle modifications and medication, and the patient profile, then determines the presence of an indication of RDN based on shared decision making with each patient. Once approval for real-world clinical use in Japan, however, the joint RDN committee will update the indication and treatment implementation guidance as appropriate (annually if necessary) based on future real-world evidence.