Villarraga, Hector R.

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 INTRODUCTION Accelerated atherosclerosis has been described in breast cancer patients receiving cardiac exposure from adjuvant radiotherapy (RT). As a result of multidisciplinary care, breast cancer cure rates have improved in recent decades. Therefore, evaluating radiation-induced heart disease (RIHD), especially coronary artery disease (CAD), is essential. The 2022 cardio-oncology European Society of Cardiology (ESC) guidelines recommend screening patients 5 to 10 years after RT for CAD according to cardiovascular risk factors. This screening is generally recommended with exercise stress echocardiography since it can assess the physiological functional performance. Until now, it is unknown if dobutamine stress echocardiography (DSE) is an equal screening tool and if it can predict major adverse cardiovascular events (MACE) (myocardial infarction, stroke, cardiac death, revascularization). PURPOSE Evaluate if DSE is an adequate tool to stratify and predict MACE in post-radiotherapy patients. Methods A retrospective, descriptive cohort study was conducted. Patients who had chest RT for breast cancer and underwent DSE from 2000 to 2022 were included. A bivariate analysis, including Kruskal Wallis and Pearson Chi-Squared test, was done to identify variables associated with a positive DSE. A multivariable Cox Model for MACE and a time-to-event curve for MACE were also performed. Results We identified 163 patients that underwent DSE after a median time of 5.8 years from the end of RT. The median age was 74 years, 98.2% were female, 50% had left and 45% right breast cancer, 81% had hypertension, 41% diabetes mellitus, 71% dyslipidemia, 34% were smokers, and 19% had a prior myocardial infarction. The average dose of photon RT to the chest was 55Gy in the cohort, and 40% received chemotherapy before RT. Patients were divided into two groups: positive and negative DSE. A positive DSE was seen in 19.6%. The median (Q1, Q3) regional wall motion abnormalities (RWMA) of patients with a positive DSE was 1 (1, 1.015) at baseline and 1.280 (1.190, 1.520) at peak stress, and for a negative DSE, was 1 (1, 1) at baseline and peak stress. 88.2% of negative DSE and 87.5% of positive DSE achieved the target heart rate of 85%. HTN, dyslipidemia, and prior MI were significantly associated with a positive DSE (p <0.023). The cumulative incidence of MACE was higher in the group of positive DSE (p<0.001), even after adjusting for hypertension, diabetes mellitus, dyslipidemia, smoking, and prior myocardial infarction, with a hazard ratio of 2.500 (1.51 – 4.13) and a p< 0.001. Similar results were observed regardless of RT laterality. Conclusions In breast cancer survivors that received adjuvant radiotherapy as part of multidisciplinary care, a positive DSE was an independent predictor of MACE compared to a negative result. These results support the usefulness of dobutamine stress echocardiography as a screening tool in breast cancer survivors.Kaplan-Meier Curve for MACE

Abstract Background Staging classification for severe aortic stenosis (AS) based on the extent of cardiac damage has been correlated with outcomes in the general population. This is categorized based on the following echocardiographic findings: stage 1 (increase in the left ventricular mass index; E/e’>14; and left ventricular ejection fraction <50%); stage 2 (left atrial volume index >34ml/m2; moderate to severe mitral regurgitation and atrial fibrillation), stage 3 (systolic pulmonary hypertension> 60mmHg and moderate to severe tricuspid regurgitation) and stage 4 (moderate to severe right ventricular dysfunction); its applicability in a cancer population exposed to chemo+/- radiotherapy and its correlation with MACE has not been explored. Purpose To evaluate if this staging system predicts MACE (cardiovascular death, myocardial infarction, coronary revascularization, stroke, and hospitalization for heart failure) at 18 months after TAVR in cancer patients who were previously exposed to cardiotoxic therapies. Methods We retrieved data of patients that underwent TAVR from 2013 to 2021. 544 patients were included in this study and divided in 3 groups: 187 patients with prior chest Radiotherapy and Chemotherapy (RT/CT), 155 with CT only, and 202 cancer patients not exposed to CT or RT control group. This was further subdivided in two groups based on the staging system in: stage ≤ 2 and ≥3. Fisher's exact test or chi-square was used to compare categorical variables and clinical outcomes among groups and ANOVA for continuous variables. Echocardiographic findings and correlation with the outcome were evaluated by a multivariable Cox model analysis and assessed by a proportional hazards model for time to event. Kaplan–Meier curves were performed to determine the event-free survival rate. Significance was considered as a p<0.05. Results RT/CT had a higher prevalence of moderate to severe mitral regurgitation (11.8%) p <0.001 and tricuspid regurgitation (13.9%) p=0.02. Stage ≥3 was (24.1%) in the RT/CT, (9.4%) in CT, and (16.1%) in controls p= 0.004. Additionally, stage ≥3 was a predictor of MACE at 18 months: RT/CT group HR 6.43 (3.06 – 13.1) p<0.001, CT HR 4.49 CI (2.27 – 8.89) p<0.001 and control HR 2.20 CI (1.13 – 4.26) p=0.02 (Table 1). MACE at 18 months for stage ≥3 was higher for all groups vs. stage ≤ 2. MACE at 18 months after TAVR was significantly higher in stage >3 for RT/CT (57.4%) and CT only (61.2%) vs. CL (27.2%) p<0.001 (Figure 1B). Conclusions In addition to predicting aortic stenosis risk in cancer patients before TAVR, cardiac damage staging is a strong predictor of MACE at 18 months in patients post-RT/CT and CT and suggests that these patients may benefit from earlier stratification for TAVR prior to reaching stage 3. Future studies with longer follow-up should be explored to evaluate its usefulness in this complex population.

Abstract Background Exercise stress echocardiography (ESE) is a non-invasive, radiation-free, and widely available technique that has demonstrated a reliable accuracy for the detection of coronary artery disease (CAD). Chest radiotherapy (RT) is associated with accelerated age-related atherosclerosis and fibrosis in a dose-dependent manner. ESE plays a role as a screening tool of RT induced heart disease, however, the prognostic value of changes in regional wall motion abnormalities in this population during ESE has not been evaluated. Methods This is a retrospective cohort study of breast cancer survivors treated with adjuvant RT that underwent ESE from 2000-2020 after treatment completion. Outcomes evaluated were: major adverse cardiovascular events (MACE: cardiovascular death, myocardial infarction, revascularization and stroke); and all-cause mortality. A univariate analysis was performed to characterize the population. Continuous variables were presented as means ± standard deviation (SD) or median with quartile 1 and 3 (Q1, Q3), and categorical variables as numbers and percentages. A Cox regression model adjusted by age and cardiovascular risk factors was used to evaluate variables associated with outcomes, and a time to first event approach was used. A p-value of <0.05 was considered statistically significant. Results From 2000-2020, 507 patients, with a mean age 66 ± 10 years, underwent ESE at a median of 5.8 years after RT completion. The most prevalent comorbidities were dyslipidemia (59%), HTN (55%) and obesity (37%). 55% underwent RT for left-sided breast cancer and 45% for right-sided, and median RT dose was 6000 cGy. Baseline characteristics are presented in Table 1. Most patients underwent Bruce Protocol (92%). Patients exercised a mean time of 6.6 minutes achieving 7.3 METS and 109% of functional aerobic capacity (Table 2). At a median follow up of 7.8 years, 61 MACE events occurred. Predictors of MACE were double product, baseline and stress EF, baseline and peak regional wall motion abnormalities (RWMA), development of new ischemic RWMA, inability to reach 85% of maximum HR, and an abnormal EF response with stress after adjusting for age, HTN, DM, smoking history, dyslipidemia, obesity, prior MI and cancer staging (Fig 1). Predictors of all-cause mortality were METS, LV mass index, baseline and peak RWMA, development of new ischemic RWMA and an abnormal EF change with stress even after adjusting for variables described previously (Fig 2). Conclusions The development of new or worsening RWMA of just 2 segments with stress, was a significant predictor of MACE and all-cause mortality in a large cohort of breast cancer survivors undergoing multidisciplinary management including adjuvant RT. Special emphasis on management of cardiovascular comorbidities and closer surveillance are recommended for these patients.

Introduction: Exercise Stress Echocardiography (ESE) is recommended as a screening tool for the evaluation of Coronary Artery Disease (CAD) in patients with suspected Radiation-Induced Heart Disease (RIHD). Up to now, studies have only evaluated its association with the extent of CAD. Hypothesis Cancer survivors treated with chest Radiotherapy (RT) that undergo an ESE and have a +ESE develop more MACE than those who have -ESE. Methods: A retrospective, descriptive, cohort study was conducted. Patients who had chest RT and underwent ESE with Treadmill Bruce Stress Protocol, from 2000 to 2012, at Mayo Clinic Rochester and Mayo Clinic Health System were included. A univariate analysis was performed to characterize the population. An analysis including Kruskal Wallis and Pearson Chi-Squared tests was completed to identify variables associated with + SE (Table 1). Multivariable Cox Model for MACE was conducted and is shown in Table 2. A time-to-event curve using Kaplan-Meier estimates is shown in Figure 1. Results: We identified 113 patients, with a mean age of 67 years and a median follow-up of 15.1 years. Of those, 99% were female, 98% were breast cancer survivors, 59% had HTN, 14% DM, 11% AFib, 2% COPD, and 12% had a history of MI. All the patients received >3000cGy of Photon RT, and 57% were treated with systemic cancer therapies. A +ESE was seen in 20.3% of the patients with no significant difference in METS achieved compared with patients who had a -ESE. COPD, RT dose, and systemic therapies, specifically doxorubicin, were associated with a +ESE. The cumulative incidence of MACE was higher in the group of +ESE (p=0.029). After adjustment for HTN, DM, smoking history, hyperlipidemia, and prior MI, the HR for MACE associated with a +ESE was 1.97 (1.09-3.59). Conclusion: MACE was more frequent in patients with a +ESE who received chest RT and doxorubicin versus -ESE. These results support the usefulness of ESE in cancer survivors after RT as a cardiovascular screening tool.

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

Abstract Background Obesity, defined by the World Health Organization (WHO) as a BMI greater than 30k g/m2, has reached epidemic proportions worldwide, related to approximately 2.8 million deaths/year as of June 2021. WHO sub-classifies obesity based on BMI in Class 1: 30–34.9 kg/m2, Class 2: 35–39.9 kg/m2, and Class 3: ≥40 kg/m2. This state of increased body weight is associated with an increased risk of cardiovascular disease. Cardiac remodeling can be affected by obesity and/or other cardiovascular risk factors (CVRF) as an adaptive physiological response. The remodeling patterns, Normal Geometry (NG), Concentric Remodeling (CR), Concentric Hypertrophy (CH), and Eccentric Hypertrophy, are classified by changes in Relative Wall Thickness (RWT), ≤ or >0.42, and/or Left Ventricular Mass Index (LVMI g/m2), ≤ or >88 for women and ≤ or >102 for men. Left Ventricular Ejection Fraction (LVEF) can remain within normal limits in patients with obesity with multiple CVRF and cardiac remodeling. Left Ventricular Global Longitudinal Strain (LV-GLS) and Right ventricular free wall strain (RV-FWS) can be useful to detect subclinical myocardial dysfunction. The aim of this study was to evaluate if these strain variables are affected in patients with obesity associated to other CVRF in relation to cardiac remodeling type when compared to controls. Methods 2859 patients with BMI ≥30 kg/m2 and 2616 normal-weight controls (BMI between 18.5 and 24.9 kg/m2), with normal and abnormal cardiac geometry, and normal ejection fraction by echocardiography performed between 01/01/2008 and 12/31/2018, were compared. Obesity was classified based on the World Health Organization. CVRF included were Hypertension (HTN), Diabetes Mellitus (DM), Dyslipidemia, history of Vascular Event (myocardial infarction and/or stroke), and Obstructive sleep apnea (OSA). Results BMI, cardiac geometry, CVRF, and the number of comorbidities independently affected GLS and RV-FWS (Figure 1 and Figure 2). LV-GLS and RV-FWS values [mean (SD)] in obesity classes 1, 2, and 3 were −19 (2.9), −18.9 (2.9), −18.7 (2.9) & −24.2 (5.2), −23.8 (6.2), −24.5 (5.9), respectively. In the control group LV-GLS and RV-FWS values [mean (SD)] were −20.1 (3.0) & −27 (5.6), respectively. CH was associated with the greatest decrease in LV-GLS and RV-FWS in males and females, regardless of BMI (Figure 2). LV-GLS values [mean (SD)] associated to CH for obesity class 1, 2, and 3, and controls in females were −18.4 (3.4), −18 (3.1) −17.6 (3.6), and −17.8 (4), respectively, and for obesity class 1, 2, and 3, and controls in males were −16.1 (3.5), 16.5 (3.2), −14.4 (2.7), and −16.6 (4.7), respectively (Figure 1). Conclusion Obesity associated to CVRF and CH have the lowest values of GLS in patients with normal ejection fraction. These values were exceedingly below average compared to other groups. These parameters should be used as reference values for this population. Funding Acknowledgement Type of funding sources: None.