Daily Cardiology Research Analysis
Three impactful cardiology studies emerged: a Circulation cohort proposes an age- and phenotype-tailored screening algorithm for PKP2-associated arrhythmogenic right ventricular cardiomyopathy; a JCI mechanistic study identifies Listerin E3 ligase as a protector against atherosclerosis via K63-linked ubiquitination and stabilization of ABCA1; and a JAMA Network Open cohort shows ventilations during bystander CPR improve neurologic outcomes in opioid-associated out-of-hospital cardiac arrest.
Summary
Three impactful cardiology studies emerged: a Circulation cohort proposes an age- and phenotype-tailored screening algorithm for PKP2-associated arrhythmogenic right ventricular cardiomyopathy; a JCI mechanistic study identifies Listerin E3 ligase as a protector against atherosclerosis via K63-linked ubiquitination and stabilization of ABCA1; and a JAMA Network Open cohort shows ventilations during bystander CPR improve neurologic outcomes in opioid-associated out-of-hospital cardiac arrest.
Research Themes
- Genotype-informed family screening strategies in inherited cardiomyopathy
- Ubiquitin-mediated regulation of cholesterol efflux in atherosclerosis
- Context-specific bystander CPR techniques in opioid-associated cardiac arrest
Selected Articles
1. Family Screening in Relatives at Risk for Plakophilin-2-Associated Arrhythmogenic Right Ventricular Cardiomyopathy.
In 295 PKP2-variant relatives followed a median of 8.5 years, 37% had definite ARVC at baseline, 34% of the remainder progressed to definite ARVC, and 12% experienced ventricular arrhythmias—all after fulfilling definite ARVC criteria. Borderline ARVC progressed about 5 times faster than genotype-positive/phenotype-negative status, with highest progression risk at ages 20–40, informing a tailored screening algorithm.
Impact: Provides genotype- and phenotype-informed risk stratification for ARVC families with concrete progression rates and age windows, enabling more efficient and safer surveillance.
Clinical Implications: Increase screening intensity (e.g., ECG/echo/Holter/CMR) in 20–40-year-old PKP2-positive relatives and those meeting borderline criteria; de-escalate frequency in genotype-positive/phenotype-negative individuals while maintaining surveillance; reserve arrhythmic prophylaxis for those achieving definite ARVC.
Key Findings
- At baseline, 37% (110/295) of PKP2-positive relatives had definite ARVC.
- Over median 8.5 years, 34% (62/185) without definite ARVC progressed to definite ARVC.
- 12% (35/295) experienced ventricular arrhythmias, exclusively after definite ARVC diagnosis.
- Borderline ARVC progressed ~5× faster than genotype-positive/phenotype-negative status.
- Ages 20–40 had increased risk of developing definite ARVC (HR ≈2.23).
Methodological Strengths
- Longitudinal cohort with median 8.5-year follow-up and multistate modeling of progression.
- Phenotype-specific outcomes (progression and ventricular arrhythmias) with genotype focus (PKP2).
Limitations
- Observational design susceptible to referral and ascertainment bias.
- Findings limited to PKP2; generalizability to other ARVC genotypes is uncertain.
Future Directions: External validation in diverse cohorts; cost-effectiveness of genotype-informed surveillance intervals; integration of wearable arrhythmia monitoring.
2. E3 ubiquitin ligase Listerin regulates macrophage cholesterol efflux and atherosclerosis by targeting ABCA1.
Listerin acts as atheroprotective by stabilizing ABCA1 via K63-linked polyubiquitination (K1884/K1957), thereby countering oxLDL-triggered ESCRT-mediated lysosomal degradation, enhancing macrophage cholesterol efflux, and attenuating plaque progression in macrophage-specific models.
Impact: Reveals a previously unrecognized post-translational mechanism regulating ABCA1 stability, nominating ubiquitination machinery as a druggable axis for atherosclerosis.
Clinical Implications: Therapeutic strategies that enhance Listerin activity or mimic its K63-ubiquitination of ABCA1 could boost cholesterol efflux in plaque macrophages; ABCA1-stabilizing agents (e.g., erythrodiol-like agonists) merit translational development.
Key Findings
- Listerin expression increases with atherosclerosis progression in humans and rodents.
- Macrophage-specific Listerin deficiency reduces cholesterol efflux, promotes foam cell formation, and worsens plaque (macrophage infiltration, lipid deposition, necrotic cores).
- Listerin stabilizes ABCA1 by K63-linked polyubiquitination at K1884/K1957, preventing ESCRT-mediated lysosomal degradation induced by oxLDL.
- ABCA1 agonist erythrodiol rescues cholesterol efflux in Listerin-deficient macrophages; ABCA1 knockout abolishes Listerin’s effects.
Methodological Strengths
- Integrated single-cell and bulk RNA-Seq to identify target, with in vivo macrophage-specific knockout and overexpression models.
- Mechanistic dissection of ABCA1 ubiquitination (site-specific K63 linkage) and ESCRT pathway involvement.
Limitations
- Preclinical models; therapeutic translation to humans remains to be demonstrated.
- Human validation primarily expression-level; functional confirmation in human tissues is limited.
Future Directions: Develop small molecules/biologics to enhance Listerin-ABCA1 interaction or K63-ubiquitination; test ABCA1-stabilizing strategies in advanced plaque regression models and translational trials.
3. Bystander CPR Technique and Outcomes for Cardiac Arrest With and Without Opioid Toxicity.
Among 10,923 EMS-treated OHCAs, bystander chest compression plus ventilation (CCV-CPR) was associated with better neurologic outcomes than compression-only CPR in opioid-associated arrests (AOR 2.85), but not in undifferentiated arrests. The interaction suggests tailored dispatcher guidance emphasizing ventilations in suspected opioid overdoses.
Impact: Challenges one-size-fits-all CPR guidance by demonstrating context-dependent benefit of ventilations in opioid-associated OHCA, a growing public health problem.
Clinical Implications: Dispatcher-assisted CPR and public training should include ventilations when opioid overdose is suspected; EMS and public health protocols may need to differentiate guidance by presumed etiology.
Key Findings
- In opioid-associated OHCA (n=1343), CCV-CPR vs CC-CPR increased odds of favorable neurologic outcome (AOR 2.85; 95% CI 1.21–6.75).
- In undifferentiated OHCA (n=9556), CCV-CPR vs CC-CPR showed no significant association (AOR 1.16; 95% CI 0.80–1.67).
- No CPR reduced odds of favorable neurologic outcome in undifferentiated OHCA (AOR 0.69; 95% CI 0.55–0.87).
- Significant interaction between etiology (opioid-associated vs undifferentiated) and CPR technique (P for interaction = .04).
Methodological Strengths
- Large, population-based registry with Utstein-adjusted multivariable modeling.
- Etiology classification using toxicology, death certificates, and hospital diagnoses; prespecified interaction testing.
Limitations
- Observational design with potential residual confounding and misclassification of etiology.
- Cannot account for bystander naloxone use or quality of ventilations and compressions.
Future Directions: Prospective trials or pragmatic cluster-randomized dispatcher guidance studies; evaluation of combined ventilation-plus-naloxone protocols for suspected opioid overdoses.