Higher Serum Angiopoietin 2 Levels Are Independently Associated with Coronary Microvascular Dysfunction in Patients with Angina in the Absence of Obstructive Coronary Artery Disease
Introduction
Coronary microvascular dysfunction (CMD) has emerged as a critical contributor to myocardial ischemia and angina in patients without obstructive coronary artery disease (CAD). Approximately 20%–30% of patients undergoing coronary angiography for angina exhibit no significant epicardial coronary artery stenosis, yet up to 60% of these individuals may have underlying CMD. Coronary flow reserve (CFR), a measure of the microvasculature’s capacity to augment blood flow during stress, serves as a key diagnostic marker for CMD. Impaired CFR, defined as values below 2.5, reflects microvascular dysfunction and is associated with adverse clinical outcomes.
Angiopoietin-2 (Ang-2), a glycoprotein secreted by endothelial cells, plays a dual role in vascular biology. While it destabilizes blood vessels by antagonizing the Tie-2 receptor under physiological conditions, elevated circulating Ang-2 levels have been linked to endothelial dysfunction, inflammation, and cardiovascular diseases, including obstructive CAD. However, its relationship with CMD remains unexplored. This study investigates whether serum Ang-2 levels correlate with impaired CFR in patients with angina and non-obstructive CAD, offering insights into the pathophysiological mechanisms of CMD.
Study Design and Methodology
Patient Cohort
This cross-sectional study enrolled 125 patients (mean age 61.3 ± 9.2 years; 62.4% female) presenting with typical or atypical angina and non-obstructive CAD (<50% stenosis on invasive angiography or coronary computed tomography angiography). Exclusion criteria included acute coronary syndromes, prior revascularization, structural heart disease, chronic inflammatory conditions, and contraindications to adenosine.
Measurement of Coronary Flow Reserve
CFR was assessed non-invasively using trans-thoracic Doppler echocardiography. The distal left anterior descending coronary artery (LAD) was visualized in a modified apical two-chamber view. Peak diastolic flow velocities were recorded at rest and during adenosine-induced hyperemia (140 μg/kg/min infusion for 2 minutes). CFR was calculated as the ratio of hyperemic to baseline flow velocities. Patients were stratified into two groups: impaired CFR (CFR <2.5, n=35) and preserved CFR (CFR ≥2.5, n=90).
Laboratory Assessments
Serum Ang-2 levels were quantified using enzyme-linked immunosorbent assay (ELISA; R&D Systems, USA) with a detection limit of 156 pg/mL. Additional biomarkers, including N-terminal pro-B-type natriuretic peptide (NT-pro BNP), high-sensitivity C-reactive protein (hs-CRP), and lipid profiles, were analyzed. Echocardiographic parameters, such as left atrial volume index (LAVI) and left ventricular ejection fraction (LVEF), were also evaluated.
Statistical Analysis
Continuous variables were compared using Student’s t-test or Mann-Whitney U test, while categorical variables were analyzed via Chi-squared tests. Correlations between Ang-2 levels and CFR were assessed using Pearson’s coefficient. Binary logistic regression identified independent predictors of impaired CFR, incorporating variables with p<0.10 in univariate analysis (age, sex, Ang-2, NT-pro BNP, LAVI) and comorbidities (hypertension, diabetes, dyslipidemia). Receiver-operating characteristic (ROC) curve analysis evaluated Ang-2’s predictive accuracy for impaired CFR.
Key Findings
Demographic and Clinical Characteristics
Patients with impaired CFR were older (66.5 ± 7.6 vs. 58.9 ± 8.8 years, p<0.001) and more likely to be female (77.1% vs. 56.7%, p=0.034). Typical angina (54.3% vs. 31.1%, p=0.016) and positive stress tests (71.4% vs. 35.6%, p=0.001) were more prevalent in the impaired CFR group. No significant differences were observed in comorbidities, blood pressure, or lipid profiles between groups.
Biomarker and Echocardiographic Profiles
Serum Ang-2 levels were markedly elevated in the impaired CFR group (763.3 ± 264.9 pg/mL vs. 579.7 ± 169.3 pg/mL, p<0.001). NT-pro BNP levels (66.5 [36.7–109.0] vs. 46.0 [22.2–75.0] pg/mL, p=0.046) and LAVI (29.6 ± 5.0 vs. 26.4 ± 5.9 cm³/m², p=0.017) were also higher in this group. CFR values were inversely correlated with Ang-2 levels (r=−0.386, p<0.001) and age (r=−0.259, p=0.003).
Independent Predictors of Impaired CFR
Binary logistic regression identified Ang-2 (OR: 1.004 per pg/mL; 95% CI: 1.001–1.006; p=0.003) and age (OR: 1.088 per year; 95% CI: 1.023–1.156; p=0.007) as independent predictors of impaired CFR. Sex, NT-pro BNP, and LAVI did not retain significance in the multivariable model.
Diagnostic Performance of Ang-2
ROC curve analysis demonstrated that Ang-2 predicts impaired CFR with an area under the curve (AUC) of 0.712 (95% CI: 0.612–0.813; p<0.001). A cutoff value of 648 pg/mL yielded 71.4% sensitivity and 67.8% specificity, with positive and negative predictive values of 68.9% and 70.3%, respectively.
Discussion
Ang-2 as a Biomarker of Microvascular Dysfunction
This study establishes a strong, independent association between elevated serum Ang-2 levels and impaired CFR in patients with angina and non-obstructive CAD. The mechanistic link may involve Ang-2’s role in endothelial destabilization and inflammation. By antagonizing Tie-2 signaling, Ang-2 sensitizes endothelial cells to pro-inflammatory cytokines, exacerbating microvascular permeability and impairing vasodilatory responses. Hypoxia, a hallmark of myocardial ischemia, upregulates Ang-2 expression, further perpetuating microvascular dysfunction.
Clinical Implications
The identification of Ang-2 as a biomarker for CMD has diagnostic and prognostic implications. Elevated Ang-2 levels may aid in risk stratification, particularly in patients with angina and normal coronary arteries. Moreover, targeting the Ang-2/Tie-2 axis could offer therapeutic benefits. Preclinical studies suggest that Ang-2 inhibition reduces vascular leakage and inflammation, though clinical trials are needed to validate these effects in CMD.
Study Limitations
The cross-sectional design precludes causal inferences between Ang-2 and CMD. The modest sample size and single-center recruitment limit generalizability. Future studies should explore longitudinal outcomes, such as major adverse cardiovascular events, to assess Ang-2’s prognostic value.
Conclusion
This study highlights serum Ang-2 as a novel biomarker of coronary microvascular dysfunction in patients with angina and non-obstructive CAD. Elevated Ang-2 levels independently correlate with impaired CFR, reflecting its potential role in endothelial dysregulation and microvascular pathophysiology. These findings underscore the need for further research into Ang-2-targeted therapies and its integration into diagnostic algorithms for CMD.
doi.org/10.1097/CM9.0000000000000812
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