A Comparative Study of Coronary Sinus Flow in Normal Healthy Controls with that of Patients of ST Segment Elevation Myocardial Infarction and Significant Coronary Artery Disease by Transthoracic Echocardiography. Is there any Gender Difference?

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INTRODUCTION

Coronary artery diseases (CADs) have become a significant global health burden, with atherosclerosis being a leading killer.^[1,2] In India and low and middle socioeconomic countries, 75% of CAD-related deaths occur.^[3] Accurate diagnosis and early detection are crucial for further management protocol, emphasizing the importance of prevention. Historically, invasive diagnostic approaches were widely used. However, for the detection of epicardial vessel pathology, technology advancements have now made possible non-invasive methods to effectively compete with invasive methods.

Atherosclerotic plaque formation in the coronaries in CAD patients leads to a decrease in coronary flow reserve (CFR). This decreased CFR is calculated indirectly with coronary sinus flow (CSF) measurement under echocardiography (ECHO). CSF can therefore be used to decide myocardial infarction (MI) prognosis and treatment protocol. Previously, in patients with left anterior descending (LAD) artery significant stenosis, transesophageal echo was used to measure CFR.^[4,5] As per some recent articles, coronary sinus flow (CSF) determines myocardial flow reserve (MFR) and myocardial blood flow (MBF). MFR is a robust predictor for deciding prognosis and treatment protocol of CAD.^[6] Hence, the main objective of our work was to estimate the blood flow in the coronary sinus in patients of STEMI with significant stenosis of coronary arteries, using transthoracic echo, undergoing the procedure, and coronary angiography (CAG). Smaller coronary arteries, hormonal factors, fluctuations in estrogen levels during menstrual cycles, and menopause can impact coronary blood flow regulation. As per various coronary sinus flow studies, women exhibit less coronary flow velocity reserve (CFVR) and more resting MBF and lower CFVR compared to men, suggesting potential differences in coronary microvascular function.^[7-9] The study also aimed to compare these measurements with coronary sinus flow in healthy subjects without any risk factors and CAD and to identify any gender differences.

MATERIALS AND METHODS

This is a case–control, retrospective study done in the Cardiology department at MKCG Medical College and Hospital, Berhampur, over a 2-month period. A total of 50 STEMI patients (either thrombolysed or not thrombolysed) admitted to the cardiology ward were selected as cases using purposive sampling, while 50 healthy individuals, primarily attendants of previous patients, served as controls. Both groups were further stratified by gender. IEC approval was granted from the Institutional Review Board, MKCG MC, and Hospital, Berhampur. Each study individual was informed regarding methodology, purpose, and protocols. Then, written informed consents were kept in their preferred language. Patient confidentiality was strictly maintained throughout the study.

Patients aged 18–80 years with STEMI, whether thrombolysed or non-thrombolysed, were included as cases based on symptoms, electrocardiographic (ECG) changes, elevated troponin levels, or evidence of regional wall motion abnormality in echo. The control group consisted of healthy individuals without any heart disease or risk factors. Exclusion criteria consist of patients with bad echocardiographic windows, hemodynamically unstable patients, with mitral or tricuspid regurgitation exceeding grade 2+, and those contraindicated for CAG.

A complete medical history was obtained for each subject, followed by general and cardiovascular examinations. Using a mercury sphygmomanometer, blood pressure was measured in sitting posture, 15 min of rest. A 12-lead ECG was recorded using the EDAN SE-1201 machine with automated analysis software, following the 2022 American Heart Association/American College of Cardiology (ACC)/American Society of Echocardiography (ASE) guidelines for STEMI ECG manifestations. Transthoracic echocardiography (TTE) was performed on the day of hospitalization using a GE VIVID system equipped with a 5S MHz transducer. The procedure was conducted in the left lateral position (Recommendation-ASE). ECG recordings were simultaneously obtained in a dimly lit room to enhance image quality. Parasternal long-axis view was then acquired, along with M-mode. LVEDD, LVESD, and left ventricular ejection fraction (LVEF) were estimated. Next, the parasternal right ventricular inflow view is taken to visualize the coronary sinus ostium [Figure 1]. For minimizing atrial contraction effects, the coronary sinus diameter (CSD) was measured with the help of ECG gating, 1 cm from the ostium of coronary sinus before the P-wave. Then, pulsed-wave sample volume (3 mm) was placed at the same distance, with slight rotation to maintain an optimal Doppler angle (<30°) for accurate spectral flow recordings. The antegrade phase of coronary sinus flow entering the right atrium was analyzed, with peak velocity (cm/s), peak pressure gradient (mmHg), and mean velocity (cm/s) recorded [Figure 2a and b]. Mean pressure gradient (mmHg) and velocity time integral (VTI) (cm) were determined using Doppler method, with coronary sinus flow calculated per stroke (mL/stroke) and per minute (mL/min) using the formulas: Blood flow per min = π× D²/4 × VTI × heart rate, where D = CSD and blood flow per stroke = π× D²/4 × VTI. Angiography was done by radial or femoral route under local anesthesia, utilizing a catheterization laboratory system for analysis. Quantitative angiography was conducted in multiple projections to assess arterial stenosis and lesion features, with measurements of minimum lumen diameter and percentage of stenosis, where stenosis ≥50% was considered significant. Study categorical variables were expressed as counts and percentages and continuous variables were reported as mean ± SD. Statistical analysis was done by student’s t-test and Chi-square test to evaluate the efficacy of coronary sinus flow measurement by TTE in diagnosing significant coronary artery stenosis. A P < 0.05 was considered statistically significant, and all data were analyzed using the Statistical Package for the Social Sciences version 29.

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Figure 1:

Coronary sinus in echocardiography. Source: Current Study.

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Figure 2:

(a) Coronary sinus velocity time integral in echocardiography-1, (b) Coronary sinus velocity time integral in echocardiography-2. Source: Current Study.

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RESULTS

A total of 50 patients and 50 healthy individuals were enrolled over a 2-month period, with careful consideration given to all inclusion and exclusion criteria. The baseline features of the cases and controls in the study are mentioned in Table 1. Average age of cases was 56.14 years and mean age of controls was 47.22 years, when compared it was seen that maximum number of patients were in the 50–59-year group (42%) followed by 60 –69-year group (30%), suggesting CAD is more common in elderly population [Figure 3].

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Figure 3:

Age distribution among case and control. (Source: Current Study).

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The number of males were higher in cases and controls with 70% in cases and 56% in controls, respectively, depicting CAD is more prevalent in males than females [Figure 4].

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Figure 4:

Gender distribution in cases (n=50) and controls (n=50). (Source: Current Study).

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Ejection fraction (EF) was significantly decreased in CAD patients (EF = 48%) while comparing healthy controls (EF = 63%). CSF was statistically less in cases (3.18 mL) than in controls (11.78 mL) in controls, with P < 0.05. BMI was higher in cases (28.7 kg/m²) than controls (21.4 kg/m²) but it was statistically not significant (P = 0.17). CSD was 0.5 cm that is reduced in cases while it was 0.9 cm in controls which was significant (P <0.05).

The CSVTI was 14.48 ± 2.6 cm in cases and 17.9 ± 1.1 cm in controls, which was statistically lower in cases than in controls (P < 0.05). When VTI was compared among cases male versus female (P = 0.408) and controls male versus female (P = 0.341), it was found to be statistically not significant [Figure 5]. CSF was 3.18 ± 1.0 mL in cases and 11.78 ± 2.5 mL in controls, which was statistically significant (P < 0.05). However, when CSF was compared among cases, male versus female (P = 0.151), and control, male versus female (P = 0.185), shown statistically not significant, although CSF was little higher in both case and control females than males [Figure 6]. CSF/min was 260.66 mL/min in cases and 967.36 mL/min in controls, when compared it was statistically significant (P < 0.05). However, CSF/min when compared cases, male versus female (P = 0.113) and controls, male versus female (P = 0.124), was statistically not significant; however, CSF/min was little higher in both female cases and controls [Figure 7]. Hence, irrespective of sex, the mean values of CSVTI, CSF, and CSF/min were lower in cases than controls [Table 2].

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Figure 5:

Velocity time integral (VTI) among cases and controls. (Source: Current Study).

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Figure 6:

CSF among cases and controls. (CSF: Coronary sinus flow), Source: Current Study).

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Figure 7:

CSF mL/min among cases and controls. (Source: Current study). (CSF: Coronary sinus flow.)

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It was seen that VTI, CSF/min, and CSF values were decreased when number of arteries involved in STEMI patients undergoing CAG is increased, with P < 0.001 and R-value −0.753, suggesting a significant negatively correlated whereas the BMI and CSF were not correlated [Table 3].

From this graph, the area under the curve gave the sensitivity and specificity value. The best cut-off value of CSF was 6.4ml, which has 99% sensitivity and 98% specificity in differentiating case from controls [Table 4 and Figure 8].

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Figure 8:

Receiver operating characteristic analysis of coronary blood flow. (Source: Current Study).

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DISCUSSION

Nowadays, non-invasive methods such as TTE, transesophageal echocardiography (TEE), CT angiography, and positron emission tomography have increased in number. The non-invasive method gives equivalent information like invasive methods.^[10-12] Recently, severe coronary artery stenosis can be detected indirectly by estimating CSF with the help of TEE or TTE, especially in LAD lesions. TEE, which is a semi-invasive method, measures CSF accurately and also helpful in CSF monitoring pre and post vasodialator therapy. Vasodilators sometimes cause angina in CAD patients.^[10] Hence, TTE is increased in number to evaluate coronary vascular pathology. Liu et al. studied coronary sinus physiology with the help of TTE in the pig heart. They said that coronary sinus flow is the best indicator of coronary artery blood flow.^[13] Zheng et al. 1^st studied CSF estimation with the help of TTE in the case of hypertensive patients.^[14] They estimated the CSF value in 275 subjects. Their main objective was to discriminate patients with CAD with significant stenosis from healthy individuals. They gave a conclusion that, for the detection of significant stenosis of coronary artery, CSF/min is the best indicator. Toufan et al.^[15] conducted a study in acute myocardial infarction patients. They had taken CSF, VTI, LVEF, and wall motion scoring index (WMSI). They found that significant correlation between CSF and LVEF (r = 0.52, P < 0.05), WMSI (r = −0.77, P < 0.05), CSF and in-hospital mortality (r = 0.58, P < 0.05), and also between VTI and EF (r = 0.85, P < 0.05). CSF in MI patients was 287 ± 128 mL/min and in controls was 415 ± 127 mL/min with P < 0.05. VTI was significantly lowered in MI patients than controls (11.16 ± 2.85 and 17.56 ± 2.72, P < 0.05). Their study gave risk stratification based up on the CSF. In another study, Meenakshi et al.^[16] used TTE for measuring CSF in 232 CAD patients including acute coronary syndrome, thrombolysed patients, symptomatic old CAD patients hospitalized for CAG and AWMI patients waiting for percutaneous coronary intervention using bare metal stents. They compared cases with controls. In CAG patients, the relation between CSF and lesion severity was obtained. While in thrombolysis and percutaneous coronary intervention undergoing patients, CSF values before and after treatment were estimated. Control group was showing more CSD (8.73 ± 2.08 mm) and more CSF/min (5.64 ± 2.24). Both CSD (7.42 ± 1.69 mm) and CSF/min (3.93 ± 1.9) were significantly lowered in CAD patients. According to Kobayashi et al.^[7] Journal of the American College of Cardiology: Cardiovascular intervention 2015 September coronary sinus flow study, despite similar microvascular function in females and males by index of microcirculatory resistance, CFR is lower in females, meaning their coronary arteries dilate less in response to increased blood flow needs. In different coronary sinus flow studies,^[7-9] females show higher resting MBF and lower CFVR compared to males. This suggests potential differences in coronary microvascular function. Studies show that females tend to have higher MBF both at rest and during peak stress compared to males. Females with signs or symptoms of ischemia and non-obstructive CAD have lower CFVR compared to males. The lower CFVR in females, despite higher resting flow, suggests a potential difference in how the coronary vessels respond to increased demand, which could contribute to a higher prevalence of coronary microvascular dysfunction in females. Females with signs or symptoms of ischemia and non-obstructive CAD have lower CFVR, higher resting CBF, lower hyperemic CBF when compared to males.^[9] At present, there are no specific studies to see the gender differences in CSF in STEMI patients with significant coronary artery stenosis although males and females have different coronary vascular physiology. Our study was conducted to measure CSF by TTE by enrolling 50 STEMI patients and 50 healthy individuals. The number of males was more in both cases and controls, which is similar to Porwal et al.’s European JCM 2024^[17] where most of the patients were males. However, statistically significance between the genders is not shown in that study. In DIAD study, males had more incidence of STEMI due to large perfusion defect.^[18] The CSVTI was 14.48 ± 2.6 cm in cases and 17.9 ± 1.1 cm in controls, which was statistically lower in cases than in controls (P < 0.05). The CSF was 3.18 ± 1.0 mL in cases and 11.78 ± 2.5 mL in controls, when compared it was statistically significant (P < 0.05). Mean CSF/min was 968 ± 197 mL/min in normal subjects and 260 ± 91 mL/min in patients with CAD, when compared it was statistically significant. Sensitivity, specificity, and cutoff value of CSF for the detection of significant coronary artery stenosis were 99%, 98%, and 6.4 mL, respectively. These findings were similar to Rao et al.^[19] CSF by TTE in STEMI patients and healthy individuals in 2019. In their study, CSD and CSVTI were statistically lower in MI patients than in normal persons (P < 0.05). CSF/min was 8.9 mL in patients and 13.9 mL in normal subjects with P < 0.05. With the help of ROC analysis, CSF of 11.7 mL was the calculated cut-off value to differentiate between cases and controls that were 90% sensitive and 80% specific. They said that, to detect significant stenosis, CSF estimation is the best indicator.^[19]

This study also showed a negative correlation between CSF and number of arteries involved (P < 0.05) similar to our study. However, we also did sex comparison as there were less number of studies regarding this. Hence, mean values of CSVTI, CSF, and CSF/min when compared among gender with in cases and control group, they did not show statistical significance, although CSF and CSF/min were little higher in the female groups of cases and controls, as the study was a short duration study involving very less sample size.

CONCLUSION

In view of these findings, it can be concluded that the coronary sinus flow estimation by TTE is one of the earliest, simple, accurate methods, to find significant stenosis of coronary arteries in STEMI patients in both genders. The coronary sinus flow is reduced in STEMI patients with significant coronary artery stenosis. Coronary sinus flow decreases when the number of vessels with significant involvement increases. Although coronary sinus flow was found to be higher in female subjects, that was statistically not significant. And also based on coronary sinus flow, CAD patients cannot be diagnosed. So, to discriminate CAD patients from healthy individuals by measuring coronary sinus flow with the help of transthoracic echocardiography and to detect the gender variability, we may require further studies with large sample size.