Daily Cardiology Research Analysis
Mechanistic advances link hepatocyte FXR signaling and the oral microbiome to thromboinflammation and myocardial injury, while a large comparative analysis suggests intravascular imaging–guided PCI may approach CABG outcomes in complex coronary disease. These studies collectively span basic-to-clinical translation, highlighting druggable pathways (FXR–PAI-1), microbiota–B cell axes, and optimization of revascularization strategy.
Summary
Mechanistic advances link hepatocyte FXR signaling and the oral microbiome to thromboinflammation and myocardial injury, while a large comparative analysis suggests intravascular imaging–guided PCI may approach CABG outcomes in complex coronary disease. These studies collectively span basic-to-clinical translation, highlighting druggable pathways (FXR–PAI-1), microbiota–B cell axes, and optimization of revascularization strategy.
Research Themes
- Thrombosis biology and hepatocyte FXR–PAI-1 regulation
- Oral microbiome–immune (B2 cell) axis in myocardial infarction
- Imaging-guided revascularization strategies in complex coronary disease
Selected Articles
1. Targeting FXR in hepatocytes: a promising approach to enhance fibrinolysis and reduce deep vein thrombosis risk.
In murine obesity models, hepatocyte FXR activation directly repressed Serpine1/PAI-1 transcription, improving fibrinolysis and reducing DVT burden. Loss of hepatocyte FXR increased circulating PAI-1 and worsened thrombosis, and the FXR agonist tropifexor lowered PAI-1 and thrombus load, supporting FXR as a hepatocentric, druggable regulator of fibrinolysis.
Impact: This work uncovers a direct transcriptional mechanism linking hepatocyte FXR to PAI-1 and fibrinolysis, and demonstrates pharmacologic tractability with tropifexor in obese mice. It provides a mechanistic and therapeutic framework to mitigate obesity-associated venous thrombosis.
Clinical Implications: If translated to humans, FXR agonists could reduce PAI-1 and enhance fibrinolysis in high-risk obese patients, potentially lowering DVT risk. This supports clinical testing of FXR-targeted therapies and monitoring PAI-1 as a pharmacodynamic biomarker.
Key Findings
- Hepatocyte FXR activation directly represses Serpine1/PAI-1 transcription (dual-luciferase and ChIP evidence).
- FXR-null and hepatocyte-specific Fxr-deleted mice have elevated plasma PAI-1, impaired fibrinolysis, and increased DVT burden.
- Tropifexor treatment in obese mice lowers plasma PAI-1 and reduces thrombus load, improving fibrinolysis.
- Human single-cell liver transcriptomes from obesity suggest reduced hepatocyte FXR signaling associates with higher PAI-1.
Methodological Strengths
- Multi-level validation across in vivo (global and hepatocyte-specific FXR loss), primary hepatocytes, and transcriptomic datasets.
- Mechanistic assays (dual-luciferase reporter and ChIP) establishing direct transcriptional repression of Serpine1 by FXR.
Limitations
- Preclinical models; human causal validation and dose–response/safety of FXR agonists for thrombosis are untested.
- Potential pleiotropic effects of FXR agonism and context-dependent metabolic actions may complicate translation.
Future Directions: Prospective human studies to correlate FXR activity and PAI-1 with fibrinolytic capacity and DVT outcomes; early-phase trials of FXR agonists (e.g., tropifexor) in obesity-related hypercoagulability with PAI-1-guided dosing.
Obesity is a major health issue and a risk factor for venous thromboembolic disease. Plasminogen activator inhibitor 1 (PAI-1), encoded by the gene SERPINE1, is a negative regulator of fibrinolysis and has been associated with obesity. The liver, which senses obesity-induced metabolic stress, is a key determinant of circulating PAI-1 levels. However, the mechanisms underlying the increased PAI-1 expression in obesity are unclear. This study investigated the upstream regulation of PAI-1 and its role in fibrinolysis and deep vein thrombosis (DVT). Compared with lean mice, diet-induced obesity mice presented significantly shorter fibrinolysis times and larger venous thrombi, largely due to increased hepatocyte expression of PAI-1. A publicly available single-cell RNA sequence data set from the livers of individuals with obesity suggested that increased PAI-1 expression may be related to reduced hepatocyte farnesoid X receptor (FXR) signaling. FXR activation also suppressed Serpine1 mRNA and PAI-1 protein expression levels in both mice and primary mouse hepatocytes (MPHs), but a decrease in PAI-1 in MPHs of Fxr-null mice after FXR activation was not observed. Both Fxr-null mice and Fxrfl/fl mice with AAV8-TBG-Cre exhibited significantly elevated plasma PAI-1, resulting in further impaired fibrinolysis and increased DVT burden. Dual-luciferase reporter assays and chromatin immunoprecipitation suggested that FXR activation directly represses Serpine1 transcription. Importantly, tropifexor treatment of obese mice lowered plasma PAI-1 levels and further alleviated fibrinolysis and the DVT load. These findings suggest that targeting FXR in hepatocytes may improve fibrinolysis and reduce DVT risk.
2. Oral Pathobionts Aggravate Myocardial Infarction Through Mobilization of B2 Cells.
Ligature-induced periodontitis and human subgingival plaque transfer worsened MI in mice via ectopic cardiac accumulation of oral pathobionts and mobilization of reactive B2 cells. Genetic and gnotobiotic experiments identified a B cell–dependent, cytokine-modulated mechanism linking the oral microbiome to myocardial injury.
Impact: This study provides causal, mechanistic evidence that specific oral microbes and B2 cell responses exacerbate MI, reframing the oral–cardiac axis from association to actionable biology.
Clinical Implications: Aggressive periodontal care and strategies to modulate oral pathobionts or B cell responses may reduce MI injury. Risk stratification could incorporate periodontal status and microbiome signatures.
Key Findings
- Ligature-induced periodontitis and transfer of human subgingival plaques exacerbated MI in mice.
- Oral pathobionts ectopically accumulated in infarcted myocardium (sequencing and FISH evidence).
- Reactive B2 cells specific to oral pathobionts mediated MI worsening; effects modulated by cytokine pathways (e.g., IL-6, TNF-α) and chemokine signaling.
- Gnotobiotic and knockout models (Ighm, Rag1, CXCL13, S1pr) delineated a B cell–dependent mechanism.
Methodological Strengths
- Causal inference through combined microbiota transfer, gnotobiotic systems, and genetic knockouts.
- Multiplex readouts (bacterial sequencing, FISH, flow cytometry) linking microbes to immune cell dynamics and cardiac injury.
Limitations
- Predominantly murine models; human interventional validation is lacking.
- Specificity of implicated pathobionts and generalizability across diverse oral microbiomes need clarification.
Future Directions: Identify and prioritize culprit oral pathobionts for targeted suppression; test periodontal and immunomodulatory interventions (e.g., B cell–directed) in MI outcomes; develop microbiome-based risk tools.
BACKGROUND: Myocardial infarction (MI) is a high-prevalence disease that threatens human survival and quality of life worldwide. Considerable evidence has suggested that periodontitis (PD) is detrimental to MI. However, the direct impact of PD on MI is unclear; which oral pathobionts contribute to and how microbial signals regulate the pathogenesis of MI remain obscure. METHODS: The effect of PD on MI was assessed in a mouse model that combined ligature-induced PD with MI. Ectopic accumulation of oral pathobionts in infarcted hearts was identified by bacterial sequencing and fluorescence in situ hybridization. Oral pathobionts-reactive B2 cells detrimental for MI were determined by flow cytometry and verified in gnotobiotic mice. Several mouse strains, including CD45.1, Kaede, and knockout strains for Ighm, Rag1, C-X-C motif chemokine ligand 13, S1pr, interleukin-6, and tumor necrosis factor-α, were used for mechanistical exploration. Mutant strains of RESULTS: Ligature-induced PD and subgingival plaques of patients with PD exacerbated MI in mice by oral pathobionts. CONCLUSIONS: Oral pathobionts and proinflammatory B2 cells significantly exacerbate MI, supporting the oral-heart axis as a novel pathogenic pathway. Interventions targeting PD, oral pathobionts, or related immunological mechanisms may improve the therapy of MI.
3. Intravascular Imaging-Guided PCI vs Coronary Artery Bypass Grafting for Left Main or 3-Vessel Disease.
Across pooled trial and registry data in left main/3-vessel disease, overall PCI had higher 3-year composite events than CABG, but IVI-guided PCI achieved outcomes comparable to CABG in adjusted and propensity-matched analyses. These findings suggest that intravascular imaging optimization may mitigate the historical outcome gap between PCI and CABG in complex disease.
Impact: Provides large-scale, contemporary evidence that IVI guidance may enable PCI to approach CABG outcomes in complex anatomy, supporting broader adoption of imaging-guided strategies and informing trial design.
Clinical Implications: In complex CAD (left main/3-vessel), routine intravascular imaging to optimize PCI (e.g., stent expansion, plaque/modifier strategies) may narrow outcome gaps with CABG for selected patients; decisions should remain multidisciplinary pending randomized confirmation.
Key Findings
- Overall PCI had higher 3-year composite of death/MI/stroke than CABG (13.3% vs 10.8%; HR 1.23).
- IVI-guided PCI had event rates comparable to CABG (8.7% vs 10.8%; HR 0.77; P=0.058), confirmed in propensity-matched analysis (HR 0.98).
- Angiography-guided PCI underperformed CABG, highlighting the potential value of imaging guidance.
Methodological Strengths
- Large pooled cohort including a randomized trial dataset and a high-volume institutional registry.
- Robust adjusted and propensity score–matched analyses comparing IVI-guided PCI, angiography-guided PCI, and CABG.
Limitations
- Nonrandomized comparison of IVI-guided PCI vs CABG; residual confounding and selection bias remain possible.
- Heterogeneity in imaging modalities, operators, and lesion complexity not fully standardized.
Future Directions: Randomized trials of IVI-guided PCI versus CABG in left main/3-vessel disease; standardized imaging protocols and core-lab adjudication to define best practices and thresholds.
BACKGROUND: Previous trials have shown that coronary artery bypass graft (CABG) has better clinical outcomes compared with percutaneous coronary intervention (PCI) for patients with left main coronary artery or 3-vessel disease. However, it is unclear whether intravascular imaging (IVI)-guided PCI would reduce the difference in clinical events compared to CABG. OBJECTIVES: The present study sought to compare the clinical outcomes of patients with left main or 3-vessel disease who underwent IVI-guided PCI with those who underwent CABG. METHODS: A total of 6,962 patients with left main or 3-vessel disease from the RENOVATE-COMPLEX-PCI trial (n = 1,639) and the institutional registry of Samsung Medical Center (2,972 patients underwent PCI and 6,600 patients underwent CABG) were analyzed. The primary outcome was a composite of death from any cause, nonfatal myocardial infarction, or stroke at 3 years. RESULTS: Among the study population, 848 patients underwent IVI-guided PCI, 987 patients underwent angiography-guided PCI, and 5,127 patients underwent CABG. Patients treated with PCI had significantly higher risk of primary outcome than patients who underwent CABG (13.3% vs 10.8%; HR: 1.23; 95% CI: 1.05-1.44; P = 0.013). However, the risk of primary outcome was comparable between IVI-guided PCI and CABG (8.7% vs 10.8%; HR: 0.77; 95% CI: 0.59-1.01; P = 0.058). The propensity score-matched analysis showed similar results between IVI-guided PCI and CABG (9.5% vs 9.4%; HR: 0.98; 95% CI: 0.69-1.40; P = 0.914). CONCLUSIONS: In this hypothesis-generating study, PCI had significantly higher risk of a composite of death, nonfatal myocardial infarction, or stroke than CABG. However, IVI-guided PCI had comparable risk of clinical events compared with CABG.