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Background: Single-pill combinations of 3 or more low-dose blood pressure (BP)-lowering drugs hold promise for initial or early treatment of hypertension., Objectives: We conducted a placebo-controlled trial of a new single-pill combination containing low doses of telmisartan, amlodipine, and indapamide in 2 dose options to assess efficacy and safety., Methods: This international, randomized, double-blind, placebo-controlled, parallel-group trial enrolled adults with hypertension receiving 0 to 1 BP-lowering drugs. After a 2-week placebo run-in during which any BP-lowering medication was stopped, participants were eligible if home systolic BP (SBP) was 130 to 154 mm Hg. Participants were randomized in a 2:2:1 ratio to GMRx2 ¼ dose (telmisartan 10 mg/amlodipine 1.25 mg/indapamide 0.625 mg), GMRx2 ½ dose (telmisartan 20 mg/amlodipine 2.5 mg/indapamide 1.25 mg), or placebo. The primary efficacy outcome was difference in change in home SBP from randomization to week 4, and primary safety outcome was treatment discontinuation due to an adverse event., Results: From June 14, 2021 to October 18, 2023, a total of 295 participants (mean age: 51 years; 56% female) were randomized and 96% completed the trial. Baseline mean home BP was 139/86 mm Hg and clinic BP was 138/86 mm Hg after placebo run-in. The placebo-corrected least square mean differences in home SBP at Week 4 were -7.3 mm Hg (95% CI: -4.5 to -10.2) for GMRx2 ¼ dose and -8.2 mm Hg (95% CI: -5.2 to -11.3) for GMRx2 ½ dose; reductions for clinic BP were 8.0/4.0 and 9.5/4.9 mm Hg. At Week 4, clinic BP control (<140/90 mm Hg) was 37%, 65%, and 70% for placebo, GMRx2 ¼ dose, and GMRx2 ½ dose, respectively (both doses P < 0.001 vs placebo). Placebo, GMRx2-triple ¼, and GMRx2 ½ treatment discontinuation due to an adverse event occurred in 1 (1.6%), 0, and 6 (5.1%), respectively; out of normal range serum sodium or potassium was observed in 4 (6.3%), 12 (10.6%), and 12 (10.1%), respectively, but no participant had a serum sodium <130/>150 mmol/L or potassium <3.0/>6.0 mmol/L. Serious adverse events were reported by 2 participants in the placebo and GMRx2 ½ groups and none in the GMRx2 ¼ group., Conclusions: In a population with mild-to-moderate BP elevation, both dose versions of the novel low-dose triple single-pill combination showed good tolerability and clinically relevant BP reductions compared with placebo. (Efficacy and Safety of GRMx2 Compared to Placebo for the Treatment of Hypertension: NCT04518306)., Competing Interests: Funding Support and Author Disclosures This trial was funded by George Medicines Pty Ltd (GM). The trial was designed by The Steering Committee, who were responsible for the study protocol. The funder of the study consulted with the U.S. Food and Drug Administration to ensure the trial design was suitable to inform an application for regulatory approval; the funder GM provided comments on a draft of the publication. The Steering Committee had full access to all the data, wrote and had final responsibility for the publication. Prof Rodgers, Dr Salam, Prof Schutte, C. ianacas, M. Shanthakumar, Dr Liu, and Dr Wang are employed at The George Institute for Global Health (TGI), which holds an interest in GM via its social enterprise arm, George Institute Ventures. None of the TGI staff have any personal financial interest in GM. Prof Rodgers is seconded part-time to GM. TGI holds patents for ultra -low-dose fixed-dose combination products for the treatment of hypertension and diabetes, and Prof Rodgers is listed as one of the inventors (granted: U.S. 10,369,156; U.S. 10,799,487; U.S. 10,322,117; U.S. 11,033,544; U.S. 11,478,462; pending: U.S. 17/932,982; U.S. 18/446,268; U.S. 17/ 598,122; U.S. 17/317,614; U.S. 17/527,084; U.S. 17/527,085; U.S. 17/ 527,087). Prof Rodgers does not have a financial interest in these patents. None of the other authors have a financial interest in GM or have received funding for their independent contribution to the GMRx2 program. Dr Schutte has received consulting fees and/or speaker honoraria from Omron Healthcare, Aktiia, Medtronic, Servier, Abbott, Sanofi, Sun Pharmaceuticals, Novartis, and Skylabs; is co-chair of the National Hypertension Taskforce of Australia; is a board member of Hypertension Australia, and Australian Cardiovascular Alliance; and is supported by an investigator grant from the National Health and Medical Research Council of Australia (GNT 2017504). Dr Ojji has received speaker honoraria from Novartis, AstraZeneca, Servier, Swipha, and Boehringer Ingelheim for speaking at educational meetings. Dr Narkiewicz has received speaker and consulting honoraria from Bausch Health, Berlin-Chemie/Menarini, Egis, Gedeon Richter, Gilead, Idorsia, Janssen, Krka, Novo Nordisk, Polpharma, Recordati, Sandoz, Servier, and Zentiva. Dr Schlaich has received consulting fees, and/or travel fees and research support from Medtronic, Abbott, ReCor, Novartis, Servier, Pfizer, and Boehringer Ingelheim; and is the current president of Hypertension Australia and Treasurer of the World Hypertension League. Dr Cushman has received institutional grants from Recor Medical and George Medicines; and has received consulting fees from Alnylam Pharmaceuticals. Dr Poulter has received financial support from several pharmaceutical companies that manufacture BP-lowering agents; has received consultancy fees from Servier and Aktiia; has received consultancy fees for research projects and staff from Servier and Pfizer; has received consultancy fees for arranging and speaking at educational meetings from AstraZeneca, Lri Therapharma, Napi, Servier, Sanofi, Eva Pharma, Pfizer, Emcure India, Dr Reddy's Laboratories, and Zydus; and has received support from the National Institute for Health Research Senior Investigator Awards, Biomedical Research Centre funding, and the British Heart Foundation Research Centre Excellence Award. Dr Wright has received support from NIH, Ohio Department of Medicaid, Agency for Health Care Research and Quality, Medtronic, Inc, and the Northeast Ohio Neighborhood Health Center Community Board of Directors. Dr Grobbee receives funding to his department as part of the EU Horizon Hypermarker project. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Renal denervation (RDN) reduces blood pressure (BP) in patients with uncontrolled hypertension in the absence of antihypertensive medications., Objectives: This trial assessed the safety and efficacy of RDN in the presence of antihypertensive medications., Methods: SPYRAL HTN-ON MED is a prospective, randomized, sham-controlled, patient- and assessor-blinded trial enrolling patients from 56 clinical centers worldwide. Patients were prescribed 1 to 3 antihypertensive medications. Patients were randomized to radiofrequency RDN or sham control procedure. The primary efficacy endpoint was the baseline-adjusted change in mean 24-hour ambulatory systolic BP at 6 months between groups using a Bayesian trial design and analysis., Results: The treatment difference in the mean 24-hour ambulatory systolic BP from baseline to 6 months between the RDN group (n = 206; -6.5 ± 10.7 mm Hg) and sham control group (n = 131; -4.5 ± 10.3 mm Hg) was -1.9 mm Hg (95% CI: -4.4 to 0.5 mm Hg; P = 0.12). There was no significant difference between groups in the primary efficacy analysis with a posterior probability of superiority of 0.51 (Bayesian treatment difference: -0.03 mm Hg [95% CI: -2.82 to 2.77 mm Hg]). However, there were changes and increases in medication intensity among sham control patients. RDN was associated with a reduction in office systolic BP compared with sham control at 6 months (adjusted treatment difference: -4.9 mm Hg; P = 0.0015). Night-time BP reductions and win ratio analysis also favored RDN. There was 1 adverse safety event among 253 assessed patients., Conclusions: There was no significant difference between groups in the primary analysis. However, multiple secondary endpoint analyses favored RDN over sham control. (SPYRAL HTN-ON MED Study [Global Clinical Study of Renal Denervation With the Symplicity Spyral Multi-electrode Renal Denervation System in Patients With Uncontrolled Hypertension in the Absence of Antihypertensive Medications]; NCT02439775)., Competing Interests: Funding Support and Author Disclosures This study was funded by Medtronic. Dr Kandzari has received institutional research/grant support from Biotronik, Boston Scientific, Cardiovascular Systems, Inc, Orbus Neich, Teleflex, Medtronic, and Ablative Solutions; and has received personal consulting honoraria from Cardiovascular Systems, Inc, Medtronic, and Abbott Vascular. Dr Townsend is a consultant for Medtronic, Cytel, and Janssen. Dr Kario has received personal fees from Medtronic during the conduct of the study; has received grants from A&D Company, Omron Healthcare, Fukuda Denshi, CureApp, Sanwa Kagaku Kenkyusho, Teijin Pharma, Boehringer Ingelheim Japan, and Fukuda Lifetec; has received consulting fees from A&D Company, JIMRO, Omron Healthcare, CureApp, Terumo, and Fukuda Denshi; has received honoraria from Otsuka Pharmaceuticals and Omron Healthcare; and has participated on the Advisory Board of Fukuda Denshi, outside of the submitted work. Dr Mahfoud is supported by Deutsche Gesellschaft für Kardiologie (DGK), Deutsche Forschungsgemeinschaft (SFB TRR219), and Deutsche Herzstiftung; has received scientific support from Ablative Solutions, Medtronic, and ReCor Medical; and has received speaker honoraria/consulting fees from Ablative Solutions, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Inari, Medtronic, Merck, ReCor Medical, Servier, and Terumo. Dr Weber has received consulting fees from Medtronic, ReCor, Ablative Solutions, Johnson and Johnson, and Urovant. Dr Schmieder has received grants and personal fees from Medtronic, Recor, and Ablative Solutions. Dr Pocock has received personal fees from Medtronic outside of the submitted work. Dr Tsioufis has received institutional research/grant support from Medtronic and ReCor Medical; and has received personal consulting honoraria from AstraZeneca, Bayer, Boehringer Ingelheim, Medtronic, ReCor Medical, SERVIER, WinMedica, and ELPEN. Dr Konstantinidis receives payments from Medtronic for work as research center secondary investigator. Dr Choi has received consulting fees from Medtronic, outside of the submitted work. Dr East has received consulting fees from Medtronic. Dr Lauder has received speaker fees and honoraria from Medtronic and ReCor Medical. Dr Cohen has received research support and consultant fees from Medtronic and ReCor; and receives fees from Metavention, outside of the submitted work. Dr Kobayashi is on the advisory board and Speakers Bureau for Medtronic and ReCor Medical. Dr Lee has received grants from and serves on the advisory board for Medtronic, outside of the submitted work. Dr Weil has received support from Medtronic, Recor Medical, Novartis, and AstraZeneca. Dr Agdirlioglu receives speaker honoraria from AstraZeneca, Boehringer Ingelheim, and Novartis, outside of the submitted work. Dr Schlaich has received consulting fees and/or travel and research support from Medtronic, Abbott, Novartis, Servier, Pfizer, and Boehringer Ingelheim. Dr Shetty has received consulting and speaker fees from Medtronic. Dr Devireddy has received personal fees from Edwards Lifesciences, Medtronic, ReCor Medical, and Shockwave Medical, outside of the submitted work. Dr Sharp has received personal fees from Medtronic, Boston Scientific, Recor Medical, and Philips, outside the submitted work. Dr Anderson has received speaker fees from Shockwave Medical, Edwards Lifesciences, and Medtronic. Mr Fahy, Mrs DeBruin, and Dr Brar are employees of Medtronic. Dr Böhm is supported by the Deutsche Forschungsgemeinschaft (German Research Foundation; TTR 219, project number 322900939); and has received personal fees from Abbott, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Medtronic, Novartis, ReCor, Servier, and Vifor during the conduct of the study. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Three recent renal denervation studies in both drug-naïve and drug-treated hypertensive patients demonstrated a significant reduction of ambulatory blood pressure compared with respective sham control groups. Improved trial design, selection of relevant patient cohorts, and optimized interventional procedures have likely contributed to these positive findings. However, substantial variability in the blood pressure response to renal denervation can still be observed and remains a challenging and important problem. The International Sympathetic Nervous System Summit was convened to bring together experts in both experimental and clinical medicine to discuss the current evidence base, novel developments in our understanding of neural interplay, procedural aspects, monitoring of technical success, and others. Identification of relevant trends in the field and initiation of tailored and combined experimental and clinical research efforts will help to address remaining questions and provide much-needed evidence to guide clinical use of renal denervation for hypertension treatment and other potential indications., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Clinical trials applying catheter-based radiofrequency renal denervation (RDN) demonstrated a favorable safety profile with minimal acute or procedural adverse events. Whether ablation of renal nerves adversely affects compensatory responses to hemodynamic challenge has not been extensively investigated., Objectives: The aim of this study was to examine the effect of RDN on mean arterial pressure, renal function, and the reflex response to hemorrhage in sheep with normotension (control) or with hypertensive chronic kidney disease (CKD)., Methods: Sheep underwent RDN (control-RDN, n = 8; CKD-RDN, n = 7) or sham procedures (control-intact, n = 6; CKD-intact, n = 7). Response to hemorrhage (20% loss of blood volume), including plasma renin activity, was assessed at 2 and 5 months post-procedure., Results: RDN caused a complete reversal of hypertension and improved renal function in CKD-RDN sheep (p < 0.0001 for 2 and 5 months vs. pre-RDN). In response to hemorrhage, mean arterial pressure fell in all groups, with the fall being greater in the RDN than the intact group (2-month fall in mean arterial pressure: control-intact, -10 ± 1 mm Hg; control-RDN, -15 ± 1 mm Hg; p < 0.05; CKD-intact, -11 ± 3 mm Hg; CKD-RDN, -19 ± 9 mm Hg; p < 0.001). Hemorrhage increased heart rate and plasma renin activity in intact sheep, but these responses were significantly attenuated in control-RDN and CKD-RDN animals. Responses to hemorrhage were remarkably similar at 2 and 5 months post-RDN, which suggests that nerve function had not returned within this time frame., Conclusions: In hypertensive CKD sheep, RDN reduced blood pressure and improved basal renal function but markedly compromised compensatory hemodynamic responses to hemorrhage. Therefore, the capacity to respond to a physiological challenge to body fluid homeostasis may be compromised following RDN., (Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Catheter-based radiofrequency ablation technology to disrupt both efferent and afferent renal nerves has recently been introduced to clinical medicine after the demonstration of significant systolic and diastolic blood pressure reductions. Clinical trial data available thus far have been obtained primarily in patients with resistant hypertension, defined as standardized systolic clinic blood pressure ≥ 160 mm Hg (or ≥ 150 mm Hg in patients with type 2 diabetes) despite appropriate pharmacologic treatment with at least 3 antihypertensive drugs, including a diuretic agent. Accordingly, these criteria and blood pressure thresholds should be borne in mind when selecting patients for renal nerve ablation. Secondary forms of hypertension and pseudoresistance, such as nonadherence to medication, intolerance of medication, and white coat hypertension, should have been ruled out, and 24-h ambulatory blood pressure monitoring is mandatory in this context. Because there are theoretical concerns with regard to renal safety, selected patients should have preserved renal function, with an estimated glomerular filtration rate ≥ 45 ml/min/1.73 m(2). Optimal periprocedural management of volume status and medication regimens at specialized and experienced centers equipped with adequate infrastructure to cope with potential procedural complications will minimize potential patient risks. Long-term safety and efficacy data are limited to 3 years of follow-up in small patient cohorts, so efforts to monitor treated patients are crucial to define the long-term performance of the procedure. Although renal nerve ablation could have beneficial effects in other conditions characterized by elevated renal sympathetic nerve activity, its potential use for such indications should currently be limited to formal research studies of its safety and efficacy., (Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: We investigated whether improvement of endothelial dysfunction in hypercholesterolemia can be achieved with short-term lipid-lowering therapy., Background: Impaired endothelium-dependent vasodilation plays a pivotal role in the pathogenesis of atherosclerosis and acute coronary syndromes., Methods: In a randomized, double-blind, placebo-controlled trial, we studied 37 patients (52 +/- 11 yrs) with low density lipoprotein cholesterol > or = 160 mg/dl (196 +/- 44 mg/dl) randomly assigned to either cerivastatin (0.4 mg/d) or placebo. Endothelium-dependent vasodilation of the forearm vasculature was measured by plethysmography and intra-arterial infusion of acetylcholine (ACh 12, 48 microg/min) and endothelium-independent vasodilation by intra-arterial infusion of nitroprusside (3.2, 12.8 microg/min)., Results: Low density lipoprotein cholesterol decreased after two weeks of treatment (cerivastatin -33 +/- 4% vs. placebo + 2 +/- 4%, x +/- SEM, p < 0.001). Endothelium-dependent vasodilation improved after two weeks of therapy with cerivastatin compared with baseline (ACh 12 microg/min: + 22.3 +/- 5.2 vs. + 11.2 +/- 1.9 ml/min/100 ml, p < 0.01; ACh 48 microg/min: +31.2 +/- 6.3 vs. +19.1 +/- 3.1 ml/min/100 ml, p < 0.05). In contrast, changes in forearm blood flow to ACh were similar before and after therapy in the placebo group (ACh 12 microg/min: + 12.9 +/- 3.6 vs. + 9.0 +/- 1.9 ml/min/100 ml, NS; ACh 48 microg/min: +20.7 +/- 3.7 vs. 19.4 +/- 2.9 ml/min/100 ml, NS). Endothelium-dependent vasodilation improved in comparison with placebo (ACh 48 microg/min: +203 +/- 85% [cerivastatin] vs. -26 +/- 71% [placebo], p < 0.05). This improvement in endothelium-dependent vasodilation was no longer observed when the nitric oxide-synthase inhibitor N(G)-monomethyl-L-arginine was coinfused (ACh 48 microg/min + N(G)-monomethyl-L-arginine 4 micromol/min -48 +/- 85% [cerivastatin])., Conclusions: Short-term lipid-lowering therapy with cerivastatin can improve endothelial function and NO bioavailability after two weeks in patients with hypercholesterolemia.

Objectives: This study was undertaken to test the hypothesis that lipoprotein(a) [Lp(a)] impairs endothelial function., Background: Elevated Lp(a) plasma levels have been demonstrated to be associated with an increased risk of coronary heart disease. In atherosclerosis, endothelial dysfunction is known to be an early indicator of vascular changes. However, the effect of Lp(a) on nitric oxide (NO)-dependent vasodilator response has not yet been determined. We therefore examined the influence of Lp(a) on basal and stimulated NO-mediated vasodilator response in the forearm vascular bed., Methods: Strain gauge plethysmography was used to measure changes in forearm blood flow produced by intraarterial infusion of increasing doses of acetylcholine (3, 12, 24 and 48 microg/min), sodium nitroprusside (200, 800 and 3,200 ng/min) and N-monomethyl L-arginine (L-NMMA) (1, 2 and 4 micromol/min) in 57 white subjects (mean age +/- SD 37 +/- 14 years). Lp(a) plasma concentrations were determined by rocket immunoelectrophoresis., Results: Endothelium-dependent vasodilation tested by intraarterial acetylcholine and endothelium-independent vascular relaxation tested by intraarterial sodium nitroprusside were not correlated with Lp(a). Similarly, no significant differences in forearm blood flow changes were observed when patients were classified into tertiles according to their individual Lp(a) concentration. In contrast, changes in forearm blood flow after intraarterial L-NMMA indicating basal production and release of NO differed significantly among tertiles. Patients in the highest Lp(a) tertile (49.2 +/- 20.3 mg/dl) had a much greater vasoconstrictive response to L-NMMA than patients in the lowest Lp(a) tertile (4.8 +/- 2.5 mg/dl): 2 micromol/min of L-NMMA, -23.6 +/- 22.5% vs. -10.4 +/- 9.1% (p < 0.02); 4 micromol/min of L-NMMA, -27.8 +/- 10.3% vs. -17.6 +/- 9.9% (p < 0.03). Lp(a) plasma level consistently correlated negatively with the forearm blood flow responses to 4 micromol/min of intraarterial L-NMMA (r = -0.38, p < 0.01). Multiple stepwise regression analysis of variables, including total and high and low density lipoprotein cholesterol, further confirmed that plasma Lp(a) remained a significant independent determinant of forearm blood flow changes in response to L-NMMA (p < 0.02)., Conclusions: The endothelium-dependent vasoconstrictive response to L-NMMA was enhanced in subjects with relatively high Lp(a) plasma levels, suggesting an increased basal production and release of NO. This response seemed to reflect a compensatory mechanism of the endothelium to yet unknown Lp(a)-induced atherosclerotic effects.