Coronary slow-flow phenomenon in takotsubo syndrome: the prevalence, clinical determinants and long-term prognostic impact

Patients with takotsubo syndrome (TTS) may present coronary slow flow (CSF) in angiography performed in the acute myocardial infarction (MI). However, the detailed clinical relevance and its long-term impact remain poorly understood. Among 7771 MI patients hospitalized between 2012 and 2019, TTS was identified in 82 (1.1%) subjects. The epicardial blood flow was assessed with thrombolysis in myocardial infarction (TIMI) scale and corrected TIMI frame count (TFC), whereas myocardial perfusion with TIMI myocardial perfusion grade (TMPG). CSF was defined as TIMI-2 or corrected TFC > 27 frames in at least one epicardial vessel. CSF was identified in 33 (40.2%) TTS patients. In the CSF-TTS versus normal-flow-TTS group, lower values of left ventricular ejection fraction on admission (33.5 (25-40) vs. 40 (35-45)%, p = 0.019), more frequent midventricular TTS (27.3 vs. 8.2%, p = 0.020) and the coexistence of both physical and emotional triggers (9.1 vs. 0%, p = 0.032) were noted. Within a median observation of 55 months, higher all-cause mortality was found in CSF-TTS compared with normal-flow TTS (30.3 vs. 10.2%, p = 0.024). CSF was identified as an independent predictor of long-term mortality (hazard ratio 10.09, 95% confidence interval 2.12-48.00, p = 0.004). CSF identified in two-fifths of TTS patients was associated with unfavorable long-term outcomes.

Introduction: Association of takotsubo syndrome (TTS) with spontaneous coronary artery dissection (SCAD) has been described previously. Characteristics and in-hospital prognosis of SCAD patients with concomitant TTS remain unclear. Methods: Patients with angiography-confirmed SCAD were selected from the iSCAD Registry and underwent core lab adjudication of left ventriculography (LVG) and coronary angiography including assessment of SCAD lesion characteristics, TIMI Flow Grade (TFG), and TIMI Myocardial Perfusion Grade (TMPG). Classic TTS was defined as wall motion abnormality (WMA) presenting as apical ballooning. TTS variants were defined as non-apical WMA discordant to dissected coronary territory with apical sparing. In-hospital event was defined as composite of recurrent myocardial infarction (MI), cerebrovascular accident, heart failure requiring diuretics, or new arrhythmia. Results: On blinded review of LVG from 216 patients, TTS was identified in 38 (17.6%) patients (classic, midventricular, and focal pattern: 86.8%, 2.6%, and 10.5%, respectively). There was no significant difference in age, cardiovascular risk factors, history of anxiety or depression, recreational substance use, emotional or physical stressors, extracoronary vascular abnormalities, peak troponin levels, or TFG of dissected arteries between TTS and non-TTS groups. TTS patients were more likely to present with ST-segment elevation MI (47.4% vs 27.5%; p=0.02), left anterior descending artery (LAD) involvement (89.5% vs 59.0%; p=0.0004), and TMPG < 3 (68.4% vs 48.3%; p=0.02) compared to non-TTS patients. TTS patients had a greater risk of in-hospital events (32.4% vs 15.1%; p=0.01), mainly attributed to new arrhythmia (27.0% vs 6.5%; p=0.0009) and heart failure (11.4% vs 3.0%; p=0.03). Conclusion: Coexistence of TTS and SCAD was associated with ST-elevation MI, LAD involvement, impaired microvascular myocardial perfusion, and adverse in-hospital outcomes.

ObjectivePatients with Takotsubo syndrome (TTS) present an acute microvascular dysfunction that leads to an impaired myocardial perfusion and, in more severe forms, an impaired epicardial flow. However, clinical relevance of...

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Background: Takotsubo syndrome (TTS) is a syndrome with ambiguous pathophysiology. Impaired kidney function (KF) seems to impact the outcome of patients with TTS. We hypothesized that KF worsens the outcome among TTS patients and furthermore, TTS patients with concomitant KF experience more adverse events compared to myocardial infarction (MI) patients with concomitant KF. Methods and Results: This retrospective single-center study comprised two groups (cohorts) of patients including patients with TTS and concomitant KF (n = 61, 27.1%) and patients with MI and concomitant KF (n = 164, 72.9%). The clinical outcomes were delineated as short-term outcomes defined as in-hospital adverse events during index hospitalization and long-term outcomes defined as adverse events over five-year clinical follow-ups. All-cause mortality, stroke, cardiopulmonary resuscitation (CPR), life-threatening arrhythmias, need for respiratory support, and cardiogenic shock with subsequent use of inotropic agents during index hospitalization were denoted as in-hospital adverse events. All-cause mortality, rehospitalization due to heart failure, stroke, thromboembolic events, and the recurrence of primary pathology (TTS and MI) were analyzed during five-year follow-ups after index hospitalization. A higher mortality rate was noted among TTS patients with KF compared to TTS without KF. In addition, in-hospital event rates in patients with TTS and concomitant KF compared to MI and concomitant KF were comparable with the exception of a higher rate of respiratory support in TTS patients. The mortality rate was significantly higher among patients with TTS and KF at 4 years (29.5% vs. 15.9%, p = 0.02) and 5 years (34.4% vs. 20.7%, p = 0.03) in comparison to patients with MI and concomitant KF. In contrast, the rate of re-hospitalization related to heart failure was higher at 30 days, and at one-, four-, and five-year follow-ups in patients suffering from MI and KF compared to TTS and concomitant KF. Additionally, the recurrence of MI after 4 and 5 years was higher than the recurrence of TTS (4.9% vs. 15.2%; 4.9% vs. 16.5%). There were no differences in life-threatening arrhythmias and stroke in both groups. Conclusions: Patients with TTS and concomitant KF have higher all-cause mortality when compared to MI and concomitant KF. The mechanisms responsible remain to be determined.

BACKGROUNDSlow coronary flow (SCF) phenomenon is an angiographic finding which is defined as slow contrast passage through coronary arteries which may predispose patients to serious cardiac complications such as fatal arrhythmias. P-wave and QT-interval dispersion are electrocardiographic findings which are related to atrial fibrillation and ventricular tachyarrhythmias. In the present study, the relation between SCF and presence of P-wave and QT-interval dispersion in electrocardiography has been evaluated.METHODS47 patients with normal coronary arteries and SCF and 40 patients with normal coronary artery flow without SCF were enrolled in this case control study. Standard electrocardiogram (ECG) was analyzed for P-wave and QT-interval dispersion. SCF was identified in normal coronary vessels by use of Thrombolysis in Myocardial Infarction (TIMI) frame count (TFC) method (TFC > 27). Corrected TIMI frame count (CTFC) of coronary vessels as well as mean CTFC along with QT-interval and P-wave dispersion were compared between 2 groups. The study data were analyzed by SPSS software and P value less than 0.050 was considered to be significant.RESULTSQT-interval [76.17 (35.23) ms versus 39.25 (19.26) ms] and P-wave [39.74 (17.48) ms versus 19.50 (8.54) ms] dispersion were significantly higher among patients with SCF phenomenon (P < 0.050). In addition, there was a positive significant linear correlation between TFC and P-wave and QT-dispersion (r = 0.857, r = 0.861, respectively, P < 0.050).CONCLUSIONAccording to the results, increasing TFC among patients with SCF will result in P wave and QT interval dispersion and therefore this finding can be considered as an indicative marker for cardiac events.

Takotsubo syndrome (TTS), commonly perceived as a benign and reversible condition has received attention due to emerging registry data revealing its prognosis to be comparable to acute coronary syndrome (ACS). Following ACS, a notable subset of patients develops autonomic dysfunction, whith unfavourable prognostic implications. Periodic repolarization dynamics (PRD) and deceleration capacity (DC), derived from ECG signals, are parameters capable of quantifying cardiac autonomic function. In this study, we aimed to assess autonomic dysfunction in patients with TTC in comparison to ST-elevation myocardial infarction (STEMI) patients. Consecutive patients diagnosed with TTS were prospectively recruited into an observational, single-centre cohort study. All patients underwent a 30-minute high-resolution ecg recording. Subsequent recordings were conducted at 4 and 12 months post-acute event. PRD and DC as markers for sympathetic and parasympathetic activity, respectively, were assessed using established methods. The control group comprised patients with STEMI. Statistical comparisons between groups were performed using the Mann-Whitney U-test, with a corrected significance level for multiple testing of α&amp;lt; .017. Between July 2021 and December 2023, 57 patients diagnosed with TTS were recruited (interquartile range [IQR]) 69.0 years (62.0-78.0), 98.3% women. A control group was derived from a pre-existing cohort of STEMI patients, matched through propensity score matching to adjust for age and sex (median age [IQR]: 69.0 [59.0-76.0] years, 98.3% women). At baseline, there was no significant difference in PRD between TTS patients and controls (median [IQR]: TTS: 5.28deg² [3.43-9.93], STEMI: 4.40deg² [2.24-7.21]; p = .04). However, at 4 months post-acute event, PRD was notably higher in TTS patients compared to controls (median [IQR]: TTS: 5.20deg² [2.71-8.17], STEMI: 2.63deg² [1.86-4.92]; p = .011). Interestingly, at 12-month follow-up, PRD in TTS patients did not differ from that of controls (median [IQR]: TTS: 4.55deg² [2.89-8.40], STEMI: 4.15deg² [2.42-6.85]; p = .68). Regarding DC, no significant differences were observed between TTS and STEMI patients at any time point (baseline: median [IQR]: TTS: 3.95 ms [2.27-5.51], STEMI: 3.52 ms [2.30-7.24], p = .51; 4 months: median [IQR]: TTS: 6.63 ms [4.59-8.64], STEMI: 7.41 ms [4.63-9.25], p = .39; 12 months: median [IQR]: TTS: 4.98 ms [4.19-6.67], STEMI: 7.48 ms [4.92-10.28], p = .17). Patients with TTS show substantial signs of cardiac autonomic dysfunction, similar or even higher than acute STEMI patients. This dysfunction persists even up to 4 months after the acute event, whereas STEMI patients show recovery of autonomic function in this 4 month period. DC remained consistent between TTS and STEMI patients across all time points. Further research elucidating the long-term implications of these autonomic alterations is warranted to refine risk stratification and therapeutic strategies in TTS management.

Objective: Although the pathophysiological mechanisms underlying coronary slow flow (CSF) phenomenon still remains uncertain, the microvascular dysfunction has been first implicated. The CSF phenomenon may not only affect the coronary arteries but it may also be a part of vascular problem that affect other arteries. The aim of the present study is to evaluate the relationship between CSF phenomenon and subfoveal choroidal thickness (SFCT) and to investigate the effect of short-term atorvastatin therapy on SFCT in patients with CSF. Methods: The study population consisted of 48 patients with CSF and 41 healthy control participants. Coronary flow patterns of the patients were determined by thrombolysis in myocardial infarction (TIMI) frame count method. Spectral-domain optical coherence tomography (SD-OCT) measurements of SFCT and lipid parameters were obtained before and after 2 weeks of daily single dose of 80 mg atorvastatin therapy. Results: We found that patients with CSF had thinner SFCT compared with control group. There was a significant negative correlation between mean TIMI frame count and baseline SFCT (r=-0.69, p=0.001). ROC curve analysis revealed that SFCT <259 m predicted CSF with a 85% sensitivity and 88% specificity. The SFCT significantly increased after the short-term atorvastatin therapy. Conclusion: There was a close negative correlation between CSF phenomenon and SFCT. Endothelial dysfunction (ED) and the resultant microvascular dysfunction might be operative on both coronary and ocular choriocapillary arteries in patients with CSF. Increase of SFCT after the short-term atorvastatin therapy might be an indicator of microvascular dysfunction improvement in patients with CSF.

Although improved epicardial blood flow (as assessed with either TIMI flow grades or TIMI frame count) has been related to reduced mortality after administration of thrombolytic drugs, the relationship of myocardial perfusion (as assessed on the coronary arteriogram) to mortality has not been examined. A new, simple angiographic method, the TIMI myocardial perfusion (TMP) grade, was used to assess the filling and clearance of contrast in the myocardium in 762 patients in the TIMI (Thrombolysis In Myocardial Infarction) 10B trial, and its relationship to mortality was examined. TMP grade 0 was defined as no apparent tissue-level perfusion (no ground-glass appearance of blush or opacification of the myocardium) in the distribution of the culprit artery; TMP grade 1 indicates presence of myocardial blush but no clearance from the microvasculature (blush or a stain was present on the next injection); TMP grade 2 blush clears slowly (blush is strongly persistent and diminishes minimally or not at all during 3 cardiac cycles of the washout phase); and TMP grade 3 indicates that blush begins to clear during washout (blush is minimally persistent after 3 cardiac cycles of washout). There was a mortality gradient across the TMP grades, with mortality lowest in those patients with TMP grade 3 (2.0%), intermediate in TMP grade 2 (4.4%), and highest in TMP grades 0 and 1 (6.0%; 3-way P=0.05). Even among patients with TIMI grade 3 flow in the epicardial artery, the TMP grades allowed further risk stratification of 30-day mortality: 0.73% for TMP grade 3; 2.9% for TMP grade 2; 5.0% for TMP grade 0 or 1 (P=0.03 for TMP grade 3 versus grades 0, 1, and 2; 3-way P=0.066). TMP grade 3 flow was a multivariate correlate of 30-day mortality (OR 0.35, 95% CI 0.12 to 1.02, P=0.054) in a multivariate model that adjusted for the presence of TIMI 3 flow (P=NS), the corrected TIMI frame count (OR 1.02, P=0.06), the presence of an anterior myocardial infarction (OR 2.3, P=0.03), pulse rate on admission (P=NS), female sex (P=NS), and age (OR 1.1, P<0.001). Impaired perfusion of the myocardium on coronary arteriography by use of the TMP grade is related to a higher risk of mortality after administration of thrombolytic drugs that is independent of flow in the epicardial artery. Patients with both normal epicardial flow (TIMI grade 3 flow) and normal tissue level perfusion (TMP grade 3) have an extremely low risk of mortality.

Increasing evidence suggests an inverse relationship between bilirubin levels and cardiovascular disease. The present study evaluated the effect of bilirubin level on the slow coronary flow (SCF) phenomenon. This study was cross-sectional and observational. We enrolled 222 consecutive patients who underwent coronary angiography for suspected ischaemic heart disease and were found to have normal or near-normal coronary arteries. Then, bilirubin levels were measured and coronary flow rate was assessed using the thrombolysis in myocardial infarction (TIMI) frame count. SCF was defined as a TIMI frame count > 27 frames. SCF was observed in at least one coronary vessel in 22 of the 222 subjects, indicating a prevalence of 10%. Serum bilirubin levels were significantly decreased in the SCF group. In multivariate logistic regression analysis, total bilirubin and diabetes mellitus were independent risk factors for SCF. Furthermore, after adjusting for age, sex, and cardiovascular disease risk factors, serum bilirubin level (B = -0.34, p < 0.001) was independently associated with TIMI frame count. These findings suggest that serum total bilirubin levels may be a useful marker for patients with the SCF phenomenon. We believe that further studies are needed to clarify the role of bilirubin in patients with SCF.

Mean platelet volume (MPV) is an indicator of platelet activation, a central process in the pathophysiology of coronary heart disease (CAD). The importance of slow coronary flow (SCF) phenomenon results from its association with angina pectoris, acute myocardial infarction, hypertension and sudden cardiac death. The aim of this study is to evaluate the values of MPV in patients with SCF. MPV was measured in 84 consecutive patients with SCF and 88 patients with CAD and 84 control subjects. The association between thrombolysis in myocardial infarction (TIMI) frame count (TFC) and MPV level and other clinical and laboratory parameters were evaluated. There were no statistically significant differences in MPV between SCF group and CAD group. MPV was significantly higher in patients in the both SCF and CAD groups, compared with control group. The TFC for all the epicardial coronary arteries and the mean TFC were significantly higher in the SCF group than the both CAD group and control group. The mean TFC was positively and moderately correlated with MPV in the whole study population. To determine the independent predictors of mean TFC, a stepwise linear regression analysis was performed by including the parameters that were correlated with the mean TFC in the bivariate analysis. MPV level was the only independent predictor of the mean TFC (b = 0.312, p < 0.001). These findings have shown that MPV level is significantly associated with coronary blood flow and that elevated MPV level might be an independent predictor for the presence of SCF. We believe that further studies are needed to clarify the role of MPV in SCF complicatedCAD, especially in relation to angiographic and clinical parameters, before we conclude that MPV to be used as a follow-up marker during the management of relevant patients.

Objective: To investigate the relationship between miR-126 in plasma and coronary slow flow (CSF) phenomenon. Methods: A total of 109 patients without coronary artery disease who underwent coronary angiography at Beijing Anzhen Hospital Affiliated to Capital Medical University from August 2016 to March 2018 were enrolled. The patients were divided into CSF groups (53 cases) and the control group (56 cases) according to CSF existing or not. Clinical data and blood samples of the participants in two groups were collected. Real-time quantitative PCR (RT-qPCR) was used to determine the expression of miR-126 in plasma, and the relationship between miR-126 and CSF and its predictive effect were analyzed. Results: Mean TIMI frame counts (34±4 vs 20±3), left anterior descending TIMI frame counts (35±5 vs 21±3), left gyroscopic TIMI frame counts (36±5 vs 20±3), right coronary TIMI frame counts (34±5 vs 20±35) and expression level of hypersensitive C-reactive protein (hs-CRP, (3.0±1.2) mg/L vs (2.1±0.9) mg/L) and plasma miR-126 (0.25±0.09 vs 0.19±0.10) of the CSF group were significantly higher than those of the control group (P<0.05). Correlation analysis showed that miR-126 and hs-CRP levels were significantly correlated with mean TIMI frame count (r=0.367, P<0.05), and miR-126 was also significantly associated with the hs-CRP level (r=0.388, P<0.05). Logistic regression analysis showed that miR-126 (OR=2.513) and hs-CRP (OR=1.568) were independent risk factors for coronary slow flow. The area under the ROC curve of miR-126 predicting for CSF was 0.661. When the cutoff value was set at 0.225, the Youden index reached the maximum with a sensitivity of 0.660 and a specificity of 0.714. Conclusion: The expression level of miR-126 in plasma is significantly correlated with CSF, and miR-126 can be used as a predictor of coronary slow flow phenomenon.

Prevalence and long-term prognostic impact of malignancy in patients with Takotsubo syndrome.

The coronary slow-flow phenomenon is an angiographic phenomenon characterized by delayed opacification of vessels in the absence of any evidence of obstructive epicardial coronary disease. Several studies have demonstrated myocardial ischemia in patients with slow coronary artery flow. In the present study, we aimed at evaluating the effects of slow coronary artery flow on QT interval duration and QT dispersion as a possible indicator of increased risk for ventricular arrhythmias and sudden cardiac death. The study population included 49 patients with angiographically proven normal coronary arteries and slow coronary flow in all three coronary vessels (group I, 33 males, 16 females, mean age = 48 +/- 9 years), and 71 patients with angiographically proven normal coronary arteries without associated slow coronary flow (group II, 47 males, 24 females, mean age = 50 +/- 8 years). Coronary flow rates of all subjects were documented by thrombolysis in myocardial infarction frame count (TIMI frame count). QT interval duration and QT dispersion of all subjects were measured on the standard 12-lead electrocardiogram. There was no statistically significant difference between the two groups in respect to age, gender, presence of hypertension, and diabetes mellitus. There was a significant difference between the two groups in respect to the presence of cigarette smoking, typical angina, and positive exercise test results. TIMI frame counts of group I patients were significantly higher than those of group II patients for all three coronary arteries (P < 0.001). Maximum corrected QT interval (QTcmax) of group I did not differ from the QTcmax of group II (P > 0.05). However, minimum corrected QT interval (QTcmin) of group I was significantly lower than that for group II (P = 0.008). Consequently, corrected QT dispersion (QTcd) in group I was found to be significantly higher than in group II (P < 0.001). QTcd, indicating increased risk for ventricular arrhythmias and cardiovascular mortality, was found to be significantly higher in patients with slow coronary artery flow. However, further long-term prospective studies should be carried out to establish the significance of QTcd as a risk factor for ventricular arrhythmias and subsequent sudden cardiac death in patients with slow coronary artery flow.

Background: The coronary slow-flow phenomenon is frequently seen in patients with coronary stenosis, coronary endothelium dysfunction, microvascular dysfunction, etc. It is diagnosed as TIMI-2 flow grade (requiring ≥ 3 cardiac cycles to opacify the vessel) or a corrected TIMI frame count (TFC) greater than 27 frames. However, the TFC has variability due to its dependence on injection force. In cases without autonomic injection, how could to quantify frame count with minimal bias? Methods: All patients underwent the angiogram included, and the exclusive criteria were patients with heart failure, cardiomyopathy, congenital heart disease, valvular disease, and multivessel disease. The angiographic recording began with the injection of contrast into the coronary artery and continued with the white-colored blood moving until all the contrast had been washed out from the arteries. The review of coronary was 15 frames per second and focused on the white-colored blood flow against a black contrast background. The arterial phase (AP) calculation started when the blood began moving and ended when all the contrast was washed out of the distal arterial vasculature. The artificial intelligence program was built based on U-net and Densenet-121. At first, a segmentation model and a Convolutional neural network (CNN) model are responsible for detecting the starting frame of AP with a full index of contrast. In the end, the CNN model will detect the ending frame of AP. Results: 151 patients met the inclusion criteria, and 76.8% were males. Subgroup analysis of patients with patent coronary arteries showed that the AP of the group with slow flow at the distal segment was 32.3 ± 4.4 frames. There was a statistically significant difference compared to the no-slow-flow group (p&lt;0.001). The AP of patients with patent coronary artery was 25.8 ± 4.4 frames, compared with the AP of the group with a significant lesion, which was 32.2 ± 4.0 frames (p&lt;0.001). The cut-off value of the AP frame count in diagnosing coronary slow flow was 27.5 frames, with a sensitivity of 91% and a specificity of 67%. Moreover, the Deep Learning model for calculating AP frames was successfully trained, achieving a root mean square error of 5.1 frames. Conclusion: In addition to TIMI frame count, AP frame count analysis is feasible for cath labs without autonomic injection. The preliminary results suggest AP is a potential marker for diagnosing the slow flow phenomenon.