Highlight
– The junctional protein associated with coronary artery disease (JCAD) independently predicts recurrent major adverse cardiovascular events (MACE) in acute coronary syndrome (ACS) patients with residual lipid and/or inflammatory risk despite guideline-recommended care.
– JCAD levels correlate positively with impaired endogenous fibrinolysis, linking this protein mechanistically to coagulation and thrombotic pathways.
– The findings were robust across two large prospective cohorts, emphasizing JCAD as a promising biomarker and potential therapeutic target to address persistent ischemic risk in ACS.
– Measuring JCAD in ACS patients with residual lipid or inflammatory risk could improve risk stratification and guide novel anticoagulant or fibrinolytic therapies.
Study Background
Acute coronary syndromes (ACS), comprising unstable angina and myocardial infarction, remain a global leading cause of morbidity and mortality. Despite widespread use of guideline-directed therapies including statins and antiplatelets, many ACS patients sustain residual risk of recurrent ischemic events. This residual risk is understood to reflect multifactorial pathophysiology involving cholesterol dysregulation, persistent inflammation, and other less characterized mechanisms.
While low-density lipoprotein cholesterol (LDL-c) and high-sensitivity C-reactive protein (hs-CRP) have emerged as markers and therapeutic targets for lipid and inflammatory risk respectively, they do not fully account for recurrent cardiovascular events. Identifying novel molecular markers linked to unexplored pathways is essential.
The junctional protein associated with coronary artery disease (JCAD), a recently identified endothelial junctional protein, has been implicated in modulating coagulation and fibrinolysis. Since thrombus formation after plaque rupture is a final common pathway of ACS events, JCAD’s role may represent a critical residual risk factor beyond lipids and inflammation.
Study Design
This investigation analyzed two prospective ACS cohorts. The discovery cohort (SPUM-ACS; n=4,787) included patients receiving statin therapy who were categorized based on residual lipid risk (RLR: LDL-c ≥70 mg/dL), residual inflammatory risk (RIR: hs-CRP ≥2.0 mg/L), or combined residual ischemic risk (RILR: both criteria). Each risk group was matched with controls using propensity scores.
The primary endpoint was recurrent major adverse cardiovascular events (MACE) at 1 year. Multivariable-adjusted Cox proportional hazard models evaluated associations between hs-CRP, LDL-c, and JCAD levels with MACE risk.
An independent validation cohort (RISK-PPCI; n=496) was used to confirm JCAD’s associations with endogenous coagulation and fibrinolysis parameters, and the predictive value for MACE.
Key Findings
At 1 year follow-up, patients with RLR, RIR, or RILR showed significantly higher MACE risks compared with their matched controls:
- RLR: Hazard ratio (HR) 1.55 (95% confidence interval (CI) 1.08–2.23)
- RIR: HR 1.80 (95% CI 1.24–2.61)
- RILR: HR 1.75 (95% CI 1.12–2.75)
Within the RLR group, increasing hs-CRP and JCAD concentrations each independently predicted higher MACE risk. The adjusted hazard ratios per log2 metric increase were 1.16 (95% CI 1.03–1.30) for hs-CRP and 1.27 (95% CI 1.01–1.60) for JCAD.
Among RIR patients, JCAD remained an independent predictor with an adjusted HR of 1.31 (95% CI 1.04–1.65). In the combined RILR group, JCAD conferred an even greater risk (adjusted HR 1.47, 95% CI 1.11–1.97), demonstrating an almost linear association.
Biologically, plasma JCAD concentrations correlated positively with indicators of impaired endogenous fibrinolysis, a key process that normally limits thrombus growth by breaking down fibrin. This mechanistic link was supported both clinically and experimentally.
The RISK-PPCI cohort confirmed the association between elevated JCAD levels and increased MACE, thereby externally validating the biomarker’s predictive utility.
Expert Commentary
These findings illuminate JCAD as an important, previously underappreciated mediator of residual ischemic risk in ACS. By modulating coagulation and fibrinolysis pathways at the endothelial junction, JCAD potentially exacerbates thrombus formation even in patients controlled for cholesterol and inflammation.
Clinicians and researchers should consider the multifaceted nature of residual risk, extending beyond traditional lipid and inflammatory markers. JCAD emerges as a biomarker that may be useful for more precise risk stratification and for identifying candidates who might benefit from targeted anticoagulant or fibrinolytic interventions.
Limitations include observational design and need for further mechanistic studies to validate causality and elucidate therapeutic strategies to modulate JCAD. Diverse populations and longer follow-up durations would help assess generalizability and prognostic performance over time.
Conclusion
Acute coronary syndrome patients with residual lipid and/or inflammatory risk remain vulnerable to recurrent cardiovascular events despite optimal care. JCAD, a junctional protein influencing coagulation and fibrinolysis, independently predicts MACE and mechanistically links to impaired endogenous fibrinolysis.
These robust findings across independent cohorts identify JCAD as a promising candidate biomarker and therapeutic target to address high residual ischemic risk in ACS. Further research should explore JCAD-targeted interventions to improve outcomes.
Funding and ClinicalTrials.gov Identifiers
This research was supported in part by institutions associated with the SPUM-ACS and RISK-PPCI studies. ClinicalTrials.gov registration numbers are NCT01000701 and NCT02562690.
References
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