Changes in cardiac performance and sympathetic stimulation during and after fractionated radiotherapy in a rat model (original) (raw)
The British Journal of Radiology, 1997
Comparison of in vivo cardiac function with ex vivo cardiac performance of the rat heart after thoracic irradiation 1,2N A P FRANKEN, 3J A J CAMPS, 1F J M VAN RAVELS, 4A VAN DER LAARSE, 3E K J PAUWELS and 1J WONDERGEM Abstract. The aim of the study was to compare in vivo cardiac function with ex vivo cardiac performance after local heart irradiation in the same rat. Left ventricular ejection fraction (LVEF) was measured in vivo by radionuclide ventriculography in Sprague-Dawley rats up to 16 months after a single dose of 20 Gy. Four days after in vivo measurements, cardiac performance was determined ex vivo, using the isolated working rat heart preparation. After irradiation, cardiac performance measured ex vivo deteriorated more rapidly than the in vivo measured LVEF. Within 4 months post-treatment, ex vivo cardiac output and stroke volume started to decrease and declined continuously throughout the observation period of 16 months. The reduction in stroke volume was already significant ( p<0.04) at 4 months post-treatment, whereas the decline in cardiac output was significant ( p<0.05) at 12 months post-treatment. In vivo, no change in LVEF was observed during the first 12 months post-treatment. Thereafter, LVEF decreased rapidly from 65±2% to 46±8% ( p<0.01), at 16 months post-treatment. Up to 12 months post-irradiation, LVEF was not correlated to ex vivo cardiac output. At 16 months post-treatment, when clinical symptoms of heart failure become evident, a positive relation between both parameters was found. The lack of correlation between the in vivo and ex vivo measurements of cardiac function during the first 12 months post-treatment might be explained by the involvement of compensatory mechanisms being operative in vivo to maintain suÃcient cardiac output.
Radiation Matters of the Heart: A Mini Review
Frontiers in Cardiovascular Medicine, 2018
Radiation Therapy (RT) has been critical in cancer treatment regimens to date. However, it has been shown that ionizing radiation is also associated with increased risk of damage to healthy tissues. At high radiation doses, varied effects including inactivation of cells in treated tissue and associated functional impairment are seen. These range from direct damage to the heart; particularly, diffuse fibrosis of the pericardium and myocardium, adhesion of the pericardium, injury to the blood vessels and stenosis. Cardiac damage is mostly a late responding end-point, occurring anywhere between 1 and 10 years after radiation procedures. Cardiovascular disease following radiotherapy was more common with radiation treatments used before the late 1980s. Modern RT regimens with more focused radiation beams, allow tumors to be targeted more precisely and shield the heart and other healthy tissues for minimizing the radiation damage to normal cells. In this review, we discuss radiation therapeutic doses used and post-radiation damage to the heart muscle from published studies. We also emphasize the need for early detection of cardiotoxicity and the need for more cardio-protection approaches where feasible.
Physiological Interaction of Heart and Lung in Thoracic Irradiation
International journal of radiation oncology, biology, physics
INTRODUCTION: The risk of early radiation-induced lung toxicity (RILT) limits the dose and efficacy of radiation therapy of thoracic tumors. In addition to lung dose, coirradiation of the heart is a known risk factor in the development RILT. The aim of this study was to identify the underlying physiology of the interaction between lung and heart in thoracic irradiation. METHODS AND MATERIALS: Rat hearts, lungs, or both were irradiated to 20 Gy using high-precision proton beams. Cardiopulmonary performance was assessed using breathing rate measurements and F(18)-fluorodeoxyglucose positron emission tomography ((18)F-FDG-PET) scans biweekly and left- and right-sided cardiac hemodynamic measurements and histopathology analysis at 8 weeks postirradiation. RESULTS: Two to 12 weeks after heart irradiation, a pronounced defect in the uptake of (18)F-FDG in the left ventricle (LV) was observed. At 8 weeks postirradiation, this coincided with LV perivascular fibrosis, an increase in LV end-d...
Radiation and the heart: systematic review of dosimetry and cardiac endpoints
Expert Review of Cardiovascular Therapy, 2018
Introduction: Recent trials in radiotherapy have associated heart dose and survival, inadequately explained by the existing literature for radiation-related late cardiac effects. Authors aimed to review the recent literature on cardiac dosimetry and survival/cardiac endpoints. Areas covered: A systematic review of the literature in the past 10 years (2008-2017) was performed to identify manuscripts reporting both cardiac dosimetry and survival/cardiac endpoints. Authors identified 64 manuscripts for inclusion, covering pediatrics, breast cancer, lung cancer, gastrointestinal diseases (primarily esophageal cancer), and adult lymphoma. Expert commentary: In the first years after radiotherapy, high doses (>40 Gy) to small volumes of the heart are associated with decreased survival from an unknown cause. In the long-term, mean heart dose is associated with a small increased absolute risk of cardiac death. For coronary disease, relative risk increases roughly 10% per Gy mean heart dose, augmented by age and cardiac risk factors. For valvular disease and heart failure, doses >15 Gy substantially increase risk, augmented by anthracyclines. Arrhythmias after radiotherapy are poorly described but may account for the association between upper heart dose and survival. Symptomatic pericardial effusion typically occurs with doses >40 Gy. Close follow-up and mitigation of cardiovascular risk factors is necessary after thoracic radiotherapy.
Experimental Radiation-Induced Heart Disease: Past, Present, and Future
Radiation Research, 2012
Radiation-induced heart disease (RIHD) is a serious side effect of radiotherapy for intrathoracic and chest wall tumors. The threshold dose for development of clinically significant RIHD is believed to be lower than previously assumed. Therefore, research into mechanisms of RIHD has gained substantial momentum. RIHD becomes clinically apparent ten to fifteen years after radiation exposure. Chronic manifestations of RIHD include accelerated atherosclerosis, cardiomyopathy, and valve abnormalities. Reducing exposure of the heart during radiotherapy is the only known method of preventing RIHD, and there are no approaches to reverse RIHD once it occurs. We use a combination of pharmacological and genetic animal models to determine biological mechanisms of RIHD. Major technological advances in small animal research have made this type of study more valuable. The long-term goal of this work is to identify targets for intervention in RIHD, thereby enhancing the efficacy and safety of thoracic radiotherapy. It is truly a great honor to receive the Radiation Research Society's 2011 Michael Fry Award, which recognizes the contributions of a junior investigator to the field of radiation research. The main focus of my research has always been radiation-induced heart disease (RIHD). This side effect of radiation therapy captured my attention both as a clinical problem and from a radiation biology standpoint. Here, I am very pleased to have the opportunity to present and describe this line of research, as I hope to convey to you my fascination with it. Radiation-induced heart disease is a long-term side effect of radiotherapy of thoracic and chest wall tumors when all or part of the heart is exposed to radiation. For instance, RIHD can occur among survivors of Hodgkin's disease (1,2) or breast cancer (3-5) because radiation therapy fields for those patients can encompass the heart. Manifestations of RIHD include accelerated atherosclerosis, pericardial and myocardial fibrosis, conduction abnormalities, and injury to cardiac valves (6, 7). Both incidence and severity of the disease increase with higher radiation dose, larger volume exposed, younger age at time of exposure, and greater time elapsed since treatment. From a clinical perspective, the only approach to reduce late complications in the heart is through efforts to reduce cardiac exposure during therapy. Indeed, radiotherapy has undergone many such improvements over the last decades. Nonetheless, recent studies indicate that despite safety advances in radiotherapy some patients with Hodgkin's disease, lung, esophageal or proximal gastric cancers still receive either a high dose of radiation to a small part of the heart or a low dose to the whole heart (8-13). In addition, there is increasing use of concomitant therapies, with the consequences of many combinations yet to be determined. While certain cardio-toxic
The Impact of Heart Irradiation on Dose–Volume Effects in the Rat Lung
International Journal of Radiation Oncology*Biology*Physics, 2007
Purpose: To test the hypothesis that heart irradiation increases the risk of a symptomatic radiation-induced loss of lung function (SRILF) and that this can be well-described as a modulation of the functional reserve of the lung. Methods and Materials: Rats were irradiated with 150-MeV protons. Dose-response curves were obtained for a significant increase in breathing frequency after irradiation of 100%, 75%, 50%, or 25% of the total lung volume, either including or excluding the heart from the irradiation field. A significant increase in the mean respiratory rate after 6-12 weeks compared with 0-4 weeks was defined as SRILF, based on biweekly measurements of the respiratory rate. The critical volume (CV) model was used to describe the risk of SRILF. Fits were done using a maximum likelihood method. Consistency between model and data was tested using a previously developed goodness-of-fit test. Results: The CV model could be fitted consistently to the data for lung irradiation only. However, this fitted model failed to predict the data that also included heart irradiation. Even refitting the model to all data resulted in a significant difference between model and data. These results imply that, although the CV model describes the risk of SRILF when the heart is spared, the model needs to be modified to account for the impact of dose to the heart on the risk of SRILF. Finally, a modified CV model is described that is consistent to all data. Conclusions: The detrimental effect of dose to the heart on the incidence of SRILF can be described by a dose dependent decrease in functional reserve of the lung. Ó 2007 Elsevier Inc.
Radiation Dose–Volume Effects in the Heart
International Journal of Radiation Oncology*Biology*Physics, 2010
The literature is reviewed to identify the main clinical and dose-volume predictors for acute and late radiationinduced heart disease. A clear quantitative dose and/or volume dependence for most cardiac toxicity has not yet been shown, primarily because of the scarcity of the data. Several clinical factors, such as age, comorbidities and doxorubicin use, appear to increase the risk of injury. The existing dose-volume data is presented, as well as suggestions for future investigations to better define radiation-induced cardiac injury. Ó 2010 Elsevier Inc.
An overview of radiation-induced heart disease
Radiation Oncology Journal
Radiation therapy (RT) has dramatically improved cancer survival, leading to several inevitable complications. Unintentional irradiation of the heart can lead to radiation-induced heart disease (RIHD), including cardiomyopathy, pericarditis, coronary artery disease, valvular heart disease, and conduction system abnormalities. Furthermore, the development of RIHD is aggravated with the addition of chemotherapy. The screening, diagnosis, and follow-up for RIHD in patients who have undergone RT are described by the consensus guidelines from the European Association of Cardiovascular Imaging (EACVI) and the American Society of Echocardiography (ASE). There is compelling evidence that chest RT can increase the risk of heart disease. Although the prevalence and severity of RIHD are likely to be reduced with modern RT techniques, the incidence of RIHD is expected to rise in cancer survivors who have been treated with old RT regimens. However, there remains a gap between guidelines and clin...
Effects of ionizing radiation on the heart
Mutation Research/Reviews in Mutation Research, 2016
This article provides an overview of studies addressing effects of ionizing radiation on the heart. Clinical studies have identified early and late manifestations of radiation-induced heart disease, a side effect of radiation therapy to tumors in the chest when all or part of the heart is situated in the radiation field. Studies in preclinical animal models have contributed to our understanding of the mechanisms by which radiation may injure the heart. More recent observations in human subjects suggest that ionizing radiation may have cardiovascular effects at lower doses than was previously thought. This has led to examinations of low-dose photons and low-dose charged particle irradiation in animal models. Lastly, studies have started to identify noninvasive methods for detection of cardiac radiation injury and interventions that may prevent or mitigate these adverse effects. Altogether, this ongoing research should increase our knowledge of biological mechanisms of cardiovascular radiation injury, identify non-invasive biomarkers for early detection, and potential interventions that may prevent or mitigate these adverse effects.
Sub-Clinical Heart Damage Enhances Radiation-Induced Lung Function Loss
International Journal of Radiation Oncology*Biology*Physics, 2005
Purpose: To test the hypothesis that heart irradiation increases the risk of a symptomatic radiation-induced loss of lung function (SRILF) and that this can be well-described as a modulation of the functional reserve of the lung. Methods and Materials: Rats were irradiated with 150-MeV protons. Dose-response curves were obtained for a significant increase in breathing frequency after irradiation of 100%, 75%, 50%, or 25% of the total lung volume, either including or excluding the heart from the irradiation field. A significant increase in the mean respiratory rate after 6-12 weeks compared with 0-4 weeks was defined as SRILF, based on biweekly measurements of the respiratory rate. The critical volume (CV) model was used to describe the risk of SRILF. Fits were done using a maximum likelihood method. Consistency between model and data was tested using a previously developed goodness-of-fit test. Results: The CV model could be fitted consistently to the data for lung irradiation only. However, this fitted model failed to predict the data that also included heart irradiation. Even refitting the model to all data resulted in a significant difference between model and data. These results imply that, although the CV model describes the risk of SRILF when the heart is spared, the model needs to be modified to account for the impact of dose to the heart on the risk of SRILF. Finally, a modified CV model is described that is consistent to all data. Conclusions: The detrimental effect of dose to the heart on the incidence of SRILF can be described by a dose dependent decrease in functional reserve of the lung. Ó 2007 Elsevier Inc.
Radiation-associated cardiovascular disease
Critical Reviews in Oncology/Hematology, 2003
As the number of cancer survivors grows because of advances in therapy, it has become more important to understand the longterm complications of these treatments. This article presents the current knowledge of adverse cardiovascular effects of radiotherapy to the chest. Emphasis is on clinical presentations, recommendations for follow-up, and treatment of patients previously exposed to irradiation. Medline TM literature searches were performed, and abstracts related to this topic from oncology and cardiology meetings were reviewed. Potential adverse effects of mediastinal irradiation are numerous and can include coronary artery disease, pericarditis, cardiomyopathy, valvular disease and conduction abnormalities. Damage appears to be related to dose, volume and technique of chest irradiation. Effects may initially present as subclinical abnormalities on screening tests or as catastrophic clinical events. Estimates of relative risk of fatal cardiovascular events after mediastinal irradiation for Hodgkin's disease ranges between 2.2 and 7.2 and after irradiation for left-sided breast cancer from 1.0 to 2.2. Risk is life long, and absolute risk appears to increase with length of time since exposure. Radiation-associated cardiovascular toxicity may in fact be progressive. Long-term cardiac follow-up of these patients is therefore essential, and the range of appropriate cardiac screening is discussed, although no specific, evidencebased screening regimen was found in the literature. #
International Journal of Radiation Oncology*Biology*Physics, 2004
for 100 plans were performed for all structures. Plans were compared by using the mean dose (Dmean) and the volume that received more than 30 Gy (V 30 ) and 45 Gy (V 45 ) for each structure. Results: Cobalt and 20/80 techniques delivered higher Dmeans to the whole heart and individual cardiac chambers (RA, RV, LA, and LV) as compared with the other three techniques. The heart received a Dmean of 21.03 ؎ 3.5 Gy from Co and 11.87 ؎ 5.22 Gy from 20/80. The remaining techniques delivered heart Dmeans of 2.90 -4.94 Gy. When V 30 was used as a metric, all techniques had comparably low V 30 to the heart, except for Co, which resulted in a significantly higher irradiated volume of right-sided cardiac chambers (59.06% ؎ 30.7 for RA F-test < 0.0001; and 61.46% ؎ 22.13 for RV, F-test < 0.0001). Dmean to the proximal LAD (LAD_p) was significantly higher for RHS (17.64 ؎ 7.43 Gy) and 20/80 (20.52 ؎ 8.36 Gy) and lowest for PWTF (9.5 ؎ 4.16 Gy). The Dmean for the distal LAD (LAD_d) was significantly lower with PWTF (11.02 ؎ 7.34 Gy) than with all other techniques, including TAN (p < 0.0001). Similar results for PWTF and TAN were observed when V30 and V45 were used. Conclusions: Cardiac substructures receive the most radiation exposure after PMRT with CO, 20/80 or both and least exposure with PWTF. Although TAN resulted in significant sparing of the majority of the cardiac structures, a significantly higher dose and volume of LAD was exposed when compared with PWTF. Although the clinical relevance of these dose differences is not clearly understood, these dosimetric estimates can serve as a baseline in the development of new techniques for locoregional treatment that will further reduce cardiac exposure.
Radiation Toxicity to the Cardiovascular System
Current Oncology Reports, 2016
Radiation therapy is an important component of cancer treatment, and today, it is applied to approximately 50 % of malignancies, including valvular, myocardial, pericardial, coronary or peripheral vascular disease, and arrhythmias. An increased clinical suspicion and knowledge of those mechanisms is important to initiate appropriate screening for the optimal diagnosis and treatment. As the number of cancer survivors has been steadily increasing over the last decades, cardio-oncology, an evolving subspecialty of cardiology, will soon play a pivotal role in raising awareness of the increased cardiovascular risk and formulate strategies to optimally manage patients in this unique population. Keywords Radiation-induced cardiovascular toxicity. Valvular pericardial heart disease This article is part of the Topical Collection on Cardio-oncology * Konstantinos Marmagkiolis
Radiation-Induced Heart Disease: From Diagnosis to Prevention
ACI (Acta Cardiologia Indonesiana), 2021
Radiotherapy has become an important component of multimodal treatment of malignancy. After 50 years, there was a drastic increase in outcomes of patients with malignancy. However, improvement of the survival is also accompanied by some inevitable complications on cardiovascular system which are often called radiation-induced heart disease (RIHD). RIHD comprises a spectrum of heart disease including pericardial disease, coronary artery disease, valvular heart disease, conduction system abnormalities, cardiomyopathy, and medium or large vessel vasculopathy. The underlying mechanisms include direct effects on function and structure of the heart, or accelerate development of cardiovascular disease, especially with the presence of previous cardiovascular risk factors. Recent studies have identified non-invasive methods for evaluation of RIHD. Furthermore, potential options preventing or at least attenuating RIHD have been developed. This review provides an overview of pathogenesis, clin...
Radiation Damage to the Heart Enhances Early Radiation-Induced Lung Function Loss
Cancer Research, 2005
In many thoracic cancers, the radiation dose that can safely be delivered to the target volume is limited by the tolerance dose of the surrounding lung tissue. It has been hypothesized that irradiation of the heart may be an additional risk factor for the development of early radiation-induced lung morbidity. In the current study, the dependence of lung tolerance dose on heart irradiation is determined. Fifty percent of the rat lungs were irradiated either including or excluding the heart. Proton beams were used to allow very accurate and conformal dose delivery. Lung function toxicity was scored using a breathing rate assay. We confirmed that the tolerance dose for early lung function damage depends not only on the lung region that is irradiated but also that concomitant irradiation of the heart severely reduces the tolerance of the lung. This study for the first time shows that the response of an organ to irradiation does not necessarily depend on the dose distribution in that organ alone. (Cancer Res 2005; 65(15): 6509-11)
Radiation-associated cardiovascular disease: manifestations and management
Seminars in Radiation Oncology, 2003
As the number of cancer survivors grows because of advances in therapy, it has become more important to understand the longterm complications of these treatments. This article presents the current knowledge of adverse cardiovascular effects of radiotherapy to the chest. Emphasis is on clinical presentations, recommendations for follow-up, and treatment of patients previously exposed to irradiation. Medline TM literature searches were performed, and abstracts related to this topic from oncology and cardiology meetings were reviewed. Potential adverse effects of mediastinal irradiation are numerous and can include coronary artery disease, pericarditis, cardiomyopathy, valvular disease and conduction abnormalities. Damage appears to be related to dose, volume and technique of chest irradiation. Effects may initially present as subclinical abnormalities on screening tests or as catastrophic clinical events. Estimates of relative risk of fatal cardiovascular events after mediastinal irradiation for Hodgkin's disease ranges between 2.2 and 7.2 and after irradiation for left-sided breast cancer from 1.0 to 2.2. Risk is life long, and absolute risk appears to increase with length of time since exposure. Radiation-associated cardiovascular toxicity may in fact be progressive. Long-term cardiac follow-up of these patients is therefore essential, and the range of appropriate cardiac screening is discussed, although no specific, evidencebased screening regimen was found in the literature. #
A Pilot Study of Safer Radiation Dosage to the Heart and Its Subregions
Medicina, 2021
Background and Objectives: The real impact of ionizing radiation on the heart and poorer overall survival for patients with non small cell lung cancer (NSCLC) remains unclear. This study aims to determine the safe dose constraints to the heart’s subregions that could prevent patients’ early non-cancerous death and improve their quality of life. Methods and Materials: A retrospective cohort study was performed containing 51 consecutive patients diagnosed with stage III NSCLC and treated using 3D, Intensity-modulated radiation therapy (IMRT), and Volumetric modulated arc therapy (VMAT) radiotherapy. For a dosimetric analysis, these structures were chosen: heart, heart base (HB), and region of great blood vessels (GBV). Dose–volume histograms (DVH) were recorded for all mentioned structures. Maximum and mean doses to the heart, HB, the muscle mass of the HB, and GBV were obtained. V10–V60 (%) parameters were calculated from the DVH. After performed statistical analysis, logistic regres...
Journal of Cancer Therapy, 2021
Purpose: To examine possible association between heart irradiation and Overall Survival (OS) in lung SBRT patients and to compare observed associations with cardiac toxicity models previously derived in LA-NSCLC patient studies. Materials and Methods: 197 Patients treated with lung SBRT at Mayo Clinic Arizona were selected for this IRB-approved study. Multivariate Cox model with Akaike Information Criterion (AIC) was used to select patient specific covariates associated with OS. Heart dosimetry was represented by V D indices, which is a percentage of volume exposed to dose D or greater. Multivariate Cox models with patient specific covariates and single V D index per model was used to find a range of doses which were predictive for OS. A digital subdivision of the heart was further used to determine the spatial distribution of doses which were predictive for OS. A coarse subdivision divided heart into 4 segments, while the fine subdivision divided heart into 64 segments. Knowledge constrained Fused Lasso operator was used to derive a more complete model which correlated heart dosimetry with OS. Results of statistical analysis were compared to predictions of a model of cardiac toxicity in LA-NSCLC patients. Results: Higher age (p < 0.001), higher stage (p < 0.001) and squamous cell histology (p = 0.001) were associated with reduced OS. Whole heart DVH analysis did not reveal associations between heart irradiation and reduced OS. Coarse subdivision of the heart into four segments revealed that the irradiation of two inferior segments of the heart with low doses was associated with reduced OS, V 2Gy in the right-inferior segment