New target to reduce residual cardiovascular risk in ACS patients?

January 2026

The junctional protein associated with coronary artery disease (JCAD), which modulates coagulation and fibrinolysis pathways, may represent a novel target to address the high residual cardiovascular risk in patients with acute coronary syndromes (ACS) .

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; doi.org/10.1093/eurheartj/ehaf979.  

STUDY SUMMARY.

Objective

To investigate whether JCAD, a protein implicated in coagulation and fibrinolysis, may be a novel marker or potential therapeutic target to address the high residual risk in ACS patients.

 

 

Study design

The SPUM-ACS study is a multicentre, prospective cohort study in Switzerland involving 4,787 ACS patients. This represented the discovery cohort.

 

The RISK-PPCI study was a single-centre prospective cohort study in the UK involving 496 ACS patients undergoing thrombotic status assessment prior to primary percutaneous coronary intervention. This study was used for external validation of the association between JCAD and major adverse cardiovascular events (MACE).

 

 

Study population

Patients in the SPUM-ACS study were adults with a main diagnosis of ACS. These were then categorized as residual lipid risk (RLR, on-treatment low-density lipoprotein cholesterol [LDL-C] ≥70 mg/dL or ≥1.8 mmol/L); residual inflammatory risk (RIR, on-treatment high-sensitivity C-reactive protein [hs-CRP] ≥2.0 mg/L), or meeting both criteria (RILR).

 

Patients in both the SPUM-ACS and RISK-PPCI cohorts were treated according to current guideline recommendations, which includes a loading dose of antithrombotic therapy prior to coronary angiography.

 

 

Main study variables

 

The primary endpoint was MACE during 1-year of follow-up, defined as a composite measure of non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death.

 

 

Methods

Patients at RLR, RIR, and RILR were compared with propensity-score matched controls.  The predictive utility of LDL-C, hs-CRP, and JCAD in patients at RLR, RIR, or RILR was assessed using uni- and multivariable-adjusted Cox proportional hazard regression models. The relationships of biomarker data with the primary endpoint were assessed in linear models with log2-transformed data (i.e. one unit increase corresponds to a doubling in biomarker levels), and in non-linear models, using restricted cubic spline analysis.

 

Results

Key characteristics of patients in each residual risk category are summarized (Table 1). At 1 year, patients with RLR, RIR, and both residual risks (RILR) were at higher risk of MACE than matched propensity controls (Table 1).

Table 1. Characteristics of residual risk category of SPUM-ACS cohort and risk for MACE

 

RLR (n=892, 18.6%)

RIR (n=683, 14.3%)

RILR (n=460, 9.6%)

Age ≥65 years, n (%)

482 (54)

407 (59.6)

248 (53.9)

Female; n (%)

182 (20.9)

152 (22.3)

113 (24.6)

PAD; n (%)

92 (10.3)

98 (14.3)

58 (12.6)

Stroke; n (%)

61 (6.8)

59 (8.6)

38 (8.3)

Statin (highest dose)

322 (36.1)

248 (36.3)

169 (36.7)

hs-CRP, mg/L

Median (IQR)

2.5 (1.00–7.50)

7.00 (3.55–19.20)

6.05 (3.50–16.22)

JCAD, ng/mL

Median (IQR)

1.18 (0.46–1.88)

1.05 (0.41–1.91)

1.05 (0.42–1.92)

Risk for MACE*

HR (95% CI)

1.55 (1.08–2.23)

1.80 (1.24–2.61)

1.75 (1.12–2.75)

*Compared with propensity-matched control

In the RLR category, hs-CRP was linked to 1-year MACE risk in univariable analysis (HR 1.17, 95% CI 1.06–1.30, p=0.002) and this association persisted in multivariable analysis. In the RIR and RILR categories, neither LDL-C nor hs-CRP were associated with 1-year MACE risk in multivariable-adjusted analyses. 

In each residual risk category, MACE risk increased per log2 increase in JCAD in both univariate and multivariable adjusted models (Table 2). The JCAD–MACE association was similar in the external validation cohort.

Table 2. MACE risk per log2 increase in JCAD; Hazard ratio (95% CI)

 

RLR (n=892, 18.6%)

RIR (n=683, 14.3%)

RILR (n=460, 9.6%)

Univariate analysis

1.29 (1.03–1.62)

p=0.015

1.28 (1.03–1.59)

p=0.026

1.45 (1.09–1.92)

p=0.01

Multivariable adjusted analysis

1.27 (1.01–1.60)

p=0.039

1.31 (1.04–1.65)

p=0.022

1.47 (1.11–1.97)

p=0.008

The RISK-PPCI cohort independently showed an association between high JCAD levels and risk for MACE. High JCAD levels were also linked with higher levels of pro-thrombotic mediators, including tissue factor (TF), thrombin activatable fibrinolysis inhibitor (TAFI), plasminogen activator inhibitor-1 (PAI-1), and impaired endogenous fibrinolysis.

Author conclusions

Acute coronary syndrome patients at RLR, RIR, or both are at high ischaemic risk. By modulating coagulation and endogenous fibrinolysis, JCAD represents a promising candidate to address the high residual risk that persists in ACS patients receiving guideline-recommended care.

 

Comment

Patients with ACS remain at high residual cardiovascular risk despite guideline-directed clinical management. This study reinforces this point, as patients with RLR were at 55% higher risk of MACE, those with RIR were at 80% higher risk, and those with both lipid and inflammatory risk were at 75% higher risk of recurrent MACE compared with propensity-score matched controls.  Targeting this risk with aggressive lowering of LDL-C, or anti-inflammatory or anti-coagulant therapies can reduce the risk of recurrent MACE (1-4). However, even among those patients who attain a median LDL-C <1.4 mmol/l (or 50 mg/dL), about 5% will experience a MACE during 1 year of follow-up (1,2). Taken together, the evidence implicates other pathways as contributors to this residual risk and underlines the urgent need to identify such pathways and associated potential targets for therapeutic intervention.

 

JCAD has been identified as a risk locus for coronary artery disease in genome-wide association studies (5,6). Mechanistic studies have demonstrated antiatherosclerotic effects of JCAD, partly driven by modulation of vascular inflammation (7), promoting prothrombotic mediators, and impairing fibrinolysis (8), thus addressing risk factors that are not reflected by LDL-C or hs-CRP. The current study has important findings that provide support for JCAD as a novel biomarker for residual risk and potential therapeutic target.  First, both the SPUM-ACS and RISK-PPCI cohorts showed that plasma levels of JCAD associate consistently with MACE risk irrespective of the type of residual risk. Additionally, in the RISK-PPCI study cohort, JCAD correlated with prothrombotic factors, including TF, TAFI, and PAI-1, which accords with previous studies showing that JCAD promotes arterial thrombus formation in an experimental model (8).

 

This study has several strengths that add to the robustness of these findings. These include the large size and prospective nature of the SPUM-ACS cohort, central measurement of biomarkers (JCAD and hs-CRP), with LDL-C levels derived using the validated Sampson equation. Residual risk was defined by lipid and inflammatory markers measured during the index hospitalization, which may not reflect steady-state post-treatment levels and possibly favour distinct risk stratification.  However, the researchers argued that this approach is more relevant to the real-world ACS setting when treatment decisions must be made promptly.

 

In conclusion, the study findings not only reaffirm the need for more aggressive clinical management of patients with recent ACS but also underline the need for identify novel targets beyond lipids and inflammation. JCAD may be a promising target, warranting further study. 

 

References

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  3. Liberale L, Montecucco F, Schwarz L, Luscher TF, Camici GG. Inflammation and cardiovascular diseases: lessons from seminal clinical trials. Cardiovasc Res 2021;117:411–22.
  4. Fiolet ATL, Thompson PL, Mosterd A. Colchicine in coronary disease: another renaissance

of an ancient drug. Cardiovasc Res 2021;117:e4–e6.

  1. Erdmann J, Willenborg C, Nahrstaedt J, et al. Genome-wide association study identifies a new locus for coronary artery disease on chromosome 10p11.23. Eur Heart J 2011;32:158–68.
  2. Coronary Artery Disease (C4D) Genetics Consortium. A genome-wide association study in Europeans and South Asians identifies five new loci for coronary artery disease. Nat Genet 2011;43:339–44.
  3. Guzik TJ, Channon KM. JCAD: a new GWAS target to reduce residual cardiovascular risk? Eur Heart J 2023;44:1834–6.
  4. Liberale L, Puspitasari YM, Ministrini S, et al. JCAD promotes arterial thrombosis through PI3K/Akt modulation: a translational study. Eur Heart J 2023;44:1818–33.

Key words: Acute coronary syndrome; residual risk; inflammation; lipids; Junctional protein associated with coronary artery disease; JCAD