RADIOTHERAPY-ASSOCIATED CARDIOVASCULAR COMPLICATIONS IN CANCER (review). / SERTsEVO-SUDYNNI USKLADNENNIa, ASOTsIIOVANI Z PROMENEVOIu TERAPIIeIu (ogliad literatury).

The review is devoted to the current issues of radiation-induced cardiovascular complications, their diagnostics andincidence depending on the radiation doses and exposure regimens, potential efficiency of the screening strategiesfor cardiotoxicity monitoring after radiotherapy in cancer patients by analyzing the data from literature and clinical trials, based on recommendations of European Society of Cardiology and European Society of Medical Oncology.

Changes of the Heart Valves in the Long Term After Chemoradiotherapy According to Different Protocols for Hodgkin's Lymphoma in Children and Adolescents.

Purpose: The purpose of our work was to study late cardiac complications after treatment for Hodgkin's lymphoma (HL) in children and adolescents. Methods: Sixty-seven patients were examined in the long term (>5 years) after chemoradiotherapy for HL according to two different programs of treatment (groups I and II). Mean total doses of radiotherapy (RT) to the mediastinum were 37.2 and 28.9 Gy, respectively. The status of the heart was assessed at the mean age of 22.7 years with electrocardiography (ECG) and echocardiography (EchoCG). Mean terms of follow-up were 16.4 and 9.5 years for group I and group II, respectively. Results: Incidence of ECG changes was equal between the groups (88% and 90%). The prevalence of signs of valvular calcifications and fibrosis was 70.9% after mediastinal doses ≥30 Gy, and 16.6% after lower doses (p = 0.002). Those changes led to considerable valvular dysfunction in four patients. EchoCG signs of pulmonary hypertension were seen in 33.3% patients of group I versus 4.8% in group II (p = 0.047). Pericardial effusion was observed in 7.4% and 5.1%, respectively (p = 1.0). Left ventricular ejection fraction decreased slightly only in two patients (one in each group). Conclusions: The RT mediastinal dose level is the important risk factor of late heart complications. Nevertheless, the differences in the rate and severity of those complications between the groups should be viewed with caution because of differences in the age at baseline and in follow-up terms. The survivors of HL should undergo life-long regular examinations of the heart status.

The risk of reoperative cardiac surgery in radiation-induced valvular disease.

OBJECTIVE: Mediastinal radiation therapy (MRT) increases the risk for adverse outcomes after cardiac surgery and is not incorporated in the Society of Thoracic Surgeons (STS) risk algorithm. We aimed to quantify the surgical risk conferred by MRT in patients undergoing primary and reoperative valvular operations. METHODS: A retrospective analysis of 261 consecutive patients with prior MRT who underwent valvular operations between January 2002 and May 2015. Short- and long-term outcomes were compared for STS predicted risk of mortality, surgery type, gender, year of surgery, and age-matched patients stratified by reoperative status. RESULTS: Mean age was 62.6 ± 12.1 years and 174 (67%) were women. The majority had received MRT for Hodgkin lymphoma (48.2%) and breast cancer (36%). Overall, 214 (82%) were primary and 47 (18%) were reoperative procedures. Reoperation carried a higher operative mortality than primary cases (17% vs 3.7%; P = .003). Compared with the 836 nonradiated matches, operative mortality and observed-to-expected STS mortality ratios were higher in primary (3.8% [1.4] vs 0.8% [0.32]; P = .004) and reoperative (17% [3.35] vs 2.3% [0.45]; P = .001) patients with prior MRT. Cox proportional hazard modeling revealed that in patients with previous MRT, primary (hazard ratio, 2.24; 95% confidence interval, 1.73-2.91) and reoperative status (hazard ratio, 3.19; 95% confidence interval, 1.95-5.21) adversely affected long-term survival compared with nonradiated matches. CONCLUSIONS: Surgery for radiation-induced valvular heart disease has a higher operative mortality than predicted by STS predicted risk of mortality. Reoperations are associated with increased morbidity and mortality compared with primary cases. Careful patient selection is paramount and expanded indications for transcatheter therapies should be considered, especially in reoperative patients.

Low-Dose Gamma Irradiation of Decellularized Heart Valves Results in Tissue Injury In Vitro and In Vivo.

BACKGROUND: Decellularized heart valves are emerging as a potential alternative to current bioprostheses for valve replacement. Whereas techniques of decellularization have been thoroughly examined, terminal sterilization techniques have not received the same scrutiny. METHODS: This study evaluated low-dose gamma irradiation as a sterilization method for decellularized heart valves. Incubation of valves and transmission electron microscopy evaluation after different doses of gamma irradiation were used to determine the optimal dose of gamma irradiation. Quantitative evaluation of mechanical properties was done by tensile mechanical testing of isolated cusps. Sterilized decellularized heart valves were tested in a sheep model (n = 3 [1 at 1,500 Gy and 2 at 3,000 Gy]) of pulmonary valve replacement. RESULTS: Valves sterilized with gamma radiation between 1,000 Gy and 3,000 Gy were found to be optimal with in vitro testing. However, in vivo testing showed deteriorating valve function within 2 months. On explant, the valve with 1,500 Gy gamma irradiation showed signs of endocarditis with neutrophils on hematoxylin and eosin staining, and positive gram stain resembling streptococcus infection. The 3,000 Gy valves had no evidence of infection, but the hematoxylin and eosin staining showed evidence of wound remodeling with macrophages and fibroblasts. Tensile strength testing showed decreased strength (0 Gy: 2.53 ± 0.98 MPa, 1,500 Gy: 2.03 ± 1.23 MPa, and 3,000 Gy: 1.26 ± 0.90 MPa) with increasing levels of irradiation. CONCLUSIONS: Low-dose gamma irradiation does not maintain the mechanical integrity of valves, and the balance between sterilization and damage may not be able to be achieved with gamma irradiation. Other methods of terminal sterilization must be pursued and evaluated.

Radiation-induced valvular heart disease.

Radiation to the mediastinum is a key component of treatment with curative intent for a range of cancers including Hodgkin's lymphoma and breast cancer. Exposure to radiation is associated with a risk of radiation-induced heart valve damage characterised by valve fibrosis and calcification. There is a latent interval of 10-20 years between radiation exposure and development of clinically significant heart valve disease. Risk is related to radiation dose received, interval from exposure and use of concomitant chemotherapy. Long-term outlook and the risk of valve surgery are related to the effects of radiation on mediastinal structures including pulmonary fibrosis and pericardial constriction. Dose prediction models to predict the risk of heart valve disease in the future and newer radiation techniques to reduce the radiation dose to the heart are being developed. Surveillance strategies for this cohort of cancer survivors at risk of developing significant heart valve complications are required.

Predicting radiation-induced valvular heart damage.

PURPOSE: To develop a predictive multivariate normal tissue complication probability (NTCP) model for radiation-induced heart valvular damage (RVD). The influence of combined heart-lung irradiation on RVD development was included. MATERIAL AND METHODS: Multivariate logistic regression modeling with the least absolute shrinkage and selection operator (LASSO) was used to build an NTCP model to predict RVD based on a cohort of 90 Hodgkin lymphoma patients treated with sequential chemo-radiation therapy. In addition to heart irradiation factors, clinical variables, along with left and right lung dose-volume histogram statistics, were included in the analysis. To avoid overfitting, 10-fold cross-validation (CV) was used for LASSO logistic regression modeling, with 50 reshuffled cycles. Model performance was assessed using the area under the receiver operating characteristic (ROC) curve (AUC) and Spearman's correlation coefficient (Rs). RESULTS: At a median follow-up time of 55 months (range 12-92 months) after the end of radiation treatment, 27 of 90 patients (30%) manifested at least one kind of RVD (mild or moderate), with a higher incidence of left-sided valve defects (64%). Fourteen prognostic factors were frequently selected (more than 100/500 model fits) by LASSO, which included mainly heart and left lung dosimetric variables along with their volume variables. The averaged cross-validated performance was AUC-CV = 0.685 and Rs = 0.293. The overall performance of a final NTCP model for RVD obtained applying LASSO logistic regression to the full dataset was satisfactory (AUC = 0.84, Rs = 0.55, p < 0.001). CONCLUSION: LASSO proved to be an improved and flexible modeling method for variable selection. Applying LASSO, we showed, for the first time, the importance of jointly considering left lung irradiation and left lung volume size in the prediction of subclinical radiation-related heart disease resulting in RVD.

Valvular abnormalities detected by echocardiography in 5-year survivors of childhood cancer: a long-term follow-up study.

PURPOSE: To determine the prevalence of valvular abnormalities after radiation therapy involving the heart region and/or treatment with anthracyclines and to identify associated risk factors in a large cohort of 5-year childhood cancer survivors (CCS). METHODS AND MATERIALS: The study cohort consisted of all 626 eligible 5-year CCS diagnosed with childhood cancer in the Emma Children's Hospital/Academic Medical Center between 1966 and 1996 and treated with radiation therapy involving the heart region and/or anthracyclines. We determined the presence of valvular abnormalities according to echocardiograms. Physical radiation dose was converted into the equivalent dose in 2-Gy fractions (EQD2). Using multivariable logistic regression analyses, we examined the associations between cancer treatment and valvular abnormalities. RESULTS: We identified 225 mainly mild echocardiographic valvular abnormalities in 169 of 545 CCS (31%) with a cardiac assessment (median follow-up time, 14.9 years [range, 5.1-36.8 years]; median attained age 22.0 years [range, 7.0-49.7 years]). Twenty-four CCS (4.4%) had 31 moderate or higher-graded abnormalities. Most common abnormalities were tricuspid valve disorders (n=119; 21.8%) and mitral valve disorders (n=73; 13.4%). The risk of valvular abnormalities was associated with increasing radiation dose (using EQD2) involving the heart region (odds ratio 1.33 per 10 Gy) and the presence of congenital heart disease (odds ratio 3.43). We found no statistically significant evidence that anthracyclines increase the risk. CONCLUSIONS: Almost one-third of CCS treated with potentially cardiotoxic therapy had 1 or more asymptomatic, mostly mild valvular abnormalities after a median follow-up of nearly 15 years. The most important risk factors are higher EQD2 to the heart region and congenital heart disease. Studies with longer follow-up are necessary to investigate the clinical course of asymptomatic valvular abnormalities in CCS.

Multivariate normal tissue complication probability modeling of heart valve dysfunction in Hodgkin lymphoma survivors.

PURPOSE: To establish a multivariate normal tissue complication probability (NTCP) model for radiation-induced asymptomatic heart valvular defects (RVD). METHODS AND MATERIALS: Fifty-six patients treated with sequential chemoradiation therapy for Hodgkin lymphoma (HL) were retrospectively reviewed for RVD events. Clinical information along with whole heart, cardiac chambers, and lung dose distribution parameters was collected, and the correlations to RVD were analyzed by means of Spearman's rank correlation coefficient (Rs). For the selection of the model order and parameters for NTCP modeling, a multivariate logistic regression method using resampling techniques (bootstrapping) was applied. Model performance was evaluated using the area under the receiver operating characteristic curve (AUC). RESULTS: When we analyzed the whole heart, a 3-variable NTCP model including the maximum dose, whole heart volume, and lung volume was shown to be the optimal predictive model for RVD (Rs = 0.573, P<.001, AUC = 0.83). When we analyzed the cardiac chambers individually, for the left atrium and for the left ventricle, an NTCP model based on 3 variables including the percentage volume exceeding 30 Gy (V30), cardiac chamber volume, and lung volume was selected as the most predictive model (Rs = 0.539, P<.001, AUC = 0.83; and Rs = 0.557, P<.001, AUC = 0.82, respectively). The NTCP values increase as heart maximum dose or cardiac chambers V30 increase. They also increase with larger volumes of the heart or cardiac chambers and decrease when lung volume is larger. CONCLUSIONS: We propose logistic NTCP models for RVD considering not only heart irradiation dose but also the combined effects of lung and heart volumes. Our study establishes the statistical evidence of the indirect effect of lung size on radio-induced heart toxicity.

Recruitment of bone marrow-derived valve interstitial cells is a normal homeostatic process.

Advances in understanding of the maintenance of the cardiac valves during normal cardiac function and response to injury have led to several novel findings, including that there is contribution of extra-cardiac cells to the major cellular population of the valve: the valve interstitial cell (VIC). While suggested to occur in human heart studies, we have been able to experimentally demonstrate, using a mouse model, that cells of bone marrow hematopoietic stem cell origin engraft into the valves and synthesize collagen type I. Based on these initial findings, we sought to further characterize this cell population in terms of its similarity to VICs and begin to elucidate its contribution to valve homeostasis. To accomplish this, chimeric mice whose bone marrow was repopulated with enhanced green fluorescent protein (EGFP) expressing total nucleated bone marrow cells were used to establish a profile of EGFP(+) valve cells in terms of their expression of hematopoietic antigens, progenitor markers, fibroblast- and myofibroblast-related molecules, as well as their distribution within the valves. Using this profile, we show that normal (non-irradiated, non-transplanted) mice have BM-derived cell populations that exhibit identical morphology and phenotype to those observed in transplanted mice. Collectively, our findings establish that the engraftment of bone marrow-derived cells occurs as part of normal valve homeostasis. Further, our efforts demonstrate that the use of myeloablative irradiation, which is commonly employed in studies involving bone marrow transplantation, does not elicit changes in the bone marrow-derived VIC phenotype in recipient mice.

Gamma radiation alters the ultrastructure in tissue-engineered heart valve scaffolds.

OBJECTIVES: Xenogenic extracellular heart valve matrices have been suggested as scaffolds for tissue engineering. However, these matrices are immunogenic and stimulate an intense cell-mediated immune response and calcification. Mitigating the immunogenicity was attempted by different doses of gamma irradiation. METHODS: Mechanical properties of gamma-irradiated porcine matrices and control matrices (nonirradiated) were examined by tensile strength testing. Irradiated matrices (1, 10, 50, and 100 gray [Gy]) and control matrices were implanted subcutaneously in Wistar rats (n = 20). After 24 h, 1, 2, 3, and 4 weeks the explants were examined by light microscopy and transmission electron microscopy. Calcium (Ca) content was determined using inductively coupled plasma-mass spectrometry. Antibody reaction against porcine tissue in the rat serum was determined. RESULTS: Tensile strength increased in irradiated matrices at the expense of elasticity. Ten gray-irradiated leaflets showed minimal lymphocytic inflammatory infiltration with preservation of ultrastructure. Ca levels after 2 weeks were as follows: control (0 Gy), 388 +/- 264 microg/mg; 1 Gy, 240 +/- 95 microg/mg; 10 Gy, 188 +/- 54 microg/mg; 50 Gy, 289 +/- 94 microg/mg; 100 Gy, 651 +/- 57 microg/mg. All implants still elicit an antibody immunoglobulin G reaction. CONCLUSIONS: Exposure to 10 Gy gamma irradiation reduces lymphocytic inflammatory infiltrates and Ca levels in acellular porcine matrices with preservation of structural integrity. This could prolong the durability of these matrices.

Successful performance of Cox-Maze procedure on beating heart using bipolar radiofrequency ablation: a feasibility study in animals.

BACKGROUND: The Cox-Maze procedure is the gold standard for the surgical treatment of atrial fibrillation with proven long-term efficacy. However, its application has been limited by its complexity and significant morbidity. The purpose of this study was to test the feasibility and safety of performing the Cox-Maze procedure using bipolar radiofrequency ablation on the beating heart without cardiopulmonary bypass. METHODS: After median sternotomy, 6 Hanford mini-pigs underwent a modified Cox-Maze procedure using bipolar radiofrequency energy. The animals survived for 30 days. Atrial function, coronary artery, pulmonary vein anatomy, and valve function were assessed by magnetic resonance imaging. At reoperation, pacing documented electrical isolation of the pulmonary veins. Induction of atrial fibrillation was attempted by burst pacing with cholinergic stimulation. Histologic assessment was performed after sacrifice. RESULTS: There were no perioperative mortalities or neurologic events. At 30 days, atrial fibrillation was unable to be induced, and pulmonary vein isolation was confirmed by pacing. Magnetic resonance imaging assessment revealed no coronary artery or pulmonary vein stenoses. Although atrial ejection fraction decreased slightly from 0.344 +/- 0.0114 to 0.300 +/- 0.055 (p = 0.18), atrial contractility was preserved in every animal. Histologic assessment showed all lesions to be transmural, and there were no significant stenoses of the coronary vessels or injuries to the valves. CONCLUSIONS: Virtually all of the lesions of the Cox-Maze procedure can be performed without cardiopulmonary bypass using bipolar radiofrequency energy. There were no late stenoses of the pulmonary veins. Clinical trials of this new technology on the beating heart are warranted.

[Radiation-induced cardiac disease]. / Strahlenschaden des Herzens.

Radiation-induced effects may damage various cardiac structures chronically and cause heart valve dysfunction as well as occlusive lesions of coronary and other arteries exposed to radiation. A 72-year-old woman with a history of radiation treatment after breast cancer was admitted 25 years later with symptoms of tachycardia and acute dyspnea. We found valvular thickening, medium to severe valvular dysfunction and high grade occlusive coronary artery disease in proximal portions. The left subclavian artery also was affected. Surgical treatment was required immediately. Long-term follow-up cardiac evaluation even in asymptomatic patients is mandatory to uncover cardiac injuries by radiation. To lower the risk and maximize the benefit, early intervention by valvular replacement and myocardial revascularization is indicated. Restrictive myopathy and chronic pericarditis increase risk and have to be clarified. Diagnosis in these radiation exposed patients can be made by typical findings. Echocardiography is of eminent relevancy.

Radiation-induced heart disease after Hodgkin's disease and breast cancer treatment: dental implications.

BACKGROUND: People with Hodgkin's disease and breast cancer often receive therapeutic irradiation to the chest (mediastinum) as an element of treatment. While the therapy often cures the malignancy, it has been implicated in causing late-onset heart disease that may influence the provision of dental treatment. TYPE OF STUDIES REVIEWED: The authors conducted a MEDLINE search of the years 1995 through 2002 using the key terms "Hodgkin's disease," "breast cancer," "radiation therapy," "cardiac valves" and "coronary artery" to define the pathophysiology of the disorder, its epidemiology and dental implications. The articles they selected for further review included those published in English in peer-reviewed journals. RESULTS: Therapeutic irradiation of the chest results in the inadvertent inclusion of the heart within the irradiation field. Over the next 10 to 20 years, some of these people may experience pathological changes of the heart valves that could predispose them to endocarditis, accelerated atherosclerosis of the coronary artery that heightens their risk of experiencing a fatal myocardial infarction or both. CLINICAL IMPLICATIONS: Dentists need to identify patients who have received therapeutic irradiation to the chest and consult with the patients' physicians to determine whether the therapy has damaged the heart valves or coronary arteries. Patients with radiation-induced valvular disease may require prophylactic antibiotics when undergoing specific dental procedures that are known to cause a bacteremia and a heightened risk of developing endocarditis. Patients with radiation-induced coronary artery disease should be administered only limited amounts of local anesthetic agents containing a vasoconstrictor, and they may require the administration of sedative agents and cardiac medications to preclude ischemic episodes.

Valvular heart operation in patients with previous mediastinal radiation therapy.

BACKGROUND: The outcome of valvular heart operations in patients with previous mediastinal radiation therapy was studied. METHODS: This is a single center retrospective study of 60 patients (37 females, 23 males) with a mean age of 62 +/- 15 years (28 to 88 years old) operated on from January 1976 to December 1998. Valvular heart operations performed included aortic valve replacements (n = 26), mitral valve procedures (n = 16), tricuspid valve procedures (n = 6), and multiple valve procedures (n = 12). A total of 264 clinical, hemodynamic, electrocardiographic and echocardiographic variables were analyzed. RESULTS: Total follow-up was 199 patient-years with a mean of 3.3 +/- 3.1 years and a range of 0 to 12.4 years old. Early mortality was 7 patients (12%). Early mortality in patients with constrictive pericarditis was 40% (4 of 10) compared with 6% (3 of 50) in patients without constrictive pericarditis. By univariate analysis, early mortality was associated with constrictive pericarditis (p = 0.011), reduced preoperative ejection fraction (p = 0.015), and longer cardiopulmonary bypass times (p = 0.037). A total of 14 patients (23%) required permanent pacemaker placement before (n = 7), during (n = 1), or early (n = 6) after valvular heart operations. There were 19 late deaths (malignancies, 7; heart failures, 5; other cardiac, 4; and other noncardiac, 3). Overall survival and freedom from late cardiac death and cardiac reoperation at 5 years for hospital survivors were 66% +/- 8%, 82% +/- 7%, and 93% +/- 4%, respectively. By univariate analysis, late cardiac death was associated with low ejection fraction (p = 0.002), New York Heart Association (NYHA) functional class IV (p = 0.004), preoperative congestive heart failure (p = 0.02), and preoperative atrial fibrillation (p = 0.038). Eighty-five percent of the discharged patients were in NYHA functional class I or II at follow-up. CONCLUSIONS: Early results of valve replacement after mediastinal radiation therapy were good except in the presence of constrictive pericarditis. Long-term outcome was limited by malignancy and heart failure. Early surgical intervention is recommended before the development of risk factors for late death, namely, severe symptoms, left ventricular dysfunction, and atrial fibrillation.

Acute continuous argon-laser induced tissue effects in the isolated canine heart.

Fresh isolated myocardial, elastic-arterial, and valvular tissues from seven canine hearts were irradiated by argon laser. Irradiation was transmitted through 300 and 400 micron flexible quartz fiberoptic elements. Minimal power densities for vaporization of the myocardial, arterial, and valvular tissues were 80, 90, and 110 W/cm2, respectively, with maximal vaporization distances (fiberoptic tip to tissue) of 4 mm, 1 mm, and 1 mm, respectively. Irradiation of the valves at power densities approaching perforation caused contraction of the tissue. When tissue vaporization occurred, histologic examination of irradiated tissues showed a central crater surrounded by sequential layers of char, vaporization, and coagulation necrosis. These findings were common to all cardiac tissues. Additional findings unique to myocardium were a normal-appearing myocardial layer (skip-area), circumferential halo, and tissue clefts. Elastic arteries showed concentration of necrosis around the collagen and elastic fibers. Valvular damage was the most extensive and also included contraction of adjacent valvular tissue and endocardial sloughing.

Identification of photoproducts liberated by in vitro argon laser irradiation of atherosclerotic plaque, calcified cardiac valves and myocardium.

To determine how laser light effects alterations in cardiovascular tissue, photoproducts liberated as the result of argon laser irradiation of atherosclerotic plaque, myocardium and calcified aortic valve leaflets were analyzed by gas chromatography, gas chromatography-mass spectrometry and absorbance spectroscopy. The products formed in gas phase are those expected when proteins and porphyrins are pyrolyzed--light hydrocarbon fragments, carbon monoxide and water vapor. The laser-generated products dissolved in solution are those expected when a protein chain or porphyrin ring is degraded in a thermal reaction, namely protein fragments and nitrogen heterocyclic ring fragments. These photoproducts are those typical of combustion or thermal degradation, and indicate that the fundamental nature of laser irradiation of coronary plaque, myocardium and calcified valve leaflets is thermal rather than photochemical. Thermal degradation of myocardium is more extensive than thermal degradation of atherosclerotic arteries or calcified valves because the red hue of myoglobin-containing myocardium enhances the absorption of the blue-green argon laser light. In contrast, the yellow-white hue of both atherosclerotic plaque and calcified aortic valve leaflets allows less complete absorbance of the argon laser light, leading to a lesser amount of converted heat and, therefore, less complete thermal degradation.

Light and electron microscopy studies on homograft and heterograft heart valves.

Light and electron microscopical changes were studied in 23 valvular homografts and six pig aortic heterografts, which had been inserted into patients for lengths of time varying from three days to 54 months. Prior to insertion, eleven of the homografts had been sterilised by beta-propriolactone and freeze-dried, the other twelve had been sterilised by gamma-radiation. The morphological changes in the freeze-dried group were characterised by moderate to severe structural changes including gross vacuolation, fibrinoid degeneration and calcification in the absence of any significant cellular events. It is concluded that the structural changes were due to physico-chemical degradation of the collagen due to improper preservation of the graft, prior to insertion. The morphological changes in the homografts treated with gamma-radiation were fewer and less severe in that there was less vacuolation of the matrix, less fibrinoid degeneration and no examples of calcification. Clear-cut examples of graft regeneration were never observed in either group, but the significance of minor cellular infiltrates in two of the gamma-irradiated grafts is discussed in terms of abortive regeneration. The heterografts showed moderate to intense cellularity, predominantly of macrophages. It is postulated that graft rejection phenomena are responsible for the graft failure in this group.