Daily Cardiology Research Analysis

BACKGROUND: Penetrance and risk of ventricular arrhythmias (VAs) in arrhythmogenic right ventricular cardiomyopathy (ARVC) are increasingly recognized as being genotype specific. Therefore, genotype-informed family screening protocols may lead to safer and more personalized recommendations than the current one-size-fits-all screening recommendations. We aimed to develop a safe, evidence-based plakophilin-2 ( METHODS: We included 295 relatives (41% male; age 30.9 years [18.0-47.7 years]) with a pathogenic or likely pathogenic RESULTS: At baseline, 110 relatives (37%) had definite ARVC. During 8.5 years (4.2-12.9 years) of follow-up, 62 of 185 relatives (34%) without definite ARVC at baseline progressed to definite ARVC diagnosis, and 35 of 295 of all relatives (12%) had VA. VAs occurred only in relatives who previously fulfilled definite ARVC diagnosis. Relatives with borderline ARVC (fulfillment of one minor criterion plus the major family history criterion) progressed 5 times faster in the multistate model to definite ARVC diagnosis and compared with genotype-positive/phenotype-negative (G+/P-) relatives (ie, major family history criterion alone). Relatives 20 to 40 years of age had increased risk for developing definite ARVC (hazard ratio, 2.23; CONCLUSIONS: An evidence-based longitudinal screening algorithm that integrates age, symptoms, and baseline clinical phenotype may improve patient care and improve efficiency of clinical resource allocation.

Atherosclerosis arises from disrupted cholesterol metabolism, notably impaired macrophage cholesterol efflux leading to foam cell formation. Through single-cell and bulk RNA-Seq, we identified Listerin E3 ubiquitin protein ligase 1 (Listerin) as a regulator of macrophage cholesterol metabolism. Listerin expression increased during atherosclerosis progression in humans and rodents. Its deficiency suppressed cholesterol efflux, promoted foam cell formation, and exacerbated plaque features (macrophage infiltration, lipid deposition, necrotic cores) in macrophage-specific KO mice. Conversely, Listerin overexpression attenuated these atherosclerotic manifestations. Mechanistically, Listerin stabilizes ABCA1, a key cholesterol efflux mediator, by catalyzing K63-linked polyubiquitination at residues K1884/K1957, countering ESCRT-mediated lysosomal degradation of ABCA1 induced by oxidized LDL (oxLDL). ABCA1 agonist erythrodiol restored cholesterol efflux in Listerin-deficient macrophages, while KO of ABCA1 abolished Listerin's effects in Tsuchiya human monocytic leukemia line (THP-1) cells. This study establishes Listerin as a protective factor in atherosclerosis via posttranslational stabilization of ABCA1, offering a potential therapeutic strategy targeting ABCA1 ubiquitination to enhance cholesterol efflux.

IMPORTANCE: Previous studies support bystander provision of chest compression-only cardiopulmonary resuscitation (CC-CPR) for out-of-hospital cardiac arrest (OHCA). However, it is unknown whether OHCA secondary to opioid toxicity may benefit from chest compression plus ventilation CPR (CCV-CPR). OBJECTIVE: To examine the association between bystander CPR technique and outcomes among both opioid-associated OHCA (OA-OHCA) and otherwise undifferentiated OHCA. DESIGN, SETTING, AND PARTICIPANTS: This cohort study (performed from August 1, 2023, to December 31, 2024) analyzed cases of adult emergency medical services-treated OHCA that occurred from December 1, 2014, to March 31, 2020, as identified through the British Columbia Cardiac Arrest Registry. EXPOSURES: Cases were classified as OA-OHCA based on positive postmortem toxicologic investigations, death certificates, or opioid-specific hospital-based diagnoses. All other cases were classified as undifferentiated OHCA. MAIN OUTCOMES AND MEASURES: Favorable neurologic outcome at hospital discharge (cerebral performance category ≤2). A multivariable Utstein-adjusted logistic regression model of complete cases was used to assess the association between bystander CPR technique (CC-CPR [reference] vs both CCV-CPR and no CPR individually) with outcomes. An interaction term between the OA-OHCA and bystander CPR technique was used to estimate associations among OA-OHCA and undifferentiated OHCA cases separately. RESULTS: The study included 10 923 OHCAs. After removing 24 cases only treated with ventilatory support, there were 1343 OA-OHCAs (median [IQR] patient age, 40 [31-50] years; 1015 [76%] male) and 9556 undifferentiated OHCAs (median [IQR] patient age, 70 [58-81] years; 6636 (69%) male). In the OA-OHCA group, bystander CCV-CPR was associated with an increased odds of a favorable neurologic outcome (adjusted odds ratio [AOR], 2.85; 95% CI, 1.21-6.75) when compared with CC-CPR. No association was detected with favorable neurologic outcome (AOR, 1.52; 95% CI, 0.82-2.82) when no CPR was compared with CC-CPR. Among undifferentiated OHCAs, no association was detected with a favorable neurologic outcome (AOR, 1.16; 95% CI, 0.80-1.67) when CCV-CPR was compared with CC-CPR. No CPR was associated with a decreased odds of a favorable neurologic outcome (AOR, 0.69; 95% CI, 0.55-0.87) when compared with CC-CPR. The interaction term was statistically significant (P for interaction = .04). CONCLUSIONS AND RELEVANCE: In this cohort study of OHCA, bystander CCV-CPR (compared with CC-CPR) was associated with improved outcomes in opioid-associated OHCA; however, this association was not observed among undifferentiated cardiac arrests. These results suggest that the optimal bystander CPR technique for OA-OHCA and undifferentiated OHCA may differ and that ventilations may improve outcomes in OA-OHCA resuscitation.