Efficacy and safety of sympathetic mapping and ablation of renal nerves for the treatment of hypertension (SMART): 6-month follow-up of a randomised, controlled trial.

Background: Previous trials of renal denervation (RDN) have been designed to investigate reduction of blood pressure (BP) as the primary efficacy endpoint using non-selective RDN without intraoperatively verified RDN success. It is an unmet clinical need to map renal nerves, selectively denervate renal sympathetic nerves, provide readouts for the interventionalists and avoid futile RDN. We aimed to examine the safety and efficacy of renal nerve mapping/selective renal denervation (msRDN) in patients with uncontrolled hypertension (HTN) and determine whether antihypertensive drug burden is reduced while office systolic BP (OSBP) is controlled to target level (＜140 mmHg). Methods: We conducted a randomized, prospective, multicenter, single-blinded, sham-controlled trial. The study combined two efficacy endpoints at 6 months as primary outcomes: The control rate of patients with OSBP ＜140 mmHg (non-inferior outcome) and change in the composite index of antihypertensive drugs (Drug Index) in the treatment versus Sham group (superior outcome). This design avoids confounding from excess drug-taking in the Sham group. Antihypertensive drug burden was assessed by a composite index constructed as: Class N (number of classes of antihypertensive drugs) × (sum of doses). 15 hospitals in China participated in the study and 220 patients were enrolled in a 1:1 ratio (msRDN vs Sham). The key inclusion criteria included: age (18-65 years old), history of essential HTN (at least 6 months), heart rate (≥70 bpm), OSBP (≥150 mmHg and ≤180 mmHg), ambulatory BP monitoring (ABPM, 24-h SBP ≥130 mmHg or daytime SBP ≥135 mmHg or nighttime SBP ≥120 mmHg), renal artery stenosis (＜50%) and renal function (eGFR ＞45 mL/min/1.73 m2). The catheter with both stimulation and ablation functions was inserted in the distal renal main artery. The RDN site (hot spot) was selected if SBP increased (≥5 mmHg) by intra-renal artery (RA) electrical stimulation; an adequate RDN was confirmed by repeated electronic stimulation if no increase in BP otherwise, a 2nd ablation was performed at the same site. At sites where there was decreased SBP (≥5 mmHg, cold spot) or no BP response (neutral spot) to stimulation, no ablation was performed. The mapping, ablation and confirmation procedure was repeated until the entire renal main artery had been tested then either treated or avoided. After msRDN, patients had to follow a predefined, vigorous drug titration regimen in order to achieve target OSBP (＜140 mmHg). Drug adherence was monitored by liquid chromatography-tandem mass spectrometry analysis using urine. This study is registered with ClinicalTrials.gov (NCT02761811) and 5-year follow-up is ongoing. Findings: Between July 8, 2016 and February 23, 2022, 611 patients were consented, 220 patients were enrolled in the study who received standardized antihypertensive drug treatments (at least two drugs) for at least 28 days, presented OSBP ≥150 mmHg and ≤180 mmHg and met all inclusion and exclusion criteria. In left RA and right RA, mapped sites were 8.2 (3.0) and 8.0 (2.7), hot/ablated sites were 3.7 (1.4) and 4.0 (1.6), cold spots were 2.4 (2.6) and 2.0 (2.2), neutral spots were 2.0 (2.1) and 2.0 (2.1), respectively. Hot, cold and neutral spots was 48.0%, 27.5% and 24.4% of total mapped sites, respectively. At 6 M, the Control Rate of OSBP was comparable between msRDN and Sham group (95.4% vs 92.8%, p = 0.429), achieved non-inferiority margin -10% (2.69%; 95% CI -4.11%, 9.83%, p ＜ 0.001 for non-inferiority); the change in Drug Index was significantly lower in msRDN group compared to Sham group (4.37 (6.65) vs 7.61 (10.31), p = 0.010) and superior to Sham group (-3.25; 95% CI -5.56, -0.94, p = 0.003), indicating msRDN patients need significantly fewer drugs to control OSBP ＜140 mmHg. 24-hour ambulatory SBP decreased from 146.8 (13.9) mmHg by 10.8 (14.1) mmHg, and from 149.8 (12.8) mmHg by 10.0 (14.0) mmHg in msRDN and Sham groups, respectively (p < 0.001 from Baseline; p > 0.05 between groups). Safety profiles were comparable between msRDN and Sham groups, demonstrating the safety and efficacy of renal mapping/selective RDN to treat uncontrolled HTN. Interpretation: The msRDN therapy achieved the goals of reducing the drug burden of HTN patients and controlling OSBP <140 mmHg, with only approximately four targeted ablations per renal main artery, much lower than in previous trials. Funding: SyMap Medical (Suzhou), LTD, Suzhou, China.

Extracardiac Abnormalities of Preload Reserve: Mechanisms Underlying Exercise Limitation in Heart Failure with Preserved Ejection Fraction, Autonomic Dysfunction, and Liver Disease.

While many of the cardiac limitations to exercise performance are now well-characterized, extracardiac limitations to exercise performance have been less well recognized but are nevertheless important. We propose that abnormalities of cardiac preload reserve represents an under-recognized but common cause of exercise limitations. We further propose that mechanistic links exist between conditions as seemingly disparate as heart failure with preserved ejection fraction, nonalcoholic fatty liver disease, and pelvic venous compression/obstruction syndromes (eg, May-Thurner). We conclude that extracardiac abnormalities of preload reserve serve as a major pathophysiologic mechanism underlying these and other disease states.

Interventional procedures and future drug therapy for hypertension.

Hypertension management poses a major challenge to clinicians globally once non-drug (lifestyle) measures have failed to control blood pressure (BP). Although drug treatment strategies to lower BP are well described, poor control rates of hypertension, even in the first world, suggest that more needs to be done to surmount the problem. A major issue is non-adherence to antihypertensive drugs, which is caused in part by drug intolerance due to side effects. More effective antihypertensive drugs are therefore required which have excellent tolerability and safety profiles in addition to being efficacious. For those patients who either do not tolerate or wish to take medication for hypertension or in whom BP control is not attained despite multiple antihypertensives, a novel class of interventional procedures to manage hypertension has emerged. While most of these target various aspects of the sympathetic nervous system regulation of BP, an additional procedure is now available, which addresses mechanical aspects of the circulation. Most of these new devices are supported by early and encouraging evidence for both safety and efficacy, although it is clear that more rigorous randomized controlled trial data will be essential before any of the technologies can be adopted as a standard of care.

The ROX coupler: creation of a fixed iliac arteriovenous anastomosis for the treatment of uncontrolled systemic arterial hypertension, exploiting the physical properties of the arterial vasculature.

OBJECTIVES: Uncontrolled hypertension, whether due to drug resistance or poor adherence and persistence, remains a problem in many patients. The ROX coupler is a novel technology designed to reduce arterial blood pressure consequent to the predicted physical effects of reducing vascular resistance and improving arterial compliance. This article describes the technical aspects of the device and implantation procedure, results from a preclinical study, patient selection criteria, and potential complications of this therapy for uncontrolled hypertension. BACKGROUND: The coupler is a self-expanding, stent-like device that exploits the mechanical effects of the creation of a low-resistance, high-compliance venous segment to the central arterial tree, and can be implanted in a standard catheterization laboratory under fluoroscopic guidance. METHODS: Preclinical studies were conducted in sheep with acute or chronic hypertension. The devices were implanted in the aorta for up to 12 months. The anastomoses were evaluated for patency, healing, conformation into the artery and vein, and complications. RESULTS: Deployment of the anastomotic device in ovine aortas for up to 12 months showed optimal anastomotic patency in all animals with proper healing and conformation of the device into the artery and the vein. There was no significant residual mural thrombus and minimal to moderate intimal thickening at the vein outflow, consistent with expected arterialization. CONCLUSIONS: A novel arteriovenous coupler for percutaneous placement in the iliac vasculature is under clinical investigation as a potential treatment modality for selected patients with uncontrolled hypertension. Initial results from patients with uncontrolled hypertension are expected in Autumn 2014.

Renal denervation: a potential new treatment modality for polycystic ovary syndrome?

OBJECTIVE: Polycystic ovary syndrome (PCOS) is associated with sympathetic nervous system activation, insulin resistance, and blood pressure elevation. Renal nerve ablation has been demonstrated to reduce sympathetic outflow and improve blood pressure control. Here we report on the effects of renal denervation on hemodynamic, metabolic, and renal parameters in two obese PCOS patients with hypertension. METHODS: Sympathetic nerve activity was assessed at baseline using microneurography and norepinephrine spillover measurements. Insulin sensitivity was assessed by euglycemic hyperinsulinemic clamp. Measurements of cystatin-C, creatinine clearance, and urinary albumin-creatinine ratio were also obtained. All measurements were repeated 3 months after bilateral renal denervation achieved via percutaneous endovascular radiofrequency ablation. RESULTS: Muscle sympathetic nerve activity and whole body norepinephrine spillover were substantially elevated at baseline in both patients by approximately 2.5-3-fold. Bilateral renal nerve ablation reduced both indices of sympathetic nerve activity. This was associated with moderate reductions in blood pressure and a substantial improvement in insulin sensitivity by approximately 17.5% in the absence of weight changes at 3-month follow-up. Glomerular hyperfiltration and urinary albumin excretion were also reduced. CONCLUSION: These findings corroborate the relevance of sympathetic activation in PCOS and suggest that renal denervation exerts beneficial effects not only on blood pressure control but also on insulin sensitivity, renal, and endocrine abnormalities characteristic of PCOS.