Daily Cardiology Research Analysis

BACKGROUND: The PRAETORIAN trial (A Prospective, Randomized Comparison of Subcutaneous and Transvenous Implantable Cardioverter Defibrillator Therapy) investigated the efficacy and safety of the subcutaneous implantable cardioverter defibrillator (S-ICD) compared with a transvenous ICD (TV-ICD) and showed noninferiority of the S-ICD with regard to the composite end point of device-related complications and inappropriate shocks after 49.1 months. Complications associated with transvenous leads are expected to occur after longer follow-up. The PRAETORIAN-XL trial aims to investigate whether the S-ICD is superior to the TV-ICD with respect to device-related complications at 8-year follow-up. METHODS: The PRAETORIAN trial randomized patients with a class I or IIa indication for ICD therapy without the need for pacing to either S-ICD or TV-ICD among 39 centers in the United States and Europe between March 2011 and January 2017. The follow-up was extended after 49.1 months by an additional 4 years for the PRAETORIAN-XL trial. The primary end point was the composite of all device-related complications. Complications could be related or unrelated to the lead and minor or major, with major complications being those requiring an invasive intervention. End points were analyzed according to the modified intention-to-treat principle using a Fine-Gray subdistribution hazards model to account for competing risks. An as-treated analysis was performed using a Cox proportional hazards model with device type as time-dependent variable. RESULTS: Patients were randomized to S-ICD (n=426) and TV-ICD (n=423). Twenty-one percent of the S-ICD group versus 18% of the TV-ICD group were women. The median age at implantation was 63 (interquartile range, 54-69) years for the S-ICD and 64 (interquartile range, 56-69) years for the TV-ICD. After a median follow-up of 87.5 months, all device-related complications (major and minor combined) were not significantly different in the modified intention-to-treat analysis (subdistribution hazard ratio, 0.73 [95% CI, 0.48-1.12]); CONCLUSIONS: The PRAETORIAN-XL trial demonstrated that there was no significant difference between the S-ICD and TV-ICD in all device-related complications during long-term follow-up. However, the TV-ICD carries a higher risk of major and lead-related complications compared with S-ICD therapy. The S-ICD should therefore be considered for all patients without a pacing indication who are evaluated for ICD therapy. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01296022.

BACKGROUND AND AIMS: The benefits of heart rate (HR)-lowering drug treatment in hypertension remain controversial. The effects of HR lowering on cardiovascular (CV) outcomes, mortality, and adverse events in patients with hypertension and/or CV disease were evaluated. METHODS: PubMed, the Embase, and the Cochrane Library were searched for randomized trials comparing HR-lowering drugs with placebo or less intensive treatment. Risk ratios and 95% confidence intervals for eight outcomes were calculated (random-effects model). Subgroup analyses for a standard HR reduction were used to compare risk estimates in different HR groups or age strata (PROSPERO CRD42024540924). RESULTS: The database included 74 HR-lowering treatment trials (n = 157 764 patients). The average HR reduction over 2.7 years was 8.2 b.p.m. (baseline/attained HR: 76.2/65.6 b.p.m.). HR-lowering reduced coronary heart disease by 16%, heart failure by 9%, CV mortality by 14%, and all-cause mortality by 13% but increased adverse event-driven discontinuations by 25%. Significant mortality reductions were noted in post-acute myocardial infarction and heart failure. No significant outcome changes were observed with HR reduction in hypertension without CV disease, while the entire hypertensive population experienced increased stroke and mortality. Threshold analysis revealed that the effect on outcomes was not different across cutoffs (from ≥80 b.p.m. to almost 70 b.p.m.), except for heart failure. Treatment outcome effects were not different across progressively lower targets (from ≥70 b.p.m. to <65 b.p.m.), except for permanent discontinuations, which showed an incremental trend. CONCLUSIONS: The HR reduction benefits are context-dependent. Optimising outcomes while considering potential risks, targeting 65-70 b.p.m. for all HR thresholds above 70 b.p.m. seems reasonable.

Despite advancements in interventional coronary reperfusion technologies following myocardial infarction, a notable portion of patients continue to experience elevated mortality rates as a result of myocardial ischemia-reperfusion (MI/R) injury. An in-depth understanding of the mechanisms underlying MI/R injury is crucial for devising strategies to minimize myocardial damage and enhance patient survival. Here, it is discovered that during MI/R, double-stranded DNA (dsDNA)-cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signal accumulates, accompanied by high rates of myocardial ferroptosis. The specific deletion of cgas or Sting in cardiomyocytes, resulting in the inhibition of oxidative stress, has been shown to mitigate ferroptosis and I/R injury. Conversely, activation of STING exacerbates ferroptosis and I/R injury. Mechanistically, STING directly targets glutathione peroxidase 4 (GPX4) to facilitate its degradation through autophagy, by promoting the fusion of autophagosomes and lysosomes. This STING-GPX4 axis contributes to cardiomyocyte ferroptosis and forms a positive feedback circuit. Blocking the STING-GPX4 interaction through mutations in T267 of STING or N146 of GPX4 stabilizes GPX4. Therapeutically, AAV-mediated GPX4 administration alleviates ferroptosis induced by STING, resulting in enhanced cardiac functional recovery from MI/R injury. Additionally, the inhibition of STING by H-151 stabilizes GPX4 to reverse GPX4-induced ferroptosis and alleviate MI/R injury. Collectively, a novel autophagy-dependent ferroptosis mechanism is identified in this study. Specifically, STING autophagy induced by anoxia or ischemia-reperfusion leads to GPX4 degradation, thereby presenting a promising therapeutic target for heart diseases associated with I/R.