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Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of cancer; however, at the potential cost of serious adverse events including cardiac injury.To assess the baseline and longitudinal changes in high sensitivity-Troponin (hs-Tn) in patients treated with pembrolizumab as a potential predictor for the development of major adverse cardiac events (MACE) and survival.We performed a retrospective analysis of cancer patients treated with pembrolizumab at our center. All participants had baseline measurements of hs-TnI prior to initiation of pembrolizumab (T1), with half of the patients performing follow-up measurements at their second encounter for therapy introduction (T2). We first evaluated the prevalence of abnormally elevated serum hs-TnI ( 50 nanogram per liter) at T1 and T2. We then evaluated the predictive value of abnormal levels at T1 or T2 in relation to the development of MACE (composite outcomes of myocarditis, acute coronary syndrome, heart failure, venous thromboembolism, cardiovascular hospitalization and cardiovascular mortality) and all-cause mortality.Among 135 patients, the mean age was 72 years, predominantly male (61%). Abnormally elevated hs-TnI at T1 was observed in 7 (5%) patients and emerged as a significant independent predictor for MACE (HR 8.1, 95% CI 1.67-37.4, p = 0.009) and all-cause mortality (HR 5.37, 95% CI 2.1-13.57, p 0.001). Abnormally elevated hs-TnI at T2 was observed in 8 (11%) patients and emerged as a significant independent predictor for MACE (HR 10.49, 95% CI 1.68-65.5, p = 0.009), but not for mortality (p = 0.200).Abnormally elevated baseline and follow-up hs-TnI served as significant independent predictors for MACE, with an increased risk of development being 8-tenfold. Furthermore, elevated baseline hs-TnI showed a predictive value for all-cause mortality. Central illustration: Novel immune checkpoint inhibitor (ICIs) therapy has been found to revolutionize cancer therapy through increased activation of host immune systems to target and reduce tumor burden, but may come at the cost of serious adverse cardiac events. Identification of early biomarkers for the prediction and detection of these events is necessary.

Aims There are no comprehensive machine learning (ML) tools used by oncologists to assist with risk identification and referrals to cardio-oncology. This study applies ML algorithms to identify oncology patients at risk for cardiovascular disease for referrals to cardio-oncology and to generate risk scores to support quality of care. Methods and results De-identified patient data were obtained from Vanderbilt University Medical Center. Patients with breast, kidney, and B-cell lymphoma cancers were targeted. Additionally, the study included patients who received immunotherapy drugs for treatment of melanoma, lung cancer, or kidney cancer. Random forest (RF) and artificial neural network (ANN) ML models were applied to analyse each cohort: A total of 20 023 records were analysed (breast cancer, 6299; B-cell lymphoma, 9227; kidney cancer, 2047; and immunotherapy for three covered cancers, 2450). Data were divided randomly into training (80%) and test (20%) data sets. Random forest and ANN performed over 90% for accuracy and area under the curve (AUC). All ANN models performed better than RF models and produced accurate referrals. Conclusion Predictive models are ready for translation into oncology practice to identify and care for patients who are at risk of cardiovascular disease. The models are being integrated with electronic health record application as a report of patients who should be referred to cardio-oncology for monitoring and/or tailored treatments. Models operationally support cardio-oncology practice. Limited validation identified 86% of the lymphoma and 58% of the kidney cancer patients with major risk for cardiotoxicity who were not referred to cardio-oncology.

Immune-checkpoint inhibitor-associated myocarditis (ICI-myocarditis) often presents with arrhythmias, but the prognostic value of early electrocardiogram findings is unclear. Although ICI-myocarditis and acute cellular rejection (ACR) following cardiac transplantation use similar treatment strategies, differences in arrhythmia burden are unknown.To evaluate the association of electrocardiogram findings in ICI-myocarditis with myocarditis-related mortality and life-threatening arrhythmia.A total of 125 cases of ICI-myocarditis were identified retrospectively across 49 hospitals worldwide; 50 cases of grade 2R or 3R ACR were included as comparators. Two cardiologists blinded to clinical data interpreted electrocardiograms. Associations between electrocardiogram features, myocarditis-related mortality and the composite of myocarditis-related mortality and life-threatening arrhythmias were examined. Adjusted hazard ratios (aHRs) were calculated.The cohort had 78 (62.4%) men; median (interquartile range) age was 67 (58-76) years. At 30 days, myocarditis-related mortality was 20/124 (16.1%), and 28/124 (22.6%) met the composite endpoint. Patients who developed complete heart block (aHR by subdistribution hazards model [aHR(sh)] 3.29, 95% confidence interval [CI] 1.24-8.68; P=0.02) or life-threatening cardiac arrhythmias (aHR(sh) 6.82, 95% CI: 2.87-16.21; P0.001) had a higher risk of myocarditis-related mortality. Pathological Q waves (aHR(sh) 3.40, 95% CI: 1.38-8.33; P=0.008), low QRS voltage (aHR(sh) 6.05, 95% CI: 2.10-17.39; P0.001) and Sokolow-Lyon index (aHR(sh)/mV 0.54, 95% CI: 0.30-0.97; P=0.04) on admission electrocardiogram were also associated with increased risk of myocarditis-related mortality. These associations were mirrored in the composite outcome analysis. Compared with ACR, ICI-myocarditis had a higher incidence of life-threatening cardiac arrhythmias (15/125 [12.0%] vs 1/50 [2%]; P=0.04) and third-degree heart block (19/125 [15.2%] vs 0/50 [0%]; P=0.004).Electrocardiograms in ICI-myocarditis with ventricular tachycardias, heart block, low-voltage and pathological Q waves were associated with myocarditis-related mortality and life-threating arrhythmia. Arrhythmia burden in ICI-myocarditis exceeds that of ACR after heart transplant.

Aims We aim to assess changes in routine echocardiographic and longitudinal strain parameters in patients recovering from Coronavirus disease 2019 during hospitalization and at 3-month follow-up. Methods and results Routine comprehensive echocardiography and STE of both ventricles were performed during hospitalization for acute coronavirus disease 2019 (COVID-19) infection as part of a prospective pre-designed protocol and compared with echocardiography performed ∼3 months after recovery in 80 patients, using a similar protocol. Significantly improved right ventricle (RV) fractional area change, longer pulmonary acceleration time, lower right atrial pressure, and smaller RV end-diastolic and end-systolic area were observed at the recovery assessment (P < 0.05 for all). RV global longitudinal strain improved at the follow-up evaluation (23.2 ± 5 vs. 21.7 ± 4, P = 0.03), mostly due to improvement in septal segments. Only eight (10%) patients recovering from COVID-19 infection had abnormal ejection fraction (EF) at follow-up. However, LV related routine (E, E/e′, stroke volume, LV size), or STE parameters did not change significantly from the assessment during hospitalization. A significant proportion [36 (45%)] of patients had some deterioration of longitudinal strain at follow-up, and 20 patients (25%) still had abnormal LV STE ∼3 months after COVID-19 acute infection. Conclusion In patients previously discharged from hospitalization due to COVID-19 infection, RV routine echocardiographic and RV STE parameters improve significantly concurrently with improved RV haemodynamics. In contrast, a quarter of patients still have LV systolic dysfunction based on STE cut-offs. Moreover, LV STE does not improve significantly, implying subclinical LV dysfunction may be part and parcel of recovering from COVID-19 infection., Graphical Abstract Graphical Abstract

Myocardial perfusion defect, assessed with single photon emission computed tomography (SPECT), is useful for patient management and risk stratification. Left ventricle Global Longitudinal Strain (LV GLS) has gained interest for observing subclinical LV dysfunction. We aimed to investigate the utility of LV GLS in evaluating myocardial perfusion defect. A retrospective study of all patients who underwent SPECT and LV GLS at Tel Aviv Sourasky medical center. Overall, 86 patients were included. LV GLS and SPECT correlated in the base and apex sections for infraction, and in the apex only for ischemia. Adjusted analysis showed a significant correlation between LV GLS of both the mid and apical section and infarction by SPECT, but no association with ischemia. No associations were found by arterial supply territory. A sub-analysis of patients without left bundle branch block (LBBB) strengthened the correlations, with a 58-70% higher chance of both fixed and reversible defects for every 1-unit decrease LV GLS in the mid and apical sections. LV GLS effectively evaluated the presence of infarction by SPECT in the mid and apical sections, particularly in patients without LBBB. Due to its high availability, LV GLS may have a role in evaluating myocardial perfusion defect.

AimsCardiovascular involvement is common in COVID-19. We sought to describe the haemodynamic profiles of hospitalized COVID-19 patients and determine their association with mortality.Methods and resultsConsecutive hospitalized patients diagnosed with COVID-19 infection underwent clinical evaluation using the Modified Early Warning Score (MEWS) and a full non-invasive echocardiographic haemodynamic evaluation, irrespective of clinical indication, as part of a prospective predefined protocol. Patients were stratified based on filling pressure and output into four groups. Multivariable Cox-Hazard analyses determined the association between haemodynamic parameters with mortality. Among 531 consecutive patients, 44% of patients had normal left ventricular (LV) and right ventricular (RV) haemodynamic status. In contrast to LV haemodynamic parameters, RV parameters worsened with higher MEWS stage. While RV parameters did not have incremental risk prediction value above MEWS, LV stroke volume index, E/e′ ratio, and LV stroke work index were all independent predictors of outcome, particularly in severe disease. Patients with LV or RV with high filling pressure and low output had the worse outcome, and patients with normal haemodynamics had the best (P ConclusionIn hospitalized patients with COVID-19, almost half have normal left and right haemodynamics at presentation. RV but not LV haemodynamics are related to easily obtainable clinical parameters. LV but not RV haemodynamics are independent predictors of mortality, mostly in patients with severe disease.

The conveyed risk of mild diastolic dysfunction (MDD) according to age had not been thoroughly studied. We aimed to investigate the mortality-risk of MDD by age-groups among inpatients with preserved ejection fraction (EF), and determine ranges of diastolic function parameters by prognosis.In a single-center retrospective study we identified inpatients who underwent echocardiography between 2012 and 2018 and had preserved EF without significant valvulopathies. Propensity scores were used to adjust for baseline characteristics and main diagnoses at discharge. Comparisons for all-cause mortality between MDD and normal diastolic function were conducted by age groups. Using classification and regression trees (CART) modeling we determined age-specific cut-offs according to outcome.The cohort consisted of 15,777 inpatients. Mortality rate during a 33.9-months median follow-up was 21.6%. MDD was associated with increased mortality risk among all ages up to 90 years, thereafter no difference was detected. Adjusted hazard ratios inversely related to age - 1.99(95%CI 1.25-3.16, p = 0.004), 1.82(95%CI1.46-2.26, p0.001), 1.88(95%CI1.64-2.15, p0.001), 1.78(95%CI1.59-2.01, p0.001), and 1.32(95%CI0.95-1.83, p = 0.093), for 18-44, 45-59, 60-74, 75-89, and ≥90 years, respectively (Pinteraction = 0.009). New cut-offs of E/e' for ages 75-89(16), e' lateral for ages ≥90(6 cm/s), e' septal for ages 60-74(5 cm/s), and E/A ratio for ages 18-44(1.5), predicted outcome more accurately than guidelines-based recommendations. The remaining cut-offs were not better predictors compared to guidelines-based recommendations.MDD is a consequential finding at all ages up to 90 years among inpatients with preserved EF, although its significance decreases with age. Diastolic function of several age-groups may be better delineated by cut-offs that presage adverse prognoses. Helsinki committee approval number: 0170-17-TLV.

The aim of this study was to evaluate sonographic features that may aid in risk stratification and to propose a focused cardiac and lung ultrasound (LUS) algorithm in patients with coronavirus disease 2019.Two hundred consecutive hospitalized patients with coronavirus disease 2019 underwent comprehensive clinical and echocardiographic examination, as well as LUS, irrespective of clinical indication, within 24 hours of admission as part of a prospective predefined protocol. Assessment included calculation of the modified early warning score (MEWS), left ventricular systolic and diastolic function, hemodynamic and right ventricular assessment, and a calculated LUS score. Outcome analysis was performed to identify echocardiographic and LUS predictors of mortality or the composite event of mortality or need for invasive mechanical ventilation and to assess their adjunctive value on top of clinical parameters and MEWS.A simplified echocardiographic risk score composed of left ventricular ejection fraction50% combined with tricuspid annular plane systolic excursion18 mm was associated with mortality (P = .0002) and with the composite event (P = .0001). Stepwise analyses evaluating echocardiographic and LUS parameters on top of existing clinical risk scores showed that addition of tricuspid annular plane systolic excursion and stroke volume index improved prediction of mortality when added to clinical variables but not when added to MEWS. Once echocardiography was added, and patients were recategorized as high risk only if having both high-risk MEWS and high-risk cardiac features, specificity increased from 63% to 87%, positive predictive value from 28% to 48%, and accuracy from 66% to 85%. Although LUS was not associated with incremental risk prediction for mortality above clinical and echocardiographic criteria, it improved prediction of need for invasive mechanical ventilation.In hospitalized patients with coronavirus disease 2019, a very limited echocardiographic examination is sufficient for outcome prediction. The addition of echocardiography in patients with high-risk MEWS decreases the rate of falsely identifying patients as high risk to die and may improve resource allocation in case of high patient load.

Item does not contain fulltext BACKGROUND: Diastolic dysfunction is a common finding in patients receiving cancer therapy. This study evaluated the correlation of diastolic strain slope (Dss) with routine echocardiography diastolic parameters and its role in early detection of systolic dysfunction and cardiovascular (CV) mortality within this population. METHODS: Data were collected from the Israel Cardio-Oncology Registry (ICOR), a prospective registry enrolling adult patient receiving cancer therapy. All patients performed at least three echocardiography exams (T1, T2, T3), including left ventricle Global Longitudinal Strain (LV GLS) and Dss. Systolic dysfunction was determined by either LV GLS relative reduction of ≥ 15% or LV ejection fraction reduction > 10% to

Background: Cardiotoxicity, defined mainly as left ventricle (LV) dysfunction, is a significant side effect of anthracyclines (ANT) therapy. The need for an early simple marker to identify patients at risk is crucial. High Neutrophil-to-Lymphocyte Ratio (NLR) has been associated with poor prognosis in cancer patients, however, its role as a predictor for cardiotoxicity development is unknown. Objective: We aimed to evaluate whether elevated NLR, following ANT exposure, plays a predictive role in the development of cardiotoxicity as defined by LV global longitudinal strain (LV GLS) relative reduction (≥10%).Methods and results: Data were prospectively collected as part of the Israel Cardio-Oncology Registry (ICOR). A total of 74 female patients with breast cancer, scheduled for ANT therapy were included. NLR levels were assessed at baseline (T1) and during ANT therapy (T2). All patients underwent serial echocardiography at baseline (T1) and after the completion of ANT therapy (T3). NLR≥ 2.58 was found to be the optimal predictive cut-off for LV GLS deterioration. A relative LV GLS reduction ≥10% was significantly more common among patients with high NLR (50% vs. 20%, p=0.009). NLR ≥ 2.58 increases the risk for LV GLS reduction by 4-fold (OR 4.63, 95%CI 1.29-16.5, p = 0.02), with each increase of 1-point NLR adding an additional 15% risk (OR 1.15, 95%CI 1.01-1.32, p = 0.046).Conclusions: Our study provides novel data that high NLR levels, following ANT exposure, have an independent association with the development of LV dysfunction. Routine surveillance of NLR may be an effective means of risk-stratifying.

Recently, several therapeutic agents have decreased the progression to critical disease in patients with mild/moderate COVID-19. However, their use is limited to patients with ≥1 clinical risk factor. We aimed to evaluate echocardiographic features that may aid in risk stratification for patients with mild/moderate COVID-19.278 consecutive patients with mild/moderate COVID-19 underwent prospective clinical and echocardiographic examination, ≤7 days of symptoms, as part of a predefined protocol. Analysis to identify echocardiographic predictors of outcome was performed.In the multivariable risk model, E/e', TAPSE, and pulmonary acceleration time (PAT) were associated with the composite outcome (p = 0.01, 0.005, 0.05, respectively). Stepwise analyses showed that the addition of echocardiography on top of having ≥1 clinical risk factor and even using each parameter separately improved the prediction of outcomes. If patients were re-categorized as high risk only if having both ≥1 clinical and ≥ 1 echocardiography risk parameter (E/e' 8, TAPSE1.8 cm, PAT90 msec), or even one echo parameter separately, then specificity, positive predictive value, and accuracy improved. If patients were re-classified as high risk if having either ≥1 clinical risk factor or ≥ 1 high-risk echocardiography parameter, all five individuals who were missed by the ≥1 risk factor "rule", were correctly diagnosed as high risk. Similar analyses, including only patients with mild disease, showed that the addition of TAPSE improved the prediction of outcomes.In patients with mild/moderate COVID-19, a very limited echocardiographic exam is sufficient for improved outcome prediction, and may improve resource allocation for new anti-COVID-19 agents.We show that among patients with mild/moderate COVID-19, several easily obtained echocardiographic findings are strongly correlated with mortality or progression to the need for invasive/non-invasive mechanical ventilation, even when adjusted for the presence or absence of ≥1 clinical risk factor. Furthermore, even a limited echocardiographic exam is sufficient to develop a strategy of risk stratification. We believe that our data have important implications for the clinicians involved in the acute treatment of patients with COVID-19.

Parasympathetic dysfunction is associated with increased risk for major adverse cardiovascular events (MACE). However, clinically validated biomarkers that reflect parasympathetic activity are not yet available. We sought to assess the ability of serum cholinesterase activity to predict long term survival in patients undergoing coronary angiography.We prospectively followed 1002 consecutive patients undergoing clinically indicated coronary angiography (acute coronary syndrome or stable angina). We measured blood acetylcholinesterase (AChE) activity using the acetylcholine analog acetylthiocholine. Mortality rates were determined up to 10 years of follow-up. We divided our cohort into 3 groups with low, intermediate and high AChE activity by a Chi-square automatic interaction detection method (CHAID).Patients with lower than cutoff levels of AChE (300 nmol/min/ml) had higher mortality rates over 10 years of follow-up, after adjusting for conventional risk factors, biomarkers, clinical indication, and use of medications (HR = 1.6, 95% CI 1.1-2.5, p = 0.02). Patients with intermediate levels of AChE (300-582 nmol/min/ml) were also at increased risk for death (HR = 1.4, 95% CI 1.1-1.9, p = 0.02). AChE was inversely correlated with C-reactive protein, troponin I, fibrinogen and neutrophil/lymphocyte ratio levels.Patients presenting for coronary angiography with low levels of serum AChE activity are at increased risk for death during long term follow-up.

Purpose Information regarding the use of lung ultrasound (LUS) in patients with Coronavirus disease 2019 (COVID-19) is quickly accumulating, but its use for risk stratification and outcome prediction has yet to be described. We performed the first systematic and comprehensive LUS evaluation of consecutive patients hospitalized with COVID-19 infection, in order to describe LUS findings and their association with clinical course and outcome. Methods Between 21/03/2020 and 04/05/2020, 120 consecutive patients admitted to the Tel Aviv Medical Center due to COVID-19, underwent complete LUS within 24 h of admission. A second exam was performed in case of clinical deterioration. LUS score of 0 (best)—36 (worst) was assigned to each patient. LUS findings were compared with clinical data. Results The median baseline total LUS score was 15, IQR [7–20]. Baseline LUS score was 0–18 in 80 (67%) patients, and 19–36 in 40 (33%) patients. The majority had patchy pleural thickening (n = 100; 83%), or patchy subpleural consolidations (n = 93; 78%) in at least one zone. The prevalence of pleural thickening, subpleural consolidations and the total LUS score were all correlated with severity of illness on admission. Clinical deterioration was associated with increased follow-up LUS scores (p = 0.0009), mostly due to loss of aeration in anterior lung segments. The optimal cutoff point for LUS score was 18 (sensitivity = 62%, specificity = 74%). Both mortality and need for invasive mechanical ventilation were increased with baseline LUS score > 18 compared to baseline LUS score 0–18. Unadjusted hazard ratio of death for LUS score was 1.08 per point [1.02–1.16], p = 0.008; Unadjusted hazard ratio of the composite endpoint (death or need for invasive mechanical ventilation) for LUS score was 1.12 per point [1.05–1.2], p = 0.0008. Conclusion Hospitalized patients with COVID-19, at all clinical grades, present with pathological LUS findings. Baseline LUS score strongly correlates with the eventual need for invasive mechanical ventilation and is a strong predictor of mortality. Routine use of LUS may guide patients’ management strategies, as well as resource allocation in case of surge capacity. Electronic supplementary material The online version of this article (10.1007/s00134-020-06212-1) contains supplementary material, which is available to authorized users.

Immune checkpoint inhibitors (ICI) have transformed the standard care of cancer treatment. Recent case reports describe ICI-mediated myocarditis with an atypical presentation and fatal potential which lead to permanent interruption of immunotherapy. To characterize ICI-mediated myocarditis and re-introduction to immunotherapy. During 2019, 849 patients were treated with ICI at Tel Aviv Sourasky Medical Center for the diagnosis of lung adenocarcinoma, gastric adenocarcinoma, urothelial carcinoma, and hepatocellular carcinoma. Overall, seven (0.8%) patients were diagnosed with ICI-mediated myocarditis, according to the European Society of Cardiology guidelines of myocarditis 2013. We retrospectively evaluated their presentation, severity, and clinical outcomes. Among the seven patients, only one had a history of cardiac disease. The majority were diagnosed with lung adenocarcinoma and treated with anti-programmed death-1 antibody. All patients were treated with single-agent ICI. Most patients presented with cardiac symptoms, elevated troponin and typical cardiac magnetic resonance; however, only three had reduced ejection fraction. Overall, three patients were chosen for re-introduction with concomitant low dose steroids and weekly troponin follow-up. Two patients diagnosed with grade I and II renewed therapy successfully with no recurrence of symptoms and improvement in disease burden. The one patient diagnosed with grade III developed worsening of cardiac symptoms after the 1st cycle and, therefore, therapy was interrupted permanently. ICI-mediated myocarditis is potentially fatal and leads to permanent interruption of life-saving cancer therapy. The current data suggest that re-introduction may be considered in low-grade patients; however, a better definition of the diagnosis and grading is needed.

While the impact of mitral regurgitation (MR) prior to transcatheter aortic valve replacement (TAVR) has been intensively studied, the implications of post-procedural MR on outcome are unknown. We investigated the clinical and physiological impact of significant MR after TAVR.Clinical and echocardiographic data of 486 patients who underwent TAVR between March 2009 and December 2014 were evaluated. Clinical endpoints included overall mortality and combined endpoint of mortality, heart failure re-hospitalization and new atrial fibrillation. Echocardiographic parameters were analyzed at baseline, 30-day and 6-month after TAVR.MR severity improved in 25%, worsened in 19% and did not change in 56% of patients 30-days post TAVR (p = 0.3). Post TAVR MR grade ≥ moderate was present in 16.1%. Predictive accuracy of post TAVR MR was low (AUC = 0.63). Median follow-up was 4.3 years (interquartile range, 2.5 to 6.1). Post TAVR MR grade ≥ moderate was associated with increased mortality and combined cardiac events (p = 0.013 and p 0.001) even when adjusted for all clinical and echo parameters and when analyzed with propensity score matching. In patients with MR ≥ moderate, LV filling pressure and RV hemodynamics worsened 6 months post TAVR, while improving in patients with less significant post procedural MR.Post procedural, but not pre-procedural MR grade ≥ moderate was independently associated with mortality and adverse cardiac events after TAVR. Significant MR post TAVR resulted in adverse LV and RV remodeling and poor hemodynamic. Our study strengthens the rational for initiating early treatment to reduce post TAVR MR.

Advanced heart failure (HF) patients usually poorly tolerate guideline-directed HF medical therapy (GDMT) and suffer high rates of morbidity and mortality. The use of continuous inotropes in the outpatient settings is hampered by previous data showing excess morbidity. We aimed to assess the safety and efficacy of repetitive, intermittent, short-term intravenous milrinone therapy in advanced HF patients with an intention to introduce and up-titrate GDMT and improve functional class.Repetitive, intermittent milrinone therapy may assist with the stabilization of advanced HF patients.Advanced HF patients treated with beta-blockers and implanted with defibrillators were initiated with repetitive, intermittent short-term intravenous milrinone therapy at our HF outpatient unit. Patients were prospectively followed with defibrillator interrogation, functional class assessment, B-natriuretic peptide (BNP) levels, and echocardiography parameters.The cohort included 24 patients with a mean 330 ± 240 days of milrinone therapy exposure. Mean age was 73 ± 6 years with male predominance (96%). Following milrinone therapy, median BNP levels decreased significantly (882 [286-3768] to 631 [278-1378] pg/ml, p = .017) with a significant reduction in the number of patients with New York Heart Association (NYHA) Class III and IV (p = .012, 0.013) and an increase in number of patients on GDMT. Importantly, the number of total sustained ventricular tachycardia events and HF hospitalizations did not change.In this small cohort of advanced HF, repetitive, intermittent, short-term milrinone therapy was found to be safe and potentially efficacious.

Importance In the last decade, immune checkpoint inhibitors (ICIs) have been approved for the treatment of many cancer types. Immune checkpoint inhibitor–associated myocarditis has emerged as a significant and potentially fatal adverse effect. Recognizing, diagnosing, and treating ICI-associated myocarditis poses new challenges for the practicing clinician. Here, the current literature on ICI-associated myocarditis is reviewed. Observations Clinical presentation and cardiac pathological findings are highly variable in patients with ICI-associated myocarditis. Although endomyocardial biopsy is the criterion standard diagnostic test, a combination of clinical suspicion, cardiac biomarkers (specifically troponin), and cardiac imaging, in addition to biopsy, is often needed to support the diagnosis. Importantly, the combination of a cytotoxic T-lymphocyte–associated protein 4 inhibitor with a programmed cell death protein 1 or programmed death-ligand 1 inhibitor increases the risk of developing ICI-associated myocarditis. Conclusion and Relevance This review aims to provide a standardized diagnostic and therapeutic approach for patients with suspected ICI-associated myocarditis. A complete history of recent cancer treatments and physical examination in combination with cardiac biomarkers, cardiac imaging, and endomyocardial biopsy represent a pragmatic diagnostic approach for most cases of ICI-associated myocarditis. The addition of novel biomarkers or imaging modalities is an area of active research and should be evaluated in larger cohorts.

Myocardial perfusion defect, assessed with single photon emission computed tomography (SPECT), is useful for patient management and risk stratification. Left ventricle Global Longitudinal Strain (LV GLS) has gained interest for observing subclinical LV dysfunction. We aimed to investigate the utility of LV GLS in evaluating myocardial perfusion defect. A retrospective study of all patients who underwent SPECT and LV GLS at Tel Aviv Sourasky medical center. Overall, 86 patients were included. LV GLS and SPECT correlated in the base and apex sections for infraction, and in the apex only for ischemia. Adjusted analysis showed a significant correlation between LV GLS of both the mid and apical section and infarction by SPECT, but no association with ischemia. No associations were found by arterial supply territory. A sub-analysis of patients without left bundle branch block (LBBB) strengthened the correlations, with a 58-70% higher chance of both fixed and reversible defects for every 1-unit decrease LV GLS in the mid and apical sections. LV GLS effectively evaluated the presence of infarction by SPECT in the mid and apical sections, particularly in patients without LBBB. Due to its high availability, LV GLS may have a role in evaluating myocardial perfusion defect.

Background Small scale cohorts demonstrated an association between body mass index (BMI) and diastolic function in a metabolically healthy population. We aimed to characterize the relation between BMI and diastolic function in a relatively large cohort of metabolically healthy obese with preserved ejection fraction. Methods and results Echocardiograms of metabolically healthy patients between 2011 and 2016, who had no significant valvulopathies or atrial fibrillation, and had preserved ejection fraction, were retrospectively identified and analyzed. Metabolically healthy was defined as lack of known diabetes mellitus, hypertension, and hyperlipidemia. Patients were categorized into 4 groups according to BMI - normal BMI 18.5‐25, overweight 25.01‐30, obese 30.01‐35, morbidly obese >35 kg/m2. The cohort consisted of 7057 individuals, 54.9% males, with a mean age 54 years. Patients in higher BMI groups more commonly demonstrated abnormalities in most echocardiographic parameters associated with diastolic dysfunction, including left atrial volume index>34 ml/m2, E/e′>14, e' lateral 2.8 m/s and systolic pulmonary artery pressure≥36 mmHg (p Conclusion High BMI is associated with increased risk of diastolic dysfunction even in metabolically healthy patients. Additional trials are needed in order to evaluate whether these echocardiographic findings translate into clinical implications.

Studies performed in controlled laboratory conditions have shown that environmental thermal application may induce various circulatory changes. We aimed to demonstrate the effect of local climate on hemodynamics according to echocardiography. Echocardiographic studies conducted in ambulatory patients, 18 yr of age or older, between January 2012 and July 2016, at our medical center, for whom climate data on the day of the echocardiogram study were available, were retrospectively included in case climate data. Discomfort index, apparent temperature, temperature-humidity index, and thermal index were computed. Echocardiograms conducted in hotter months (June–November) were compared with those done in colder months (December–May). The cohort consisted of 11,348 individuals, 46.2% women, and mean age of 57.9 ± 18.1 yr. Climate indexes correlated directly with stroke volume ( r = 0.039) and e′ (lateral r = 0.047; septal r = 0.038), and inversely with systolic pulmonary artery pressure (SPAP; r = −0.038) (all P values < 0.05). After adjustment for age and sex, echocardiograms conducted during June–November had a lower chance to show e′ septal < 7 cm/s (odds ratio 0.88, 95% confidence interval 0.78–0.98, P = 0.017) and SPAP > 40 mmHg (odds ratio 0.81, 95% confidence interval 0.67–0.99, P = 0.04) compared with those conducted in other months. The authors concluded that climate may affect hemodynamics, according to echocardiographic assessment in ambulatory patients. NEW & NOTEWORTHY In the present study, we examined 11,348 individuals who underwent ambulatory echocardiography. Analyses of the echocardiographic studies demonstrated that environmental thermal stress, i.e., climate, may affect hemodynamics. Most notably were the effects on diastolic function. Higher values of mitral e′, stroke volume, as well as ejection fraction, and lower values of systolic pulmonary artery pressure and tricuspid regurgitation were demonstrated on hotter days and seasons.

Background Routine, short-term use of inotropic agents is still applied in advanced heart failure (HF) patients either as a bridge to definitive treatment or as a mean to improve quality of life, despite the paucity of scientific evidence. Intermittent levosimendan was shown to be efficacious compared to placebo in advanced HF patients, however no prospective data comparing it to other inotropes and in particular, to milrinone are available. We aimed to assess the clinical effects of intermittent levosimendan in a small group of milrinone-treated advanced HF patients. Methods This was a prospective, un-blinded study. Consecutive ambulatory advanced HF patients intermittently treated with ≥ 4 cycles of once-weekly 6-hours 0.25–0.5 mg/kg/min milrinone at our HF outpatient clinic, were switched to levosimendan. All patients were evaluated using B-natriuretic peptide (BNP) levels, echocardiography, cardio-pulmonary exercise test and HF questionnaire before and after 4 weeks of intermittent once-weekly 6-hours therapy with levosimendan 0.1–0.2 mcg/kg/min. Results The cohort included 11 patients, 10 men, mean age 76±12 years. After 4 weeks of levosimendan therapy, Vo2 max improved by a mean of 2.28 ml/kg [95% CI -0.22-3.38, p = 0.05], BNP levels decreased from a median of 1015 ng/l [261–1035] to 719 ng/l [294–739], (p

Background Increased survival among active cancer patients exposes a wide range of side effects, including cardiotoxicity, manifested by systolic dysfunction and associated with morbidity and mortality. Early diagnosis of subclinical function changes and cardiac damage is essential in the management of these patients. Diastolic dysfunction is considered common among cancer patients; however, its effect on systolic dysfunction or mortality is still unknown. Methods Data were collected as part of the Israel Cardio-Oncology Registry, enrolling and prospectively following all patients evaluated in the cardio-oncology clinic in the Tel Aviv Sourasky Medical Center. All patients underwent echocardiographic examinations including evaluation of diastolic parameters and global longitudinal strain (GLS). Systolic dysfunction was defined as either an absolute reduction >10% in left ventricular ejection fraction to a value below 53% or GLS relative reduction >10% between the 1st and 3rd echocardiography examinations. Results Overall, 190 active cancer patients were included, with a mean age of 58 ± 15 years and a female predominance (78%). During a median follow-up of 243 days (interquartile ranges [IQR]: 164-401 days), 62 (33%) patients developed systolic dysfunction. Over a median follow-up of 789 days (IQR: 521-968 days), 29 (15%) patients died. There were no significant differences in baseline cardiac risk factors between the groups. Using multivariate analysis, E/e' lateral and e' lateral emerged as significantly associated with systolic dysfunction development and all-cause mortality (P = .015). Conclusion Among active cancer patients, evaluation of diastolic function may provide an early marker for the development of systolic dysfunction, as well as all-cause mortality.

Contains fulltext : 231547.pdf (Publisher’s version ) (Open Access) With the improvement in survival rate, cardiotoxicity has emerged as a significant adverse effect of cancer therapy. Early diagnosis of subclinical cardiac injury may allow the initiation of cardioprotective therapy and preventing the interruption of optimal cancer therapy and the development of irreversible cardiac dysfunction. In this article, we review the role of two-dimensional speckle tracking echocardiography (2D-STE), beyond the common left ventricle global longitudinal strain in the diagnosis of early subclinical cardiac injury in patients treated with cancer therapies.

The widespread use of immune checkpoint inhibitors (ICI) has become a mainstay of care for a variety of malignancies. However, these therapies portend a range of adverse effects, including a potentially fatal form of cardiotoxicity which to date has not been elucidated. We aimed to evaluate the baseline characteristics of ICI-mediated cardiotoxicity. We performed a retrospective study evaluating patients treated with ICI who performed at least 2 echocardiography examinations, before and after the initiation of ICI. Cardiotoxicity was defined as Cancer Therapeutics-related Cardiac Dysfunction (CTRCD) development, with an absolute left ventricular ejection fraction reduction of >10%, to a value

Progress in the treatment of breast cancer has led to substantial improvement in survival, but at the cost of increased side effects, with cardiotoxicity being the most significant one. The commonly used definition is cancer therapeutics-related cardiac dysfunction (CTRCD), defined as a left ventricular ejection fraction reduction of10%, to a value below 53%. Recent studies have implied that the incidence of CTRCD among patients with breast cancer is decreasing due to lower doses of anthracyclines and low association to trastuzumab and pertuzumab treatment.To evaluate the prevalence of CTRCD among patients with active breast cancer and to identify significant associates for its development.Data were collected as part of the Israel Cardio-Oncology Registry, which enrolls all patients who are evaluated at the cardio-oncology clinic at our institution. Patients were divided to two groups: CTRCD and no-CTRCD.Among 103 consecutive patients, five (5%) developed CTRCD. There were no significant differences in the baseline cardiac risk factors between the groups. Significant correlations of CTRCD included treatment with trastuzumab (P = 0.001) or pertuzumab (P0.001), lower baseline global longitudinal strain (GLS) (P = 0.016), increased left ventricular end systolic diameter (P0.001), and lower e' septal (P0.001).CTRCD is an important concern among patients with active breast cancer, regardless of baseline risk factors, and is associated with trastuzumab and pertuzumab treatment. Early GLS evaluation may contribute to risk stratification and allow deployment of cardioprotective treatment.

Introduction: Immune checkpoint inhibitor (ICI)-myocarditis is a new syndrome with estimated 50% mortality. Similar to acute cellular rejection (ACR), it is pathologically characterized by lymphocytic infiltration. We aimed to characterize the electrocardiograph features of ICI-myocarditis, compare them to ACR, and evaluate their association with adverse outcome. Methods: Presenting ECG of 130 cases of ICI-myocarditis were collected from a multicenter network spanning 12 countries and compared to 50 cases of ACR. ECG were quantified and interpreted by two blinded cardiologists. 53 patients with ICI-myocarditis had baseline ECG available for comparison via paired univariate analysis. Cox models correcting for age and sex determined association with a composite outcome of life-threatening arrhythmia or myocarditis-related death. Results: ICI-myocarditis patients had average age of 68(58-76), were 61.2% male, and 64.8% had prior cardiovascular disease. QRS prolongation (26% vs 13%, p=0.008), conduction disorders (67% vs 44%, p=0.007) such as left bundle branch block (LBBB) (18% vs 4% p=0.008), ST/T wave changes (50% vs 24%, p=0.004), and PVCs (16% vs 6%, p=0.020) were more prevalent on presenting ECG compared to baseline. ICI-myocarditis showed more PVCs (16% vs 2%, p=0.011) and less ST/T wave changes (41% vs 66%, p=0.002) when compared to ACR. On multivariate analysis, the combined outcome of life-threatening arrhythmia or myocarditis-related death was associated with pathological Q waves (HR=3.60 (1.78-7.27) p Conclusions: ICI-myocarditis manifests as new conduction delays, ST/T-wave changes, and PVCs. QRS prolongation, LBBB, pathological Q waves, and supraventricular arrhythmias were associated with subsequent adverse outcomes.

Cardiotoxicity has become a significant adverse effect of cancer therapy, with Anthracyclines (ANT) in particular. There is a crucial need for new imaging techniques for the early subclinical detection of cardiotoxic effect. We aimed to evaluate left atrial strain (LAS) changes during ANT therapy and to assess the correlation between LAS and the routine echocardiographic diastolic parameters.Data were prospectively collected as part of the Israel Cardio-Oncology Registry (ICOR). All female patients with breast cancer, planned for ANT therapy were included. All patients underwent serial echocardiography exams including baseline LAS (before chemotherapy, T1) and shortly after the completion of ANT therapy (T3). LAS was assessed in 3 phases: Reservoir (LASr), Conduit (LASc) and Pump (LASp). Significant reduction in LASr was determined by either a relative reduction of10% or an absolute value of35%. From September 2016 to June 2019, 40 patients were evaluated with a mean Doxorubicin (type of ANT) dose of 237±13.24mg/m2. At T3, significant reduction in LASr was observed among 50% of the patients with a mean LASr reduction from 40.15 ± 6.83% to 36.04 ± 7.73% (p0.001). LASc showed significant reduction as well (p0.004) as opposed to LASp (p=0.076). Both LASr and LASc showed significant correlation to the routine diastolic parameters.LASr and LASc reduction are frequent and occur early in the course of ANT therapy, showing significant correlation to the routine echocardiographic diastolic parameters, which may imply a role in the detection of early cardiotoxicity.

Objective Subclinical myocardial dysfunction has been reported to occur early in systemic lupus erythematous (SLE). The study aim was to search for biomarkers of subclinical myocardial dysfunction which may correlate with disease activity in SLE patients. Methods This is a prospective, controlled, cross-sectional study of 57 consecutive patients with SLE and 18 controls. Serum samples were obtained to determine serum soluble ST2 (sST2), CXCL-10 and high-sensitivity troponin (hs-troponin) levels. All participants underwent an echocardiographic tissue Doppler study. Results sST2, CXCL-10 and hs-troponin levels were higher in patients with higher SLE disease activity (SLEDAI). sST2 and CXCL-10 levels were higher in patients with more disease damage as measured by the SLE damage index. Measures of diastolic dysfunction, as assessed by echocardiographic tissue Doppler negatively correlated with log CXCL-10: including E/A; E/e′lateral and E/e′septal, while E/e′ positively correlated with CXCL-10. Diastolic dysfunction parameters also correlated with log sST2 levels, a negative correlation was seen with E/e′lateral and a positive correlation was seen with E/e′. Systolic dysfunction parameters positively correlated with hs-troponin: LVED, LVES, IVS, LVMASS and LVMASS index. In a multivariate analysis, sST2 and CXCL-10 were found to be significantly different in SLE vs. healthy controls, independent of each other and independent of cardiovascular risk factors. Conclusions Soluble ST2 and CXCL-10 are markers of disease activity and accrued damage in SLE and may serve as sensitive biomarkers for detection of subclinical diastolic dysfunction, independent of traditional cardiovascular risk factors.

Diastolic dysfunction is a common finding in patients receiving cancer therapy. This study evaluated the correlation of diastolic strain slope (Dss) with routine echocardiography diastolic parameters and its role in early detection of systolic dysfunction and cardiovascular (CV) mortality within this population.Data were collected from the Israel Cardio-Oncology Registry (ICOR), a prospective registry enrolling adult patient receiving cancer therapy. All patients performed at least three echocardiography exams (T1, T2, T3), including left ventricle Global Longitudinal Strain (LV GLS) and Dss. Systolic dysfunction was determined by either LV GLS relative reduction of ≥ 15% or LV ejection fraction reduction 10% to 53%. Dss was assessed as the early lengthening rate, measured by the diastolic slope (delta%/sec).Among 144 patients, 114 (79.2%) were female with a mean age of 57.31 ± 14.3 years. Dss was significantly correlated with e' average. Mid segment Dss change between T1 and T2 showed significant association to systolic dysfunction development (Odds Ratio (OR) = 1.04 [1.01,1.06]. p = 0.036). In multivariate prediction, Dss increase was a significant predictor for the development of systolic dysfunction (OR = 1.06 [1.03,1.1], P 0.001).An 8% increase in Dss between T1 and T2 was associated with a trend in increased CV mortality (HR = 3.4 [0.77,15.4], p = 0.085).This study is the first to use the novel measurement of Dss in patients treated with cancer therapies and to show significant correlation between routine diastolic dysfunction parameters and Dss. Changes in the mid segment were found to have significant independent early predictive value for systolic dysfunction development in univariate and multivariate analyses.

Item does not contain fulltext BACKGROUND: Current methods do not allow a thorough assessment of causes associated with limited exercise capacity in patients with chronic obstructive pulmonary disease (COPD). METHODS: Twenty patients with COPD and 20 matched control subjects were assessed using combined cardiopulmonary and stress echocardiographic testing. Various echocardiographic parameters (left ventricular [LV] volumes, right ventricular [RV] area, ejection fraction, stroke volume, S', and E/e' ratio) and ventilatory parameters (peak oxygen consumption [Vo(2)] and A-Vo(2) difference) were measured to evaluate LV and RV function, hemodynamics, and peripheral oxygen extraction (A-VO(2) difference). RESULTS: Significant differences (both between groups and for group-by-time interaction) were seen in exercise responses (LV volume, RV area, LV volume/RV area ratio, S', E/e' ratio, tricuspid regurgitation grade, heart rate, stroke volume, and Vo(2)). The major mechanisms of reduced exercise tolerance in patients with COPD were bowing of the septum to the left in 12 (60%), abnormal increases in E/e' ratio in 12 (60%), abnormal stroke volume reserve in 16 (80%), low peak A-Vo(2) difference in 10 (50%), chronotropic incompetence in 13 (65%), or a combination of several mechanisms. Patients with COPD and poor exercise tolerance showed attenuated increases in stroke volume, heart rate, and A-Vo(2) difference and exaggerated changes in LV/RV ratio and LV compliance (ratio of LV volume to E/e' ratio) compared with patients with COPD with good exercise tolerance. CONCLUSIONS: Combined cardiopulmonary and stress echocardiographic testing can be helpful in determining individual mechanisms of exercise intolerance in patients with COPD. In patients with COPD, exercise intolerance is predominantly the result of chronotropic incompetence, limited stroke volume reserve, exercise-induced elevation in left filling pressure, and peripheral factors and not simply obstructive lung function. Limited stroke volume is related to abnormal RV contractile reserve and reduced LV compliance introduced through septal flattening and direct ventricular interaction.

This study applies L-wave measurements of mid-diastolic trans-mitral flow. Although considered to be a marker of elevated filling pressure or delayed myocardial relaxation, its clinical and prognostic value is yet to be completely elucidated. It has been shown that transcatheter aortic valve replacement (TAVR) induces reverse remodeling and improves diastolic function and prognosis in patients with severe aortic stenosis (AS). Our purpose was to evaluate the prognostic value of L-wave following TAVR. We examined clinical and echocardiographic data of patients undergoing TAVR. L-Wave presence and velocity were recorded at baseline and at 1 month and 6 months following TAVR. The effect of the procedure on L-wave measurements and its impact on mortality and other clinical outcomes were analyzed. A total of 502 patients (mean age 82.58 ± 5.9) undergoing TAVR were included. Patients with baseline L-wave (n = 68, 12%) had a smaller stroke volume index by 5.7 ± 2.3 ml/m2 (p = 0.01) as compared to patients without L-wave at baseline. L-waves disappeared In 35% and 70% of patients at 1 month and at 6 months respectively. Baseline L-wave velocity was 34.8 ± 11.5 (cm/s) and decreased significantly at follow-up examinations. Patients with persistent L-wave following TAVR had higher 3-year adjusted mortality rates (HR 5.7, 95% CI 3.7–8.9, p

Immune checkpoint inhibitors (ICI) have transformed the standard care of cancer treatment. Recent case reports describe ICI-mediated myocarditis with an atypical presentation and fatal potential which lead to permanent interruption of immunotherapy.To characterize ICI-mediated myocarditis and re-introduction to immunotherapy.During 2019, 849 patients were treated with ICI at Tel Aviv Sourasky Medical Center for the diagnosis of lung adenocarcinoma, gastric adenocarcinoma, urothelial carcinoma, and hepatocellular carcinoma. Overall, seven (0.8%) patients were diagnosed with ICI-mediated myocarditis, according to the European Society of Cardiology guidelines of myocarditis 2013. We retrospectively evaluated their presentation, severity, and clinical outcomes.Among the seven patients, only one had a history of cardiac disease. The majority were diagnosed with lung adenocarcinoma and treated with anti-programmed death-1 antibody. All patients were treated with single-agent ICI. Most patients presented with cardiac symptoms, elevated troponin and typical cardiac magnetic resonance; however, only three had reduced ejection fraction. Overall, three patients were chosen for re-introduction with concomitant low dose steroids and weekly troponin follow-up. Two patients diagnosed with grade I and II renewed therapy successfully with no recurrence of symptoms and improvement in disease burden. The one patient diagnosed with grade III developed worsening of cardiac symptoms after the 1st cycle and, therefore, therapy was interrupted permanently.ICI-mediated myocarditis is potentially fatal and leads to permanent interruption of life-saving cancer therapy. The current data suggest that re-introduction may be considered in low-grade patients; however, a better definition of the diagnosis and grading is needed.

Background Chemotherapy induced cardio-toxicity has been recognized as a serious side effect since the first introduction to anthracyclines (ANT). Cardio-toxicity among patients with breast cancer is well studied but the impact on patients with sarcoma is limited, even though they are exposed to higher ANT doses. The commonly used term for cardio-toxicity is cancer therapeutics related cardiac dysfunction (CTRCD), defined as a left ventricular ejection fraction (LVEF) reduction of > 10%, to a value below 53%. The aim of our study was to estimate the prevalence of CTRCD in patients diagnosed with sarcoma and to describe the baseline risk factors and echocardiography parameters among that population. Methods Data were collected as part of the Israel Cardio-Oncology Registry (ICOR), enrolling all patients evaluated in the cardio-oncology clinic at our institution. The registry was approved by the local ethics committee and is registered in clinicaltrials.gov (Identifier: NCT02818517). All sarcoma patients were enrolled and divided into two groups - CTRCD group vs. non-CTRCD group. Results Among 43 consecutive patients, 6 (14%) developed CTRCD. Baseline cardiac risk factors were more frequent among the non-CTRCD group. Elevated left ventricular end systolic diameter and reduced Global Longitudinal Strain were observed among the CTRCD group. During follow-up, 2 (33%) patients died in the CTRCD group vs. 3 (8.1%) patients in the non-CTRCD group. Conclusions CTRCD is an important concern among patients with sarcoma, regardless of baseline risk factors. Echocardiography parameters may provide an early diagnosis of cardio-toxicity.