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.
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.
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.