Radiation-induced Myocardial Damage Research Articles

TFAM Modulates Cardiomyocytes Pyroptosis Induced by Ionizing Radiation through mtDNA/TLR9/NF-kB Pathway

Mitochondrial transcription factor A (TFAM) is a pivotal factor for regulating mitochondrial DNA (mtDNA) replication, transcription and biogenesis. Previous studies have reported that cytosolic mtDNA stress can lead to cardiomyocytes pyroptosis, which is characterized by inflammasome formation. In this study, we attempted to investigate the mechanism of TFAM regulate cardiomyocytes pyroptosis induced by ionizing radiation. The peripheral blood serum of patients with esophageal cancer before and after definitive chemoradiotherapy was collected for Luminex multiplex cytokine assays. C57BL/6 mice were irradiated with the whole heart using small animal radiation research platform (SARRP) to construct a radiation-induced myocardial damage (RIMD) mouse model, and the ventricular function was evaluated using 9.4T Bruker magnetic resonance (MR) scanner. The function changes of cardiomyocytes exposed to radiation were observed in vitro and in vivo after knocking out GSDMD. Furthermore, the changes of mitochondrial function, the levels of cytosolic mtDNA, and the protein levels of NF-kB and pyroptosis pathway in irradiated cardiomyocytes were analyzed by knockdown and overexpression of TFAM in vitro and in vivo. By multifactor cytokine assays we found that pyroptosis related IL-1β and IL-18 were significantly increased in patients with high mean heart dose (MHD) after radiotherapy, while those with low MHD were not significantly increased after radiotherapy. Next, we successfully constructed the RIMD mouse model using a single heart irradiation of 20 Gy. We found that the gene expression of pyroptosis pathway was significantly up-regulated after cardiac irradiation by myocardial tissue transcriptomic sequencing. Compared with wild-type (WT) mice, cardiac systolic function of Gsdmd-/- mice was significantly improved at 1, 2, 6, 12, and 24 weeks after heart irradiation. In vitro, we also demonstrated increased viability of irradiated cardiomyocytes by knocking out GSDMD. In vitro and in vivo experiments confirmed the expression of TFAM decreased after radiation. By overexpression of TFAM, we found that irradiated cardiomyocytes showed improved mitochondrial function, decreased release of mtDNA into cytoplasm through mitochondrial permeability transition pores (mPTPs), decreased binding of cytosolic mtDNA to TLR9, and decreased expression of NF-kB and pyroptosis pathway proteins. Dual luciferase gene reporter assays and Chromatin immunoprecipitation (CHIP) assay confirmed that p65 could bind the NLRP3 promoter region. In addition, we found that ventricular function deteriorated and improved in mice with knockdown and overexpression of TFAM through adeno-associated virus serotype 9 (AAV9), respectively. Our study indicated that TFAM regulate irradiated cardiomyocytes pyroptosis through mtDNA/TLR9/NF-kB pathway. We provide a novel mechanism of RIMD, revealing an underappreciated intervention target for RIMD.

Clinical impact of radiation-induced myocardial damage detected by cardiac magnetic resonance imaging and dose-volume histogram parameters of the left ventricle as prognostic factors of cardiac events after chemoradiotherapy for esophageal cancer.

This prospective study aimed to evaluate whether radiation (RT)-induced myocardial damage by cardiac magnetic resonance (CMR) imaging could be a predictor of cardiac events after chemoradiotherapy (CRT) for esophageal cancer and determine the dose-volume histogram (DVH) parameters of the left ventricle (LV) in predicting cardiac events. CMR imaging was performed before and 6months after CRT in patients receiving definitive CRT. RT-induced myocardial damage was defined as abnormal CMR findings indicating myocardial fibrosis corresponding to an isodose line of ≥30Gy. The cutoff values of the LV DVH parameters were calculated using the receiver operating characteristic curve based on the presence of RT-induced myocardial damage. The prognostic factors related to cardiac events of Grade 3 or higher were examined. Twenty-three patients were enrolled in the study. RT-induced myocardial damage by late gadolinium enhancement and/or an increase of 100ms or higher in native T1 post-CRT was detected in 10 of the 23 patients. LV V45 was the best predictive factor for RT-induced myocardial damage with a cutoff value of 2.1% and an area under the curve of 0.75. The median follow-up period was 82.1months. The 5- and 7-year cumulative incidences of cardiac events of Grade 3 or higher were 14.7 and 22.4%, respectively. RT-induced myocardial damage and LV V45 were significant risk factors (P = 0.015 and P = 0.013, respectively). RT-induced myocardial damage is a significant predictor of cardiac events. LV V45 is associated with RT-induced myocardial damage and subsequent cardiac events.

Plasma Markers for Early Prediction of Radiation-Induced Myocardial Damage.

There is no sensitive and effective method to predict radiation-induced myocardial damage (RIMD). The aim of this study was to explore effective plasma biomarkers for early prediction of RIMD after radiotherapy (RT) in lung cancer patients and in a rat model. Biomarker levels were measured in plasma samples collected before and after thoracic RT from 17 lung cancer patients. For the animal model, a single radiation dose of 40 Gy was delivered to the cardiac apex of female Wistar rats. Control rats received sham irradiation (0 Gy). Dynamic plasma biomarker detection and histopathological analysis to confirm RIMD were performed in rats up to 6 months after RT. In lung cancer patients, the plasma caspase-3 concentration was significantly increased after thoracic RT (P = 0.0479), with increasing but nonsignificant trends observed for caspase-1, CCL2, vascular endothelial growth factor (VEGF), interleukin-1β, and IL-6 (P > 0.05). Changes in caspase-3, VEGF, and IL-6 correlated significantly with mean heart dose (P < 0.05). In the RIMD rat model, caspase-1, caspase-3, CCl-2, VEGF, CCl-5, and TGF-β1 levels were significantly elevated in the first week post-RT (P < 0.05), which was earlier than pathological changes. Myocardial tissue of the RIMD rats also showed significant macrophage infiltration at 1 month (P < 0.01) and fibrosis at 6 months postradiation (P < 0.0001). Macrophage infiltration correlated significantly with plasma caspase-3, CCL2, CCL5, VEGF, and TGF-β1 levels from 3 weeks to 2 months post-RT. Increased plasma caspase-1, caspase-3, CCl-2, and VEGF levels were detected before RIMD-related pathological changes, indicating their clinical potential as biomarkers for early prediction of RIMD.

Molecular Imaging of Fibroblast Activity in Radiation-Induced Acute Myocardial Damage Using a [18F]AlF-Labeled Fibroblast Activation Protein Inhibitor, FAPI-04

<h3>Purpose/Objective(s)</h3> A previous retrospective analysis revealed increased [¹⁸F]AlF-NOTA-FAPI uptake in myocardial tissue of patients with esophageal squamous cell cancer (ESCC) treated with concurrent chemoradiotherapy (CCRT). The present study investigated and verified the feasibility of [¹⁸F]AlF-NOTA-FAPI positron emission tomography (PET)/computed tomography (CT) imaging for detecting radiation-induced myocardial damage (RIMD). <h3>Materials/Methods</h3> Myocardial FAPI uptake was analyzed before radiotherapy and during radiotherapy (36–50 Gy) in 13 ESCC patients treated with CCRT. In an animal study, a single dose of 50 Gy was delivered to the cardiac apex of female Wistar rats using conformal radiotherapy. RIMD model rats were scanned with [¹⁸F]AlF-NOTA-FAPI PET/CT weekly for 12 weeks, and then MRI was conducted. Dynamic, competition, and [¹⁸F]FDG PET/CT studies were performed on RIMD rats at 5 weeks post-radiation, and histopathological analyses were conducted. <h3>Results</h3> Three patients showed potentially increased FAPI uptake in myocardial tissue after radiotherapy. In the RIMD rat model, a significant increase in FAPI uptake in the damaged myocardium was observed from the 2nd week post-radiation exposure, with peak values observed in the 5th week. Significantly more intense tracer accumulation was observed in the damaged myocardial region than in remote myocardial tissue, as identified by decreased [¹⁸F]FDG uptake and confirmed by autoradiography, Masson's trichrome staining and immunohistochemical staining. The left ventricular ejection fraction (LVEF) remained unchanged from baseline at the 3rd week post-radiation exposure but was remarkably decreased compared with that in the control group at the 8th week. <h3>Conclusion</h3> An increase in myocardial uptake of [¹⁸F]AlF-NOTA-FAPI occurred in patients with ESCC after radiotherapy. These results indicated that FAPI PET/CT imaging can detect RIMD noninvasively and before a decrease in LVEF is detected, indicating the clinical potential of FAPI as a radiotracer for in vivo imaging of RIMD.

Early detection of radiation-induced myocardial damage by [18F]AlF-NOTA-FAPI-04 PET/CT imaging.

Retrospective analysis revealed increased [18F]AlF-NOTA-FAPI-04 uptake in the myocardium of patients with esophageal squamous cell cancer (ESCC) treated with concurrent chemoradiotherapy (CCRT). This study investigated and verified the feasibility of [18F]AlF-NOTA-FAPI-04 PET/CT for detecting radiation-induced myocardial damage (RIMD). Myocardial FAPI uptake was analyzed before and during radiotherapy in thirteen ESCC patients treated with CCRT. In the animal study, a single dose of 50Gy was delivered to the cardiac apex of Wistar rats (24 rats, including 16 RIMD model rats and 8 control model rats). RIMD model rats were scanned with [18F]AlF-NOTA-FAPI-04 PET/CT weekly for 12weeks, and left ventricular ejection fraction (LVEF) was measured by magnetic resonance imaging. Dynamic, blocking, and [18F]FDG PET/CT studies (4 rats/group) were performed on RIMD rats at 5weeks post-radiation, and histopathological analyses were conducted. Increased FAPI uptake in the myocardium was found after CCRT (1.53 ± 0.53 vs 1.88 ± 0.70, P = 0.015). In RIMD rats, significantly increased FAPI uptake in the damaged myocardium was observed from the 2nd week post-radiation exposure and peaked in the 5th week. Significantly more intense tracer accumulation was observed in the damaged myocardium than in the remote myocardium, as identified by decreased [18F]FDG uptake and confirmed by autoradiography, hematoxylin-eosin, Masson's trichrome, and immunohistochemical staining. The LVEF remained unchanged at the 3rd week post-radiation exposure but was remarkably decreased compared with that in the control group at the 8th week. Through clinical phenomena and animal experimental studies, this study indicated that [18F]AlF-NOTA-FAPI-04 PET/CT imaging can detect RIMD noninvasively and before a decrease in LVEF, indicating the clinical potential of [18F]AlF-NOTA-FAPI-04 as a PET/CT tracer for early monitoring of RIMD.

Dose-Dependent Radiation-Induced Myocardial Damage in Esophageal Cancer Treated With Chemoradiotherapy: A Prospective Cardiac Magnetic Resonance Imaging Study

PurposeThe purpose of this prospective study was to evaluate radiation-induced myocardial damage after mediastinal radiation therapy (RT) using late gadolinium-enhancement (LGE) magnetic resonance imaging (MRI). Methods and MaterialsWe enrolled 19 patients with esophageal cancer who were expected to have long-term survival by definitive treatment. They underwent delayed contrast-enhanced MRI (19 patients before treatment, 19 patients 6 months after treatment, and 12 patients 1.5 years after treatment). Dose distribution of the left ventricle was made using computed tomography, and the dose volume histogram of the left ventricle was calculated. Myocardial signal intensities in individual MRIs were normalized by the mean values in regions receiving low doses (<5 Gy). Changes in the normalized signal intensities after mediastinal radiation therapy were compared among regions where irradiation doses were 0 to 10 Gy, 10 to 20 Gy, 20 to 30 Gy, 30 to 40 Gy, 40 to 50 Gy, and 50 to 60 Gy, and we investigated whether intensity change was detected in a dose-dependent manner. ResultsThe registered patients were treated with concurrent chemoradiotherapy with a median total dose of 60 Gy (50.4-66 Gy). Chemotherapy consisting of cisplatin and 5-fluorouracil was administered. In the population-based dose-response curve, dose-dependent intensity changes progressively increased in regions receiving more than 30 Gy. The averages of relative intensity change at 6 months and 1.5 years after treatment were 1.1% and −1.9% at 20 to 30 Gy and 37.5% and 17.5% at 40 to 50 Gy, respectively. LGE in regions receiving more than 30 Gy was detected in 68% (13/19) of the patients. ConclusionsA dose-dependent relationship for myocardial signal intensity change was found by using LGE MRI. It may be necessary to reduce the volume of the myocardium receiving more than 30 Gy.

13N-Ammonia PET/CT Detection of Myocardial Perfusion Abnormalities in Beagle Dogs After Local Heart Irradiation.

Our objective was to determine the potential value of 13N-ammonia PET/CT myocardial perfusion imaging (MPI) for early detection of myocardial perfusion changes induced by radiation damage. Methods: Thirty-six Beagle dogs were randomly divided into a control group (n = 18) or an irradiation group (n = 18). The latter underwent local irradiation to the left ventricular anterior cardiac wall with a single dose of 20 Gy, whereas the former received sham irradiation. All dogs underwent 13N-ammonia PET/CT MPI 1 wk before irradiation and at 3, 6, and 12 mo after sham or local irradiation. One week after undergoing 13N-ammonia PET/CT MPI, the irradiation group underwent coronary angiography. Six randomly selected dogs from each group were sacrificed and used to detect pathologic cardiac injury at 3, 6, and 12 mo after irradiation. Results: Compared with the control group and baseline, the irradiation group showed significantly increased perfusion in the irradiated area of the heart at 3 mo after irradiation, perfusion reduction at 6 mo after irradiation, and a perfusion defect at 12 mo after irradiation. There was no significant difference in the left ventricular ejection fraction between the control and irradiation groups at baseline or at 3 mo after irradiation. The irradiation group showed a reduction of left ventricular ejection fraction compared with the control group at 6 mo (50.0% ± 8.1% vs. 59.3% ± 4.1%, P = 0.016) and 12 mo (47.2% ± 6.7% vs. 57.4% ± 3.3%, P = 0.002) after irradiation. No coronary stenosis was observed in the irradiation group. Regional wall motion abnormalities appeared in the irradiated area at 6 mo after irradiation, and its extent was enlarged at 12 mo after irradiation. Pathologic changes were observed; radiation-induced myocardial tissue damage and microvascular fibrosis in the irradiated area progressively increased over time. Conclusion:13N-ammonia PET/CT MPI can dynamically detect myocardial perfusion changes together with global and regional left ventricular dysfunction induced by irradiation and may be a valuable method for monitoring radiation-induced heart disease.

Pathological manifestations of acute-stage radioactive myocardial damage and related mechanisms

Objective To investigate the pathological manifestations of acute-stage radioactive myocardial damage and related mechanisms using an experimental animal model. Methods A total of 12 adult male Sprague-Dawley rats were randomly divided into control group and radiation group. In the radiation group, the model of radiation-induced myocardial damage was established by the irradiation of the anterior myocardial territory with 6-MV X-ray at a single dose of 20 Gy, and at 14 days after irradiation, HE staining was used to observe the morphological changes of cardiomyocytes and intercellular matrix, and Masson staining was used to observe the distribution of collagen fibers. The collagen volume fraction (CVF) was used for semi-quantitative analysis. ELISA was used to measure the activity of total superoxide dismutase (T-SOD) and the concentration of malondialdehyde (MDA), and Western blot was used to measure the expression of the fibrosis marker protein collagen type I (COL-1) and the endoplasmic reticulum stress-related proteins GRP78 and CHOP. The t-test, t’-test, or nonparametric rank sum test was used for comparison between groups. Results At 14 days after local irradiation of the heart, the radiation group had disordered arrangement of cardiomyocytes, marked edema, rupture of some cardiomyocytes, mild karyopyknosis in cardiomyocytes, and infiltration of inflammatory cells in the myocardial interstitium, compared with the control group. Collagen fibers in the myocardial tissue were mainly distributed in the perivascular area and cardiomyocyte interstitium. The radiation group had a significantly higher CVF than the control group (11.35% vs. 5.23%, P=0.000) and a significant increase in the expression of COL-1 compared with the control group (P=0.000). The radiation group had significant increases in the activity of T-SOD and the concentration of MDA in the myocardial tissue compared with the control group (T-SOD: 156.61 U/mgprot vs. 137.06 U/mgprot, P=0.042; MDA: 2.36 nmol/mgprot vs. 1.31 U/mgprot, P=0.007). Compared with the control group, the radiation group showed significant increases in the expression of endoplasmic reticulum stress-related proteins GRP78 and CHOP (P=0.037 and 0.009). Conclusions The pathological manifestations of acute-stage myocardial damage include degeneration of cardiomyocytes, inflammatory exudation in the interstitium, and deposition of collagen in the perivascular area and myocardial interstitium. Myocardial fibrosis can be observed in the acute stage of radiation-induced myocardial damage, and the mechanism may be related to oxidative stress and endoplasmic reticulum stress induced by radioactive rays. Key words: Radiation induced heart disease; Histopathology; Fibrosis; Oxidative stress; Endoplasmic reticulum stress

Research advances in the pathogenesis of radiation-induced myocardial damage

The Medline and CNKI databases were searched with the key words of myocardial damage, damage pathway, pathogenesis, and intervention , and 37 articles were obtained. The pathogenesis of radiation-induced myocardial damage may be related to various mechanisms such as oxidative stress, transforming growth factor-β, renin-angiotensin system, mast cells, and endothelial dysfunction. The pathogenesis of radiation-induced myocardial damage is a complex process involving various mechanisms, and currently, there are ongoing studies on the cellular and molecular mechanisms involved in its pathogenesis and interventions. Key words: Radiation induced cardiac injury; Pathogenesis; Thoracic neoplasms/radiotherapy

Detection of Myocardial Metabolic Abnormalities by 18F-FDG PET/CT and Corresponding Pathological Changes in Beagles with Local Heart Irradiation.

ObjectiveTo determine the efficacy of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) in the detection of radiation-induced myocardial damage in beagles by comparing two pre-scan preparation protocols as well as to determine the correlation between abnormal myocardial FDG uptake and pathological findings.Materials and MethodsThe anterior myocardium of 12 beagles received radiotherapy locally with a single X-ray dose of 20 Gy. 18F-FDG cardiac PET/CT was performed at baseline and 3 months after radiation. Twelve beagles underwent two protocols before PET/CT: 12 hours of fasting (12H-F), 12H-F followed by a high-fat diet (F-HFD). Regions of interest were drawn on the irradiation and the non-irradiation fields to obtain their maximal standardized uptake values (SUVmax). Then the ratio of the SUV of the irradiation to the non-irradiation fields (INR) was computed. Histopathological changes were identified by light and electron microscopy.ResultsUsing the 12H-F protocol, the average INRs were 1.18 ± 0.10 and 1.41 ± 0.18 before and after irradiation, respectively (p = 0.021). Using the F-HFD protocol, the average INRs were 0.99 ± 0.15 and 2.54 ± 0.43, respectively (p < 0.001). High FDG uptake in irradiation field was detected in 33.3% (4/12) of 12H-F protocol and 83.3% (10/12) of F-HFD protocol in visual analysis, respectively (p = 0.031). The pathology of the irradiated myocardium showed obvious perivascular fibrosis and changes in mitochondrial vacuoles.ConclusionHigh FDG uptake in an irradiated field may be related with radiation-induced myocardial damage resulting from microvascular damage and mitochondrial injury. An F-HFD preparation protocol used before obtaining PET/CT can improve the sensitivity of the detection of cardiotoxicity associated with radiotherapy.

MRI findings of radiation-induced myocardial damage in patients with oesophageal cancer

To evaluate radiation-induced myocardial damage after mediastinal radiotherapy using MRI. Between May 2010 and April 2011, delayed contrast-enhanced MRI was performed for patients who had maintained a complete response to curative radiotherapy for oesophageal cancer for more than 6 months. The patients received radiotherapy with a median total dose of 66Gy (60-70Gy) for the primary tumour and metastatic lymph nodes. Images of MRI were analysed by a 17-segment method recommended by the American Heart Association. A segment included mainly in the 40Gy dose line was defined as Segment 40Gy, a segment included mainly in the 60Gy dose line as Segment 60Gy, and a segment out of the radiation fields as Segment OUT. The percentage of late gadolinium enhancement (LGE) was examined in those categories. The layer in which LGE was predominantly distributed was evaluated for each patient. Four hundred and eight segments in 24 patients were analysed. The median interval from completion of radiotherapy to MRI was 23.5 months (range 6-88 months). LGE was detected in 12 of the 24 patients. LGE was detected in 15.38% of Segment 40Gy cases, 21.21% of Segment 60Gy cases, and 0% of Segment OUT cases. LGE in mid-myocardial and subendocardial layers was detected in 11 patients and one patient, respectively. LGE suggesting radiation induced myocardial fibrosis was observed by performing delayed contrast-enhanced MRI. Care should be taken when planning radiotherapy to avoid late cardiac damage.

Magnetic Resonance Imaging Findings of Radiation-Induced Myocardial Damage in Patients With Esophageal Cancer

Magnetic Resonance Imaging Findings of Radiation-Induced Myocardial Damage in Patients With Esophageal Cancer

Evaluation of radiation-induced myocardial damage using iodine-123  -methyl-iodophenyl pentadecanoic acid scintigraphy

We evaluated radiation-induced myocardial damage using iodine-123 β-methyl-iodophenyl pentadecanoic acid (I-123 BMIPP) scintigraphy. Between May 2010 and April 2011 we performed I-123 BMIPP scintigraphy for patients who had maintained complete response to curative radiotherapy (RT) for esophageal cancer for more than six months. We compared the area of the myocardium in the RT fields with that of reduced I-123 BMIPP uptake using a 15-segment model that is based on axial computed tomography (CT) images. We classified the segments into three categories: segments receiving 40 Gy (Segment 40 Gy), segments receiving 60 Gy (Segment 60 Gy) and segments out of the radiation fields (Segment 0 Gy). A segment with reduced uptake in the RT fields was defined as positive. A total of 510 segments in 34 patients were used for analysis. The median interval from completion of RT to I-123 BMIPP scintigraphy was 22 months (range, 6–103 months). The numbers of Segment 0 Gy, Segment 40 Gy and Segment 60 Gy were 324, 133 and 53, respectively. Reduced uptake was detected in 42.9% (57/133) of Segment 40 Gy, 67.9% (36/53) of Segment 60 Gy and 13.3% (43/324) of Segment 0 Gy. The odds ratios of 40 Gy and 60 Gy compared with regions out of the RT fields were 5.2 (95% confidence interval [CI]: 3.7–7.4) and 15.4 (95% CI: 6.9–34.6), respectively. Reduced myocardial I-123 BMIPP uptake in RT fields, suggesting RT-induced myocardial damage, was frequently observed. I-123 BMIPP myocardial scintigraphy may be useful for identifying RT-induced myocardial damage.

The analysis of correlation between changes of myocardial enzymes level in serum before and after radiation and dose-volume histogram parameters of the heart

Objective To analyze the correlation between the changes of myocardial enzyme level in serum before and after radiotherapy and dose - volume histogram ( DVH ) parameters of the heart.Methods A total of 102 patients with 68 cases of lung cancer and 34 cases of esophageal cancer were recruited.All patients received three-dimensional conformal radiotherapy (3DCRT) or intensity-modulated radiotherapy (IMRT),with the radiation beams passing through the heart.Aspertate aminotransferase (AST),creatine kinase (CK),creatine kinase isozyme ( CK-MB ),lactate dehydrogenase ( LDH ),α-hydroxybutyrate dehydrogenase (α-HBDH) were determined in the serum before and after radiotherapy.All the enzyme levels before and after radiotherapy were compared through paired t-test.Independent sample t-test was conducted between sub-groups.And the dose-volume histogram (DVH) parameters of the heart were calculated ( the volume percentage of heart receiving dose equal to or exceeding x Gy ( Vx ).The correlation between myocardial enzyme level and DVH parameters was analyzed through Pearson method.Results Serum AST,CK-MB,LDH,α-HBDH levels increased significantly after radiotherapy ( 19.42∶ 27.89,14.72∶19.57,178.80 ∶ 217.57,140.32 ∶ 176.25,t =-3.39 - -6.92,all P=0.000).In Group IMRT,significant correlations between the increase of myocardial enzyme concentration and DVH parameters of the heart are found,AST with V20,V25,V30 of heart ( r=0.302 - 0.431,P =0.039 - 0.003 ),CK with V30of heart (r=0.345,P=0.013),and CK-MB,LDH,α-HBDH with V25,V30(r=0.465 -0.376,P=0.001-0.005).In Group CRT,there are significant correlations between changes of CK-MB,LDH level and V30 of heart (r =0.330,0.274,P=0.014,0.033),α-HBDH and V25,V30,and V35 of heart (r=0.270-0.331,P=0.046-0.014).When the irradiation dose was more than 50 Gy,significant correlations were found between the concentration changes of AST,LDH,α-HBDH and V25,V30 of heart (r=0.256-0.359,P =0.019-0.006),CK-MB and V30(r=0.233,P=0.037).When the irradiation dose was 50 Gy or less,only the concentration change of serum CK has significant correlation with V5 and V45 of heart (r=0.581,0.536,P=0.023,0.043).Conclusions There exists certain correlations between changes of myocardial enzymes level before and after radiation and DVH parameters of the heart,which indicates that the DVH parameters of heart are helpful to evaluate the radiation-induced myocardial damage. Key words: Thoracic neoplasma; Three-dimensional radiotherapy; Myocardial enzyme; Dose-volume histogram

Temporal Change in Brain Natriuretic Peptide After Radiotherapy for Thoracic Esophageal Cancer

To investigate the relationships of plasma levels of brain natriuretic peptide (BNP) with abnormal (18)F-fluorodeoxyglucose (FDG) accumulation in the myocardium corresponding to irradiated fields and temporal changes in BNP, which is used as an index of heart remodeling, after radiotherapy for the mediastinum. Brain natriuretic peptide concentrations were measured before and after radiotherapy for thoracic esophageal cancer, and the change in BNP concentration after radiotherapy was investigated. Moreover, FDG accumulation in the myocardium was investigated in patients who had undergone FDG positron emission tomography less than 14 days before or after measurement of BNP concentration, and the Mann-Whitney U test was used to detect significant difference between BNP concentrations in patients with and without abnormal FDG accumulation corresponding to the irradiated field. There was significant difference between the levels of BNP in patients without abnormal FDG accumulation in the irradiated myocardium and in patients with abnormal FDG accumulation (p < 0.001). The levels of BNP in the 9-24 months after radiotherapy group and in the >24 months after radiotherapy group were significantly higher than the levels in the before radiotherapy group, immediately after radiotherapy group, 1-2 months after radiotherapy group, and control group. The level of BNP was significantly increased more than 9 months after the start of radiotherapy and was significantly higher in patients who had high FDG accumulation corresponding to the irradiated field. The results of this study indicate that BNP concentration might be an early indicator of radiation-induced myocardial damage.

The utility of 18F-fluorodeoxyglucose positron emission tomography for early diagnosis of radiation-induced myocardial damage

We evaluated the clinical significance of focal increased uptake in the basal myocardium on F-fluorodeoxyglucose positron emission tomography (FDG-PET) in patients with esophageal cancer after radiotherapy. Between August 2004 and July 2005, a total of 64 patients who had been irradiated for thoracic esophageal cancer underwent FDG-PET at least three months after the completion of chemoradiotherapy. Some patients showed increased FDG uptake in the basal portion of the myocardium. To clarify the clinical significance of these findings, further examinations of hearts were performed. The dose distribution in the myocardium with high FDG uptake was also analyzed retrospectively. Thirteen (20.3%) of the 64 patients showed high FDG uptake in the basal myocardium corresponding to the irradiated fields compared with FDG uptake in the myocardium outside the irradiated fields. Eight of the 13 patients consented to undergo examinations of the heart. Five of those eight patients showed low 123I-BMIPP uptake and four showed low 201TlCl uptake in the myocardium corresponding with high FDG uptake regions. In two patients, delayed enhancement was found in some parts of the area with high FDG uptake on Gd-DTPA magnetic resonance imaging (MRI), and the delay-enhanced lesion showed hypokinesia on cine-MRI in one patient. FDG-PET often shows focal increased uptake in the basal myocardium after radiotherapy for esophageal cancer. This finding indicates the possibility of radiation-induced cardiac damage, and cardiac function and symptoms of such patients should be followed carefully.

Detection of radiation-induced myocardial damage by technetium-99m sestamibi scintigraphy

Detection of radiation-induced myocardial damage by technetium-99m sestamibi scintigraphy

Detection of radiation-induced myocardial damage by technetium-99m sestamibi scintigraphy.

A prospective study was initiated to assess the side-effects of postoperative adjuvant radiotherapy in patients with left-sided early breast cancer. Twelve patients with early breast cancer were examined before and a year after radiotherapy. Echocardiography, ECG and bicycle ergometry stress test with technetium-99m sestamibi myocardial perfusion scintigraphic were carried out to assess changes in regional myocardial blood flow. Six of the 12 patients had new fixed scintigraphic defects after radiotherapy (as compared with the preradiation examination). The localization of the defects corresponded well with the irradiated volume of the left ventricle. These defects were probably due to microvascular damage to the myocardium. Neither ECG changes nor left ventricular segmental wall motion abnormalities could be detected by echocardiography. To our knowledge this study is the first to show that radiation-induced micro-vascular damage to the myocardium may be detected by perfusion scintigraphy. This may limit the use of scintigraphy in diagnosing coronary artery disease in patients treated with thoracic radiotherapy. Long-term follow-up is necessary to assess whether the presence of microvascular damage is a prognostic sign for the development of radiation-induced coronary artery disease.

Poor outcome in radiation-induced constrictive pericarditis

Purpose : To compare the outcome of patients with radiation-induced constrictive pericarditis versus patients with constriction due to another etiology. Methods and materials : Twenty patients with constrictive pericarditis seen during 1975–1986 at a single medical center. Six had radiation-induced constrictive pericarditis (Group A). The etiology was idiopathic in ten subjects and secondary to carcinomatous encasement, chronic renal failure, purulent infection and tuberculosis in one patient each (Group B, N = 14). Mean age was 53.4 ± 15.5 years. Results : Extensive pericardiectomy was performed in 3 6 Group A and 13 14 Group B patients. All Group A patients died, 4 weeks—11 years post-diagnosis (median = 10 months). Two Group A patients died suddenly, one died post-operatively of respiratory failure, another of pneumonia and two of recurrent carcinoma. Thirteen Group B patients are alive (median follow-up = 72 months). The only death in this group was due to metastatic cancer. Conclusion : The poor outcome with radiation-induced constriction is probably multi-factorial. Poor surgical outcome is to be expected in patients with evidence of recurrent tumor, high-dose irradiation, pulmonary fibrosis or associated radiation-induced myocardial, valvular or coronary damage.

Creatine Phosphokinase and Other Serum Enzymes During Radiotherapy

Twenty-one patients receiving irradiation to major portions of the heart and 24 patients receiving noncardiac irradiation had serial determinations of serum enzymes including lactic acid dehydrogenase (LDH), serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT), and creatine phosphokinase (CPK) before, during, and after therapy. The following conclusions were reached: (1) the serum LDH and SGOT values are not useful to detect radiation-induced myocardial damage since they (as well as the SGPT) are frequently abnormal and likely to reflect a variety of complications related to the neoplastic disease itself; (2) the CPK remains normal in patients receiving irradiation to various tumors, including large areas of skeletal muscle and the right border of the heart, but excluding the major muscular portion of the heart; and (3) a rise in CPK value, noted in five patients during and in two patients following irradiation to the heart, may reflect radiationinduced myocardial damage.