Radiation-induced Cardiomyopathy Research Articles

Sirtuin 3 controls cardiac energetics and protects against oxidative stress in electromagnetic radiation-induced cardiomyopathy

Electromagnetic radiation can cause injuries to both the structures and functions of the heart. No therapy is currently available to inhibit these untoward effects. Mitochondrial energetic damage and oxidative stress are drivers of electromagnetic radiation-induced cardiomyopathy (eRIC); however, the pathways that mediate these events are poorly defined. Sirtuin 3 (SIRT3) has been emerged as a key target for maintaining mitochondrial redox potential and metabolism, but its role in eRIC remains unknown. Here, Sirt3-KO mice and cardiac-specific SIRT3 transgenic mice were subjected to the investigation of eRIC. We found that Sirt3 protein expression level was down-regulated in eRIC mice model. Sirt3-KO markedly exaggerated decreases in cardiac energetics and increases in oxidative stress in microwave irradiation (MWI)-stressed mice. Conversely, cardiac-specific SIRT3 overexpression protected the hearts from these effects and rescued cardiac malfunction. Mechanistically, Sirt3 maintained AMP-activated protein kinase (AMPK) signaling pathway in MWI-stressed hearts in vivo. In conclusion, electromagnetic radiation repressed SIRT3 expression and disturbed cardiac energetics and redox homeostasis. The increased SIRT3 expression and AMPK activation in vivo prevented eRIC, indicating that SIRT3 will be a potential therapeutic target for curative interventions in eRIC.

Radiation-induced Cardiomyopathy: Gender Differences In Trends And Outcomes

Radiation-induced Cardiomyopathy: Gender Differences In Trends And Outcomes

Current view on radiation-induced heart disease and methods of its diagnosis

In recent years, cardiologists and cardiovascular surgeons are increasingly encountering radiation-induced heart disease (RIHD) in their practice. This complication is described in literature but is poorly understood and clinically challenging. Radiation therapy (RT) is widely used in the treatment of many cancers. Despite the considerable risk of RT complications, it is used in 20–55% of cancer patients. Radiation-associated cardiotoxicity appears to be delayed, typically 10 to 30 years following treatment. Mediastinal irradiation significantly increases the risk of non-ischemic cardiomyopathy. Recent reviews estimate the prevalence of radiation-induced cardiomyopathy at more than 10%. Therefore, it is important to understand the pathophysiology of RIHD, consider risk factors associated with radiation injury, and detect the condition early.

New insights into the development of radiation-induced cardiac damage using a mouse model

Abstract Background The improvement of anticancer-therapy results in a greater amount of long-term survivors after radiotherapy. Therefore, the understanding of cardiotoxicity after irradiation is of increasing importance. Long-term adverse cardiovascular events may become evident years or decades after radiotherapy. The relative contribution of irradiation in relation to other cancer treatments can often only be estimated. Recent experimental and clinical evidence suggests that cardiovascular symptoms, including exertional dyspnoea, may be caused by heart failure with preserved ejection fraction (HFpEF), which remains incompletely understood in patients after radiation therapy. Purpose We aim to characterize the development of radiation-induced cardiomyopathy and elucidate underlying patho-mechanisms. Methods Mice received a single dose of whole thorax irradiation (12.5 Gy) and were sacrificed at 1 and 3 days or 3, 6, 12, 16, 20 and 25–30 weeks. Endothelial cells and immune cells at different time points were quantified using flow cytometry (FACS). Structural changes and localization of endothelial cell damage was imaged using light-sheet fluorescence microscopy (LSFM) with CD31 staining. Development of fibrosis was determined using qRT-PCR (fibronectin and TGFβ), western blot (collagen-1,α-smooth muscle) and (immune-)histological analyses. Functional analyses were conducted using echocardiography and pressure-volume-(PV-)catheterization. Results Endothelial damage was determined by significant reduction of CD31 expression in mouse hearts 6 weeks after irradiation compared to sham-treated control mice using FACS analyses. LSFM showed structural changes especially in the edge zone of left ventricle presented as less densely CD31 stained regions. Additionally, we investigated cardiac immune cell response regarding innate and adaptive immunity, showing specific response to tissue damage at different time points. Invasion of monocytes started 6 weeks after irradiation and highest level of monocytes and macrophages was measured at 12 weeks. Regarding cardiac long-term damage, myocardial fibrosis was detected on RNA- and protein-level as well as in histological analyses with significant changes 20 weeks after chest irradiation. This could be correlated with echocardiographic parameters for diastolic dysfunction (elevated isovolumic relaxation time/mitral valve deceleration time). Also functional reserve of irradiated mice was reduced, investigated by measurement of cardiac output and stroke volume after dobutamine injection in PV-catheterization. Conclusion We described a novel time-dependent endothelial cell damage and immune cell response after thoracic irradiation in mice, which could also be imaged using LSFM. Characterization of long-term damage showed cardiac fibrosis correlating with diastolic dysfunction and reduced contractile reserve. Furthermore, therapeutic approaches will be investigated using the established mouse model. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): Dr. S.M. Mrotzek acknowledges the following funding source: IFORES research grant from the Medical Faculty, University Duisburg-Essen, Germany.

A Small Peptide Ac-SDKP Inhibits Radiation-Induced Cardiomyopathy.

Advances in radiotherapy for thoracic cancers have resulted in improvement of survival. However, radiation exposure to the heart can induce cardiotoxicity. No therapy is currently available to inhibit these untoward effects. We examined whether a small tetrapeptide, N-acetyl-Ser-Asp-Lys-Pro (Ac-SDKP), can counteract radiation-induced cardiotoxicity by inhibiting macrophage-dependent inflammatory and fibrotic pathways. After characterizing a rat model of cardiac irradiation with magnetic resonance imaging protocols, we examined the effects of Ac-SDKP in radiation-induced cardiomyopathy. We treated rats with Ac-SDKP for 18 weeks. We then compared myocardial contractile function and extracellular matrix by cardiac magnetic resonance imaging and the extent of inflammation, fibrosis, and Mac-2 (galectin-3) release by tissue analyses. Because Mac-2 is a crucial macrophage-derived mediator of fibrosis, we performed studies to determine Mac-2 synthesis by macrophages in response to radiation, and change in profibrotic responses by Mac-2 gene depleted cardiac fibroblasts after radiation. Cardiac irradiation diminished myocardial contractile velocities and enhanced extracellular matrix deposition. This was accompanied by macrophage infiltration, fibrosis, cardiomyocyte apoptosis, and cardiac Mac-2 expression. Ac-SDKP strongly inhibited these detrimental effects. Ac-SDKP migrated into the perinuclear cytoplasm of the macrophages and inhibited radiation-induced Mac-2 release. Cardiac fibroblasts lacking the Mac-2 gene showed reduced transforming growth factor β1, collagen I, and collagen III expression after radiation exposure. Our study identifies novel cardioprotective effects of Ac-SDKP in a model of cardiac irradiation. These protective effects are exerted by inhibiting inflammation, fibrosis, and reducing macrophage activation. This study shows a therapeutic potential of this endogenously released peptide to counteract radiation-induced cardiomyopathy.

Prevalence of Takayasu arteritis in young women with acute ischemic heart disease

Takayasu arteritis (TA), a systemic vasculitis typically occurring in female patients aged ≤40, can affect coronary arteries and cause ischemic heart disease (IHD). In this study, we investigated the prevalence of TA in young women presenting with IHD in the Emergency Department. We evaluated hospital records of 158,860 consecutive female patients aged <40, who accessed the Emergency Department of our institution over 8 consecutive years (2007-2015). The prevalence of different etiologies of IHD was determined. Diagnosis of TA was established based on the 1990 ACR criteria. Overall, 1950 women aged <40 presented to the Emergency Department with chest pain, dyspnea, palpitations, angina, heart failure, or cardiac arrest; 40 had acute IHD. The etiology was 'classic' atherosclerosis in 24 cases (60%), TA in 4 cases (10%), vasospasm and sympathomimetic drug abuse in 3 cases each (7.5%), coronary artery dissection and microvascular angina in 2 cases each (5%), Takotsubo and radiation-induced cardiomyopathy in 1 case each (2.5%). Although a diagnosis of TA is likely to be overlooked, TA is not infrequent in younger females presenting with acute IHD, a finding relevant to the diagnosis and management of these patients.

Liver Allograft Provides Immunoprotection for the Cardiac Allograft in Combined Heart-Liver Transplantation.

When transplanted simultaneously, the liver allograft has been thought to have an immunoprotective role on other organs; however, detailed analyses in simultaneous heart-liver transplantation (SHLT) have not been done to date. We analyzed patient outcomes and incidence of immune-mediated injury in 22 consecutive SHLT versus 223 isolated heart transplantation (IHT) recipients between January 2004 and December 2013, by reviewing 3912 protocol- and indication-specific cardiac allograft biopsy specimens. Overall survival was similar (86.4%, 86.4%, and 69.1% for SHLT and 93.3%, 84.7%, and 70.0% for IHT at 1, 5, and 10 years; p = 0.83). Despite similar immunosuppression, the incidence of T cell-mediated rejection (TCMR) was lower in SHLT (31.8%) than in IHT (84.8%) (p < 0.0001). Although more SHLT patients had preexisting donor-specific HLA antibody (22.7% versus 8.1%; p = 0.04), the incidence of antibody-mediated rejection was not different in SHLT compared with IHT (4.5% versus 14.8%, p = 0.33). While the left ventricular ejection fraction was comparable in both groups at 5 years, the incidence and severity of cardiac allograft vasculopathy were reduced in the SHLT recipients (42.9% versus 66.8%, p = 0.03). Simultaneously transplanted liver allograft was associated with reduced risk of TCMR (odds ratio [OR] 0.003, 95% confidence interval [CI] 0-0.02; p < 0.0001), antibody-mediated rejection (OR 0.04, 95% CI 0-0.46; p = 0.004), and cardiac allograft vasculopathy (OR 0.26, 95% CI 0.07-0.84; p = 0.02), after adjusting for other risk factors. These data suggest that the incidence of alloimmune injury in the heart allograft is reduced in SHLT recipients.

Radiation-induced coronary artery disease: a second survivorship challenge?

10.2217/FON.15.121 © 2015 Future Medicine Ltd The role of adjuvant mediastinal radiation (RT) in improving disease-free survival in Hodgkin’s disease and breast cancer (BC) is well known. However, this survival advantage is accompanied by the late cardiac sequelae of radiation. Radiationinduced coronary artery disease (RICAD) is a challenging clinical entity and a major contributor to cardiovascular (CV) mortality in cancer survivors. In this review, we discuss the pathophysiology, surveillance and management challenges of RICAD.

A Practical Approach to the Oncology Patient With Heart Failure

Left ventricular systolic dysfunction is a significant cause of morbidity among cancer patients in whom this unfortunate complication develops. Investigation and management of chemotherapy- and radiation-induced cardiomyopathy in the emerging field of cardio-oncology involves a multidisciplinary approach between cardiology and oncology departments. The purpose of this article is to provide a practical approach to the cardiologist's assessment and management of cancer treatment–related cardiomyopathies.

Advanced heart failure due to cancer therapy.

Certain chemotherapeutic agents and mediastinal irradiation can be cardiotoxic and place cancer survivors at risk for developing advanced heart failure (HF). Anthracyclines are the prototypical agents associated with left ventricular (LV) dysfunction. Newer agents including trastuzumab and certain tyrosine kinase inhibitors such as sunitinib can also cause cardiomyopathy. Cancer survivors with advanced HF refractory to standard medical management should be considered for advanced therapies, including mechanical circulatory support (MCS) and transplantation. While overall outcomes after MCS and transplantation are similar in cancer survivors compared to other etiologies of HF, patients with radiation-induced restrictive cardiomyopathy have a significantly worse prognosis after transplantation. The increased need for right ventricular (RV) support after MCS in cancer survivors necessitates a careful evaluation for pre-operative RV dysfunction. Special consideration must also be given to the risk for recurrent malignancy, neurocognitive dysfunction, and increased psychological needs in this patient population.

Role of Interleukin-1 in Radiation-Induced Cardiomyopathy.

Thoracic X-ray therapy (XRT), used in cancer treatment, is associated with increased risk of heart failure. XRT-mediated injury to the heart induces an inflammatory response leading to cardiomyopathy. The aim of this study was to determine the role of interleukin (IL)-1 in response to XRT injury to the heart and on the cardiomyopathy development in the mouse. Female mice with genetic deletion of the IL-1 receptor type I (IL-1R1 knockout mice [IL-1R1 KO]) and treatment with recombinant human IL-1 receptor antagonist anakinra, 10 mg/kg twice daily for 7 d, were used as independent approaches to determine the role of IL-1. Wild-type (wt) or IL-1R1 KO mice were treated with a single session of XRT (20 or 14 gray [Gy]). Echocardiography (before and after isoproterenol challenge) and left ventricular (LV) catheterization were performed to evaluate changes in LV dimensions and function. Masson's trichrome was used to assess myocardial fibrosis and pericardial thickening. After 20 Gy, the contractile reserve was impaired in wt mice at d 3, and the LV ejection fraction (EF) was reduced after 4 months when compared with sham-XRT. IL-1R1 KO mice had preserved contractile reserve at 3 d and 4 months and LVEF at 4 months after XRT. Anakinra treatment for 1 d before and 7 d after XRT prevented the impairment in contractile reserve. A significant increase in LV end-diastolic pressure, associated with increased myocardial interstitial fibrosis and pericardial thickening, was observed in wt mice, as well as in IL-1R1 KO-or anakinra-treated mice. In conclusion, induction of IL-1 by XRT mediates the development of some, such as the contractile impairment, but not all aspects of the XRT-induced cardiomyopathy, such as myocardial fibrosis or pericardial thickening.

Cardiac Transplantation for Radiation-Induced Cardiomyopathy: The Mayo Clinic Experience

High-dose radiotherapy to the mediastinum for the treatment of malignancies causes injury to the intrathoracic organs. Coronary artery disease, valvular dysfunction, cardiomyopathy, and chronic constrictive pericarditis are common cardiovascular sequelae during long-term follow-up. Cardiac transplantation is indicated for the surgical treatment of heart failure due to radiation-induced end-stage cardiac disease. A retrospective study of radiation-induced cardiomyopathy requiring cardiac transplantation was undertaken from December 1992 to August2010. Twelve patients (7 men, 5 women), with a mean age of 47.4 years, underwent orthotopic cardiac transplantation. Redo cardiac operations were performed in 9 patients. Lymphoma was the primary malignancy in all patients. Adjuvant chemotherapy was used in 9 patients, and splenectomy was performed in 7. Restrictive cardiomyopathy (n= 8) was the predominant diagnosis. Restrictive lung disease was present in 10 patients (83%). Postoperative chronic kidney injury developed in 3 patients (25%). Hospital mortality was 8.3%. Survival at 1, 5, and 10years was 91.7%, 75%, and 46.7%, respectively. The overall mean follow-up was 7.7 years (median, 6.1; range, 1.8 to 16.4 years). Late respiratory failure accounted for 3 deaths. Cardiac transplantation provides satisfactory medium-term to long-term outcome in patients withradiation-induced cardiomyopathy. Secondary malignancies, kidney injury, and respiratory failure contribute tosignificant postoperative morbidity and death.

Radiation associated coronary occlusion: Overlooked as trastuzumab-induced cardiomyopathy

Trastuzumab is an agent used for receptor-positive breast cancer. Up to a third of patients treated with trastuzumab might develop cardiomyopathy. Many patients with breast cancer have taken pre- or co-administration of mediastinal radiotherapy. Both of treatment modalities have toxic effects on myocardium. It may result with diagnostic confusion between radiation-induced CAD (riCAD) and trastuzumab cardiomyopathy in the case with dilated cardiomyopathy. TTE may offer clues of differential diagnosis.

A mouse model of radiation-induced cardiomyopathy

A mouse model of radiation-induced cardiomyopathy

Use of 2-Dimensional Strain Echocardiography in Detecting Radiation-Induced Cardiomyopathy in Rats

Objective: Radiation exposure is a potential hazard to human population in the event of a nuclear bomb explosion. Early detection of radiation induced cardiomyopathy is important. We have shown that 2-dimensional strain echocardiography (2DSE) is more sensitive in detecting cardiomyopathy in rats from ischemic and doxorubicin injury compared to conventional ejection fraction (EF) measurement. Our aim is to compare 2DSE radial and circumferential strain and EF between rats exposed to radiation versus controls.

Radiation-induced cardiomyopathy as a function of radiation beam gating to the cardiac cycle

Portions of the heart are often unavoidably included in the primary treatment volume during thoracic radiotherapy, and radiation-induced heart disease has been observed as a treatment-related complication. Such complications have been observed in humans following radiation therapy for Hodgkin's disease and treatment of the left breast for carcinoma. Recent attempts have been made to prevent re-stenosis following angioplasty procedures using external beam irradiation. These attempts were not successful, however, due to the large volume of heart included in the treatment field and subsequent cardiac morbidity. We suggest a mechanism for sparing the heart from radiation damage by synchronizing the radiation beam with the cardiac cycle and delivering radiation only when the heart is in a relatively hypoxic state. We present data from a rat model testing this hypothesis and show that radiation damage to the heart can be altered by synchronizing the radiation beam with the cardiac cycle. This technique may be useful in reducing radiation damage to the heart secondary to treatment for diseases such as Hodgkin's disease and breast cancer.

Continuously infused carboplatin used as radiosensitizer in locally unresectable non-small-cell lung cancer: a multicenter phase III study

To determine the radiosensitizing effect of prolonged exposure of carboplatin in patients with locally unresectable non-small-cell lung cancer (NSCLC). Patients with histologically proven NSCLC, performance score <2, weight loss <10%, and normal organ functions were randomized between carboplatin 840 mg/m2 administered continuously during 6 weeks of radiotherapy or thoracic radiotherapy alone (both 60 Gy). Toxicity was evaluated with National Cancer Institute Common Toxicity Criteria (NCI CTC) and the Radiation Therapy Oncology Group (RTOG) criteria. Quality of life was measured with European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30/LC13 questionnaires. One-hundred and sixty patients were included. Pathologically confirmed persistent tumor was present in 53% of patients in the combination arm versus 58% in the radiotherapy alone arm (P=0.5). Median survival in the combination arm was 11.8 [95% confidence interval (CI) 9.3-14.2] months and in the radiotherapy alone arm 11.7 (95% CI 8.1-15.5) months; progression-free survival was not different between arms [6.8 and 7.5 months, respectively (P=0.28)]. Acute toxicity was mild, late toxicity was radiation-induced cardiomyopathy (three patients) and pulmonary fibrosis (five patients). Quality of life was not different between arms, but in all measured patients cough and dyspnea improved, pain became less, and slight paresthesia developed 3 months after treatment. Addition of continuously administered carboplatin as radiosensitizer for locally unresectable NSCLC does not improve local tumor control or overall survival.

Radiation-Induced Heart Disease: Morphology, Changes in Catecholamine Synthesis and Content, β-Adrenoceptor Density, and Hemodynamic Function in an Experimental Model

To study further the pathophysiology of radiation-induced cardiomyopathy, we investigated resting hemodynamics, myocardial catecholamine synthesis and storage, and beta-adrenoceptor density after local heart irradiation. In Wistar rats, a radiation dose of 20 Gy eventually leads to compromised myocardial function which is characterized by a reduction in cardiac output to 43 +/- 11% and in the left ventricular ejection fraction to 66 +/- 7.5%, and an increase in the left ventricular end-diastolic volume to 187 +/- 17% of control values. This reduction in function is correlated with focal degeneration of 23 +/- 4% of the myocardium. Measurement of tyrosine hydroxylase activity and catecholamine content revealed that catecholamine biosynthesis is unchanged in the adrenals but is significantly reduced in the hearts of irradiated animals, while cardiac beta-adrenoceptor density is increased to about 140% of that in age-matched controls. This is in contrast to findings in dilated or ischemic cardiomyopathy. Time-course studies showed that the development of myocardial degeneration starts simultaneously with the decrease in cardiac output and ejection fraction and the increase in beta-adrenoceptors at 50-80 days postirradiation. Myocardial degeneration is maximal in extent and severity at 100 days and does not progress thereafter. Cardiac output decreases at 80-100 days postirradiation to 60 +/- 7% of control values. A significant further decrease is seen only when congestive heart failure becomes manifest at 249 +/- 21 days after 20 Gy. Thus there is a delay between structural myocardial injury and hemodynamic deterioration which could be due to a compensatory increase in beta-adrenoceptor density during the initial stages of the cardiomyopathy.(ABSTRACT TRUNCATED AT 250 WORDS)

Radiation-Induced Cardiomyopathy in the Dog

Sequential necropsies and histologic evaluations of young adult beagle dogs were performed after irradiation of the thorax. Total doses to the heart were 36, 44, or 52 Gy given in 4-Gy fractions in 4 weeks. One month after irradiation there was little histologic evidence of damage visible by light microscopy. However, ventricular and septal weights were increased, probably due to edema. At 3 months damage to endothelial and mesothelial cells was evident. By 12 months the myocardium was thinned and focal degeneration and loss of muscle cells and Purkinje fibers were observed. There was extensive subendocardial and epicardial fibrosis as well as intimal proliferation in coronary arteries. Morphometric analyses were performed on the myocardium, pericardium, atria, and aorta. There was a slight increase in perivascular connective tissue in the myocardium. The pericardium was increased in thickness and the ratio of smooth muscle to elastin was decreased in the aorta. Severe fibrosis occurred only in the right atrium. At 1 year there was no clinical evidence of heart failure; however, evidence of myocardial damage was present histologically and functionally. Additional stress and continued aging are likely to enhance the damage and lead to serious complications. The interactions of irradiated lung and heart require further investigation.

Isoeffect curves for radiation-induced cardiomyopathy in the dog.

Canine hearts were irradiated with a range of total doses given in 2, 3, or 4 Gy per fraction. Echocardiography was done before irradiation and at 3 and 6 months after irradiation. Histologic analyses were done of tissues taken at necropsy 6 months after irradiation. The percentage vascular component in the ventricles decreased with increasing total doses. The connective tissue component increased at lower doses and then decreased at higher doses. There was more fibroblastic proliferation and collagen production in the lower dose range and there may have been more cell killing by the higher doses. There was some evidence of myocardial hypertrophy at higher doses, which would have caused an apparent decrease in the connective tissue component. In either case, surviving fibroblasts would be expected to continue proliferating and producing collagen. At longer time intervals after irradiation the connective tissue component would likely continue to increase as observed clinically. That increase would be proportional to dose, but might not be closely related to initial killing of fibroblasts. Many factors such as changes in blood supply, continued loss of myocardium, and other stresses on the heart could influence the degree of fibrosis at later times. A relationship of response to cell killing appeared to exist based on alpha/beta ratios that were less than 3 Gy whether determined at the mid-range or for the greatest response of vasculoconnective tissues. Alpha/beta ratios ranged from 2.7 to 5 Gy for increases in diastolic wall thickness of the left ventricle at 3 and 6 months after irradiation. The low alpha/beta ratios reflect relatively steep isoeffect curves and have important implications for use of coarser fractionation schedules for treatment volumes that include the heart. The risk of cardiac damage could be significantly increased.