Abstract
Background
Coronary sinus filling time (CSFT) has been proposed as a simple method for assessment of coronary microvascular function in patients with angina and normal coronaries. But its correlation with inducible ischemia and prognostic significance in predicting future cardiovascular events has not been studied. The present study assessed the prognostic significance of CSFT during one year of follow up.
Methods
We compared coronary sinus filling time of patients with angina and normal coronaries with that of control population. Control group was formed by those patients with supraventricular arrhythmia undergoing radiofrequency ablation and having normal coronaries. Baseline treadmill test (TMT) parameters like workload, duration and Duke Score were assessed. Patients were followed up for one year and a composite of cardiovascular mortality and non-fatal myocardial infarction was analyzed. Number of patients presenting to emergency or outpatient department with recurrent chest pain symptoms during one year follow up was considered for secondary outcome analysis. Coronary sinus filling time was analyzed with respect to cardiovascular events, repeat hospitalization for recurrent angina and TMT parameters.
Results
Total 72 patients and 16 controls were studied. Mean CSFT value in the study group was 5.31 ± 1.03 sec and in the control group was 4.16 ± 0.72 sec and the difference was significant (p value = 0.0001). No correlation was found between baseline and repeat TMT parameters with CSFT. There was no cardiovascular mortality or hospitalization for non-fatal MI during one year follow up. But patients with frequent emergency or outpatient department visits with chest pain had a high CSFT compared with asymptomatic patients (p value = 0.005).
Conclusion
Coronary sinus filling time may be used as a simple marker of microvascular dysfunction in patients with angina and normal coronaries. Patients with recurrent chest pain symptoms after one year follow up were found to have high CSFT compared to asymptomatic patients.
Keywords: Microvascular dysfunction, Coronary sinus filling time, Angina, Normal coronaries
1. Introduction
Cardiac syndrome X is characterized by angina, positive exercise stress test, normal coronaries on angiogram and no evidence of coronary artery spasm.1,2 Myocardial ischemia is proven to be one of the reasons for persistent angina in this group of patients (using MRI and nuclear perfusion studies).3–5 Coronary microvascular dysfunction is identified as the cause of myocardial ischemia.6,7 Studies have proved that prognosis of patients with persistent angina and normal epicardial coronaries is not benign.8–10 Women Ischemic Symptom Evaluation (WISE) trial showed that persistent angina in patients with normal epicardial coronaries is associated with more than two fold increases in cardiovascular events.8,9 This study concluded that such patients should undergo further studies of vascular function and aggressive risk factor modification. There are no simple investigative modalities to assess the coronary microcirculation. Noninvasive as well as invasive modes of investigation have yielded inconsistent results.11 Recent studies have shown that patients with angina and normal coronaries have prolongation of coronary sinus filling time (CSFT) and this can be used as a marker of coronary microvascular function.12,13 But the prognostic significance of CSFT has not been studied. In the present study we assessed the prognostic significance of CSFT in predicting cardiovascular events on follow up.
2. Patients and method
In this prospective cohort study, patients undergoing coronary angiogram for evaluation of chest pain in cardiology department of a large tertiary hospital were screened. Study population was selected after applying exclusion criteria. Patients with abnormal coronaries (irregularities, ectasia, stenosis, myocardial bridging), history of acute coronary syndrome with raised cardiac markers and echocardiography showing more than mild valvular heart disease, cardiomyopathies, significant left ventricular dysfunction defined as M-mode ejection fraction less than 50%, regional wall motion abnormality and pulmonary artery hypertension defined as peak pulmonary artery pressure more than 30 mmHg (estimated from tricuspid regurgitant jet velocity) were excluded. Control population comprised of patients above 40 years of age without structural heart disease undergoing electrophysiology (EP) study and radiofrequency (RF) ablation for supraventricular tachycardia (atrioventricular node reentrant, atrioventricular reentrant tachycardia) with ST segment depression during tachycardia and having normal coronaries on angiogram. Baseline evaluation, ECG, echocardiography and treadmill test (TMT) were done in all cases.
2.1. CSFT estimation
A repeat injection in the left coronary system was taken with 7 ml contrast at approximate rate of 2 ml/s. Injection was taken with 5F Tiger catheter through radial approach or 6F JL catheter through femoral route. Coronary sinus was evaluated in 40° left anterior oblique (LAO) view with 20° cranial angulation. In this view the tract and effluent could be clearly seen draining into the right atrium after six to eight cycles on average. Coronary angiogram was done with Philips Allura Xper FD 20 (Philips electronics, Eindhoven, The Netherlands) at a rate of 15 frames per seconds.
Coronary sinus filling time is defined as the time taken in seconds for the contrast agent in the epicardial coronary artery to traverse the coronary microvasculature and reach the coronary sinus origin. Assessment of CSFT was done offline. Coronary sinus filling time was estimated as the difference between the frame count of maximum left anterior descending artery (LAD) system opacification at first diagonal (D1) or first septal (S1) to that of the starting point of opacification of coronary sinus origin (Fig. 1A, B). Frame count at the maximum opacification of LAD at D1 or S1 whichever is earlier was taken as the first frame count. The frame count in which dye is first seen at the origin of coronary sinus was counted as the last frame and the frame count was noted. Coronary sinus origin is defined as the point where great cardiac vein joins the posterolateral vein. The CSFT is calculated in seconds as (last frame count – first frame count)/15.
Fig. 1.
(A): Frame showing LAD opacification at the origin of first diagonal branch (arrow). (B): Frame showing coronary sinus origin (arrow) at the confluence of great cardiac vein with posterolateral vein.
2.2. Follow up
Patients were followed up for a period of one year with data collected at 1 month, 6 month and at 12 month by direct evaluation. At 1 year they were evaluated for cardiovascular mortality, hospitalization for non-fatal myocardial infarction and emergency or outpatient department visits for recurrent chest pain symptoms. Treadmill test (TMT) was repeated at one year to assess the workload, exercise duration and Duke Score.
2.3. Outcome
Primary outcome was composite of cardiovascular mortality and hospitalization for non-fatal myocardial infarction. Secondary outcomes were emergency or outpatients department visits for recurrent chest pain symptoms and conversion rate from negative to positive TMT.
2.4. Analysis
Baseline comparison of CSFT was done between the study and control population. Among the study population CSFT was compared between patients with positive and negative TMT results. CSFT was correlated with baseline TMT parameters like workload, exercise duration and Duke Score. At 1 year TMT was repeated to assess Duke Score, exercise level, workload and conversion rate from negative to positive TMT. Coronary sinus filling time was analyzed with respect to cardiovascular mortality, hospitalization for non-fatal myocardial infarction, repeat TMT parameters and emergency or outpatient department visits with recurrent chest pain.
2.5. Statistical analysis
The continuous variables are presented as the means and standard deviations. The categorical variables are presented as percentages. To test for differences across all groups, the chi square and ANOVA tests were used. Statistical analysis was performed using Statistical Package for Social Science software (SPSS Inc Chicago, Illinois version 18). A p-value less than 0.05 were considered statistically significant.
3. Results
There were 72 patients and 16 controls. Baseline characteristics of patients are given in Table 1. All baseline characteristics, except hypertension, were similar in two groups. Hypertension was more prevalent in study group.
Table 1.
Baseline characteristics.
| Parameter | Study group (n = 72) | Controls (n = 16) | p Value |
|---|---|---|---|
| Male n (%) | 29 (40.8) | 6 (37.5) | 0.805 |
| Mean age (SD) year | 54.07 (9.4) | 52.8 (9.8) | 0.627 |
| DM n (%) | 23 (32.4) | 2 (12.5) | 0.112 |
| Hypertension n (%) | 26 (36.6) | 1 (6.3) | 0.018 |
| Dyslipidemia n (%) | 11 (15.5) | 0 (0) | 0.092 |
| Smoking n (%) | 6 (8.5) | 0 (0) | 0.228 |
| CSFT sec (SD) | 5.31 (1.03) | 4.16 (0.72) | 0.0001 |
CSFT: coronary sinus filling time, SD: standard deviation, DM: Diabetes mellitus.
Among the study group, 54.3% (n = 38) were TMT positive; 37.1% (n = 26) were TMT negative and 8.6% (n = 6) had inconclusive results. In the study group, mean workload attained was 9.31 ± 2.21 METS; mean exercise duration was 7.89 ± 2.21sec and Duke Score was 3.94 ± 4.31. The mean CSFT value in the study group and in the control population was significantly different (p value = 0.0001). When CSFT was analyzed separately in TMT positive (5.70 ± 1.04 s) and TMT negative group (4.82 ± 0.83 s) the difference was significant (p value = 0.001). There was no correlation between CSFT value and baseline TMT parameters like workload and exercise duration. A weak negative correlation was found between Duke Score and CSFT (p value = 0.002) (Table 2). Follow up data was collected after one year in study group (Table 3). There was no primary outcome in the study group. When secondary outcomes were analyzed 17 patients attended emergency or outpatient department with recurrent chest pain during one year follow up. The mean CSFT (5.91 ± 1.12) of these patients was significantly different compared to those patients who remained asymptomatic (5.12 ± 0.9) (p value = 0.005) shown in Table 4. Repeat TMT performed after one year showed no statistically significant change from baseline TMT results. There was no correlation found between repeat TMT parameters like workload, exercise duration, and CSFT but negative correlation with Duke Score and CSFT remained significant (Table 5).
Table 2.
Correlation of CSFT and baseline TMT parameters.
| TMT parameter | Mean (SD) | Pearson correlation | p Value |
|---|---|---|---|
| Duration (sec) | 7.89 (2.2) | 0.054 | 0.656 |
| Workload (MET) | 9.31 (2.2) | 0.056 | 0.649 |
| Duke Score | 3.94 (4.4) | −0.368 | 0.002 |
CSFT: coronary sinus filling time, TMT: treadmill test, MET: metabolic equivalent.
Table 3.
Follow up event data at one year.
| Parameter | |
|---|---|
| Cardiovascular mortality | 0 |
| Non-fatal MI | 0 |
| Number of patients with emergency/outpatient visits with recurrent chest pain | 17 |
MI: myocardial infarction.
Table 4.
Comparison of CSFT between symptomatic and asymptomatic patients at one year.
| CSFT mean (SD) | p Value | |
|---|---|---|
| Symptomatic patients | 5.91 (1.12) | 0.005 |
| Asymptomatic patients | 5.12 (0.91) |
CSFT: coronary sinus filling tome, SD: standard deviation.
Table 5.
Correlation of CSFT and 1 year TMT parameters.
| Parameter | Mean (SD) | Pearson correlation | p Value |
|---|---|---|---|
| Duration (sec) | 8.75 (1.81) | −0.051 | 0.676 |
| Workload (MET) | 9.82 (1.6) | 0.070 | 0.656 |
| Duke Score | 5.47 (3.91) | −0.353 | 0.003 |
TMT: treadmill test,CSFT: coronary sinus filling time, SD: standard deviation, MET: metabolic equivalent.
4. Discussion
Coronary microvascular dysfunction has been proven to be one of the causes of persistent angina in patients with normal coronaries. Different investigation modalities, including MRI and nuclear perfusion studies, have proven ischemia as the cause of persistent angina in patients with normal coronaries. Prognosis of patients with angina and normal coronaries is not as benign as previously thought. This has been proven in WISE study8,9 where women with persistent angina and normal coronaries have increased cardiovascular mortality on long term follow up. Patients with positive stress test and normal coronaries are also at increased risk of cardiovascular events compared to those with negative stress test. There is no simple investigation modality to assess the function of coronary microcirculation. In a recent study conducted by Haridasan et al, patients with angina and normal coronaries were found to have prolonged CSFT compared with control population (Patients with severe rheumatic mitral stenosis undergoing balloon mitral valvotomy).13 In contrast to the previous study, our study recruited patients with structurally normal heart as controls (Patients with supraventricular arrhythmias undergoing radiofrequency ablation). The prognostic significance of CSFT in patients with normal coronaries has not been studied previously. In the present study we assessed its prognostic significance in predicting future cardiovascular events at one year follow up. We tested for relation between CSFT and cardiovascular events. There was no cardiovascular mortality in our study after one year follow up. We also assessed the correlation between baseline TMT parameters like workload, mean exercise duration and Duke Score with CSFT. But no significant correlation was found at baseline or even after one year follow up. We could identify a significant difference between the CSFT of patients with positive stress test compared with negative stress test (p value = 0.0001) and this difference was maintained after one year of follow up (p value 0.005). When secondary outcomes were analyzed, patients who attended emergency or outpatient department with recurrent chest pain symptoms were found to have high CSFT value compared to asymptomatic patients (p value = 0.005).
Limitation of our study was a short period of follow up. In our study, follow up period was one year which may account for the absence of cardiovascular events. Future studies with a longer follow up may address this issue. Another limitation was the inter observer variability in injections. We have not standardized the injection speed as we have not used automated injectors. But Gibson et al had previously shown that changes in hardware, injection methods do not significantly affect the corrected TIMI frame count calculation.14
5. Conclusion
Coronary sinus filling time can be used as a marker of microvascular dysfunction in patients with angina and normal coronaries. Patients with recurrent chest pain symptoms after one year follow up were found to have significantly high CSFT value compared with asymptomatic patients. Studies with long term follow-up are required to assess the impact on future cardiovascular events.
Conflicts of interest
All authors have none to declare.
References
- 1.Chierchia L., Fragasso G. Angina with normal coronary arteries: diagnosis, pathophysiology and treatment. Eur Heart J. 1996;17:14–19. doi: 10.1093/eurheartj/17.suppl_g.14. [DOI] [PubMed] [Google Scholar]
- 2.Kaski J.C., Rosano G.M.C., Collins P. Cardiac syndrome X: clinical characteristics and left ventricular function: long term follow-up study. J Am Coll Cardiol. 1995;25:807–814. doi: 10.1016/0735-1097(94)00507-M. [DOI] [PubMed] [Google Scholar]
- 3.Hudsmit J.E., Ireuladers Magnetic resonance spectroscopy in myocardial disease. J Am Coll Cardiol. 2009;2:87–96. doi: 10.1016/j.jcmg.2008.08.005. [DOI] [PubMed] [Google Scholar]
- 4.Buchtha S.D., den Hollander J.A., Merz C.N.B. Abnormal myocardial phosphorus-31 nuclear magnetic resonance spectroscopy in women with chest pain but normal angiogram. N Engl J Med. 2000;342:829–839. doi: 10.1056/NEJM200003233421201. [DOI] [PubMed] [Google Scholar]
- 5.Legrand V., Hodgson J.M., Bates E.R. Abnormal coronary flow reserve and abnormal radionuclide exercise test results in patients with normal coronary angiograms. J Am Coll Cardiol. 1985;6:1245–1253. doi: 10.1016/s0735-1097(85)80209-6. [DOI] [PubMed] [Google Scholar]
- 6.Cannon R.O., Camici P.G., Epstein S.E. Pathophysiological dilemma of syndrome X. Circulation. 1992;85:883–892. doi: 10.1161/01.cir.85.3.883. [DOI] [PubMed] [Google Scholar]
- 7.Maseri A., Crea F., Kaski J.C., Crake T. Mechanisms of angina pectoris in syndrome X. J Am Coll Cardiol. 1991;17:499–506. doi: 10.1016/s0735-1097(10)80122-6. [DOI] [PubMed] [Google Scholar]
- 8.Prognosis in women with myocardial ischemia in the absence of obstructive CAD: results from the National Institute of Health-National Heart, Lung, Blood Institute – sponsored Women Ischemic Syndrome Evaluation Trial (WISE) Circulation. 2004;109:2993. doi: 10.1161/01.CIR.0000130642.79868.B2. [DOI] [PubMed] [Google Scholar]
- 9.Johnson B.D., Pepera C.J. Persistent chest pain predicts cardiovascular events in women without obstructive CAD: results from NIH-NHLBI-sponsored Women Ischemic Syndrome Evaluation (WISE) study. Eur Heart J. 2006;27:1408. doi: 10.1093/eurheartj/ehl040. [DOI] [PubMed] [Google Scholar]
- 10.Bugiardini R. Women, “nonspecific” chest pain, normal or near normal CAG are not synonymous with favorable outcome. Eur Heart J. 2006;27:1387. doi: 10.1093/eurheartj/ehi758. [DOI] [PubMed] [Google Scholar]
- 11.Ng M.K.C., Yeung A.C., Fearon W.F. Invasive assessment of coronary microcirculation, superior reproducibility and less hemodynamic dependence of index of microcirculatory resistance compared with coronary flow reserve. Circulation. 2000;101:1344–1351. doi: 10.1161/CIRCULATIONAHA.105.603522. [DOI] [PubMed] [Google Scholar]
- 12.Sangareddi V, Alagesan R. Coronary sinus filling and emptying time: a new parameter to assess coronary microcirculation by a simple angiographic frame count. 59th Annual Conference of the Cardiological Society of India December 7–10, 2008. (Abstract).
- 13.Haridasan V., Nandan D. Coronary sinus filling time: a novel method to assess microcirculatory function in patients with angina and normal coronaries. Indian Heart J. 2013;65:142–146. doi: 10.1016/j.ihj.2013.02.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Gibson C.M., Cannon C.P., Daley W.L. TIMI frame count: a quantitative method of assessing coronary artery flow. Circulation. 1996;93:879–888. doi: 10.1161/01.cir.93.5.879. [DOI] [PubMed] [Google Scholar]