Daily Cardiology Research Analysis
Three impactful studies span clinical, translational, and systems science. A Circulation analysis shows that withdrawing renin–angiotensin inhibitors/ARNi or MRAs in heart failure with improved ejection fraction increases 1‑year cardiovascular risk, while beta‑blocker withdrawal may be safer when EF ≥50%. A Circulation Research study demonstrates gene augmentation of TMEM43 rescues a lethal arrhythmogenic cardiomyopathy in mice, pointing to disease‑specific gene therapy. A large multicenter surg
Summary
Three impactful studies span clinical, translational, and systems science. A Circulation analysis shows that withdrawing renin–angiotensin inhibitors/ARNi or MRAs in heart failure with improved ejection fraction increases 1‑year cardiovascular risk, while beta‑blocker withdrawal may be safer when EF ≥50%. A Circulation Research study demonstrates gene augmentation of TMEM43 rescues a lethal arrhythmogenic cardiomyopathy in mice, pointing to disease‑specific gene therapy. A large multicenter surgical registry identifies unplanned reinterventions after congenital heart surgery (7.6%) as a powerful mortality signal and highlights disparities.
Research Themes
- Heart failure therapy de‑escalation and outcomes
- Gene therapy for inherited arrhythmogenic cardiomyopathy
- Quality, safety, and equity in congenital cardiac surgery
Selected Articles
1. Overexpression of Wild-Type TMEM43 Improves Cardiac Function in Arrhythmogenic Right Ventricular Cardiomyopathy Type 5.
Using transgenic and AAV-mediated gene delivery models, restoring wild-type TMEM43 counteracted the dominant S358L mutation in ARVC5 mice: delaying disease onset, improving contraction, reducing ECG abnormalities and fibrosis, and prolonging survival. A single systemic AAV dose carrying WT‑TMEM43 prevented ventricular dysfunction and ECG abnormalities induced by mutant TMEM43.
Impact: Represents a disease‑specific, gene‑augmentation strategy for one of the most lethal inherited cardiomyopathies, with rigorous in vivo rescue across models. It charts a translational path for precision gene therapy in ARVC5.
Clinical Implications: Although preclinical, the data support developing AAV‑mediated TMEM43 augmentation for TMEM43 p.S358L carriers, with implications for early intervention in genotype‑positive individuals and trial design (dose, timing, endpoints).
Key Findings
- Double transgenic overexpression of WT plus S358L TMEM43 delayed ARVC5 onset, improved contraction, reduced ECG abnormalities and myocardial fibrosis, and increased survival versus S358L alone.
- Systemic AAV delivery of codon-optimized WT‑TMEM43 prevented ventricular dysfunction and ECG abnormalities induced by mutant TMEM43.
- Cardiomyocyte death and fibrosis were reduced by WT TMEM43 overexpression, indicating target engagement and disease modification.
Methodological Strengths
- Multiple complementary in vivo models (transgenic and AAV gene delivery) for convergent validation
- Robust phenotyping (ECG, echocardiography, histology) with survival analyses
Limitations
- Preclinical mouse data; human safety, dosing, and long‑term durability remain unknown
- Potential off‑target effects and immune responses to AAV not fully characterized
Future Directions: IND‑enabling studies for AAV‑TMEM43 (toxicology, biodistribution, immunogenicity), large‑animal validation, and early‑phase trials in TMEM43 p.S358L carriers with biomarkers and imaging endpoints.
2. Withdrawal of Guideline-Directed Medical Therapy in Patients With Heart Failure and Improved Ejection Fraction.
In 8,728 HFimpEF patients, withdrawal at EF improvement was infrequent but clinically relevant: stopping RASi/ARNi or MRAs increased 1‑year risk of CV death/HF hospitalization by 38% and 36%, respectively. Beta‑blocker withdrawal showed no overall association but appeared harmful when EF was 40–49% versus safer when EF ≥50%.
Impact: Provides the largest real‑world evidence to date guiding de‑escalation in HF with improved EF, directly informing medication continuation policies and trial priorities.
Clinical Implications: Continue RASi/ARNi and MRAs after EF improves; avoid de‑escalation unless compelling reasons. Consider beta‑blocker step‑down only when EF has normalized (≥50%) and with close monitoring. Randomized trials on BB withdrawal are warranted.
Key Findings
- Withdrawal rates at EF improvement: 4.4% (RASi/ARNi), 3.3% (beta‑blocker), 17.2% (MRA).
- After overlap weighting, stopping RASi/ARNi or MRAs increased 1‑year CV death/HF hospitalization risk by 38% and 36%, respectively.
- Beta‑blocker withdrawal showed effect modification: harmful when improved EF was 40–49%, but not when EF ≥50%.
Methodological Strengths
- Nationwide registry with large sample (n=8,728) and contemporary timeframe
- Causal inference strengthened by overlap weighting and prespecified composite outcomes
Limitations
- Observational design with potential residual confounding and indication bias
- Reasons for withdrawal and adherence dynamics not fully captured
Future Directions: Randomized trials of beta‑blocker withdrawal stratified by EF bands; pragmatic trials testing guided de‑escalation algorithms; biomarker/imaging predictors of safe withdrawal.
3. Unplanned reinterventions after congenital cardiac surgery and hospital mortality: A report from the Pediatric Cardiac Critical Care Consortium (PC
Across 34,495 congenital cardiac operations at 62 centers, unplanned reinterventions occurred in 7.6% with substantial center variation and were strongly associated with in‑hospital mortality (16.1% vs 1.3%; adjusted OR 6.45). Risk factors included Black race, extracardiac/chromosomal anomalies, younger age, lower weight‑for‑age, prior surgeries, and higher surgical complexity; mortality peaked when both reoperation and catheterization were required.
Impact: Defines a high‑value surgical quality target and equity gap in congenital heart care using contemporary, multicenter data. Quantifies mortality risk and actionable risk factors for QI programs.
Clinical Implications: Prioritize prevention and early detection of residual lesions; standardize postoperative surveillance; deploy center‑level QI to reduce reintervention rates; address disparities (e.g., focused follow‑up for high‑risk groups). Multidisciplinary planning to avoid dual reoperation and catheterization where feasible.
Key Findings
- Unplanned reinterventions occurred in 7.6% (2,635/34,495) with wide center variation.
- Unplanned reintervention was associated with markedly higher in‑hospital mortality (16.1% vs 1.3%; adjusted OR 6.45, 95% CI 5.51–7.56).
- Risk factors included Black race, extracardiac/chromosomal anomalies, younger age, lower weight‑for‑age, prior surgeries, and higher STS/EACTS category; mortality highest with combined reoperation + catheterization (31.9%).
Methodological Strengths
- Very large, contemporary multicenter cohort (62 centers) with center‑effect adjustment
- Granular capture of reintervention type and integration with mortality outcomes
Limitations
- Observational registry; residual confounding and heterogeneity in indications/protocols
- Timing, causes, and preventability of reinterventions not fully adjudicated
Future Directions: Benchmarking and feedback to reduce center variation; prospective QI collaboratives targeting residual lesions; equity‑focused interventions to reduce disproportionate risk in Black children.