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Abstract Background Takotsubo syndrome (TTS) is an acute heart failure syndrome with symptoms similar to acute myocardial infarction. TTS is often triggered by acute emotional or physical stress and is a significant cause of morbidity and mortality. Predictors of mortality in patients with TS are not well understood, and there is a need to identify high-risk patients and tailor treatment accordingly. This study aimed to assess the importance of various clinical factors in predicting 30-day mortality in TTS patients using a machine learning algorithm. Methods We analyzed data from the nationwide Swedish Coronary Angiography and Angioplasty Registry (SCAAR) for all patients with TTS in Sweden between 2015 and 2022. Gradient boosting was used to assess the relative importance of variables in predicting 30-day mortality in TTS patients. Results Of 3,180 patients hospitalized with TTS, 76.0% were women. The median age was 71.0 years (interquartile range 62–77). The crude all-cause mortality rate was 3.2% at 30 days. Machine learning algorithms by gradient boosting identified treating hospitals as the most important predictor of 30-day mortality. This factor was followed in significance by the clinical indication for angiography, creatinine level, Killip class, and age. Other less important factors included weight, height, and certain medical conditions such as hyperlipidemia and smoking status. Conclusions Using machine learning with gradient boosting, we analyzed all Swedish patients diagnosed with TTS over seven years and found that the treating hospital was the most significant predictor of 30-day mortality.

Abstract Aims Takotsubo syndrome (TS) is a heart condition mimicking acute myocardial infarction. TS is characterized by a sudden weakening of the heart muscle, usually triggered by physical or emotional stress. In this study, we aimed to investigate the effect of pharmacological interventions on short‐ and long‐term mortality in patients with TS. Methods and results We analysed data from the SWEDEHEART (the Swedish Web System for Enhancement and Development of Evidence‐based care in Heart disease Evaluated According to Recommended Therapies) registry, which included patients who underwent coronary angiography between 2009 and 2016. In total, we identified 1724 patients with TS among 228 263 individuals in the registry. The average age was 66 ± 14 years, and 77% were female. Nearly half of the TS patients (49.4%) presented with non‐ST‐elevation acute coronary syndrome, and a quarter (25.9%) presented with ST‐elevation myocardial infarction. Most patients (79.1%) had non‐obstructive coronary artery disease on angiography, while 11.7% had a single‐vessel disease and 9.2% had a multivessel disease. All patients received at least one pharmacological intervention; most of them used beta‐blockers (77.8% orally and 8.3% intravenously) or antiplatelet agents [aspirin (66.7%) and P2Y12 inhibitors (43.6%)]. According to the Kaplan–Meier estimator, the probability of all‐cause mortality was 2.5% after 30 days and 16.6% after 6 years. The median follow‐up time was 877 days. Intravenous use of inotropes and diuretics was associated with increased 30 day mortality in TS [hazard ratio (HR) = 9.92 (P

Background Elevated troponin levels are a sensitive biomarker for cardiac injury. The quick and reliable prediction of troponin elevation for patients with chest pain from readily available ECGs may pose a valuable time-saving diagnostic tool during decision-making concerning this patient population.Methods and results The data used included 15 856 ECGs from patients presenting to the emergency rooms with chest pain or dyspnoea at two centres in Sweden from 2015 to June 2023. All patients had high-sensitivity troponin test results within 6 hours after 12-lead ECG. Both troponin I (TnI) and TnT were used, with biomarker-specific cut-offs and sex-specific cut-offs for TnI. On this dataset, a residual convolutional neural network (ResNet) was trained 10 times, each on a unique split of the data. The final model achieved an average area under the curve for the receiver operating characteristic curve of 0.7717 (95% CI±0.0052), calibration curve analysis revealed a mean slope of 1.243 (95% CI±0.075) and intercept of −0.073 (95% CI±0.034), indicating a good correlation between prediction and ground truth. Post-classification, tuned for F1 score, accuracy was 71.43% (95% CI±1.28), with an F1 score of 0.5642 (95% CI±0.0052) and a negative predictive value of 0.8660 (95% CI±0.0048), respectively. The ResNet displayed comparable or surpassing metrics to prior presented models.Conclusion The model exhibited clinically meaningful performance, notably its high negative predictive accuracy. Therefore, clinical use of comparable neural networks in first-line, quick-response triage of patients with chest pain or dyspnoea appears as a valuable option in future medical practice.

Background Dual antiplatelet therapy (DAPT) reduces ischemic events but increases bleeding risk, especially in patients with high bleeding risk (HBR). This study aimed to compare outcomes of abbreviated versus standard DAPT strategies in patients with HBR with acute coronary syndrome undergoing percutaneous coronary intervention. Methods and Results Patients from the SWEDEHEART (Swedish Web‐system for Enhancement and Development of Evidence‐Based Bare in Heart Disease Evaluated According to Recommended Therapies) registry with at least 1 HBR criterion who underwent percutaneous coronary intervention for acute coronary syndrome were identified and included. Patients were divided into 2 groups based on their planned DAPT time at discharge: 12‐month DAPT or an abbreviated DAPT strategy and matched according to their prescribed P2Y12 inhibitor at discharge. The primary outcome assessed was time to net adverse clinical events at 1 year, which encompassed cardiac death, myocardial infarction, ischemic stroke, or clinically significant bleeding. Time to major adverse cardiovascular events and the individual components of net adverse clinical events were considered secondary end points. A total of 4583 patients were included in each group. The most frequently met HBR criteria was age older than 75 years (65.6%) and Predicting Bleeding Complications in Patients Undergoing Stent Implantation and Subsequent Dual Antiplatelet Therapy score ≥25 (44.6%) in the standard DAPT group and oral anticoagulant therapy (79.6%) and age 75 years and older (55.2%) in the abbreviated DAPT group. There was no statistically significant difference in net adverse clinical events (12.9% versus 13.1%; hazard ratio [HR], 0.99 [95% CI, 0.88–1.11], P=0.83), major adverse cardiovascular events (8.6% versus 7.9%; HR, 1.08 [95% CI, 0.94–1.25]), or their components between groups. The results were consistent among all of the investigated subgroups. Conclusions In patients with HBR undergoing percutaneous coronary intervention due to acute coronary syndrome, abbreviated DAPT was associated with comparable rates of net adverse clinical events and major adverse cardiovascular events to a DAPT duration of 12 months.

Abstract In an era focused on value-based healthcare, the quality of healthcare and resource allocation should be underpinned by empirical evidence. Pragmatic clinical trials (pRCTs) are essential in this endeavor, providing randomized controlled trial (RCT) insights that encapsulate real-world effects of interventions. The rising popularity of pRCTs can be attributed to their ability to mirror real-world practices, accommodate larger sample sizes, and provide cost advantages over traditional RCTs. By harmonizing efficacy with effectiveness, pRCTs assist decision-makers in prioritizing interventions that have a substantial public health impact and align with the tenets of value-based health care. An international network for pRCT provides several advantages, including larger and diverse patient populations, access to a broader range of healthcare settings, sharing knowledge and expertise, and overcoming ethical and regulatory barriers. The hypothesis and study design of pRCT answers the decision-maker’s questions. pRCT compares clinically relevant alternative interventions, recruits participants from diverse practice settings, and collects data on various health outcomes. They are scarce because the medical products industry typically does not fund pRCT. Prioritizing these studies by expanding the infrastructure to conduct clinical research within the healthcare delivery system and increasing public and private funding for these studies will be necessary to facilitate pRCTs. These changes require more clinical and health policy decision-makers in clinical research priority setting, infrastructure development, and funding. This paper presents a comprehensive overview of pRCTs, emphasizing their importance in evidence-based medicine and the advantages of an international collaborative network for their execution. It details the development of PRIME-9, an international initiative across nine countries to advance pRCTs, and explores various statistical approaches for these trials. The paper underscores the need to overcome current challenges, such as funding limitations and infrastructural constraints, to leverage the full potential of pRCTs in optimizing healthcare quality and resource utilization.

Background: ST-elevation myocardial infarction (STEMI) and Takotsubo syndrome (TS) are two distinct cardiac conditions that both result in sudden loss of cardiac dysfunction and that are difficult to distinguish clinically. This study compared plasma protein changes in 24 women with STEMI and 12 women with TS in the acute phase (days 0–3 post symptom onset) and the stabilization phase (days 7, 14, and 30) to examine the molecular differences between these conditions. Methods: Plasma proteins from STEMI and TS patients were extracted during the acute and stabilization phases and analyzed via quantitative proteomics. Differential expression and functional significance were assessed. Data are accessible on ProteomeXchange, ID PXD051367. Results: During the acute phase, STEMI patients showed higher levels of myocardial inflammation and tissue damage proteins compared to TS patients, along with reduced tissue repair and anti-inflammatory proteins. In the stabilization phase, STEMI patients exhibited ongoing inflammation and disrupted lipid metabolism. Notably, ADIPOQ was consistently downregulated in STEMI patients in both phases. When comparing the acute to the stabilization phase, STEMI patients showed increased inflammatory proteins and decreased structural proteins. Conversely, TS patients showed increased proteins involved in inflammation and the regulatory response to counter excessive inflammation. Consistent protein changes between the acute and stabilization phases in both conditions, such as SAA2, CRP, SAA1, LBP, FGL1, AGT, MAN1A1, APOA4, COMP, and PCOLCE, suggest shared underlying pathophysiological mechanisms. Conclusions: This study presents protein changes in women with STEMI or TS and identifies ADIPOQ, SAA2, CRP, SAA1, LBP, FGL1, AGT, MAN1A1, APOA4, COMP, and PCOLCE as candidates for further exploration in both therapeutic and diagnostic contexts.

Modelling human diseases serves as a crucial tool to unveil underlying mechanisms and pathophysiology. Takotsubo syndrome (TS), an acute form of heart failure resembling myocardial infarction, manifests with reversible regional wall motion abnormalities (RWMA) of the ventricles. Despite its mortality and clinical similarity to myocardial infarction, TS aetiology remains elusive, with stress and catecholamines playing central roles. This review delves into current animal models of TS, aiming to assess their ability to replicate key clinical traits and identifying limitations. An in-depth evaluation of published animal models reveals a variation in the definition of TS among studies. We notice a substantial prevalence of catecholamine-induced models, particularly in rodents. While these models shed light on TS, there remains potential for refinement. Translational success in TS research hinges on models that align with human TS features and exhibit the key features, including transient RWMA. Animal models should be comprehensively evaluated regarding the various systemic changes of the applied trigger(s) for a proper interpretation. This review acts as a guide for researchers, advocating for stringent TS model standards and enhancing translational validity.

Background and aimsIschemic preconditioning (IPC), i.e., brief periods of ischemia, protect the heart from subsequent prolonged ischemic injury, and reduces infarction size. Myocardial stunning refers to transient loss of contractility in the heart after myocardial ischemia that recovers without permanent damage. The relationship between IPC and myocardial stunning remains incompletely understood. This study aimed primarily to examine the effects of IPC on the relationship between ischemia duration, stunning, and infarct size in an ischemia-reperfusion injury model. Secondarily, this study aimed to examine to which extent the phosphoproteomic changes induced by IPC relate to myocardial contractile function.Methods and resultsRats were subjected to different durations of left anterior descending artery (LAD) occlusion, with or without preceding IPC. Echocardiograms were acquired to assess cardiac contraction in the affected myocardial segment. Infarction size was evaluated using triphenyl tetrazolium chloride staining. Phosphoproteomic analysis was performed in heart tissue from preconditioned and non-preconditioned animals. In contrast to rats without IPC, reversible akinesia was observed in a majority of the rats that were subjected to IPC and subsequently exposed to ischemia of 13.5 or 15 min of ischemia. Phosphoproteomic analysis revealed significant differential regulation of 786 phosphopeptides between IPC and non-IPC groups, with significant associations with the sarcomere, Z-disc, and actin binding.ConclusionIPC induces changes in phosphosites of proteins involved in myocardial contraction; and both accentuates post-ischemic myocardial stunning and reduces infarct size.

Abstract Survival in left-sided valvular heart disease (VHD; aortic stenosis [AS], aortic regurgitation [AR], mitral stenosis [MS], mitral regurgitation [MR]) in out-of-hospital cardiac arrest (OHCA) is unknown. We studied all cases of OHCA in the Swedish Registry for Cardiopulmonary Resuscitation. All degrees of VHD, diagnosed prior to OHCA, were included. Association between VHD and survival was studied using logistic regression, gradient boosting and Cox regression. We studied time to cardiac arrest, comorbidities, survival, and cerebral performance category (CPC) score. We included 55,615 patients; 1948 with AS (3,5%), 384 AR (0,7%), 17 MS (0,03%), and 704 with MR (1,3%). Patients with MS were not described due to low case number. Time from VHD diagnosis to cardiac arrest was 3.7 years in AS, 4.5 years in AR and 4.1 years in MR. ROSC occurred in 28% with AS, 33% with AR, 36% with MR and 35% without VHD. Survival at 30 days was 5.2%, 10.4%, 9.2%, 11.4% in AS, AR, MR and without VHD, respectively. There were no survivors in people with AS presenting with asystole or PEA. CPC scores did not differ in those with VHD compared with no VHD. Odds ratio (OR) for MR and AR showed no difference in survival, while AS displayed OR 0.58 (95% CI 0.46–0.72), vs no VHD. AS is associated with halved survival in OHCA, while AR and MR do not affect survival. Survivors with AS have neurological outcomes comparable to patients without VHD.

Aim: The aim of this study was to present a comprehensive overview of out-of-hospital cardiac arrests (OHCA) in young adults. Methods: The data set analyzed included all cases of OHCA from 1990 to 2020 in the age-range 16–49 years in the Swedish Registry of Cardiopulmonary Resuscitation (SRCR). OHCA between 2010 and 2020 were analyzed in more detail. Clinical characteristics, survival, neurological outcomes, and long-time trends in survival were studied. Logistic regression was used to study 30-days survival, neurological outcomes and Utstein determinants of survival. Results: Trends were assessed in 11,180 cases. The annual increase in 30-days survival during 1990–2020 was 5.9% with no decline in neurological function among survivors. Odds ratio (OR) for heart disease as the cause was 0.55 (95% CI 0.44 to 0.67) in 2017–2020 compared to 1990–1993. Corresponding ORs for overdoses and suicide attempts were 1.61 (95% CI 1.23–2.13) and 2.06 (95% CI 1.48–2.94), respectively. Exercise related OHCA was noted in roughly 5%. OR for bystander CPR in 2017–2020 vs 1990–1993 was 3.11 (95% CI 2.57 to 3.78); in 2020 88 % received bystander CPR. EMS response time increased from 6 to 10 minutes. Conclusion: Survival has increased 6% annually, resulting in a three-fold increase over 30 years, with stable neurological outcome. EMS response time increased with 66% but the majority now receive bystander CPR. Cardiac arrest due to overdoses and suicide attempts are increasing.

Abstract Aims The aim was to describe the prevalence, characteristics, and outcome of patients with acute myocardial infarction (MI) developing left ventricular (LV) systolic dysfunction or pulmonary congestion by applying different criteria to define the population. Methods and results In patients with MI included in the Swedish web‐system for enhancement and development of evidence‐based care in heart disease (SWEDEHEART) registry, four different sets of criteria were applied, creating four not mutually exclusive subsets of patients: patients with MI and ejection fraction (EF)

Abstract The association between type 2 diabetes (T2D) and the development of cardiac arrhythmias and conduction disturbances has not been extensively studied. Arrhythmia was defined as atrial fibrillation and flutter (AF/AFl), ventricular tachycardia (VT) and ventricular fibrillation (VF), and conduction abnormality as sinus node disease (SND), atrioventricular (AV) block or pacemaker implantation, and intraventricular conduction blocks (IVCB). Incidence rates and Cox regression were used to compare outcomes, and to assess optimal levels for cardiometabolic risk factors and risk associated with multifactorial risk factor control (i.e., HbA1c, LDL-C, systolic blood pressure (SBP), BMI and eGFR), between patients with versus without T2D. The analyses included data from 617,000 patients with T2D and 2,303,391 matched controls. Patients with diabetes and the general population demonstrated a gradual increase in rates for cardiac conduction abnormalities and virtually all age-groups for AF/AFI showed increased incidence during follow-up. For patients with versus without T2D, risks for cardiac arrhythmias were higher, including for AF/AFl (HR 1.17, 95% CI 1.16–1.18), the composite of SND, AV-block or pacemaker implantation (HR 1.40, 95% CI 1.37–1.43), IVCB (HR 1.23, 95% CI 1.18–1.28) and VT/VF (HR 1.08, 95% CI 1.04–1.13). For patients with T2D who had selected cardiometabolic risk factors within target ranges, compared with controls, risk of arrythmia and conduction abnormalities for T2D vs not were: AF/AFl (HR 1.09, 95% CI 1.05–1.14), the composite of SND, AV-block or pacemaker implantation (HR 1.06, 95% CI 0.94–1.18), IVCB (HR 0.80, 95% CI 0.60–0.98), and for VT/VF (HR 0.97, 95% CI 0.80–1.17). Cox models showed a linear risk increase for SBP and BMI, while eGFR showed a U-shaped association. Individuals with T2D had a higher risk of arrhythmias and conduction abnormalities than controls, but excess risk associated with T2D was virtually not evident among patients with T2D with all risk factors within target range. BMI, SBP and eGFR displayed significant associations with outcomes among patients with T2D.

Abstract Aims Ischaemic coronary artery disease (CAD) remains the leading cause of mortality globally due to sudden death and heart failure (HF). Invasive coronary angiography (CAG) is the gold standard for evaluating the presence and severity of CAD. Our objective was to assess temporal trends in CAG utilization, patient characteristics, and prognosis in HF patients undergoing CAG at a national level. Methods and results We used data from the Swedish Coronary Angiography and Angioplasty Registry. Data on all patients undergoing CAG for HF indication in Sweden between 2000 and 2018 were collected and analysed. Long‐term survival was estimated with multivariable Cox proportional hazards regression adjusted for differences in patient characteristics. In total, 22 457 patients (73% men) with mean age 64.2 ± 11.3 years were included in the study. The patients were increasingly older with more comorbidities over time. The number of CAG specifically for HF indication increased by 5.5% per calendar year (P 50% diameter stenosis in one or more coronary arteries (HF‐CAD). The median follow‐up time was 3.6 years in HF‐CAD and 5 years in HF‐NCAD. Age and sex‐adjusted survival improved linearly by 1.3% per calendar year in all patients. Compared with HF‐NCAD, long‐term mortality was higher in HF‐CAD patients. The risk of death increased with the increasing severity of CAD. Compared with HF‐NCAD, the risk estimate in patients with a single‐vessel disease was higher [hazard ratio (HR) 1.3; 95% confidence interval (CI) 1.20–1.41; P

Background: Electrocardiography (ECG) on admission is similar in ST elevation myocardial infarction (STEMI) and Takotsubo syndrome (TTS). ECG on admission has been extensively investigated and compared between STEMI and TTS, however, only a few studies have compared temporal ECG. Our aim was to compare ECG in anterior STEMI versus female TTS from admission to day 30. Methods: Adult patients with anterior STEMI or TTS treated at Sahlgrenska University Hospital (Gothenburg, Sweden) from December 2019 to June 2022 were prospectively enrolled. Baseline characteristics, clinical variables and ECGs from admission to day 30 were analyzed. Using a mixed effects model, we compared temporal ECG between female patients with anterior STEMI or TTS, as well as between female and male patients with anterior STEMI. Results: A total of 101 anterior STEMI patients (31 female, 70 male) and 34 TTS patients (29 female, 5 male) were included. The temporal pattern of T wave inversion was similar between female anterior STEMI and female TTS, as well as between female and male anterior STEMI. ST elevation was more common, whereas QT prolongation was less common, in anterior STEMI compared with TTS. Q wave pathology was more similar between female anterior STEMI and female TTS than between female and male anterior STEMI. Conclusions: The pattern of T wave inversion and Q wave pathology from admission to day 30 was similar in female patients with anterior STEMI and female patients with TTS. Temporal ECG in female patients with TTS may be interpreted as following a “transient ischemic” pattern.

Summary: Background: A prediction model that estimates survival and neurological outcome in out-of-hospital cardiac arrest patients has the potential to improve clinical management in emergency rooms. Methods: We used the Swedish Registry for Cardiopulmonary Resuscitation to study all out-of-hospital cardiac arrest (OHCA) cases in Sweden from 2010 to 2020. We had 393 candidate predictors describing the circumstances at cardiac arrest, critical time intervals, patient demographics, initial presentation, spatiotemporal data, socioeconomic status, medications, and comorbidities before arrest. To develop, evaluate and test an array of prediction models, we created stratified (on the outcome measure) random samples of our study population. We created a training set (60% of data), evaluation set (20% of data), and test set (20% of data).We assessed the 30-day survival and cerebral performance category (CPC) score at discharge using several machine learning frameworks with hyperparameter tuning. Parsimonious models with the top 1 to 20 strongest predictors were tested. We calibrated the decision threshold to assess the cut-off yielding 95% sensitivity for survival. The final model was deployed as a web application. Findings: We included 55,615 cases of OHCA. Initial presentation, prehospital interventions, and critical time intervals variables were the most important. At a sensitivity of 95%, specificity was 89%, positive predictive value 52%, and negative predictive value 99% in test data to predict 30-day survival. The area under the receiver characteristic curve was 0.97 in test data using all 393 predictors or only the ten most important predictors. The final model showed excellent calibration. The web application allowed for near-instantaneous survival calculations. Interpretation: Thirty-day survival and neurological outcome in OHCA can rapidly and reliably be estimated during ongoing cardiopulmonary resuscitation in the emergency room using a machine learning model incorporating widely available variables. Funding: Swedish Research Council (2019–02019); Swedish state under the agreement between the Swedish government, and the county councils (ALFGBG-971482); The Wallenberg Centre for Molecular and Translational Medicine.

Abstract Aims Left ventricular (LV) dysfunction can be triggered by non‐cardiac disease, such as sepsis, hypoxia, major haemorrhage, or severe stress (Takotsubo syndrome), but its clinical importance is not established. In this study, we evaluate the incidence and impact on mortality of LV dysfunction associated with critical illness. Methods and results In this single‐centre, observational study, consecutive patients underwent an echocardiographic examination within 24 h of intensive care unit (ICU) admission. LV systolic dysfunction was defined as an ejection fraction (EF)

Abstract Aims Takotsubo syndrome (TTS) is an acute potentially reversible cardiac syndrome characterized by variable regional myocardial akinesia that cannot be attributed to a culprit coronary artery occlusion. TTS is an important differential diagnosis of acute heart failure where brain natriuretic peptides are elevated. Sacubitril/valsartan is a novel and effective pharmacological agent for the treatment of patients with heart failure. Our aim was to explore whether treatment with sacubitril/valsartan could prevent isoprenaline‐induced takotsubo‐like phenotype in rats. Methods and results A total number of 186 Sprague–Dawley male rats were randomized to receive pretreatment with water (CONTROL, n = 62), valsartan (VAL, n = 62), or sacubitril/valsartan (SAC/VAL, n = 62) before receiving isoprenaline for induction of TTS. We recorded heart rate and blood pressure invasively. Cardiac morphology and function were evaluated by high‐resolution echocardiography 90 min after the administration of isoprenaline. We documented the survival rate at the time of echocardiography. Compared with the CONTROL group, the SAC/VAL group had less pronounced TTS‐like cardiac dysfunction and lower mortality rate, while the VAL group did not differ. Heart rate and blood pressure were not significantly different between the groups. Analysis of cardiac lipids was performed with mass spectrometry. The VAL and SAC/VAL groups had significantly higher levels of lysophosphatidylcholine (LPC), in particular LPC 18:1 and LPC 16:0. Conclusions Pretreatment with sacubitril/valsartan but not with valsartan reduces mortality and attenuates isoprenaline‐induced apical akinesia in the TTS‐like model in rats. Sacubitril/valsartan could be a potential treatment option in patients with TTS in humans.

Background The long‐term course of coronary atherosclerosis has not been studied in large nationwide cohorts. Understanding the natural history of coronary atherosclerosis could help identify patients at risk for future coronary events. Methods and Results All coronary artery segments with

Takotsubo syndrome (TTS) is an acute heart failure syndrome. Emotional or physical stressors are believed to precipitate TTS, while the pathophysiological mechanism is not yet completely understood. During the coronavirus disease (COVID-19) pandemic, an increased incidence of TTS has been reported in some countries; however, the precise pathophysiological mechanism for developing TTS with acute COVID-19 infection is unknown. Nevertheless, observing the symptoms of COVID-19 might lead to new perspectives in understanding TTS pathophysiology, as some of the symptoms of the COVID-19 infection could be assessed in the context of an orexin/hypocretin-system dysfunction. Orexin/hypocretin is a cardiorespiratory neuromodulator that acts on two orexin receptors widely distributed in the brain and peripheral tissues. In COVID-19 patients, autoantibodies against one of these orexin receptors have been reported. Orexin-system dysfunction affects a variety of systems in an organism. Here, we review the influence of orexin-system dysfunction on the cardiovascular system to propose its connection with TTS. We propose that orexin-system dysfunction is a potential novel explanation for the pathophysiology of TTS due to direct or indirect dynamics of orexin signaling, which could influence cardiac contractility. This is in line with the conceptualization of TTS as a cardiovascular syndrome rather than merely a cardiac abnormality or cardiomyopathy. To the best of our knowledge, this is the first publication to present a plausible connection between TTS and orexin-system dysfunction. We hope that this novel hypothesis will inspire comprehensive studies regarding orexin's role in TTS pathophysiology. Furthermore, confirmation of this plausible pathophysiological mechanism could contribute to the development of orexin-based therapeutics in the treatment and prevention of TTS.

Takotsubo syndrome is a well-characterized cause of acute yet reversible heart failure associated with periods of intense emotional stress, often mimicking on presentation an acute coronary syndrome. Animal models of Takotsubo syndrome have been developed, either through the application of a stressor, or administration of exogenous catecholamine. We found that in a model of isoproterenol-induced Takotsubo syndrome in anesthetized rats hyperthermia (40–41°C) would occur after the administration of isoproterenol. Maintenance of this hyperthermia would result in an apical hypocontractility typical of the syndrome, whereas prevention of hyperthermia with active cooling to maintain a euthermic core body temperature prevented (but did not subsequently reverse) apical hypocontractility. In vitro experimentation with isolated cardiomyocytes showed no effect of hyperthermia on either baseline contractility or contractility change after beta-adrenoceptor stimulation. We suggest that the rise in body temperature that is characteristic of catecholamine storm may be a component in the development of Takotsubo syndrome.

Aim: In the event of an out of hospital cardiac arrest (OHCA) it is recommended for a sole untrained bystander to perform compression only CPR (CO-CPR). However, it remains unknown if CO-CPR is inferior to standard CPR (S-CPR), including both compressions and ventilation, in terms of survival. One could speculate that due to the current pandemic, bystanders may be more hesitant performing mouth-to-mouth ventilation. The aim of this study is to assess the association between type of bystander CPR and survival in OHCA. Methods: This study included all patients with a bystander treated OHCA between year 2015–2019 in ages 18–100 using The Swedish Registry for Cardiopulmonary Resuscitation (SRCR). We compared CO-CPR to S-CPR in terms of 30-day survival using a propensity score approach based on machine learning adjusting for a large number of covariates. Results: A total of 13,481 patients were included (5,293 with S-CPR and 8,188 with CO-CPR). The matched subgroup consisted of 2994 cases in each group.Gradient boosting were the best models with regards to predictive accuracy (for type of bystander CPR) and covariate balance. The difference between S-CPR and CO-CPR in all 30 models computed on covariate adjustment and 1-to-1 matching were non-significant. In the 30 weighted models, three comparisons (S-CPR vs. CO-CPR) were significant in terms of improved survival; odds ratio for men was 1.21 (99% confidence interval (CI) 1.02–1.43; Average treatment effect (ATE)); for patients ≥73 years 1.57 (99% CI 1.17–2.12) for Average treatment effect on treated (ATT) and 1.63 (99% CI 1.18–2.25) for ATE. Remaining 27 models showed no differences. No significances remain after adjustment for multiple testing. Conclusion: We found no significant differences between S-CPR and CO-CPR in terms of survival, supporting current recommendations for untrained bystanders regarding CO-CPR.

Background: Previous studies comparing electrocardiogram (ECG) in Takotsubo syndrome (TS) versus ST elevation myocardial infarction (STEMI) included TS patients without ST elevation, did not consider the culprit lesion in STEMI or had groups that were unbalanced regarding sex and age. Accounting for these factors, we sought to conduct a more reliable comparison of ECG in TS with ST-elevation (STE-TS) versus STEMI. The secondary aim was to investigate if ST segment changes, T wave inversion or prolonged QT interval predicted ventricular arrhythmia or death in STE-TS and STEMI. Methods: All STE-TS patients who presented at Sahlgrenska University Hospital between 2008 and 2019 were matched by sex and age to STEMI patients. STEMI patients were subcategorized according to whether or not the culprit lesion was located in the left anterior descending artery (LAD). Baseline characteristics, in‐hospital outcomes and admission ECGs were analyzed. Results: 104 STE-TS patients were sex- and age-matched with 274 STEMI patients (113 LAD-STEMI, 161 non-LAD STEMI). Admission ECG in STE-TS was more similar to LAD STEMI than non-LAD STEMI. Reciprocal ST depression was less common in STE-TS (7/104, 6.7%) compared with STEMI (112/274, 41%; p=

Abstract Aims The risk of life‐threatening ventricular arrhythmias (LTVA) has been reported to be lower in Takotsubo syndrome (TS) compared with ST‐elevation myocardial infarction (STEMI). However, the extent to which these differences relate to the fact that most patients with TS are women (who have a lower risk of LTVA) and a relatively larger proportion of patients with STEMI are men is incompletely understood. We aimed to investigate the risk of LTVA or death in sex‐matched and age‐matched patients with TS, anterior STEMI, and non‐anterior STEMI. Methods and results We systematically reviewed the charts of all patients with TS who were treated at Sahlgrenska University Hospital (Gothenburg, Sweden) between 2008 and 2019. A total of 155 patients with confirmed TS (according to the European Society of Cardiology diagnostic criteria for TS) were sex‐matched and age‐matched 1:1:1 to patients with anterior and non‐anterior STEMI. Baseline characteristics and in‐hospital outcomes were recorded directly from the patient charts for all patients, and all admission electrocardiographs were analysed. The primary outcome was the composite of death or LTVA [defined as sustained ventricular tachycardia (>30 s) or ventricular fibrillation] within 72 h. The risk of LTVA or death within 72 h after admission was considerably lower in TS (2.6%) vs. anterior STEMI (14%; P = 0.002) and non‐anterior STEMI (9.0%; P = 0.02), despite similar or greater risks of acute heart failure, and similar risks of cardiogenic shock. Compared with STEMI, TS was associated with a lower risk of sustained and non‐sustained ventricular tachycardia and ventricular fibrillation. Conclusions In a predominantly female age‐matched and sex‐matched cohort of patients with TS, anterior STEMI, and non‐anterior STEMI, the adjusted risk of in‐hospital LTVA or death was considerably lower in TS compared with STEMI, despite similar or greater risk of acute heart failure and similar risk of cardiogenic shock.

Abstract Aims Takotsubo syndrome (TS) is an acute cardiac syndrome characterized by regional myocardial akinesia that cannot be attributed to a culprit lesion in coronary arteries. Cardiac overstimulation by catecholamines in the setting of stress is implicated in the pathogenesis of TS. While catecholamine‐induced alterations in cardiac contractility have been studied as part of the causal pathway in TS, the importance of catecholamine‐mediated tachycardia has not been studied. Our aim was to explore whether the reduction in heart rate, either by pharmacological suppression of the sinoatrial node with ivabradine or by surgical induction of third‐degree atrioventricular block, prevents isoprenaline‐induced TS‐like akinesia in an experimental animal model. Methods and results We used 142 female Sprague–Dawley rats in two separate protocols. The TS‐like phenotype was induced by an intraperitoneal bolus dose of isoprenaline (ISO) 50 mg/kg. In the first protocol, we randomized 54 rats to ivabradine 10 min before ISO (IVAB1), ivabradine 10 min after ISO (IVAB2), or saline 10 min before ISO (CONTROL). In the second protocol, we randomized 88 rats to surgically induced complete heart block (CHB) or sham operation (CTRL) 10 min before the administration of ISO. All drugs were administered intraperitoneally. We recorded heart rate and blood pressure invasively in the right carotid artery. Cardiac morphology and function were evaluated by high‐resolution echocardiography (VisualSonics 770 VEVO, Toronto, Ontario, Canada) 90 min after ISO injection. IVAB1 and IVAB2 rats had significantly lower heart rate and less pronounced TS‐like cardiac dysfunction than CONTROL. CHB rats had a lower (54%) heart rate, and no animal developed left ventricular akinesia. In the first protocol, the CONTROL group had a median degree of akinesia of 10.2 [inter‐quartile range (IQR) 0.0–18.6]. The IVAB1 group showed a median of akinesia of 0% (IQR 0.0–0.0, P

Abstract Takotsubo syndrome was featured in various sessions and posters at the recent Heart Failure Congress and World Congress on Acute Heart Failure 2019 held in Athens. The importance and increasing recognition of this acute heart failure syndrome is reflected by the growing activity at Heart Failure Association congresses over the last 8 years. Two dedicated sessions to Takotsubo syndrome with comprehensive lectures from experts in the field and several posters highlighted new scientific progress, important aspects of epidemiology, pathophysiology, risk stratification, and management of the syndrome and discussed gaps in knowledge of this intriguing entity. This paper will summarize the topics discussed in these sessions including the most recent data from large registries, clinical, and pre‐clinical studies presented at the meeting.

Background Takotsubo syndrome (TS) is a potentially life‐threatening acute cardiac syndrome with a clinical presentation similar to myocardial infarction and for which the natural history, management, and outcome remain incompletely understood. Our aim was to assess the relative short‐term mortality risk of TS, ST‐segment–elevation myocardial infarction (STEMI), and non‐STEMI (NSTEMI) and to identify predictors of in‐hospital complications and poor prognosis in patients with TS. Methods and Results This is an observational cohort study based on the data from the SCAAR (Swedish Coronary Angiography and Angioplasty Registry). We included all patients (n=117 720) who underwent coronary angiography in Sweden attributed to TS (N=2898 [2.5%]), STEMI (N=48 493 [41.2%]), or NSTEMI (N=66 329 [56.3%]) between January 2009 and February 2018. We compared patients with TS to those with NSTEMI or STEMI. The primary end point was all‐cause mortality at 30 days. Secondary outcomes were acute heart failure (Killip Class ≥2) and cardiogenic shock (Killip Class 4) at the time of angiography. Patients with TS were more often women compared with patients with STEMI or NSTEMI. TS was associated with unadjusted and adjusted 30‐day mortality risks lower than STEMI (adjusted hazard ratio [adjHR], 0.60; 95% CI, 0.48–0.76; P

Background Obesity along with clustering of cardiovascular risk factors is a promoter for coronary artery disease. On the other hand, a high body mass index (BMI) appears to exert a protective effect with respect to outcomes after a coronary artery event, termed the obesity paradox.Methods The Swedish Coronary Angiography and Angioplasty Registry collects information on all patients who undergo percutaneous coronary intervention (PCI) for ST-elevation myocardial infarction (STEMI) in Sweden along with demographic and procedure-related data. We studied the predictability of four categories of BMI for 1-year all-cause mortality in people with STEMI undergoing PCI.Results Among 25 384 patients, mean (SD) age 67.7 (12.1) years and 70.2% male, who underwent PCI for STEMI, a total of 5529 (21.8%) died within 1 year. Using normal weight (BMI 18.5–24.9 kg/m2) as a reference, subjects with obesity (BMI ≥30 kg/m2) had a low 1-year all-cause mortality risk in unadjusted analysis, HR 0.59 (95% CI 0.53 to 0.67). However, after adjustment for age, sex and other covariates, the difference became non-significant, HR 0.88 (95% CI 0.75 to 1.02). Patients with overweight (BMI 25.0–29.9 kg/m2) had the lowest 1-year mortality risk in analysis adjusted for age, sex and other covariates, HR 0.87 (95% CI 0.79 to 0.97), whereas those with underweight (BMI

BackgroundChloroquine was promoted as a COVID-19 therapeutic early in the pandemic. Most countries have since discontinued the use of chloroquine due to lack of evidence of any benefit and the risk of severe adverse events. The primary aim of this study was to examine if administering chloroquine during COVID-19 imposed an increased risk of ischemic heart injury or heart failure.MethodsMedical records, laboratory findings, and electrocardiograms of patients with COVID-19 who were treated with 500 mg chloroquine phosphate daily and controls not treated with chloroquine were reviewed retrospectively. Controls were matched in age and severity of disease.ResultsWe included 20 patients receiving chloroquine (500 mg twice daily) for an average of five days, and 40 controls. The groups were comparable regarding demographics and biochemical analyses including C-reactive protein, thrombocytes, and creatinine. There were no statistically significant differences in cardiac biomarkers or in electrocardiograms. Median troponin T was 10,8 ng/L in the study group and 17.9 ng/L in the control group, whereas median NT-proBNP was 399 ng/L in patients receiving chloroquine and 349 ng/L in the controls.ConclusionsWe found no increased risk of ischemic heart injury or heart failure as a result of administering chloroquine. However, the use of chloroquine to treat COVID-19 outside of clinical trials is not recommended, considering the lack of evidence of its effectiveness, as well as the elevated risk of fatal arrythmias.

Background Ticagrelor reduces ischaemic end points in acute coronary syndromes. However, outcomes of ticagrelor versus clopidogrel in real‐world patients with acute coronary syndromes treated with percutaneous coronary intervention (PCI) remain unclear. We sought to examine whether treatment with ticagrelor is superior to clopidogrel in unselected patients with acute coronary syndromes treated with PCI. Methods and Results We used data from SCAAR (Swedish Coronary Angiography and Angioplasty Registry) for PCI performed in Västra Götaland County, Sweden. The database contains information about all PCI performed at 5 hospitals (∼20% of all data in SCAAR). All procedures between January 2005 and January 2015 for unstable angina/non‒ST‐segment‒elevation myocardial infarction and ST‐segment‒elevation myocardial infarction were included. We used instrumental variable 2‐stage least squares regression to adjust for confounders. The primary combined end point was mortality or stent thrombosis at 30 days, secondary end points were mortality at 30 days and 1‐year, stent thrombosis at 30 days, in‐hospital bleeding, in‐hospital neurologic complications and long‐term mortality. A total of 15 097 patients were included in the study of which 2929 (19.4%) were treated with ticagrelor. Treatment with ticagrelor was not associated with a lower risk for the primary end point (adjusted odds ratio [aOR], 1.20; 95% CI, 0.87–1.61; P=0.250). Estimated risk of death at 30 days (aOR, 1.18; 95% CI, 0.88–1.64; P=0.287) and at 1‐year (aOR, 1.28; 95% CI, 0.86–1.64; P=0.556) was not different between the groups. The risk of in‐hospital bleeding was higher with ticagrelor (aOR, 2.88; 95% CI, 1.53–5.44; P=0.001). Conclusions In this observational study, treatment with ticagrelor was not superior to clopidogrel in patients with acute coronary syndromes treated with PCI.

Background: The prognostic role of hypertension on long-term survival after percutaneous coronary intervention (PCI) is limited and inconsistent. We hypothesize that hypertension increases long-term mortality after PCI. Methods: We analyzed data from SCAAR (Swedish Coronary Angiography and Angioplasty Registry) for all consecutive patients admitted coronary care units in Sweden between January 1995 and May 2013 and who underwent PCI due to ST-elevation myocardial infarction (STEMI), non-ST-elevation myocardial infarction (NSTEMI)/unstable angina (UA) or stable angina pectoris. We used Cox proportional-hazards regression for statistical modelling on complete-case data as well as on imputed data sets. We used interaction test to evaluate possible effect-modulation of hypertension on risk estimates in several pre-specified subgroups: age categories, gender, diabetes, smoking and indication for PCI (STEMI, NSTEMI/UA and stable angina). Results: During the study period, 175,892 consecutive patients underwent coronary angiography due to STEMI, NSTEMI/UA or stable angina. 78,100 (44%) of these had hypertension. Median follow-up was 5.5 years. After adjustment for differences in patient’s characteristics, hypertension was associated with increased risk for mortality (HR 1.12, 95% CI 1.09–1.15, p

BackgroundThrombus aspiration is still being used in a substantial number of patients despite 2 large randomized clinical trials showing no favorable effect of routine thrombus aspiration during primary percutaneous coronary intervention in patients with ST‐segment–elevation myocardial infarction. The aim of this observational study was to evaluate the impact of thrombus aspiration on mortality, stent thrombosis, and stroke using all available data from the Swedish Coronary Angiography and Angioplasty Registry (SCAAR). Methods and ResultsWe identified 42 829 consecutive patients registered in SCAAR between January 2005 and September 2014 who underwent percutaneous coronary intervention for ST‐segment–elevation myocardial infarction. Thrombus aspiration was used in 25% of the procedures. We used instrumental variable analysis with administrative healthcare region as the treatment‐preference instrumental variable to evaluate the effect of thrombus aspiration on mortality, stent thrombosis, and stroke. Thrombus aspiration was not associated with mortality at 30 days (risk reduction: −1.2; 95% confidence interval [CI], −5.4 to 3.0; P=0.57) and 1 year (risk reduction: −2.4; 95% CI, −7.6 to 3.0; P=0.37). Thrombus aspiration was associated with a lower risk of stent thrombosis both at 30 days (risk reduction: −2.7; 95% CI, −4.1 to −1.4; P

BackgroundAdenosine‐assisted transthoracic Doppler‐derived coronary flow reserve (TDE‐CFR) reflects coronary vascular function. The prognostic and incremental value of left anterior descending coronary artery TDE‐CFR above myocardial perfusion scintigraphy in patients with suspected myocardial ischemia has not yet been studied. Methods and ResultsThree hundred seventy‐one patients (mean age, 62.3±8.7 years; 46.8% males) referred to myocardial perfusion scintigraphy attributed to suspected myocardial ischemia were included in the study. The TDE‐CFR result was blinded to the referring physician. Patients were followed up regarding major cardiovascular events, defined as cardiovascular death, myocardial infarction, or acute revascularization during a median follow‐up time of 4.5 years. A TDE‐CFR value of ≤2.0 was considered reduced. Major cardiovascular events occurred during follow‐up in 60 patients (16.2%). A reduced TDE‐CFR was detected in 76 patients (20.5%). Patients with reduced TDE‐CFR had an event rate of 36.8% compared to 10.8% in patients with normal TDE‐CFR (unadjusted hazard ratio, 4.63; 95% CI, 2.78–7.69; P

Elmir Omerovic, Truls Råmunddal, Per Albertsson, Mikael Holmberg, Per Hallgren, Jan Boren, Lars Grip, Göran MatejkaDepartment of Cardiology, Sahlgrenska University Hospital, Gothenburg, SwedenBackground: The aim of this study was to evaluate the effect of levosimendan on mortality in cardiogenic shock (CS) after ST elevation myocardial infarction (STEMI).Methods and results: Data were obtained prospectively from the SCAAR (Swedish Coronary Angiography and Angioplasty Register) and the RIKS-HIA (Register of Information and Knowledge about Swedish Heart Intensive Care Admissions) about 94 consecutive patients with CS due to STEMI. Patients were classified into levosimendan-mandatory and levosimendan-contraindicated cohorts. Inotropic support with levosimendan was mandatory in all patients between January 2004 and December 2005 (n = 46). After the SURVIVE and REVIVE II studies were presented, levosimendan was considered contraindicated and was not used in consecutive patients between December 2005 and December 2006 (n = 48). The cohorts were similar with respect to pre-treatment characteristics and concomitant medications. There was no difference in the incidence of new-onset atrial fibrillation, in-hospital cardiac arrest and length of stay at the coronary care unit. There was no difference in adjusted mortality at 30 days and at one year.Conclusion: The use of levosimendan neither improves nor worsens mortality in patients with CS due to STEMI. Well-designed randomized clinical trials are needed to define the role of inotropic therapy in the treatment of CS.Keywords: shock, myocardial infarction, inotropic agents, heart failure, pharmacology

Elmir Omerovic, Gerhard Brohall, Markus Müller, Truls Råmunddal, Göran Matejka, Finn Waagstein, Björn FagerbergThe Wallenburg Laboratory at Sahlgrenska Academy, Department of Cardiology, Sahlgrenska University Hospital, Gothenburg University, 413 45, Gothenburg, Sweden; Department of Cardiology and Department of Radiology, Sahlgrenska University Hospital, Gothenburg, SwedenIntroduction: The aim of this study was to investigate whether asymptomatic women with diabetes mellitus (DM) without previous history of ischemic heart disease (IHD) and normal electrocardiogram (ECG) have suffered silent myocardial infarction (MI).Methods: The study population consisted of 64-years old women with DM and albuminuria (n = 15) and aged- and body mass index-matched controls (n = 16). The patients were selected after screening of 240 women with previously known or unknown DM. The individuals with previous history of IHD and ECG suggesting the presence of IHD were excluded. All subjects were investigated with magnetic resonance imaging (MRI).Results: MRI investigation has revealed the presence of subendocardial MI in the two DM women (13%). No MI was detected in the control group. MR coronary angiography detected the presence of significant stenosis in the proximal segment of left anterior descending (LAD) coronary artery in one DM woman. This patient developed unstable angina 1 week after the MRI investigation. The conventional angiography has confirmed the presence of significant stenosis in LAD demanding invasive revascularization by percutaneous coronary angioplasty. No difference was found in indices of left ventricular (LV) systolic function while diastolic function was disturbed in the DM group. There was a tendency for increased LV mass in the DM group. No difference was found in the LV volumes.Conclusion: Clinically significant proportion of the women with DM and albuminuria without previous history of IHD have had silent MI. MRI screening of these high risk female patient is valuable diagnostic tool which may increase diagnostic accuracy and improve prognosis in DM patients with IHD.Keywords: asymptomatic, diabetes mellitus, ischemic heart disease, silent myocardial infarction

The expression of the tissue plasminogen activator (t-PA) gene appears to be under epigenetic control and can be affected by histone deacetylation inhibition. The study aimed to test if histone deacetalyase inhibitor treatment lead to increased t-PA release or reduced exhaustion in t-PA release in response to stimulation, as well as change in plasminogen activator inhibitor-1 (PAI-1) in subjects with coronary disease. In this clinical study, 16 post-myocardial infarction subjects, the perfused forearm model was used with isoprenaline provocation during 20 minutes, to stimulate local t-PA release. Each subject was measured twice on the same day (repeated stimuli sequences) as well as on two different occasions, without treatment and after four weeks of treatment with valproic acid (500 mg, twice daily). Net forearm release for t-PA in response to isoprenaline at minutes 1.5, 3, 6, 9, 12, 15 and 18 was measured, allowing assessment of cumulative t-PA release. There was a reduction in the exhaustion of cumulative t-PA release during repeated and prolonged stimulation with valproic acid treatment compared to non-treatment. Plasma PAI-1 antigen was decreased following treatment compared to non-treatment (18.4 ± 10.0 vs. 11.0 ± 7.1 nanograms/ml respectively, mean with 95% confidence interval). These findings demonstrate that histone deacetylation inhibition increases the capacity for endogenous t-PA release in subjects with vascular disease. Furthermore, the fibrinolytic balance is favored with suppressed PAI-1 levels. More studies are needed to establish the clinical relevance of these findings.EU Clinical Trials Register 2012-004950-27.

INTRODUCTION: Evidence for the current guidelines for the treatment of patients with chronic total occlusions (CTO) in coronary arteries is limited. In this study we identified all CTO patients registered in the Swedish Coronary Angiography and Angioplasty Registry (SCAAR) and studied the prevalence, patient characteristics and treatment decisions for CTO in Sweden. METHODS AND RESULTS: Between January 2005 and January 2012, 276,931 procedures (coronary angiography or percutaneous coronary intervention) were performed in 215,836 patients registered in SCAAR. We identified all patients who had 100% luminal diameter stenosis known or assumed to be ≥ 3 months old. After exclusion of patients with previous coronary artery bypass graft (CABG) surgery or coronary occlusions due to acute coronary syndrome, we identified 16,818 CTO patients. A CTO was present in 10.9% of all coronary angiographies and in 16.0% of patients with coronary artery disease. The majority of CTO patients were treated conservatively and PCI of CTO accounted for only 5.8% of all PCI procedures. CTO patients with diabetes and multivessel disease were more likely to be referred to CABG. CONCLUSION: CTO is a common finding in Swedish patients undergoing coronary angiography but the number of CTO procedures in Sweden is low. Patients with CTO are a high-risk subgroup of patients with coronary artery disease. SCAAR has the largest register of CTO patients and therefore may be valuable for studies of clinical importance of CTO and optimal treatment for CTO patients.