Villarraga, Hector R.

Background: To identify factors that increase the specificity of the treadmill exercise test (TMET), and develop a novel scoring system which accounts for functional capacity to aid in determining the need for further testing. Methods: We retrospectively evaluated the electronic health records of 600 patients who had positive TMET results and follow-up stress echocardiography from 1-January-2004, through 31-December-2016. Correlations between clinical and aerobic variables and multivessel disease (MVD) were determined. Duke Treadmill Score (DTS) was calculated and compared with a novel scoring system titled the Intermediate-High-Workload Treadmill Score (IHWTS) that used variables associated with MVD. Results: In total, 124 of 600 patients (21%) had coronary catheterization, and 51 of these patients (41%) had MVD. Mean (SD) DTS was –2.10 (6.3) among patients with MVD vs –0.16 (5) among patients without MVD (p = 0.06). Mean (SD) functional aerobic capacity (FAC) was 76% (20%) among patients with MVD vs 90% (21%) among patients without MVD (p < 0.001). Mean (SD) metabolic equivalent (MET) was 7 (2) among patients with MVD vs 8 (2) among patients without MVD (p = 0.002). Only 6 (12%) of patients with MVD achieved 9 MET or greater on TMET. DTS less than 4 did not distinguish between patients with and without MVD (p = 0.67). Age, hypertension and FAC were independently associated with MVD (all p < 0.05). Conclusions: Our novel scoring system IHWTS utilized age, hypertension, and FAC appeared comparable to DTS to risk-stratify patients regardless of baseline symptoms. Clinical parameters such as hypertension along with exercise functional capacity should be considered when evaluating a positive TMET result in patients that achieve an intermediate-high workload >5 Metabolic Equivalents (METs).

The field of malignant hematology is transforming with novel immunotherapeutic approaches. Unfortunately, quality of life, treatment efficacy, and life expectancy are negatively affected by cardiotoxic side effects of treatment. To date, the exact mechanism and incidence of cardiotoxicity associated with these therapies is unclear. These events are believed to be triggered or occur concurrently with cytokine release syndrome. Furthermore, there are no formal guidelines to provide evaluation, treatment, and surveillance. We aim to synthesize available literature with updates on the cardiotoxic effects of novel therapies used in malignant hematologic disorders, with a focus on chimeric antigen receptor T-cell therapy and bispecific T-cell engager therapy, along with a proposed algorithm that may guide pretreatment evaluation, monitoring during treatment, and post-treatment surveillance.

Abstract Purpose/Objectives: Proton therapy is under investigation in breast cancer as a strategy to reduce heart and lung exposure, which is associated with late cardiopulmonary adverse events and secondary malignancy. To date, studies investigating postmastectomy radiotherapy (PMRT) with protons have used conventional fractionation. We hypothesized that condensing treatment to 15 fractions would be safe based on evidence that breast cancer is more sensitive to higher dose fractions than surrounding normal tissues. Materials/Methods: We conducted a randomized non-inferiority phase II trial comparing conventional and hypofractionated proton PMRT with primary endpoint of 24-month complication rate (defined as grade 3 or higher late adverse events using CTCAE, v 4.0 and/or unplanned surgical intervention in patients undergoing mastectomy with reconstruction). With a 10% non-inferiority margin the study ensured 80% power and had a one sided-type I error rate of 0.05. Cardiotoxicity was assessed with serial transthoracic conventional and 2-dimensional speckle tracking echocardiography (2D-STE). Eligibility included age ≥ 18 years with non-inflammatory breast cancer resected by mastectomy with indications for PMRT. Assignment of treatments was balanced with respect to immediate breast reconstruction (IBR). Conventional fractionation group received 50 Gy in 25 fractions of 2 Gy, and hypofractionation group received 40.05 Gy in 15 fractions of 2.67 Gy (RBE 1.1). Target volume included the chest wall and axillary, supraclavicular, and internal mammary lymph nodes. All patients were treated with multi-field optimized pencil beam scanning (intensity modulated proton therapy). Results: Between 2016 and 2018, 82 patients were enrolled and randomized (41 conventional, 41 hypofractionation). Median patient age was 52 years. 32.9% were staged T3-T4 and 79.3% node positive at diagnosis. 57 of 82 patients (69.5%) elected IBR. The median mean heart dose was 0.49 Gy and the median ipsilateral lung volume receiving 40% of prescription or greater (V40%) was 13.6%. No significant changes on conventional or 2D-STE at end-of-treatment or 3-month follow-up compared to baseline were observed. The rate of ≥ grade 2 acute dermatitis was lower with hypofractionation (44% vs 15%, p = 0.006). Other ≥ grade 2 acute adverse events including esophagitis (0 vs 5%), infection (5% vs 2.4%) and skin hyperpigmentation (7.3% vs 4.8%) were not significantly different between the two arms. With a median follow-up of 38.3 months, the 24-month complication rate was conventional 14.6% vs hypofractionation 17.1% (absolute difference 2.4%, p=0.17, 95% CI [-, 15.7%]). In patients with IBR, 6 of 28 (21.4%) conventional and 7 of 29 (24.1%) hypofractionated patients developed complications (p =0.80). There was no significant difference in 3-year disease-free survival between the conventional (89.4%; 95% CI 80.0 – 99.8%) and hypofractionated (92.4%, 95% CI 84.5 – 100.0%) arms (p = 0.91). One local recurrence occurred in the hypofractionated arm simultaneous with regional and distant relapse. The remaining 6 recurrences were isolated distant events. Conclusions: Proton PMRT provided excellent locoregional control and normal tissue sparing. There were no subclinical echocardiographic changes indicative of radiation-induced cardiac dysfunction. Hypofractionation resulted in comparable disease control, tolerability and reconstruction outcomes as conventional fractionation. Although non-inferiority of hypofractionation could not be established based on the upper bound of the 95% confidence interval for complication rate being greater than 10%, both conventional and hypofractionation may be considered appropriate regimens for ongoing phase 3 randomized trials comparing photon and proton radiotherapy. Citation Format: Robert Mutter, Sharmila Giri, Briant Fruth, Nicholas Remmes, Aman Anand, Kathryn Ruddy, Hector Villarraga, Sebastian Santos Patarroyo, Elizabeth Yan, Kenneth Merrell, Lisa McGee, Tamara Vern-Gross, Bradley Stish, Robert Gao, Judy C. Boughey, Sean Park, Kimberly Corbin, Carlos Vargas. Phase II randomized trial of conventional versus hypofractionated post-mastectomy proton radiotherapy [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS4-05.

ImportanceAnthracyclines increase the risk for congestive heart failure (CHF); however, long-term cumulative incidence and risk factors for CHF after anthracycline therapy are not well defined in population-based studies.ObjectiveTo compare the long-term cumulative incidence of CHF in patients with breast cancer or lymphoma treated with anthracycline therapy compared with healthy controls from the same community.Design, Setting, and ParticipantsThis retrospective population-based case-control study included data from the Rochester Epidemiology Project. Participants included residents of Olmsted County, Minnesota, diagnosed with breast cancer or lymphoma from January 1985 through December 2010 matched for age, sex, and comorbidities with healthy controls, with a final ratio of 1 case to 1.5 controls. Statistical analysis was performed between July 2017 and February 2022.ExposuresCancer treatment and CHF risk factors.Main Outcomes and MeasuresThe main outcome was new-onset CHF, as defined by the modified Framingham criteria. Cox proportional hazards regression was used to estimate hazard ratios (HRs) to compare the risk of CHF in participants with cancer vs controls, adjusted for age, sex, diabetes, hypertension, hyperlipidemia, coronary artery disease, obesity, and smoking history.ResultsA total of 2196 individuals were included, with 812 patients with cancer and 1384 participants without cancer. The mean (SD) age was 52.62 (14.56) years and 1704 participants (78%) were female. Median (IQR) follow-up was 8.6 (5.2-13.4) years in the case group vs 12.5 (8.7-17.5) years in the control group. Overall, patients with cancer had higher risk of CHF compared with the control cohort even after adjusting for age, sex, diabetes, hypertension, coronary artery disease, hyperlipidemia, obesity, and smoking status (HR, 2.86 [95% CI, 1.90-4.32]; P &amp;lt; .001). After adjusting for the same variables, CHF risk was greater for patients with cancer receiving anthracycline (HR, 3.25 [95% CI, 2.11-5.00]; P &amp;lt; .001) and was attenuated and lost statistical significance for patients with cancer not receiving anthracyclines (HR, 1.78 [95% CI, 0.83-3.81]; P = .14). Higher cumulative incidence for patients treated with anthracyclines vs comparator cohort was observed at 1 year (1.81% vs 0.09%), 5 years (2.91% vs 0.79%), 10 years (5.36% vs 1.74%), 15 years (7.42% vs 3.18%), and 20 years (10.75% vs 4.98%) (P &amp;lt; .001). There were no significant differences in risk of CHF for patients receiving anthracycline at a dose of less than 180 mg/m2 compared with those at a dose of 180 to 250 mg/m2 (HR, 0.54 [95% CI, 0.19-1.51]) or at a dose of more than 250 mg/m2 (HR, 1.23 [95% CI, 0.52-2.91]). At diagnosis, age was an independent risk factor associated with CHF (HR per 10 years, 2.77 [95% CI, 1.99-3.86]; P &amp;lt; .001).Conclusions and RelevanceIn this retrospective population-based case-control study, anthracyclines were associated with an increased risk of CHF early during follow-up, and the increased risk persisted over time. The cumulative incidence of CHF in patients with breast cancer or lymphoma treated with anthracyclines at 15 years was more than 2-fold that of the control group.

Abstract Background The literature describing the complications following kyphoplasty is limited. This case report is a reminder that novel therapeutic strategies can be associated with unexpected complications. Case summary A 61-year-old woman with rheumatoid arthritis and degenerative lumbar disc disease underwent open posterior instrumented fusion with bilateral open L2 vertebroplasty elsewhere. A month after discharge, she presented to our institution with acute chest pain and dyspnoea. A subsequent gated cardiac computed tomography (CT) angiogram showed three distinct cardiopulmonary emboli. One of the cement fragments had perforated the inferior wall of the right ventricle close to the base of the posterior tricuspid valve leaflet with a moderate circumferential pericardial effusion. Operative extraction of multiple cement emboli as well as repair of the tricuspid valve was pursued. Postoperative echocardiogram showed trivial tricuspid regurgitation after repair. The patient had an uneventful postoperative course and was discharged from the hospital on postoperative Day 5. Discussion Cement embolization following kyphoplasty can be associated with serious complications such as vascular injury, hypoxaemia, pulmonary artery obstruction, and cardiac perforation. Clinicians must maintain a high index of suspicion as cement embolism may not always present acutely.

Introduction: Right ventricle (RV) dysfunction linked with acute Pulmonary embolism (PE) is associated with significant mortality. Several studies have documented use of RV free wall strain (RVS) for assessing mortality, but RV free wall systolic (RVSRs) and early diastolic strain rate (RVSRe) have not been explored. Hypothesis: The study aims to assess the RV function in longitudinal domain of contractility using 2 D speckle tracking echocardiography and evaluate if it was able to predict all-cause mortality at 30 days. Methods: This is a single center prospective study done between November 2012 to June 2020. 293 adult patients with acute PE having echocardiogram performed within 24 hours were enrolled and baseline comorbidities were recorded. 2 D Speckle tracking echocardiography was performed offline. Multiple logistic regression analyses and ROC were performed to evaluate if RV Strain (RVS) and strain rate (systolic-SRs, early diastolic-SRe) were able to predict all-cause mortality at 30 days. Results: Mean age was 65 ± 15 years, 60.7 % males and 41% had coronary artery disease, 29% had cancer and 11% had COPD. Mean free wall (FW) RVS was -19.7±7.7%, FW RV SRs was -0.9±0.4 s -1 , FW RV SRe was 0.8±0.3 s -1 . (Figure A) All-cause mortality was present in 11 patients (3.8%) at 30 days, 17 (5.8%) at 3 months and 29 (9.9%) at 6 months. In the Univariate analysis, FW RVS and FW RVSRs were significantly associated with 30 days all-cause, but after adjusting for age, cancer, and COPD, only FW RVSRs remains significant (p=0.02) with an AUC to predict 30-day all-cause mortality of 0.73 (95% CI 0.54-0.88) a cut-off value of -0.7 had a sensitivity of 73% and specificity of 64% (Figure B) Conclusions: The study demonstrated that RV Free wall SRs measured by 2 D STE is a good prognostic indicator for 30 days all-cause mortality in patients with acute PE. This novel modality could be used for risk stratification in the setting of acute PE.

Introduction: Subclinical cardiovascular involvement in COVID-19 patients has not been well described. 2D-Speckle Tracking Echocardiography derived global longitudinal strain (GLS) and systolic and early diastolic strain rate (SRs, SRe) measurements are more sensitive than standard echocardiographic parameters to diagnose subclinical mechanical dysfunction in patients with normal Left Ventricle Ejection Fraction (LVEF). Hypothesis: Evaluate subclinical myocardial mechanical function and reserve in active COVID-19 systemic disease patients with normal LVEF vs controls and between survivors and non survivors of COVID-19 in the longitudinal domain of contractility. Methods & Results: 166 adult patients with active COVID 19 having normal LVEF were included and compared to 89 healthy volunteers. Baseline parameters were recorded. Peak GLS, SRs and SRe, were measured offline. Mean age was 62.53 ± 18.96 years and 87 (52%) were males and Mean LVEF was 62±5%. COVID-19 patients had higher GLS compared to controls (-20.93%±0.30 vs. -18.48%±0.40; p value <0.0001), SRs was similar (-0.97 s -1 ±0.10 vs. -0.98 s -1 ±0.02, p value 0.2528) and SRe was lower (0.85 s -1 ±0.0 vs. 1.05 s -1 ±0.02; p value <0.0001) respectively. After adjusting for age and sex, GLS, SRs and SRe was significant (p<0.001). GLS, SRs and SRe were similar in survivors vs. non survivors (p NS), both groups had elevated biomarkers (cardiac troponin, NT-pro BNP, CRP), but non survivors had higher levels (3.22±0.18 vs 3.62±0.28, p = 0.2371, 5.86±0.19 vs 7.15±0.27, p = 0.0004, 3.75±0.14 vs 4.31±0.21, p = 0.0422, 7.64±0.17 vs 8.26±0.25, p=0.0487 respectively) (Table 1). Conclusions: In our cohort, COVID-19 patients had better systolic reserve and abnormal relaxation compared to controls. There was no significant difference in strain (GLS) and strain rate (SRs & SRe) amongst survivors and non survivors in the longitudinal domain of contractility despite of higher inflammatory biomarkers in non-survivors.

Introduction: Anthracyclines are a first-line chemotherapeutic agent used in the treatment of lymphoma. Myocardial injury can occur with cumulative doses of 250 to 350 mg/m 2 . Echocardiography is the imaging modality for identifying cardiac dysfunction; however, identifying diastolic changes in patients who received anthracyclines is not well represented in the literature. Variables used to identify diastolic dysfunction include lateral e’, medial e’, mitral E velocity, mitral A velocity, E/A, E/e’, and left atrial volume index (LAVI). This study aims to identify if diastolic abnormalities develop in a prospective cohort of patients with HL or NHL who received anthracycline-based chemotherapy. Methods: Lymphoma patients treated with anthracyclines from 2013 to 2020 were prospectively enrolled. Echocardiography was obtained at 3-time points: before the start of chemotherapy (T1), at 3-6 months (T2), and 9-12 months (T3). Diastolic variables were measured and analyzed based on the total cumulative dose of Doxorubicin per body surface area. Those that received greater than 250 mg/m 2 and greater than 300 mg/m 2 of Doxorubicin were compared to those that did not. Statistical analysis was done using one-way ANOVA, adjusting for age and gender. Results: 151 total patients (90 males, mean age 61 + 16 years); 21 (14%) HL, 130 (85%) NHL. 114 and 66 patients received a total cumulative dose of Doxorubicin greater than 250 mg/m 2 and 300 mg/m 2 , respectively. There was no significant association with 250 mg/m2. Lateral e’ at T3 vs. T1, was lower in those that received greater than 300 mg/ m 2 compared to those received less (0.09 vs 0.10, p < 0.02) (Table 1). Conclusions: Lateral e’ decreased at 1-year follow-up in those that received higher doses of Doxorubicin. These changes in the lateral e’ could reflect early relaxation abnormalities related to anthracycline-based chemotherapy and suggest that changes in lateral e’ should be considered by itself since E/e’ was normal.

A 69-year-old woman with history of right breast cancer status post lumpectomy and radiation (4.2 cGy) 18 months prior, presented with progressive NYHA class III dyspnea. TTE obtained prior to her cancer diagnosis was notable for normal LV size and wall thickness, a subaortic membrane with systolic mean Doppler gradient of 21 mmHg and a mildly thickened mitral valve without significant stenosis or regurgitation. On presentation, TTE was notable for severely increased concentric LV wall thickness (LV mass index 140 g/m 2 ), preserved ejection fraction, increased RV wall thickness, subaortic stenosis with systolic mean Doppler gradient 35 mmHg, moderate-severe aortic regurgitation, thickened mitral valve with posterior leaflet tethering and anterior leaflet override causing severe mitral regurgitation and moderate mitral stenosis (valve area 1.7 cm 2 by pressure half-time). She underwent a surgical intervention with septal myectomy, subaortic membrane resection, aortic root reconstruction, aortic and mitral valve replacement with bioprostheses. She did well post-operatively and had complete resolution of symptoms following cardiac rehabilitation. Radiation-induced valvular heart disease is linked to the total dose of radiation, use of sequential chemotherapy and time since irradiation, with a typical latency of 10-20 years. However, there is paucity of data regarding the influence of these variables in patients with pre-existing valve disease. This case illustrates dramatic acceleration of underlying aortic and mitral valve pathology in a patient with a subaortic membrane, 18 months after radiation. We also noted development of significant concentric LV hypertrophy that was disproportionate to the degree of obstruction across the sub-aortic membrane. Potential candidates for radiation therapy must be carefully screened for pre-existing valve disease, which should warrant increased vigilance and early screening for progressive valve disease.

With stress echo (SE) 2020 study, a new standard of practice in stress imaging was developed and disseminated: the ABCDE protocol for functional testing within and beyond CAD. ABCDE protocol was the fruit of SE 2020, and is the seed of SE 2030, which is articulated in 12 projects: 1-SE in coronary artery disease (SECAD); 2-SE in diastolic heart failure (SEDIA); 3-SE in hypertrophic cardiomyopathy (SEHCA); 4-SE post-chest radiotherapy and chemotherapy (SERA); 5-Artificial intelligence SE evaluation (AI-SEE); 6-Environmental stress echocardiography and air pollution (ESTER); 7-SE in repaired Tetralogy of Fallot (SETOF); 8-SE in post-COVID-19 (SECOV); 9: Recovery by stress echo of conventionally unfit donor good hearts (RESURGE); 10-SE for mitral ischemic regurgitation (SEMIR); 11-SE in valvular heart disease (SEVA); 12-SE for coronary vasospasm (SESPASM). The study aims to recruit in the next 5 years (2021–2025) ≥10,000 patients followed for ≥5 years (up to 2030) from ≥20 quality-controlled laboratories from ≥10 countries. In this COVID-19 era of sustainable health care delivery, SE2030 will provide the evidence to finally recommend SE as the optimal and versatile imaging modality for functional testing anywhere, any time, and in any patient.