Ischemic heart disease, specifically stable angina pectoris, affects over 100 million people worldwide. A significant proportion of patients who undergo coronary angiography due to angina or a positive ischemia test result have non-obstructive coronary artery disease (CAD).^[1–3] In such cases, the terms “angina with non-obstructive coronary arteries” (ANOCA) and “ischemia with non-obstructive coronary arteries” (INOCA) are used to describe patients with symptoms or documented ischemia despite the absence of significant epicardial stenoses.^[4]

In these patients, ischemia is usually attributable to coronary vascular dysfunction, involving vasomotor abnormalities of the epicardial arteries and/or microvascular dysfunction (MVD). Microvascular disease frequently remains undiagnosed, leading to inadequate treatment, persistent symptoms, frequent hospitalizations, and diminished quality of life.^{[5, 6]}

The European guidelines for the management of chronic coronary syndromes emphasize the importance of diagnosing microvascular angina through invasive assessment of coronary flow reserve (CFR) and the index of microvascular resistance (IMR) in patients with persistent symptoms and angiographically normal coronary arteries.^[2] Despite these recommendations, the widespread application of these techniques remains limited due to low accessibility, additional time requirements, procedural risks, and the necessity for well-trained personnel to accurately interpret the results and avoid errors. Non-invasive methods, such as Doppler echocardiographic measurement of CFR, cardiac magnetic resonance imaging (CMR), and positron emission tomography (PET), are also utilized for CFR assessment. However, these approaches demonstrate lower sensitivity and specificity, restricting their clinical applicability, and are assigned a lower class of recommendation in the guidelines.^[7]

Fluoroscopic techniques, such as thrombolysis in myocardial infarction (TIMI) frame count and myocardial blush grade (MBG), are used to evaluate epicardial coronary blood flow and provide an indirect assessment of microvascular function. Studies suggest their potential role in diagnosing MVD, as affected patients exhibit a higher TIMI frame count and reduced MBG values.^{[8, 9]} Other fluoroscopic indices, including coronary clearance frame count (CCFC) and coronary sinus filling time (CSFT), have also been proposed for assessing microvascular function, with varying clinical and prognostic significance.^{[10, 11]}

The exact time required for contrast to transit from the coronary arteries to the coronary sinus has not been fully established and remains an underexplored aspect of clinical practice. Our hypothesis suggests that this interval may correlate with the presence of microvascular angina, potentially reflecting the degree of microvascular dysfunction. This study aims to define contrast transit time from the catheter tip to the coronary sinus in patients with angina and non-obstructive epicardial coronary disease and to analyze whether this parameter is influenced by hemodynamic factors, myocardial mass, or traditional coronary artery disease risk factors. Establishing the time for contrast to pass through the myocardium could offer a new diagnostic perspective for microvascular angina evaluation and contribute to a more precise and individualized therapeutic approach.

This study presents preliminary data aimed at establishing a standardized method for measuring TCPM in patients with ANOCA, laying the foundation for future research focused on correlation with symptom burden and treatment response, clinical validation and prognostic relevance.

Sixty-two patients were included in the study between February 15, 2023, and November 15, 2024. The mean age of the group was 62 years, with 58% being female. The demographic characteristics and the main cardiovascular risk factors of the study group are presented in Table 1. Fifty-six percent of the patients were classified as CCS class II or higher (Table 2). Nine of the patients had previously undergone coronary angiography, revealing non-obstructive CAD with three of them having undergone the procedure twice. The mean myocardial mass in the study group was 194.50 g.

All patients underwent a resting electrocardiogram (ECG) upon admission to the clinic, with the following findings recorded. Sixteen patients had negative T waves, fourteen had significant ST-segment depressions, and among them, four exhibited both ST depressions and negative T waves. Right bundle branch block was observed in three patients, while left bundle branch block was recorded in two. Anatomical variations observed during angiography included vascular tortuosity in 11 patients (17.7%), myocardial bridging of the LAD in three patients (4.8%), and coronary-cameral microfistulas in seven patients (11.3%).

The mean TCPM was 4.99±1.01 seconds, with the lowest value recorded at 3.1 seconds and the highest at 7.7 seconds. Fig. 2 illustrates the normal distribution of TCPM.

A multiple linear regression analysis was conducted to identify significant predictors of TCPM. The initial model included multiple clinical and demographic variables, and through the backward elimination method, the model was optimized. The complete regression coefficients, confidence intervals, and statistical significance levels are presented in Table 3 and Fig. 3.

The final model identified three statistically significant predictors: hypertension (p=0.019), which was positively associated with TCPM; female sex (p=0.040), which showed a negative association with TCPM; and mean arterial pressure (p=0.009), which also demonstrated a negative association with TCPM(Table 4, Fig. 4).

The final model explained 21.1% of the variation in TCPM (R²=0.211, adjusted R²=0.170). Residual analysis confirmed that the model met the assumptions of linearity, homoscedasticity, and independence (Durbin-Watson =1.959). Collinearity among predictors was evaluated using the variance inflation factor (VIF). Minor deviations from normality were observed in the Q-Q plot (Figs 5, 6).

This study examines the time for contrast to pass through the myocardium (TCPM) as a potential indicator of MVD in patients with angina and non-obstructive coronary artery disease. The mean TCPM in patients with angina and non-obstructive coronary artery disease was determined. Our main findings indicate that TCPM is associated with specific factors, including hypertension, mean arterial pressure, and female sex.

Hypertension was positively associated with TCPM, suggesting that patients with hypertension experience delayed contrast passage. This corresponds with well-established mechanisms of endothelial dysfunction, structural microvascular alterations, and elevated left ventricular end-diastolic pressure, all of which contribute to increased vascular resistance and prolonged transit time. Similar findings have been reported in previous studies, where hypertension was linked to impaired coronary microcirculatory function and reduced CFR.^{[12, 13]} Furthermore, fluoroscopic indices such as TIMI Frame Count and Myocardial Blush Grade have demonstrated significantly poorer results in hypertensive patients compared to normotensive individuals.^[14]

Mean arterial pressure demonstrated an inverse relationship with TCPM, suggesting that higher mean arterial pressure is associated with a shorter contrast transit time. This aligns with the concept that higher perfusion pressure is expected to result in an increased coronary blood flow velocity, although significant autoregulation ensures that coronary blood flow remains relatively stable across different mean arterial pressures.^{[15, 16]}

The observed divergence between hypertension and mean arterial pressure may reflect the difference between chronic vascular remodeling in hypertension and the acute hemodynamic influence of MAP during contrast injection, which can directly affect myocardial contrast transit time.

An interesting result from the analysis was the negative association between female sex and TCPM. This finding is somewhat surprising given the higher prevalence of MVD among women.^[17] Possible explanations include physiological differences such as smaller left ventricular size, differences in endothelial reactivity, and hormonal influences, which may contribute to this observation. This relationship warrants further investigation, as women are more frequently affected by MVD and have a documented worse prognosis.^[18]

Data regarding the association between traditional cardiovascular risk factors and microvascular disease remain inconsistent. Some studies report that smoking, age, diabetes, hypertension, and dyslipidemia are associated with microvascular dysfunction.^{[17, 19]} Other studies suggest that diabetes is less prevalent among patients with angina and non-obstructive CAD, while hypertension and dyslipidemia are relatively more common.^[20] Overall, in patients with MVD, traditional cardiovascular risk factors appear to be less pronounced than in those with obstructive coronary disease.^[21] In our study, no significant association was found between TCPM, age, and traditional risk factors such as dyslipidemia, diabetes, and smoking.

TCPM can be easily recorded during coronary angiography by prolonging the fluoroscopic recording and represents an objective, reproducible, and quantitative index with potential utility in assessing coronary microcirculation. An advantage of this method over previously described fluoroscopic indices is the possibility of standardization using an automated injection system, which delivers a predefined contrast volume at a known rate, eliminating operator-dependent variability in injection speed.

Limitations of this study include the lack of ischemia confirmation using functional imaging methods in all patients, the inability to synchronize ECG timing with the initial contrast injection, as the cardiac cycle phase might introduce minor deviations in the transit time calculation, and the potential for minimal variability in determining the first frame where the coronary sinus is visualized. The lack of coronary functional testing and validation of this method against an established microcirculation assessment technique such as IMR limits definitive diagnostic correlation. In addition, the analysis did not account for the potential influence of cardiovascular medications (e.g., beta-blockers, calcium channel blockers, nitrates), which may independently affect coronary flow and TCPM values. The relatively small sample size limits statistical power and generalizability, and the findings should therefore be interpreted as exploratory and hypothesis-generating. Minor deviations observed in the Q-Q plot of residuals suggest mild skewness or the influence of outliers, which may slightly affect the assumption of normality and are acknowledged as a limitation of the regression analysis.

These findings lay the groundwork for subsequent studies involving larger cohorts, correlation of TCPM with symptom burden (e.g., CCS class, Seattle Angina Questionnaire), assessment of medication effects, and validation against gold-standard physiological tests such as IMR. Further investigation is planned to determine the diagnostic and prognostic utility of TCPM to identify patients with microvascular angina and potentially guiding individualized treatment strategies.

This study established the mean TCPM in patients with angina and non-obstructive coronary arteries. A positive association was observed between TCPM and hypertension, whereas mean arterial pressure and female sex exhibited an inverse relationship with this parameter. TCPM measurement is a simple, quantitative, and reproducible method that may have potential applications in the assessment of patients with angina and non-obstructive coronary arteries.

The authors have no funding to report.

The authors have declared that no competing interests exist.