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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 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.

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

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.

Introduction Heart failure is the most concerning cardiovascular side effect of anthracycline chemotherapy. Pediatric cancer patients and survivors of childhood cancer are particularly vulnerable to cancer therapy-related cardiotoxicity. Cardiac biomarkers may be beneficial for screening and diagnosis of anthracycline-related heart failure in pediatric cancer patients and survivors of childhood cancer but systematic data is not yet available. Purpose To evaluate (N-terminal pro) brain natriuretic peptide (BNP/NT-proBNP) and cardiac troponin for screening and prediction of cancer therapy-related cardiotoxicity in pediatric cancer patients and survivors of childhood cancer. Methods Cochrane, PubMed, Web of Science, and Wiley Library were screened for studies investigating cardiac troponin or BNP/NT-proBNP in pediatric cancer patients receiving anthracycline therapy or survivors of childhood cancer. The primary endpoint was left ventricular (LV) dysfunction as defined by decreased ejection fraction (EF) or fractional shortening (FS). The study was registered at the International prospective register of systematic reviews (PROSPERO) (CRD42018106616). Results A total of 1643 subjects from 27 studies were included. BNP/NT-proBNP levels were higher in patients post-treatment compared to control subjects or pre-treatment values (standardized mean difference = 1.0; 95% CI: 0.6–1.4; n=239). The risk for left ventricular (LV) dysfunction was increased in patients with elevated BNP/NT-proBNP (OR=5.5; 95% CI: 2.0–15.2; n=357). This was demonstrated for acute cardiotoxicity (OR=22.3; 95% CI: 3.3–151.1; n=88) and in survivors of childhood cancer (OR=3.2; 95% CI: 1.0–10.0; n=269). Sensitivity for the prediction of acute or subacute LV dysfunction was 28.9% and specificity was at 91.7%. The frequency of troponin elevations was increased after anthracycline therapy (OR=3.6; 95% CI: 2.0–6.5; n=305) but troponin was not associated with LV dysfunction (OR=0.2; 95% CI: −0.2 to 0.5; n=273). Conclusion BNP/NT-proBNP is elevated in pediatric patients receiving anthracycline chemotherapy and serves as a marker for the prediction of cardiotoxicity and screening for late cardiotoxicity in survivors of childhood cancer. So far, there is no systematic evidence on a benefit of cardiac troponin for the detection of anthracycline cardiotoxicity in children. Standardized recommendations on the role of cardiac biomarkers are needed for the optimal detection of anthracycline cardiotoxicity in childhood cancer patients. Acknowledgement/Funding IFORES research grant of the Medical Faculty, University Duisburg-Essen, Essen, Germany

Aims The myocardial effect of tonically released nitric oxide (NO) in humans is still not known. We tested the hypothesis that low-dose NO exerts positive effects on left ventricular (LV) function. Methods and results Twelve healthy volunteers, 26±4 years, were enrolled in this study. Magnetic resonance imaging was used to precisely measure the direct effects of NO on stroke volume index (SVI). The NO pool was monitored by chemiluminescence. We reduced endogenous NO levels with intravenous infusion of the NO synthase-inhibitor N G-monomethyl-l-arginine. Replenishment of the NO pool was achieved with the NO donor S -nitrosoglutathione (GSNO) (0.5 µmol iv). To differentiate load-dependent from the direct effects of NO on LV function, changes in SVI in response to GSNO were compared with changes in the NO-independent vasodilator dihydralazine (2.5 mg iv) at matched arterial pressure and heart rate. Inhibition of NO synthesis was followed by reduction in SVI. Subsequent replenishment of the circulating NO with GSNO significantly increased SVI (39±8 to 54±7 mL m−2; P =0.001), whereas no significant changes were observed with the NO-independent vasodilator dihydralazine (39±8 to 46±8 mL m−2; P =0.0626). Conclusion Inhibition of endogenous NO release reduces, whereas replenishment with exogenous NO increases LV function, pointing towards a positive effect of tonically released NO on LV function in healthy humans.