A clinical study demonstrates that transthoracic echocardiographic measurement of epicardial fat thickness serves as an independent non-invasive predictor of coronary microvascular disease in patients with ischemia and non-obstructive coronary arteries. Published in Cardiovascular Ultrasound by researchers at the First Affiliated Hospital of Harbin Medical University, the investigation evaluated associations among epicardial adipose thickness, peripheral endothelial function measured by flow-mediated dilation, and coronary flow reserve. Coronary microvascular disease remains difficult to diagnose among patients presenting with persistent angina despite having normal or non-obstructive coronary arteries on angiography. By integrating resting echocardiography, peripheral vascular ultrasound, and pharmacologic vasodilator stress testing, the investigators demonstrated that epicardial fat thickness is significantly higher in patients with impaired coronary flow reserve and provides an independent diagnostic marker for microvascular dysfunction in this clinical population.
Coronary microvascular disease involves structural and functional disorders of the coronary microcirculation that impair myocardial blood flow, decrease coronary flow reserve, and cause myocardial ischemia. The condition represents a major underlying cause of hospital admissions for individuals presenting with ischemia with non-obstructive coronary arteries. Microvascular impairment arises from multifactorial interactions, including microvascular structural abnormalities, micro-thrombosis, coronary spasm, oxidative stress, endothelial damage, and chronic inflammatory stimulation. In addition to provoking persistent angina, coronary microvascular dysfunction increases the risk of adverse cardiovascular outcomes, including myocardial infarction and death. Coronary flow reserve represents the ratio of coronary blood flow during maximal hyperemia to resting flow, reflecting epicardial and microcirculatory perfusion. In the absence of obstructive coronary disease, a coronary flow reserve below 2.0 indicates microvascular dysfunction, yet accessible non-invasive imaging techniques for routine clinical evaluation remain limited.
Between March and August 2023, investigators performed vasodilator drug stress echocardiography on 215 hospitalized patients experiencing exertional angina or chest tightness. Eligible participants were adults aged 18 to 80 years with myocardial ischemia symptoms whose coronary angiography within three months showed normal coronary arteries or stenosis under 50 percent. Exclusion criteria eliminated patients with unstable vital signs, severe hypertension, bronchial stenosis or bronchospasm, regadenoson allergy, acute coronary syndromes, old myocardial infarction, clinically ruled-out coronary spasm, cardiomyopathy, congenital heart disease, atrial fibrillation, second-degree or third-degree atrioventricular block, valvular heart disease, pulmonary hypertension, hyperthyroidism, rheumatism, poor ultrasound image quality, or incomplete data. Following these criteria, the final cohort comprised 66 patients, including 29 men and 37 women, with a mean age of 60.3 ± 11.2 years.
Coronary flow reserve measurement was conducted via regadenoson stress echocardiography after subjects completed flow-mediated dilation testing. To avoid pharmacologic interference, beta-adrenergic blockers, calcium channel blockers, cardiac glycosides, and adenosine-enhancing agents such as dipyridamole and ticagrelor were discontinued for 24 hours. Continuous blood pressure, heart rate, and electrocardiographic monitoring were maintained throughout. Sonographers captured blood flow spectra in the left anterior descending coronary artery from the apical region at end-exhalation using a Philips EPIQ 7C system equipped with an S5-1 transducer. Regadenoson was injected intravenously at 0.4 mg in a five-milliliter solution over 10 to 20 seconds, immediately flushed with five milliliters of saline. Maximal hyperemic coronary filling occurred within two minutes and persisted for approximately eight minutes. Hyperemic flow velocities were recorded across multiple cardiac cycles, and values from the three highest heartbeats were averaged to calculate coronary flow reserve.
Patients were divided into two groups: 29 patients with decreased coronary flow reserve below 2.0 (43.94 percent) and 37 patients with preserved flow reserve of 2.0 or higher (56 percent). Baseline conventional echocardiographic parameters were documented to characterize cardiac structure and function. Left atrial anteroposterior diameter was measured at end-systole using the leading edge–to–leading edge method at the aortic root level from parasternal long-axis images. Left ventricular internal dimension at end-diastole was measured below the mitral valve leaflet tips, and left ventricular ejection fraction was calculated using biplane Simpson’s method. Diastolic functional indices included mitral peak E velocity, peak A velocity, the E/A ratio, and tissue Doppler mitral annular e’ velocity to calculate the E/e’ ratio. Baseline echocardiographic indices showed no statistically significant differences between patients with decreased coronary flow reserve and those with normal reserve.
Epicardial fat thickness was measured using standard linear criteria on the right ventricular free wall from parasternal long-axis and midventricular short-axis views. Using the aortic annulus as an anatomical landmark, long-axis thickness was measured along the midline of the ultrasound beam perpendicular to the aortic annulus, while short-axis thickness was measured perpendicular to the interventricular septum across three cardiac cycles. To evaluate measurement reproducibility, two independent senior sonographers conducted standardized consistency assessments across all 66 participants. Intra-observer evaluation demonstrated high agreement, with mean thicknesses of 5.458 ± 1.166 mm and 5.374 ± 1.165 mm, a mean difference of 0.084 mm, a Cronbach’s alpha of 0.997, and an intraclass correlation coefficient of 0.994. Inter-observer analysis showed mean values of 5.374 ± 1.165 mm and 5.401 ± 1.156 mm, a mean difference of 0.027 mm, and an intraclass correlation coefficient of 0.994. Bland-Altman analyses confirmed minimal bias without outliers, confirming excellent measurement stability.
Brachial artery flow-mediated dilation was performed to assess peripheral endothelial function non-invasively using a dedicated ultrasound system equipped with a 7.0-MHz linear array transducer. Prior to testing, participants fasted, avoided physical activity, and refrained from consuming caffeine, vitamin C, polyphenols, alcohol, and tobacco. Patients rested supine in a quiet room maintained at 20 to 25 degrees Celsius for 10 to 15 minutes before scanning. A blood pressure cuff was positioned on the forearm near the elbow fossa, and longitudinal scans of the brachial artery were captured five to ten centimeters above the elbow to record baseline arterial diameter. The cuff was inflated to 50 mmHg above systolic pressure for five minutes before deflation. Maximum hyperemic internal diameter was documented within two minutes, and percentage dilation was calculated from baseline measurements to quantify endothelium-dependent, nitric oxide-mediated vasodilatory capacity in response to reactive shear stress.
Baseline comparisons showed that patients in the decreased coronary flow reserve group were significantly older (P = 0.026), had a higher prevalence of hypertension, thicker epicardial fat (6.063 ± 1.732 mm vs. 5.95 ± 1.718 mm, P = 0.003), and lower flow-mediated dilation [median 4.05% vs. 5.30%, P = 0.011]. No significant differences emerged regarding gender, body mass index, cholesterol, triglycerides, diabetes, hyperlipidemia, or smoking history. In univariate logistic regression, epicardial fat thickness, flow-mediated dilation, age, and hypertension showed statistically significant associations with coronary microvascular disease. In multivariable binary logistic regression incorporating these factors, thicker epicardial fat remained an independent predictor of microvascular disease (odds ratio 1.626, 95% confidence interval: 1.282–5.540, P = 0.009). Bootstrap validation across 1,000 resamples confirmed model stability, showing an odds ratio of 5.084 (P = 0.013). In contrast, flow-mediated dilation was not an independent predictor after multivariable adjustment (P = 0.092).
Receiver operating characteristic curve analysis demonstrated that epicardial fat thickness exceeding 5.51 mm predicted reduced coronary flow reserve in the overall cohort with 90 percent sensitivity and 71 percent specificity (area under the curve 0.745, 95% confidence interval: 0.593–0.896, P < 0.006). Sex-stratified analyses revealed that for male patients, epicardial fat thickness greater than 5.51 mm predicted microvascular disease with 88 percent sensitivity and 90 percent specificity (area under the curve 0.825, P < 0.021). For female patients, a cut-off greater than 5.55 mm predicted microvascular dysfunction with 92 percent sensitivity and 67 percent specificity (area under the curve 0.767, P < 0.026). Analysis of flow-mediated dilation indicated that values below 4.65% predicted microvascular disease with 60 percent sensitivity and 83 percent specificity (area under the curve 0.725, P < 0.011). Furthermore, correlation analyses detected no significant correlation between epicardial fat thickness and flow-mediated dilation across all subjects or within subgroups, indicating that these markers evaluate separate pathophysiological processes.
The physiological mechanisms linking epicardial adipose tissue to coronary microvascular impairment involve endocrine, metabolic, and paracrine interactions. Under normal physiological conditions, epicardial adipose tissue encloses roughly 80 percent of the cardiac surface, secreting anti-atherosclerotic cytokines, generating heat, and providing mechanical cushioning to protect against atherosclerosis and regulate coronary tone. However, excessive accumulation of epicardial fat reduces protective cytokine secretion and causes local tissue hypoxia. Hypoxic fat tissue releases inflammatory mediators and atherogenic cytokines that diffuse into adjacent myocardium and directly penetrate the outer membrane of coronary vessels. This outside-to-inside inflammatory signaling damages coronary ultrastructure, impairs nitric oxide synthesis, and compromises coronary flow reserve. The observed diagnostic cut-off of 5.51 mm aligns with earlier investigations by Kaya, who identified an epicardial fat threshold of 5.8 mm for coronary disease, and Green, who established a 5.6 mm cut-off for myocardial flow reserve impairment.
The authors highlighted several methodological limitations that contextualize their results and guide future research. First, diagnosis of coronary microvascular disease was established using regadenoson stress echocardiography rather than myocardial flow reserve measurement via positron emission tomography, which remains the gold standard. In addition, while transthoracic echocardiography provides an accessible measurement of linear epicardial fat thickness, it does not specifically isolate pericoronary adipose tissue, and computed tomography could offer more precise quantification of total volumetric fat depots. Second, the modest sample size of 66 patients from a single medical center limits the generalizability of these diagnostic thresholds across broader clinical populations. Third, the cross-sectional investigation lacked long-term patient follow-up, leaving the longitudinal prognostic value of epicardial fat thickness and flow-mediated dilation unverified. Future multicenter investigations utilizing gold-standard diagnostic validation and long-term longitudinal tracking are warranted to evaluate these non-invasive ultrasound indicators in microvascular disease management.
Subject of Research: Ultrasound evaluation of epicardial fat thickness and endothelial function in coronary microvascular disease
Article Title: Relationship between epicardial fat tissue, endothelial function, and coronary flow reserve in coronary microvascular disease patients
Article References: Li, M., Huang, Y., Bai, L., Li, W., Chu, C., & Liu, H. (2026). Relationship between epicardial fat tissue, endothelial function, and coronary flow reserve in coronary microvascular disease patients. Cardiovascular Ultrasound, 24(1), Article 2. https://doi.org/10.1186/s12947-025-00365-z
Image Credits: AI Generated
DOI: 10.1186/s12947-025-00365-z
Keywords: coronary microvascular disease, epicardial fat thickness, coronary flow reserve, flow-mediated dilation, echocardiography, endothelial function, INOCA, cardiology, Relationship, between, epicardial, tissue
