Jelena R Ghadri’s research while affiliated with University of Zurich and other places

Background Previously considered a rare and relatively benign cardiac condition, Takotsubo syndrome (TTS) has undergone a significant shift in perception over the last two decades. This shift was mainly driven by results indicating that TTS is associated with signicant mortality and morbidity. Consequently, also the criteria for diagnosing TTS have been updated to reflect its recognition as a complex, multifactorial disease. Purpose The aim of the present study was to investigate trends in clinical presentation, demographics, and outcomes of patients with TTS. Methods The study analyzed 3,675 patients diagnosed with TTS from 2004 to 2021. Participants were divided into groups based on diagnosis, using three-year intervals, to perform trend analyses on demographics, risk factors, clinical presentations, and outcomes. The Cochran-Mantel-Haenszel test was used for categorical data trends, while the Mann-Kendall test assessed numerical variables. Mortality rates were compared using the log-rank test. Findings: The study period saw a steady increase in male patients (from 10% to 15%, p = 0.003). While apical TTS continued to be the most common type, the occurrence of midventricular TTS increased (from 18% to 37%, p = 0.002). Emotional triggers remained constant, whereas the prevalence of physical triggers significantly rose (from 35% to 50%, p = 0.034). The incidence of cardiogenic shock increased (from 11% to 20%, p=0.030), leading to a rise in in-hospital mortality rates (from 2% to 9%, p<0.001). A landmark analysis showed a significant increase in 60-day mortality rates (p < 0.001), but no difference in one-year mortality over the years (p = 0.140, Figure 1). Summary: This study of temporal trends in TTS highlights a shift in patients demographic with agrowing prevalence among males, increasing recognition of midventricular TTS type, and increased rates of cardiogenic shock and mortality in recent years. This shift aligns with the rising prevalence of physical triggers, as an expression of increased recognition of TTS in association with acute comorbidities.

Background The clinical relevance of cardiac troponin (cTn) elevation in takotsubo syndrome (TTS) remains uncertain. The present study sought to investigate the role of cardiac troponin (cTn) elevations in mortality prediction of patients with Takotsubo syndrome (TTS). Methods Patients enrolled in the International Takotsubo (InterTAK) Registry from January 2011 to February 2020 with available data on peak cTn levels were included in the analysis. Peak cTn levels during the index hospitalization were used to define clinically relevant myocardial injury. The threshold at which clinically relevant myocardial injury drives mortality at 1 year was identified using restricted cubic spline analysis. Results Out of 2′938 patients, 222 (7.6%) patients died during 1‐year follow‐up. A more than 28.8‐fold increase of cTn above the upper reference limit was identified as threshold for clinically relevant myocardial injury. The presence of clinically relevant myocardial injury was significantly associated with an increased risk of mortality at 5 years (adjusted HR 1.58, 95% CI 1.18–2.12, p =.002). Clinically relevant myocardial injury was related to an increased 5‐year mortality risk in patients with apical TTS (adjusted HR 1.57, 95% CI 1.21–2.03, p =.001), in presence of physical stressors (adjusted HR 1.60, 95% CI 1.22–2.11, p =.001), and in absence of emotional stressors (adjusted HR 1.49, 95% CI, 1.17–1.89, p =.001). Conclusion This study for the first time determined a troponin threshold for the identification of TTS patients at excess risk of mortality. These findings advance risk stratification in TTS and assist in identifying patients in need for close monitoring and follow‐up.

Background Spontaneous coronary artery dissection (SCAD) is the most important cause of acute coronary syndromes during pregnancy and in the post-partum period and involves a spontaneous intimal tear or intramural haematoma of a coronary artery. Pregnancy-associated SCAD accounts for a minority of SCAD cases but is associated with a high rate of adverse events. Case summary We present a series of three cases with pregnancy-associated SCAD. All patients presented with acute coronary syndromes in the post-partum period, between 12 days and 5 months after delivery. They all had additional conditions that are associated with SCAD, such as fibromuscular dysplasia and migraine. The management of one patient was uncomplicated, however, the courses of the other two were characterized by adverse events. One presented after an out-of-hospital cardiac arrest, the other presented with multivessel SCAD and developed progression and recurrence of SCAD during follow-up. In conclusion, the patients could be successfully treated conservatively and were in good condition at their latest follow-ups. Discussion This case series highlights the wide range of clinical courses that could exist in pregnancy-associated SCAD, from a benign manifestation to a life-threatening condition. Importantly, those patients are at an increased risk for acute and late adverse events.

Background Coronary microvascular dysfunction (CMD) has been proposed as a crucial factor in the pathophysiology of Takotsubo syndrome (TTS). The angiography-derived index of microcirculatory resistance (caIMR) offers an alternative to conventional hyperemic wire-based IMR to assess CMD. We aimed to evaluate CMD’s prevalence, transience, and impact on in-hospital outcomes in TTS. Methods All three coronary arteries of 96 patients with TTS were assessed for their coronary angiography derived Index of microcirculatory Resistance (caIMR) and compared to non-obstructed vessels of matched patients with ST-elevation myocardial infarction. Further, the association between caIMR and the TTS-specific combined in-hospital endpoint of death, cardiac arrest, ventricular arrhythmogenic events and cardiogenic shock was investigated. Results Elevated IMR was present in all TTS patients, with significantly elevated caIMR values in all coronary arteries compared to controls. CaIMR did not differ between apical and midventricular TTS types. CaIMR normalized in TTS patients with follow-up angiographies performed at a median of 28 months (median caIMR at event vs follow-up: LAD 34.8 [29.9–41.1] vs 20.3 [16.0–25.3], p < 0.001; LCX: 38.7 [32.9–50.1] vs 23.7 [19.4–30.5], p < 0.001; RCA: 31.7 [25.0–39.1] vs 19.6 [17.1–24.0], p < 0.001). The extent of caIMR elevation significantly correlated with the combined in-hospital endpoint (p = 0.036). Conclusion TTS patients had evidence of elevated caIMR in at least one coronary artery with a trend towards higher LAD caIMR in apical type TTS and normalization after recovery. Furthermore, extent of caIMR elevation was associated with increased risk of in-hospital MACE of TTS patients. Graphical abstract

Background Coronary microvascular dysfunction (CMD) has been proposed to be a major contributing factor in the pathophysiology of Takotsubo syndrome (TTS). To asses CMD, the angiography-derived index of microcirculatory resistance (caIMR) has been developed as a wire-free alternative to the conventional hyperemic wire-based index (IMR). This study aimed at evaluating the extent and transience of CMD and its implications on in-hospital outcome in TTS using caIMR. Methods Microcirculatory function of the three main coronary arteries of 96 TTS patients (48 with apical- and 48 with midventricular type) was assessed using caIMR. Measurements were compared with those of non-culprit vessels of 96 matched patients with ST-elevation myocardial infarction, as non-culprit vessels have previously been demonstrated to have an intact microcirculatory function [1]. In ten patients, follow-up caIMR was determined from angiographies without any cardiac event and was compared with event-caIMR. The prognostic role of caIMR on the in-hospital combined endpoint of death, cardiac arrest, ventricular arrhythmia, and vasopressor dependency was assessed via a binomial logistic regression analysis. Results CMD was present in all patients with TTS in at least one coronary vessel (caIMR>25), most frequently observed in the LCX (86 of 88 measurable LCXs [98%]). CaIMR in all three coronary arteries was significantly higher compared to the respective vessels of the control group. No significant difference in caIMR was observed comparing the apical and midventricular type of TTS. We could demonstrate normalization of caIMR in patients with follow-up angiographies performed at a median of 22 months (median [IQR] caIMR during event vs. follow-up: LCX 39.5 [33.9-52.0] vs. 25.1 [20.5-31.3]; LAD 34.2 [29.4-38.3] vs. 17.2 [15.9-23.9]; RCA: 31.7 [25.0-39.1] vs. 19.6 [17.1-24.0], Figure 1). The in-hospital combined endpoint correlated with the extent of CMD (p=0.036, Figure 2). Conclusion CMD was present during the acute TTS event and normalized during follow-up, suggesting that CMD is only a phenomenon of the acute phase of TTS and IMR values recover to normal dimensions. In addition, LAD caIMR was associated with the in-hospital end point of death, cardiac arrest, ventricular arrhythmia, and vasopressor dependence, however prospective validation will be necessary to further substantiate these findings.

Background Takotsubo syndrome has long been thought to be a benign condition once the acute event has been overcome. However, an increasing number of studies suggest that there might be long-term consequences. The aim of the present study was to evaluate long term functional cardiac changes in patients after Takotsubo Syndrome. Methods In the present study, a total of 131 TTS patients were prospectively included and age and gender matched with 131 ACS patients. Out of this cohort, a total of 66 patients (TTS: N=33, ACS: N=33) without any known respiratory diseases (e.g. Asthma or COPD) had a follow-up examination one to six months after the index event, including cardiopulmonary exercise testing (CPET) and echocardiography. CPET indices were compared between TTS and ACS patients in those who achieved an RER of at least 1.05. Results Mean age of patients was 65.4 in the TTS group and 65.0 in the ACS group (p=0.541). In each group, 118 (90%) patients were female. At follow-up, TTS patients had a significantly higher LVEF (%, TTS: 59 [56 to 63] vs ACS: 56.5 [51 to 60], p<0.001) and significantly lower levels of BNP (ULN, TTS: 0.5 [0.2 to 0.9] vs ACS: 1.0 [0.5 to 2.6], p<0001), compared to TTS patients. TTS patients were significantly more frequently suffering from persistent symptoms compared to ACS patients (TTS: 78 [60%] vs. ACS: 60 [45.8%], p=0.035, figure 1). Twenty-four TTS Patients (72%) had an RER over 1.05 and were age and gender matched with 24 ACS patients. VO2max was comparable between the two groups (TTS: 20.2 [±5.4] vs ACS: 18.9 [±7.6], p=0.47) as well as Peak Mets (TTS: 5.7 (±1.6) vs ACS: 5.5 (±1.9), p=0.68). However, there was a trend towards a lower oxygen pulse in TTS compared to ACS patients (TTS: 9.4 [±2.2] vs ACS: 10.9 [±3.1], p=0.055) and a significant higher oxygen cost of work (ΔV’O2/ΔW, TTS: 12.9 [11.3 to 15.5] vs ACS: 10.9 [9.7 to 12.2], p=0.019). Conclusion TTS patients were more frequently suffering from persistent symptoms compared to ACS patients. Moreover, TTS patients demonstrated long-term functional cardiac changes reflected in impaired CPET parameters comparable to or worse than those of ACS patients. These findings highlight the long-term consequences of TTS and further challenge the concept that TTS is a benign disease.

Aims: Takotsubo syndrome (TTS) is associated with a substantial rate of adverse events. We sought to design a machine-learning (ML) based model to predict the risk of in-hospital death and to perform a clustering of TTS patients to identify different risk profiles. Methods and results: A Ridge Logistic Regression-based ML model for predicting in-hospital death was developed on 3482 TTS patients from the International Takotsubo Registry, randomly split in a train and an internal validation cohort (75% and 25% of the sample size, respectively) and evaluated in an external validation cohort (1037 patients). 31 clinically relevant variables were included in the prediction model. Model performance represented the primary endpoint and was assessed according to area under the receiver-operating characteristic curve (AUC), Sensitivity and Specificity. As secondary endpoint, a K-Medoids clustering algorithm was designed to stratify patients into phenotypic groups based on the ten most relevant features emerging from the main model. The overall incidence of in-hospital death was 5.2%. The InterTAK-ML model showed an AUC of 0.89 (0.85-0.92), Sensitivity 0.85 (0.78-0.95) and Specificity 0.76 (0.74-0.79) in the internal validation cohort and an AUC of 0.82 (0.73-0.91), a sensitivity of 0.74 (0.61-0.87) and a specificity of 0.79 (0.77-0.81) in the external cohort for in-hospital death prediction. By exploiting the 10 variables showing the highest feature importance, TTS patients were clustered into six groups associated with different risks of in-hospital death (28.8% vs 15.5% vs 5.4% vs 0.8% vs 0.5%) which were consistent also in the external cohort. Conclusion: A ML-based approach for the identification of TTS patients at risk of adverse short-term prognosis is feasible and effective. The InterTAK-ML model showed unprecedented discriminative capability for the prediction of in-hospital death. This article is protected by copyright. All rights reserved.