Daily Cardiology Research Analysis

BACKGROUND: The nonsteroidal mineralocorticoid receptor antagonist finerenone has been reported to improve kidney and cardiovascular outcomes in persons with type 2 diabetes and chronic kidney disease (CKD). The efficacy and safety of finerenone in persons with type 1 diabetes and CKD are unknown. METHODS: We conducted a phase 3 trial involving adults who had type 1 diabetes, CKD (estimated glomerular filtration rate [eGFR], 25 to <90 ml per minute per 1.73 m RESULTS: A total of 242 participants underwent randomization. The median urinary albumin-to-creatinine ratio decreased from 574.6 at baseline to 373.5 at 6 months among all the participants assigned to receive finerenone and from 506.4 to 475.6 among those assigned to receive placebo. Over a period of 6 months, the urinary albumin-to-creatinine ratio decreased by 34% with finerenone (geometric mean ratio to baseline, 0.66; 95% confidence interval [CI], 0.60 to 0.73) and 12% with placebo (geometric mean ratio to baseline, 0.88; 95% CI, 0.79 to 0.98), which corresponded to a 25% greater reduction with finerenone than with placebo (geometric mean ratio for finerenone vs. placebo, 0.75; 95% CI, 0.65 to 0.87; P<0.001). The most common adverse event was hyperkalemia (in 12 participants [10.1%] with finerenone and in 4 [3.3%] with placebo); 2 participants (1.7%) discontinued finerenone because of hyperkalemia. At 6 months, the change in the eGFR was -5.6 ml per minute per 1.73 m CONCLUSIONS: In adults with type 1 diabetes and CKD, finerenone resulted in a significantly greater decrease in the urinary albumin-to-creatinine ratio than placebo. (Funded by Bayer; FINE-ONE ClinicalTrials.gov number, NCT05901831.).

BACKGROUND: Pulmonary hypertension (PH) is characterized by increased pulmonary artery pressure and can lead to right heart failure. Parathyroid hormone (PTH) is secreted by the parathyroid gland and plays a crucial role in calcium homeostasis. PTH also acts on the cardiovascular system and affects cardiovascular prognosis. We hypothesized that PTH would play a potential role in the pathogenesis of PH. METHODS: Serum PTH levels were measured in patients with PH or suspected PH who underwent evaluation using right heart catheterization. We assessed whether the regulation of PTH and the PTH1R (PTH receptor) affected PH in a hypoxia-induced PH mouse model and a Sugen/hypoxia-induced PH rat model. To examine PTH1R regulation and the direct effects of PTH, human pulmonary artery smooth muscle cells were cultured. RESULTS: In the clinical study, we found that serum PTH concentration was associated with both mean pulmonary artery pressure and pulmonary vascular resistance, with a cutoff PTH level of 46.0 pg/mL (68.2% sensitivity, 100% specificity) for predicting PH. In the PH animal models-Sugen/hypoxia rats and hypoxia mice-PTH treatment exacerbated right ventricular hypertrophy and right ventricular systolic pressure. Conversely, PTH reduction by parathyroidectomy attenuated right ventricular hypertrophy and reduced pulmonary vascular remodeling in Sugen/hypoxia rats. In vitro studies revealed that HIF1α (hypoxia-inducible factor-1 alpha) promoted the PTH1R. Moreover, knockdown of the PTH receptor in the lungs ameliorated PH in Sugen/hypoxia rats and hypoxia mice. Treatment with PTH increased proliferation and migration of pulmonary artery smooth muscle cells through the PTH receptor-β-arrestin-ERK (extracellular signal-regulated kinase) signaling axis. CONCLUSIONS: Our clinical and experimental data suggest a potential involvement of PTH/PTH1R signaling in the development and progression of PH, highlighting PTH1R as a possible therapeutic target for further investigation.

BACKGROUND: Conventional antiarrhythmic drugs that target cardiac ion channels carry proarrhythmic risks, highlighting the need for alternative therapeutic approaches. Cardiac nicotinic acetylcholine receptors (nAChRs) represent a novel electrophysiological target. OBJECTIVES: The aim of this exploratory, proof-of-concept phase 2 trial was to evaluate the effect of varenicline, a partial nAChR agonist, on frequent premature ventricular complexes (PVCs) after myocardial infarction (MI) and to assess its short-term safety and biological target engagement. METHODS: In this multicenter, randomized, double-blind, placebo-controlled trial, adults with frequent PVCs (≥1,000/24 h) assessed using 72-hour ambulatory electrocardiographic monitoring at ≥4 weeks post-MI were randomly assigned (1:1) to varenicline 0.5 mg twice daily or matching placebo for 45 days, in addition to guideline-directed medical therapy. The primary endpoint was the percentage change in 24-hour PVC count from baseline to week 6. Key secondary endpoints included responder rate (≥50% reduction in PVC count) and the incidence of nonsustained ventricular tachycardia (VT). RESULTS: Among 118 randomized patients, varenicline produced a 60.1 percentage point greater reduction in PVC burden compared with placebo (95% CI: 21.3-98.8 percentage points; P = 0.001). The responder rate was higher with varenicline (67.8% vs 30.5%; RR: 2.22; 95% CI: 1.46-3.39; P < 0.0001), and nonsustained VT incidence was lower (20.3% vs 37.3%; RR: 0.49; 95% CI: 0.29-0.85; P = 0.007). No deaths or malignant ventricular arrhythmias occurred in the varenicline group, with comparable adverse event rates between groups. CONCLUSIONS: In this phase 2 trial, varenicline significantly reduced PVC burden and nonsustained VT incidence in post-MI patients without evidence of a proarrhythmic effects. These findings support cardiac nAChRs as a potential antiarrhythmic target and justify further evaluation in larger outcome-driven trials. (Efficacy of Varenicline Tartrate in Treating Frequent Premature Ventricular Contractions: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial [Var-PVC]; NCT06780215).