Ruschitzka, Frank T.

Abstract Background and Aims Acute myocarditis (AM) is a T cell-mediated myocardial disease with clinical manifestations ranging from mild chest pain to cardiogenic shock. Reliable biomarkers to stratify patients and guide therapy are currently lacking. In particular, the extent of the dysregulation of inflammatory pathways, and the impact on myocardial dysfunction, remain elusive. Methods Serum analyses were performed in prospectively recruited AM patients (n = 103) from two independent cohorts. Multimodal data integration combining profiling of cytokine and chemokine dysregulation with clinical biomarkers was used to define clinical phenotypes with distinct inflammatory signatures. Machine-learning and regression models were applied to determine biomarkers that indicate clinical severity. Results Immuno-proteomic profiling revealed conserved inflammatory patterns across AM cohorts, dominated by T cell-related cytokines and chemokines. In addition, AM patients showed dysregulation of fibroblast-derived cytokines, including hepatocyte growth factor (HGF), bone morphogenic protein 4 (BMP4) and the BMP4 inhibitors Gremlin-1 (GREM1) and Gremlin-2 (GREM2). Data integration and unsupervised clustering revealed two immuno-clinical phenotypes, linking T cell activation and fibroblast dysregulation to disease severity. Machine learning-based analysis identified CXCL10, GREM2 and LVEF as critical parameters for stratifying disease severity. Conclusions These findings highlight a systemic T cell activation signature as diagnostic hallmark of AM. In addition, dysregulation of fibroblast-derived tissue cytokines serves as an indicator for distinct immuno-clinical phenotypes in myocardial inflammatory disease. Thus, the clinically relevant link between T cell-driven immune activation, myocardial inflammation and fibroblast-driven remodelling provides a versatile set of parameters to identify severe manifestations of AM. Graphical Abstract Key Question: Are serological immune signatures linked to clinical severity in acute myocarditis and do they enable patient stratification? Key Findings: T cell- and fibroblast associated proteomic signatures indicate disease severity in acute myocarditis. Novel immuno-clinical phenotypes stratify patients according to distinct immune responses and clinical manifestations. CXCL10, GREM2 and LVEF are the most important parameters to identify immuno-clinical phenotypes. Take Home Message: CXCL10, GREM2 and LVEF emerge as key determinants for a severe immuno-clinical phenotype in acute myocarditis, highlighting the role of T cell-fibroblast interaction in the disease process and linking T cell activation, fibroblastic tissue remodelling and impaired cardiac function.

BACKGROUND: No large registries of patients with acute eosinophilic myocarditis (EM) are available. However, EM is perceived as a cardiac disease with high mortality, affecting mainly young and middle-aged adults according to small series and case reports. Awareness of the clinical presentation, associated systemic conditions, treatments, and outcomes of this uncommon condition is an unmet need. METHODS: In this international, multicenter, retrospective cohort study, 53 centers screened 193 patients with histologically proven acute EM between 1992 and 2023. After the exclusion of patients with insufficient data (n=10), symptoms lasting >30 days (n=19), or histological diagnosis not confirmed after review (n=8), 156 patients were included. RESULTS: Median age at presentation was 48 years (first to third quartile, 34–59 years) with male predominance (67.3%), and only 2 were pediatric cases (≤16 years of age; 1.3%). The main signs and symptoms at presentation were dyspnea (75.6%), fever (61.3%), and chest pain (53.2%). Unexpectedly, peripheral eosinophilia was reported in only 57.4% of cases, with a median cell count of 630 eosinophils/μL. The median left ventricular ejection fraction at presentation was 32% (first to third quartile, 25%–48%). The disorders most frequently associated with EM were eosinophilic granulomatosis with polyangiitis (22.4% of cases) and hypersensitivity forms (14.1%). Idiopathic/undefined forms accounted for 44.9% of cases, and miscellaneous causes accounted for 18.6%. In-hospital death or need for heart transplantation (HTx) occurred in 23 patients (14.7%; 22 deaths and 1 HTx), despite 43.6% being treated with temporary mechanical circulatory support and 92.9% being treated with immunosuppressive agents. Estimated rates of death or HTx at 1 and 3 years were 19.0% and 23.8%. Increased age, decreased left ventricular ejection fraction on admission, and no immunosuppressive therapy during hospitalization were independent predictors of death or HTx. A nonsignificant higher occurrence of deaths or HTx was observed in the hypersensitivity form (46.1%) compared with the eosinophilic granulomatosis with polyangiitis–associated form (13.1%) at 3 years ( P =0.15). CONCLUSIONS: Acute EM can often present without peripheral eosinophilia, and rates of in-hospital and midterm mortality or HTx are high. Endomyocardial biopsy is required to reach the final diagnosis of EM because relying on peripheral eosinophilia can lead to missing diagnosis. In-hospital immunosuppression is associated with HTx-free survival, although tailored immunosuppressive therapies are needed to improve outcomes. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT06447935.

AbstractBackgroundThe 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).MethodsPatients 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.ResultsOut 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).ConclusionThis 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.

ABSTRACT 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 (InterTAK) 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). Thirty-one clinically relevant variables were included in the prediction model. Model performance represented the primary endpoint and was assessed according to area under the curve (AUC), sensitivity and specificity. As secondary endpoint, a K-medoids clustering algorithm was designed to stratify patients into phenotypic groups based on the 10 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), a sensitivity of 0.85 (0.78–0.95) and a specificity of 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. 1.0.8% 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.

Abstract Funding Acknowledgements Type of funding sources: None. Background. Recent evidence shows epicardial adipose tissue (EAT) acts as a paracrine organ and may directly alter myocardial function by exerting mechanical compression. Purpose. We evaluated EAT thickness through transthoracic echocardiography and investigated its relationship with cardiopulmonary fitness and cardiovascular haemodynamics at rest and during exercise in a population of heart failure (HF) patients with reduced (HFrEF) and preserved (HFpEF) ejection fraction. Methods. We prospectively enrolled 393 consecutive HF outpatients (205 HFrEF, 188 HFpEF) who had been referred to our hospital due to dyspnoea and/or effort intolerance, together with 44 healthy controls. We performed a resting state-of-the-art echocardiographic evaluation, followed by combined cardiopulmonary-echocardiography exercise stress. Results. EAT thickness was higher in HFpEF (median 8 mm, interquartile range [IQR] 4–12 mm) and progressively reduced in controls (median 5 mm, IQR 3–7 mm; p < 0.0001) and HFrEF (median 3 mm, IQR 2–6 mm). In HFpEF, EAT thickness was inversely correlated with peak oxygen consumption (VO2) and peripheral oxygen extraction (AVO2diff), while a direct association was observed for the same parameters in HFrEF (Figure 1). Furthermore, EAT independently predicted peak VO2 and AVO2diff in HFrEF and HFpEF regardless of body mass index and waist circumference. These relationships were direct in HFrEF (standard regression coefficient [SRC] for peak VO2: 0.18, p = 0.02; SRC for peak AVO2diff: 0.17, p = 0.03) and indirect in HFpEF (SRC for peak VO2: -0.33, p < 0.0001; SRC for peak AVO2diff: -0.25, p < 0.0001). As there are no definite cut-off values to define increased EAT, patients were divided based on the median EAT value (5 mm) of the overall population. Thinner EAT (≤5 mm) was associated with worse LV systolic dysfunction (peak average S’) and remodeling (3D LV mass index) in HFrEF. In HFpEF, on the other hand, increased EAT (>5 mm) was related to worse right ventricular systolic dysfunction (3D right ventricular ejection fraction) and more severe left atrio-ventricular (left atrium reservoir strain/left ventricle global longitudinal strain) and right ventriculo-arterial (tricuspid annular plane systolic excursion/systolic pulmonary artery pressure) coupling (Figure 2). Conclusion. In HFpEF, increased EAT thickness is associated with a worse hemodynamic profile and functional capacity. Conversely, in HFrEF, EAT thinning portends more advanced LV dysfunction and impaired cardiopulmonary fitness. Abstract Figure 1 Abstract Figure 2

Abstract Funding Acknowledgements Type of funding sources: None. Background. Recent evidence shows that increased epicardial adipose tissue (EAT) thickness is associated with metabolic syndrome, microvascular dysfunction and enhanced pericardial restraint. Purpose. We measured echocardiography-derived EAT thickness in a population of heart failure (HF) patients with reduced (HFrEF) and preserved (HFpEF) ejection fraction to examine the relationship between EAT and prognosis at clinical follow-up. Methods. We prospectively enrolled 393 consecutive HF outpatients (205 HFrEF, 188 HFpEF) who had been referred to our hospital due to dyspnoea and/or effort intolerance. We performed a resting clinical and biohumoral evaluation, followed by combined cardiopulmonary-echocardiography exercise stress. We considered a composite endpoint of cardiovascular death and HF-related hospitalization during follow-up. Results. Patients with HFpEF displayed greater EAT thickness (median 8 mm, interquartile range [IQR] 4–12 mm) than HFrEF (median 3 mm, IQR 2–6 mm; p < 0.0001). During a median follow-up of 20.9 months (IQR 15-25 months), 34 cardiovascular deaths and 146 HF hospitalizations were reported, with no significant differences between the two HF phenotypes. EAT was shown to predict adverse events independently from body mass index, waist circumference and other well-established prognostic markers in HF (such as NT-proBNP and peak oxygen consumption). The risk of adverse events increased with increasing EAT thickness in HFpEF and with EAT thinning in HFrEF. Kaplan-Meier analyses for the composite endpoint showed that in HFpEF, the survival probability was significantly lower in patients with thicker EAT than those with thinner EAT. In HFrEF, conversely, patients with increased EAT thickness had a higher survival probability than those with reduced EAT thickness (Figure 1). Conclusion. EAT accumulation is increased in HFpEF compared to HFrEF and carries different prognostic meanings in the two subsets. In HFpEF, EAT thickening portends adverse outcomes, which may be due to the secretion of pro-inflammatory and pro-atherogenic adipokines and increased mechanical restraint. In HFrEF, EAT thinning is associated with a worse prognosis, probably reflecting a more advanced catabolic state (e.g., cardiac cachexia). Larger studies are needed to determine whether or not EAT has a causal role in influencing progression and survival in the different HF phenotypes. Abstract Figure 1

Abstract Background Increased epicardial adipose tissue (EAT) thickness correlates with metabolic syndrome, insulin resistance, microvascular dysfunction and enhanced pericardial restraint. Purpose We measured echocardiographic EAT thickness in heart failure (HF) patients with reduced (HFrEF) or preserved (HFpEF) ejection fraction to determine whether EAT could bear prognostic significance at clinical follow-up. Methods We prospectively enrolled 393 consecutive HF outpatients (205 HFrEF, 188 HFpEF) referred to our hospital due to dyspnoea and/or effort intolerance. We performed a resting clinical and biohumoral evaluation, followed by combined cardiopulmonary-echocardiography exercise stress. A composite of cardiovascular death and HF-related hospitalization was chosen as endpoint during follow-up. Results Patients with HFpEF displayed higher EAT thickness (median 8 mm, interquartile range [IQR] 4–12 mm) than HFrEF (median 3 mm, IQR 2–6 mm; p<0.0001). During a median follow-up of 20.9 months (IQR 15–25 months), we reported 34 cardiovascular deaths and 146 HF hospitalizations, with no significant differences between the two HF subsets. EAT predicted adverse events independently from body mass index and well-established markers of poor prognosis (e.g., NT-proBNP, peak oxygen consumption). The risk of adverse events increased with increasing EAT thickness in HFpEF and with EAT thinning in HFrEF. Kaplan-Meier analyses for the composite endpoint showed that in HFpEF, the survival probability was significantly lower in patients with thicker EAT than those with thinner EAT. In HFrEF, conversely, patients with thicker EAT had a higher survival probability than those with reduced EAT thickness (Figure 1). Conclusion EAT accumulation is more marked in HFpEF than HFrEF and carries different prognostic meanings in the two subsets. In HFpEF, EAT thickening portends adverse outcome, which may be due to increased mechanical restraint and secretion of pro-inflammatory and pro-atherogenic adipokines. In HFrEF, greater EAT thickness seems to have a protective role, while EAT thinning is associated with a worse prognosis, likely reflecting a catabolic state (i.e. cardiac cachexia). Larger studies will clarify whether EAT is a bystander or an active player in the different HF phenotypes. Funding Acknowledgement Type of funding sources: None. Figure 1

Abstract Background Epicardial adipose tissue (EAT) acts as a paracrine organ and could exert direct mechanical compression on the myocardium. Purpose We investigated the impact of echocardiographic EAT thickness on metabolic profile and cardiovascular hemodynamics at rest and during exercise in heart failure (HF) patients with reduced (HFrEF) and preserved (HFpEF) ejection fraction Methods We prospectively enrolled 393 consecutive HF outpatients (205 HFrEF, 188 HFpEF) referred to the our hospital due to dyspnoea and/or effort intolerance. We performed a resting clinical and biohumoral evaluation, followed by combined cardiopulmonary-echocardiography exercise stress. The protocol also included 44 healthy controls. Results Patients with HFpEF displayed the greatest EAT thickness (median 8 mm, interquartile range [IQR] 4–12 mm), while those with HFrEF had thinner EAT (median 3 mm, IQR 2–6 mm) than controls (median 5 mm, IQR 3–7 mm; p<0.0001). In HFrEF, EAT thickness was inversely associated with natriuretic peptides, Troponin T, and C-reactive protein levels. In HFpEF, it was directly correlated with Troponin-T and C-reactive protein levels. EAT thickness was inversely correlated with peak oxygen consumption (VO2) and peripheral oxygen extraction (AVO2diff) in HFpEF, while a direct association was observed in HFrEF (Fig 1). EAT resulted in an independent predictor of peak VO2 and AVO2diff in HFrEF and HFpEF regardless of body mass index, but the relationships were direct in HFrEF (standard regression coefficient [SRC] for peak VO2: 0.18, p=0.02; SRC for peak AVO2diff: 0.17, p=0.03) and indirect in HFpEF (SRC for peak VO2: −0.33, p<0.0001; SRC for peak AVO2diff: −0.25, p<0.0001). The analysis of cardiac mechanics revealed that thinner EAT was associated with worse left ventricle systolic dysfunction (average S') and remodeling (3D left ventricle mass) in HFrEF. In HFpEF, increased EAT was related to more severe left atrio-ventricular (left atrium reservoir strain/left ventricle global longitudinal strain) and right ventriculo-arterial (tricuspid annular plane systolic excursion/systolic pulmonary artery pressure) coupling (Figure 2). Conclusion In HFpEF, EAT accumulation is associated with worse hemodynamic and metabolic profile. In HFrEF, conversely, EAT thinning portends more severe LV dysfunction and impaired global functional capacity. Funding Acknowledgement Type of funding sources: None. Figure 1Figure 2

Abstract Aims We evaluated the impact of echocardiographic epicardial adipose tissue (EAT) on cardiovascular haemodynamics, metabolic profile and prognosis in heart failure (HF) using combined cardiopulmonary‐echocardiography exercise stress. Methods and results We analysed EAT thickness of HF patients with reduced (HFrEF, n = 205) and preserved (HFpEF, n = 188) ejection fraction, including 44 controls. HFpEF patients displayed the highest EAT, while HFrEF patients had lower values than controls. EAT showed an inverse correlation with natriuretic peptides, troponin T and C‐reactive protein in HFrEF, while having a direct association with troponin T and C‐reactive protein in HFpEF. EAT was independently associated with peak oxygen consumption (VO 2 ) and peripheral extraction (AVO 2 diff), regardless of body mass index. EAT was inversely correlated with peak VO 2 and AVO 2 diff in HFpEF, while a direct association was observed in HFrEF, where lower EAT values were associated with worse left ventricular systolic dysfunction. In HFpEF, increased EAT was related to right ventriculo–arterial (tricuspid annular plane systolic excursion/systolic pulmonary artery pressure) uncoupling. After 21 months of follow‐up, 146 HF hospitalizations and 34 cardiovascular deaths were recorded in the HF population. Cox multivariable analysis supported an independent differential role of EAT in HF cohorts (interaction P = 0.01): higher risk of adverse events for increasing EAT in HFpEF [hazard ratio (HR) 1.12, 95% confidence interval (CI) 1.04–1.37] and for decreasing EAT in HFrEF (HR 0.75, 95% CI 0.54–0.91). Conclusion In HFpEF, EAT accumulation is associated with worse haemodynamic and metabolic profile, also affecting survival. Conversely, lower EAT values imply higher left ventricular dysfunction, global functional impairment and adverse prognosis in HFrEF.