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.
BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy type 5 (ARVC5) is the most aggressive type of ARVC, caused by a fully penetrant missense mutation (p.S358L) in TMEM43 (transmembrane protein 43). Pathologically, the disease is characterized by dilation of the cardiac chambers and fibrofatty replacement of the myocardium, which results in heart failure and sudden cardiac death. Current therapeutic options are limited, and no specific therapies targeting the primary cause of the disease have been proposed. METHODS: We investigated whether overexpression of wild-type (WT) TMEM43 could ov
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.
BACKGROUND: Limited evidence exists on the prognostic role of continuing medical therapy in patients with heart failure (HF) and an ejection fraction (EF) that has improved over time. This study assessed rates of, patient profiles, and associations with morbidity/mortality of renin-angiotensin inhibitors (RASi), angiotensin receptor-neprilysin inhibitors (ARNi), beta-blockers (BBL), and mineralocorticoid receptor antagonists (MRA) withdrawal in patients with HF with improved EF. METHODS: Patients with a first recorded EF <40% and a later EF ≥40% from the Swedish HF registry between June 11, 2000, and December 31, 2023, were included in this retrospective observational study. Withdrawal was defined as a patient on treatment at the first (reduced) but not at the second (improved) registration. The association between withdrawal and time to first cardiovascular mortality/hospitalization for HF with censoring at 1 year was assessed by Cox regression model using overlap weighting. RESULTS: Of 8728 patients with HF with improved EF (median age, 70 years [25th to 75th percentile, 61-78], 2611 [29.9%] women), 96%, 94%, and 46% received RASi/ARNi, BBL, and MRA, respectively, when EF was <40%. The withdrawal rates at the time of the improved EF registration were 4.4% for RASi/ARNi, 3.3% for BBL, and 17.2% for MRA. Predictors of withdrawal included lower use of other HF medications, higher EF at the later EF registration, and a longer time between the 2 EF assessments. After weighting, withdrawal was independently associated with a higher risk of cardiovascular mortality/hospitalization for HF by 38% for RASi/ARNi and 36% for MRA, but not for BBL. Withdrawal of BBL was associated with a higher risk of the primary outcome in the subgroup of patients with an improved EF of 40% to 49% versus ≥50% ( CONCLUSIONS: In patients with HF with improved EF, HF therapy withdrawal was rare. Withdrawing RASi/ARNi and MRA was associated with higher mortality/morbidity at 1 year. No association was found for BBL withdrawal, albeit with a significant heterogeneity for EF at improvement, suggesting better outcomes with continuing BBL only until EF improves up to 50%. These results are hypothesis-generating and highlight the need for randomized controlled trials testing BBL withdrawal in patients with HF with improved EF.
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.
OBJECTIVES: Unplanned cardiac reinterventions after congenital cardiac surgery may complicate the postoperative course. We sought to identify incidence rates and risk factors for unplanned cardiac reinterventions and associations between unplanned cardiac reinterventions and hospital mortality. METHODS: Patients in the Pediatric Cardiac Critical Care Consortium registry undergoing an index cardiac operation from February 2019 to January 2022 were included. Multivariable logistic regression, adjusted for center effect, was used to evaluate patient risk factors for unplanned cardiac reinterventions and the impact of reintervention on hospital mortality. RESULTS: Included were 34,495 patients from 62 centers. Unplanned cardiac reinterventions occurred in 2635 patients (7.6%) with wide center variation. Risk factors for unplanned cardiac reinterventions included Black race, extracardiac and chromosomal anomalies, younger age, lower weight for age, prior cardiac surgeries, and higher surgical complexity category. The performance of an unplanned cardiac reintervention was associated with higher hospital mortality (16.1%) compared with those who did not undergo reintervention (1.3%) (adjusted odds ratio, 6.45; 95% CI, 5.51-7.56, P < .001). The odds of mortality after unplanned cardiac reinterventions increased with higher Society of Thoracic Surgeons and European Association for Cardiothoracic Surgery category. Mortality was highest in patients who underwent both reoperation and interventional catheterization (31.9%) compared with those who underwent only reoperation (16.3%) or catheterization (9.8%). CONCLUSIONS: Unplanned cardiac reinterventions occur in approximately 1 in 13 patients after congenital cardiac surgery, and approximately 1 in 6 patients with an unplanned cardiac reintervention will die. Patients at greatest risk for unplanned cardiac reinterventions may share patient and disease-specific risk factors. Further investigation is needed to minimize the incidence of residual lesions, understand why Black children have more unplanned cardiac reinterventions, and explore modifiable risk factors for and optimal timing of unplanned cardiac reinterventions.