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Biomarkers and Coronary Microvascular Dysfunction in ANOCA
Quick Takes
- Biomarkers of importance in pathways and prediction models in patients with coronary microvascular dysfunction (CMD) were REN, GDF15, BNP (and its prohormone, NT-proBNP), ADM, CHI3L1, TRAILR2, and IL-6.
- Overall, the biomarker profile in patients with angina and no obstructive coronary artery disease (ANOCA)/CMD is consistent with inflammation, hypertension, and ventricular remodeling being intrinsically linked to CMD.
- Additional studies are indicated to determine whether biomarkers are causally related to CMD development and whether modification of the underlying pathways may lead to improved coronary microvascular function.
Study Questions:
What is the protein biomarker signature for coronary microvascular dysfunction (CMD)?
Methods:
The investigators quantified 184 unique cardiovascular proteins with proximity extension assay in 1,471 women with angina and no obstructive coronary artery disease (ANOCA) characterized for CMD by coronary flow velocity reserve (CFVR) by transthoracic echo Doppler. They performed Pearson’s correlations of CFVR and each of the 184 biomarkers, and principal component analyses and weighted correlation network analysis to identify clusters linked to CMD. For prediction of CMD (CFVR <2.25), the authors applied logistic regression and machine learning algorithms (least absolute shrinkage and selection operator, random forest, extreme gradient boosting, and adaptive boosting) in discovery and validation cohorts.
Results:
Sixty-one biomarkers were correlated with CFVR with strongest correlations for renin (REN), growth differentiation factor 15 (GDF15), B-type natriuretic protein (BNP), N-terminal-proBNP (NT-proBNP), and adrenomedullin (ADM) (all p < 1e-06). Two principal components with highest loading on BNP/NT-proBNP and interleukin-6, respectively, were strongly associated with low CFVR. Weighted correlation network analysis identified two clusters associated with low CFVR reflecting involvement of hypertension/vascular function and immune modulation. The best prediction model for CFVR <2.25 using clinical data had area under the receiver operating characteristic curve (ROC-AUC) of 0.61 (95% confidence interval, 0.56-0.66). ROC-AUC was 0.66 (0.62-0.71) with addition of biomarkers (p for model improvement 0.01). Stringent two-layer cross-validated machine learning models had ROC-AUC ranging from 0.58 to 0.66; the most predictive biomarkers were REN, BNP, NT-proBNP, GDF15, and ADM.
Conclusions:
The authors report that CMD was associated with pathways particularly involving inflammation (interleukin-6), blood pressure (REN, ADM), and ventricular remodeling (BNP/NT-proBNP) independently of clinical risk factors.
Perspective:
This analysis reports that biomarkers of importance in pathways and prediction models in patients with ANOCA were REN, GDF15, BNP (and its prohormone, NT-proBNP), ADM, CHI3L1, TRAILR2, and IL-6. These data suggest that there may be multiple underlying mechanisms of CMD, both structural and functional, that have different protein signatures. Overall, the biomarker profile in patients with ANOCA is consistent with inflammation, hypertension, and ventricular remodeling being intrinsically linked to CMD. Additional studies are indicated to determine whether biomarkers are causally related to CMD development and whether modification of the underlying pathways such as with anti-inflammatory agents may lead to improved coronary microvascular function.
Clinical Topics: Dyslipidemia, Noninvasive Imaging, Prevention, Stable Ischemic Heart Disease, Atherosclerotic Disease (CAD/PAD), Lipid Metabolism, Novel Agents, Echocardiography/Ultrasound, Hypertension, Chronic Angina
Keywords: Angina Pectoris, Biomarkers, Coronary Artery Disease, Diagnostic Imaging, Echocardiography, Echocardiography, Doppler, Growth Differentiation Factor 15, Hypertension, Inflammation, Interleukin-6, Machine Learning, Microvascular Angina, Myocardial Ischemia, Natriuretic Peptide, Brain, Renin, Secondary Prevention, Vascular Diseases, Women
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