Radiation-induced Cardiotoxicity Research Articles

Heart is a heavy burden: cardiac toxicity in radiation oncology.

Over the years, radiotherapy has seen continual improvements and has become a standard treatment for most malignant tumors. Cardiotoxicity is a well-known radiotherapy side effect, leading to the risk of long-term morbidity and mortality in cancer survivors. Therefore, minimizing radiotherapy-related cardiotoxicity remains an important challenge in cancer care management. Indeed, multiple dose constraints were proposed for the heart and its substructures. In addition, sparing techniques were developed to reduce the exposure of the heart to ionizing radiation and are currently used in daily clinical routine. The purpose of this review is to summarize the current knowledge about radiation-induced cardiotoxicity, to discuss the previously cardiac dose constraints, and to evaluate the various management strategies.

Statin Therapy Reduces Radiation-Induced Cardiotoxicity in Patients With Breast Cancer Receiving Adjuvant Radiotherapy.

To evaluate the efficacy of statin therapy in reducing major adverse cardiovascular event (MACE) risk among patients with breast cancer undergoing breast-conserving surgery and adjuvant whole breast radiotherapy. A retrospective cohort study was conducted using data from the Taiwan Cancer Registry Database linked to the National Health Insurance Research Database. Patients diagnosed with left-sided early breast invasive ductal carcinoma between 2016 and 2019 were included. Propensity score matching was employed to compare MACE risk between statin users and nonusers. Cox regression models were used to estimate adjusted hazard ratios (aHRs) for MACE, considering cumulative defined daily doses and daily defined doses of statins. Among 1481 patients undergoing breast-conserving surgery and adjuvant whole breast radiotherapy, statin use significantly reduced MACE risk (aHR, 0.34 [95% CI, 0.25-0.44]). Hydrophilic statins, particularly rosuvastatin and pravastatin, demonstrated the greatest risk reduction. Higher cumulative defined daily doses and daily intensity doses of statins were associated with lower MACE risk, indicating a dose-response relationship. The 5-year cumulative incidence of MACE was significantly lower in statin users compared with nonusers (12.24% versus 31.70%). Statin therapy is associated with a reduced risk of MACE in patients with breast cancer undergoing breast-conserving surgery and adjuvant whole breast radiotherapy. Hydrophilic statins rosuvastatin and pravastatin exhibit the most pronounced cardioprotective effects. These findings suggest a potential role for statins in mitigating cardiovascular complications in this population and highlight the need for further research to optimize statin therapy in survivors of breast cancer undergoing radiotherapy.

Predictive value of changes in basal myocardial 18F-fluorodeoxyglucose uptake for cardiotoxicity in locally advanced esophageal cancer patients receiving definitive radiotherapy

To investigate the predictive value of changes in segmental myocardial 18F-fluorodeoxyglucose (FDG) uptake for major adverse cardiac events (MACEs) in patients with locally advanced esophageal cancer undergoing definitive radiation therapy (RT). Between August 2012 and January 2019, 482 patients with stages II and III esophageal cancer from 2 institutions were enrolled and divided into the training (n = 285) and external validation (n = 197) cohorts. All patients underwent 18F-FDG positron emission tomography within 1 week before treatment and within 3 months of treatment. Myocardial delineation was performed using the Carimas software based on the American Heart Association 17-segment model and was automatically divided into basal, middle, and apical regions. The main endpoint was the occurrence of MACEs, including unstable angina, myocardial infarction, coronary revascularization, hospitalization for heart failure or urgent visits, and cardiac death. Analyses included competing risk and Cox regression. Model performance was assessed using the area under the receiver operating characteristic curve and Brier score. Thirty-four patients (11.9%) developed MACEs at a median follow-up of 78 months. The basal region (median, 19.44 Gy) of the myocardium received the highest radiation dose, followed by the middle (median, 13.02 Gy) and apical regions (median, 9.32 Gy). Multivariate analysis showed that the change ratio in pretreatment and posttreatment basal myocardial mean standardized uptake value (SUV) remained significant after adjusting for age, pre-existing cardiac disease, and dosimetric parameters. The area under the receiver operating characteristic curves and Brier scores demonstrated favorable predictive accuracies of models integrating variables with significant differences in the multivariate analysis when predicting MACEs in the training and validation cohorts. The basal change ratio of mean SUV was an independent predictor of MACEs in patients with locally advanced esophageal cancer receiving definitive RT. Changes in basal myocardial FDG uptake are promising biomarkers for predicting radiation-induced cardiotoxicity.

Abstract Mo024: Integrated analysis of ex vivo biomechanical ventricular remodeling and imaging-based in vivo strain changes in a pre-clinical murine model of radiation-induced cardiotoxicity

Introduction: Thoracic radiation therapy (RT) is commonly used for the treatment of many common malignancies, such as lung and breast cancer, but carries a high risk of radiation-induced cardiotoxicity (RIC). Existing diagnosis of RIC is challenged by subclinical ventricular dysfunction, not captured by global indices of cardiac function. Understanding RIC-driven biomechanical remodeling of the myocardium will provide novel insights into developing high-fidelity imaging approaches for early detection of RIC. Methods: A pre-clinical model of RIC was developed by administering whole heart irradiation under image guidance in mice (8 Gy x 5) over five consecutive days. A longitudinal study was carried out to investigate the biomechanical response of the left ventricle (LV). Cardiac magnetic resonance imaging was performed to estimate end-systolic strains. Mechanical testing was performed on the harvested LV free wall (LVFW) specimens to measure passive stiffness, calculated as the tangent to the ensemble stress-strain curve at 30% strain. Results: A significant increase in passive LVFW stiffness was observed at 3M post-RT (Figs. 1A and B). Significant declines in both global circumferential strain (GCS) and global radial strain (GRS) at 3M post-RT, compared to respective measurements at pre-RT, were observed (Figs. 1C and D). Suppressed contractile strains suggested biomechanical remodeling of the LV, including impaired contractility and passive stiffening of the LVFW, consistent with ex-vivo measurements. Conclusion: We have established a direct correlation between ex-vivo mechanical testing (elevated stiffness) and reduced contractile strains in in-vivo analysis in a mouse model of RIC. Such integrated analysis will pave the way towards developing highly sensitive imaging approaches that non-invasively recapitulate the ventricular remodeling events associated with RIC, thereby enabling early detection of RIC in patients receiving thoracic RT.

A Comprehensive Review of Cancer Drug-Induced Cardiotoxicity in Blood Cancer Patients: Current Perspectives and Therapeutic Strategies.

Cardiotoxicity has emerged as a serious outcome catalyzed by various therapeutic targets in the field of cancer treatment, which includes chemotherapy, radiation, and targeted therapies. The growing significance of cancer drug-induced cardiotoxicity (CDIC) and radiation-induced cardiotoxicity (CRIC) necessitates immediate attention. This article intricately unveils how cancer treatments cause cardiotoxicity, which is exacerbated by patient-specific risks. In particular, drugs like anthracyclines, alkylating agents, and tyrosine kinase inhibitors pose a risk, along with factors such as hypertension and diabetes. Mechanistic insights into oxidative stress and topoisomerase-II-B inhibition are crucial, while cardiac biomarkers show early damage. Timely intervention and prompt treatment, especially with specific agents like dexrazoxane and beta-blockers, are pivotal in the proactive management of CDIC.

Comparison of the Effects of Rosmarinic Acid and Electromagnetic Radiation-Induced Cardiotoxicity on Rats.

Electromagnetic radiation (EMR) causes stable aggregation of reactive oxygen species (ROS), producing oxidative stress. Rosmarinic acid (RA), a plant-origin antioxidant, has been proposed against the side effects of cell phone and ultrahigh-frequency waves. Forty-two male Wistar rats were randomly divided into 6 groups. Group 1 (controls) received 5 mL of normal saline with the gavage method, Group 2 received 915 MHz radiation, Group 3 received 2450 MHz radiation, Group 4 received RA plus 915 MHz radiation, Group 5 received RA plus 2450MHz radiation, and Group 6 received oral RA (5 mg/kg). Treatment and radiation (1 hour per day) continued for up to 30 days. EMR significantly reduced the activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx), the content of glutathione (GSH), and the level of total antioxidant capacity (TAC) and significantly increased oxidative stress indices, such as the levels of malondialdehyde (MDA) and nitric oxide (NO), and the content of protein carbonyl (PC). In contrast, RA significantly elevated TAC level (all groups), GSH content (the RA/cell phone radiation group), GPx activity (the RA/ultrahigh-frequency radiation group), SOD activity (all groups), and CAT activity (RA/ultrahigh-frequency radiation group) and conversely reduced MDA level (all groups), NO level (all groups), and PC content (all groups) in the RA/cell phone and RA/ultrahigh-frequency radiation groups compared with the NS/cell phone and NS/ultrahigh-frequency radiation groups, respectively. The administration of RA resulted in a significant reversal of cardiac markers in EMR-intoxicated rats. RA treatment showed a significant protective effect against EMR-induced cardiotoxicity.

Tracking Changes in Global Longitudinal Strain in Lung Cancer Patients Receiving Thoracic Radiation

Thoracic radiation improves survival in many lung cancer patients. However, radiation-induced cardiotoxicity is a major source of morbidity and mortality in such patients. Global longitudinal strain (GLS), a novel echocardiography (ECHO) method of assessing left ventricular function, has been shown to predict long-term adverse cardiovascular risk in diverse patient populations. We hypothesized that receipt of thoracic radiation is associated with GLS changes in lung cancer patients. We retrospectively identified patients with lung cancer treated at our institution between 2005-2020 who had ECHOs performed both before and after RT, and in whom GLS was extractable. ECHO Board-Certified cardio-oncologists measured GLS and left ventricular ejection fraction (LVEF) from these ECHOs. A total of 40 patients met inclusion criteria. Median time to ECHO was 78 days prior and 172 days after RT. Two chamber (2C), 3C, 4C, and average GLS were significantly decreased after RT on paired t-test [mean difference (SD) 2.23 (3.29), 2.99 (2.78), 2.25 (3.63), 2.51 (2.66) respectively, all p < 0.001]. Thirteen patients (32.5%) had abnormal GLS (<18%) prior to RT. 5 of those 13 patients (38.5%) had abnormal LVEF (< 50%). 27/40 patients (67.5%) had an abnormal GLS or clinically significant (≥15%) drop in GLS after RT. This difference (32.5% patients pre-RT vs 67.5% post-RT) was statistically significant (p < 0.01). Among patients (n = 27) who had normal LVEF before RT, 1 patient (3.7%) developed abnormal LVEF (<50%) after RT. Backwards logistic regression showed significant interaction between heart volume receiving 5 Gray and change in GLS. This cohort exhibited a significant decrease in 2C, 3C, 4C, and average GLS after RT. ∼1/3 of patients had abnormal GLS at baseline (suggesting a high-risk group for cardiac complications) and 67.5% of patients had clinically significant decrease in GLS after RT. Among the patients with normal GLS before RT, although 51.9% of patients demonstrated a clinically significant drop in GLS after RT, only 3.7% of patients developed abnormal LVEF, suggesting that this is a late occurrence. GLS changes may serve as a valuable tool for early identification of patients who are at high risk for future cardiac complications after receiving thoracic radiation.

The Predictive Value of Changes in Basal Myocardial F-18 Fluorodeoxyglucose Uptake for Cardiotoxicity in Locally Advanced Esophageal Cancer Patients Receiving Definitive Radiotherapy

To investigate the predictive value of changes in myocardial 18F-FDG uptake for major adverse cardiac events (MACEs) in locally advanced esophageal cancer patients receiving definitive radiotherapy. Between August 2012 and January 2018, 400 patients with stage II-III esophageal cancer receiving definitive radiotherapy at two institutions were divided into the training (n = 240) and external validation cohorts (n = 160). All patients underwent FDG-PET imaging within 1 week before treatment and 3 months after treatment. Myocardium delineation was performed by Carimas software (version 2.10) based on the AHA 17-segment model. When contouring the left ventricle, the myocardium was automatically divided into basal (segments 1-6), middle (segments 7-12), and apical (segments 13-16) regions, and the mean dose and FDG uptake parameters of each region were obtained by Carimas. Our primary endpoint was MACEs. Patient clinicopathologic factors, dosimetric parameters for the whole heart and cardiac substructures, and myocardial changes within the three regions on 18F-FDG PET were utilized to seek the best predictive models for cardiotoxicity. To avoid multicollinearity between dose-volume histogram (DVH) parameters, we selected the variables with the lowest Akaike Information Criterion (AIC) value from the DVH parameters of the same cardiac structure for the actual modeling procedure. Competing risk analysis and Cox regressions analysis were performed. The predictive performance of the models was evaluated using the area under the receiver operating characteristic curve (AUC) and Brier score. At a median follow-up interval of 78 months, 28 patients (11.7%) developed MACEs. The basal region of the myocardium received the highest radiation dose, followed by the middle and the apex region. The basal myocardial SUVmax and SUVmean significantly increased after radiotherapy while the apical and middle myocardial SUVmax and SUVmean not significantly increased. In univariate analysis, age, pre-existing cardiac disease, changes in pre- and post-treatment basal myocardial SUVmax and SUVmean (∆SUVmax and ∆SUVmean), and dosimetric parameters for MHD, mean LCX, mean LAD, and mean LV dose were associated with an increased hazard of MACEs. Multivariate analysis showed that basal ∆SUVmean retained significance after adjusting for age, pre-existing cardiac disease, and dosimetric parameters for whole heart and cardiac substructures. The AUCs and Brier scores demonstrated favorable predictive accuracies of the model's integrating variables with significant difference in multivariate analysis when predicting MACEs in the training and validation cohorts. ∆SUVmean was an independent indicator of MACE in locally advanced esophageal cancer patients receiving definitive radiotherapy. Changes in basal myocardial FDG uptake is a promising biomaker for predicting radiation-induced cardiotoxicity.

Current Cardioprotective Strategies for the Prevention of Radiation-Induced Cardiotoxicity in Left-Sided Breast Cancer Patients.

Breast cancer (BC) is the most common malignancy in females, accounting for the majority of cancer-related deaths worldwide. There is well-established understanding about the effective role of radiotherapy (RT) in BC therapeutic strategies, offering a better local-regional control, prolonged survival, and improved quality of life for patients. However, it has been proven that conventional RT modalities, especially in left-sided BC cases, are unable to avoid the administration of high RT doses to the heart, thus resulting in cardiotoxicity and promoting long-term cardiovascular diseases (CVD). Recent radiotherapeutic techniques, characterized by dosimetric dose restrictions, target volume revision/modifications, an increased awareness of risk factors, and consistent follow-ups, have created an advantageous context for a significant decrease inpost-RT CVD incidence. This review presents the fundamental role of current cardioprotective strategies in the prevention of cardiotoxic effects in left-BCRT. A literature search was conducted up to January 2023 using the Cochrane Central Register of Controlled Trials and PubMed Central databases. Our review refers to new radiotherapeutic techniques carried out on patients after BC surgery. Specifically, a dose evaluation of the heart and left anterior descending coronary artery (LADCA) was pointed out for all the included studies, depending on the implemented RT modality, bed positioning, and internal mammary lymph nodes radiation. Several studies reporting improved heart sparing with new RT techniques in BC patients were searched. In addition to the RT modality, which definitely determines the feasibility of achieving lower doses for the organs at risk (OARs), better target coverage, dose conformity and homogeneity, and the patient's position, characteristics, and anatomy may also affect the evaluated RT dose to the whole heart and its substructures. Modern BC RT techniques seem to enable the administration of lower doses to the OARs without compromising on the target coverage. The analysis of several anatomical parameters and the assessment of cardiac biomarkers potentiate the protective effect of these new irradiation modalities, providing a holistic approach to the radiation-associated risks of cardiac disease for BC patients. Despite technological advances, an inevitable cardiac radiation risk still exists, while adverse cardiac events may be observed even many years after RT. Studies with longer follow-ups are required in order to determine the effectiveness of modern breast RT techniques.

Differences in radiation-induced heart dysfunction in male versus female rats

Purpose Radiation therapy remains part of the standard of care for breast, lung, and esophageal cancers. While radiotherapy improves local control and survival, radiation-induced heart dysfunction is a common side effect of thoracic radiotherapy. Cardiovascular dysfunction can also result from non-therapeutic total body radiation exposures. Numerous studies have evaluated the relationship between radiation dose to the heart and cardiotoxicity, but relatively little is known about whether there are differences based on biological sex in radiation-induced heart dysfunction (RIHD). Materials and Methods We evaluated whether male and female inbred Dahl SS rats display differences in RIHD following delivery of 24 Gy in a single fraction to the whole heart using a 1.5 cm beam size (collimater). We also compared the 2.0 cm vs. 1.5 cm collimator in males. Pleural and pericardial effusions and normalized heart weights were measured, and echocardiograms were performed. Results Female SS rats displayed more severe RIHD relative to age-matched SS male rats. Normalized heart weight was significantly increased in females, but not in males. A total of 94% (15/16) of males and 55% (6/11) of females survived 5 months after completion of radiotherapy (p < .01). Among surviving rats, 100% of females and 14% of males developed moderate-to-severe pericardial effusions at 5 months. Females demonstrated increased pleural effusions, with the mean normalized pleural fluid volume for females and males being 56.6 mL/kg ± 12.1 and 10.96 mL/kg ± 6.4 in males (p = .001), respectively. Echocardiogram findings showed evidence of heart failure, which was more pronounced in females. Because age-matched female rats have smaller lungs, a higher percentage of the total lung was treated with radiation in females than males using the same beam size. After using a larger 2 cm beam in males which results in higher lung exposure, there was not a significant difference between males and females in terms of the development of moderate-to-severe pericardial effusions or pleural effusions. Treatment of males with a 2 cm beam resulted in comparable increases in LV mass and reductions in stroke volume to female rats treated with a 1.5 cm beam. Conclusion Together, these results illustrate that there are differences in radiation-induced cardiotoxicity between male and female SS rats and add to the data that lung radiation doses, in addition to other factors, may play an important role in cardiac dysfunction following heart radiation exposure. These factors may be important to factor into future mitigation studies of radiation-induced cardiotoxicity.

Abstract 3584: Early and non-invasive detection of radiation-induced cardiotoxicity in pre-clinical and clinical models

Abstract Background: Nearly half of all patients receive radiation therapy as a component of their cancer care. Despite the efficacy of radiation therapy as a cancer treatment, cardiotoxicity is a major concern in patients receiving chest radiotherapy. There are currently no standardized approaches for early detection of radiation-induced cardiotoxicity as a stage that offers potential for early intervention. In this study, we employ hyperpolarized 13C- pyruvate magnetic resonance spectroscopy to non-invasively characterize early metabolic changes in the heart in response to radiation. Methods: We established a pre-clinical model of radiation induced heart disease (RIHD) by performing whole heart irradiation (8Gy x 5) in rats. Echocardiography was used characterize mechanical changes in the heart following radiation. To non-invasively detect myocardial mitochondrial dysfunction following cardiac irradiation in vivo, we employed hyperpolarized 13C- pyruvate magnetic resonance spectroscopy (MRS) to track the fate of pyruvate, an intermediate of glucose metabolism, as it is metabolized in the heart. Hyperpolarized 13C- pyruvate MRS was also employed in a patient who received thoracic radiation for treatment of thymoma to non-invasively study changes in glucose metabolism in response to radiation. Results: We identified evidence of early cardiac mitochondrial dysfunction prior to onset of mechanical changes in the heart. Following cardiac irradiation, due to mitochondrial dysfunction, pyruvate was preferentially metabolized to lactate in the cytoplasm (as opposed to bicarbonate in the mitochondria in non-irradiated hearts). The ratio of products of 13C- pyruvate metabolism in the mitochondria and cytoplasm as ascertained by hyperpolarized 13C- pyruvate MRS served as a biomarker for metabolic dysfunction in the heart both in a pre-clinical rat model and in a patient who received thoracic radiation. Conclusions: We have developed a non-invasive approach for detection of cardiac mitochondrial dysfunction, which may serve as a biomarker for early detection of radiation-induced cardiotoxicity, and shown feasibility in a human patient. Clinical adoption of this approach may enable early identification of patients who are at high risk for future cardiac complications and may benefit from mitigation strategies. Citation Format: Taylor-Jade Higgins, Jayesh Sharma, Elizabeth R. Zhang-Velten, Sarah Elliott, Junjie Ma, Jun Chen, Gabriele Schiattarella, Chantal Vidal, Nan Jiang, Daniel Daou, Joseph Hill, Thomas Gillette, Craig Malloy, Vlad Zaha, Jae Mo Park, Prasanna Alluri. Early and non-invasive detection of radiation-induced cardiotoxicity in pre-clinical and clinical models. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3584.

Abstract 3209: Metabolic characterization of radiation-induced cardiotoxicity

Abstract Background: Approximately 50% of all cancer patients receive radiation therapy as a component of their cancer care. While radiation therapy has demonstrable benefit in improving survival in patients, radiation-induced heart disease (RIHD) is a major contributor to morbidity and mortality in cancer survivors with history of thoracic radiation. Understanding metabolic changes underlying RIHD may enable development of novel diagnostic and therapeutic approaches for early detection and treatment of RIHD. The high energetic demands of the heart require properly functioning mitochondria to meet the ATP production needs. Fatty acids are the primary metabolic substrates for energy production in a healthy heart. However, under conditions of stress, the cardiac metabolism shifts towards increased glucose utilization. In this study, we characterize the impact of radiation of cardiac substrate utilization and energy production. Methods: Pre-clinical RIHD models were established by administering whole heart radiation (8Gy x 5) in mice and rats followed by structural and biochemical characterization. Transmission electron microscopy and western blot analyses were used to characterize structural and biochemical changes in the heart in response to radiation. Spectrophotometric assays and Western blot analyses were used to characterize changes in pyruvate dehydrogenase (PDH) activity and function in the heart in response to radiation. Results: Our studies identified myocardial mitochondrial dysfunction as an early event following exposure of heart to radiation. Cardiac irradiation resulted in increased mitochondrial fusion and higher expression of MFN1, a key protein that mediates mitochondrial fusion. The pathological structural and biochemical changes in the myocardial mitochondria are associated with reduced glucose metabolism due to impaired PDH activity. This decline was mediated by increased phosphorylation of PDH in irradiated hearts, which inhibits its activity. Conclusion: Cardiac irradiation results in early metabolic dysregulation, especially in glucose metabolism, which may be exploited for early detection and mitigation of radiation-induced cardiotoxicity. Citation Format: Sarah C. Elliott, Jayesh Sharma, Elizabeth R. Zhang-Velten, Abdallah Elnwasany, Chantal Vidal, Luke Szweda, Prasanna Alluri. Metabolic characterization of radiation-induced cardiotoxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3209.

Cardiotoxicity of Anti-Cancer Radiation Therapy: a Focus on Heart Failure.

As the percentage of patients achieving long-term survival following treatment of their cancer grows, it is increasingly important to understand the long-term toxicities of cancer-directed treatment. In this review, we highlight the recent findings regarding radiation-induced cardiotoxicity across multiple disease sites, with a particular focus on heart failure. Despite its relative lack of study historically, radiation-induced heart failure has now recently been implicated in several studies of breast cancer, lung cancer, esophageal cancer, and lymphoma as a non-trivial potential consequence of thoracic radiotherapy. Data regarding specific cardiac dosimetric endpoints relevant to cardiotoxicity continue to accumulate. Radiation-induced heart failure is a rare but significant toxicity of thoracic radiotherapy, that is likely underreported. Important areas for future focus include understanding the interplay between thoracic radiotherapy and concurrent cardiotoxic systemic therapy as well as development of potential mitigation strategies and novel therapeutics.

Methods to assess radiation-induced cardiotoxicity in rodent models.

Cancer survivors who have received thoracic radiation as part of their primary treatment are at risk for developing radiation-induced cardiotoxicity (RICT) due to incidental radiation delivered to the heart. In recent decades, advancements in radiation delivery have dramatically improved the therapeutic ratio of radiation therapy (RT)-efficiently targeting malignancies while sparing the heart; yet, in many patients, incidental radiation to the heart cannot be fully avoided. Cardiac radiation exposure can cause long-term morbidity and contribute to poorer survival in cancer patients. Severe cardiac effects can occur within 2years of treatment. Currently, there is no way to predict who is at higher or lower risk of developing cardiotoxicity from radiation, and the critical factors that alter RICT have not yet been clearly identified. Thus, pre-clinical investigations are an important step towards better prevention, detection, and management of RICT in cancer survivors. The overarching aim of this chapter is to provide researchers with foundational and technical knowledge in the use of mice and rats for RICT investigations. After a brief overview of RICT pathophysiology and clinical manifestations, we discuss important considerations of RICT study design, including animal selection and radiation planning. We then provide example protocols for murine tissue harvesting and processing that can support use in downstream applications of the reader's choosing.

Myocardial Contractility Pattern Characterization in Radiation-Induced Cardiotoxicity Using Magnetic Resonance Imaging: A Pilot Study with ContractiX.

Radiation therapy (RT) plays an integral role in treating thoracic cancers, despite the risk of radiation-induced cardiotoxicity. We hypothesize that our newly developed magnetic resonance imaging (MRI)-based contractility index (ContractiX) is a sensitive marker for early detection of RT-induced cardiotoxicity in a preclinical rat model of thoracic cancer RT. Adult salt-sensitive rats received image-guided heart RT and were imaged with MRI at 8 weeks and 10 weeks post-RT or sham. The MRI exam included cine and tagging sequences to measure left-ventricular ejection fraction (LVEF), mass, myocardial strain, and ContractiX. Furthermore, ventricular torsion, diastolic strain rate, and mechanical dyssynchrony were measured. Statistical analyses were performed between the sham, 8 weeks post-RT, and 10 weeks post-RT MRI parameters. The results showed that both LVEF and myocardial mass increased post-RT. Peak systolic strain and ContractiX significantly decreased post-RT, with a more relative reduction in ContractiX compared to strain. ContractiX showed an inverse nonlinear relationship with LVEF and continuously decreased with time post-RT. While early diastolic strain rate and mechanical dyssynchrony significantly changed post-RT, ventricular torsion changes were not significant post-RT. In conclusion, ContractiX measured via non-contrast MRI is a sensitive early marker for the detection of subclinical cardiac dysfunction post-RT, and it is superior to other MRI cardiac measures.

Pre-irradiation effects of ectoine on radiation-induced cardiotoxicity in female Swiss albino mice model

Pre-irradiation effects of ectoine on radiation-induced cardiotoxicity in female Swiss albino mice model

Changes in CT Attenuation Values of Pericardium Months after Radiotherapy as Surrogates for Later Major Cardiotoxicity

<h3>Purpose/Objective(s)</h3> Radiation-induced pericardial disease (RIPD) can manifest as pericardial swelling, thickening, effusion, fluid or calcification. While mostly asymptomatic or underdetected due to self-limiting nature, RIPD could be a surrogate marker for radiation-induced cardiotoxicity. Pericardial screening is not part of standard of care (SOC) for thoracic cancer patients' radiotherapy (RT). Here, we analyze SOC images in patients treated with thoracic RT for radiographically identifiable pericardial changes. We hypothesize that these changes have potential signatures for predicting late major cardiac events. <h3>Materials/Methods</h3> In this retrospective study, pericardium was manually contoured following standard contouring atlases in 30 locally advanced non-small cell lung cancer patients (15 females, 15 males) treated with chemoradiation. A 4mm inner wall was generated as the region of interest. Using pre-RT and (average 10-month) post-RT CT scans, we investigated whether changes in pericardium Hounsfield unit (HU) could predict major late cardiac events reported in patients' clinical records. Taking the effect of contrast-enhancement in some scans into account, HU value ranges representing effusion/fluid, normal tissue and calcification were considered as [-10,30], [31,132] and [133,500], respectively. Support vector machine analysis was performed using data from 24 patients with ≤12 months follow-up for training, and data from the remaining 6 patients for testing. Other parameters of interest for late cardiotoxicity were pericardial doses (mean and max), patient age at the time of RT, sex, history of cardiovascular diagnoses, smoking status, diabetes and hypertension. The CT scans were also revisited by a radiologist for verification of the existence of effusion, fluid, calcification or implants. <h3>Results</h3> In the training group, 11 patients, and in the testing group, 1 patient had a reported major cardiotoxicity several years post-RT. In the cohort of 30 patients, median changes, from pre-RT to post-RT, in the volumes of low, mid, and high HU regions were 17, 24 and 27cc, respectively. In the training set, the volumes of [31,132] HU region showed significant reduction (Mann-Whitney non-parametric test) from pre-RT to post-RT in CT scans of the patients with late cardiotoxicity (p=0.049) compared to those without. Also, patient age at the time of RT was a significant predictor of late cardiotoxicity (p=0.008), while mean dose to pericardium showed borderline significance (p = 0.09). Due to the confounding effect of both contrast-enhancement and implants on the higher HU value analysis, the accuracy of the classification model was limited in training group to 92% and in the test group to 67% (total 4 errors in patients with pre-existing calcifications). <h3>Conclusion</h3> Our preliminary study suggests that radiation-induced cardiotoxicity may be modelled based on patient demographic, dosimetric parameters, and detectable changes in pericardium sac HU volumes.

Seeking a Method to Detect Radiation-Induced Cardiotoxicity

Seeking a Method to Detect Radiation-Induced Cardiotoxicity

Abstract 3659: Early in vivo detection of radiation-induced cardiotoxicity

Abstract Background: Radiation-Induced Heart Disease (RIHD) is a major source of morbidity and mortality in patients receiving thoracic radiation, which is a common treatment for malignancies like lung cancer. There is currently no standardized program for follow-up of RIHD in cancer survivors. Therefore, there is an acute need for developing detection of RIHD at a stage that offers potential for early intervention and reversibility. The gold standard for detection of global cardiac dysfunction is echocardiography. However, this current paradigm detects cardiac changes in metrics such as Left Ventricular Ejection Fraction (LVEF), which are relatively late manifestations in the pathology of cardiotoxicity, decreasing the possibility of reversing such damage. We sought to assess radiation-induced changes significantly earlier than the current standard of care by measuring the efficiency of the tricarboxylic acid cycle in cardiac mitochondria; we hypothesized that radiation leads to impaired mitochondrial function, causing increased conversion of pyruvate to lactate in the cytosol and decreased conversion in the mitochondria. In order to non-invasively measure this impairment, we utilized Magnetic Resonance Spectroscopy (MRS) to track the fate of hyperpolarized (HP) C-13 pyruvate. Methods: Sprague-Dawley rats underwent baseline and post treatment echocardiography and HP C-13 pyruvate MRS at multiple timepoints. Half of the animals underwent image-guided cardiac radiation with cone-beam CT, to a total dose of 40 Gy in 5 fractions, a paradigm similar to a common dose given to lung cancer patients. Results: In the cardiac radiation group, C-13 pyruvate MRS demonstrated a statistically significant decrease in cardiac function (determined by bicarbonate-to-lactate ratio in myocardial mitochondria) compared to pre-radiation baseline (p=0.02, one-tailed paired t-test) as early as 1 week post treatment. No significant decrease in this ratio was observed in the non-irradiated, age matched controls (p=0.95). Comparatively, no significant changes in LVEF or global longitudinal strain were observed in either the cardiac irradiation or control group of rats until 2 months post treatment. Conclusion: Radiation-induced myocardial mitochondrial dysfunction is an early event that can be characterized and detected in vivo by hyperpolarized C-13 pyruvate MRS within 1 week after radiation prior to onset of echocardiographic changes. For the first time, we have demonstrated feasibility of employing HP C-13 pyruvate MRS for detecting radiation-induced myocardial mitochondrial metabolic changes in a pre-clinical rat model. This technology has the potential to serve as a platform for building radiation-focused cardio-oncology programs for early detection and mitigation of radiation-induced cardiac injury in hundreds of thousands of patients receiving thoracic radiation annually. Citation Format: Jayesh Sharma, Elizabeth Zhang, Xuliang Wang, Junjie Ma, Jun Chen, Gabriele Schiattarella, Joseph Hill, Jaemo Park, Craig Malloy, Vlad Zaha, Prasanna Alluri. Early in vivo detection of radiation-induced cardiotoxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3659.

Cardiovascular Magnetic Resonance in Early Detection of Radiation Associated Cardiotoxicity With Chest Radiation.

BackgroundChest radiation therapy (RT) is known to be associated with cardiotoxicity. However, the changes in myocardial tissue characterization with radiation-induced cardiotoxicity are not well-understood.ObjectivesThis study sought to assess the changes in left ventricular function and tissue characterization using cardiovascular magnetic resonance (CMR) in patients receiving RT.Materials and MethodsBetween June 2015 and July 2018, we enrolled patients with breast, lung cancer, or lymphoma with plan to receive chest radiation after chemotherapy. CMR was performed using a 1.5T scanner at baseline and 6 months after RT. Myocardial volume, function, strain analysis using feature tracking, and tissue characterization including late gadolinium enhancement (LGE), T1, T2, T1ρ (rho), and extracellular volume fraction (ECV) were measured and compared using non-parametric methods.ResultsThe final cohort consisted of 16 patients, 11 of whom completed both baseline and follow-up CMRs. Patients were matched to 10 healthy controls. At baseline prior to RT, compared to controls, patients had lower global circumferential strain (GCS) (15.3 ± 2.2% vs.18.4 ± 2.1%, p = 0.004), and elevated T2 (47.9 ± 4.8 ms vs. 45.0 ± 1.5 ms, p = 0.04) and T1ρ values (78.4 ± 5.9 vs. 66.9 ± 4.6 ms, p < 0.001). Two patients had LGE. There was no significant difference in the average T1 values or ECV. There was a trend toward lower LV ejection fraction and global longitudinal strain (GLS). At 6-month follow-up after RT, there were no significant changes in all the CMR parameters.ConclusionAt 6-month following chest radiation therapy, there was no change in LV and RV EF, LV and RV GLS, LV GCS, and myocardial tissue characterization using LGE, T1, ECV, T2, and T1ρ in a small cohort of patients. However, the baseline T2 and T1ρ were elevated and LV GCS was reduced compared to controls indicating ongoing myocardial edema and subclinical dysfunction post-chemotherapy.