A Synergistic Effect between Plasma Dickkopf-1 and Obstructive Coronary Artery Disease on the Prediction of Major Adverse Cardiac Events in Patients with Angina: An Observational Study

Q: What are the key findings of this study?

High plasma DKK-1 combined with obstructive CAD was associated with a 10.6-fold higher risk of MACEs (HR 10.640, 95% CI 1.350-83.874, p=0.025) compared to low DKK-1 without obstructive CAD.

Q: What is the clinical evidence from this study?

Study design: Cohort. Population: Angina with suspected ischemic heart disease (n=470). Intervention: High plasma Dickkopf-1 (DKK-1 ≥ 610 pg/mL) with obstructive coronary artery disease (CAD) vs. Low plasma Dickkopf-1 (DKK-1 < 610 pg/mL) without obstructive CAD. Primary outcome: Major adverse cardiac events (MACEs: composite of all-cause death, first nonfatal myocardial infarction, or nonfatal stroke) (HR 10.640, 95% CI 1.350-83.874, p=0.025).

Q: What does this research mean for the field?

High plasma Dickkopf-1 (DKK-1) combined with obstructive coronary artery disease synergistically increases the risk of major adverse cardiac events in patients with angina. Novelty: ClaimNovelty.INCREMENTAL. Consensus alignment: ConsensusAlignment.NEUTRAL.

Yu‐Hsuan Li; Min‐Huan Wu; Wen‐Jane Lee; I‐Te Lee

doi:10.3390/biom12101408

October 2, 2022BiomoleculesOpen Access

A Synergistic Effect between Plasma Dickkopf-1 and Obstructive Coronary Artery Disease on the Prediction of Major Adverse Cardiac Events in Patients with Angina: An Observational Study

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Key result

High DKK-1 plus obstructive CAD is linked to ~10.6-fold higher MACE risk.

HR 10.640
95% CI 1.350-83.874
P=0.025
n=470

Figures

Why the study?

The canonical beta-catenin-dependent Wnt pathway is associated with endothelial function, prompting evaluation of the effect of plasma DKK-1, a Wnt pathway inhibitor, on predicting MACEs.

Does the combination of high plasma Dickkopf-1 (DKK-1) levels and obstructive coronary artery disease predict a higher risk of major adverse cardiac events in patients with angina?

Key Points

To examine whether plasma levels of dickkopf-1, an inhibitor of the canonical Wnt signaling pathway, interact with obstructive coronary artery disease to predict major adverse cardiac events in patients with angina.
Prospective observational study enrolling 470 patients who underwent selective coronary angiography for angina and had fasting plasma dickkopf-1 measured at an outpatient visit.
Participants were stratified into four groups using median plasma dickkopf-1 (610 pg/mL) and presence or absence of obstructive coronary artery disease.
Patients were monitored over a median follow-up of 4.8 years for the primary endpoint of major adverse cardiac events.
Major adverse cardiac events occurred in 48 patients: 1.1% (1/94) in the low dickkopf-1 without obstructive disease group, 9.7% (9/93) in the high dickkopf-1 without obstructive disease group, 8.5% (12/141) in the low dickkopf-1 with obstructive disease group, and 18.3% (26/142) in the high dickkopf-1 with obstructive disease group (log-rank p = 0.001).
Multivariable Cox proportional hazards regression showed that patients with high dickkopf-1 and obstructive coronary disease had a significantly higher risk of major adverse cardiac events compared with the low dickkopf-1 without obstructive disease group (hazard ratio 10.640, 95% CI: 1.350–83.874, p = 0.025).
Adding dickkopf-1 to models with Framingham risk score and coronary artery disease significantly improved risk prediction (net reclassification improvement 0.215, 95% CI: 0.009–0.370, p = 0.033; integrated discrimination improvement 0.012, 95% CI: 0.001–0.038, p = 0.027).

Study Design

Type

Cohort (n=470)

Multicenter

No

Structured PICO

Does the combination of high plasma Dickkopf-1 (DKK-1) levels and obstructive coronary artery disease predict a higher risk of major adverse cardiac events in patients with angina?

P

Population

470 adults (19.1% female) with angina and suspected ischemic heart disease without known diabetes mellitus undergoing selective coronary angiography in Taiwan, followed for a median of 4.8 years.

E

Exposure

High fasting plasma Dickkopf-1 (DKK-1 ≥ median of 610 pg/mL) combined with obstructive coronary artery disease (CAD, defined as history of MI, coronary revascularization, or angiographic lumen narrowing ≥50%)

C

Comparator

Low fasting plasma Dickkopf-1 (DKK-1 < 610 pg/mL) without obstructive coronary artery disease (also compared across 4 groups stratified by median DKK-1 and presence/absence of obstructive CAD)

O

Outcome

Major adverse cardiac events (MACEs), defined as a composite of death due to any cause or the first episode of nonfatal myocardial infarction (MI) or nonfatal stroke, over a median follow-up of 4.8 yearscomposite

Main Result

Hazard Ratio: 10.64 (95% CI 1.35–83.874)

Absolute Event Rate: 18.3% vs 1.1%

p-value: p=0.025

Fasting plasma DKK-1 acts synergistically with obstructive CAD to improve risk stratification and prediction of long-term MACEs in non-diabetic patients presenting with angina.

Limitations

Did not directly assess the underlying mechanism involved in DKK-1 and MACEs in patients with angina.
Did not examine microvascular dysfunction using invasive stress tests in patients without significant coronary obstruction.
Observational design did not investigate the effect of any specific intervention on lowering plasma DKK-1 levels.
Excluded patients with known diabetes mellitus, limiting generalizability to the diabetic population.
Did not directly assess the underlying mechanism involved in DKK-1 and MACEs in patients with angina
Did not examine microvascular dysfunction using invasive stress tests in patients without significant coronary obstruction
Observational study design; did not investigate the effect of any specific intervention on lowering plasma DKK-1 levels
Excluded patients with known diabetes mellitus, so results cannot be applied to the diabetic population

Implication

May refine MACE risk stratification in angina patients; leaves open prospective validation before clinical adoption.

Abstract

The canonical β-catenin-dependent wingless (Wnt) pathway is associated with endothelial function. We examined the effect of plasma dickkopf-1 (DKK-1), an inhibitor of the Wnt pathway, on the prediction of major adverse cardiac events (MACEs). We enrolled patients who had undergone selective coronary angiography for angina. DKK-1 levels were determined using plasma collected at the outpatient visit after fasting. MACEs served as the primary endpoint. All 470 enrolled patients were divided into four groups according to their median plasma DKK-1 levels and the presence of obstructive coronary artery disease (CAD). Forty-eight patients reached the primary endpoint during a median follow-up time of 4.8 years. Kaplan–Meier survival analysis indicated that the group with high DKK-1 and obstructive CAD had a significantly higher mortality rate than the other three groups (log-rank test p = 0.001). Compared with the low plasma DKK-1 without significant coronary obstruction group, the high DKK-1 with obstructive CAD group had a hazard ratio of 10.640 (95% confidence interval: 1.350–83.874) for MACEs, as determined by multivariable Cox proportional hazard regression analysis. In conclusion, we observed a synergistic effect between high plasma DKK-1 and obstructive CAD on the prediction of MACEs in patients with angina.

Discussion

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Cite This Study

Li et al. (2022) conducted a cohort in Angina with suspected ischemic heart disease (n=470). High plasma Dickkopf-1 (DKK-1 ≥ 610 pg/mL) with obstructive coronary artery disease (CAD) vs. Low plasma Dickkopf-1 (DKK-1 < 610 pg/mL) without obstructive CAD was evaluated on Major adverse cardiac events (MACEs: composite of all-cause death, first nonfatal myocardial infarction, or nonfatal stroke) (HR 10.640, 95% CI 1.350-83.874, p=0.025). High plasma DKK-1 combined with obstructive CAD was associated with a 10.6-fold higher risk of MACEs (HR 10.640, 95% CI 1.350-83.874, p=0.025) compared to low DKK-1 without obstructive CAD.

synapsesocial.com/papers/6a79c9a2756812e39589444d https://doi.org/10.3390/biom12101408

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A Synergistic Effect between Plasma Dickkopf-1 and Obstructive Coronary Artery Disease on the Prediction of Major Adverse Cardiac Events in Patients with Angina: An Observational Study

Figures

Key Points

Study Design

Structured PICO

Main Result

Limitations

Implication

Abstract

Discussion

Cite This Study

A Synergistic Effect between Plasma Dickkopf-1 and Obstructive Coronary Artery Disease on the Prediction of Major Adverse Cardiac Events in Patients with Angina: An Observational Study

Figures

Key Points

Study Design

Structured PICO

Main Result

Limitations

Implication

Abstract

Discussion

Cite This Study

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