Daily Cardiology Research Analysis
Three impactful cardiology studies stood out: a landmark NEJM dual RCT (CREST-2) shows carotid-artery stenting plus intensive medical therapy reduces 4-year stroke/death versus medical therapy alone in asymptomatic high-grade carotid stenosis, while endarterectomy shows no significant benefit. A Circulation Research study reveals OTUD7a as a deubiquitinase that stabilizes TAK1 to drive pathological cardiac hypertrophy, nominating an actionable OTUD7a–TAK1 axis. An AI model integrating sinus ECGs
Summary
Three impactful cardiology studies stood out: a landmark NEJM dual RCT (CREST-2) shows carotid-artery stenting plus intensive medical therapy reduces 4-year stroke/death versus medical therapy alone in asymptomatic high-grade carotid stenosis, while endarterectomy shows no significant benefit. A Circulation Research study reveals OTUD7a as a deubiquitinase that stabilizes TAK1 to drive pathological cardiac hypertrophy, nominating an actionable OTUD7a–TAK1 axis. An AI model integrating sinus ECGs with CHARGE-AF features improved prediction of incident paroxysmal atrial fibrillation and validated across international cohorts.
Research Themes
- Revascularization strategy for asymptomatic carotid stenosis
- Mechanistic drivers and therapeutic targets of pathological cardiac hypertrophy
- AI-enabled ECG risk stratification for incident paroxysmal atrial fibrillation
Selected Articles
1. Medical Management and Revascularization for Asymptomatic Carotid Stenosis.
In CREST-2, carotid-artery stenting plus intensive medical management reduced the 4-year risk of perioperative stroke/death or ipsilateral stroke compared with medical therapy alone in asymptomatic ≥70% carotid stenosis, whereas endarterectomy did not show a significant benefit. Early periprocedural events were higher in the interventional arms but were offset by lower late ipsilateral stroke risk in the stenting arm.
Impact: This dual, observer-blinded, multicenter RCT directly informs management of common asymptomatic carotid stenosis and is likely to influence guidelines by differentiating benefits of stenting versus endarterectomy on top of modern medical therapy.
Clinical Implications: For high-grade asymptomatic carotid stenosis, consider carotid-artery stenting plus intensive risk-factor management; routine endarterectomy confers no clear added benefit over medical therapy alone. Periprocedural risk should be weighed, and patient selection and operator expertise remain critical.
Key Findings
- Stenting trial: 4-year primary composite 2.8% with stenting vs 6.0% with intensive medical therapy alone (P=0.02).
- Endarterectomy trial: 4-year primary composite 3.7% with endarterectomy vs 5.3% with medical therapy (P=0.24).
- Periprocedural (0–44 days) events were higher in interventional arms (stenting: 7 strokes, 1 death; endarterectomy: 9 strokes) compared with medical therapy alone.
Methodological Strengths
- Two parallel, observer-blinded randomized trials across 155 centers with standardized intensive medical management.
- Prespecified composite endpoint with 4-year follow-up and adequate sample size (n≈2,485).
Limitations
- Early periprocedural risk in revascularization arms; treatment unblinded to operators/patients.
- Follow-up limited to 4 years; generalizability depends on operator expertise and center volume.
Future Directions: Define subgroups with greatest net benefit from stenting, optimize perioperative risk mitigation, and assess longer-term (≥5–10 years) durability versus contemporary medical therapy.
BACKGROUND: Improvements in medical therapy, carotid-artery stenting, and carotid endarterectomy call into question the preferred management of asymptomatic carotid stenosis. Whether adding revascularization to intensive medical management would provide greater benefit than intensive medical management alone is unclear. METHODS: We conducted two parallel, observer-blinded clinical trials that enrolled patients with high-grade (≥70%) asymptomatic carotid stenosis across 155 centers in five countries. The stenting trial compared intensive medical management alone (medical-therapy group) with carotid-artery stenting plus intensive medical management (stenting group); the endarterectomy trial compared intensive medical management alone (medical-therapy group) with carotid endarterectomy plus intensive medical management (endarterectomy group). The primary outcome was a composite of any stroke or death, assessed from randomization to 44 days, or ipsilateral ischemic stroke, assessed during the remaining follow-up period up to 4 years. RESULTS: A total of 1245 patients underwent randomization in the stenting trial and 1240 in the endarterectomy trial. In the stenting trial, the 4-year incidence of primary-outcome events was 6.0% (95% confidence interval [CI], 3.8 to 8.3) in the medical-therapy group and 2.8% (95% CI, 1.5 to 4.3) in the stenting group (P = 0.02 for the absolute difference). In the endarterectomy trial, the 4-year incidence of primary-outcome events was 5.3% (95% CI, 3.3 to 7.4) in the medical-therapy group and 3.7% (95% CI, 2.1 to 5.5) in the endarterectomy group (P = 0.24 for the absolute difference). From day 0 to 44, in the stenting trial, no strokes or deaths occurred in the medical-therapy group and seven strokes and one death occurred in the stenting group; in the endarterectomy trial, three strokes occurred in the medical-therapy group and nine strokes occurred in the endarterectomy group. CONCLUSIONS: Among patients with high-grade stenosis without recent symptoms, the addition of stenting led to a lower risk of a composite of perioperative stroke or death or ipsilateral stroke within 4 years than intensive medical management alone. Carotid endarterectomy did not lead to a significant benefit. (Funded by the National Institute of Neurological Disorders and Stroke and others; CREST-2 ClinicalTrials.gov number, NCT02089217.).
2. OTUD7a Accelerates Pathological Cardiac Hypertrophy via TAK1 Activation.
OTUD7a is upregulated in pathological hypertrophy and directly stabilizes TAK1 by inhibiting its ubiquitination, thereby activating TAK1–JNK/p38 signaling to drive hypertrophic remodeling. Genetic OTUD7a loss mitigates hypertrophy, and pharmacologic TAK1 inhibition blocks OTUD7a’s detrimental effects, nominating the OTUD7a–TAK1 axis as a translational target.
Impact: This work uncovers a previously unrecognized deubiquitinase-driven mechanism of hypertrophy and provides target validation using genetic perturbation and a selective TAK1 inhibitor, paving a mechanistic route to anti-hypertrophic therapies.
Clinical Implications: Although preclinical, targeting the OTUD7a–TAK1 axis could yield first-in-class therapies to prevent or reverse pathological hypertrophy and downstream heart failure; TAK1 inhibition emerges as a plausible approach.
Key Findings
- OTUD7a expression is induced by hypertrophic stimuli (TAC in vivo; phenylephrine in vitro).
- Cardiac-specific OTUD7a deficiency attenuates pathological hypertrophy; overexpression exacerbates it.
- OTUD7a directly interacts with TAK1, prevents its ubiquitin-mediated degradation, and augments TAK1 phosphorylation with downstream JNK/p38 activation; TAK1 inhibition (5Z-7-oxozeaenol) abrogates OTUD7a-driven hypertrophy.
Methodological Strengths
- Convergent in vivo (TAC model, AAV9 modulation) and in vitro (cardiomyocyte) validation with loss- and gain-of-function.
- Mechanistic target identification using RNA-seq, interactome mapping, and pharmacologic rescue with a selective TAK1 inhibitor.
Limitations
- Preclinical murine and cellular models may not fully recapitulate human hypertrophy.
- Potential off-target or systemic effects of chronic TAK1 inhibition require careful safety evaluation.
Future Directions: Validate OTUD7a–TAK1 signaling in human cardiac tissues, develop selective OTUD7a modulators, and test TAK1/OTUD7a targeting in large-animal models and early-phase clinical studies.
BACKGROUND: Cardiac hypertrophy is one of the major causes of heart failure and sudden cardiac death. OTUD7a (OTU domain-containing protein 7a) is identified as a deubiquitinizing enzyme and a possible tumor suppressor. The present study is aimed at exploring the potential role and key downstream effectors of OTUD7a in cardiac hypertrophy. METHODS: The expression level of OTUD7a was detected in the cardiomyocytes with phenylephrine stimuli and the hearts subjected to transverse aortic constriction surgery. Then, the potential effects of OTUD7a on cardiac hypertrophy were evaluated in vivo by using cardiac-specific OTUD7a knockout mice and adeno-associated virus serotype 9-OTUD7a-infected mice. To further explore the direct modulation of OTUD7a on cardiomyocytes, hypertrophic parameters were detected in phenylephrine-stimulated cardiomyocytes with adenovirus system-induced OTUD7a overexpression or depletion. Furthermore, RNA-sequencing and interactome analysis, which were followed by multiple molecular biological methodologies, were combined to identify the direct target and corresponding molecular events contributing to OTUD7a function. RESULTS: Cardiac hypertrophy stimulates expression of OTUD7a in vitro and in vivo. Our data clearly showed that OTUD7a deficiency alleviates pathological cardiac hypertrophy in the transverse aortic constriction mouse model as well as in phenylephrine-treated cardiomyocytes, whereas overexpression of OTUD7a aggravated hypertrophic heart in vivo and enhanced cardiomyocyte enlargement in vitro. Mechanistically, TAK1 (transforming growth factor-β-activated kinase 1) was identified as a direct and essential target of OTUD7a in cardiac hypertrophy. To be more specific, OTUD7a directly interacts with TAK1 to inhibit the ubiquitination degradation of TAK1 and subsequently increase the phosphorylation levels of TAK1 and its downstream JNK (c-Jun N-terminal kinase)/P38. 5Z-7-oxozeaenol, a TAK1 inhibitor, blocked the detrimental effects of OTUD7a. Moreover, overexpression of TAK1 abolished the protection of OTUD7a depletion. CONCLUSIONS: Our findings, for the first time, provide evidence supporting OTUD7a as a novel promoter of pathological cardiac hypertrophy and indicate that targeting the OTUD7a-TAK1 axis represents a promising therapeutic strategy for cardiac hypertrophy and related heart failure.
3. Artificial intelligence-enabled sinus electrocardiograms for the detection of paroxysmal atrial fibrillation benchmarked against the CHARGE-AF score.
A CNN trained on sinus rhythm ECGs with CHARGE-AF clinical features achieved AUC 0.89 on the internal test set and 0.85–0.90 in two external cohorts, outperforming CHARGE-AF alone for predicting incident paroxysmal AF. Performance was robust across demographic subgroups, and an ECG-only model retained strong predictive ability when clinical data were missing or inaccurate.
Impact: This large, externally validated AI approach leverages ubiquitous sinus ECGs to enable scalable, opportunistic AF screening and risk stratification beyond traditional risk scores.
Clinical Implications: AI-ECG models could flag high-risk individuals for targeted rhythm monitoring (e.g., prolonged ambulatory ECG) or early preventive strategies, especially where comprehensive clinical data are incomplete.
Key Findings
- Internal test performance: AUC 0.89, AUPRC 0.69, surpassing CHARGE-AF alone.
- External validation: AUC 0.90 (US outpatient cohort) and 0.85 (Greek tertiary cohort), with strong AUPRC.
- ECG-only CNN retained strong predictive ability under simulated missing or inaccurate clinical data; consistent performance across age, sex, and race.
Methodological Strengths
- Very large development cohort with two geographically and clinically distinct external validation cohorts.
- Benchmarking against a guideline-recognized risk score (CHARGE-AF) and subgroup robustness analyses.
Limitations
- Retrospective design; label definitions and ECG acquisition variability may introduce bias.
- Clinical utility needs prospective testing to assess impact on monitoring strategies and outcomes.
Future Directions: Prospective trials integrating AI-ECG triage into AF screening pathways, cost-effectiveness analyses, and evaluation of downstream outcomes (stroke, AF burden, therapy adoption).
AIMS: We aimed to develop and externally validate a convolutional neural network (CNN) using sinus rhythm electrocardiograms (ECGs) and CHARGE-AF features to predict incident paroxysmal atrial fibrillation (AF), benchmarking its performance against the CHARGE-AF score. METHODS AND RESULTS: We curated 157 192 sinus ECGs from 76 986 patients within the New York University (NYU) Langone Health system, splitting data into training, validation, and test sets. Two cohorts, from suburban US outpatient practices and Greek tertiary hospitals, were used for external validation. The model utilizing the sinus ECG signal and all CHARGE-AF features achieved the highest test set area under the receiver operator curve (AUC) (0.89) and area under the precision recall curve (AUPRC) (0.69), outperforming the CHARGE-AF score alone. Model robustness was maintained in the external US cohort (AUC 0.90, AUPRC 0.67) and the European cohort (AUC 0.85, AUPRC 0.78). Subgroup analyses confirmed consistent performance across age, sex, and race strata. A CNN using ECG signals alone retained strong predictive ability, particularly when simulating missing or inaccurate clinical data. CONCLUSION: Our CNN integrating sinus rhythm ECGs and CHARGE-AF features demonstrated superior predictive performance over traditional risk scoring alone for detecting incident paroxysmal AF. The model maintained accuracy across geographically and clinically diverse external validation cohorts, supporting its potential for broad implementation in AF screening strategies.