Daily Cardiology Research Analysis

BACKGROUND: Angiotensinogen production represents the rate-limiting step in activation of the renin-angiotensin-aldosterone system. Tonlamarsen is an investigational antisense oligonucleotide directed against hepatic angiotensinogen synthesis; its efficacy and safety among patients with hypertension are unknown. OBJECTIVES: The aim of this study was to assess the safety and efficacy of 90 mg tonlamarsen administered subcutaneously once monthly for 5 months compared with a single dose of tonlamarsen and subsequent placebo. METHODS: This randomized, placebo-controlled trial enrolled adults with office systolic blood pressure (BP) >135 mm Hg receiving 2 to 5 antihypertensive medications. Participants entered a 3-part treatment period with monthly administration of the study drug, consisting of a 4-week placebo lead-in, followed by 4-week active run-in with a single dose of tonlamarsen and subsequent randomization to 4 additional doses of tonlamarsen or matching placebo for 16 weeks. The coprimary endpoints were the between-group differences in the change from baseline to week 20 in plasma angiotensinogen and in office systolic BP. RESULTS: A total of 279 participants received placebo lead-in, 206 received 90 mg tonlamarsen during the active run-in, and 198 were randomized. The mean BP among randomized participants before and after the placebo lead-in was 147/90 and 147/89 mm Hg, respectively. Following active run-in with tonlamarsen, the mean BP was 140/87 mm Hg. Twenty weeks following the first dose of tonlamarsen, least squares (LS) mean percentage changes in plasma angiotensinogen levels were -23.0% (95% CI: -27.8% to -18.2%) with a single dose of tonlamarsen and subsequent placebo and -67.2% (95% CI: -71.9% to -62.4%) with monthly tonlamarsen administration, with a LS mean difference of -44.1% (97.5% CI: -51.9% to -36.4%; P < 0.0001). The LS mean changes in office systolic BP were -6.7 mm Hg (95% CI: -9.8 to -3.5 mm Hg) for participants following a single dose of tonlamarsen and subsequent placebo and -6.7 mm Hg (95% CI: -9.8 to -3.6 mm Hg) for participants treated with monthly tonlamarsen, with a LS mean difference of -0.1 mm Hg (95% CI: -4.5 to -4.4 mm Hg; P = 0.97). Serious adverse events were infrequent and similar between treatment groups. CONCLUSIONS: Among individuals with uncontrolled hypertension, monthly tonlamarsen administration was more effective at lowering plasma angiotensinogen compared with a single tonlamarsen dose, but there was no additional BP reduction. (A Study to Investigate Tonlamarsen for the Treatment of Adults With Uncontrolled Hypertension [KARDINAL]; NCT06864104).

Loss-of-function variants in the gene encoding angiopoietin-like protein 3 (ANGPTL3) are associated with decreased triglyceride and low-density lipoprotein cholesterol levels, as well as with lower cardiovascular risk. Here we describe a 16-week phase 1 trial of zodasiran, an ANGPTL3‑targeting small interfering RNA, in patients on lipid-lowering therapy with either hyperlipidemia (with a placebo control arm) (n = 9; 7 male and 2 female), familial hypercholesterolemia (n = 17; 9 male and 8 female) or moderate-to-severe hypertriglyceridemia (n = 6; 4 male and 2 female). Patients received zodasiran subcutaneously on days 1 and 29, followed by a 48-week open-label extension in the familial hypercholesterolemia cohort (n = 13; 7 male and 6 female) in which zodasiran was dosed every 12 weeks. No serious treatment-related adverse events, the primary endpoint of the trial, were observed. Moreover, no elevations in hepatic aminotransferases, bilirubin or glycated hemoglobin were observed, and there were no drug discontinuations. All cohorts showed reductions at week 16 (12 weeks postdosing) in serum ANGPTL3 (≤-85.4%) and triglycerides (≤-67.1%), which were secondary endpoints. Reduction in ANGPTL3 was sustained to end-of-open-label extension in the familial hypercholesterolemia cohort. These results indicate a favorable safety profile for zodasiran, with promise for correcting isolated hypercholesterolemia and moderate-to-severe hypertriglyceridemia, and support further studies of zodasiran in treating a wide spectrum of dyslipidemias. ClinicalTrials.gov registration: NCT03747224 .

BACKGROUND: Epicardial adipose tissue (EAT) is a metabolically active visceral fat depot that is both a sensor and a modulator of myocardial biology and changes its composition in response to paracrine signals from the myocardium. We hypothesized that radiomic characterization of EAT from routine coronary computed tomographic angiography (CCTA) can noninvasively capture this adverse remodeling and enable early heart failure (HF) risk stratification. OBJECTIVES: We sought to develop and externally validate a reproducible radiomic signature of EAT associated with incident HF. METHODS: We conducted a multicenter cohort study of 72,751 adults without known HF or myocardial infarction undergoing CCTA across 9 UK centers (2007-2022). We deployed a fully automated pipeline to segment EAT and extract 1,655 volumetric, shape, and higher-order radiomic texture features. Using a harmonized survival autoencoder architecture, we derived the fat radiomic profile for HF (FRP RESULTS: Over a median follow-up of 5.1 and 4.0 years, 1,737 (2.9%) and 363 (2.7%) participants developed HF in the internal and external validation cohorts, respectively. FRP CONCLUSIONS: Automated radiomic phenotyping of EAT from routine CCTA enables scalable, biologically informed stratification of future HF risk before clinical onset, positioning opportunistic imaging-based visceral fat profiling as a potential tool for precision prevention.