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OA Förderung 2022 Aims The initial and dynamic levels of B-type natriuretic peptide (BNP) and N-terminal-prohormone BNP (NT-proBNP) are routinely used in clinical practice to identify patients with acute and chronic heart failure. In addition, BNP/NT-proBNP levels might be useful for risk stratification in patients with and without heart failure. We performed a meta-analysis to investigate, whether the value of BNP/NT-proBNP as predictors of long-term prognosis differentiates in cohorts with and without heart failure. Methods and results We systematically searched established scientific databases for studies evaluating the prognostic value of BNP or NT-proBNP. Random effect models were constructed. Data from 66 studies with overall 83 846 patients (38 studies with 46 099 patients with heart failure and 28 studies with 37 747 patients without heart failure) were included. In the analysis of the log-transformed BNP/NT-proBNP levels, an increase in natriuretic peptides by one standard deviation was associated with a 1.7-fold higher MACE rate (hazard ratio [95% confidence interval]: 1.74[1.58-1.91], P < 0.0001). The effect sizes were comparable, with a substantial overlap in the confidence intervals, when comparing studies involving patients with and without heart failure (1.75[1.54-2.0], P < 0.0001 vs. 1.74[1.47-2.06], P < 0.0001). Similar results were observed when stratifying by quartiles of BNP/NT-proBNP. In studies using pre-defined cut-off-values for BNP/NT-proBNP, elevated levels were associated with the long-term prognosis, independent of the specific cut-off value used. Conclusions BNP/NT-proBNP levels are predictors for adverse long-term outcome in patients with and without known heart failure. Further research is necessary to establish appropriate thresholds, especially in non-heart failure cohorts.

Background: Body wasting in patients with cancer can affect the heart. Objectives: The frequency, extent, and clinical and prognostic importance of cardiac wasting in cancer patients is unknown. Methods: This study prospectively enrolled 300 patients with mostly advanced, active cancer but without significant cardiovascular disease or infection. These patients were compared with 60 healthy control subjects and 60 patients with chronic heart failure (ejection fraction

Background and aims: Available data suggest that the use of IVUS for guidance of percutaneous coronary interventions (PCIs) improves the prognosis of patients undergoing complex interventions. We aimed to examine how the utilization of intravascular ultrasound (IVUS) affects patient survival irrespective of procedure complexity. Methods: The present analysis is based on the longitudinal ECAD registry of consecutive patients undergoing coronary angiography between 2004 and 2019. The incidence of death due to any cause was evaluated during a mean follow-up of 3.4 years. Cox regression analysis was used to determine the association of IVUS utilization with incident mortality. Results: Overall, data from 30,814 coronary angiography exams (mean age 64.9 ± 12.5 years, 70.3% male) were included, among which 4991 procedures (16.2%) were guided by IVUS. Utilization of IVUS was associated with a 35% reduction in mortality, independent of traditional risk factors (0.64(0.58–0.71), p

Background The use of transcatheter aortic valve replacement (TAVR) in cancer survivors and patients with active cancer (AC) in cancer survivors and patients with active cancer (AC) is expanding, suggesting a need to adjust the indications and risk assessment pre-TAVR. Objectives The purpose of this study was to determine the impact of cancer on peri-procedural complications and survival in a long-term, single-center cohort of patients treated with TAVR. Methods Patients treated with TAVR between January 2006 and December 2018 were grouped as follows: controls (patients without cancer), stable cancer (SC), and AC. The primary endpoints were peri-procedural complications and 30-day survival. A secondary endpoint was 10-year survival. Results A total of 1,088 patients (age 81 ± 5 years, 46.6% men) treated with transfemoral TAVR were selected: 839 controls, 196 SC, and 53 AC. Predominant malignancies were breast, gastrointestinal, and prostate cancer. No differences were observed between patients with cancer and controls regarding peri-procedural complications. Patients with AC had similar 30-day survival compared with controls and SC (94.3% vs. 93.3% vs. 96.9%, p = 0.161), but as expected, reduced 10-year survival. AC was associated with a 1.47 (95% CI 1.16 to 1.87) fold increased risk of all-cause 10-year mortality in multivariable adjusted models. Conclusions TAVR should be performed in patients with cancer when indicated, considering that patients with cancer have similar periprocedural complications and short-term survival compared with control patients. However, patients with AC have worse 10-year survival. Future studies are needed to define cancer-specific determinants of worse long-term survival.

Immune checkpoint inhibitor (ICI) therapy induces an immune response against cancer cells. Immune checkpoint inhibitor therapy has tremendously improved the prognosis for a large number of cancers, but is associated with considerable immune-related adverse events (irAEs). Cardiovascular complications from ICI therapy occur in a modest proportion of patients, but show the highest lethality rates of all ICI-related complications. While ICI-related myocarditis is the most dangerous complication, its clinical manifestation varies, e.g., asymptomatic reduction of left ventricular function, isolated increase in cardiac troponins, and arrhythmias. This review delineates current data on cardiovascular complications of ICI therapy. The effects of ICI therapy on the cardiovascular system are classified in the context of preclinical data on the biochemical and immunological function of the immune checkpoint signaling pathways in the heart and the vascular system. Incidence, suspected pathomechanisms, typical symptoms, as well as recommended diagnostics are summarized. Current therapy recommendations for ICI-related cardiotoxicity are outlined and innovative new approaches with high potential for improving outcome in ICI-related myocarditis are delineated. A better understanding of cardiovascular complications is essential for the best possible oncocardiology care of the growing number of patients undergoing ICI therapy.

Background Parameters that mark the timing of left ventricular (LV) reverse remodeling following transcatheter aortic valve replacement (TAVR) are incompletely defined. This study aims to identify the dynamics of LV strain derived from speckle tracking echocardiography in a cohort of patients with severe aortic stenosis (AS) who underwent TAVR and its correlation with postprocedural outcomes. Methods We selected 150 consecutive patients (82 ± 4 years old, STS score 6.4 ± 6.2) who underwent transfemoral TAVR between 07/2016 and 12/2017 at our tertiary care center. All patients were evaluated at baseline, 1 week after TAVR, and 3 months following TAVR. Results The global longitudinal strain (GLS) 1 week following TAVR was comparable to that at baseline (− 15,9 ± 4.3 vs − 16.8 ± 4.1; p = NS) but significantly improved at 3 months following TAVR (− 15.9 ± 4.3% vs. -19.5 ± 3.5%; p p = 0.005). The linear regression analysis showed that the main predictors of the improvement in the GLS at 3 months in our cohort were baseline GRS and GCS. Conclusion GLS improves at 3 months after TAVR, while LV ejection fraction does not show a substantial change, signaling an early recovery of LV longitudinal function after the intervention. Additionally, GLS has a direct correlation with the postprocedural outcomes. GLS improvement might emerge as a valuable parameter for a tailored follow-up in TAVR patients.

The acute and long-lasting side effects of modern multimodal tumour therapy significantly impair quality of life and survival of patients afflicted with malignancies. The key components of this therapy include radiotherapy, conventional chemotherapy, immunotherapy and targeted therapies. In addition to established tumour therapy strategies, up to 30 new therapies are approved each year with only incompletely characterised side effects. This consensus paper discusses the risk factors that contribute to the development of a potentially adverse reaction to tumour therapy and, in addition, defines specific side effect profiles for different treatment groups. The focus is on novel therapeutics and recommendations for the surveillance and treatment of specific patient groups.

We aimed to determine, whether epicardial adipose tissue (EAT) as local source of inflammation, as well as its change over time, associates with the development of heart failure with preserved ejection fraction (HFpEF) in patients with coronary artery disease.We retrospectively included 379patients (aged 65.2 ± 11.7 years, 70.2%male) with coronary artery disease but without heart failure at baseline, undergoing clinical and echocardiographic assessment in 2010-2013 and receiving a second assessment in 2014-2018. EAT thickness was defined as space between the myocardium and the pericardium and indexed (EATi) by body surface area. Change in EATi was calculated as the difference of follow-up and baseline EATi. HFpEF was defined according to presence of dyspnea, elevated natriuretic peptides, and structural and/or functional alterations on echocardiography in accordance with current European Society of Cardiology guidelines. During a median follow-up of 4.3 years, 142patients (37.5%) developed HFpEF. Patients with onset of HFpEF had higher EATi at baseline (2.4 ± 1.3 vs. 1.9 ± 0.9 mm/mEATi is associated with the development of HFpEF. The finding of changes in EATi altering the risk of HFpEF manifestation support the rationale for further research on epicardial fat modulation as a treatment target for HFpEF.

Chimeric antigen receptor (CAR)-T cell therapy is the next revolutionary advance in cancer therapy. By using ex vivo engineered T cells to specifically target antigens, a targeted immune reaction is induced. Chimeric antigen receptor-T cell therapy is approved for patients suffering from advanced and refractory B cell and plasma cell malignancies and is undergoing testing for various other haematologic and solid malignancies. In the process of triggering an anticancer immune reaction, a systemic inflammatory response can emerge as cytokine release syndrome (CRS). The severity of CRS is highly variable across patients, ranging from mild flu-like symptoms to fulminant hyperinflammatory states with excessive immune activation, associated multiorgan failure and high mortality risk. Cytokine release syndrome is also an important factor for adverse cardiovascular (CV) events. Sinus tachycardia and hypotension are the most common reflections, similar to what is seen with other systemic inflammatory response syndromes. Corrected QT interval prolongation and tachyarrhythmias, including ventricular arrhythmias and atrial fibrillation, also show a close link with CRS. Events of myocardial ischaemia and venous thromboembolism can be provoked during CAR-T cell therapy. Although not as closely related to CRS, changes in cardiac function can be observed to the point of heart failure and cardiogenic shock. This may also be encountered in patients with severe valvular heart disease in the setting of CRS. This review will discuss the pertinent CV risks of the growing field of CAR-T cell therapy for today’s cardiologists, including incidence, characteristics, and treatment options, and will conclude with an integrated management algorithm.

Background The improvement of anticancer-therapy results in a greater amount of long-term survivors after radiotherapy. Therefore, the understanding of cardiotoxicity after irradiation is of increasing importance. Long-term adverse cardiovascular events may become evident years or decades after radiotherapy. The relative contribution of irradiation in relation to other cancer treatments can often only be estimated. Recent experimental and clinical evidence suggests that cardiovascular symptoms, including exertional dyspnoea, may be caused by heart failure with preserved ejection fraction (HFpEF), which remains incompletely understood in patients after radiation therapy. Purpose We aim to characterize the development of radiation-induced cardiomyopathy and elucidate underlying patho-mechanisms. Methods Mice received a single dose of whole thorax irradiation (12.5 Gy) and were sacrificed at 1 and 3 days or 3, 6, 12, 16, 20 and 25–30 weeks. Endothelial cells and immune cells at different time points were quantified using flow cytometry (FACS). Structural changes and localization of endothelial cell damage was imaged using light-sheet fluorescence microscopy (LSFM) with CD31 staining. Development of fibrosis was determined using qRT-PCR (fibronectin and TGFβ), western blot (collagen-1,α-smooth muscle) and (immune-)histological analyses. Functional analyses were conducted using echocardiography and pressure-volume-(PV-)catheterization. Results Endothelial damage was determined by significant reduction of CD31 expression in mouse hearts 6 weeks after irradiation compared to sham-treated control mice using FACS analyses. LSFM showed structural changes especially in the edge zone of left ventricle presented as less densely CD31 stained regions. Additionally, we investigated cardiac immune cell response regarding innate and adaptive immunity, showing specific response to tissue damage at different time points. Invasion of monocytes started 6 weeks after irradiation and highest level of monocytes and macrophages was measured at 12 weeks. Regarding cardiac long-term damage, myocardial fibrosis was detected on RNA- and protein-level as well as in histological analyses with significant changes 20 weeks after chest irradiation. This could be correlated with echocardiographic parameters for diastolic dysfunction (elevated isovolumic relaxation time/mitral valve deceleration time). Also functional reserve of irradiated mice was reduced, investigated by measurement of cardiac output and stroke volume after dobutamine injection in PV-catheterization. Conclusion We described a novel time-dependent endothelial cell damage and immune cell response after thoracic irradiation in mice, which could also be imaged using LSFM. Characterization of long-term damage showed cardiac fibrosis correlating with diastolic dysfunction and reduced contractile reserve. Furthermore, therapeutic approaches will be investigated using the established mouse model. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): Dr. S.M. Mrotzek acknowledges the following funding source: IFORES research grant from the Medical Faculty, University Duisburg-Essen, Germany.

Background Current ESC guidelines for non-ST-segment elevation myocardial infarction suggest the utilization of echocardiography in patients with inconclusive initial electrocardiography and cardiac enzymes. Besides detection of alternative pathologies associated with chest pain, echocardiography can screen for wall motion abnormalities (WMA) as sign of myocardial necrosis. Purpose We evaluated the ability of the assessment of regional WMA, detected via transthoracic echocardiography, to predict the presence of culprit lesions in patients presenting with acute chest pain to the emergency department. Methods In this prospective single-centre observational cohort study, we included consecutive patients presenting to the emergency department of our University Hospital with acute chest pain, suggestive of an acute coronary syndrome, between December 2018 and August 2020. Patients with ST-elevation myocardial infarction, hemodynamic instability, or known coronary artery disease were excluded. As part of initial workup, patients received bedside echocardiography for the assessment of regional WMA by a dedicated study physician, blinded to all patients' characteristics. The primary endpoint was defined as the presence of culprit lesions as detected in subsequent invasive coronary angiography, requiring coronary revascularization therapy. Logistic regression analysis was performed in different models adjusted for traditional cardiovascular risk factors, cardiac biomarkers as well as established risk scores. Area under the receiver operating characteristics curve (AUC) was calculated to assess a potential improvement in the prediction of culprit lesions. Results Overall, 657 patients (age 58.06±18.04 years, 53% male) were included in our study. WMA were detected in 76 patients (11.6%). Patients with WMA were older (66.92±13.85 vs. 56.90±18.21 years, p Conclusion WMA strongly and independently predict the presence of culprit lesions in patients presenting with acute chest pain to the emergency department. Our results suggest that routine bedside echocardiography for assessment of WMA in emergency department may improve diagnostic algorithms in suspected acute coronary syndrome. Funding Acknowledgement Type of funding sources: None.

Background The clinical value of positive family history of premature coronary artery disease (CAD) in risk prediction of cardiovascular diseases is controversial. While an association with risk factors and disease manifestation has been described in observational studies, it is not implemented in clinically established risk algorithms. Purpose We evaluated the association of positive family history of premature CAD with cardiovascular risk factors, presence of obstructive CAD, and long-term mortality. Methods The present analysis is based on the ECAD registry of patients undergoing invasive coronary angiography at the Department of Cardiology and Vascular Medicine at the University Clinic Essen between 2004 and 2019. For this analysis, we excluded all patients with missing follow-up information. Self-reported family history of premature CAD was categorized as positive, negative, or unknown. Baseline characteristics and presence of obstructive CAD were compared between patient with and without positive family history. Cox regression analysis was used to determine the association of positive family history with morality. Results Overall, data from 33,865 patient admissions (mean age: 65.0±13.1 years, 69% male) were included. Positive family history was present in 4,995 (14.8%) patients, negative family history in 17,806 patients (52.6%), while family history of premature CAD was unknown in 11,064 (32.7%) patients. Patients with positive family history were significantly younger (63.6±12.4 vs. 65.9±13.3 years, p Conclusion Positive family history of premature CAD is associated with younger age, higher rates of smoking and diabetes, and higher frequency of obstructive coronary artery disease, while long-term survival was improved as compared to patients without family history of premature CAD. In contrast, patients with unknown status regarding family history of CAD seem to represent a heterogeneous cohort and may qualify for intensified workup, as they have highest rates of obstructive CAD and poorest short- to intermediate survival. Funding Acknowledgement Type of funding sources: None. Figure 1. Survival by status of family history

Background High-density lipoprotein-cholesterol (HDL-C) has anti-atherogenic, anti-inflammatory, anti-oxidative, anti-apoptotic, and vasodilatory properties. While a linear inverse relationship between HDL-C levels and all-cause mortality is established, recent observational studies suggest a U-shaped association between HDL-C and outcome. Purpose We tested the hypothesis that both low and high HDL-C levels associate with long-term mortality. Methods The present analysis is based on the longitudinal ECAD registry of consecutive patients undergoing coronary angiography at the West German Heart and Vascular Center between 2004 and 2019. HDL-C was quantified at hospital admission using standardized enzymatic methods. The incidence of death due to any cause was evaluated during follow-up. Cox regression analysis was used to determine the association of HDL-C with incident mortality, adjusting for age, sex, systolic blood pressure, low-density lipoprotein cholesterol, smoking status, and family history of premature cardiovascular disease. In addition to the analysis on HDL-C as continuous variable, the association of HDL-groups ( Results Among 17,433 patients, mean age was 65.9±12.6 years and 70.1% were men. Mean HDL-C was 48.7±16.2 mg/dL. During a mean follow-up 3.38±2.10 years, 2,401 patients (13.8%) died. In multivariable analysis, higher HDL-C levels were independently associated with lower all-cause mortality [hazard ratio (95% confidence interval): 0.83 (0.76, 0.91) per 1 standard deviation change in HDL-C, p Conclusions In a large longitudinal registry cohort of patients undergoing invasive coronary angiography, only very low HDL-C levels were associated with increased long-term mortality. We found no signs of a U-shaped association between HDL-C and prognosis. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Iryna Dykun was supported by the German Research Foundation (DY 149/2-1)Stefanie Hendricks was supported by the Universitätsmedizin Essen Clinician Scientist Academy (UMEA)

Aims Cardiac biomarkers are a mainstay in diagnosis of cardiovascular disease but their role in cardio-oncology has not yet been systematically evaluated. This meta-analysis aims to determine whether cardiac troponins and (N-terminal pro) brain natriuretic peptide (BNP/NT-proBNP) predict cancer therapy-related left ventricular (LV) dysfunction. Methods and results Scientific databases were searched for studies that assessed troponins or BNP/NT-proBNP in adult patients undergoing cancer therapy. Data from 61 trials with 5691 patients were included. Cancer therapy was associated with an increase in troponin levels [odds ratio (OR) 14.3, 95% confidence interval (CI) 6.0-34.1; n = 3049]. Patients with elevated troponins receiving chemotherapy or human epidermal growth factor receptor 2 inhibitor therapy were at higher risk for LV dysfunction (OR 11.9, 95% CI 4.4-32.1; n = 2163). Troponin had a negative predictive value of 93%. Mean BNP/NT-proBNP levels were increased in patients post-treatment (standardized mean difference 0.6, 95% CI 0.3-0.9; n = 912), but the available evidence did not consistently indicate prediction of LV dysfunction (OR 1.7, 95% CI 0.7-4.2; n = 197). β-blocker and angiotensin-converting enzyme inhibitor therapy to mitigate cardiotoxicity during cancer therapy was associated with a decline in serum troponins (OR 4.1, 95% CI 1.7-9.8; n = 466). Conclusion Elevated troponin levels predict LV dysfunction in patients receiving cancer therapy. Assessment of troponin levels may qualify as a screening test to identify patients who require referral to cardio-oncology units and benefit from preventive strategies. Further evidence is required for both biomarkers.

Current therapy of advanced cancers is based on several modalities including radiotherapy, cytotoxic chemotherapy, molecularly targeted inhibitors and antibodies targeting immune checkpoints. All of those these modalities can negatively impact the cardiovascular system, and there is considerable experience in relation to radiotherapy and chemotherapy. In contrast, the knowledge base on cardiovascular toxicities of novel agents targeting signal transduction pathways and immune regulation is quite limited. In particular, potential late effects are of concern as cardiovascular pathology can negatively impact quality of life and prognosis in cancer survivors, particularly when additional cardiovascular risk factors are present. Treatment-associated adverse events include hypertension, venous thromboembolism, coronary artery disease, valvular heart disease, heart failure and arrhythmias. Early diagnosis of subclinical cardiotoxic effects of cancer therapies remains challenging. Integrated care, as provided by multidisciplinary cardio-oncology teams is the best option for prevention, diagnosis and treatment of cardiovascular diseases associated with cancer therapy. This review considers the cardiotoxic effects of specific cancer therapies and discusses novel diagnostic and therapeutic approaches as a reference for optimizing the care of cancer patients receiving novel cancer therapies.

Background With improvement of cancer-specific survival, comorbidities and treatment-related side effects, particularly cardiovascular toxicities, need close attention. The aim of the present study was to evaluate clinical characteristics and outcomes of cancer patients requiring coronary angiography during inpatient care. Methods We performed a retrospective analysis of patients hospitalized between 02/2011 and 02/2018 in our two university hospital cancer centers. From a cohort of 60,676 cancer patients, we identified 153 patients (65.7 ± 11.6 years, 73.2% male), who underwent coronary angiography and were eligible for analysis. These were compared to a control group of 153 non-cancer patients pair-matched with respect to age, sex, and indication for catheterization. Results Cancer patients presented in 66% with an acute coronary syndrome (ACS). The most prevalent cancer entities were lymphoma (19%) and lung cancer (18.3%). The rate of primary percutaneous coronary interventions (PCI) was significantly lower in the cancer cohort (40.5% vs. 53.6%, p = 0.029), although manifestation of coronary artery disease (CAD) and PCI results were comparable (SYNergy between PCI with TAXus and cardiac surgery (SYNTAX)-score, delta pre- and post-PCI − 9.8 vs. − 8.0, p = 0.2). Mortality was remarkably high in cancer patients (1-year mortality 46% vs. 8% in non-cancer patients, p Conclusion Strategies to effectively control cardiovascular risks in cancer patients are needed. Additionally, suspected CAD in cancer patients should not prevent prompt diagnostic clarification and optimal revascularization as PCI results in cancer patients are comparable to non-cancer patients and occurrence of troponin-positive ACS leads to a significantly increased risk of mortality. Graphic Abstract

Background The amount of epicardial adipose tissue (EAT) is associated with prevalent and incident myocardial infarction. However, clinical studies, specifically designed to determine, how the assessment of EAT can affect patient management, are lacking. Within Epicardial adipose tissue thickness PredIcts obstructive Coronary artery disease in Acute Coronary Syndrome patients (EPIC-ACS) study we tested the hypothesis that EAT quantification improves the prediction of the presence of culprit lesions in patients presenting with acute chest pain to the emergency department. Methods In this observational cohort study, we prospectively included consecutive patients presenting to the emergency department with acute chest pain suggestive of acute coronary syndrome between December 2018 and August 2020. Patients with ST-elevation myocardial infarction, hemodynamic instability, or known coronary artery disease were excluded. As part of the initial workup, bedside echocardiography for quantification of EAT thickness was performed by a dedicated study physician, blinded to all patients' characteristics. Treating physicians remained unaware of the results of the EAT assessment. The primary endpoint was defined as presence of a culprit lesion, as detected in subsequent invasive coronary angiography within 90 days after initial presentation. Logistic regression analysis was performed in different models adjusted for traditional cardiovascular risk factors, cardiac biomarkers as well as established cardiovascular risk scores. Results Overall, 657 patients (mean age 58.06±18.04 years, 53% male) were included in our study. Patients reaching the primary endpoint had significantly more EAT than patients without culprit lesions (7.90±2.56mm vs. 3.96±1.91mm, p Conclusion EAT strongly and independently predicts the presence of culprit lesions in patients presenting with acute chest pain to the emergency department. Our results suggest that the bedside echocardiographic assessment including the quantification of EAT may improve diagnostic algorithms of patients with acute chest pain. Funding Acknowledgement Type of funding sources: None. Distribution of EAT thickness

BACKGROUND: With the 2019 update of European Society of Cardiology (ESC) guidelines for chronic coronary syndromes, the pre-test probabilities (PTPs) based on age, sex, and symptoms have undergone major revisions. We aimed to determine implications of these alterations on diagnostic accuracy of dobutamine stress echocardiography (DSE). METHODS: We retrospectively included consecutive patients undergoing pharmacological stress-echocardiography for evaluation of suspected obstructive coronary artery disease. DSE was performed as non-invasive imaging test and was indicated by individual treating physician's decision. Sensitivity, specificity, positive and negative predictive value as well as accuracy were assessed for detection of obstructive coronary artery disease, defined as revascularization therapy following DSE. RESULTS: We included 206 patients (mean age 63.2 ± 12.4 years, 59.7% male). 51% of the cohort had a PTP of < 15% according to both scores. 9.2% of patients with PTP < 15% according to the original Diamond and Forrester score had a PTP > 15% according to 2019 ESC guidelines, predominantly due to the accountancy of dyspnea. In contrast, 13.6% of patient had a PTP ≥ 15% according to the original Diamond and Forrester score, while PTP was assessed below this threshold by updated guidelines. The differences in patient selection according to updated guidelines did not alter the diagnostic accuracy of DSE (68% for both). CONCLUSIONS: Changes in assessment of PTP according to updated ESC guidelines from 2019 led to a relevant reclassification of patients with suspected coronary artery disease, ultimately changing the group of patients appropriate for DSE for evaluation of myocardial ischemia. Comparing the diagnostic performance in appropriate PTP groups, however, led to similar results. OA platinum

Background The characterization of five different clinical types of acute myocardial infarction (MI) was recently updated in 2018. Type 1 MI is caused by plaque rupture leading to an acute atherothrombotic coronary event. Type 2 MI is an entity where a condition other than coronary artery disease leads to a critical imbalance between oxygen supply and demand. There exist controversial data about the prognosis of patients with type 2 MI. While some studies have shown that type 2 MI is associated with higher mortality rates compared to type 1 MI, other trials revealed comparable mortality rates after multivariate adjustment. Purpose The aim of the present study was to compare the mortality rates of patients without MI with patients, which presented with type 1 and type 2 MI. Methods The present analysis is a longitudinal registry analysis based on the Essen Registry of Coronary Artery Disease (ECAD registry) of patients undergoing coronary angiography at the West German Heart and Vascular Center, Department of Cardiology and Vascular Medicine, at the University Hospital Essen between 2004 and 2019. Type 1 MI was defined as a significant increased troponin level (Siemens Troponin I (Dimension) >0,1 ng/ml and Troponin I Ultra (Centaur) >40 ng/l) and coronary stenosis requiring intervention. Type 2 MI was defined as a significant troponin increase without percutaneous coronary intervention. During follow up, the all-cause mortality of patients without MI and patients with type 1 and 2 MI was investigated. Cox regression analysis was used to determine the association of type 1 and 2 MI with all-cause mortality. Multivariable adjustment was performed for age, sex, low-density lipoprotein cholesterol, systolic blood pressure, diabetes, family history of coronary artery disease and nicotine abuse. Results Overall, data from 18,286 coronary angiography exams (mean age 65.3±13.0 years, 71.6% male) were included in our analysis. 14,883 patients (81.3%) had no MI, 1,699 patients (9.3%) presented with type 1 MI and 1,704 patients (9.3%) presented with type 2 MI. During a mean follow-up of 3.4±3.6 years, 3321 deaths occurred (18.2%). Compared to patients without MI (16.1%), patients with type 1 MI (25.2%) and type 2 MI (29.1%) had significant higher mortality rates (p= Conclusion In this large longitudinal registry cohort of patients undergoing invasive coronary angiography, type 2 MI was associated with impaired long-term survival. Prospective studies are required to determine risk stratification for these high-risk populations. Funding Acknowledgement Type of funding sources: None. Figure 1

Aims Cardiac immune-related adverse events (irAEs) from immune checkpoint inhibition (ICI) targeting programmed death 1 (PD1) are of growing concern. Once cardiac irAEs become clinically manifest, fatality rates are high. Cardio-oncology aims to prevent detrimental effects before manifestation of severe complications by targeting early pathological changes. We therefore aimed to investigate early consequences of PD1 inhibition for cardiac integrity to prevent the development of overt cardiac disease. Methods and results We investigated cardiac-specific consequences from anti-PD1 therapy in a combined biochemical and in vivo phenotyping approach. Mouse hearts showed broad expression of the ligand PDL1 on cardiac endothelial cells as a main mediator of immune-crosstalk. Using a novel melanoma mouse model, we assessed that anti-PD1 therapy promoted myocardial infiltration with CD4+ and CD8+ T cells, the latter being markedly activated. Left ventricular (LV) function was impaired during pharmacological stress, as shown by pressure–volume catheterization. This was associated with a dysregulated myocardial metabolism, including the proteome and the lipidome. Analogous to the experimental approach, in patients with metastatic melanoma (n = 7) receiving anti-PD1 therapy, LV function in response to stress was impaired under therapy. Finally, we identified that blockade of tumour necrosis factor alpha (TNFα) preserved LV function without attenuating the anti-cancer efficacy of anti-PD1 therapy. Conclusions Anti-PD1 therapy induces a disruption of cardiac immune homeostasis leading to early impairment of myocardial functional integrity, with potential prognostic effects on the growing number of treated patients. Blockade of TNFα may serve as an approach to prevent the manifestation of ICI-related cardiotoxicity.

Coronavirus disease 2019 (COVID-19) is challenging the care for cardiovascular patients, resulting in serious consequences with increasing mortality in pre-diseased heart failure patients. In the current state of the pandemic, the physiopathology of COVID-19 affecting pre-diseased hearts and the management of terminal heart failure in COVID-19 patients remain unclear. We outline the findings of a young COVID-19 patient suffering from idiopathic cardiomyopathy who was treated for acute multi-organ failure and required cardiac surgery with implantation of a temporary right ventricular and durable left ventricular assist device (LVAD). For deeper translational insights, we used in-depth tissue analysis by electron and light sheet fluorescence microscopy revealing evidence for spatial distribution of severe acute respiratory syndrome coronavirus 2 in the heart. This indicates that in-depth analysis may represent a valuable tool in understanding indistinct clinical cases. We conclude that COVID-19 directly affects pre-diseased hearts, but the consequences can be treated successfully with LVAD implantation. OA Förderung 2020

Background Immune checkpoint inhibitor (ICI) therapy has improved treatment of advanced cancers but is associated with yet incompletely characterized cardiotoxic side effects. While inflammatory cardiac complications were initially described as a rare phenomenon, emerging evidence indicates frequent cardiotoxicity, particularly latent left ventricular (LV) dysfunction. Distinct clinical characteristics and potential pathomechanisms are so far unknown. Purpose This study aims to investigate incidence and frequency of LV dysfunction in patients receiving ICI therapy for malignant melanoma. Using a suitable melanoma mouse model, ICI-related cardiotoxicity will be reenacted to identify potential underlying pathomechanisms. Methods Patients receiving ICI therapy for stage IV melanoma that presented in our cardio-oncology unit were evaluated at baseline and four weeks after initiation of therapy including echocardiography, cardiac biomarkers, and dobutamine stress echocardiography in the absence of contraindications. Patients with decreased LV ejection fraction (LVEF) were further evaluated by 18-fludeoxyglucose PET-MRI to assess manifest myocarditis. To elucidate underlying pathomechanisms, we established a melanoma mouse model that showed profound response to anti-programmed death 1 (PD1) ICI therapy. Immune cell infiltration was assessed by flow cytometry and light sheet fluorescence microscopy. Myocardial biochemical function was analyzed using a multi-omics mass spectrometry-based approach. Results Seven patients were included to the analysis. Six patients received a combination ICI therapy with ipilimumab and nivolumab, and one patient received nivolumab monotherapy. Echocardiography revealed significantly decreased 3D-LVEF after 4 weeks of therapy in treated patients (p=0.021). A reduced global longitudinal strain was found in six of seven patients. Remarkably, dobutamine stress echocardiography revealed a more pronounced LVEF-decrease (p=0.009) as a sign for impaired myocardial contractility with a mean decrease of 5 percentage points. Using the melanoma mouse model, we were able to recapitulate the disease phenotype as indicated by decreased LVEF and impaired response to inotropic stress during mouse pressure/volume catheterization. Increased concentrations of intramyocardial CD4+ and CD8+ T cells were found in mice treated with anti-PD1 ICI therapy compared to controls (p=0.01). Mass spectrometry revealed disrupted energy metabolism and calcium homeostasis as a putative underlying pathomechanism for impaired myocardial function. Conclusions ICI-related left ventricular dysfunction may affect a large proportion of patients and potentially increase cardiac morbidity and mortality. Preclinical data proposes myocardial lymphocyte infiltration and disruption of cardiomyocyte metabolism as the underlying pathomechanism. Prospective studies are now needed for a further characterization of this novel form of ICI-related cardiotoxicity. Funding Acknowledgement Type of funding source: Public hospital(s). Main funding source(s): IFORES research grant, Medical Faculty, University Duisburg-Essen, Germany

Oncocardiology is an emerging field in cardiovascular healthcare. Besides establishing surveillance and follow-up strategies for cancer patients, it will be essential to set up specialized oncocardiology services. However, there is a lack of clinical studies to give evidence-based recommendations regarding cardiological diagnostic and therapeutic approaches for cancer patients. An oncocardiology service is a patient-centered structure that aims to integrate research and interdisciplinary patient care to bridge this gap. We discuss the current challenges in developing an oncocardiology service and review the literature on this topic. We further provide an overview of the essential diagnostic tools and upcoming ethical issues to be considered in the management of oncology patients.

OBJECTIVES To evaluate the impact of baseline left ventricular ejection fraction (LVEF) and its interaction with low-gradient aortic stenosis (LGAS) on all-cause mortality after transfemoral aortic valve implantation (TF-TAVI). METHODS We reviewed mortality data of 624 consecutive single center TF-TAVI patients and categorized LVEF according to current ASE/EACVI recommendations (normal, mildly-, moderately-, and severely abnormal). RESULTS Baseline LVEF was normal in 336 (53.8%), mildly abnormal in 160 (25.6%), moderately abnormal in 91 (14.6%), and severely abnormal in 37 (5.9%) patients, and 1-year mortality was 19%, 17%, 23%, and 43% (P = 0.002), respectively. Patients with LGAS had a similar 1-year mortality compared to those without LGAS in groups with normal (19% vs 19%, P = 0.899) and mildly abnormal LVEF (16% vs 17%, P = 0.898). One-year mortality of patients with LGAS was significantly greater than in those without LGAS in presence of moderately abnormal LVEF (31% vs 11%, P = 0.022), and it was numerically greater than in those without LGAS in presence of severely abnormal LVEF (48% vs 25%, P = 0.219). In multivariate analysis, only the combination of moderately/severely abnormal LVEF and LGAS predicted increased 1-year mortality (HR: 2.12, 95% CI: 1.4-3.2, P

Background Immune checkpoint inhibitors (ICI) have tremendously improved survival in patients with melanoma. By unbalancing the immune system, ICI also generate immune-related adverse events (IRAEs) that could affect any tissue, including the heart. Early detection of IRAEs is essential to avoid life-threatening adverse events like myocarditis and to maintain patients under this effective therapy. Aim To identify whether patients treated with ICI that develop extra-cardiac IRAEs additionally show a subclinical impairment of the heart function. Methods We have analysed the patients with melanoma without established cardiac disease evaluated in our cardio-oncology unit between July 2018 and December 2019. Data was collected at two timepoints: before initiating the ICI therapy (baseline) and one month after ICI treatment begin (follow-up). Evaluation was performed using clinical data, laboratory parameter including biomarkers, electrocardiography, comprehensive 2D, 3D, tissue Doppler, and speckle tracking echocardiography assessment, and cardiac magnetic imaging. Results A total of 69 patients with melanoma (59±12 years old, 63% males, 93.8% metastatic disease), without known cardiovascular disease were included. Patients were divided in two groups: patients with extra-cardiac IRAEs (Group 1, n=22) and without IRAEs (Group 2, n=46) after one month of ICI therapy. One patient was diagnosed with immune-related myocarditis at follow-up and was excluded from the analysis. Patients in Group 1 developed colitis (n=10), thyroiditis/hypophysitis (n=8), hepatitis (n=2), and pneumonitis (n=2). There were no differences in age, gender distribution, cardiovascular risk factors, or proportion of metastatic disease between the two groups. The proportion of patients treated with combination ICI therapy (nivolumab plus ipilimumab) was significantly higher in Group 1 (72% vs. 33%, p=0.04). The left ventricular systolic and diastolic function were similar at baseline and after one month of therapy between the two groups, except for the global longitudinal strain (GLS), which showed a significant reduction at follow-up for patients in Group 1 vs. Group 2 (−18.8±2.6% vs. −21±1.2%, p=0.03). The radial and circumferential strain were similar. Follow-up GLS had a good correlation with the extra-cardiac IRAEs rate (r=0.43; p=0.03). Patients with combination ICI therapy had a 5 times higher risk to develop extra-cardiac IRAEs (OR 5.33, 95% CI (1.07–26.61), p=0.04). Troponin and NT-proBNP were not significantly different at follow-up between the two groups. Conclusion The abnormal function of the immune system triggered by ICI therapy in patients with extra-cardiac IRAEs seems to induce a subclinical left ventricular dysfunction, signalized by a reduction of the GLS. However, the diagnosis criteria for myocarditis were fulfilled in only one patient. The mechanism of these changes should be further investigated and addressed. Funding Acknowledgement Type of funding source: None

Background Increasing use of immune checkpoint inhibitor (ICI) therapy has recently been associated with latent left ventricular dysfunction as a common cardiotoxic side effect during early therapy. Considering the potential impact on morbidity and mortality, strategies to prevent ICI-related cardiotoxicity are urgently needed, but established immunosuppressive measures prevent the anti-tumor effect of the ICI therapy, thereby limiting its applicability to severe, life-threatening cases. Recently, tumor necrosis factor alpha (TNFα) blockade was shown to prevent ICI-related gut toxicity while preserving, or even enhancing, anti-tumor efficacy. Purpose This study aims to investigate a cardioprotective effect of TNFα blockade during anti programmed death 1 (PD1) ICI therapy in a preclinical model as a basis for a potential new, preventive therapeutic approach for ICI-related cardiotoxicity. Methods A melanoma mouse model was established as the basis to study PD1 blocking therapy and protective measures in a preclinical setting. Mice were subcutaneously transplanted with a syngeneic melanoma cell line and treated with anti-PD1 antibodies for 15 days. Response to therapy was monitored by assessment of tumor size. Cardiotoxicity was confirmed by mouse echocardiography. Mice were then simultaneously treated with anti-PD1 antibodies and TNFα-blocking antibodies. A cardioprotective effect was evaluated by echocardiography and flow cytometry was used to characterize myocardial immune cells. Results Mice receiving anti-PD1 showed smaller tumor sizes with increased immune cell infiltration compared to control littermates as a sign for a profound response to therapy. Cardiotoxicity was confirmed as demonstrated by reduced left ventricular ejection fraction and reduced global radial strain in anti-PD1-treated mice. Mice receiving anti-PD1 ICI therapy showed 2-fold elevated concentrations of CD4+ and CD8+ T-lymphocytes in the murine heart as determined by flow cytometry. CD44 expression was upregulated in cytotoxic T-cells as a marker of enhanced T-cell activity in anti-PD1 treated mice. Administration of TNFα-blocking antibodies did not alter tumor sizes during anti-PD1 treatment as a sign for a sustained response to therapy. Remarkably, mice receiving TNFα-blocking antibodies together with anti-PD1 ICI therapy showed increased left ventricular function compared to mice receiving anti-PD1 monotherapy. Flow cytometry revealed increased expression of T cell exhaustion markers in mice receiving TNFα blockade as a potential underlying mechanism. Conclusions ICI therapy targeting PD1 induces latent cardiotoxicity with left ventricular dysfunction. TNFα blockade may serve as a novel cardioprotective treatment without compromising the anti-tumor efficacy of ICI therapy. Prospective studies are needed to further characterize ICI-related cardiotoxicity in patients and to evaluate the cardioprotective effect of TNFα blockade. Funding Acknowledgement Type of funding source: Public hospital(s). Main funding source(s): IFORES research grant, Medical Faculty, University Duisburg-Essen, Essen, Germany

Background Natriuretic peptides (BNP/NT-proBNP) are routinely used for the diagnosis of heart failure and predicts outcome in patients with both heart failure with preserved and reduced ejection fraction. In addition, natriuretic peptides are associated with incident cardiovascular disease manifestation in primary prevention cohorts. Whether the assessment of BNP/NT-proBNP is of value in patients with coronary artery disease but without heart failure has not been investigated in detail. We here evaluate the association of BNP/NT-pro BNP with mortality patients with coronary artery disease but without known chronic heart failure. Methods The present analysis is based on the ECAD registry of patients undergoing conventional coronary angiography at the Department of Cardiology and Vascular Medicine between 2004 and 2019. For this analysis, we excluded all patients with a diagnosis of heart failure or with elevated BNP/NT-proBNP values at baseline (>100pg/nl for BNP, >400pg/nl for NTproBNP). Moreover, patients with missing follow-up information or without BNP/NT-proBNP levels at admission were excluded. As either BNP or NT-proBNP was available for singular patients, we standardized BNP and NT pro BNP levels based on percentile rank in levels from 0 to 99. Cox regression analysis was used to determine the association of BNP/NT-proBNP with morality in unadjusted and risk factor adjusted models with effect sizes depicted per one standard deviation change in BNP/NT-proBNP rank. Results Overall, 3738 patients (mean age: 62.8±12.6 years, 71% male) were included in our analysis. During a mean follow-up of 2.6±3.5 years, 172 deaths of any cause occurred. Patients without fatal events had significantly lower BNP/NT-prBNP values compared to patients who died (48.4±28.8 vs. 58.4±27.5, p Conclusion In patients without heart failure undergoing coronary angiography, BNP/NT-proBNP levels stratify mortality risk independently of traditional cardiovascular risk factors. Our results support the routine assessment of natriuretic peptides also in patients without heart failure to identify patients at increased risk. Funding Acknowledgement Type of funding source: None

Background Anemia is a frequent comorbidity in patients with coronary artery disease (CAD). Besides a complemental effect on myocardial oxygen undersupply of CAD and anemia, available data suggests that it may independently impact the prognosis in CAD patients. We aimed to determine the association of anemia with long-term survival in a longitudinal registry of patients undergoing conventional coronary angiography. Methods The present analysis is based on the ECAD registry of patients undergoing conventional coronary angiography at the Department of Cardiology and Vascular Medicine at the University Clinic Essen between 2004 and 2019. For this analysis, we excluded all patients with missing hemoglobin levels at baseline admission or missing follow-up information. Anemia was defined as a hemoglobin level of Results Overall, data from 28,917 patient admissions (mean age: 65.3±13.2 years, 69% male) were included in our analysis (22,570 patients without and 6,347 patients with anemia). Prevalence of anemia increased by age group (age Conclusion In this large registry of patients undergoing conventional coronary angiography, anemia was a frequent comorbidity. Anemia relevantly influences log-term survival, especially in patients receiving percutaneous coronary interventions. Our results confirm the important role of anemia for prognosis in patients with coronary artery disease, demonstrating the need for specific treatment options. Figure 1. Kaplan Meier analysis Funding Acknowledgement Type of funding source: None

Background: An increasing number of high-risk percutaneous coronary interventions (PCI) are performed with mechanical circulatory support (MCS) to minimize the risk of periprocedural hemodynamic compromise. Prior studies have demonstrated that an elevated left-ventricular end-diastolic pressure (LVEDP) is associated with worse outcome after acute myocardial infarction or cardiac surgery. Although LVEDP is frequently measured, little is known about the usefulness for predicting periprocedural hemodynamic deterioration in high-risk PCI. The objective of this study is to assess the impact of preprocedural measured LVEDP in non-shock patients undergoing high-risk PCI with MCS on periprocedural hemodynamic deterioration. Methods and Results: We reviewed the PCI protocol and the Automated Impella Controller in a consecutive series of 64 patients (mean age 73 years, 80% male), who underwent high-risk PCI with Impella MCS (period 01/2017–12/2018). LVEDP (17 ± 8 mm Hg) was measured in all cases before Impella insertion and start of PCI. Periprocedural hemodynamic deterioration was defined as: systolic blood pressure (SBP) drop (decrease ≥20 mm Hg or ≤90 mm Hg), or transient loss of arterial pressure pulsatility. Hemodynamic deterioration occurred in 33% (n = 21) of all patients but did not lead to a hemodynamic compromise due to the Impella support. Regression analysis of LVEDP for periprocedural hemodynamic deterioration or in-hospital major adverse cardiac and cerebrovascular events (MACCE) showed no significant results. Conclusion: LVEDP was not associated with periprocedural hemodynamic deterioration or a higher rate of in-hospital MACCE. Our data propose that LVEDP may not be used as a risk stratification variable for MCS usage in non-shock patients undergoing high-risk PCI. Keywords: Coronary artery disease, Impella, High-risk PCI, Mechanical circulatory support, Percutaneous coronary intervention

The improvement of anticancer-therapies results in a greater amount of long-term survivors after radiotherapy. Therefore, the understanding of cardiotoxicity after irradiation is of increasing importance. Cardiovascular adverse events after chest irradiation have been acknowledged for a long time but remain difficult to diagnose. Long-term cardiovascular adverse events may become evident years or decades after radiotherapy and the spectrum of potential cardiovascular side effects is large. Recent experimental and clinical data indicate that cardiovascular symptoms may be caused especially by heart failure with preserved ejection fraction, which remains incompletely understood in patients after radiation therapy. Heart radiation dose and co-existing cardiovascular risk factors represent some of the most important contributors for incidence and severity of radiation-induced cardiovascular side effects. In this review, we aim to elucidate the underlying patho-mechanisms and to characterize the development of radiation-induced cardiovascular damage. Additionally, approaches for clinical management and treatment options are presented.

The outcome of transfemoral transcatheter aortic valve implantation (TF-TAVI) with a self-expanding (SEP) versus a balloon-expandable prosthesis (BEP) in patients with a reduced ejection fraction (rEF, ≤40%) has not been previously investigated. Patients with rEF have an increased risk of death after TF-TAVI compared to patients with a preserved ejection fraction (pEF), and prosthesis choice might influence the outcome of these patients. We, therefore, sought to compare all-cause mortality of patients with rEF using a SEP versus a BEP. We retrospectively analyzed data of 679 single-center TF-TAVI patients. Patients were censored at death or completion of 1-year follow-up, whichever occurred first. Patients with rEF (n = 141, 21%) had an increased 1-year mortality compared to patients with pEF (28% vs 19%, p = 0.007). SEP were implanted in 149 patients (49 with rEF, 33%), while BEP were implanted in 530 patients (92 with rEF, 17%). In patients with pEF, 1-year mortality was similar after SEP- and BEP-implantation (16% vs 19%, p = 0.516). In patients with rEF, however, 1-year mortality was higher after SEP- than after BEP-implantation (43% vs 21%, p = 0.004). These patients had a higher incidence of new permanent pacemaker implantation (26.5% vs 13%, p = 0.046) and paravalvular leak ≥II° (21% vs 10%, p = 0.07), but both factors could not explain the excess mortality after SEP-implantation in the multivariate analysis. In patients with rEF, the use of a SEP was an independent predictor of 1-year mortality (HR 2.44, 95% CI 1.27 to 4.27, p = 0.007). In conclusion, patients with rEF had a higher 1-year mortality after TF-TAVI when a SEP instead of a BEP was used.

Fibroblast activation protein (FAP) as a specific marker of activated fibroblasts can be visualized by positron emission tomography (PET) using Ga-68-FAP inhibitors (FAPI). Gallium-68-labeled FAPI is increasingly used in the staging of various cancers. In addition, the first cases of theranostic approaches have been reported. In this work, we describe the phenomenon of myocardial FAPI uptake in patients who received a Ga-68 FAPI PET for tumor staging.Ga-68 FAPI PET examinations for cancer staging were retrospectively analyzed with respect to cardiac tracer uptake. Standardized uptake values (SUV) were correlated to clinical covariates in a univariate regression model. From 09/2018 to 11/2019 N = 32 patients underwent FAPI PET at our institution. Six out of 32 patients (18.8%) demonstrated increased localized myocardial tracer accumulation, with remote FAPI uptake being significantly higher in patients with vs without localized focal myocardial uptake (SUVOur study indicates an association of CAD, age, and LVEF with FAPI uptake. Further studies are warranted to assess if fibroblast activation can be reliably measured and may be used for risk stratification regarding early detection or progression of CAD and left ventricular remodeling.Proteína de activación de fibroblastos (FAP) como marcador específico de fibroblastos maduros activados se puede visualizar mediante tomografía por emisión de positrones (PET) usando inhibidores de Ga-68-FAP (FAPI). El FAPI marcado con galio 68 se usa cada vez más en la estatificación de varios tipos de cáncer.Además, se han reportado los primeros casos de abordajes teranósticos. En este trabajo describimos el fenómeno de la captación de FAPI miocárdica en pacientes que recibieron Ga-68 FAPI PET para estatificación tumoral. MéTODO Y RESULTADOS: Los exámenes de PET Ga-68 FAPI para estadificación de cáncer se analizaron retrospectivamente con respecto a la captación del marcador cardíaco. Los valores de absorción estandarizados (SUV) se correlacionaron con covariables clínicas en un modelo de regresión univariante. Del 09/2018 al 11/2019 con una n = 32 pacientes fueron sometidos a PET FAPI en nuestra institución. Seis de 32 pacientes (18.8%) demostraron un aumento de acumulación del marcador localizado en el miocardio, con la captación remota de FAPI siendo significativamente mayor en pacientes con aumento de la captación vs sin captación focalizada de miocardio (SUVmax 2.2 ± 0.6 vs. 1.5 ± 0.4, p0.05 y SUV mean 1.6 ± 0.4 vs. 1.2 ± 0.3, p0.05, respectivamente). La regresión univariante demostró una correlación significativa de la enfermedad de la arteria coronaria (CAD), la edad y la fracción de eyección ventricular izquierda (FEVI) con absorción SUV remota, esta última con una muy fuerte correlación con la captación remota (R² = 0.74, p0.01). CONCLUSIóN: Nuestro estudio indica una asociación de CAD, edad y FEVI con la captación de FAPI. Se necesitan más estudios para evaluar si la activación de fibroblastos se puede medir de manera confiable y se puede usar para la estratificación de riesgo con respecto a la detección temprana o la progresión de la CAD y la remodelación ventricular izquierda.背景 : 成纤维细胞活化蛋白(FAP)作为活化成纤维细胞的一种特异性标志物,可以通过Ga-68-FAP抑制剂(FAPI)的正电子发射断层扫描(PET)显像进行活体可视化。Ga-68标记的FAPI已被越来越多地用于各种癌症的分期。并且已有第一个诊疗一体化的病例报道。本文在接受Ga-68 FAPI PET进行肿瘤分期患者中研究了心肌FAPI摄取结果。 方法和结果 : 回顾性分析了Ga-68 FAPI PET检查癌症分期的心脏示踪剂摄取情况。摄取值(SUV)作为因变量,临床资料作为协变量,纳入单变量回归模型。 从2018年9月到2019年11月,共纳入32例在我院接受了FAPI PET检查的患者。其中6例患者(18.8%)表现为局灶性心肌摄取。与无局灶性心肌摄取的患者相比,有局灶性摄取患者远处心肌FAPI摄取值更高(SUVLa protéine d’activation des fibroblastes (FAP) activés et matures peut être visualisée par tomographie à émission de positons (TEP) à l’aide d’inhibiteurs de l’activation des fibroblastes (FAPI). FAPI marqué au gallium 68 est de plus en plus utilisé dans la stratification de divers cancers. De plus, les premiers exemples d’approches théranostiques ont été rapportés. Dans ce travail nous décrivons la captation myocardique de FAPI chez les patients qui bénéficié d’une TEP au Ga-68 FAPI pour stratification tumorale. MéTHODE ET RéSULTATS: Les examens TEP Ga-68 FAPI pour la stratification oncologique ont été analysés rétrospectivement pour l’absorption du traceur au niveau cardiaque. Les valeurs d’absorption normalisées (SUV) font été corrélées aux variables cliniques selon un modèle de régression univarié. A partir de septembre 2018 jusqu’en novembre 2019, 32 patients ont bénéficié d’une TEP FAPI dans notre établissement. Six de nos 32 patients (18,8%) ont démontré une augmentation focale de captation du tracer au niveau myocardique. Les foyers systémiques se sont révélés significativement plus élevé chez les patients avec foyers myocardiques localisés (SUV max 2,2 ± 0,6 vs 1,5 ± 0,4, p0,05 et SUV mean 1,6 ± 0,4 vs 1,2 ± 0,3, p0,05, respectivement). Nous avons observé une corrélation significative entre la maladie coronarienne, l’âge, la fraction d’éjection du ventricule gauche et la présence de foyer myocardiques FAPI (R² = 0,74, p0,01) CONCLUSION: Notre étude indique une association entre la maladie cardiovasculaire coronarienne, l’âge et la FEVG et la captation myocardique de FAPI. Des études additionnelles sont nécessaires pour déterminer si l’activation des fibroblastes peut être mesurée de manière fiable et utilisée pour la détection et la progression de la maladie coronarienne et le remodelage du ventricule gauche.

Background: Coronary microvascular dysfunction (CMD) is a common disorder, leading to symptoms similar to obstructive coronary artery disease. We aimed to determine whether measures of left ventricular (LV) diastolic function and hypertrophy may predict presence of CMD. Methods: We retrospectively included patients undergoing diagnostic coronary angiography and transthoracic echocardiography, excluding patients with obstructive coronary artery disease, previous revascularization therapy, moderate or severe mitral valve disease, or atrial fibrillation. The following markers of LV diastolic function and hypertrophy were assessed: E- and A-wave velocity, E-wave deceleration time, E/A- and E/E′-ratio, left atrial area, left LV mass index, LV ejection time (LVET) and mitral valve closure to opening time. Logistic regression analysis was used to determine the association of echocardiographic parameters with presence of CMD. Results: From 378 patients (mean age ± SD 59.7 ± 13.6 years, 45.6% male) included, the majority had CMD (n = 293, 77.5%). Patients with CMD were older (60.5 ± 13.4 years vs. 56.9 ± 14.3 years, p = 0.03), were less frequent male (42.3% vs. 57.0%, p = 0.02), and had higher systolic blood pressure (137.9 ± 25.7 mmHg vs. 124.7 ± 25.6 mmHg, p

Background Cardiovascular diseases are the most prominent global health threats. For optimal treatment, myocardial biopsies are an indispensable requirement. Current analysis includes histological and biochemical assays with particular limits. Here we present a first approach utilizing light sheet fluorescence microscopy (LSFM) to visualize the 3D vasculatory architecture in the murine heart after experimental myocardial infarction (MI) and in human cardiac biopsies with simultaneously imaging of various immunological infiltrates for disease investigation. Methods and results For murine hearts, cardiac vasculature was stained using CD31-AF790 antibody, where we found distinct spots of negative staining, which correlated in size and localisation with other markers of cardiac damage such as triphenyl tetratzolium chloride (TTC) staining, ejection fraction (EF) reduction and plasma cardiac troponin I levels. Using a Ly6G-AF647 antibody, we were able to visualize neutrophil infiltrates 24 h after MI, which localized at the border of the I/R-injury zone. 5 d after MI we imaged the healing vasculatory network using the CD31 marker as well as infiltrated macrophages using F4/80 staining. Human cardiac vasculature was stained using CD31-AF790 antibody in a whole-mount staining approach. In short, human samples were fixed in 4% PFA and permeabelized using saponin-based detergents. Antibody staining was conducted at 30 °C in the dark over several days. Immunological infiltrates were visualized using human CD66b, CD16, CD64, CD3 and CD19 antibodies in various, simultaneous approaches. After staining, cardiac samples were dehydrated and cleared using ethyl cinnamate (ECi) for light sheet microscopy. The spatial resolution of cardiac blood vessels was determined by CD31 staining, revealing a highly organized and structured vascular tree. Simultaneous staining for immunological infiltrates showed association with areas of enhanced CD31 staining, displaying activated endothelium at sites of inflammation. Ly6G events in a murine heart Conclusion Light sheet-guided analysis of cardiac samples shows promising results in terms of synchronous vascular and immunological investigation. We highlighted its applicability in identifying specific immune cells based on immune-phenotyping. This novel technique may enable future clinical heart disease investigation with a powerful tool for visualization of 3D cardiac structure and identification of multiple immune cell infiltrates.

Background Immune checkpoint inhibitor therapy has significantly improved treatment of advanced malignant diseases. However, patients receiving immune checkpoint inhibitor therapy with programmed death 1 (PD1) blocking agents are at risk for cardiotoxicity with high mortality. The underlying pathomechanisms have not yet been elucidated. Purpose This study aims to evaluate the cardiotoxic effect of PD1-blocking agents and its underlying mechanism with focus on myocardial inflammation and metabolism. Methods A transplantable melanoma mouse model was used to study PD1 blocking therapy in a preclinical setting. In brief, mice were subcutaneously transplanted with a melanoma cell line and treated with anti-PD1 antibodies or non-specific immunoglobulin control for 14 days. Murine transthoracic echocardiography including strain analysis was conducted to assess left ventricular (LV) function. Pressure/volume analysis was performed using a micro-tip catheter introduced into the LV via the right commune carotid artery. Inotropic stress was induced by dobutamine. Myocardial immune cell infiltration and expression of PD1/PD-L1 was assessed using flow cytometry. A combined approach for mass spectrometry-guided profiling of proteome, lipids and metabolites was applied to evaluate changes in cardiomyocyte function and metabolism. Results Reduced tumor size in anti-PD1-treated animals confirmed response to treatment (n=7; p=0.018). Echocardiographic examination revealed reduced LV ejection fraction (EF) (n=7–8; p=0.001) and reduced global radial strain in anti-PD1-treated mice compared to control littermates (n=3–4; p=0.004). Remarkably, pressure/volume catheterization indicated reduced EF, stroke volume and stroke work under dobutamine stress in anti-PD1-treated mice (p=0.013; n=3–4). Anti-PD1 treatment was associated with a 2-fold elevated level of CD4+ and CD8+ T-cells in murine hearts (n=8; p=0.009 and p=0.049). CD44 expression was upregulated in CD8+ T-cells of anti-PD1-treated animals (n=8; p=0.024). Proteomics revealed downregulation of proteins critical for cardiomyocyte contraction, e.g. ryanodine receptor 2 and L-type calcium channel beta 2 (n=4; p Conclusion The obtained results point towards a cardiotoxic effect of PD1 blocking therapy with severely disturbed cardiac function and disrupted cardiomyocyte functional integrity. Myocardial expression of the PD1 receptor could mediate the observed effect. This could potentially promote the development of PD1 immune checkpoint inhibitor-associated myocarditis in patients. Acknowledgement/Funding IFORES research grant of the Medical Faculty, University Duisburg-Essen, Essen, Germany

Background Lipid lowering therapy is a key cornerstone in secondary prevention of patients with coronary artery disease. However, only a minority of patients with statin therapy reach LDL thresholds as suggested by the ESC. Ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK-9) inhibitors allow for reduction in LDL-cholesterol in addition to statin therapy. Purpose To perform a meta-analysis of existing trials, evaluating how lipid lowering therapy beyond statins impacts cardiovascular outcome. Methods We performed a systematic search using the Pubmed, Cochrane, SCOPUS, and Web of Science databases for studies, evaluating the impact of an intensified lipid lowering therapy via ezetimibe or PCSK-9 inhibitor in addition to statin therapy compared to statin therapy alone. Manuscript and congress presentations, published until 1st of November 2018, were included. We made our search specific and sensitive using Medical Subject Headings terms and free text and considered studies published in English language. Search terms used were “ezetimibe”, “evolocumab”, “alirocumab”, or “bococizumab” and “cardiovascular events”. Results A total of 100,610 patients from 9 randomized controlled trials (IMPROVE-IT, FOURIER, ODYSSEY Outcomes, SIPRE I, SPIRE II, ODYSSEY LONG TERM, OSLER-1 and OSLER-2, HIJ-PROPER) were included. Treatment with ezetimibe or a PCSK-9 inhibitor was associated with a 18% risk reduction in cardiovascular events (OR [95% CI]: 0.82 [0.75–0.89]). Effect sizes were similar for myocardial infarction (0.84 [0.76–0.92]) and even more pronounced for ischemic stroke (0.77 [0.67–0.83]). In contrast, all-cause mortality was not improved by the intensified lipid lowering therapy (0.94 [0.85–1.05]). No relevant heterogeneity and inconsistency between groups was present in all analyses (detailed data not shown). Comparing efficacy of LDL-reduction and relative risk redaction of cardiovascular events, a linear relationship was observed (figure). Figure 1. Correlation of reduction of LDL-cholesterol at one year with relative risk reduction (95% confidence interval) of cardiovascular events in included trials. Conclusion Intensified LDL-lowering therapy with ezetimibe or PCSK-9 inhibitors, in addition to statins, reduces the risk of myocardial infarction and stroke, however, does not impact overall mortality. There is a linear relationship between LDL reduction and cardiovascular risk reduction, confirming the beneficial effects of LDL lowering therapy beyond statins in secondary prevention.

Background Outcomes of transfemoral transcatheter aortic valve implantation (TF-TAVI) with a self-expanding (SEP) and a balloon-expandable prosthesis (BEP) seem to be comparable, though head-to-head comparisons, especially in certain patient subsets, are sparse. In addition, patients with a reduced left-ventricular ejection fraction (rEF, ≤40%) appear to be at higher risk for an increased mortality after TF-TAVI than patients with a preserved left-ventricular ejection fraction (pEF). As it remains unclear, whether outcomes of patients with rEF differ between TF-TAVI using SEP and BEP, we sought to compare all-cause mortality of patients with rEF using a SEP or a BEP. Methods We retrospectively analyzed data of 679 single-center TF-TAVI patients, which were stratified by baseline ejection fraction (rEF versus pEF) and type of implanted prosthesis (SEP versus BEP). Patients were censored at death or completion of 1-year follow-up, whichever occurred first. Results Twenty-one percent of patients had rEF, and these patients had a higher 1-year mortality compared to patients with pEF (28% vs. 19%, p=0.007). SEP were implanted in 149 patients (49 patients with rEF), while BEP were implanted in 538 patients (92 patients with rEF). All-cause 1-year mortality was similar after SEP- and BEP-implantation (16% vs 19%, p=0.516) in patients with pEF. In patients with rEF, however, 1-year mortality was higher after SEP- than after BEP-implantation (43% vs. 21%, p=0.004, see figure). Patients with rEF had a higher incidence of new permanent pacemaker implantation (26.5% vs. 13%, p=0.046) and paravalvular leak ≥2 (21% vs. 10%, p=0.07) after SEP- than after BEP-implantation, but both factors could not explain the excess mortality after SEP-implantation in multivariate analysis. Conclusion Patients with rEF had a higher 30-day and 1-year mortality after TF-TAVI when a SEP instead of a BEP was used. Further studies are needed to confirm and explain this finding.

Background Cancer therapy-related heart failure is the most concerning cardiac adverse event in patients undergoing cancer therapy. Valid diagnostic measures are fundamental for a timely diagnosis but systematic data on the use of diagnostic parameters in this collective is sparse. Cardiac biomarkers may be beneficial for diagnosis and screening of cancer therapy-related heart failure. Purpose Systematic data for cardiac biomarkers in cancer therapy-related cardiotoxicity is urgently needed to establish guideline recommendations. We therefore conducted the present systematic review and meta-analysis to assess cardiac troponin and (N-terminal pro) brain natriuretic peptide (BNP/NT-proBNP) in the prediction of left ventricular (LV) systolic dysfunction in cancer patients. Methods Cochrane, PubMed, Web of Science, and Wiley Library were screened for studies investigating cardiac troponin or BNP/NT-proBNP in cancer patients receiving cytotoxic chemotherapy with and without anthracyclines, human epidermal growth factor receptor 2 (HER2) inhibitor therapy and radiotherapy. Reduced LV ejection fraction (LVEF) was defined as primary endpoint. Results A total of 5772 patients from 58 studies were included. Chemotherapy and HER2 inhibitor therapy was associated with an elevation of troponin levels above the 99th percentile (odds ratio (OR) = 14.3; 95% confidence interval (CI): 6.9–29.5). Patients treated with anthracyclines and high-dose chemotherapy had the highest rates of troponin elevation (OR = 17.5; 95% CI: 10.1–30.2 for anthracyclines; OR = 75.1; 95% CI: 4.4–1296.9 for high-dose chemotherapy, respectively). The risk for LVEF impairment was increased in troponin positive patients compared to troponin negative patients under high-dose regimens (OR = 97.9; 95% CI: 52.1–183.8) and anthracyclines with and without concomitant HER2 inhibitors (OR = 7.0; 95% CI: 1.4–34.1 and OR = 10.5; 95% CI: 2.0–54.3). Cardiac troponin below the 99th percentile had a negative predictive value of 94% for the prediction of cardiotoxicity. Absolute plasma BNP/NT-proBNP was increased in patients with LV dysfunction (standardized mean difference = 0.6; 95% CI = 0.0–1.2) but pathologically increased BNP/NT-proBNP did not predict decreased LVEF (OR = 2.0; 95% CI: 0.9–7.2). Preventive β-blocker therapy and angiotensin converting enzyme (ACE) inhibitor therapy was associated with decreased troponin elevation compared to control (OR = 2.9; 95% CI: 1.1–7.3; Figure 4). The effect was more pronounced in ACE inhibitor-treated patients compared to β-blocker-treated patients (Chi2 = 4.4; p=0.04; I2 = 77.4%). Conclusion Elevated troponin levels predict left ventricular dysfunction in cancer patients and a decrease in troponin may indicate response to cardioprotective therapy in cancer therapy-related cardiotoxicity. Cardiac troponin qualifies as a screening test to identify patients at high risk for manifest cardiotoxicity who require referral to cardio-oncology units. Acknowledgement/Funding IFORES research grant of the Medical Faculty, University Duisburg-Essen, Essen, Germany

Introduction In patients with coronary artery disease (CAD), lipid lowering therapy is recommended as cornerstone of secondary prevention. Treatment of elderly patients inherits a medical challenge, as they experience higher absolute risk reduction with more intensive lipid lowering regimes but may be more prone to side effects by therapy. Purpose To evaluate the treatment patterns in lipid lowering therapy comparing CAD-patients above vs. below 75 years of age. Methods We retrospectively included patients with known CAD, admitted to the West German Heart and Vascular Center in the years of 2009–2010 (n=500), 2012–2013 (n=500), and 2015–2016 (n=500). LDL-cholesterol levels and intensity of stain therapy (based on dosage and type of statin) were assessed from all available hospital records. Lipid levels and treatment regimens were evaluated comparing patients ≥75 vs. Results A total of 1,500 patients (mean age: 68.4±11.2 years, 75.8% male) from 813 referring treating primary care physicians in 98 cities of Germany were included in our analysis. 983 patients were Conclusion Evaluating lipid lowering treatment patters of 1500 patients from 813 treating physicians, we observed that patients ≥75 years of age receive lower doses of statin therapy, but reached slightly lower LDL-cholesterol-levels. However, the majority of elderly patients miss current recommendations regarding LDL-thresholds. Interestingly, no signs of a higher frequency of statin-induced myopathy in the elderly were observed in our analysis.

Background Cardiovascular adverse events (CVAE) following treatment with B-Raf proto-oncogene serine/threonine kinase inhibitors and mitogen-activated protein kinase (BRAF/MEK) inhibitors in patients with melanoma remain incompletely characterized. We conducted the first detailed meta-analysis focused on BRAF/MEK inhibitor-associated CVAE. Purpose To determine the type and risk of BRAF/MEK inhibitor-associated CVAE. Methods We systematically searched Pubmed, Cochrane, and Web of Science for keywords “vemurafenib”, “dabrafenib”, “encorafenib”, “trametinib”, “binimetinib”, “cobinimetinib” through November 30, 2018. We selected randomized controlled trails (RCT) reporting on CVAE in melanoma patients under BRAF/MEK inhibitors. The selected endpoints were: decrease in left ventricular ejection fraction (LVEF), pulmonary embolism, atrial fibrillation, arterial hypertension, myocardial infarction, heart failure, pericarditis, and QTc interval prolongation. All-grade and high-grade (grade 3 or higher) CVAE were recorded. Results 9 RCTs including 4,616 patients with melanoma were selected. The treatment with BRAF/MEK inhibitors was associated with an increased risk in a decrease in LVEF, pulmonary embolism, atrial fibrillation, and arterial hypertension. The relative risks (RR) of myocardial infarction, heart failure, pericarditis, and QTc prolongation were similar between the BRAF/MEK inhibitors group and control group (Figure). These results were consistent for high-grade CVAE. The subgroup analysis showed that the combination therapy with BRAF/MEK inhibitors resulted in a higher risk of a decrease in LVEF, pulmonary embolism, and arterial hypertension, while the risk for atrial fibrillation was increased in BRAF inhibitors monotherapy group compared to controls. There was no significant difference between melanoma patients with mean age below and above 55 years old, except for the increased risk of atrial fibrillation in the older population group. The endpoints were similar between studies with mean follow-up times under and over 24 months. RR of cardiovascular adverse events Conclusions The therapy with BRAF and MEK inhibitors is associated with a higher risk of CVAE. This study increases the awareness on CVAE under these therapies and help to balance between beneficial melanoma treatment options and increased cardiovascular morbidity and mortality.