Daryanani, Andres

Background: Major adverse cardiovascular events (MACE), including myocardial infarction, acute coronary syndrome, ischemic heart disease requiring revascularization, stroke, and heart failure, have been documented as significant contributors to mortality in cancer survivors. Coronary artery calcium (CAC) can predict MACE in non-cancer populations, while calcium in the aorta (CA) has not been evaluated as a prognostic marker. Every patient diagnosed with cancer undergoes a standard-of-care Positron Emission Tomography-Computed Tomography (PET-CT) or a chest CT before the initiation of chemotherapy. Hypothesis: To determine whether the CAC or CA of patients with Hodgkin's or non-Hodgkin's lymphoma, derived from standard-of-care PET-CT/chest CT, can predict the incidence of MACE. Methods: Patients treated with anthracycline-based chemotherapy, diagnosed and followed from January 1, 2013, through June 30, 2023, were included. Patients who did not undergo a PET-CT or CT, and/or developed MACE before treatment initiation were excluded. Univariate and multivariate adjusted Cox regression models were employed to assess whether the presence of CAC, CA, or CAC-CA was associated with the development of MACE. Calcium was retrospectively quantified using TeraRecon software (Durham NC) and categorized as: 0, 1-99, and >100. Outcome analyses was estimated using the Kaplan-Meier method. Results: 326 patients were included, mean age of 55 years (range: 52-60), predominantly male 201 (61%) and white 314 (96%), CAC was found in 89 patients and CA in 140. In the univariate regression model, a statistically significant association was found with values >100 for CA, CAC and CAC-CA with the risk of MACE. (Fig 1a/b/c). CAC equal to 0 demonstrated a significant protective effect against MACE. (Fig 1a). In the multivariable analysis, these associations persisted even after adjusting for comorbidities. (Table 1). Conclusion: CAC, CA and CAC/CA >100 in the standard-of-care CT/PET CT are predictors of MACE in lymphoma patients undergoing anthracycline treatment, a CAC equal to 0 has protective effect, these relationships remained statistically significant after adjusting for comorbidities.

Abstract Introduction Anthracyclines (ACs) have been identified as cardiotoxic drugs. They are associated with contractile dysfunction of the heart, which can manifest as heart failure. However, differentiating between HFrEF (left ventricular ejection fractions [LVEF] ≤40%) or HFpEF (LVEF >40%) has been overlooked. Purpose Using a retrospective cohort of patients with breast cancer (BC), Hodgkin (HL) or non-Hodgkin lymphoma (NHL) and controls from the Rochester Epidemiology Project, we evaluated the association of ACs use with risk of HFrEF and/or HFpEF. Methods 797 subjects with BC, HL or NHL diagnosed from 1988 to 2010 were identified, 658 treated with ACs (ACs group) and 139 not treated with ACs (no-ACs group). Controls (n=1526) were subjects without cancer. The median (Q1, Q3) follow up was 11.5 years (7.4, 16.7). Cox proportional hazards regression was used to compare the risk of HFpEF and HFrEF in the three cohorts, adjustment for sex, CV comorbidities (type 2 diabetes [T2D], hypertension [HTN] and dyslipidemia), radiotherapy (RT), and ACs cumulative dose was performed. Results Baseline characteristics are shown in table 1. HFpEF occurred in 29/1526 subjects in the control group, 3/139 in the no-ACs group and in 14/658 in the ACs group. Compared to the control group, there was not an increased risk of developing HFpEF in the no-ACs group (HR 1.67, CI 95%: 0.5 – 5.53, p = 0.39) or in the ACs group (HR 1.83, CI 95%: 0.95 – 3.52, p = 0.06) (Figure 1). Compared with no-ACs group, the ACs group had a similar risk of developing HFpEF (HR 1.09, CI 95%: 0.3 – 3.87, p = 0.88). RT was associated with a lower risk of HFpEF (HR 0.21, CI 95%: 0.06 – 0.75, p = 0.01). In the multivariable analysis, T2D (HR 6.91, CI 95%: 3.07-15.56, p = <0.0001) was associated with higher risk of HFpEF. A cumulative dose of ACs > 250 mg/m2 was not associated with increased risk of HFpEF. HFrEF occurred in 25/1526 subjects in the control group, in 4/139 in the no-ACs group and in 31/658 in the ACs group. Compared to the control group, the ACs group had a significant increase in the risk of HFrEF (HR 4.77, CI 95%: 2.76 – 8.22, p < 0.0001), the no-ACs group did not (HR 2.81, CI 95%: 0.97 – 8.12, p = 0.055) (figure 2). RT was associated with lower risk of HFrEF (HR 0.29, CI 95%: 0.13 – 0.65, p = 0.002). In the multivariable analysis, ACs (HR 4.23, CI 95%: 2.4-7.47, p = < 0.0001) being male (HR 2.45, CI 95%: 1.43 – 4.15, p < 0.0001), smoking history (HR 2, CI 95%: 1.16 – 3.44, p < 0.01), and HTN (HR 3.23, CI 95%: 1.9 – 5.61, p < 0.0001), were associated with higher risk of HFrEF. A cumulative dose of ACs > 250 mg/m2 was not associated with increased risk of HFrEF. Conclusion To our knowledge this is the first study to differentiate between HFpEF and HFrEF in this cohort. ACs were not associated with increased risk of HFpEF. However, ACs were associated with increased risk of HFrEF, but not with a specific dose. These results should be validated in other population cohorts.

Abstract Background Breast cancer survivorship has markedly improved in the last two decades due to improved therapies. Among these, adjuvant chest radiotherapy stands out as an integral part of the current treatment. Chest radiotherapy can trigger accelerated atherosclerosis, which, coupled with cardiovascular (CV) risk factors common to this population, can lead to increased rates of coronary artery disease (CAD). ESC 2022 guidelines have established both Exercise Stress Echocardiography (ESE) and Dobutamine Stress Echocardiography (DSE) as cost-efficient and reliable tools for screening this patient population. Recommendations include ESE or DSE 5 years after radiotherapy as a screening tool. Double product (DP), an index common to both tests, parallels myocardial oxygen consumption. It has been used to predict major adverse cardiovascular events (MACE) in other cohorts. Purpose We sought to evaluate if DP could be used as a prognostic indicator for MACE (myocardial infarction, stroke, cardiovascular death, and heart failure) in this population. Methods Breast cancer patients treated with adjuvant radiotherapy from 2000 to 2022 were included. ESE or DSE was done after a mean of 5.4 years (1Q-2.2, 3Q-7.5) post-radiotherapy. Uni and multivariable adjusted Cox regression models were performed to evaluate the association between DP quartiles achieved and the risk of MACE in DSE and ESE groups. MACE-free survival among different quartiles was plotted with the Kaplan Meier method. Results 696 patients were included, with a mean age of 65 (SD 10.0) and 72 (SD 9.4) in ESE and DSE respectively. 61% of patients had ESE. In ESE, we observed increased rates of MACE in the 1st quartile when compared to the other quartiles (Figure 1a). On the other hand, univariate and multivariate Cox models established that for every increase of 1000 units of DP achieved during ESE, there is a risk-reduction of 9% [HR=0.91 (0.86-0.95); p=<0.01] in the future incidence of MACE, thus establishing DP as a protective marker. Additionally, advanced age was shown to be a major risk factor as well [HR=4.58 (1.91-10.9); p=<0.01]. In the DSE cohort however, the development of MACE was equally distributed across DP quartiles even after adjusting for existing comorbidities (Figure 1b). Cox analysis did not establish DP as a prognostic tool in this cohort (Table 1). Conclusion DP is established as an excellent prognostic tool for the detection of MACE in patients who underwent ESE. Patients who achieve higher DP quartiles during these tests have lower future rates of MACE. Regarding DSE, DP is not a good prognostic tool. This could be explained by higher burden of cardiovascular risk factors in this patient population. ESE should be recommended when possible.

Abstract Background Major adverse cardiovascular events (MACE), commonly defined as acute myocardial infarction, acute coronary syndrome/ischemic heart disease requiring revascularization, stroke, and heart failure, represent a significant cause of mortality among patients with cancer. With increased rates of both cancer and cancer survivorship, the identification of new predictive markers for the development of MACE in this population is crucial for implementing effective preventive and risk-mitigation strategies. Purpose To determine whether the presence of calcifications in the coronary arteries (CAC) or aorta (CA) of lymphoma patients, as reported in standard-of-care PET-CT (Positron Emission Tomography-Computed Tomography) or chest CT (Computed Tomography) scan, can predict the occurrence of MACE. Methods A Retrospective analysis was conducted on a cohort of patients diagnosed with Hodgkin or non-Hodgkin lymphoma and treated with anthracycline-based chemotherapy. Patients were diagnosed from January 1, 2013, and followed through to June 30, 2023. The reference point for the study was the radiologist’s report of the PET-CT or chest CT conducted before the initiation of anthracycline therapy. Patients who did not undergo a PET-CT or CT before the start of treatment, and/or developed MACE before treatment initiation were excluded. Univariate and multivariate adjusted Cox regression models were employed to assess whether the presence of CA and CAC was associated with the development of MACE. Associations with outcomes were evaluated using the Kaplan-Meier method and Cox regression. Results 326 patients were included with a mean age of 55 years (range: 52-60), predominantly male 201 (61%) and white 314 (96%), CAC was reported in 75 patients (23%) and CA in 18 (6%). In the univariate regression model, a statistically significant association was found between the presence of both CA and CAC with the risk of MACE. CAC showed a stronger association with the development of MACE than CA (HR: 3.7 [1-7.9], p=0.0005 vs HR: 2.9 [1- 8.5], p=0.050). In multivariable analysis CAC emerged as the strongest predictor of MACE (HR: 2.9 [1.3 – 6.4], p=0.01), after accounting for hypertension, diabetes, dyslipidemia, and GFR <60 (Table 1), while the association with CA attenuated (HR: 2.01 [0.7-6.5], p=0.2010) and was no longer significant (Table 2). Conclusion CAC in the standard-of-care PET/-CT scans was a predictor of MACE in lymphoma patients treated with anthracyclines, while the association with CA weakened in multivariable analyses and was likely underpowered given the small number of patients with CA. If replicated, this finding warrants closer surveillance of this group of patients and can be considered as a non-invasive cardiovascular risk marker.

Introduction: Multiple Valvular Heart Disease (VHD), defined as at least moderate stenotic or regurgitant lesions in ≥2 valves, mixed VHD as combination of lesions in the same valve and mitral annular calcification (MAC) are common conditions. Association between multiple-mixed VHD (MMVHD), MAC and MACE in patients exposed to Radiation Therapy (RT) and/or chemotherapy (CT) who underwent Transcatheter Aortic Valve Replacement (TAVR) has not been studied. Aim: Assess the presence of MMVHD and MAC in cancer patients with prior RT and/or CT and their correlation with MACE (cardiovascular death, myocardial infarction, revascularization, stroke and hospitalization for heart failure) after TAVR. Methods: 544 patients were included and divided into 3 groups: 187 with prior chest RT and CT (RT/CT), 155 CT only, and 202 without CT/RT as controls (Table 1). Data was obtained from the pre-procedure echocardiogram and quantified in a 1-6 scale (none, mild, mild/moderate, moderate, moderate/severe and severe). Fisher’s exact test or chi-square were used to compare categorical. Multiple VHD-MACE correlation was evaluated through multivariable Cox analysis using a proportional hazards model. Results: The prevalence of Multiple VHD was 37.4% in RT/CT, 23.2% in CT, and 13.9% in controls p<0.001(Figure 1). The RT/CT group had a significantly higher prevalence of severe MAC. Multiple VHD predicted MACE at 18 months after TAVR in RT/CT (HR 3.42, CI 1.93-6.08, p<0.001) and in CT (HR 2.55, CI 1.39-4.66, p=0.002) (Table 2). In RT/CT, severe MAC also predicted MACE (HR 3.68, CI 2.13-6.37, p<0.001), while it was not a predictor in the other groups. Stenotic or regurgitant VHD was more prevalent in the RT/CT group (Figure 2). Conclusions: Multiple VHD was found higher in RT/CT and predicted MACE at 18 months post-TAVR, including CT only patients. Severe MAC was also a strong predictor of the outcome in RT/CT patients. Pre-TAVR evaluation of MMVHD lesions is crucial for optimal patient management.

Introduction: Assessing baseline cardiovascular (CV) risk factors is crucial for identifying cancer patients at higher risk of cardiotoxicity (CT). While both CT specific scores, including Heart Failure Association-International Cardio Oncology Society (HFA-ICOS) and our institutional score, as well as general CV scores like Atherosclerotic cardiovascular disease (ASCVD), have been used to assess CT risk; in lymphoma patients undergoing anthracycline therapy, their utility remains unknown. Aim: Evaluate the performance of each risk score to predict CT in a cohort of newly diagnosed lymphoma patients undergoing anthracycline treatment, followed for a median of 5.4 years. Methods: 326 Hodgkin and non-Hodgkin lymphoma patients treated and followed from 2013 to 2021 were prospectively assessed. Baseline measurements of the three risk scores were obtained. ASCVD score was not assessed in patients >80 or <40 years old or without baseline cholesterol. CT was defined during or after one year of chemotherapy as severe, moderate, or mild according to 2022 ESC guidelines. Logistic regression and AUC were used to assess the association of each score and compare the models. Results: Among 326 patients, 78 developed CT (8 severe, 21 moderate, 49 mild). A high-risk score from HFA-ICOS was significantly associated with severe and moderate CT(OR: 6.1, p=0.001), sensitivity 37%, and specificity 88%. A very high-risk classification of the institutional score was associated with severe and moderate CT (OR: 8.4, p=0.006), sensitivity 44%, and specificity 81%. No association was found between the ASCVD score stratification and CT. When mild CT was included in the analysis, the AUC values were lower (see Table 1). Conclusions: Cardio-oncology risk scores were associated with severe and moderate CT, outperforming ASCVD, but their predictive capacity was weak. Incorporating other serum or imaging biomarkers into the models may improve the predictive accuracy of CT risk assessment.

Background: CD19 CAR T-cell therapy is a novel cancer treatment for B-cell malignancies. Systemic inflammation due to Cytokine Release Syndrome (CRS) can occur. Elevated levels of cytokines have been linked to valve damage. Hypothesis: Evaluate changes in valve morphology or progression of valvular heart disease in adult patients after CD19 CAR T-cell therapy and by clinical CRS grade. Methods: Patients that underwent CD19 CAR T-cell therapy with both a baseline and a post-treatment transthoracic echocardiogram (TTE) were included. Patient characteristics and outcomes were abstracted from the electronic medical record. CRS was categorized as CRS<2 and CRS ≥2 for all patients using the ASTCT 2019 criteria. Valve thickening was graded as a dichotomous variable. Valve disease (regurgitation or stenosis) was ranked on a 1-to-6-point numeric scale (none, mild, mild-moderate, moderate, moderate-severe, severe) and grade point value difference was calculated. Variables were compared by Chi Squared and Student’s t tests. Results: 114 patients were included with a median TTE follow-up of 44 days, 54% developed CRS ≥2 (Table 1a). Overall, no statistically significant changes in valve morphology and valve disease progression were observed in the cohort (Figure 1a, 1b). Among CRS groups, valve morphology changes and valve disease progression were similarly distributed (21% in CRS <2 vs 19% in CRS ≥2, p=0.623 and 28% in CRS <2 vs 24% in CRS ≥2, p=0.62 respectively) (Fig. 1a). In the cases that progression was observed, it was mostly mild, and regurgitation was the most common pattern (Fig. 1c). Conclusions: This is the first study to evaluate the incidence of cardiac valve disease progression or thickening in patients treated with CD19 CAR T therapies. We can conclude that no progression of valve disease or changes in valve morphology were observed in its entirety or by CRS groups. Longer follow up is needed to validate these findings.

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 &lt;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 &gt;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=&lt;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 &lt;24% and &lt;25% were associated with CT at T1 and T2, respectively. Values &gt;26% had an excellent NPV for the development of CT. Baseline TAPSE values &lt;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 &lt;0.023). The cumulative incidence of MACE was higher in the group of positive DSE (p&lt;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&lt; 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’&gt;14; and left ventricular ejection fraction &lt;50%); stage 2 (left atrial volume index &gt;34ml/m2; moderate to severe mitral regurgitation and atrial fibrillation), stage 3 (systolic pulmonary hypertension&gt; 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&lt;0.05. Results RT/CT had a higher prevalence of moderate to severe mitral regurgitation (11.8%) p &lt;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&lt;0.001, CT HR 4.49 CI (2.27 – 8.89) p&lt;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 &gt;3 for RT/CT (57.4%) and CT only (61.2%) vs. CL (27.2%) p&lt;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.