Daily Cardiology Research Analysis

BACKGROUND: XXB750 is a potent and long-acting human monoclonal antibody agonist of the natriuretic peptide receptor-1 (NPR-1), the receptor for atrial natriuretic peptide and B-type natriuretic peptide. Activation of NPR-1 may lower blood pressure (BP) in patients with resistant hypertension through increases in the second messenger cyclic guanosine monophosphate. OBJECTIVES: The aim of this study was to determine the effect of NPR-1 agonism on 24-hour BP. METHODS: This phase 2, multicenter, randomized, double-blind, placebo-controlled trial evaluated 4 once-monthly subcutaneous doses of XXB750 (30 mg, 60 mg, 120 mg, and 240 mg) administered at baseline, week 4, and week 8 in patients with resistant hypertension. Resistant hypertension was defined as 24-hour systolic BP (SBP) ≥135 mm Hg despite treatment with 3 or 4 guideline-directed antihypertensive agents. The primary endpoint was the dose-response relationship of XXB750 vs placebo in reducing the mean 24-hour SBP from baseline to week 12. RESULTS: The study population (N = 189) had a mean age of 61 years, was 69% male, 61% White, 20% Asian, and 14% Black/African American, and had a baseline mean 24-hour ambulatory BP of 148/81 ± 11/10 mm Hg. Plasma concentrations of XXB750 dose-dependently increased in the XXB750 groups, and XXB750 dose-dependently increased plasma and urine cyclic guanosine monophosphate concentrations by week 12. However, paradoxically, there was no significant dose-dependent change from baseline in mean 24-hour SBP at week 12. In fact, none of the doses of XXB750 had a greater BP-lowering effect than placebo. Changes in ambulatory BP were not affected by the development of anti-drug antibodies. Although there were no changes from baseline in urinary sodium excretion, there were small increases in plasma renin levels in the XXB750 groups. Adverse events with XXB750 were numerically higher than with placebo. Adherence to background antihypertensive medications, assessed by drug assays in 88 patients with available plasma samples, was consistent across all treatment groups at both baseline and week 12. CONCLUSIONS: XXB750, an NPR-1 agonist, had a neutral effect on 24-hour ambulatory SBP in patients with resistant hypertension, despite showing a robust dose-response relationship for engagement of the target of pharmacologic action as indicated by increases in cyclic guanosine monophosphate levels. (An Efficacy, Safety, Tolerability and Dose Finding Study of XXB750 in Resistant Hypertension Patients; NCT05562934).

BACKGROUND: Measurement of cardiac troponin (cTn) using high-sensitivity assays is recommended for the diagnosis of myocardial infarction. We determined sex-specific and uniform 99th percentile upper reference limits (URLs) using the new Elecsys® Troponin T high-sensitivity Gen 6 assay in a global, healthy reference range cohort. METHODS: Lithium-heparin (Li-Hep) plasma and serum samples were prospectively collected from apparently healthy individuals aged ≥20 years across 34 global sites in the United States, Europe, China, and Japan. cTnT was measured using the Troponin T high-sensitivity Gen 6 assay on the Cobas® e 801 analyzer. Exclusion criteria were defined according to the 2022 International Federation of Clinical Chemistry guidance. Uniform and sex-specific 99th percentile URLs and non-parametric 95% confidence intervals (CI) were determined in plasma and serum separately and combined. RESULTS: The final study population comprised 4147 participants (52.5% female) with a median (25-75th percentiles) age of 48.0 (33.0-59.0) years; 45.8%, 47.9%, 5.2% and 1.1% were White, Asian, Black, and other/unknown, respectively. For sample matrices combined (n=8294), 81.0% and 99.2% of cTnT values were above the limit of detection in females and males, respectively. Sex-specific 99th percentile URLs (95% CI) were 18 (16-23) ng/L for females and 32 (28-35) ng/L for males; the uniform 99th percentile URL was 27 (24-31) ng/L. URLs were comparable in plasma and serum samples. CONCLUSIONS: This study determined sex-specific and uniform 99th percentile URLs for the Troponin T high-sensitivity Gen 6 assay that were comparable irrespective of the matrix used, in a large, global, healthy reference population.

IMPORTANCE: Left ventricular (LV) dilatation is an established prognosticator in aortic regurgitation (AR). Current guidelines recommend aortic valve surgery (AVS) using LV end-systolic diameter index (LVESDi) with a uniform threshold, irrespective of sex. While LV end-systolic volume index (LVESVi) may better characterize LV remodeling, it was only recently included in European guideline recommendations, with a threshold of 45 mL/m2 for both men and women. OBJECTIVE: To assess sex differences in LV remodeling using linear and volumetric dimensions and their association with outcomes in AR. DESIGN, SETTING, AND PARTICIPANTS: This was a multicenter cohort study of patients with moderate-severe AR and preserved LV ejection fraction (LVEF) between December 2003 and December 2022, with a median (IQR) follow-up of 7 (4-11) years. The study took place at 5 centers in the Netherlands, Singapore, Hong Kong, Canada, and Romania. Patients with at least moderate-severe AR and preserved LVEF (≥50%) were included. Those with symptoms, acute AR, significant other valvular disease, or prior valve surgery were excluded. Data were analyzed from January to November 2024. EXPOSURE: LV dilatation assessed by LVESDi and LVESVi. MAIN OUTCOMES AND MEASURES: All-cause mortality during medical management and following AVS. RESULTS: A total of 808 patients (mean [SD] age, 56 [19] years; 488 men and 320 women) were included, 323 of whom underwent AVS. Mean (SD) baseline LVESDi did not differ between sexes (women: 20 [5] mm/m2 vs men: 20 [4] mm/m2; P = .77), whereas men had larger mean (SD) LVESVi (39 [16] mL/m2 vs 31 [15] mL/m2; P < .001). During follow-up under medical management, 74 patients died. Adjusted 6-year survival was lower in women (80% vs 89%; P = .001). Receiver operating characteristic curve analysis identified LVESDi 20 mm/m2 or greater for both sexes, LVESVi 40 mL/m2 or greater for women, and LVESVi 45 mL/m2 or greater for men as thresholds associated with mortality. These cutoffs were validated using age-adjusted cubic splines and remained associated with outcomes after multivariable adjustment, with a differential effect by sex for LVESVi but not for LVESDi. After AVS, survival did not differ by sex (85% women vs 89% men; P = .31). Only preoperative LVESVi was associated with mortality, with a significant sex interaction (HR, 1.03; 95% CI, 1.00-1.06; P = .04). CONCLUSIONS AND RELEVANCE: In this study among individuals with moderate-severe AR, similar LVESDi thresholds (20 mm/m2) for both sexes, but lower than currently recommended by guidelines, were independently associated with mortality. In turn, LVESVi thresholds were 40 mL/m2 for women and 45 mL/m2 for men, suggesting the need for sex-specific cutoffs to improve risk stratification.