Daily Cardiology Research Analysis
Analyzed 104 papers and selected 3 impactful papers.
Summary
Three high-impact cardiology studies stood out today: a mechanistic-translational investigation linking regional fibroblast and macrophage phenotypes to atrial fibrillation maintenance with promising ablation outcomes; a prespecified analysis from EXCEL showing spontaneous MI after left main revascularization is more frequent after PCI than CABG and strongly predicts mortality; and an electronic health record trial emulation indicating empagliflozin’s mortality benefit extends broadly beyond RCT-eligible patients.
Research Themes
- Mechanistic drivers and targeted ablation strategies in persistent atrial fibrillation
- Comparative outcomes after left main PCI versus CABG with focus on spontaneous MI
- Real-world effectiveness of SGLT2 inhibitors beyond trial populations
Selected Articles
1. Cardiac Macrophages and Fibroblasts Modulate Atrial Fibrillation Maintenance.
Across two porcine PsAF models and human validation, atrial driver regions were enriched for ACTA2- and PTX3-fibroblast phenotypes and resident cardiac macrophages with homeostatic/survival-supporting signatures. Targeted ablation of driver regions terminated AF in most pigs and was associated with 90% AF freedom at 2 years in humans.
Impact: This work links spatially resolved nonmyocyte phenotypes to AF maintenance and demonstrates translatable targeting with strong clinical signals, advancing mechanistic understanding and interventional strategy.
Clinical Implications: Mapping and ablating AF driver regions characterized by specific fibroblast and macrophage states may improve long-term rhythm control beyond conventional lesion sets.
Key Findings
- Driver regions showed enrichment of ACTA2-fibroblasts and PTX3-fibroblasts in porcine PsAF, with PTX3-fibroblast enrichment confined to driver areas on paired regional analysis.
- Resident cardiac macrophages with homeostatic/cell-survival gene and proteomic signatures were enriched in driver regions in pigs and humans.
- In vivo mapping-guided ablation acutely terminated PsAF in 12/14 pigs, and human driver ablation yielded 90% AF freedom at 2 years (on/off AADs).
Methodological Strengths
- Multi-model approach integrating in vivo mapping, single-cell RNA-seq, proteomics, and human validation
- Regional paired analyses distinguishing driver versus non-driver atrial territories
Limitations
- Nonrandomized human ablation outcomes and modest sample sizes may overestimate effect size
- Mechanistic causality of specific cell states requires interventional perturbation studies
Future Directions: Prospective randomized trials of driver-guided ablation and targeted modulation of fibroblast/macrophage phenotypes; development of clinical mapping biomarkers for driver identification.
BACKGROUND: Nonmyocytes may contribute to regional adaptive changes during persistent atrial fibrillation (PsAF), favoring its perpetuation. We aimed to investigate the differential features of fibroblast and macrophage populations within individual-specific atrial regions associated with PsAF maintenance. METHODS: The study was conducted in 2 pig models of PsAF with and without infarct-related substrate (N=27 and N=27, respectively) and further validated in humans with PsAF (N=20). Sham-operated pigs (N=9), healthy animals (N=4), and patients in sinus rhythm (N=7) were used as comparative controls. In pigs, in vivo high-density instantaneous frequency modulation maps were used to identify atrial regions associated with PsAF maintenance (drivers). Regional cellular composition and phenotypic states of fibroblast and myeloid lineages were determined using flow cytometry, single-cell RNA sequencing, immunohistochemistry, and proteomic analyses. The functional relevance of driver regions was further studied in patients with symptomatic PsAF undergoing ablation. Flow cytometry and single-cell RNA sequencing analyses were performed in tissue samples of the left atrial appendage in a complementary cohort of patients with PsAF undergoing thoracoscopic-guided ablation.
2. Spontaneous Myocardial Infarction After Left Main Revascularization: The EXCEL Trial.
In EXCEL, spontaneous MI within 5 years occurred about twice as often after PCI as after CABG for left main disease and was a potent predictor of subsequent cardiovascular and all-cause mortality across strategies, exceeding the prognostic impact of large procedural MI.
Impact: Clarifies the prognostic weight of spontaneous MI after left main revascularization and highlights differential risks after PCI versus CABG, informing patient counseling and surveillance.
Clinical Implications: Post-PCI surveillance for spontaneous MI in left main disease warrants particular attention; strategy selection should consider the higher spontaneous MI risk after PCI and its strong mortality linkage.
Key Findings
- Among 1,882 EXCEL participants, 5-year spontaneous MI occurred in 6.8% after PCI vs 3.4% after CABG (adjusted HR ≈2.0).
- Spontaneous MI was strongly associated with subsequent cardiovascular and all-cause mortality after both PCI and CABG.
- The prognostic association of spontaneous MI with mortality exceeded that of large procedural MI.
Methodological Strengths
- Event adjudication within a large, randomized trial framework with 5-year follow-up
- Adjusted time-to-event modeling for robust prognostic assessment
Limitations
- Secondary analysis; treatment selection effects and post-procedural management differences may confound causal inference
- Etiologic mechanisms of spontaneous MI were not fully delineated
Future Directions: Define mechanisms and predictors of spontaneous MI post-revascularization; test surveillance and secondary prevention strategies tailored to left main PCI patients.
BACKGROUND: Limited data are available regarding the relative rates, etiology, and long-term prognostic implications of spontaneous myocardial infarction (MI) after percutaneous coronary intervention (PCI) versus coronary artery bypass graft (CABG) surgery for left main coronary artery disease (LMCAD). METHODS: MIs after PCI and CABG for LMCAD were adjudicated from the EXCEL trial (Evaluation of Xience Versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization). Cox proportional hazards regression was performed to assess the association between spontaneous (and procedural) MI and cardiovascular and all-cause mortality at 5 years. RESULTS: Among 1882 patients who underwent LMCAD revascularization, spontaneous MI during 5-year follow-up occurred in 60 (6.8%) patients after PCI and in 29 (3.4%) patients after CABG (adjusted hazard ratio [adjHR], 2.01; 95 CI, 1.29-3.15; CONCLUSIONS: In the EXCEL trial, spontaneous MI occurred relatively infrequently within 5 years after LMCAD revascularization but at a higher rate after PCI compared with CABG. Spontaneous MI after revascularization was strongly related to subsequent cardiovascular and all-cause mortality, consistently after PCI and CABG, and was more strongly associated with mortality than was large procedural MI.
3. Enhancing evidence-based care using trial emulation in electronic health records: real-world effects of empagliflozin in people with type 2 diabetes.
A UK EHR-based trial emulation found empagliflozin reduced all-cause mortality versus DPP-4 inhibitors (adjusted HR 0.76) across broad T2DM populations, including 83% who would have been RCT-ineligible, with no heterogeneity by trial eligibility.
Impact: Bridges the RCT-to-real-world gap using formal emulation, supporting guideline expansion of SGLT2i use in diverse T2DM populations.
Clinical Implications: Supports broader initiation of empagliflozin in routine care for T2DM patients, including those not meeting classical RCT criteria, to reduce mortality risk.
Key Findings
- 83.2% of empagliflozin initiators were RCT-ineligible compared with EMPA-REG criteria, highlighting real-world differences.
- Empagliflozin was associated with lower all-cause mortality versus DPP-4 inhibitors (adjusted HR 0.76; 95% CI 0.69–0.83).
- No effect modification by RCT eligibility (p-interaction=0.27), indicating consistent benefit across eligibility strata.
Methodological Strengths
- Explicit trial emulation design anchored to a pivotal RCT with active-comparator new-user framework
- Adjusted Cox models with stratified analyses by RCT eligibility enhance generalizability
Limitations
- Observational design subject to residual confounding and misclassification in EHR data
- Mortality was the primary endpoint; cause-specific outcomes and safety require further study
Future Directions: Extend emulations to cardiovascular and renal endpoints and diverse health systems; evaluate comparative effectiveness across SGLT2i and in high-risk subgroups.
BACKGROUND: There is growing interest in widening the use of sodium-glucose co-transporter 2 inhibitors (SGLT2i) to all people with type 2 diabetes mellitus (T2DM). However, pivotal randomized controlled trials (RCTs) evaluated these drugs only in highly selected populations, often lacking generalizability to real-world populations. Understanding the effects of SGLT2i in populations where RCT evidence may be lacking is essential to help inform guideline development. To address this, we estimated the effect of empagliflozin in real-world users, many of whom would not have been eligible for the pivotal EMPA-REG RCT. METHODS: We designed a trial emulation in UK primary care data, based on the EMPA-REG RCT, to assess the effect of empagliflozin in a more clinically relevant population. Adults with T2DM initiating empagliflozin (intervention) or dipeptidyl peptidase-4 inhibitors (active control) between January 1, 2014 and December 31, 2022 were included. Eligibility was extended to both RCT-eligible and RCT-ineligible individuals. The effect of empagliflozin on all-cause mortality was estimated using an adjusted Cox proportional hazards model, with stratified analyses by RCT eligibility. FINDINGS: The majority of people prescribed empagliflozin would not have met the EMPA-REG RCT eligibility criteria (11,011/13,239, 83.2% RCT-ineligible). During follow-up, all-cause mortality occurred in 551 out of 13,239 (4.2%) in the empagliflozin group and 6,589 out of 49,264 (13.4%) in the active control group (adjusted HR 0.76, 95% CI 0.69 to 0.83). There was no evidence of differential treatment effect by RCT eligibility status (p-interaction=0.27). INTERPRETATION: Patients prescribed empagliflozin in real-world settings differ substantially from those enrolled in the EMPA-REG RCT. Using electronic health records, we demonstrate that the mortality benefit observed in EMPA-REG extends to a broader, more diverse real-world population, including those excluded from the original RCT. These findings provide a novel source of real-world evidence supporting the wider use of empagliflozin in routine clinical practice.