Decrease In LVEF Research Articles

Association between cardiovascular risk factors and cancer therapy-related cardiac dysfunction in patients with breast cancer

Abstract Funding Acknowledgements Type of funding sources: None. Background Cancer therapy-related cardiac dysfunction (CTRCD) is one of the major complications being reported in breast cancer (BC) patients. The clinical relevance of CTRCD and its cardiovascular risk factors (CVRF) remains unclear. Purpose Our aim was to investigate the impact of baseline CVRF on ventricular systolic function in BC patients. Methods Retrospective study of patients with BC treated with anthracyclines (A) and/or trastuzumab between Jan 2017 and Dec 2018 who underwent a transthoracic echocardiography (TTE) before, during, and after chemotherapy. CTRCD is defined as a reduction of LVEF >10% to a value <50% or as a relative reduction of GLS >15%. Results We included 128 females with median age of 54 ± 11 years-old, treated with A (78; 60.9%), T (14; 10.9%) or A followed by T (36; 28.1%). LVEF at baseline was 64,7 ± 5,7%. At baseline, hypertension was present in 34,4% (44), dyslipidaemia in 29,9% (38), overweight (BMI: 25-30kg/m2) in 33,6% (43), obesity (BMI: >30kg/m2) in 28,1% (36), diabetes in 13 (10,2%) and smoker status in 11 (8,6%). No one had ischemic heart disease. During a mean follow-up of 38 months, 35 (27%) patients developed CTRCD from which 9 (7%) suffered clinical heart failure. After multivariate analysis, in the group treated with T (with or without A), the BMI >25 kg/m2 was the only CVRF associated to the development of CTRCD (p < 0,01). In the group treated with A, no CVRF was associated with CTRCD. During follow-up, BMI >25kg/m2 was not associated to a lower survival (log-rank p test = 0.627). In the baseline TTE did not occur statistically significant differences between the groups according to the absence or presence of CVRF. Nonetheless, some statistically significant differences occurred during follow-up. In hypertensive patients, treated with T, the TTE at 2 years of follow-up had a significant decrease in LVEF (5,9 ±2,8; p = 0,047) compared to non-hypertensive patients. In diabetic patients, treated with A, there was a significant decrease in tricuspid annular systolic velocity (S") in the TTE after chemotherapy (2,8 ±1,4; P = 0,049) compared to non-diabetic. The group of patients with dyslipidaemia treated with A had a significant decrease in GLS in the TTE after chemotherapy (1,5 ± 0,7; p = 0,037) compared to patients without dyslipidaemia; The same group treated with T (without A) revealed a significant decrease in S’ in the TTE during T therapy (5,2 ± 1,6; p = 0,034). The group of patients with BMI >25 kg/m2 treated with T (without A) showed a significant decrease in the GLS during T therapy (5,1 ± 1,6; p = 0,021) and in the LVEF at 2 years of follow-up (15,3 ± 5,7; p = 0,036) compared to patients with BMI <25 kg/m2. Conclusions In our cohort, a high BMI was an independent risk factor for CTRCD among patients treated with T. This finding is in agreement with literature data. These results should encourage further research into the mechanisms linking overweight/obesity to CTRCD.

Systemic inflammation in the acute myocardial infarction can predict early negative left ventricular remodeling assessed by myocardial work analysis

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): UEFISCDI Background. Left ventricular (LV) remodeling after acute myocardial infarction (AMI) is an important predictor of heart failure (HF). Systemic inflammatory response in the acute phase of AMI is of particular interest, while the relation to the remodeling process is still under debate. New imaging techniques derived from speckle tracking echocardiography (STE), such as myocardial work (MW), are attractive tools since they can detect myocardial remodeling before decrease of global LVEF. However, there is insufficient data regarding MW in AMI patients, and its relation to the inflammatory process. Methods. We assessed 57 patients (53 ± 9 years, 45 men, 64% smokers, 59% hypertensive, 54% with type 2 diabetes) with AMI, by clinical, 2D echo, and STE. Biomarkers panel was evaluated within the first 24 hours from admission: hsTpI and CRP. A second visit with clinical and echo assessment was performed at 6-8 weeks from the baseline visit. Exclusion criteria were unstable patients, non-sinus rhythm, significant valvular disease (>grade 2), other significant pathologies leading to decreased life expectancy, and low quality 2DE. At both visits, global longitudinal stain (GLS) and MW by 2DSTE were measured, on top of conventional echo parameters: global work index (GWI), global constructive work (GCW), global wasted work (GWW), global work efficiency (GWE) (Figure 1: upper panel - an example of a patient with increase of GWE from baseline to visit 2 ; lower panel - an example of a patient with decrease of the GWE from baseline to visit 2). Results. At baseline, myocardial necrosis by hsTpI significantly corelated with GLS (r = 0.44, p = 0.001) and MW (GWI: r=-0.44, p = 0.001; GCW: r=-0.40, p = 0.002), but not with LVEF. However, systemic inflammation by CRP did not correlate with LVEF or any of the STE parameters. Interestingly, systemic inflammation by CRP significantly correlated with changes of MW between the two visits: for GWE r=-0.53, p < 0.001; and for GWW r = 0.48, p < 0.001 (Figure 2). A CRP level >28 mg/l was able to predict decrease of GWE from baseline to visit 2. Conclusions. Magnitude of necrosis, expressed by hsTpI, corelates only with GLS and MW parameters, but not with LVEF. CRP level in the acute phase of AMI correlates with myocardial work changes, as an early marker of negative LV remodeling. Abstract Figure 1 Abstract Figure 2

Cardiac Effects of BRAF and MEK Inhibitors: Mechanisms and Clinical Management.

The identification of BRAF mutation prompted the development of new class of targeted therapy for treating melanoma: BRAF inhibitors and MEK inhibitors. Cardiovascular events have been reported with these treatments and could counterbalance their long-term maintenance. LVEF decrease due to BRAF and MEK inhibitors appears fairly common (10%) but usually not severe, without impact on patient outcomes. To date, no treatment options have been tested to prevent or to treat a decrease of LVEF associated with BRAF and MEK inhibitors. QTc prolongation was observed in 3% and arterial hypertension in 20% during treatment but only one-third of cases required a therapeutic change. BRAF and MEK inhibitors have revolutionized the management and the prognosis of melanoma patients. Cardio-oncology units may be useful for a better care of potential cardiac toxicity and particularly to inappropriately avoid discontinuing BRAF and MEK inhibitors.

Balloon aortic valvuloplasty for severe aortic stenosis may reduce mitral regurgitation in mid-term follow-up.

Mitral regurgitation (MR) is a frequent complication in patients with severe aortic stenosis (AS). Echocardiographic assessment of MR was performed at baseline, at 30 days and at 6 months after balloon aortic valvuloplasty (BAV). Data of 271 patients were included in our final analysis, of which 21.2% (n = 85) had at least moderate MR at baseline (in 19 (22.3%) subjects MR was diagnosed as primary). Both groups showed similar severity of AS, but patients in the MR group had a greater left ventricle (LV) size (p = 0.003 for LVESD, p = 0002 for LVEDD) and slightly lower LV ejection fraction (p = 0.04). Mitral regurgitation parameters significantly improved both at 30 days and 6 months after BAV in the MR group (MR jet area: 7.2 (4.5-9.9) vs. 3.6 (2.3-7.2) cm2, and 7.2 (4.5-9.9) vs. 3.2 (2.1-6.7) cm2; %MR/left atrial area 34.5 (23.4-42.7) vs. 17.5 (9.3-29.5) and 34.5 (23.4-42.7) vs. 14.5 (8.3-24.5), p < 0.001 for all). In multivariate logistic regression analysis, the change at 30 days, from baseline, in the LVESD (OR = 1.87; 95% CI: 1.23-2.87; p < 0.001) and LVEF (OR = 0.95; 95% CI: 0.87-1.01; p < 0.001); MR jet area (OR = 2.2, 95% CI: 1.5-4.6; p < 0.001) and the presence of primary MR (OR = 3.2, 95% CI: 1.04-5.98; p < 0.001) were retained as independent predictors of significant persisting MR at 6 months. Balloon aortic valvuloplasty may reduce MR in mid-term follow-up. Predictors of persistent MR at 6 months after BAV included an increase of LVESD and MR jet area and decrease of LVEF at 30 days.

Acute right systolic ventricular dysfunction in permanent cardiac pacing. Insight from RV PACE trial (Right Ventricular function assessment in Permanent cArdiac paCing by Echography)

Permanent right ventricular (RV) pacing is now clearly linked to heart failure and decrease in LVEF, in non neglected proportion. Several trials and observations reported the worse impact of this heart pacing mode on left ventricular functions, but rare are those that studied RV systolic function. In this observational prospective trial, we evaluate echographic systolic RV function, before and immediately after cardiovascular implantable electronic device (CIED) implantation and at 6 months of follow-up. In this intermediate analysis, we report impact of RV pacing on systolic RV function. Between February 2020 and February 2021, we enrolled 174 [114 (65%) male, 38 (21%) with AF] consecutive patients underwent RV permanent pacing (CRT, Hisian and left bundle branch pacing excluded) in prospective study for evaluation of echographic parameters of RV systolic function (TAPSE, RV S’, RV global longitudinal strain and RV free wall strain) and severity of tricuspid regurgitation (TR). Transthoracic echography (TTE) was performed (by 3 physicians) at baseline (just before procedure) and immediately after implantation. At baseline, mean LVEF was 56% ± 15.6. TAPSE (22.8 ± 6.29 vs. 19.3 ± 5.47 mm; P < 0.001) and tissue Doppler on lateral tricuspid annular (RV S’) (12.1 ± 3.28 vs. 11.2 ± 3.28 cm/s; P < 0.001) measured before and immediately after implantation show a significant decrease in RV function. The same finding is reported for Global RV Strain (−20 ± 0.6 vs. −18 ± 0.5%; P < 0.001) and RV free wall strain (−25 ± 0.7 vs. −23 ± 0.6%; P < 0.001). TR after CEID implantation is more severe in comparison with basal echography [TR stage 1/2: 132 (89%) vs. 110 (79%); P < 0.01] (Fig. 1). Permanent RV pacing immediately decrease RV systolic function assessed traditional echocardiographic parameters and RV strain. TR also gets worsened.

Vascular Dysfunction Predicts Future Deterioration of Left Ventricular Ejection Fraction in Patients with Heart Failure with Mildly Reduced Ejection Fraction.

The purpose of this study was to evaluate whether heart failure with mildly reduced ejection fraction (HFmrEF) is associated with vascular dysfunction and whether vascular function predicts future deterioration of LVEF in patients with HFmrEF. We evaluated endothelial function assessed by flow-mediated vasodilation (FMD) and vascular smooth muscle function assessed by nitroglycerine-induced vasodilation (NID) in 69 patients with HFmrEF and 426 patients without HF and evaluated the future deterioration of LVEF, defined as a decrease in LVEF to <40%, in 39 patients with HFmrEF for up to 3 years. Both FMD and NID were significantly lower in patients with HFmrEF than in patients without HF. We categorized patients into two groups based on low tertiles of NID: a low group (NID of <7.0%) and an intermediate and high group (NID of ≥7.0%). There were significant differences between the Kaplan–Meier curves for the deterioration of LVEF in the two groups (p < 0.01). Multivariate Cox proportional hazard analysis revealed that NID of <7.0% was an independent predictor of future deterioration of LVEF in patients with HFmrEF. Both endothelial function and vascular smooth muscle function are impaired in patients with HFmrEF compared with those in patients without HF. In addition, low NID of <7.0% predicts future deterioration of LVEF.

739 Atypical presentation of Takotsubo syndrome early after pacemaker implantation

Abstract Aims Takotsubo syndrome (TTS) is an acute stress-induced cardiomyopathy showing left ventricular (LV) dysfunction without obstructive coronary arteries disease. A sudden massive surge of circulatory catecholamines from an intense physical or emotional stress may play a central role in the pathogenesis of TTS. We report the case of an 87 years-old woman who developed TTS with uncommon presentation after permanent pacemaker (PM) implantation. Methods and results The patient was referred to our hospital for PM implantation because of advanced atrio-ventricular block (3:1). She suffered by rheumatoid arthritis (RA), arterial hypertension, and chronic kidney disease. Echocardiogram, performed before PM implantation, showed normal LV kinesis and normal ejection fraction (EF 60%). She was initially administered with infusion of Isoprenaline 2 mcg/min. The subsequent day, she underwent permanent dual-chamber pacemaker implantation without any complications. After 3 days, the patient complained severe asthenia and fever, together with increase of white blood cells and C reactive protein. Blood cultures were negative. We started antibiotic therapy and, suspecting a reactivation of RA, steroid therapy with infusion of methylprednisolone 40 mg/die. Electrocardiogram showed normal sinus rhythm and paced ventricular rhythm. PM interrogation showed normal function. Surprisingly, echocardiogram showed LV dysfunction with apical and medium segments akinesia, and severe EF reduction (35%). Coronary angiography documented absence of coronary obstructive lesions, assessing diagnosis of TTS. The patient was discharged 1 week after admission in good clinical condition. One week later, an echocardiogram showed apical akinesia, partial recovery of medium segments motility, and slight increase of EF (40%). The excess of catecholamines could lead to decreased cardiac muscular function and to spasm of coronary arteries: these events can lead to acute heart failure and decrease of LVEF. Furthermore, about 90% of patients with TTS are women, especially in postmenopausal period. Peculiarities of this case were the atypical symptoms of TTS and the combination of different predisposing stressors factors: female sex in postmenopausal period, anamnesis of chronic inflammatory disease, use of stress-inducing drugs (methylprednisolone and isoprenaline, the last associated with TTS after PM-implantation), atrio-ventricular block itself, and PM implantation procedure. Our findings remark that even a low-risk procedure could be a possible cause of TTS in patient with such risk factors. In our opinion, in this subset of patients, conscious sedation could be useful to reduce the stress load, together with an early procedure and consequently the minimal use of exogenous stress drugs like Isoprenaline, even if the patient is in a good clinical condition. Conclusions This case highlights TTS as a potential complication after PM implantation, especially in post-menopausal women with high pre-existing stress load.

Abstract 12136: Detection of Sub-Clinical Left Ventricular Dysfunction in COVID-19 Patients

Introduction: Abnormalities of left ventricular (LV) strain have been shown to occur prior to impairment of global left ventricular function, measured by global LV ejection fraction (EF). Although first described in patients receiving cardiotoxic chemotherapy, impairment of LV strain prior to a decrease in EF has also been shown in many other disease states which affect LV function. This study was designed to assess impairment of LV strain in post COVID-19 patients with normal EF using cardiac MRI MyoStrain Fast-SENC (strain encoded) pulse sequences. Methods: An institutional cardiac imaging database was queried for all patients with documented COVID-19 test positivity and a normal LVEF &gt;= 55% who underwent measurement of global longitudinal strain (GLS), global circumferential strain (GCS), and regional longitudinal and circumferential strain using cardiac MRI Fast-SENC pulse sequences. Global and regional strain measurements were compared to a cohort of healthy volunteers who also underwent CMR Fast-SENC imaging. Abnormal myocardial strain was defined as a value &gt;-17%. Results: Of 50 COVID-19 patients in the cardiac imaging database who underwent CMR Fast-SENC imaging, 40 had a normal LVEF, constituting the study cohort. Mean GLS and GCS for the study cohort were -16.40% and -15.45% and for healthy volunteers were -19.71% and -20.93% respectively; both comparisons were statistically significant with an unpaired t-test (p&lt;0.01). Furthermore, the prevalence of abnormal LV strain in COVID-19 patients with normal LVEF was 77.78%. Conclusions: These data suggest that impairment of LV strain (longitudinal and circumferential) occurs in COVID-19 patients who have a normal LVEF. Whether a decrease in GLS and/or GCS precede a decrease in LVEF, is beyond the scope of this study. However, the ability to evaluate progression of LV strain abnormalities with CMR may help identify changes in LV function before the onset of a reduction in LVEF and development of heart failure. The ability to identify and quantify abnormal left ventricular GLS and GCS with cardiac MRI also opens the door to assess any benefit of therapy, including anti-inflammatory agents, anti-viral drugs and steroids.

Abstract 11697: Associations of Soluble Urokinase-Type Plasminogen Activator Receptor and Doxorubicin-Related Cardiotoxicity at Standard Treatment Doses for Breast Cancer

Introduction: Elevated soluble urokinase type plasminogen activator (suPAR) is a risk factor for renal and cardiovascular (CV) diseases in the general population. Hypothesis: We evaluated associations between suPAR and markers of subclinical cardiotoxicity in breast cancer (BCa) patients receiving standard (std) dose doxorubicin (DOX) therapy. Methods: We conducted a prospective study of patients at Rush University Medical Center who received std (≤240 mg/m2, 4 cycles) DOX-based chemotherapy for BCa between January 2017 and May 2019. We used mixed effects linear regression models to evaluate associations between suPAR and global longitudinal strain (GLS), NT-proBNP, troponin-I, and hsCRP at baseline, cycle 2 and 4 of DOX, and 3, 6, and 12 months post-DOX treatment with adjustment for baseline demographics, CV risk factors, and CV medications. Results: Of the 37 women in our study (age 47±9.3 years, 60% White, 60% left-sided BCa, and 86% adjuvant radiation therapy), the median baseline suPAR was normal at 1.83 (1.31, 3.68) ng/dL. No woman experienced clinically significant cardiotoxicity during treatment (&gt;10% decrease in LVEF to &lt;50%). Baseline GLS was normal (-20.2±2.3%) and the mean change in GLS following DOX therapy was +1.1%. Neither baseline suPAR nor suPAR levels during treatment were associated with GLS, NT-proBNP, hsCRP, and troponin-I (all p&lt;0.05). Surrogate biomarkers of cardiotoxicity such as troponin-I and hsCRP were not associated with GLS (p&lt;0.05) while NT-proBNP was negatively associated with GLS with marginal significance (p=0.04). Conclusions: In patients receiving std DOX treatment for BCa ± radiation therapy, there was minimal subclinical cardiotoxicity as evidenced by minimal changes in GLS and lack of associations between cardiac biomarkers and GLS. Furthermore, suPAR was not associated with any of these markers at this std DOX dose for BCa. A normal baseline suPAR level may be associated with low risk for DOX-associated cardiotoxicity.

Abstract 10494: The Impact of Complete versus Partial Preservation of the Sub-Valvular Apparatus on Left Ventricular Function in Mitral Valve Replacement

Introduction: In mitral valve replacement (MVR), sudden increase in afterload and disruption of the annular-chordal-papillary-left-ventricular wall causes LV dysfunction in the early postoperative period. Preservation of the posterior mitral leaflet apparatus (MVR-P) has a favourable outcome on LV function. However, there is paucity of data on the impact of complete preservation of the sub-valvular apparatus (MVR-C). Objective: We investigated the impact of MVR-P and MVR-C on baseline and 3-months postoperative LV ejection fraction (EF) and global longitudinal strain (GLS). Methods: We retrospectively analysed a cohort of 29 MVR-P and 19 MVR-C patients with complete echo data at our unit, who were operated between 2012-2017. Between-group changes in LVEF and GLS were compared using independent sample T-test. Results: Median age was 59 years (IQR 50-69 years). Baseline LVEF was 58% (51 - 60%). Baseline GLS was -18.4 (-21.2 - -15.5). There were no significant differences between all baseline demographics including age (p=0.45), underlying MV pathology (p=0.1), baseline LVEF (p=0.48) and GLS (p=0.15). There was significantly less worsening of GLS in MVR-C group as compared to the MVR-P group (p=0.023), indicating better preservation of LV function. There was also a lower decrease in LVEF in the MVR-C as compared to the MVR-P group, although the difference was not statistically significant (p=0.23). Conclusion: MVR with complete preservation of the sub-valvular apparatus shows a favourable impact on the longitudinal function of the heart at 3 months. Further studies with larger patient numbers are indicated to investigate the long-term results of this surgical approach.

Clinical and Subclinical Cardiotoxicity after Hematopoietic Stem Cell Transplantation

Introduction:Cardiovascular disease is the leading cause of death, in Uruguay it corresponds to 30%. To the known risk factors, the use of QT and RT are added. The improvement in response and overall survival of hematologic patients allow a longer time to develop cardiovascular complications. Cardiotoxicity has been extensively studied in the context of breast cancer and the use of anthracyclines; however, there are very few data on hematopoietic stem cell transplantation (HSCT).Objective:Assess subclinical myocardial damage by measuring biomarkers and echocardiography and identify patients at high risk of developing cardiotoxicity after HSCT.Methods:This is a prospective, single-center study between April 2017 and November 2020. Population: adult patients admitted in the British Hospital Transplant Unit, Montevideo Uruguay to receive either an autologous or allogeneic HSCT. Measurement: cardiac biomarkers (pro-BNP, Troponin T, Troponin I and CPK) at admission, D1, D14 and D30. Echocardiograms were performed on admission and at D30 by the same team of 3 echocardiographers with the same machine. It was repeated at D100 if some alteration was seen.Results:We included 158 transplants: 148 autologous and 10 allogeneic. The characteristics of the population and results are shown in Table 1. 126 raised some biomarker during the first 100 days (79.7%). Pro-BNP is the biomarker that most frequently rises after admission until day 100: 125/158 (79.1%). The kinetics of the biomarkers are shown in Figure 1. Regarding echocardiograms, there were no patients with a cardiotoxicity criterion defined by: a decrease in LVEF of more than 10% to a value less than 53%. Regarding myocardial deformability, there was a reduction in strain between the initial echocardiogram and D30 in 76 patients of 116 patients with both determinations (65.5%). A reduction of 15% or more was evidenced in 18 (11.3%). Of them, 13 (72.2%) had elevated biomarkers in the first 100 days. Of the patients who did not have strain changes, 78.6% had elevated biomarkers. No statistically significant relationship was found between strain reduction and the presence or absence of elevated biomarkers in the first 100 days.With a median follow-up of 23.3 months (0.89-48.62), 11 (7%) developed clinical cardiotoxicity: hypertension 6, arrhythmia 4, pulmonary embolism 1, sudden death 1. We have strain data of 6/11 patients, and there was no reduction of 15%. Of the 11, 90.9% raised some biomarker during the 100 days. Median development time of cardiotoxicity: 10.3 months (0.03-36.6). 133 had one year follow up so, the incidence of clinical cardiotoxicity at 1 year is 4.5%.There were no differences in elevated biomarkers in the first 100 days and use of Melphalan (p = 0.096) however, there was a difference with BEAM versus other plans, p = 0.035. The reduction in strain at day 30 was not influenced by Melphalan or BEAM.Patients with subclinical myocardial damage were older than those without it: mean age: 56.7 +/- 11.2 versus 44.1 +/- 13.1, p = 0.0001. There was no statistically significant difference between patients who had elevated biomarkers in the first 100 days versus those who did not in relation to a history of diabetes, hypertension, dyslipidemia, heart disease or previous use of anthracyclines. Either in patients with a 15% reduction in strain versus those without.This is one of the first studies worldwide that comprehensively evaluates cardiovascular function during HSCT. Given the small number of observed cardiac complications, greater follow-up of this subpopulation with elements of subclinical cardiotoxicity is required to determine if they are indeed predictive parameters of cardiovascular complications in the future in the transplant setting.Conclusions:Subclinical cardiotoxicity is common in transplantation: Pro-BNP is the biomarker that most frequently rises after admission until day 100: 79.1%. Strain reduction of 15% or more occurs in 11,3%. Subclinical myocardial damage parameters were not associated with type of conditioning, previous use of anthracyclines, comorbidities and clinical cardiotoxicity at 1 year. Clinical cardiotoxicity post HSCT is low, 4,5% at 1 year. We must do a longer-term follow-up in order to evaluate whether the combination of pro-BNP associated with strain reduction can be predictive factors of clinical cardiotoxicity. [Display omitted] DisclosuresOliver: Roche: Other: conference support and fees ; Abbvie: Other: conference support and fees .

3D global longitudinal strain is the best predictor of late cardiotoxicity in non-Hodgkin's lymphoma

Abstract RCHOP chemotherapy (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) in non-Hodgkin's lymphoma (NHL) has a high risk of cardiotoxicity, with increased morbidity and mortality. Aim To define new parameters, such as 3D LV deformation, arterial stiffness and biomarkers able to detect late cardiotoxicity. Methods 54 patients (26 men, 57±10 years) with NHL, scheduled to receive RCHOP, with LVEF&amp;gt;50%, were assessed at baseline, after the 4th cycle of RCHOP and 2 years after completion of therapy. Assessment included 3D echocardiography for LV EF and deformation - longitudinal, radial, circumferential, area strain (LS, RS, CS, AS), Arteriograph for pulse wave velocity (PWV) and biomarkers (troponin I, NT-pro-BNP). Cardiotoxicity was defined as a decrease of LVEF &amp;lt;50%, with &amp;gt;10% from the baseline value. Results 11 patients (group I) developed cardiotoxicity, while 43 patients did not (group II) (LVEF decreased from 59±3 to 56±2 vs 58±3 to 47±2, p&amp;lt;0.0001). From baseline to 2 years there was a significant reduction of LS, CS and AS, and an increase of arterial stiffness and troponin I; however, changes were greater in group I vs group II (p=0.001) (see table). Even if NT-pro-BNP increased from baseline to 2 years, no significant changes were found between group I and II. Decrease of 3D LVEF correlated with changes of LS, AS, PWV, and troponin (r=0.64, r=0.42, r=−0.37 and r=−0.29, p&amp;lt;0.05). LS reduction after the 4th cycle was the best independent predictor for LVEF decrease after 2 years from therapy completion (R2=0.43, p=0.001); thus, decrease of LS with more than 26% after the 4th RCHOP cycle predicted late cardiotoxicity, after 2 years, with a sensitivity of 87% and specificity of 71% (AUC=0.867). Conclusion Assessment of 3D myocardial deformation, arterial stiffness and biomarkers is able to detect late cardiovascular toxicity, and to predict further decline of LVEF in patients with NHL. LS is the best independent predictor for late cardiotoxicity. Funding Acknowledgement Type of funding sources: None. 123 Cardiovascular toxicity parameters

Exercise-induced changes of ventricular function in male and female amateur marathon runners as assessed by three-dimensional echocardiography

Abstract Introduction The long-term endurance training is associated with an increased risk of both right (RV) and left ventricular (LV) dysfunction. However, males and females exhibit different cardiac adaptation to exercise. The aim of our study was to evaluate three-dimensional (3D) echocardiographic parameters of ventricular function before and after the marathon in male and female amateur athletes, and compare them between sexes. Methods The study included 40 male (39±8 years) and 27 female (40±7 years) amateur athletes. Echocardiography was performed 2–3 weeks before (Stage 1) and immediately after (Stage 2) the marathon run. RV and LV area and function were assessed using standard and 3D echocardiography. Results After the marathon, there was a significant increase in the RV size (indexed RV end-diastolic volume, 51.1±12.0 vs. 59.0±9.1 ml/m2, p=0.003 in males; 48.8±11.0 vs. 60.0±11.1 ml/m2, p&amp;lt;0.001 in females), with a decrease in the LV dimensions (indexed LV end-diastolic volume, 57.1±11.9 vs. 53.0±9.4 ml/m2, p=0.026 in males; 66.2±7.9 vs. 60.1±9.5 ml/m2, p=0.001 in females). RV systolic contractility, as assessed by ejection fraction (EF) and fractional area change (FAC), significantly decreased at Stage 2 in both studied groups, while post-race decrease in LVEF was observed only in males (p&amp;lt;0.05 for the interaction sex and stage). Conclusions In both male and female amateur athletes, marathon running resulted in RV dilatation and reduction in function, with concomitant decrease in LV dimensions. However, 3D analysis revealed that strenuous exercise alters LV systolic function to a greater degree in men relative to women. Funding Acknowledgement Type of funding sources: None.

Role of myocardial work index in early detection of cardiotoxicity in breast cancer patient

Abstract Introduction Breast cancer patients receiving anthracyclines are particularly prone to develop cancer therapeutics-related cardiac dysfunction. Early detection of cardiotoxicity onset is required for optimal timing of cardio protection treatment. The latest guidelines consider a relative reduction of 15% in global longitudinal strain (GLS) from baseline as risk for cardiotoxicity. Nevertheless, the more recent Myocardial Work Index (MWI) offers a load-independent tool for detection of subclinical heart failure (HF). However, data in cancer patients are still scarce. Purpose This study analyses the predictive value of MWI for cardiotoxicity diagnosis after 6 months chemotherapy. Methods The study population consists of breast cancer patients referred for chemotherapy with anthracyclines and taxanes. Patients with a history of HF previous to chemotherapy or depressed LV function at baseline were excluded. Echocardiography was performed before onset of the chemotherapy (baseline) and after 6 months follow-up. LVEF, GLS and MWI were assessed offline using EchoPAC software. The values at baseline and 6 months follow-up were pairwise compared to detect subclinical cardiac dysfunction. LVEF, GLS and MWI means at baseline were taken as cut-off to compare the predictive value of each parameter. Moreover, patients were categorized in one group with GLS reduction &amp;gt;15% (Group 1) and one group with GLS reduction &amp;lt;15% (Group 2). Results From April 2016 to July 2020, 28 women with breast cancer were included (age 54±11 years, LVEF 58±4%, GLS −21±2%, MWI 2160±308 mmHg). All patients underwent the same standard chemotherapy protocol (4xEC, 12xTaxol). No difference in baseline characteristics between group 1 (n=13) and group 2 (n=15) was observed. At 6 months follow up a significant decrease in LVEF (53±8%, p=0.003), GLS (−19±3%, p=0.002) and MWI (1920±391 mmHg, p=0.005) was shown without any change in blood pressure. However, while mean LVEF and GLS at baseline did not predict any significant change, patients with MWI under the mean value at baseline (n=15) presented significant lower LVEF (50±8 vs 57±6% p=0.006), GLS (−17±3 vs −20±2%, p=0.01), MWI (1733±320 vs 2136±362 mmHg, p=0.005) after 6 months. Additionally, both groups had similar MWI at baseline (2148±335 mmHg vs 2170±294 mmHg, p=0.85), whereas those patients with GLS reduction &amp;gt;15% showed significant lower MWI after 6 months (1694±332 mmHg vs 2116±334 mmHg, p=0.003, Figure 1). Conclusions At 6 months follow up, a decline of the LV systolic function as side effect of chemotherapy can be seen. MWI at baseline shows the best predictive value for development of cardiotoxicity, in comparison to LVEF and GLS. Further studies are warranted to better understand the role of MWI for early detection of cardiotoxicity and its clinical relevance. Funding Acknowledgement Type of funding sources: Private hospital(s). Main funding source(s): Onze-Lieve-Vrouw hospital in Aalst (Belgium)

A 3D-TTE left atrial function study in cardio-oncology patients

Abstract Introduction Transthoracic Doppler echocardiography (TTE) remains the standard imaging method to evaluate cancer therapeutics-related cardiac dysfunction (CTRCD). 3D-TTE with strain analysis is a novel technique, proved useful for earlier detection of left ventricular (LV) function impairment. However, diastolic and left atrial (LA) function impact is less studied. Purpose To assess LA volumetric and LA strain (LAS) features by 3D-TTE in cardio-oncology patients. Methods A prospective study of female breast cancer patients (P) submitted to therapy (TH) who underwent serial monitoring by 2D and 3D-TTE. Standard 2D, 3D-TTE and LAS parameters were evaluated, including longitudinal (LALS) and circumferential strain (LACS) during conduit (cd), contraction (ct) and reservoir (r) phases. P were evaluated at T0, T1 and T2 (before, ≥6 and ≥12 months after starting TH). CTRCD was defined as an absolute decrease in 2D LVEF &amp;gt;10% to a value &amp;lt;54% or a relative decrease in 2D GLS &amp;gt;15%, according to literature. P with previous cancer treatment, coronary artery disease, significant valvular disease, and atrial arrhythmias were excluded. Results 98 P (mean age 54.6±12.0 years-old), mostly treated with anthracyclines (78.6%, cumulative dose 268.2±77.6mg/m2), anti-HER (70.4%) and radiotherapy (80.6%) were included. 2D LV and LA volumes had a significantly raise from baseline to T1 (2D LVEDV 82.2±18.8 vs 91.9±18.8 mL, p=0.019 and LA 43.3±12.9 vs 49.8±13.3 mL, p=0.005). 2D and 3D LVEF were significantly reduced during TH, however remaining within the limits of normality. 2D GLS was also impaired at T1 (−19.9±2.6% vs −18.6±3.1%, p=0.009). During a mean follow-up of 14.1±8.1months, 31 P (31.6%) developed CTRCD. 3D LV and LA volumes also globally increased at T1 comparing to baseline with partially recovery at T2. Maximum LA volume was significantly higher at T1 (39.1±9.3 vs 43.6±10.6 ml, p=0.024). 3D LA ejection fraction (T0 53.7±9.7%, T1 53.4±8.6%, T2 49.9±8.6%, pT0-T2=0.039) and LAS values tended to progressively worse during TH. LA dilation (vol&amp;gt;34ml/m2) at baseline was correlated to dysfunction in contraction phase at T1 (LACSct −19.6±8.6 vs −17.3±4.6%, p=0.024). LACSr has substantially decreased from baseline to T2 (31.4±11.6 vs 27.0±10.4%, p=0.05). In univariate analysis, delta LALSr (T1-T0) was a predictor of CTRCD (mean −5.2% vs 1.9%, p=0.05). Conclusion CTRCD was frequent during the earlier phase of breast cancer treatment. LA function was also affected, mirroring LV volumetric and functional changes. Diastolic dysfunction, assessed through LA reservoir strain, was impaired in association with CTRCD. 3D-TTE usefulness in the surveillance and monitoring of CTRCD goes beyond systolic LV function assessment, allowing a detailed LA function analysis. Funding Acknowledgement Type of funding sources: None.

Early increase of high-sensitivity cardiac troponin predicts mortality in cancer patients undergoing chemotherapy

Abstract Introduction High-sensitivity cardiac troponin test (hs-TnT) reveals subclinical myocardial damage in many cardiac conditions. We hypothesized that elevated hs-TnT may predict a development of cancer therapy-related cardiac dysfunction and clinical outcomes linked with antineoplastic therapies. We aimed to evaluate the predictive value of hs-TnT for all-cause mortality in a group of patients (pts) with recent diagnosis of cancer. Material and methods We included 80 pts (mean age 57±13 years; 98% women) with recently diagnosed cancer (78 breast cancer, 1 colon cancer, 1 DLBCL lymphoma). Transthoracic echocardiography and hs-TnT tests were performed at baseline and after 3, 6 and 12-months. Pts with LVEF &amp;lt;50% and significant valvular disease were excluded. Results In the study group 44% pts had arterial hypertension, 54% dyslipidemia, 9% diabetes mellitus; 94% pts were treated with anthracyclines, 30% with trastuzumab, 54% with hormone therapy, 71% with radiotherapy. A significant decrease of LVEF were observed during follow-up (LVEF at baseline, 3, 6 and 12 months: 61.7±2.0%; 60.9±2.0%*; 60.8±2.9%*; 59.9±2.9%*; *p&amp;lt;0.05 vs baseline). A significant reduction of global longitudinal strain was found only at 6-month follow-up (−19,2±2,2% vs −18,6±2,0%; p=0,003). In 38 pts at least a twofold (fourfold in37) increase in hs-TnT &amp;gt;99th percentile was observed. A rise of hs-TnT was most often seen at 3 month (n=35; 43,8%). During median 1056 (221–1906) days off follow-up 18 (24%) pts died and ROC curve analysis revealed that early (0–3 months) hs-TnT increase more than 10 pg/ml [AUC=0,693 (0,545–0,806); p=0,017)] represented a predictor of death [OR=3,4 (1,99–11,87)]. Conclusions Increase in hs-TnT in cancer patients detected at 3rd month of chemotherapy predicts mortality. Funding Acknowledgement Type of funding sources: None. Figure 1

MA02.07 T-DM1 and Osimertinib (TRAEMOS) To Target HER2 Bypass Track Resistance in EGFRm+ NSCLC: Interim Analysis of a Phase II Trial

Despite high response rates to osimertinib in patients with EGFR mutation positive (EGFRm+) NSCLC, resistance inevitably develops. HER2 overexpression and amplification is detected in 13% of NSCLC-patients with acquired TKI-resistance. Previously, we showed that trastuzumab and paclitaxel in this setting is associated with a 41% ORR. Here, we evaluated the efficacy and toxicity of trastuzumab-emtansine (T-DM1) and osimertinib in patients with HER2 overexpression and/or amplification after progression on osimertinib as last line of treatment. We report a pre-planned interim analysis. In this multicenter single arm phase II study with a safety run-in (NCT03784599), eligible patients (≥18 years, WHO PS ≤2) with EGFRm+ NSCLC, progressing on EGFR TKI treatment and with HER2 overexpression (IHC ≥2+ in ≥10% of the cells) and/or HER2 amplification (ISH and/or NGS) were included. Patients were treated with T-DM1 3.6 mg/kg (IV infusion) every 3 weeks and osimertinib 80 mg QD. For patients with progression on 1st or 2nd generation EGFR TKIs, osimertinib monotherapy was initiated and T-DM1 was added at time of progression on osimertinib. Primary endpoints were to assess the ORR after 12 weeks and to evaluate safety of the combination treatment. In the safety run in, assessed in a classical 3+3 design, the first 3 patients received T-DM1 3.0 mg/kg. If none of these 3 patients developed a dose limiting toxicity (DLT), the T-DM1 dose was escalated to the standard dose of 3.6 mg/kg. Responses were assessed every 6 weeks according to RECIST 1.1. Treatment was continued until progression or unacceptable toxicity. Sample size was calculated using Simon’s two stage minimax design (H0=41%, H1>55%, 80% power, one-sided type I error rate of 10%, sample size: 58 patients, cohort A ORR 16/36 in order to proceed to cohort B). From January 15 2019 until April 6 2021, 27 patients were included and started with T-DM1. In the safety run in, none of the patients developed a DLT. Therefore, the study continued with osimertinib 80 mg QD and T-DM1 3.6 mg/kg IV infusion q 3 weeks. ORR and DCR after 6 weeks of treatment, evaluable in 24 patients, was 0% and 63% (16/24) respectively. One patient is not yet evaluable for the primary endpoint. ORR and DCR after 12 weeks of treatment were 13% (3/23) and 43% (10/23). DCR in HER2 IHC2+ and 3+ cohort was 36% (5/14) and 55% (5/9). Median PFS was 2.8 months (95% CI, 2.3-3.3 months), median duration of disease control was 20 weeks (range 4-47 weeks). Grade 2/3 adverse events occurred in 29%/21% of patients, including pneumonitis, LVEF decrease, fatigue, erythema and CK elevation. There were no grade 4 and 5 therapy-related adverse events. TRAEMOS is the first trial combining T-DM1 and osimertinib in patients with EGFRm+ NSCLC and progression on osimertinib to target HER2 bypass track resistance. Safety profile is favorable compared to cytotoxic chemotherapy, however this treatment strategy showed very limited efficacy. Further clinical evaluation of this regimen is not warranted.

271P First-in-human, phase I dose escalation and expansion study of anti-HER2 ADC MRG002 in patients with HER2 positive solid tumors

MRG002 is an ADC composed of a humanized anti-HER2 mAb conjugated to MMAE via a vclinker. MRG002 is presently being investigated as monotherapy in an ongoing phase I study for safety, tolerability, PK, and preliminary antitumor activity in patients (pts) with HER2+ advanced or metastatic solid tumors. In phase Ia dose escalation utilizing a “3+3” design, a total of 25 pts with BC (19), SGC (3), GC (2), and CRC (1) were enrolled to identify MTD/RP2D. The median age was 53 (30, 66) years. The median number of prior therapies was 5 (1, 11). The starting dose of MRG002 was 0.3 mg/kg, followed by 0.6, 1.2, 1.8, 2.2, 2.6, and 3.0 mg/kg, all pts with BC and GC had HER2+ per CAP guidelines. For the other cancers, pts had an IHC status of 2+ or 3+, regardless of HER2 FISH results. Each pt received MRG002 Q3W for a maximum of 8 cycles. Commonly observed TRAEs were neutrophil count decrease (56%), AST increase (56%), WBC decrease (56%), lactate dehydrogenase increase (44%), alopecia (44%), CPK increase (40%), ALT increase (36%), triglyceride increase (32%), cholesterol increase (32%), GGT increase (32%), appetite decrease (32%), and hypoaesthesia (32%). Majority of AEs were mild to moderate in severity. The most commonly reported TRAEs ≥ Grade 3 were neutrophil count decrease and triglycerides increase in 3 pts (12%), respectively. The treatment-related SAEs were reported in 6 pts (24%) including GGT increase, AST/ALT increase, neutrophil count decrease, LEVF decrease, fatigue, peripheral neuropathy. There was no death due to AEs. Among 21 pts who had at least one tumor assessment, 9 PR (43%), 8 SD (38%), and 4 PD (19%). The investigator assessed ORR was 43% and the DCR was 81%. Of these 21 pts, 16 pts were HER2+ breast cancer, 8 PR, 5 SD, and ORR was 50% (8/16), DCR was 81%(13/16). There were two DLTs at 3.0 mg/kg including LVEF decrease and CPK elevation. Accordingly, the RP2D determined at 2.6 mg/kg which is currently being evaluated in the phase Ib dose expansion. The dose escalation of MRG002 showed manageable safety profile and encouraging antitumor activity in pts with HER2+ solid tumors including BC, GC and other cancer types, which will be further investigated in phase II studies.

The State Of The Cardiovascular System In Patients With Covid-19 In The Early Rehabilitation Period

Purpose of the study: assessment of the study cardiovascular status in patients with postcovid syndrome and to determine their relationship with the functional status of patients. Material and research methods. There were 281 patients under observation, with the presence of clinical manifestations of postcovid syndrome. The comparison group (CG) consisted of 20 patients who had undergone COVID-19 and whose disease ended in full recovery. All patients underwent electrocardiographic (ECG) and echocardiographic (EchoCG) studies. The assessment of the functional status of patients after suffering COVID-19 was carried out using the PCFS method - Post-COVID-19 Functional Status (https://osf.io/qgpdv/). Research results. The study revealed signs of cardiovascular pathology according to ECG and EchoCG data in 255 (90.75%) patients with postcovid syndrome. According to the ECG results, cardiac arrhythmias were recorded significantly more often in patients in the main group than in the comparison group (p &lt;0.001). The results of the echocardiography of the study showed that in the patients of the main group, compared with the comparison group, there was a significant increase in the size of the LV and RV of the heart (p &lt;0.05), a decrease in LVEF (p &lt;0.01) and a higher value of the mean pressure in the PA (p &lt;0.05). Patients with a higher PCFS score are characterized by large sizes of both ventricles (p &lt;0.05 for LV and p &lt;0.01 for RV) and low LV ejection fraction (p &lt;0.001). Conclusion. The present study showed that 255 (90.75%) patients who underwent COVID-19 in the early rehabilitation period have signs of cardiovascular pathology according to ECG and EchoCG data. Patients with a higher PCFS score (significant restriction of daily activity due to symptoms associated with the previous infection and the need for assistance in self-care) had more enlarged sizes of both ventricles and a lower LVEF.

Clinical variants of myocardial involvement in COVID-19-positive patients: a cumulative experience of 2020.

Myocardial injury, diagnosed by troponin elevation, is common in COVID-19 patients, but cardiac involvement with clinical manifestations occurs less frequently. We analyzed the literature on COVID-19 (2020) and systematically reviewed the cases where individual patient data were presented. We searched PubMed and Google Scholar for “COVID,” “COVID-19,” and “coronavirus” in combination with “myocarditis,” “heart failure,” “takotsubo,” “cardiomyopathy,” and “cardiogenic shock.” We identified 90 cases of COVID-19 with myocardial involvement, mean age 52.9 ± 18.3 years, 54.5% males. Of them, 55 survived (61.1%), 20 died (22.2%), and in 15 (16.7%) the outcome was unknown at the time of publication. Among patients with known outcome, mortality was 26%. The nadir LVEF was 31.7 ± 13.1% and recovered to 50.1 ± 16.0%. Pericardial effusion was a common finding, reported in 21 (23.3%) of patients, including moderate size effusion in 8.9% and large in 7.8%. The effusion caused tamponade in 11 (12.2%) of patients. Out of 83 patients who experienced a decrease in LVEF, 30 could be classified as takotsubo syndrome. The takotsubo patients were older than those with myocarditis, and with relatively high proportion of males. About one third of the cases was complicated by cardiogenic shock. Myocardial involvement in COVID-19 patients most often presents as a new, rapid decrease in LVEF, although normal LVEF or takotsubo-like wall motion pattern does not rule out myocarditis. Moderate and large pericardial effusion is common, and cardiac tamponade occurs in 12.2% of patients. Cardiogenic shock develops in one third of the patients. Mortality appears to be high at 26%.