Highlights
Research recently published in the European Heart Journal highlights the critical role of the junctional protein associated with coronary artery disease (JCAD) in predicting major adverse cardiovascular events (MACE) among patients with acute coronary syndromes (ACS). The study identifies JCAD as a key player in the complex landscape of residual cardiovascular risk.
1. JCAD levels independently predict MACE in ACS patients who remain at high risk due to residual lipid or inflammatory factors.
2. In patients with combined residual inflammatory and lipid risk (RILR), MACE risk increases almost linearly with JCAD concentration.
3. The protein appears to drive adverse outcomes by impairing endogenous fibrinolysis and modulating coagulation pathways.
4. JCAD represents a promising novel therapeutic target to reduce the persistent ischaemic burden in patients receiving guideline-recommended care.
The Challenge of Residual Risk in Acute Coronary Syndromes
Despite significant advances in pharmacotherapy and interventional cardiology, patients who have experienced an acute coronary syndrome (ACS) remain at a high risk of recurrent ischaemic events. This persistent vulnerability is often categorized as “residual risk.” Traditionally, clinical attention has focused on two primary drivers: residual lipid risk (RLR), characterized by elevated LDL cholesterol despite statin therapy, and residual inflammatory risk (RIR), marked by persistent elevations in high-sensitivity C-reactive protein (hs-CRP).
However, even when these factors are managed, many patients continue to suffer from major adverse cardiovascular events (MACE). This suggests the existence of yet-to-be-identified pathways that contribute to coronary instability. Recent genome-wide association studies (GWAS) have pointed toward the junctional protein associated with coronary artery disease (JCAD) as a potential culprit. Until now, its specific role in the context of residual risk in ACS patients remained poorly understood.
Study Design and Population
To investigate whether JCAD serves as a marker or target for residual risk, researchers utilized a robust two-cohort approach. The discovery cohort consisted of the SPUM-ACS study, which included 4,787 patients. Within this group, researchers identified patients at RLR (on-statin LDL-c ≥70 mg/dL), RIR (on-statin hs-CRP ≥2.0 mg/L), or both (RILR). These patients were compared with propensity-score matched controls to ensure the validity of the findings.
The investigators analyzed the individual and joint contributions of hs-CRP, LDL-c, and JCAD to recurrent MACE over a one-year follow-up period. To validate these findings and explore the underlying mechanisms, an independent external cohort—the RISK-PPCI study (n = 496)—was employed. This secondary analysis specifically gauged the effects of JCAD on endogenous coagulation and fibrinolysis, providing a mechanistic bridge to the clinical observations.
Key Findings: Quantifying the Impact of JCAD
The results from the SPUM-ACS discovery cohort confirmed that patients at RLR, RIR, or RILR were at significantly higher risk for MACE compared to matched controls at the one-year mark. Specifically, the hazard ratios (HR) were 1.55 for RLR, 1.80 for RIR, and 1.75 for RILR.
JCAD in Residual Lipid Risk (RLR)
In patients exhibiting residual lipid risk, MACE risk rose significantly with increasing levels of JCAD. In multivariable-adjusted models, the adjusted hazard ratio (aHR) was 1.27 (95% CI 1.01-1.60) per log2 increase in JCAD. This indicates that even among patients with elevated LDL-c, JCAD provides incremental prognostic value.
JCAD in Residual Inflammatory Risk (RIR)
For those with residual inflammatory risk, the association was even more pronounced. MACE risk increased 1.28-fold per log2 increase in JCAD. When adjusted for potential confounders, this association prevailed with an aHR of 1.31 (95% CI 1.04-1.65). This suggests that JCAD operates through pathways distinct from the interleukin-6/CRP inflammatory axis.
Combined Risk (RILR)
The most striking findings occurred in the RILR group—patients suffering from both high lipids and high inflammation. In this high-vulnerability subset, MACE risk increased almost linearly with JCAD levels. The multivariable-adjusted hazard ratio reached 1.47 (95% CI 1.11-1.97), highlighting JCAD as a potent predictor in the most complex patient profiles.
Mechanistic Insights: Coagulation and Fibrinolysis
A critical component of this study was the exploration of why JCAD correlates so strongly with adverse outcomes. Using the RISK-PPCI cohort, researchers found that plasma levels of JCAD correlated positively with proxies of impaired endogenous fibrinolysis. This suggests that JCAD may promote a pro-thrombotic state by interfering with the body’s natural ability to dissolve blood clots.
JCAD is localized at endothelial cell-cell junctions and has been shown in previous laboratory models to regulate endothelial dysfunction and the recruitment of inflammatory cells. By modulating the balance between coagulation and fibrinolysis, JCAD appears to stabilize or destabilize the environment following an acute coronary event, directly influencing the likelihood of a recurrent myocardial infarction or stroke.
Expert Commentary and Clinical Implications
The identification of JCAD as a marker of residual risk offers a new dimension to precision medicine in cardiology. While current guidelines emphasize aggressive lipid-lowering and, increasingly, anti-inflammatory therapies (such as colchicine), JCAD points toward a “third pillar” of residual risk: the thrombotic/fibrinolytic pathway regulated by junctional proteins.
From a clinical perspective, measuring JCAD could help clinicians further stratify risk in ACS patients who appear “well-managed” on standard therapies. Furthermore, because the association between JCAD and MACE remains significant after adjusting for LDL-c and hs-CRP, it suggests that targeting JCAD or its downstream effects on fibrinolysis could provide therapeutic benefits that existing drugs do not address.
However, the study is not without limitations. As an observational study, it establishes association rather than definitive causation in humans. Additionally, while the correlation with fibrinolysis is compelling, the exact molecular triggers that cause JCAD elevation post-ACS require further elucidation. Future research should focus on whether specific JCAD-targeted interventions can actually improve clinical outcomes.
Summary and Conclusion
The study by Kraler et al. provides compelling evidence that JCAD is a major player in the residual ischaemic risk that persists after an acute coronary syndrome. By demonstrating that JCAD independently predicts MACE in patients with RLR and RIR, and by linking the protein to impaired fibrinolysis, the research opens a new frontier for cardiovascular risk assessment and treatment.
For the modern clinician, these findings reinforce the idea that residual risk is multifactorial. Beyond the traditional focus on cholesterol and inflammation, the integrity of the vascular junctional proteins and the efficiency of the endogenous fibrinolytic system are paramount. JCAD stands out as a promising candidate for both biomarker development and novel drug discovery to protect patients from recurrent cardiovascular crises.
Funding and ClinicalTrials.gov
This research was supported by various grants, including those from the Swiss National Science Foundation and the University of Zurich. The studies involved are registered with ClinicalTrials.gov under the identifiers NCT01000701 (SPUM-ACS) and NCT02562690 (RISK-PPCI).
References
Kraler S, Liberale L, Tirandi A, et al. The junctional protein associated with coronary artery disease predicts adverse cardiovascular events in patients with acute coronary syndromes at high residual risk. Eur Heart J. 2025 Dec 23:ehaf979. doi: 10.1093/eurheartj/ehaf979. PMID: 41430589.