Purpose Pulmonary hypertension (PH) commonly complicates heart failure with preserved ejection fraction (HFpEF), driving morbidity and mortality, yet no therapies exist for HFpEF-PH. β3-adrenergic receptor (ADRB3) agonists may provide cardiometabolic and anti-inflammatory benefits. We evaluated pharmacological ADRB3 modulation in a preclinical HFpEF-PH model. Methods HFpEF-PH was induced in male and female AKR/J mice via high-fat diet feeding for 16-20 weeks. At 12-16 weeks of feeding, mice were randomized to low-dose mirabegron (LDM, 3.6 mg/kg/day), high-dose mirabegron (HDM, 14.4 mg/kg/day), nebivolol (1.0 mg/kg/day), or vehicle for 4 weeks. A separate cohort received the ADRB3 antagonist SR59230A (0.5 mg/kg/day) or vehicle. Right ventricular systolic pressure (RVSP), left ventricular end-diastolic pressure (LVEDP), body weight change, and gene expression of nitric oxide synthases ( Nos1 , Nos2 , Nos3 ), thermogenic markers ( Ucp1 , Ppargc1a ), and inflammatory cytokines ( Il1b , Il6 , Tnf ) were assessed. Results HDM and nebivolol significantly reduced RVSP compared to controls ( P =0.010 and P =1.0×10 -4 ), whereas SR59230A increased RVSP ( P =0.006). LDM did not significantly affect RVSP, and LVEDP was unchanged across all treatment groups. HDM also reduced weight gain vs. control ( P =0.023). HDM increased Ucp1 and Ppargc1a expression in adipose tissue, and nebivolol increased Ppargc1a expression in adipose tissue. These molecular findings remained significant in sensitivity analyses. Conclusion HDM and nebivolol reduced RVSP in a preclinical model of HFpEF-PH, whereas ADRB3 antagonism increased RVSP. These findings provide pharmacological evidence consistent with involvement of ADRB3 signaling and support further investigation of ADRB3-targeted approaches; the molecular pathways underlying these hemodynamic effects remain to be established.
Objective To investigate adherence to four direct oral anticoagulants (DOACs) and its influencing factors in patients with non-valvular atrial fibrillation (NVAF), providing evidence for strategies to improve adherence. Methods A retrospective cohort study included NVAF patients initiating DOAC therapy at a tertiary hospital (January 2016–November 2023). Adherence was evaluated using the proportion of days covered (PDC), with PDC ≥ 0.8 defined as good adherence. Adherence levels for dabigatran, rivaroxaban, apixaban, and edoxaban were compared at 3, 6, 9, and 12 months. Logistic regression identified factors influencing 1-year adherence, assessing the impact of initiation year and the National Volume-Based Drug Procurement (NVBP) policy. Results A total of 1,150 NVAF patients were enrolled (dabigatran: n = 401; rivaroxaban: n = 656; apixaban: n = 18; edoxaban: n = 75),In this main cohort, overall adherence progressively declined, with only 40.78% achieving PDC ≥ 0.8 at 1 year. Significant differences existed among groups (P<0.001). Dabigatran demonstrated the highest 1-year adherence (53.62%), followed by rivaroxaban (34.91%), apixaban (27.78%), and edoxaban (26.67%). Compared with dabigatran, rivaroxaban (OR=0.47) and edoxaban (OR=0.33) were independently associated with poorer adherence. Age ≥75 years (OR=0.62) and self-pay (OR=0.49) were risk factors for poor adherence, while diabetes (OR=1.48) and prior stroke (OR=1.48) predicted better adherence. Patients initiating therapy in 2017 showed the highest adherence. Post-NVBP, generic dabigatran adherence exceeded the original formulation at 6 months (P=0.038), but this difference disappeared at 1 and 2 years. Conclusion DOAC adherence among NVAF patients is suboptimal and decreases over time. Among the four DOACs, dabigatran was associated with the highest adherence. Elderly (≥75 years) and self-paying patients are at higher risk of poor adherence, whereas those with diabetes or stroke history show better adherence. The NVBP policy improves adherence short-term, but long-term effects are limited. Targeted interventions are necessary for high-risk populations.
Background Platelet reactivity varies after ST-segment-elevation myocardial infarction (STEMI). We evaluated serial platelet function-guided P2Y12 modulation after a 1-month ticagrelor run-in. Methods At month 1, 114 patients were randomized to continued ticagrelor (n=59) or an adenosine diphosphate (ADP)-guided strategy (n=55). Month-1 ADP was the preintervention baseline; months 2, 3, 6, 9, and 12 were analyzed using baseline-adjusted generalized estimating equations. Exploratory net adverse clinical events (NACE) were assessed from randomization through month 12 after STEMI. Results In the guided group, month-1 ADP was 52 U (range, 4-466); 37 patients received clopidogrel 75 mg and 18 received 150 mg, with 17 dose-threshold discordances. Adjusted postrandomization ADP was higher with the guided strategy (geometric mean ratio, 1.26; 95% confidence interval [CI], 1.05-1.51). NACE occurred in 14/59 versus 4/55 patients (risk ratio [RR], 0.31; 95% CI, 0.11-0.87; absolute risk difference, -16.5 percentage points; exact P=.020). Any investigator-classified BARC bleeding occurred in 13/59 versus 3/55 (RR, 0.25; 95% CI, 0.07-0.82; exact P=.014), and the post hoc ischemic-or-BARC ≥2 composite in 9/59 versus 2/55 (RR, 0.24; 95% CI, 0.05-1.06; exact P=.055). One ischemic event occurred in each group. Conclusions Serial ADP-guided modulation produced pharmacodynamic separation and was associated with fewer investigator-recorded, bleeding-driven events. Dose-threshold deviations, unverified extreme ADP values, incomplete BARC 2 documentation, and only 2 ischemic events restrict interpretation to hypothesis generation; efficacy and safety cannot be established.
Background Vericiguat improves outcomes in heart failure with reduced ejection fraction (HFrEF), but its vascular and hemodynamic effects remain unclear. We explored changes in flow-mediated dilation (FMD) and invasive hemodynamics after vericiguat in symptomatic patients with HFrEF receiving guideline-directed medical therapy (GDMT). Methods In this single-center, open-label, single-arm exploratory pilot study, 10 patients with symptomatic HFrEF underwent assessment of FMD, right heart catheterization at rest and during 20-W supine exercise, echocardiography, laboratory testing, and 6-min walk distance (6MWD) before and after vericiguat. Vericiguat was uptitrated to 10 mg/day where tolerated. Results After treatment, FMD increased from 4.7 (3.0-6.1) to 6.9 (5.5-7.6)% ( P = .015), GLS improved from −6.8 (−8.6 to −5.5) to −9.0 (−10.5 to −6.7)% ( P = .009), resting cardiac output increased from 3.8 (3.6-5.4) to 4.6 (3.5-5.4) L/min ( P = .047), resting systemic vascular resistance decreased from 1664.1 (1327.2-1781.2) to 1293.1 (1143.6-1623.5) dyn·s·cm −5 ( P = .002), and 6MWD increased from 334.0 (251.3-395.0) to 355.0 (262.5-453.8) m ( P = .036). During 20-W exercise, cardiac output increased from 5.4 (4.6-5.9) to 6.5 (4.8-6.9) L/min ( P = .030), whereas exercise systemic vascular resistance showed only a decreasing trend ( P = .070). Conclusions In symptomatic patients with HFrEF receiving GDMT, vericiguat was associated with changes in peripheral vascular function and resting hemodynamic indices. However, exercise systemic vascular resistance did not improve significantly. These findings are exploratory and hypothesis-generating.
