Efficacy and Safety of Aficamten in Symptomatic Nonobstructive Hypertrophic Cardiomyopathy: Results From the REDWOOD-HCM Trial, Cohort 4.

BACKGROUND: This open-label phase 2 trial evaluated the safety and efficacy of aficamten in patients with nonobstructive hypertrophic cardiomyopathy (nHCM). METHODS: Patients with symptomatic nHCM (left ventricular outflow tract obstruction gradient ≤ 30 mmHg, left ventricular ejection fraction [LVEF] ≥ 60%, N-terminal pro-B-type natriuretic peptide [NT-proBNP] > 300 pg/mL) received aficamten 5-15 mg once daily (doses adjusted according to echocardiographic LVEF) for 10 weeks. RESULTS: We enrolled 41 patients (mean ± SD age 56 ± 16 years; 59% female). At Week 10, 22 (55%) patients experienced an improvement of ≥ 1 New York Heart Association class; 11 (29%) became asymptomatic. Clinically relevant improvements in Kansas City Cardiomyopathy Questionnaire Clinical Summary Scores occurred in 22 (55%) patients. Symptom relief was paralleled by reductions in NT-proBNP levels (56%; P < 0.001) and high-sensitivity cardiac troponin I (22%; P < 0.005). Modest reductions in LVEF (mean ± SD) of -5.4% ± 10 to 64.6% ± 9.1 were observed. Three (8%) patients had asymptomatic reduction in LVEF < 50% (range: 41%-48%), all returning to normal after 2 weeks of washout. One patient with prior history of aborted sudden cardiac death experienced a fatal arrhythmia during the study. CONCLUSIONS: Aficamten administration for symptomatic nHCM was generally safe and was associated with improvements in heart failure symptoms and cardiac biomarkers. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04219826.

Effects of pericardiocentesis on renal function and cardiac hemodynamics.

BACKGROUND: Previous case studies have reported reversal of acute renal failure after pericardiocentesis in pericardial effusion. This study examines the effects of pericardiocentesis on preprocedural low cardiac output and acute renal dysfunction in patients with pericardial effusion. METHODS: This is a retrospective study of 95 patients undergoing pericardiocentesis between 2015 and 2020. Pre- and post-procedure transthoracic echocardiograms (TTE) were reviewed for evidence of cardiac tamponade, resolution of pericardial effusion, and for estimation of right atrial (RA) pressure and cardiac output. Laboratory values were compared at presentation and post-procedure. Patients on active renal replacement therapy were excluded. RESULTS: Ninety-five patients were included for analysis (mean age 62.2 ± 17.8 years, 58% male). There was a significant increase in glomerular filtration rate pre- and post-procedure. Fifty-six patients (58.9%) had an improvement in glomerular filtration rate after pericardiocentesis (termed "responders"), and these patients had a lower pre-procedure glomerular filtration rate than "non-responders." There was a significant improvement in estimated cardiac output and right atrial pressure for patients in both groups. Patients who had an improvement in renal function had significantly lower pre-procedural diastolic blood pressure and mean arterial pressure. CONCLUSIONS: Pericardial drainage may improve effusion-mediated acute renal dysfunction by reducing right atrial pressure and thus systemic venous congestion, and by increasing forward stroke volume and perfusion pressure.

Mavacamten Treatment for Symptomatic Obstructive Hypertrophic Cardiomyopathy: Interim Results From the MAVA-LTE Study, EXPLORER-LTE Cohort.

BACKGROUND: Data assessing the long-term safety and efficacy of mavacamten treatment for symptomatic obstructive hypertrophic cardiomyopathy are needed. OBJECTIVES: The authors sought to evaluate interim results from the EXPLORER-Long Term Extension (LTE) cohort of MAVA-LTE (A Long-Term Safety Extension Study of Mavacamten in Adults Who Have Completed EXPLORER-HCM; NCT03723655). METHODS: After mavacamten or placebo withdrawal at the end of the parent EXPLORER-HCM (Clinical Study to Evaluate Mavacamten [MYK-461] in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy; NCT03470545), patients could enroll in MAVA-LTE. Patients received mavacamten 5 mg once daily; adjustments were made based on site-read echocardiograms. RESULTS: Between April 9, 2019, and March 5, 2021, 231 of 244 eligible patients (94.7%) enrolled in MAVA-LTE (mean age: 60 years; 39% female). At data cutoff (August 31, 2021) 217 (93.9%) remained on treatment (median time in study: 62.3 weeks; range: 0.3-123.9 weeks). At 48 weeks, patients showed improvements in left ventricular outflow tract (LVOT) gradients (mean change ± SD from baseline: resting: -35.6 ± 32.6 mm Hg; Valsalva: -45.3 ± 35.9 mm Hg), N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels (median: -480 ng/L; Q1-Q3: -1,104 to -179 ng/L), and NYHA functional class (67.5% improved by ≥1 class). LVOT gradients and NT-proBNP reductions were sustained through 84 weeks in patients who reached this timepoint. Over 315 patient-years of exposure, 8 patients experienced an adverse event of cardiac failure, and 21 patients had an adverse event of atrial fibrillation, including 11 with no prior history of atrial fibrillation. Twelve patients (5.2%) developed transient reductions in site-read echocardiogram left ventricular ejection fraction of <50%, resulting in temporary treatment interruption; all recovered. Ten patients discontinued treatment due to treatment-emergent adverse events. CONCLUSIONS: Mavacamten treatment showed clinically important and durable improvements in LVOT gradients, NT-proBNP levels, and NYHA functional class, consistent with EXPLORER-HCM. Mavacamten treatment was well tolerated over a median 62-week follow-up.

Diverse biological functions of the renin-angiotensin system.

The renin-angiotensin system (RAS) has been widely known as a circulating endocrine system involved in the control of blood pressure. However, components of RAS have been found to be localized in rather unexpected sites in the body including the kidneys, brain, bone marrow, immune cells, and reproductive system. These discoveries have led to steady, growing evidence of the existence of independent tissue RAS specific to several parts of the body. It is important to understand how RAS regulates these systems for a variety of reasons: It gives a better overall picture of human physiology, helps to understand and mitigate the unintended consequences of RAS-inhibiting or activating drugs, and sets the stage for potential new therapies for a variety of ailments. This review fulfills the need for an updated overview of knowledge about local tissue RAS in several bodily systems, including their components, functions, and medical implications.

Echocardiographic Characteristics of Left and Right Ventricular Longitudinal Function in Patients With a History of Cardiac Surgery.

Previous studies have indicated a reduction in right ventricular (RV) longitudinal motion after cardiac surgery. However, the long-term effect of cardiac surgery on longitudinal motion and the involvement of left ventricular (LV) motion remains unclear. Therefore, this study aimed to comprehensively investigate the longitudinal function of the right ventricle and left ventricle in patients who underwent cardiac surgery. The study included patients who underwent comprehensive transthoracic echocardiography with 3-dimensional RV data sets. By propensity score matching of the clinical and echocardiographic variables, including LV and RV ejection fraction, the echocardiographic parameters were compared between patients with and without a history of cardiac surgery (the surgery and nonsurgery groups, respectively). In this study, the surgery group had significantly lower LV global longitudinal strain values than the nonsurgery group, despite having similar LV ejection fraction. The tricuspid annular plane systolic excursion (TAPSE), tricuspid annular velocity, and RV free wall longitudinal strain were also significantly smaller in the surgery group, whereas the RV ejection fraction was comparable between the 2 groups. In addition, a subgroup analysis based on the time from previous surgery to transthoracic echocardiography (≤1 and >1 year) revealed that TAPSE was reduced in both postoperative phases. In conclusion, LV and RV longitudinal parameters were reduced after cardiac surgery, despite preserved LV and RV global functions. Moreover, TAPSE was reduced even after a long time after cardiac surgery. These findings emphasize the need for careful interpretation of biventricular longitudinal motion in patients with a history of cardiac surgery.

Patient-Level Pooled Analysis of Endovascular Ultrasound Renal Denervation or a Sham Procedure 6 Months After Medication Escalation: The RADIANCE Clinical Trial Program.

BACKGROUND: The randomized, sham-controlled RADIANCE-HTN (A Study of the Recor Medical Paradise System in Clinical Hypertension) SOLO, RADIANCE-HTN TRIO, and RADIANCE II (A Study of the Recor Medical Paradise System in Stage II Hypertension) trials independently met their primary end point of a greater reduction in daytime ambulatory systolic blood pressure (SBP) 2 months after ultrasound renal denervation (uRDN) in patients with hypertension. To characterize the longer-term effectiveness and safety of uRDN versus sham at 6 months, after the blinded addition of antihypertensive treatments (AHTs), we pooled individual patient data across these 3 similarly designed trials. METHODS: Patients with mild to moderate hypertension who were not on AHT or with hypertension resistant to a standardized combination triple AHT were randomized to uRDN (n=293) versus sham (n=213); they were to remain off of added AHT throughout 2 months of follow-up unless specified blood pressure (BP) criteria were exceeded. In each trial, if monthly home BP was ≥135/85 mm Hg from 2 to 5 months, standardized AHT was sequentially added to target home BP <135/85 mm Hg under blinding to initial treatment assignment. Six-month outcomes included baseline- and AHT-adjusted change in daytime ambulatory, home, and office SBP; change in AHT; and safety. Linear mixed regression models using all BP measurements and change in AHT from baseline through 6 months were used. RESULTS: Patients (70% men) were 54.1±9.3 years of age with a baseline daytime ambulatory/home/office SBP of 150.5±9.8/151.0±12.4/155.5±14.4 mm Hg, respectively. From 2 to 6 months, BP decreased in both groups with AHT titration, but fewer uRDN patients were prescribed AHT (P=0.004), and fewer additional AHT were prescribed to uRDN patients versus sham patients (P=0.001). Whereas the unadjusted between-group difference in daytime ambulatory SBP was similar at 6 months, the baseline and medication-adjusted between-group difference at 6 months was -3.0 mm Hg (95% CI, -5.7, -0.2; P=0.033), in favor of uRDN+AHT. For home and office SBP, the adjusted between-group differences in favor of uRDN+AHT over 6 months were -5.4 mm Hg (-6.8, -4.0; P<0.001) and -5.2 mm Hg (-7.1, -3.3; P<0.001), respectively. There was no heterogeneity between trials. Safety outcomes were few and did not differ between groups. CONCLUSIONS: This individual patient-data analysis of 506 patients included in the RADIANCE trials demonstrates the maintenance of BP-lowering efficacy of uRDN versus sham at 6 months, with fewer added AHTs. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifiers: NCT02649426 and NCT03614260.

Comparison of prognostic value among echocardiographic surrogates of right ventricular-pulmonary arterial coupling: A three-dimensional echocardiographic study.

OBJECTIVES: Right ventricular (RV)-pulmonary arterial (PA) coupling is important in various cardiac diseases. Recently, several echocardiographic surrogates for RV-PA coupling have been proposed and reported to be useful in predicting outcomes. However, it remains unclear which surrogate is the most clinically relevant. This study aimed to comprehensively compare the prognostic value of different echocardiographic RV-PA coupling surrogates. METHODS: We retrospectively reviewed 242 patients with various cardiac conditions who underwent comprehensive transthoracic echocardiography with three-dimensional RV data. In addition to conventional parameters including tricuspid annular plane systolic excursion (TAPSE), fractional area change (FAC), and PA systolic pressure (PASP), we analyzed RV free wall and global longitudinal strain (FWLS and GLS). We also obtained RV ejection fraction (RVEF), stroke volume (SV), and end-systolic volume (ESV) using three-dimensional RV analysis. RV-PA coupling surrogates were calculated as TAPSE/PASP, FAC/PASP, FWLS/PASP, GLS/PASP, RVEF/PASP, and SV/ESV. The study endpoint was a composite outcome of all-cause death or cardiovascular hospitalization within 1 year. RESULTS: In multivariable analysis, all the RV-PA coupling surrogates were independent predictors of the outcome. Among the surrogates, the model with TAPSE/PASP showed the lowest prognostic value in model fit and discrimination ability, whereas the model with RVEF/PASP exhibited the highest prognostic value. The partial likelihood ratio test indicated that the model with RVEF/PASP was significantly better than the model with TAPSE/PASP (p < .024). CONCLUSION: All the RV-PA coupling surrogates were independent predictors of the outcome. Notably, RVEF/PASP had the highest prognostic value among the surrogates.

Impact of eccentric jet on outcomes in patients with atrial functional mitral regurgitation: An echocardiographic study.

BACKGROUND: Previous studies have reported the mechanisms underlying atrial functional mitral regurgitation (A-FMR). Recently, A-FMR subtypes based on mitral regurgitation (MR) mechanisms were proposed: "central jet" due to insufficient leaflet remodeling and "eccentric jet" due to atriogenic tethering. However, their prognostic value remains unclear. Therefore, this study investigated the impact of A-FMR subtypes on clinical outcomes. METHODS: Outpatients with significant A-FMR between January 2013 and December 2016 were retrospectively reviewed. They were classified into two subtypes according to the MR jet's direction. All-cause mortality, heart failure hospitalization, and any mitral valve interventions were the primary composite endpoint. RESULTS: Among 101 patients with significant A-FMR, 32% had eccentric jet. The primary endpoint was observed in 56 patients during the follow-up period (median 0.7 years, range 0.1-4.2 years). Kaplan-Meier curves demonstrated that the composite endpoint was higher among patients with eccentric jet than those with central jet (log-rank p < 0.001). Eccentric jet (hazard ratio [HR] 2.46, 95% confidence interval [CI] 1.28-4.73; p = 0.007), age (HR 1.06, 95% CI 1.02-1.11; p = 0.002), symptoms (HR 6.22, 95% CI 2.18-17.8; p < 0.001), severe MR (HR 3.97, 95% CI 1.92-8.18; p < 0.001), and significant tricuspid regurgitation (TR; HR 2.00, 95% CI 1.01-3.97; p = 0.047) were independent predictors of the composite endpoint. CONCLUSIONS: Patients with eccentric jet had poorer outcomes than those with central jet. Eccentric jet, age, symptoms, severe MR, and significant TR were independently associated with poor outcomes.

Long-Term Safety and Antihypertensive Effects of Renal Denervation: Current Insights.

Hypertension is the most potent modifiable risk factor for the development of cardiovascular morbidity and mortality worldwide. Nevertheless, blood pressure (BP) control on a broad scale appears to be insurmountable and has even worsened in the US. Barriers to sustained hypertension control are multifactorial and although lack of patient awareness and socioeconomic barriers to healthcare access may play a role, medication non-compliance and therapeutic inertia are major causes. Renal denervation (RDN) is a minimally invasive procedure that has been the subject of interest in clinical trials for more than a decade and although the first sham-controlled trial could not detect group difference between treated and untreated hypertensives, subsequent, better designed sham-controlled trials clearly demonstrated the BP lowering effect of RDN, as well as its safety. While to-date, RDN is not available for routine clinical practice, one major requirement for broad implementation is that the BP lowering effect is durable. Therefore, this review will summarize the available long-term data of the different RDN modalities with respect to both effectiveness and safety.

Outcome of Patients With Both Moderate Aortic Stenosis and Moderate Mitral Stenosis.

Aims: This study aimed to investigate the symptoms and prognosis of patients with both moderate aortic stenosis (AS) and mitral stenosis (MS). Methods and Results: We studied 82 patients with moderate AS and MS diagnosed via transthoracic echocardiography. The patients had a mean age of 79 ± 13 years and 95% of patients had degenerative MS. Out of 82 patients, 34 (41%) had heart failure (HF) symptoms (New York Heart Association class ≥ Ⅱ) or a history of HF admission. Left ventricular ejection fraction, stroke volume index, atrial fibrillation, and right ventricular systolic pressure were independent determinants of HF symptoms. The median follow-up duration was 3.2 (interquartile range, 1.0-4.9) years and clinical events occurred in 48 (59%) patients, including death in 11 (13%) patients, aortic or mitral valve interventions in 22 (27%) patients, and HF hospitalization in 15 (18%) patients. The 5-year survival free of the combined endpoint of aortic or mitral valve interventions, HF hospitalization, or death was 19%. A multivariate predictor of clinical events was HF symptoms (hazard ratio [HR], 2.32; 95% confidence interval [CI], 1.30-4.14; p = 0.0045). Kaplan-Meier survival at 5 years was 61% without intervention and HF symptoms were not associated with mortality. Conclusions: Among patients with both moderate AS and MS, left ventricular ejection fraction, stroke volume index, atrial fibrillation, and right ventricular systolic pressure were strong determinants of HF symptoms. HF symptoms were independently predictive of clinical events.

Implication of Right Atrial Pressure Estimated by Echocardiography in Patients with Severe Tricuspid Regurgitation.

BACKGROUND: Little is known about how tightly right atrial pressure (RAP) is associated with prognosis in patients with severe tricuspid regurgitation (TR). The aim of this study was to investigate the association of RAP estimated by echocardiography (RAP-echo) with cardiovascular events in patients with severe TR. METHODS: Two hundred forty outpatients (median age, 75 years; 130 women) who underwent two-dimensional transthoracic echocardiography and were diagnosed with severe TR were retrospectively studied. According to RAP-echo using the diameter of the inferior vena cava and its response to a sniff, patients were classified into two groups: low or middle and high RAP-echo. Cardiovascular events were defined as cardiovascular death and admission for heart failure. RESULTS: During follow-up (median, 428 days; range, 87-1,229 days), 64 patients experienced cardiovascular events. By multivariate analysis, high RAP-echo was independently associated with cardiovascular events (hazard ratio, 2.46; 95% CI, 1.17-5.18). Also, jugular venous distention and leg edema were not independently associated with cardiovascular events. CONCLUSIONS: The significant and stronger association of RAP-echo with clinical outcome compared with estimates of RAP on physical examination suggests that recognition of high RAP-echo can be a valuable surrogate for the clinical management of severe TR patients.

Skin sympathetic nerve activity and nocturnal blood pressure nondipping in patients with postural orthostatic tachycardia syndrome.

OBJECTIVE: Postural orthostatic tachycardia syndrome (POTS) is associated with abnormal blood pressure (BP) regulation and increased prevalence of nocturnal nondipping. We hypothesized that nocturnal nondipping of BP is associated with elevated skin sympathetic nerve activity (SKNA) in POTS. METHOD: We used an ambulatory monitor to record SKNA and electrocardiogram from 79 participants with POTS (36 ±â€Š11 years, 72 women), including 67 with simultaneous 24-h ambulatory BP monitoring. RESULTS: Nocturnal nondipping of BP was present in 19 of 67 (28%) participants. The nondipping group had a higher average SKNA (aSKNA) from midnight of day 1 to 0100 h on day 2 than the dipping group ( P  = 0.016, P  = 0.030, respectively). The differences (Δ) of aSKNA and mean BP between daytime and night-time were more significant in the dipping group compared with the nondipping group (ΔaSKNA 0.160 ±â€Š0.103 vs. 0.095 ±â€Š0.099 µV, P  = 0.021, and Δmean BP 15.0 ±â€Š5.2 vs. 4.9 ±â€Š4.2 mmHg, P  < 0.001, respectively). There were positive correlations between ΔaSKNA and standing norepinephrine (NE) (r = 0.421, P  = 0.013) and the differences between standing and supine NE levels ( r  = 0.411, P  = 0.016). There were 53 (79%) patients with SBP less than 90 mmHg and 61 patients (91%) with DBP less than 60 mmHg. These hypotensive episodes were associated with aSKNA of 0.936 ±â€Š0.081 and 0.936 ±â€Š0.080 µV, respectively, which were both significantly lower than the nonhypotensive aSKNA (1.034 ±â€Š0.087 µV, P  < 0.001 for both) in the same patient. CONCLUSION: POTS patients with nocturnal nondipping have elevated nocturnal sympathetic tone and blunted reduction of SKNA between day and night. Hypotensive episodes were associated with reduced aSKNA.

Left ventricular morphologic progression in apical hypertrophic cardiomyopathy.

BACKGROUND: Left ventricular (LV) morphologic progression in apical hypertrophic cardiomyopathy (AHC) has not been well studied. We evaluated serial echocardiographic changes in LV morphology. METHODS: Serial echocardiograms in AHC patients were assessed. LV morphology was categorized according to the presence of an apical pouch or aneurysm, and LV hypertrophic severity and extent; relative, pure, and apical-mid type defined as mild (<15 mm thickness) apical hypertrophy, significant (≥15 mm) apical hypertrophy, and both apical and midventricular hypertrophy, respectively. Adverse clinical events and late gadolinium enhancement (LGE) extent on cardiac magnetic resonance were evaluated for each morphologic type. RESULTS: In 41 patients, 165 echocardiograms (maximal interval: 4.2 [IQR, 2.3-11.8] years) were evaluated. Morphologic changes were observed in 19 (46%) patients. Eleven (27%) patients displayed the progression of LV hypertrophy toward pure or apical-mid type. Five (12%) and 6 (15%) patients developed new pouches and aneurysms. Patients with progression tended to be younger (50 ± 15.6 vs 59 ± 14.4 years, P = 0.058) and had a longer period of follow-up (12 [5-14] vs 3 [2-4] years, P < 0.001). During a follow-up of 7.6 (IQR 3.0-12.1) years, 21 (51%) experienced clinical events. The relative, pure, and apical-mid types showed different LGE extents (2%, 6%, and 19%, P = 0.004). Patients with severe hypertrophic and apical involvement showed higher clinical event rates. CONCLUSIONS: About half of AHC patients had a progression of LV morphology to more hypertrophic involvement and/or an apical pouch or aneurysm formation. Advanced AHC morphologic types were associated with higher event rates and scar burdens.

Endovascular Ultrasound Renal Denervation to Treat Hypertension: The RADIANCE II Randomized Clinical Trial.

Importance: Two initial sham-controlled trials demonstrated that ultrasound renal denervation decreases blood pressure (BP) in patients with mild to moderate hypertension and hypertension that is resistant to treatment. Objective: To study the efficacy and safety of ultrasound renal denervation without the confounding influence of antihypertensive medications in patients with hypertension. Design, Setting, and Participants: Sham-controlled, randomized clinical trial with patients and outcome assessors blinded to treatment assignment that was conducted between January 14, 2019, and March 25, 2022, at 37 centers in the US and 24 centers in Europe, with randomization stratified by center. Patients aged 18 years to 75 years with hypertension (seated office systolic BP [SBP] ≥140 mm Hg and diastolic BP [DBP] ≥90 mm Hg despite taking up to 2 antihypertensive medications) were eligible if they had an ambulatory SBP/DBP of 135/85 mm Hg or greater and an SBP/DBP less than 170/105 mm Hg after a 4-week washout of their medications. Patients with an estimated glomerular filtration rate of 40 mL/min/1.73 m2 or greater and with suitable renal artery anatomy were randomized 2:1 to undergo ultrasound renal denervation or a sham procedure. Patients were to abstain from antihypertensive medications until the 2-month follow-up unless prespecified BP criteria were exceeded and were associated with clinical symptoms. Interventions: Ultrasound renal denervation vs a sham procedure. Main Outcomes and Measures: The primary efficacy outcome was the mean change in daytime ambulatory SBP at 2 months. The primary safety composite outcome of major adverse events included death, kidney failure, and major embolic, vascular, cardiovascular, cerebrovascular, and hypertensive events at 30 days and renal artery stenosis greater than 70% detected at 6 months. The secondary outcomes included mean change in 24-hour ambulatory SBP, home SBP, office SBP, and all DBP parameters at 2 months. Results: Among 1038 eligible patients, 150 were randomized to ultrasound renal denervation and 74 to a sham procedure (mean age, 55 years [SD, 9.3 years]; 28.6% female; and 16.1% self-identified as Black or African American). The reduction in daytime ambulatory SBP was greater with ultrasound renal denervation (mean, -7.9 mm Hg [SD, 11.6 mm Hg]) vs the sham procedure (mean, -1.8 mm Hg [SD, 9.5 mm Hg]) (baseline-adjusted between-group difference, -6.3 mm Hg [95% CI, -9.3 to -3.2 mm Hg], P < .001), with a consistent effect of ultrasound renal denervation throughout the 24-hour circadian cycle. Among 7 secondary BP outcomes, 6 were significantly improved with ultrasound renal denervation vs the sham procedure. No major adverse events were reported in either group. Conclusions and Relevance: In patients with hypertension, ultrasound renal denervation reduced daytime ambulatory SBP at 2 months in the absence of antihypertensive medications vs a sham procedure without postprocedural major adverse events. Trial Registration: ClinicalTrials.gov Identifier: NCT03614260.

Patient-Level Pooled Analysis of Ultrasound Renal Denervation in the Sham-Controlled RADIANCE II, RADIANCE-HTN SOLO, and RADIANCE-HTN TRIO Trials.

Importance: Ultrasound renal denervation (uRDN) was shown to lower blood pressure (BP) in patients with uncontrolled hypertension (HTN). Establishing the magnitude and consistency of the uRDN effect across the HTN spectrum is clinically important. Objective: To characterize the effectiveness and safety of uRDN vs a sham procedure from individual patient-level pooled data across uRDN trials including either patients with mild to moderate HTN on a background of no medications or with HTN resistant to standardized triple-combination therapy. Data Sources: A Study of the ReCor Medical Paradise System in Clinical Hypertension (RADIANCE-HTN SOLO and TRIO) and A Study of the ReCor Medical Paradise System in Stage II Hypertension (RADIANCE II) trials. Study Selection: Trials with similar designs, standardized operational implementation (medication standardization and blinding of both patients and physicians to treatment assignment), and follow-up. Data Extraction and Synthesis: Pooled analysis using individual patient-level data using linear regression models to compare uRDN with sham across the trials. Main Outcomes and Measures: The primary outcome was baseline-adjusted change in 2-month daytime ambulatory systolic BP (dASBP) between groups. Results: A total of 506 patients were randomized in the 3 studies (uRDN, 293; sham, 213; mean [SD] age, 54.1 [9.3]; 354 male [70.0%]). After a 1-month medication stabilization period, dASBP was similar between the groups (mean [SD], uRDN, 150.3 [9.2] mm Hg; sham, 150.8 [10.5] mm Hg). At 2 months, dASBP decreased by 8.5 mm Hg to mean (SD) 141.8 (13.8) mm Hg among patients treated with uRDN and by 2.9 mm Hg to 147.9 (14.6) mm Hg among patients treated with a sham procedure (mean difference, -5.9; 95% CI, -8.1 to -3.8 mm Hg; P < .001 in favor of uRDN). BP decreases from baseline with uRDN vs sham were consistent across trials and across BP parameters (office SBP: -10.4 mm Hg vs -3.4 mm Hg; mean difference, -6.4 mm Hg; 95% CI, -9.1 to -3.6 mm Hg; home SBP: -8.4 mm Hg vs -1.4 mm Hg; mean difference, -6.8 mm Hg; 95% CI, -8.7 to -4.9 mm Hg, respectively). The BP reductions with uRDN vs sham were consistent across prespecified subgroups. Independent predictors of a larger BP response to uRDN were higher baseline BP and heart rate and the presence of orthostatic hypertension. No differences in early safety end points were observed between groups. Conclusions and Relevance: Results of this patient-level pooled analysis suggest that BP reductions with uRDN were consistent across HTN severity in sham-controlled trials designed with a 2-month primary end point to standardize medications across randomized groups. Trial Registration: ClinicalTrials.gov Identifier: NCT02649426 and NCT03614260.

Phase 2 Study of Aficamten in Patients With Obstructive Hypertrophic Cardiomyopathy.

BACKGROUND: Left ventricular outflow tract (LVOT) obstruction is a major determinant of heart failure symptoms in obstructive hypertrophic cardiomyopathy (oHCM). Aficamten, a next-in-class cardiac myosin inhibitor, may lower gradients and improve symptoms in these patients. OBJECTIVES: This study aims to evaluate the safety and efficacy of aficamten in patients with oHCM. METHODS: Patients with oHCM and LVOT gradients ≥30 mm Hg at rest or ≥50 mm Hg with Valsalva were randomized 2:1 to receive aficamten (n = 28) or placebo (n = 13) in 2 dose-finding cohorts. Doses were titrated based on gradients and ejection fraction (EF). Safety and changes in gradient, EF, New York Heart Association functional class, and cardiac biomarkers were assessed over a 10-week treatment period and after a 2-week washout. RESULTS: From baseline to 10 weeks, aficamten reduced gradients at rest (mean difference: -40 ± 27 mm Hg, and -43 ± 37 mm Hg in Cohorts 1 and 2, P = 0.0003 and P = 0.0004 vs placebo, respectively) and with Valsalva (-36 ± 27 mm Hg and -53 ± 44 mm Hg, P = 0.001 and <0.0001 vs placebo, respectively). There were modest reductions in EF (-6% ± 7.5% and -12% ± 5.9%, P = 0.007 and P < 0.0001 vs placebo, respectively). Symptomatic improvement in ≥1 New York Heart Association functional class was observed in 31% on placebo, and 43% and 64% on aficamten in Cohorts 1 and 2, respectively (nonsignificant). With aficamten, N-terminal pro-B-type natriuretic peptide was reduced (62% relative to placebo, P = 0.0002). There were no treatment interruptions and adverse events were similar between treatment arms. CONCLUSIONS: Aficamten resulted in substantial reductions in LVOT gradients with most patients experiencing improvement in biomarkers and symptoms. These results highlight the potential of sarcomere-targeted therapy for treatment of oHCM.