Nhola, Lara F.

Abstract Aims The objective of this study was to assess the effect of HER2-directed therapy (HER2-Tx) on peripheral vasoreactivity and its correlation with cardiac function changes and the additive effects of anthracycline/cyclophosphamide (AC) therapy and baseline cardiovascular risk. Methods and results Single-centre, prospective cohort study of women with newly diagnosed stage 1–3 HER2-positive breast cancer undergoing HER2-Tx +/− AC. All participants underwent baseline and 3-monthly evaluations with Endo-Peripheral Arterial Tonometry (Endo-PAT), vascular biomarkers [C-type natriuretic peptide (CNP) and neuregulin-1 beta (NRG-1β)], and echocardiography. Cardiotoxicity was defined as a decrease in the left ventricular ejection fraction (LVEF) of >10% to a value <53%. Of the 47 patients enrolled, 20 (43%) received AC in addition to HER2-Tx. Deterioration of reactive hyperaemia index (RHI) on Endo-PAT by ≥20% was more common in patients receiving HER-Tx plus AC than HER2-Tx alone (65% vs. 22%; P = 0.003). A decrease in CNP and log NRG-1β levels by 1 standard deviation did not differ significantly between the AC and non-AC groups (CNP: 20.0% vs. 7.4%; P = 0.20 and NRG-1β: 15% vs. 11%; P = 0.69) nor did GLS (35% vs. 37%; P = 0.89). Patients treated with AC had a significantly lower 3D LVEF than non-AC recipients as early as 3 months after exposure (mean 59.3% (SD 3) vs. 63.8% (SD 4); P = 0.02). Reactive hyperaemia index and GLS were the only parameters correlating with LVEF change. Conclusion Combination therapy with AC, but not HER2-Tx alone, leads to a decline in peripheral vascular and cardiac function. Larger studies will need to define more precisely the causal correlation between vascular and cardiac function changes in cancer patients.

Abstract Background The diagnosis of cardiotoxicity (CT) related to cancer therapy has gained significance due to its impact on morbidity and mortality. The 2022 cardio-oncology European Society of Cardiology (ESC) Guidelines defined CT as symptomatic if a patient has clinical heart failure or asymptomatic based on changes in the ejection fraction (EF) or global longitudinal strain (GLS). The role of right ventricular parameters, such as tricuspid annular plane systolic excursion (TAPSE) and right ventricular free wall strain (RVFWS), in predicting CT is unknown. AIM Evaluate if TAPSE and RVFWS can predict the development of CT in lymphoma patients treated with anthracyclines. Methods For this prospective observational study, Hodgkin & non-Hodgkin lymphoma patients (n=222) treated with anthracyclines were recruited from 2013 to 2021 and were followed for one year. Echocardiographic variables TAPSE and RVFWS were measured at baseline(T0), during treatment(T1), and up to 1 year after chemotherapy completion(T2). CT was defined according to the ESC guidelines excluding GLS changes. We performed: Kruskal-Wallis test to find differences at baseline values, logistic regression to evaluate the association of TAPSE and RVFWS with CT, area under the curve (AUC) of the receiving operator characteristic (ROC) to measure the discriminative test ability and two sample proportion test to calculate the negative predictive value (NPV). A p-value <0.05 was considered significant. Results 222 patients were enrolled and 23 developed CT: 4.5% (n=10) at T1 and 6.2% (n=13) at T2. The median of RVFWS at T0 was significantly different in patients who developed CT compared to those who did not at T1 (CT-22% vs. no CT-27% p=0.04) and T2 (CT -23%, no CT -26.5% p=0.03). RVFW values at T0 were associated with CT at T1 (OR, 1.281 95% CI,1.09-1.52 p=0.002) and T2 (OR 1.23 95% CI,1.07-1.44 p=0.003). At T0 RVFWS cutoff value of -24% had an AUC of 0.85 for the prediction of CT at T1, with a sensitivity of 83% and specificity of 76% (p=0.03). At T0, RVFWS cutoff of -25% had an AUC of 0.80 for the prediction of CT at T2, with a sensitivity of 75% and specificity of 60%, (p=0.04). RVFWS absolute values >26% at T0 and T1 had an NPV of 100% for the development of CT in T1 and T2. The median TAPSE at T0 was significantly different in patients who developed CT at T1 compared to those who did not (CT patients 18.7 mm vs no CT patients 23.6 mm p=0.04). TAPSE values at T0 were associated with CT development at T1 but not at T2 OR 0.76 (95% CI,0.66-0.87 p=<0.001). At T0, TAPSE cutoff of 21.6 mm had an AUC of 0.77 for the prediction of CT at T1, with a sensitivity of 77% and specificity of 70% (p=0.03). Conclusions Baseline absolute RVFWS values <24% and <25% were associated with CT at T1 and T2, respectively. Values >26% had an excellent NPV for the development of CT. Baseline TAPSE values <21.6 were associated with CT at T1. These parameters should be evaluated in other cancer populations.TAPSE and RVFWS association with CTRVFWS and TAPSE at T0 to predict CT

Abstract Aims Aortic stenosis (AS) induces characteristic changes in left ventricular (LV) mechanics that can be reversed after aortic valve replacement (AVR). We aimed to comprehensively characterize LV mechanics before and after AVR in patients with severe AS and identify predictors of short-term functional recovery and long-term survival. Methods and results We prospectively performed comprehensive strain analysis by 2D speckle-tracking echocardiography in 88 patients with severe AS and LV ejection fraction ≥50% (mean age 71 ± 12 years, 42% female) prior to and within 7 days after AVR. Patients were followed for up to 5.2 years until death from any cause or last encounter. Within days after AVR, we observed an absolute increase in global longitudinal strain (GLS) (−16.0 ± 2.0% vs. −18.5 ± 2.1%, P<0.0001) and a decrease in apical rotation (10.5 ± 4.0° vs. 8.3 ± 2.8°, P = 0.0002) and peak systolic twist (18.2 ± 5.0° vs. 15.5 ± 3.8°, P = 0.0008). A baseline GLS is less negative than −16.2% was 90% sensitive and 67% specific in predicting a ≥ 20% relative increase in GLS. During a median follow-up of 3.8 years, a global circumferential systolic strain rate (GCSRs) less negative than −1.9% independently predicted lower survival. Conclusion In patients with severe AS, a reversal in GLS, apical rotation, and peak systolic twist abnormalities towards normal occurs within days of AVR. Baseline GLS is the strongest predictor of GLS recovery but neither was associated with long-term survival. In contrast, abnormal baseline GCSRs are associated with worse outcomes.

Abstract Background Speckle tracking echocardiography (STE) has shown to be a good tool to foresee early myocardial dysfunction in lymphoma patients who receive anthracycline based chemotherapy. Conventional STE such as global longitudinal strain (GLS) is a good predictor of cardiotoxicity in these patients, however, a more in-depth characterization of conventional and comprehensive STE parameters to predict a hard end-point as chemotherapeutic related heart failure (HF) has not been evaluated. Purpose The aim of this prospective study was to evaluate predictability of cancer therapeutic-related clinical HF by conventional and comprehensive STE. Methods We enrolled 269 Hodgkin & non-Hodgkin lymphoma patients who underwent chemotherapy at Mayo Clinic from 2013 through 2021. All patients had an echocardiogram performed at baseline (T0), during chemotherapy (T1) and after (T2). HF was diagnosed by a cardiologist and defined as the first occurrence after the initiation of chemotherapy. Conventional (GLS) and comprehensive strain analyses that included: global circumferential strain (GCS), global radial strain (GRS), global longitudinal early diastolic strain rate (GLSRe), global longitudinal systolic strain rate (GLSRs), global circumferential early diastolic strain rate (GCSRe), global circumferential systolic strain rate (GCSRs), global radial early diastolic strain rate (GRSRe), and global radial systolic strain rate (GRSRs), were performed offline. Logistic regression analyses were used to evaluate the association of 2D and 3D STE measurements with the development of clinical HF. Results Overall, 215 (79.9%) patients had non-Hodgkin lymphoma while 54 (20.1%) had Hodgkin lymphoma. Mean age was 58.4±16.1 years and 64.7% of the patients were males. The most prevalent comorbidities were hypertension (101/37.5%), dyslipidemia (87/32.3%) and diabetes (28/10.4%). HF occurred in 21 (7.8%) patients, including 9 (3.3%) during chemotherapy and 12 (4.5%) after chemotherapy. The best predictors of HF were: i) GLSRe and GCSRs performed at baseline (T0) to predict HF at T1 with an AUC of 0.85 each and p values of 0.0006 and 0.0005 respectively (Table 1); ii) GCSRs and GCS at baseline (T0) to predict HF at T1 or T2 with AUCs of 0.82 (p, <0.0001) and 0.81 (p, 0.0004), respectively. Basic strain (GLS) was able to predict HF when measured at T0 but not when measured at T1. All the AUCs for GLS were below 0.75 (Figure 1). Conclusions To our knowledge this is the first study to evaluate the use of conventional and comprehensive STE to predict a hard end-point as heart failure in patients with lymphoma who received anthracyclines. Comprehensive STE measurements as GLSRs, GLSRe, GCS, GCSRs and GCSRe are better than GLS to predict HF in patients with lymphoma who received anthracycline based chemotherapy. These findings can be crucial for the management of these patients by guiding when to start cardioprotection and/or avoid interruptions of cancer treatment. Funding Acknowledgement Type of funding sources: Private hospital(s). Main funding source(s): Department of cardiovascular diseases, Mayo Clinic, Rochester, MN

Abstract Background Assessing cardiac performance of patients receiving chemotherapy is a cornerstone for adequate cardiovascular care. Mitral annular plane systolic excursion (MAPSE) has been considered as a surrogate for Ejection Fraction (EF). However, little is known about its role in predicting Cardiotoxicity or Heart Failure in Lymphoma patients, as its relationship with Global Longitudinal Strain (GLS) and EF. Purpose Our aims were: i) to evaluate if MAPSE and GLS can predict the development of CT and/or HF in lymphoma patients treated with anthracyclines and ii) to evaluate its correlation with GLS and EF. Methods For this prospective observational study, 325 Hodgkin (HL) & non-Hodgkin (NHL) lymphoma patients (n=325) treated with anthracyclines were recruited from 2013 to 2021 and followed for 1 year. MAPSE by M-mode and GLS by Speckle-Tracking (ST) were measured at baseline (T0), during treatment (T1), and up to 1 year after chemotherapy completion (T2). CT was defined as a decrease in EF by >10% to a value <50% and HF by a cardiologist as the first occurrence after the initiation of anthracyclines. Logistic regression analyses with Receiving operator characteristics (ROC) and Area under the curve (AUC) were performed. Pearson's correlation coefficient was also calculated. A p-value <0.05 was considered statistically significant. Results Two hundred sixty-four patients (81.2%) had NHL and 61 (18.8%) HL. Of these, fifteen (4.6%) and 21 individuals (6.4%) developed CT at T1 and T2, respectively. Nine subjects (2.8%) developed HF at T1 and 14 (4.3%) at T2. MAPSE at T0 had the highest AUC to predict both HF at T1 (AUC=0.865, cut-off 14.9, sensitivity 100%, specificity 63%, p=0.008) and at T2 (AUC=0.757, cut-off 10.9, sensitivity 67%, specificity 93%, p=0.045). This same variable at T1 predicted HF at T2 with an AUC of 0.752 (cut-off 11.4, sensitivity 67%, specificity 94%, p=0.004). For CT prediction at T2, MAPSE at T1 had an AUC of 0.738 (cut-off 12.5, sensitivity 56%, specificity 85%, p<0.0001). GLS at T0 predicted CT at T1 (AUC=0.657, cut-off −19, sensitivity 67%, specificity 63%, p=0.012) and when obtained at T1, it predicted CT at T2 (AUC=0.776, cut-off −17, sensitivity 74%, specificity 75%, p-value <0.0001) (Table 1). Pearson's correlation between MAPSE and GLS at T0 (coefficient −0.25, p=0.023) at T1 (coefficient −0.38, p<0.0001) at T2 (coefficient −0.037, p<0.0001) and MAPSE with EF at T0 (coefficient 0.33, p=0.0002) at T1 (coefficient 0.28, p<0.0001) and T2 (coefficient 0.29, p<0.001). Conclusions To our best knowledge, this is the first time that MAPSE and GLS were compared to predict CT and HF in lymphoma patients receiving anthracycline-based chemotherapy; we have demonstrated that MAPSE measured at T0 was a very good predictor of HF at T1. Either MAPSE or GLS assessment at T0 and T1 were able to predict CT or HF. Future studies could explore the combination of these two variables to predict either CT or HF. Funding Acknowledgement Type of funding sources: Private hospital(s). Main funding source(s): Department of Cardiovascular Medicine. Mayo Clinic, Rochester-MN

1044 Background: Trastuzumab is well-demonstrated to be associated with cardiotoxicity (typically reduced ejection fraction), most commonly in patients who also receive anthracycline. The vascular effects of trastuzumab and anthracycline are understudied; we aimed to compare change in endothelial function during and after trastuzumab and to assess how anthracycline receipt affects this. Methods: This is an observational prospective study of women with newly diagnosed HER2-positive breast cancer. All participants underwent baseline evaluation of endothelial function testing by use of the EndoPAT2000 device approximately every three months over the subsequent 18 months after the initiation of HER2-directed therapy +/- anthracycline. The primary endpoint was change in endothelial function over time using the reactive hyperemia index (RHI). Framingham Risk Score (FRS) and lower RHI are both known to be independent predictors of future cardiovascular events in the general population. RHI deterioration was defined as a 20% reduction from baseline RHI to any available follow-up RHI assessment. Univariate analyses assessed if age, FRS, baseline RHI, and RHI deterioration differed between recipients and non-recipients of anthracycline using the Wilcoxon test. A multivariate logistic model evaluated FRS, age, and anthracycline receipt as possible independent predictors of RHI deterioration. Results: Among 38 eligible patients who consented and completed baseline assessments in addition to at least one follow-up assessment, 17 (45%) subsequently received anthracycline. 145 total follow-up RHI assessments were available overall (5 per patient on average). There were no differences between recipients and non-recipients of anthracyclines with regard to age [mean 49 years (SD 12) vs 53 years (SD 11); p=0.25], baseline FRS [mean 1.0 (SD 1.0) vs 1.5 (SD 1.4); p= 0.28] or baseline RHI [mean 2.4 (SD 0.6) vs 2.1 (SD 0.7); p=0.09]. RHI deterioration was more common for anthracycline recipients (mean 43% vs 21%; p=0.004), and in the multivariate model, anthracycline use was the only independent predictor of RHI deterioration (odds ratio: 2.8; 95% confidence interval: 1.35-6.07; p=0.006). Conclusions: This study suggests that endothelial dysfunction is more common after combined anthracycline and HER2-directed therapy than after HER2-directed therapy alone. RHI should be further studied as a possible early biomarker of cardiovascular toxicity in patients receiving treatment for breast cancer.

Abstract Background: Aortic stenosis (AS) causes left ventricular (LV) pressure overload, leading to adverse LV remodeling and dysfunction. Identifying early subclinical markers of LV dysfunction in patients with significant AS is critical as this could provide support for earlier intervention, which may result in improved long-term outcomes. We therefore examined the impact of severe AS and its consequent increase in LV afterload on myocardial deformation and rotational mechanics by 2-dimensional (2D) and 3-dimensional (3D) speckle-tracking echocardiography. Methods: We prospectively measured various strain parameters in 168 patients (42% female, mean age 72±12 years) with severe AS and LV ejection fraction (EF) ≥50%, and compared them to normal values found in literature. 2D and 3D images were analyzed for global longitudinal strain (GLS), global circumferential strain (GCS), global radial strain (GRS), basal rotation, apical rotation, and peak systolic twist. We further assessed the degree of concordance between 2D and 3D strain, and examined their association with measures of LV preload and afterload. Results: Patients with severe AS exhibited significantly lower GLS and GRS but higher GCS, apical rotation, and twist by 2D and 3D echocardiography compared with published normal values (P=0.003 for 3D twist,P<0.001 for all others). Agreement between 2D- and 3D-GLS by concordance correlation coefficient was 0.49 (95% confidence interval: 0.39-0.57). GLS was correlated with valvulo-arterial impedance, a measure of LV afterload (r=0.34, p<0.001 and r=0.23, p=0.003, respectively). Conclusion: Patients with severe AS demonstrated lower-than-normal GLS and GRS but appear to compensate with higher-than-normal GCS, apical rotation, and twist in order to maintain a preserved LVEF. GLS showed a modest correlation with valvulo-arterial impedance.

Abstract Background: Aortic stenosis (AS) causes left ventricular (LV) pressure overload, leading to adverse LV remodeling and dysfunction. We examined the impact of severe AS and its consequent increase in LV afterload on myocardial deformation and rotational mechanics by 2-dimensional (2D) and 3-dimensional (3D) speckle-tracking echocardiography. Methods: We prospectively measured various strain parameters in 168 patients (42% female, mean age 72±12 years) with severe AS and LV ejection fraction (EF) ≥50%, and compared them to normal values found in literature. 2D and 3D images were analyzed for global longitudinal strain (GLS), global circumferential strain (GCS), global radial strain (GRS), basal rotation, apical rotation, and peak systolic twist. We further assessed the degree of concordance between 2D and 3D strain, and examined their association with measures of LV preload and afterload. Results: Patients with severe AS exhibited significantly lower GLS and GRS but higher GCS, apical rotation, and twist by 2D and 3D echocardiography compared with published normal values (P=0.003 for 3D twist,P<0.001 for all others). There was modest agreement between 2D and 3D GLS measurements (concordance correlation coefficient 0.49, 95% confidence interval 0.39-0.57). GLS was modestly correlated with valvulo-arterial impedance, a measure of LV afterload (r=0.34, p<0.001 for 2D and r=0.23, p=0.003 for 3D). Conclusion: Patients with severe AS demonstrate lower-than-normal GLS and GRS as a result of increased afterload but appear to compensate with higher-than-normal GCS, apical rotation, and twist in order to maintain a preserved LVEF. Our study provides, to our knowledge, the most comprehensive analysis to date of myocardial deformation and rotational mechanics by 2D and 3D speckle-tracking echocardiography in patients with severe AS and preserved LVEF.

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 >10% to an absolute value of <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 <-18% in 3D global longitudinal strain had a sensitivity of 82% and specificity of 99%, while for 3D global circumferential peak systolic strain of <-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

Abstract Background Left ventricular ejection fraction (LVEF), end diastolic, end systolic volumes (EDV, ESV) and global longitudinal strain (GLS) are very important parameters that are frequently reported in cardiology. Normal cardiac geometry was not considered in articles that published normal values. It is important to know normal parameters for population studies. Our hypothesis is to analyze how EF, volumes and GLS may vary by age groups, gender and BMI in a population with normal cardiac geometry. Purpose To define the values in EF, volumes and GLS measurements in a healthy population with normal cardiac geometry stratified by age groups, gender and body mass index (BMI). Methods This is a single center retrospective study conducted from 2008 to 2018. We selected 4557 subjects (2605 females, 1952 males) >18 years with ≤ mild valvular heart disease, who underwent 2D-echocardiography (2DE) at Mayo clinic, Rochester. All selected subjects had normal LV geometry (i.e., LV mass index≤88g/m2 in females and ≤102g/m2 in males and relative wall thickness ≤0.42 measured by 2DE) and without any cardiovascular risk factors or structural or functional abnormality determined by 2DE. Based on age groups, gender and BMI, we assessed the variability in volumes indexed to body surface area, EF and GLS by Mean ± SD and two sample t-test. Results Mean age was 54±15 years (females = 53±15, males = 56±16), body surface area was 1.9 m2±0.2 (females = 1.8±0.2, males = 2.1±0.2), LV GLS −20.7% ±2 SD (females = −21.2±2, males= −20.2±1.9) ranging −16.1 to −27.6 in both genders (Figure); LVEF by Biplane volume method 62.6% ± 4 SD (females = 63±4.3, males=62±4.5). The end diastolic volume 63.6±11.7 cc/m2 (female = 59.9±10.3, males = 68.1±11.8) and end systolic volume 23.9 cc/m2±5.4 (female = 22.3±4.8, males = 25.9±5.5). LV GLS, Biplane EF values were higher in females and EDV and ESV values were higher in males. LV GLS values decreased with age in females (P<0.0001). While EF increased with age in both genders (P<0.0001), EDV and ESV values decreased with age (P<0.0001). When each gender is sub-divided based on their BMI (<25 and ≥25), GLS, EDV and ESV values were higher in population with BMI <25 (P<0.0001). Normal geometry variables Conclusion To our knowledge, this is the biggest single center study to evaluate LV GLS values, LV EF, ED, ES volumes. These results can be used as reference values in a normal population. Acknowledgement/Funding None