Daily Cardiology Research Analysis

IMPORTANCE: Studies suggest that everolimus may reduce the risk of rejection, cardiac allograft vasculopathy (CAV), chronic kidney disease (CKD), and cytomegalovirus (CMV) after heart transplant. Everolimus use is controversial because of data demonstrating higher infection deaths when everolimus is introduced de novo after transplant. It is unclear whether everolimus is safe and effective when initiated at 6 months posttransplant in children, a population in which median graft survival is limited to 15 years and randomized clinical trials are lacking. OBJECTIVE: To evaluate the safety and efficacy of everolimus combined with low-dose tacrolimus to prevent major adverse transplant events (MATEs) in children after heart transplant. DESIGN, SETTING, AND PARTICIPANTS: Multicenter, randomized, open-label, clinical trial enrolling 211 patients who were alive 6 months after pediatric heart transplant at 25 US sites from February 2018 to August 2020. The last date of follow-up was April 17, 2023. INTERVENTIONS: Participants were randomized to receive everolimus and low-dose tacrolimus (n = 107) or standard-dose tacrolimus and mycophenolate mofetil (n = 104) for 30 months. MAIN OUTCOMES AND MEASURES: The primary efficacy end point was the MATE-3 score at 30 months, a validated composite ordinal end point including acute cellular rejection, CAV, and CKD. The primary safety end point was the MATE-6 score, encompassing the MATE-3 score plus antibody-mediated rejection, infection, and posttransplant lymphoproliferative disorder. RESULTS: Among 211 children randomized, the mean age was 8.2 (SD, 6.3) years, 97 (46%) underwent transplant for congenital heart disease, and 49 (23%) were treated for rejection before 6 months. At 30 months, the mean MATE-3 score did not differ between the 2 treatment groups (mean difference, -0.32; 95% CI, -0.90 to 0.20; P = .16). The mean MATE-6 score was no higher in the everolimus group than in the mycophenolate group (baseline-adjusted mean difference, -0.40; 95% CI, -1.81 to 0.93), meeting the success criterion for safety (noninferiority margin <3). There were no differences in graft survival, MATE-free survival, or freedom from any individual MATE. Everolimus was associated with greater improvement in estimated glomerular filtration rate at 12 months (mean difference, 10.5 mL/min/1.73 m2; 95% CI, 1.09-19.91 mL/min/1.73 m2) and a lower incidence of CMV infection (hazard ratio, 0.50; 95% CI, 0.26-0.93). CONCLUSIONS AND RELEVANCE: Among 6-month pediatric heart transplant survivors, everolimus and low-dose tacrolimus did not differ from tacrolimus and mycophenolate in preventing the composite of cellular rejection, CAV, and CKD at 30 months. However, everolimus and low-dose tacrolimus appear to be safe based on the total burden of 6 MATEs and may be associated with improved kidney function and less CMV infection. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03386539.

IMPORTANCE: Animal studies and meta-analysis of human observational data suggest that pneumococcal polysaccharide vaccination (PPV) could be protective against atherosclerosis; however, to the authors' knowledge, no randomized clinical trial has been conducted. OBJECTIVE: To determine whether pneumococcal vaccination (Pneumovax [Merck Sharp & Dohme Corp]) decreases the composite primary outcome of fatal and nonfatal acute coronary syndrome and ischemic stroke in people at increased risk, with an average follow-up of 7 years after immunization. DESIGN, SETTING, AND PARTICIPANTS: This was a double-blind, placebo-controlled, parallel-arm randomized clinical trial conducted at 6 centers across Australia. Participants were community-dwelling adults 55 to 60 years of age at baseline in 2016 to 2017, with at least 2 risk factors (obesity, hypertension, or hypercholesterolemia) for cardiovascular disease (CVD) but no prior CVD event or indication for early pneumococcal vaccination. Data were analyzed from February 2023 to December 2024 using competing risk proportional hazards regression models, stratified by sex and center. INTERVENTIONS: Participants received either 23-valent PPV (PPV23) or placebo (saline). MAIN OUTCOMES AND MEASURES: The primary outcome was a composite of fatal and nonfatal myocardial infarction or ischemic stroke, ascertained via electronic medical records from emergency department, admitted patient, and mortality data collections using International Statistical Classification of Diseases, Tenth Revision, Australian Modification (ICD-10-AM) codes. RESULTS: A total of 4725 participants (mean [SD] age, 58.0 [1.7] years; 2433 male [52%]) were included in this study. There was no significant difference in the primary outcome (58 of 2366 events in the active PPV23 group compared with 64 of 2357 events in the control group, hazard ratio, 0.90; 95% CI, 0.63-1.28; P = .57). Similarly, no significant differences occurred in the exploratory outcomes of all-cause mortality, all-cause hospital presentations, and CVD-related hospital procedures. These results are tempered by the lower than expected event rate leading to low power. CONCLUSIONS AND RELEVANCE: Results of this randomized clinical trial found that PPV23 did not reduce the rates of fatal and nonfatal acute coronary syndrome and ischemic stroke, although the study was underpowered. TRIAL REGISTRATION: ANZCTR Identifier: ACTRN12615000536561.

BACKGROUND: Since the existing literature on plasma metabolites and blood pressure (BP) is predominantly focused on populations of European ancestry, we aimed to study associations between metabolite profiles and BP in a multiethnic cohort. METHODS: From the HELIUS study (Healthy Life in an Urban Setting), 369 individuals of Dutch, Ghanaian, African Surinamese, and South-Asian Surinamese ethnicity were included for a cross-sectional analysis. Office BP was recorded, and plasma metabolites were measured using untargeted liquid chromatography tandem mass spectometry. Associations between metabolite profiles and BP were assessed with XGBoost machine learning prediction models, followed by linear regression models. The associations with the highest-ranked metabolite were validated in 2 cohorts, and its effects were investigated in human aortic endothelial and vascular smooth muscle cells. RESULTS: The plasma metabolite N-formylmethionine (fMet) showed the most consistent associations with BP across age, sex, and ethnicity. Notably, fMet was associated with higher systolic (+4.14 mm Hg, 95% CI, 2.11-6.17 per SD increase) and diastolic BP (+2.61 mm Hg, 1.41-3.82), and these associations were validated in 2 independent cohorts. Mechanistically, we found that fMet likely contributes to elevated BP by suppressing endothelial nitric oxide synthase expression, and inducing oxidative stress and mitochondrial dysfunction in endothelial cells. In addition, fMet elicited an early inflammatory response, disrupted the endothelial barrier and upregulated myosin light chain expression in vascular smooth muscle. CONCLUSIONS: We identified the metabolite fMet as a novel independent factor associated with BP in an ethnically diverse population. It likely contributes to higher BP by triggering endothelial cell dysfunction, while augmenting contractile proteins in vascular smooth muscle cells.