Decrease In Left Ventricular Ejection Fraction Research Articles

Abstract P5-14-18: Cardioprotective therapy in breast cancer patients with subclinical and clinical cardiotoxicty

Abstract Background: Modern breast cancer (BC) therapies have led to significant improvement in disease free and overall survival, but are associated with off target toxicity including cardiotoxicity. Current cardio-protective strategies have included all patients (pts) receiving potential cardiotoxic cancer therapy with modest clinic benefit. In this pilot study, we examined the role of cardioprotective therapy (CPT) in BC pts identified as having subclinical or clinical cardiotoxicity. Methods: Early BC patients (pts) in the PREFECT Study (NCT03543228) were serially examined for cardiac function up to 1-year after initiation of chemotherapy (CT) using cardiac magnetic resonance (CMR) imaging. CT included epirubucin and cyclophosphamide every 2 weeks x 4 followed by paclitaxel (weekly x 12 or every 2 weeks x 4) and targeted therapy (e.g trastuzumab) if human epidermal growth factor receptor 2 (HER2) positive. Myocardial strain was quantified using fast-strain encoded (fast-SENC) across 37 left and 11 right ventricular segments. The percent of segments with normal strain (≤17%) was calculated (% normal MyoStrain). Clinical cardiotoxicity (CTx) was defined as an absolute change in left ventricular ejection fraction (LVEF) > 10 % to below 53 %; subclinical CTx was defined as an asymptomatic decrease in LVEF of 15 % or worsening global longitudinal strain (GLS) > 15 %, or abnormal cardiac biomarkers (troponin, brain natriuretic peptide (BNP), N terminal-BNP). Descriptive statistics were used to summarize subject demographics, medical history, cardiovascular measures, and response to CPT. Response to CPT was defined as restoration of cardiac function, wall motion, absence of cardiac symptoms, and normalization of cardiac biomarkers. Results: A total of 40 BC pts age 50 (+/- 12.5) years and body mass index of 25.4 (+/- 5.8 kg/m2) were enrolled and followed for 273 +/- 126 days. Clinical CTx was observed in 4 (10 %) patients and subclinical CTx in 15 (37.5%). Pts with clinical CTx were older, had a higher Charlson co-morbidity index, and had significantly reduced cardiac function (49.5% +/- 9.5% normal MyoStrain) despite normal CMR LVEF (54.2% +/- 4.0%). Pts with subclinical CTx had a smaller decline in cardiac function (58.6% +/- 9.1% normal MyoStrain) despite normal CMR LVEF (56.4% +/- 4.9%). 12/19 pts with CTx showed improvement with CPT (candesartan -9, ramipril -2, lisinopril -1, and beta-blockers (BB): yes -8, no -4); 1 did not improve, 4 did not receive CPT and 2 remained on ineffective anti-hypertensive medication. Pts at baseline, without CTx, or showing improvement based on CPT, had significantly higher % normal MyoStrain (79.0% +/- 11.8%, 79.5% +/- 9.3%, and 80.4% +/- 9.8% respectively) and normal CMR LVEF (59.7% +/- 4.2%, 59.9% +/- 4.9%, and 60.7% +/- 5.1% respectively). Discussion: Identifying BC pts at high risk of experiencing cancer therapy related cardiotoxicity enables a more tailored approach to cardio-preventative strategies. In this pilot study the majority (12/19) of BC pts identified with subclinical or clinical CTx demonstrated improvement in cardiac function with CPT. Proactive tailored cardio-protection may also prevent long term permanent cardiac dysfunction and associated heart failure. Larger, multi-center trials are warranted to evaluate the short and long term benefits of CPT in this pt population. Citation Format: Susan Faye Dent, Henning Steen, Moritz Montenbruck, Sebastian Esch, Pia Wulfing, Kyle Janson, Daniel Lenihan. Cardioprotective therapy in breast cancer patients with subclinical and clinical cardiotoxicty [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-14-18.

Abstract P1-18-11: Cardiac events in patients with HER2-positive metastatic breast cancer who have low left ventricular ejection fraction prior to initiating treatment with ado-trastuzumab emtansine: A retrospective cohort study using electronic health record data

Abstract Background Cardiac events, including left ventricular ejection fraction (LVEF) decrease and congestive heart failure (CHF), are known risks with HER2-targeted antibody-based therapies. Patients with an LVEF of <50% are typically excluded from clinical trials, including ado-trastuzumab emtansine (T-DM1; Kadcyla®) trials; therefore, this study describes patients with an LVEF of 40-49% prior to initiation of treatment with T-DM1 and evaluates the risk of cardiac events. Methods Patients with HER2-positive metastatic breast cancer treated between Jan 1, 2013 and May 31, 2018 were included from the de-identified US-based Flatiron Health electronic health record-derived database. Patients initiating T-DM1 and with a recent LVEF value of 40-49% up to 60 days prior to treatment were included. Patient baseline characteristics (including cardiac history) were described, and the risk of an LVEF drop of >10% points, CHF, and other cardiac events during treatment, and the 84 days following treatment discontinuation, were examined. Results Of approximately 2000 patients with metastatic breast cancer initiating T-DM1 in the database, 32 (1.6%) had an LVEF measurement of 40-49% at baseline (as defined above). These patients had a median age of 64.5 years, median body mass index of 26.1 kg/m2, and 65.6% were white. Median T-DM1 treatment duration was 4.6 months. Cardiac history included prior breast cancer treatment discontinuation due to cardiotoxicity (62.5%), CHF signs and symptoms (34.4%), CHF (28.1%), and prior cardiac hospitalization (18.8%). LVEF monitoring was conducted during treatment for 81.0% of patients who had >2 months of T-DM1 treatment. An LVEF drop of >10% points occurred in four patients (12.5%); CHF events, in five patients (15.6%). Incidence rates were 34.4 and 8.5 per 100 person-years, respectively. These nine events occurred in seven patients, six of whom had relevant cardiac history events recorded in their electronic health record at baseline. CHF signs and symptoms were reported in nine patients (28.1%; 50.5 per 100 person-years) and cardiac tachyarrhythmia in one patient (3.1%; 5.1 per 100 person-years). In a sensitivity analysis that comprised 35 additional patients (N=67) with an LVEF of 40-50% (including overlapping LVEF ranges), the following additional events were recorded: CHF (1); cardiac tachyarrhythmia (1), and CHF signs and symptoms (6). Conclusion A small proportion of patients initiate T-DM1 with low LVEF. The risk of cardiac events observed appears to be consistent with the population profile presenting a cardiac history. The decision for physicians to prescribe T-DM1 in patients with low LVEF should be made in the context of the benefit-risk consideration for cardiac events and the availability of alternative treatment. Citation Format: Thibaut Sanglier, Jinjoo Shim, Harry Liu, Chunyan Song, Melanie Smitt, Evelyn M Flahavan. Cardiac events in patients with HER2-positive metastatic breast cancer who have low left ventricular ejection fraction prior to initiating treatment with ado-trastuzumab emtansine: A retrospective cohort study using electronic health record data [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-18-11.

Anthracycline-induced cardiotoxicity prevention with angiotensin-converting enzyme inhibitor ramipril in women with low-risk breast cancer: results of a prospective randomized study.

Anthracycline‑induced cardiotoxicity (AIC) remains the main long‑term irreversible side effect in malignancy survivors. Cardiotoxicity prevention is one of the most reasonable approaches. In this prospective randomized open‑label study, we aimed to verify whether ramipril protects from early‑onset AIC in women with breast cancer (BC). We analyzed data from 96 women (median age, 47 years) with BC after breast surgery, without significant cardiovascular diseases, who were eligible for adjuvant anthracyclines. They were randomized to a ramipril or control arm. Cardiotoxicity was estimated with repeat echocardiography and themeasurement of troponin I and N‑terminal fragment of the prohormone brain natriuretic peptide (NT‑proBNP) levels over 1‑year follow‑up. Anthracycline‑induced cardiotoxicity was defined as a decrease in left ventricular ejection fraction (LVEF), elevated biomarker levels, and/or occurrence of heart failure (HF) or cardiac death. A decrease in LVEF above 10‑percent points occurred in 6.3% of ramipril patients and 18.5% ofcontrols (P = 0.15). No cases of HF, cardiac death, or LVEF decline below 50% were reported. The percentage of patients with elevated NT‑proBNP levels increased with time in controls (P = 0.003) and remained unchanged in the ramipril arm. At the end of follow‑up, an increase in NT‑proBNP levels was more common and decline was less common in the control than ramipril arm (P = 0.01). No significant differences in troponin levels were found between the study arms. Ramipril was well tolerated in normotensive women. In relatively young women with BC without serious comorbidities, who received anthracyclines, 1‑year treatment with ramipril exerts potentially protective effects on cardiotoxicity assessed with NT‑proBNP levels.

Long-term Cardiopulmonary Consequences of Treatment-Induced Cardiotoxicity in Survivors of ERBB2-Positive Breast Cancer

Trastuzumab improves outcomes in patients with ERBB2-positive (formerly HER2) breast cancer but is associated with treatment-induced cardiotoxicity, most commonly manifest by an asymptomatic decline in left ventricular ejection fraction (LVEF). Little is known to date regarding the long-term effects of treatment-induced cardiotoxicity on cardiopulmonary function in patients who survive trastuzumab-treated breast cancer. To determine whether treatment-induced cardiotoxicity recovers or is associated with long-term cardiopulmonary dysfunction in survivors of ERBB2-positive breast cancer. This cross-sectional case-control study enrolled patients with nonmetastatic ERBB2-positive breast cancer after completion of trastuzumab-based therapy (median, 7.0 [interquartile range (IQR), 6.2-8.7] years after therapy) who met 1 of 2 criteria: (1) cardiotoxicity (TOX group) developed during trastuzumab treatment (ie, asymptomatic decrease of LVEF≥10% from baseline to <55% [n = 22]) or (2) no evidence of cardiotoxicity during trastuzumab treatment (NOTOX group [n = 20]). Patients were treated at the Memorial Sloan Kettering Cancer Center. Fifteen healthy control participants (HC group) were also enrolled for comparison purposes. All groups were frequency matched by age strata (<55, 55-64, and ≥65 years). Data were collected from September 9, 2016, to August 10, 2018, and analyzed from November 20, 2018, to August 12, 2019. Speckle-tracking echocardiography and maximal cardiopulmonary exercise testing were performed to measure indices of left ventricular function (including LVEF and global longitudinal strain [GLS]) and peak oxygen consumption (peak VO2). A total of 57 participants (median age, 60.8 [IQR, 52.7-65.7] years) were included in the analysis. Overall, 38 of 42 patients with breast cancer (90%) were treated with anthracyclines before trastuzumab. Resting mean (SD) LVEF was significantly lower in the TOX group (56.9% [5.2%]) compared with the NOTOX (62.4% [4.0%]) and HC (65.3% [2.9%]) groups; similar results were found for GLS (TOX group, -17.8% [2.2%]; NOTOX group, -19.8% [2.2%]; HC group, -21.3% [1.8%]) (P < .001). Mean peak VO2 in the TOX group (22.9 [4.4] mL/kg/min) was 15% lower compared with the NOTOX group (27.0 [5.3] mL/kg/min; P = .03) and 25% lower compared with the HC group (30.5 [3.4] mL/ kg/min; P < .001). In patients with breast cancer, GLS was significantly associated with peak VO2 (β coefficient, -0.75; 95% CI, -1.32 to -0.18). Treatment-induced cardiotoxicity appears to be associated with long-term marked impairment of cardiopulmonary function and may contribute to increased risk of late-occurring cardiovascular disease in survivors of ERBB2-positive breast cancer.

Chronic Sleep Fragmentation Mimicking Sleep Apnea Does Not Worsen Left-Ventricular Function in Healthy and Heart Failure Mice.

Aims: Obstructive sleep apnea (OSA) has been associated with heart failure (HF). Sleep fragmentation (SF), one of the main hallmarks of OSA, induces systemic inflammation, oxidative stress and sympathetic activation, hence potentially participating in OSA-induced cardiovascular consequences. However, whether SF per se is deleterious to heart function is unknown. The aim of this study was to non-invasively evaluate the effect of SF mimicking OSA on heart function in healthy mice and in mice with HF.Methods and Results: Forty C57BL/6J male mice were randomized into 4 groups: control sleep (C), sleep fragmentation (SF), isoproterenol-induced heart failure (HF), and mice subjected to both SF+HF. Echocardiography was performed at baseline and after 30 days to evaluate left ventricular end-diastolic (LVEDD) and end-systolic (LVESD) diameters, left ventricular ejection fraction (LVEF) and fraction shortening (FS). The effects of SF and HF on these parameters were assessed by two-way ANOVA. Mice with isoproterenol-induced HF had significant increases in LVEDD and LVESD, as well as a decreases in LVEF and FS (p = 0.013, p = 0.006, p = 0.027, and p = 0.047, respectively). However, no significant effects emerged with SF (p = 0.480, p = 0.542, p = 0.188, and p = 0.289, respectively).Conclusion: Chronic SF mimicking OSA did not induce echocardiographic changes in cardiac structure and function in both healthy and HF mice. Thus, the deleterious cardiac consequences of OSA are likely induced by other perturbations associated with this prevalent condition, or result from interactions with underlying comorbidities in OSA patients.

Trastuzumab chemotherapy subclinical cardiotoxicity in patients with breast cancer: A two-dimensional speckle tracking echocardiography study

Trastuzumab chemotherapy has been associated with left ventricular (LV) dysfunction. We aimed to assess early changes in LV and right ventricular (RV) mechanics associated with trastuzumab treatment for breast cancer. As well as explore whether early changes in 2-dimensional (2D)-speckle tracking echocardiography (STE) could predict later chemotherapy-induced cardiotoxicity. Thirty-one patients with breast cancer who received Trastuzumab treatment were included. Echocardiograms were available for analysis with 2D-STE at the following time points: pretreatment (T0), 4 months (T1), and 12 months (T2). All patients had a normal pretreatment LV ejection fraction (LVEF). Cardiotoxicity was defined as a decrease in LVEF of at least 10 percentage points from baseline on follow-up echocardiography. Cardiotoxicity developed in 6 of the 31 patients (19%). The mean (±SD) LVEF at T0 was 66% (± 6); at T1 60% (± 7); and at T2, 54% (± 6). Global longitudinal strain (GLS) at T1 was the strongest indicator of subsequent cardiotoxicity (area under the curve, 0.85; cutoff value, −14.7; sensitivity, 91%; specificity, 82%; P = 0.003). The average 2D LV GLS was −20.58% (± 2.2) with a statistically significant decrease at T1 and T2 (LVGLS −19.35 (± 2.1) and−18.55 (± 2.3), P < 0.001 respectively). The average 2D LV radial strain was 34.71% (± 7.8) and the circumferential strain was −18.92% (± 3.9). Compared with baseline (T0), LVGLS, LV circumferential strain, and right ventricular longitudinal strain at T1 and T2 were reduced significantly in patients with cardiotoxicity ( P < 0.05). Trastuzumab treatment leads to early deterioration of LV GLS and circumferential strain. Right ventricular GLS and radial strain were also affected. Early changes in GLS are good predictors of subsequent development of trastuzumab-induced cardiotoxicity.

New-Onset Left bundle branch block after TAVI has a deleterious impact on left ventricular systolic function

Transcatheter aortic valve implantation (TAVI) has revolutionized the management of severe aortic stenosis. The development of new-onset complete left bundle branch block (LBBB) is, however, a frequent complication. The objective of the present study was to assess the impact of new-onset LBBB after TAVI on the evolution of left ventricular ejection fraction (LVEF). Forty consecutive patients were included following the development of new-onset LBBB after TAVI implantation and were matched for age and LVEF with 40 patients implanted during the same period who did not develop LBBB. The primary endpoint was evolution of the LVEF measured by echocardiography prior to implantation and between 6-12 months after TAVI. The development of a LBBB was associated with a 5-point decrease in LVEF [− 12.5–2.5], contrary to the non-LBBB group (1.5 [− 6.5–9.5], P = 0.007) at 8 months, with the persistence of the LBBB ( n = 23) exacerbating this decrease (− 7 [− 13; 2], P = 0.009). When left ventricular dysfunction (LVEF <50%) was present prior to TAVI, the appearance of LBBB was associated with a reduction in LVEF (− 2 [− 8 – 2]) contrary to the non-LBBB group (20 [9–22]), P = 0.02. The appearance of new-onset LBBB after TAVI has a pejorative impact on left ventricular systolic function, particularly in patients with an initial LVEF < 50%, due to a lack of recovery of the latter, thereby potentially affecting their prognosis.

Alpha-lipoic acid and vitamin B complex slow down the changes in mice diabetic cardiomyopathy.

Aim: The aim of our study was to assess histologically and by cardiac ultrasound the effects of alpha-lipoic acid (ALA) and vitamin B complex, as pathogenic therapies, in diabetic cardiomyopathy (DCM) in mice. Materials and Methods: We performed an experimental animal study, in which we analyzed from a structural and functional point of view the changes produced in DCM. To produce DCM, we induced diabetes mellitus (DM) in C57BL/6 mice by intraperitoneal injection of a single 150 mg/kg body weight dose of streptozotocin (STZ). We formed a sham group (animals without DM), a control group (animals with DM but without treatment, DM_Control) and a group of animals with DM that were treated with ALA and vitamin B complex (DM_Treated). Results: At six weeks after STZ administration, there was no decrease in left ventricular ejection fraction (LVEF) in the sham group, while in the control group there was a significant decrease in LVEF, about 43.75±3.37%, compared to the group that received treatment with ALA and vitamin B complex, in which LVEF decreased to 49.6±5.02% (p=0.0432). Also, the degree of interstitial myocardial fibrosis was higher in animals with DM compared to animals without DM, but the applied therapeutic protocol considerably improved the accumulation of interstitial collagen. The same observation was maintained regarding the evaluation of polysaccharide deposits. Conclusions: We can say that the administration of ALA and vitamin B complex in mice with STZ-induced DM, improves the degree of myocardial fibrosis, the accumulation of polysaccharides, and prevents severe deterioration of systolic and diastolic function of the heart.

1185 Three-dimensional speckle tracking echocardiography for the global and regional assessment of myocardial deformation in breast cancer patients submitted to anthracyclines

Abstract Introduction Serial echocardiographic assessment of 2D/3D left ventricular ejection fraction (LVEF) and 2D global longitudinal strain (GLS) is the gold standard for screening for cancer therapeutics-related cardiac dysfunction (CTRCD). Although 3D speckle tracking echocardiography (STE) has several technical advantages, is more reproducible, and has a better correlation to magnetic resonance than 2D STE, it is still not currently used in this setting. We aimed to investigate the usefulness of 3D STE in evaluating left ventricle mechanics and its relation to CTRCD. Methods Prospective study of female breast cancer patients submitted to anthracycline chemotherapy who underwent one transthoracic echocardiography (ETT) before and at least one ETT during/after chemotherapy. Standard ETT parameters and 3D volumetric measurements were assessed. STE was used to estimate 2D GLS – average and 18 segments – and 3D GLS, global circumferential strain (GCS), global radial strain (GRS) and global area strain (GAS) – average and 17 segments. CTRCD was defined as an absolute decrease in 2D or 3D LVEF &amp;gt;10% to a value &amp;lt;54% or a relative decrease in 2D GLS &amp;gt;15%. Results 105 patients (mean age 53.8 ± 12.5 years, 52.4% immunotherapy, 77.2% radiotherapy, 2.8 echocardiograms/patient) were included. During a mean follow-up of 12.1 months, 24 patients (22.9%) developed CTRCD. During anthracycline therapy, there was a significant worsening of 2D LVEF (65.6 vs. 57.8), 3D LVEF (61.5 vs. 54.4), 2D GLS (-21.1 vs. -18.0), 3D GLS (-15.6 vs. -10.9), 3D GCS (-14.0 vs. -11.0), 3D GRS (42.0 vs. 28.5) and 3D GAS (-27.0 vs. -20.0) [all p &amp;lt;0.001]. More than 73% of patients presented 3D global strain values below the limits of normal during chemotherapy. On 3D strain regional analysis, impaired contractility was observed in the anterior, inferior and septal walls. Logistic regression analysis showed that 3D GRS and 3D GCS were associated with a higher incidence of CTRCD. In the multivariate model, 3D GRS remained the only independent predictor of CTRCD. The receiver operating curve analysis showed a good calibration and discrimination of 3D GCS and 3D GRS in predicting CTRCD with areas under de curve of 0.748 and 0.719, with the optimal cut-off values being 0.342 for GCS and 0.344 for GRS. These variations were observed a median of 45 days and 22.5 days before the diagnosis of CTRCD, respectively. Conclusion 3D strain parameters worsened during anthracycline therapy, with predominant involvement of septal, anterior and inferior walls. Variations of 3D GCS and GRS were predictive of subsequent CTRCD, and thus can be considered an earlier sign of CTRCD, with added value over the currently recommended 2D/3D LVEF and 2D GLS. Routine application of this technique should be considered in order to offer targeted monitoring and timely initiation of cardioprotective treatment.

Correlation between Changes of NT-Pro BNP and HS-Troponin I Level with Cardiotoxicity in Locally Advanced Breast Cancer After Three Cycles of Neoadjuvant CAF Chemotherapy

Chemotherapy with cyclophosphamide, adriamycin, and fluorouracil (CAF) regiment in patients with locally advanced breast cancer have a risk of cardiotoxicity. Cardiotoxicity examination standards using left ventricular ejection fraction (LVEF) by echocardiography are considered insensitive for detection of subclinical ventricular dysfunction. NT-pro BNP and Hs-Troponin I (hs-TnI) as cardiac biomarkers are expected to help detect early cardiotoxicity. This study intended to analyze the correlation between changes of NT-pro BNP and hs-TnI levels with cardiotoxicity in breast cancer after three cycles of chemotherapy.This was a cross-sectional observational study, conducted at the Dr. Soetomo General Hospital Surabaya. The subjects consisted of 23 breast cancer patients who underwent chemotherapy with CAF regiment. NT-proBNP and hs-TnI examination used CLIA methods (Immulite 1000, ADVIA Centaur TnI-Ultra). Cardiotoxicity based on decreased LVEF to more than 10% of the initial LVEF value using echocardiography. Significant increases in NT pro BNP and hs-TnI levels were obtained before and after treatment (p=0.000, p=0.002). A significant decrease in LVEF was obtained before and after treatment (p=0.000), but only 2 patients (8.7%) showed cardiotoxicity. There was no correlation between changes in NT-pro BNP and hs-TnI levels with changes in LVEF before and after chemotherapy (p=0.666 and r=0.095; p=0.254 and r=-0.28). There was no correlation between changes in NT-pro BNP and hs-TnI levels with cardiotoxicity, which was assessed based on LVEF reduction, in locally advanced breast cancer after three-cycles of chemotherapy with CAF regiment.

Prognostic Implications of Left Ventricular Cardiomyopathy in Adults With Tetralogy of Fallot

BackgroundDespite the significant risk of cardiovascular mortality after tetralogy of Fallot (TOF) repair, there are limited data about left ventricular (LV) cardiomyopathy in this population, thus creating important knowledge gaps. This study aims to address some of these knowledge gaps by describing the risk and prognostic implications of LV systolic dysfunction (LVD) after TOF repair. MethodsWe performed a cohort study of adult patients after TOF repair with an echocardiographic assessment of LV ejection fraction (LVEF) to determine the association between LVD and cardiovascular events, defined as sustained ventricular tachycardia, aborted sudden death, heart transplantation, or death. Prevalent and incidence LVD were defined as LVEF < 50% at baseline or new decrease in LVEF to < 50% during follow-up, respectively. ResultsOf 574 patients (age 38 ± 13 years), the baseline LVEF was 57% ± 9% and 68 (12%) had prevalent LVD. Cardiovascular events occurred in 126 patients (22%) during 10.5 ± 6.2 years of follow-up. LVEF was an independent predictor of mortality (hazard ratio, 1.16; 95% confidence interval, 1.16-1.24; P = 0.003) per 5%-point decrease in LVEF. Among the 357 patients with preserved LVEF and echocardiographic follow-up, incident LVD occurred in 23 (6%) during 3.8 ± 1.6 years of follow-up. Event-free survival was significantly lower in patients with incident LVD compared with patients without incident LVD (87% vs 71%, P = 0.021). ConclusionPrevalent and incident LVD occurred in 12% and 6% of this cohort, respectively, and were associated with lower event-free survival. Incident LVD suggests the presence of subclinical LV cardiomyopathy, and further studies are required to determine optimal strategies for diagnosing and treating subclinical LV cardiomyopathy to improve outcomes in the population with TOF.

Effect of right ventricular pacing on left ventricular systolic function in patients with Tetralogy of Fallot

BackgroundPrevalence of pacemaker-induced cardiomyopathy (PICM) in adults with congenital heart disease is unknown. Tetralogy of Fallot (TOF) is a common diagnosis in the adult congenital heart disease population, and the purpose of this study was to determine association between frequent right ventricular (RV) pacing and temporal decrease in left ventricular ejection fraction (LVEF) from pre-implantation to 2-years post-implantation (LVEFpost-pre) in TOF patients. MethodsWe studied TOF patients that received RV leads only (N = 51) and a reference group of 7 patients with atrial pacing or biventricular pacing. We defined PICM as a ≥10% decrease in LVEF resulting in LVEF <50%. Linear regression was used to assess relationship between frequent RV pacing (≤20%, 21–40%, >40%) and LVEFpost-pre. ResultsPICM occurred in 2 (4%) of 51 patients in RV pacing group. LVEFpost-pre was +3% (95% confidence interval [CI] 0% to +5%) in the reference group and −4% (95% CI −11% to +2%) in RV pacing group. No significant difference occured in LVEFpost-pre between the reference group (LVEFpost-pre +3%) vs RV pacing ≤20% (LVEFpost-pre +1%) vs RV pacing 21–40% (LVEFpost-pre −3%) vs RV pacing >40% (LVEFpost-pre −5%), p = 0.318. There was also no association between frequent RV pacing and LVEFpost-pre, R2 = 0.307, p = 0.10. ConclusionPICM occurred in 4% of TOF patients receiving RV pacing, and there was no association between frequent RV pacing and temporal decline in LVEF. Further studies are required to determine the long-term impact of RV pacing in the TOF population, and explore optimal treatment strategies.

CPX-351 As First Intensive Therapy for Elderly Patients with AML

CPX-351 As First Intensive Therapy for Elderly Patients with AML

Role of Echocardiography and Cardiac Biomarkers in Early Detection of Hematopoietic Stem Cell Transplantation Associated Cardiotoxicity

Introduction: Cardiovascular disease is the first cause of death worldwide; in Uruguay it corresponds to 30%. Classical risk factors are: age, smoking, male gender, diabetes, hypertension, hyperuricemia and dyslipidemia. In the last decades, the increasing use of chemotherapy and radiotherapy in oncology have augmented cardiovascular side effects. The improvement in response and overall survival of hematologic patients allow a longer time to develop cardiovascular complications. Cardiotoxicity has been studied extensively in the setting of breast cancer and anthracyclines use.However, within Hematopoietic Stem Cell Transplantation (HSCT) this is still being in research. The estimated incidence is 5-10 % but the data is little and unsystematic. The primary objective of this trial is to assess subclinical myocardial damage using biomarkers and echocardiography and identify patients at high risk of developing cardiotoxicity after HSCT. Methods: This is a prospective, single center trial that started on April 2017. Population: adult patients admitted in the British Hospital Transplant Unit, Montevideo Uruguay to receive either an autologous or allogeneic HSCT. Inclusion criteria: 18 years old or older, Eastern Cooperative Oncology Group performance status 0-1. Patients who signed informed consent. Exclusion criteria: baseline left ventricular ejection fraction (LVEF) &lt;50%, systemic amyloidosis. We have performed serial measurements of cardiac biomarkers (pro-BNP, Troponin T, Troponin I and CPK) at the admission, day 1, day 14 and day 30 after HSCT. Echocardiograms at admission and at day 30 were performed by the same physicians. Biomarkers and echocardiogram were repeated at day 100 if there were alterations in normal values of biomarkers or myocardial dysfunction measured by the echocardiography in day 30. Results: Between May 2017 and April 2019 we have perform 96 HSCT, of those, all 96 consented to enter into the study. Male gender 57 (60%). Median age 56 years old (18-74). Diseases: Multiple myeloma: 42, Non Hodgkin Lymphoma 27, Hodgkin Lymphoma 12, Acute Myeloid Leukemia 11, Solid tumors 2, Aplasia 1, Renal Amyloidosis 1. Type of transplant: Autologous were 85 and Related Allogenic 11 patients. 82 patients (85,5%) have been studied with the 4 biomarkers determinations and the 2 echocardiograms proposed by the study. Causes for which patients were not studied: 3 because they died before the time points, and 11 because violation of protocol. Forty nine (51%) patients had one biomarker elevated at Day 30, so they would have to be studied at Day 100. Of them 49% performed the echocardiogram studies at D100 and 45% the biomarkers. Biomarkers: The evolution of the biomarkers during transplant is shown in figure 1. Pro-BNP is the biomarker that has more significant changes: 71% of transplanted patients has pro-BNP elevated at day 14; at day 30 53% persists with this biomarker elevated. At day 100, Troponin T and I 0% elevated, CPK 4% and pro-BNP 75% elevated. Echocardiogram: no one patient reached the definition of cardiotoxicity in terms of a decrease in LVEF of more than 10% to a value of less than 53%. However, 12 patients (12,5%) had a reduction of the Global Longitudinal Strain (GLS) of more than 15%. Currently, the deformation index strain is an echocardiographic way to detect early cardiac involvement. The decline in rates of deformation precedes the decline in LVEF and persists during subsequent cancer treatment. A relative reduction of 15% or more of GLS has the greatest specificity in predicting subclinical left ventricular dysfunction. In 74 patients we were able to measure the strain at the admission and 81 at day 30. At day 100 there were no significant reduction of LVEF and 3 patients had a relative reduction of GLS more than 15%. Conclusions: This is a prospective and systematic analysis of biomarker and echocardiographic changes during HSCT. We found changes in biomarkers and echocardiographic measures during HSCT: pro-BNP is the biomarker that raises during transplant, and it is persistently elevated at day 30 in 53%. GLS has a significant reduction in 12,5% of patients. We hypothesized that this changes can be predictive of clinical cardiotoxicity in the future, therefore, we are planning to enroll 100 more patients to confirm this results and after that, correlate this changes with comorbidities, conditioning regimens and study the development of clinical cardiotoxicity after 1-year post HSCT. Disclosures Galeano: Szabo SA: Other: (Equity interest).

Implementation of a Cardio Oncology Protocol in Uruguay

Introduction Survival of hemato oncologic patients has significantly improved in the last 50 years due to more intensive treatments and directed therapies. This has led to a paradigm shift focused not only in achieving cure but also addressing survivors' complications such as treatment toxicities and second malignancies. Cardiac toxicity is one of the most frequent long-term complications after cancer treatment leading to a significant burden in morbidity and mortality. Anthracyclines are type 1 cardiotoxic drugs. Risk of cardiotoxicity depends on patient characteristics and drug combinations as well as anthracyclines cumulative doses. Treatment of many hematologic malignancies often includes anthracyclines. Cardiac toxicity may limit oncologic treatment along with a negative impact on functional prognosis of survivors. Cardio oncology is an emerging field aimed at prophylaxis, early detection and proper treatment in order to improve quality of life in cancer survivors. This is the first Uruguayan experience in the implementation of a cardio oncology protocol. Methods This is a prospective interventional study conducted by a multidisciplinary team formed by hematologists and cardiologists. Inclusion criteria were patients older than 18 years old with hematologic malignancies who received anthracycline treatment between march 2017 and march 2019, treated at our institution. All patients gave their informed consent. This protocol was approved by our institution Ethical Committee. Patients who entered the protocol were followed at the Cardio Oncology Unit. Trans thoracic echocardiogram (TTE) were performed using the same equipment and by experimented operators. Left ventricular ejection fraction (LVEF) by Simpson and Global Longitudinal Strain (GLS) were measured. Figure 1 shows the algorithm used. We defined cardiotoxicity as the decrease of LVEF greater than 10% (relative to baseline LVEF) to a threshold inferior to 53%; or a relative reduction of GLS greater than 15%. Results We created a Cardio Oncology Unit (COU) at our institution with hematologists and cardiologists. Forty-four patients were included (table 1). Protocol compliance was 70%. Seven percent (3/44) of patients presented structural cardiopathy and 20% (9/44) were defined as high risk (figure 1). Cardiotoxicity was diagnosed in 16% (7/44) of patients. The diagnosis was made using LVEF decrease in every case, no patient was diagnosed based on GLS. Mean time of onset was 3 months (1-6). Mean doxorubicin dose was 115 mg/m2 (50-200). Four of the patients were asymptomatic and 3 presented with heart failure. Two patients required suspension of anthracyclines due to cardiotoxicity. Six of the 7 patients diagnosed with cardiotoxicity were treated with Beta blockers and ACE inhibitors and treatment was well tolerated. Of these patients, two died due to their oncologic disease, three improved their LVEF, one maintained the LVEF stable in spite of continuing on anthracyclines. Structural cardiopathy was associated with greater risk of cardiotoxicity (p=0.013). Conclusions We present the results of the implementation of a Cardio Oncology prospective protocol at our institution. The incidence of cardiotoxicity evidenced was greater than expected according to anthracycline used doses, with early onset during treatment. We identified structural cardiopathy as a risk factor for cardiotoxicity. Our results highlight the relevance of cardiologic follow up in patients receiving anthracyclines and makes us question whether prophylaxis would be beneficial for high risk patients. We strongly believe that cardiotoxicity is a major problem for hemato oncologic patients, and that a multidisciplinary approach with health care protocols is the best way to address it. Disclosures No relevant conflicts of interest to declare.

A pooled analysis of the cardiac events in the trastuzumab adjuvant trials.

Trastuzumab-associated cardiotoxicity remains an issue for patients with HER2-positive breast cancer. This pooled analysis of 3 adjuvant trials investigated the incidence, timing, impact on treatment completion, and risk factors for trastuzumab-associated cardiotoxicity. This is an individual patient data level pooled analysis of HERA, NSBAP B-31, and NCCTG 9831 (Alliance Trials). Definitions of cardiac events were as per each individual study. A total of 7445 patients enrolled in the 3 trials were included in the analysis, of which 4017 were in the trastuzumab and 3428 in the control (observation) arms, respectively. Median follow-up exceeded 10years (119.2-137.2months). Nearly all patients (97.4%) in the trastuzumab arms received anthracycline-based chemotherapy. In total, 452 patients in the trastuzumab arms experienced a cardiac event (11.3%), with most being mildly symptomatic or asymptomatic left ventricular ejection fraction (LVEF) decrease (351 patients, 8.7%). Severe congestive heart failure was more common in the trastuzumab arm (2.3%) than in the control arm (0.8%). Most cardiac events occurred during trastuzumab treatment (78.1%) and cardiac events were the main cause of discontinuation across the sample (10.0%); nevertheless, a large majority of patients completed trastuzumab treatment (76.2%). Baseline risk factors that were significantly associated with the development of cardiac events were baseline LVEF < 60%, hypertension, body mass index > 25, age ≥ 60 and, non-Caucasian ethnicity. One year of trastuzumab increases the risk of cardiac events, though most consist of asymptomatic or mildly symptomatic LVEF drops. Adjuvant trastuzumab should be considered a safe treatment from a cardiac standpoint for most patients. Trastuzumab-associated cardiotoxicity is the main cause of discontinuation and further research is needed to individualize prevention and management.

P4623Impact of left ventricular ejection fraction in ischemic and bleeding risk after an acute coronary syndrome

Abstract Introduction Even though left ventricular ejection fraction (LVEF) is a well-documented strong predictor of mortality after an acute coronary syndrome (ACS), its differential impact on the ischemic and bleeding risk of hemorrhage and ischemia is not well established. The aim of this study was to assess the impact of LVEF, measured by echocardiography, on the risk of acute myocardial infarction (AMI) and major bleeding (MB) after hospital discharge for ACS, during treatment with dual antiplatelet therapy (DAPT). Methods The data analyzed in this study were obtained from the fusion of 3 clinical registries of ACS patients: BleeMACS (2004–2013), CardioCHUVI/ARRITXACA (2010–2016) and RENAMI (2013–2016). All 3 registries include consecutive patients discharged after an ACS with DAPT and undergoing PCI. From the initial merged data set, that contained 26,076 patients, we have excluded those without data about LVEF. So the final cohort was composed by 20,518 patients. The impact of LVEF in the ischemic and bleeding risk was assessed by a multivariable competitive risk analysis, using a Fine and Gray regression model, with death being the competitive event. All those variables with statistical (p&lt;0.05) or clinical significance for the association with AMI and MB were included in the analysis. Follow-up time was censored by DAPT suspension/withdrawal. Results During a mean follow-up of 12.2±5.2 months, 789 patients died (3.8%), 431 had an AMI (2.1%) and 537 had a MB (2.6%). The mean of LVEF was 53.2% ± 10.7%. Only 15.5% of patients had LVEF &lt;40% (n=3,179). As the LVEF decreased, the risk of AMI increased, whereas the behavior of the risk of MB was more heterogeneous (Figure). After a multivariable adjustment, LVEF (as continuous variable) was significantly associated with AMI (sHR 0.98, 95% CI 0.98–0.99; p=0.010), but not with MB (sHR 1.00, 95% CI 0.99–1.01; p=0.270). After stratifying by LVEF groups (≥ vs &lt;40%), we found an association between LVEF and AMI (sHR 1.40, 95% CI 1.10–1.76; p=0.005), but not between LVEF and bleeding (HR 0.85, 95% CI 0.67–1.08; p=0.185). Conclusions After an ACS, as the LVEF decreases, there is an increase in ischemic risk, but not in bleeding risk. A LVEF &lt;40% was independently associated with higher risk of AMI, but not with higher risk of MB.

Acute Cardiotoxicity With Concurrent Trastuzumab and Hypofractionated Radiation Therapy in Breast Cancer Patients.

Purpose: Radiotherapy for patients with non-metastatic human epidermal growth factor receptor 2 (HER2) positive breast cancer is commonly administered concurrently with adjuvant trastuzumab. However, there is limited data on the use of concurrent trastuzumab and hypofractionated radiotherapy (Hypo-RT), which is now standard of care for the majority of women receiving whole breast irradiation. In this study, we compared acute cardiotoxicity rates in HER2-positive breast cancer patients treated with concurrent trastuzumab and Hypo-RT or conventionally fractionated radiotherapy (Conv-RT).Methods: We performed a review of our institutional database to identify HER2-positive breast cancer patients treated with trastuzumab and Hypo-RT or Conv-RT from 2005 to 2018 who underwent serial cardiac Left Ventricular Ejection Fraction (LVEF) evaluation. Decrease in LVEF was assessed by either echocardiography (ECHO) or multiple gated acquisition (MUGA) scan performed at baseline and every 3 months during trastuzumab therapy. Significant LVEF decline was defined as an absolute decrease in LVEF of ≥10% below the lower limit of normal or ≥16% from baseline value.Results: We identified 41 patients treated with Hypo-RT and 100 patients treated with Conv-RT. Median follow-up was 32 months (range, 13–90 months). Baseline median LVEF was 62% (range, 50–81%) in Hypo-RT group and 64% (range, 51–76%) in Conv-RT group (p = 0.893). Final median LVEF was 60% (range, 50–75%) in both groups. Three patients (7%) in Hypo-RT and five (5%) in Conv-RT group developed significant asymptomatic LVEF decline (p = 0.203). There was no significant difference in mean heart dose in patients who developed significant asymptomatic LVEF decline vs. those who did not in Hypo-RT (p = 0.427) and Conv-RT (p = 0.354) groups. No symptomatic congestive heart failure was reported in either group.Conclusions: The rate of asymptomatic LVEF decline in patients receiving concurrent trastuzumab and Hypo-RT was low (7%) and was similar to the rate observed in patients receiving Conv-RT. Longer follow-up is warranted to assess late cardiotoxicity.

P683Cardiovascular adverse events associated with BRAF and MEK inhibitors

Abstract 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.

P674Behavior of 2D and 3D derived ejection fraction and strain in patients with Hodgkin and non-Hodgkin lymphoma undergoing anthracycline-based chemotherapy, a prospective study

Abstract Background Anthracyclines are one of the most effective chemotherapeutic agents but can lead to a decline in cardiac function. Two-dimensional (2D) speckle tracking echocardiography derived strain can predict cancer therapeutics-related cardiac dysfunction (CTRCD). However, little is known about the role of three-dimensional (3D) strain imaging in this setting. Purpose To evaluate different methods of Left Ventricular Ejection Fraction (LVEF) and strain, and to identify the best strain parameter for the prediction of CTRCD in this group of patients during treatment with anthracycline based chemotherapy. Methods Patients with Hodgkin's or non-Hodgkin's lymphoma receiving anthracycline based chemotherapy were enrolled. 2D-and 3D echocardiography was performed at 3 time points: baseline, at the completion of chemotherapy and at 1 year. 2D- and 3D LVEF (2D Modified Quinones, M-mode, 2D Biplane, 3D Philips, 3D GE and 3D TomTec), peak systolic left and right ventricular longitudinal, radial and circumferential strain and strain rate were measured. CTRCD was defined as a decrease in LVEF &gt;10% to an absolute value of &lt;53%. Lin's Concordance Correlation Coefficient (CCC) was calculated to compare LVEF methods. ANOVA, uni and multivariate analysis was performed. Results A total of 130 patients (79 males, mean age 57±16 years) were enrolled; 104 non-Hodgkin.3D Philips and GE (CCC 0.88 [0.84, 0.92]), 3D Philips and biplane (CCC 0.84 [0.79, 0.89]), 3D Philips and Modified Quinones (CCC 0.86 [0.82, 091]) as well as 3D Philips and M-mode (CCC 0.77 [0.70, 0.85]) showed strong correlation for LVEF. 15 patients (12%) developed CTRCD. Mean cumulative anthracycline dose was 263±65 mg/m2. 2D and 3D global longitudinal and circumferential peak systolic strain, 2D global longitudinal systolic and early diastolic strain rate, 2D global early diastolic strain rate, 2D right ventricular longitudinal peak systolic strain and systolic strain rate, 2D global radial peak systolic strain and systolic strain rate measured at the completion of chemotherapy were independent predictors of the development of CTRCD at 1 year post-chemotherapy. The strongest predictors of CTRCD were 3D global longitudinal and circumferential strain either individually (area under the curve, 0.90 and 0.95 respectively) or combined (area under the curve, 0.95) at the completion of chemotherapy; a cutoff value of &lt;-18% in 3D global longitudinal strain had a sensitivity of 82% and specificity of 99%, while for 3D global circumferential peak systolic strain of &lt;-24% had a sensitivity of 82% and specificity of 95%. Conclusions To our knowledge this is the first prospective trial that shows that 3D EF correlates well with other EF methods and 3D strain predicts cardiac toxicity in this group of patients with a very good sensitivity and specificity. Acknowledgement/Funding Department of Cardiovascular Medicine-Mayo Clinic Rochester MN