Metabolic Changes Precede Radiation-Induced Cardiac Remodeling in Beagles: Using Noninvasive 18F-FDG (18F-Fludeoxyglucose) and 13N-Ammonia Positron Emission Tomography/Computed Tomography Scans.

Background This study was performed to characterize the metabolic, functional, and structural cardiac changes in a canine model of radiation-induced heart disease by serial in vivo imaging and ex vivo analyses. Methods and Results Thirty-six dogs were randomly assigned to control or irradiated groups at 3 time points (months 3, 6, and 12 after radiation; each group comprised 6 dogs). The left anterior myocardium of dogs in irradiated groups was irradiated locally with a single dose of 20-Gy X-ray. The irradiated myocardial regions showed increased myocardial uptake of 18F-FDG (18F-fludeoxyglucose) in the irradiated beagles, but the increased uptake area decreased at months 6 and 12 compared with month 3 after radiation. Abnormality of myocardial perfusion and cardiac function were detected at month 6 after radiation. Compared with the control groups, the protein expression of GLUT4 (glucose transporter 4) was upregulated in the irradiated groups, correlating with significantly decreased CPT1 (carnitine acyltransferase 1) expression. Mitochondria degeneration, swelling, and count reduction in the irradiated groups were observed. The difference in CD68 of macrophage markers and the inflammatory cytokines (IL-6 [interleukin 6], TNF-α [tumor necrosis factor α]) between the irradiation and control groups was not significant. Furthermore, the progressive aggravation of apoptosis and fibrosis was displayed. Conclusions Elevated 18F-FDG uptake occurred after irradiation and subsequently led to ventricular perfusion defects and dysfunction. The process was associated with myocardial metabolic substrate remodeling, cardiac muscle cell apoptosis, and myocardial fibrosis rather than inflammation.

Cardiac Remodeling and Reversible Pulmonary Hypertension During Pneumonitis in Rats after 13-Gy Partial-Body Irradiation with Minimal Bone Marrow Sparing: Effect of Lisinopril.

Total-body irradiation causes acute and delayed toxicity to hematopoietic, pulmonary, cardiac, gastrointestinal, renal, and other organ systems. Angiotensin-converting enzyme inhibitors mitigate many of the delayed injuries to these systems. The purpose of this study was to define echocardiographic features in rats at two times after irradiation, the first before lethal radiation pneumonitis (50 d) and the second after recovery from pneumonitis but before lethal radiation nephropathy (100 d), and to determine the actions of the angiotensin-converting enzyme inhibitor lisinopril. Four groups of female WAG/RijCmcr rats at 11-12 wk of age were studied: nonirradiated, nonirradiated plus lisinopril, 13-Gy partial-body irradiation sparing one hind leg (leg-out partial-body irradiation), and 13-Gy leg-out partial-body irradiation plus lisinopril. Lisinopril was started 7 d after radiation. Echocardiograms were obtained at 50 and 100 d, and cardiac histology was assessed after 100 d. Irradiation without lisinopril demonstrated echocardiographic transient pulmonary hypertension by 50 d which was largely resolved by 100 d in survivors. Irradiated rats given lisinopril showed no increase in pulmonary artery pressures at 50 d but exhibited left ventricular remodeling. By 100 d these rats showed some signs of pulmonary hypertension. Lisinopril alone had no impact on echocardiographic end points at either time point in nonirradiated rats. Mild increases in mast cells and fibrosis in the heart were observed after 100 d following 13-Gy leg-out partial-body irradiation. These data demonstrate irradiation-induced pulmonary hypertension which was reversed in survivors of pneumonitis. Lisinopril modified cardiovascular remodeling to enhance survival in this model from 41% to 86% (p = 0.0013).

Radiotherapy-induced right ventricular remodelling: The missing piece of the puzzle.

The number of studies demonstrating that right ventricular structure, function and mechanics are valuable predictors of cardiovascular and total morbidity and mortality in patients with a wide range of cardiovascular conditions is constantly increasing. Most studies that evaluated the influence of radiotherapy on the heart focused on left ventricular remodelling, which is why current guidelines only recommend detailed assessment of the left ventricle. Data regarding right ventricular changes in cancer patients treated with radiotherapy are scarce. Given that radiotherapy more often induces late cardiac impairment - unlike chemotherapy-induced cardiotoxicity, which is usually acute - it is quite reasonable to follow these patients echocardiographically for a long time (even for 20years after initiation of radiotherapy). Investigations that have followed cancer survivors for at least 10years after radiotherapy agree that right ventricular structure, systolic/diastolic function and mechanics are significantly impaired. The mechanisms of radiation-induced right ventricular remodelling are still unclear, but it is thought that fibrosis is the dominant factor in myocardial remodelling and vascular changes. Many factors may contribute to right ventricular impairment during and after radiotherapy: cumulative radiation dose; dose per treatment; delivery technique; radiation target (chest and mediastinum); and co-morbidities. In this review, we aim to provide a comprehensive overview of the potential mechanisms of radiation-induced right ventricular remodelling, and to summarize clinical studies involving radiotherapy-treated cancer patients.

Ionizing Radiation Impairs Endogenous Regeneration of Infarcted Heart: An In Vivo 18F-FDG PET/CT and 99mTc-Tetrofosmin SPECT/CT Study in Mice.

Epidemiological studies have suggested that ionizing radiation increases cardiovascular disease risk, but the relevant mechanism is poorly understood. We recently demonstrated that adult mice exposed to whole-body irradiation with 3 Gy gamma rays significantly decreases the number and quality of cardiac stem cells. To further determine if radiation impairs myocardial regenerative potency, a myocardial infarction model was established in adult C57BL/6 mice by ligating the left anterior descending artery approximately 6 h after sham- or whole-body gamma irradiation (0 or 3 Gy). To evaluate the regenerative potency of the infarcted heart, we measured the myocardial perfusion and remodeling by 18F-FDG PET/CT and 99mTc-tetrofosmin SPECT/CT at 1-2 days (baseline) and 14-15 days (end point) after infarction, respectively. Mice were sacrificed at day 15 after infarction, and heart tissue was collected for histological analysis. The infarct area of the left ventricle was significantly larger in irradiated mice than healthy controls 14 days after infarction, although it was similar between the groups at the baseline. However, histological analysis showed that the infarct size and left ventricle wall thickness were not significantly different among the groups. Compared to the healthy controls, irradiated mice had significantly less c-kit-positive stem cells, less Sca-1-positive stem cells, less proliferating cells, more apoptotic cells and lower vessel density within the infarcted heart. The results of this study suggest that whole-body irradiation with 3 Gy gamma rays impairs the endogenous regeneration of infarcted heart, which may indirectly predict future cardiovascular disease risk.

Low-Level Laser Irradiation Precondition for Cardiac Regenerative Therapy.

OBJECTIVE: The purpose of this article was to review the molecular mechanisms of low-level laser irradiation (LLLI) preconditioning for heart cell therapy. BACKGROUND DATA: Stem cell transplantation appears to offer a better alternative to cardiac regenerative therapy. Previous studies have confirmed that the application of LLLI plays a positive role in regulating stem cell proliferation and in remodeling the hostile milieu of infarcted myocardium. Greater understanding of LLLI's underlying mechanisms would be helpful in translating cell transplantation therapy into the clinic. METHODS: Studies investigating LLLI preconditioning for cardiac regenerative therapy published up to 2015 were retrieved from library sources and Pubmed databases. RESULTS: LLLI preconditioning stimulates proliferation and differentiation of stem cells through activation of cell proliferation signaling pathways and alteration of microRNA expression. It also could stimulate paracrine secretion of stem cells and alter cardiac cytokine expression in infarcted myocardium. CONCLUSIONS: LLLI preconditioning provides a promising approach to maximize the efficacy of cardiac cell-based therapy. Although many studies have reported possible molecular mechanisms involved in LLLI preconditioning, the exact mechanisms are still not clearly understood.

Remodelado cardíaco inverso en pacientes con hipertensión pulmonar tras trasplante bipulmonar. Estudio con tomografía computarizada multidetector / Multidetector computed tomography shows reverse cardiac remodeling after double lung transplantation for pulmonary hypertension

Objetivo. Valorar mediante tomografía computarizada multidetector (TCMD) los cambios estructurales del corazón derecho y de las arterias pulmonares que se producen en los pacientes con hipertensión pulmonar (HP) grave tratados mediante trasplante bipulmonar (TxBP). Material y métodos. Estudio retrospectivo de 21 pacientes consecutivos diagnosticados de HP grave, a los que se realizó TxBP en nuestro centro hospitalario durante los años 2010-2014. Se analizó la TCMD realizada previa al trasplante pulmonar, y la primera disponible después. Se obtuvieron las siguientes variables: diámetro del tronco de la arteria pulmonar, relación diámetro tronco de la arteria pulmonar/diámetro de la aorta ascendente, diámetro del ventrículo derecho, relación diámetro ventrículo izquierdo/derecho e índice de excentricidad. Se realizó un análisis estadístico con comparación de medias de las diferentes variables recogidas. Resultados. En todos los casos analizados se observó, en la TCMD realizada, una media de 24±14 días post-TxBP, una reducción significativa del tamaño de las cavidades derechas, con mejoría de los índices de interdependencia ventricular y del tamaño del tronco de la arteria pulmonar (p<0,001 para todas las variables analizadas). Conclusión. Los pacientes con HP tratados mediante TxBP presentan un remodelado inverso precoz de los cambios estructurales cardíacos derechos y del árbol arterial pulmonar. La TCMD es útil para detectar dichos cambios (AU)

Objective. To use multidetector computed tomography (MDCT) to evaluate the structural changes in the right heart and pulmonary arteries that occur in patients with severe pulmonary hypertension treated by double lung transplantation. Material and methods. This was a retrospective study of 21 consecutive patients diagnosed with severe pulmonary hypertension who underwent double lung transplantation at our center between 2010 and 2014. We analyzed the last MDCT study done before lung transplantation and the first MDCT study done after lung transplantation. We recorded the following variables: diameter of the pulmonary artery trunk, ratio of the diameter of the pulmonary artery trunk to the diameter of the ascending aorta, diameter of the right ventricle, ratio of the diameter of the left ventricle to the diameter of the right ventricle, and eccentricity index. Statistical analysis consisted of the comparison of the means of the variables recorded. Results. In all cases analyzed, the MDCT study done a mean of 24±14 days after double lung transplantation showed a significant reduction in the size of the right heart chambers, with improved indices of ventricular interdependency index, and reduction in the size of the pulmonary artery trunk (p<0.001 for all the variables analyzed). Conclusion. Patients with pulmonary hypertension treated by double lung transplantation present early reverse remodeling of the changes in the structures of the right heart and pulmonary arterial tree. MDCT is useful for detecting these changes (AU)

Effects of local irradiation combined with sunitinib on early remodeling, mitochondria, and oxidative stress in the rat heart.

BACKGROUND AND PURPOSE: Thoracic (chemo)radiation therapy is increasingly administered with tyrosine kinase inhibitors (TKI). While TKI have adverse effects on the heart, it is unknown whether combination with other cancer therapies causes enhanced toxicity. We used an animal model to investigate whether radiation and sunitinib interact in their effects on the heart. MATERIAL AND METHODS: Male Sprague-Dawley rats received local heart irradiation (9Gy per day, 5days). Oral sunitinib (8 or 15mg/kg bodyweight per day) started on day 1 of irradiation and continued for 2weeks. Cardiac function was examined with echocardiography. Cardiac remodeling, cell death, left ventricular (LV) oxidative stress markers, mitochondrial morphology and mitochondrial permeability transition pore (mPTP) opening were assessed. RESULTS: Cardiac diameter, stroke volume, and LV volume, mass and anterior wall thickness increased in time, but only in the vehicle group. Sunitinib reduced LV inner diameter and volume in systole, which were counteracted by radiation. Sunitinib and radiation showed enhanced effects on mitochondrial morphology and mPTP opening, but not on cardiac troponin I, mast cell numbers or markers of oxidative stress. CONCLUSIONS: This study found no early enhanced effects of radiation and sunitinib on cardiac function or structure. Long-term effects remain to be determined.

Low-Level Laser Therapy to the Bone Marrow Reduces Scarring and Improves Heart Function Post-Acute Myocardial Infarction in the Pig.

OBJECTIVE: Cell therapy for myocardial repair is one of the most intensely investigated strategies for treating acute myocardial infarction (MI). The aim of the present study was to determine whether low-level laser therapy (LLLT) application to stem cells in the bone marrow (BM) could affect the infarcted porcine heart and reduce scarring following MI. METHODS: MI was induced in farm pigs by percutaneous balloon inflation in the left coronary artery for 90 min. Laser was applied to the tibia and iliac bones 30 min, and 2 and 7 days post-induction of MI. Pigs were euthanized 90 days post-MI. The extent of scarring was analyzed by histology and MRI, and heart function was analyzed by echocardiography. RESULTS: The number of c-kit+ cells (stem cells) in the circulating blood of the laser-treated (LT) pigs was 2.62- and 2.4-fold higher than in the non-laser-treated (NLT) pigs 24 and 48 h post-MI, respectively. The infarct size [% of scar tissue out of the left ventricle (LV) volume as measured from histology] in the LT pigs was 3.2 ± 0.82%, significantly lower, 68% (p < 0.05), than that (16.6 ± 3.7%) in the NLT pigs. The mean density of small blood vessels in the infarcted area was significantly higher [6.5-fold (p < 0.025)], in the LT pigs than in the NLT ones. Echocardiography (ECHO) analysis for heart function revealed the left ventricular ejection fraction in the LT pigs to be significantly higher than in the NLT ones. CONCLUSIONS: LLLT application to BM in the porcine model for MI caused a significant reduction in scarring, enhanced angiogenesis and functional improvement both in the acute and long term phase post-MI.

Análisis mediante resonancia magnética cardiaca del miocardio salvado tras infarto. Predictores e influencia en el remodelado adverso ventricular / Analysis of post-infarction salvaged myocardium by cardiac magnetic resonance. Predictors and influence on adverse ventricular remodeling

Introducción y objetivos. Analizar mediante resonancia magnética cardiaca los factores que determinan la magnitud del miocardio salvado tras infarto de miocardio y su valor predictivo del remodelado adverso ventricular. Métodos. A 118 pacientes con un primer infarto de miocardio con elevación del ST (angioplastia primaria, 65 pacientes; estrategia farmacoinvasiva, 53 pacientes) se les realizó resonancia magnética (6 [5-8] días y 6 meses; n=83). Se cuantificó el índice de miocardio salvado como el porcentaje de área en riesgo (secuencias ponderadas en T2) que no muestra realce tardío. Resultados. El índice de miocardio salvado > 31% (mediana) se asocia a menor tiempo dolor-reperfusión (153 frente a 258 min), menor frecuencia de diabetes (el 12 frente al 32%), menor retraso hasta la resonancia magnética y mejores parámetros cardiovasculares (p<0,05 para todos ellos). No existen diferencias según el tipo de reperfusión. Mediante regresión logística, los predictores de índice de miocardio salvado > 31% son el retraso hasta la reperfusión (odds ratio = 0,42 [0,29-0,63]; p<0,0001), diabetes (odds ratio=0,32 [0,11-0,99]; p<0,05) y el retraso hasta la resonancia magnética (odds ratio=0,86 [0,76-0,97]; p<0,05). Los predictores de volumen telesistólico dilatado al sexto mes son el número de segmentos con necrosis > 50% (odds ratio=1,51 [1,21-1,90]; p<0,0001) y el volumen telesistólico en la primera semana (odds ratio=1,12 [1,06-1,18]; p<0,0001). Conclusiones. La resonancia magnética permite cuantificar el miocardio salvado tras el infarto. La rapidez en recibir el tratamiento de reperfusión constituye su principal predictor. Se debe confirmar la posible relación entre el retraso en la realización de la resonancia magnética y el miocardio salvado. El miocardio salvado no mejora el valor de la resonancia para predecir remodelado adverso (AU)

Introduction and objectives. To evaluate by cardiovascular magnetic resonance those factors related to the amount of salvaged myocardium after a myocardial infarction and its value in predicting adverse ventricular remodeling. Methods. One hundred eighteen patients admitted for a first ST elevation myocardial infarction (primary angioplasty, 65 patients; a pharmacoinvasive strategy, 53 patients) underwent magnetic resonance (6 [5-8] days and 6 months; n=83). The myocardial salvage index was quantitatively assessed as the percentage of area at risk (T2-weighted sequences) not showing late enhancement. Results. Myocardial salvage index >31% (median) was associated with a shorter time to reperfusion (153min vs 258min), a lower rate of diabetes (12% vs 32%), shorter time to magnetic resonance, and better cardiovascular parameters (P<.05 for all analyses). There were no significant differences depending on the reperfusion method. In a logistic regression analysis, delayed reperfusion (odds ratio=0.42 [0.29-0.63]; P<.0001), diabetes (odds ratio=0.32 [0.11-0.99]; P<.05) and a longer time to the performance of magnetic resonance (odds ratio=0.86 [0.76-0.97]; P<.05) were independently related to a lower probability of a myocardial salvage index >31%. Predictors of increased left ventricular end-systolic volume at 6 months were the number of segments showing an extent of transmural necrosis >50% (odds ratio =1.51 [1.21-1.90]; P<.0001) and left ventricular end-systolic volume at one week (odds ratio=1.12 [1.06-1.18]; P<.0001). Conclusions. Cardiovascular magnetic resonance enables the quantification of the salvaged myocardium after myocardial infarction. The celerity with which reperfusion therapy is administered constitutes its most important predictor. The possible effect of a delay in the performance of magnetic resonance on myocardial salvage needs to be confirmed. Salvaged myocardium does not improve the value of magnetic resonance for predicting adverse remodeling (AU)

Extracorporeal shock wave therapy reverses ischemia-related left ventricular dysfunction and remodeling: molecular-cellular and functional assessment.

An optimal treatment for patients with diffuse obstructive arterial disease unsuitable for catheter-based or surgical intervention is still pending. This study tested the hypothesis that extracorporeal shock wave (ECSW) therapy may be a therapeutic alternative under such clinical situation. Myocardial ischemia was induced in male mini-pigs through applying an ameroid constrictor over mid-left anterior descending artery (LAD). Twelve mini-pigs were equally randomized into group 1 (Constrictor over LAD only) and group 2 (Constrictor over LAD plus ECSW [800 impulses at 0.09 mJ/mm(2)] once 3 months after the procedure). Results showed that the parameters measured by echocardiography did not differ between two groups on days 0 and 90. However, echocardiography and left ventricular (LV) angiography showed higher LV ejection fraction and lower LV end-systolic dimension and volume in group 2 on day 180 (p<0.035). Besides, mRNA and protein expressions of CXCR4 and SDF-1α were increased in group 2 (p<0.04). Immunofluorescence staining also showed higher number of vWF-, CD31-, SDF-1α-, and CXCR4-positive cells in group 2 (all p<0.04). Moreover, immunohistochemical staining showed notably higher vessel density but lower mean fibrosis area, number of CD40-positive cells and apoptotic nuclei in group 2 (all p<0.045). Mitochondrial protein expression of oxidative stress was lower, whereas cytochrome-C was higher in group 2 (all p<0.03). Furthermore, mRNA expressions of MMP-9, Bax and caspase-3 were lower, whereas Bcl-2, eNOS, VEGF and PGC-1α were higher in group 2 (all p<0.01). In conclusion, ECSW therapy effectively reversed ischemia-elicited LV dysfunction and remodeling through enhancing angiogenesis and attenuating inflammation and oxidative stress.

Rapid proteomic remodeling of cardiac tissue caused by total body ionizing radiation.

Accidental nuclear scenarios lead to environmental contamination of unknown level. Immediate radiation-induced biological responses that trigger processes leading to adverse health effects decades later are not well understood. A comprehensive proteomic analysis provides a promising means to identify and quantify the initial damage after radiation exposure. Early changes in the cardiac tissue of C57BL/6 mice exposed to total body irradiation were studied, using a dose relevant to both intentional and accidental exposure (3 Gy gamma ray). Heart tissue protein lysates were analyzed 5 and 24 h after the exposure using isotope-coded protein labeling (ICPL) and 2-dimensional difference-in-gel-electrophoresis (2-D DIGE) proteomics approaches. The differentially expressed proteins were identified by LC-ESI-MS-MS. Both techniques showed similar functional groups of proteins to be involved in the initial injury. Pathway analyses indicated that total body irradiation immediately induced biological responses such as inflammation, antioxidative defense, and reorganization of structural proteins. Mitochondrial proteins represented the protein class most sensitive to ionizing radiation. The proteins involved in the initial damage processes map to several functional categories involving cardiotoxicity. This prompts us to propose that these early changes are indicative of the processes that lead to an increased risk of cardiovascular disease after radiation exposure.

[Depending on exposure, functional state of left ventricle in combined cardiovascular disease among chronic uranium intoxication patients].

State of left heart contractility in patients having IHD and AH during long-term period of chronic uranium intoxication depends on duration of exposure to toxic radiation factor. The authors revealed left ventricle myocardium weight decreased by 11.7% on exposure up to 10 years and that decreased by 18.9% on the exposure over 10 years, when compared to the reference group. Longer length of service was connected with higher share of patients with pathologic remodelling of left ventricle, mostly due to increased concentric remodelling.

Low-level laser irradiation alters cardiac cytokine expression following acute myocardial infarction: a potential mechanism for laser therapy.

OBJECTIVES: Low-level laser irradiation (LLLI) has the potential of exerting cardioprotective effect following myocardial infarction (MI). The authors hypothesized that LLLI could influence the expression of cardiac cytokines and contribute to the reversal of ventricular remodeling. BACKGROUND: LLLI regulates the expression of cytokines after tissue damage. However, little is known concerning the alteration of the cardiac cytokine expression profile after LLLI. METHODS: MI was created by coronary ligation. The surviving rats were divided randomly into laser and control groups. 33 rats were exposed to a diode laser (635 nm, 5 mW, CW, laser, beam spot size 0.8 cm(2), 6 mW/cm(2), 150 sec, 0.8 J, 1J/cm(2)) as laser group. Another 33 rats received only coronary ligation and served as control group. 28 rats received a thoracotomy without coronary ligation (sham group). One day after laser irradiation, 5 rats from each group were sacrificed and the heart tissues were analyzed by cytokine antibody arrays. Enzyme-linked immunosorbent assay (ELISA) was performed to confirm its reliability. Two weeks after MI, cardiac function and structure were evaluated by echocardiography and histological study. RESULTS: Cytokine antibody array indicated 4 cytokines were significantly changed after laser therapy. ELISA confirmed that granulocyte-macrophage colony stimulating factor and fractalkine were the cytokines involved in the response to therapeutic laser irradiation. However, there was no difference in cytokine release between various groups at 2 weeks after MI. Although LLLI did not improve the damaged heart function, it did reduce the infarct area expansion. CONCLUSIONS: The antibody-based protein array technology was applied for screening the cytokine expression profile following MI, with or without laser irradiation. The expression of multiple cytokines was regulated in the acute phase after LLLI. Our results revealed a potential novel mechanism for applying laser therapy to the treatment of heart disease.

[Analysis of structural and functional indices of the children hearts with isolated abnormal chords of the left ventricle and who were born to parents irradiated during the Chernobyl accident].

156 children of the main group, born to parents irradiated in the result of Chernobyl disaster have been involved in the study. These children were identified with isolated abnormal chords of the left ventricle (AHLV) according the results of Doppler echocardiography. 39 practically healthy children and 24 children of the nosology control group have also been observed. Threshold quantity of AHLV were determined in 33 children, main group, (subgroup Ia), sub-threshold--in 123 children (subgroup I(B)). The children of the control group with threshold quantity of AHLV were found with decreased adaptation capacity of the cardio-vascular system through shifts in dynamics and energetics of the heart contraction. Reduction in systolic output, systolic and heart indices justify hypokinetic type of organization of central hemodynamics, which can be considered an early sign of tension of functional capabilities of the heart and blood vessels. This subgroup of children was found to have changes of transmitral blood flow indicating the initiation of the heart's diastolic dysfunction. Almost 1/3 of children with subthreshold number of AHLV were also revealed to have signs of initiation of the heart's diastolic dysfunction.

Valvular dysfunction and left ventricular changes in Hodgkin's lymphoma survivors. A longitudinal study.

PURPOSE: Hodgkin's lymphoma survivors (HLSs) have an elevated risk for cardiovascular diseases that appear several years after radiotherapy. This study examined the time-dependent development and evolution of valvular and myocardial function related to treatment with mediastinal radiotherapy and anthracyclines in HLSs. PATIENTS AND METHODS: In 1993, echocardiography was performed in 116 HLSs median 10 years (range 6-13 years) after treatment with mediastinal radiotherapy. None of the 116 patients had valvular stenosis in 1993 whereas 36 (31%) had moderate valvular regurgitation. In 2005-2007, 51 of 57 invited patients were included in a second echocardiographic study - median 22 years (range 11-27 years) after treatment. Of these patients, 28 (55%) had also received anthracyclines. The patients were selected on the basis of the presence or absence of moderate valvular regurgitation in 1993. RESULTS: The second echocardiographic study demonstrated that 10 out of 27 (37%) patients with only mild or no aortic or mitral regurgitation in 1993 had developed moderate regurgitation in either or both the aortic or mitral valve. Of the 24 patients with moderate (n=23) or severe (n=1) regurgitation in the aortic or mitral valve in 1993, 8 (33%) had progressed to severe regurgitation, developed moderate regurgitation in a previously normal or mild regurgitant valve or had received valvular replacement. In total, of all patients, 20 (39%) had developed mild to severe aortic stenosis and 3 patients had received valvular replacement. In a multiple linear regression the use of anthracyclines predicted left ventricular remodelling between ECHO 1993 and 2005 as demonstrated by increased left ventricular end systolic diameter (beta =0.09 (95% CI 0.01-0.17), P=0.04) and reduced thickness of the left ventricular posterior wall (beta =-0.18 (95% CI -0.33 to -0.03), P=0.02) and interventricular septum (beta =-0.16 (95% CI -0.30 to -0.03), P=0.02). CONCLUSION: Given the progressive nature of valvular dysfunction and left ventricular remodelling 20-30 years after diagnosis, we recommend life-long cardiological follow-up of HLSs treated with mediastinal radiotherapy.

Irradiated cultured apoptotic peripheral blood mononuclear cells regenerate infarcted myocardium.

BACKGROUND: Acute myocardial infarction (AMI) is followed by post AMI cardiac remodelling, often leading to congestive heart failure. Homing of c-kit+ endothelial progenitor cells (EPC) has been thought to be the optimal source for regenerating infarcted myocardium. METHODS: Immune function of viable peripheral blood mononuclear cells (PBMC) was evaluated after co-culture with irradiated apoptotic PBMC (IA-PBMC) in vitro. Viable PBMC, IA-PBMC and culture supernatants (SN) thereof were obtained after 24 h. Reverse transcription polymerase chain reaction and enzyme-linked immunosorbent assay were utilized to quantify interleukin-8 (IL-8), vascular endothelial growth factor, matrix metalloproteinase-9 (MMP9) in PBMC, SN and SN exposed fibroblasts. Cell suspensions of viable- and IA-PBMC were infused in an experimental rat AMI model. Immunohistological analysis was performed to detect inflammatory and pro-angiogenic cells within 72 h post-infarction. Functional data and determination of infarction size were quantified by echocardiography and Elastica van Gieson staining. RESULTS: The IA-PBMC attenuated immune reactivity and resulted in secretion of pro-angiogenic IL-8 and MMP9 in vitro. Fibroblasts exposed to viable and IA-PBMC derived SN caused RNA increment of IL-8 and MMP9. AMI rats that were infused with IA-PBMC cell suspension evidenced enhanced homing of endothelial progenitor cells within 72 h as compared to control (medium alone, viable-PBMC). Echocardiography showed a significant reduction in infarction size and improvement in post AMI remodelling as evidenced by an attenuated loss of ejection fraction. CONCLUSION: These data indicate that infusion of IA-PBMC cell suspension in experimental AMI circumvented inflammation, caused preferential homing of regenerative EPC and replaced infarcted myocardium.

Influence of mast cells on structural and functional manifestations of radiation-induced heart disease.

Radiation-induced heart disease (RIHD), characterized by accelerated atherosclerosis and adverse tissue remodeling, is a serious sequelae after radiotherapy of thoracic and chest wall tumors. Adverse cardiac remodeling in RIHD and other cardiac disorders is frequently accompanied by mast cell hyperplasia, suggesting that mast cells may affect the development of cardiac fibrosis. This study used a mast cell-deficient rat model to define the role of mast cells in RIHD. Mast cell-deficient rats (Ws/Ws) and mast cell-competent littermate controls (+/+) were exposed to 18 Gy localized single-dose irradiation of the heart. Six months after irradiation, cardiac function was examined by echocardiography and Langendorff-perfused isolated heart preparation, whereas structural changes were assessed using quantitative histology and immunohistochemical analysis. Mast cell-deficient rats exhibited more severe postradiation changes than mast cell-competent littermates. Hence, mast cell-deficient rats exhibited a greater upward/leftward shift in the left ventricular (LV) diastolic pressure-volume relationship (P = 0.001), a greater reduction in in vivo LV diastolic area (from 0.50 +/- 0.024 cm in age-matched controls to 0.24 +/- 0.032 cm after irradiation; P = 0.006), and a greater increase in LV posterior wall thickness (from 0.13 +/- 0.003 cm in age-matched controls to 0.15 +/- 0.003 cm after irradiation; P = 0.04). Structural analysis revealed more pronounced postradiation accumulation of interstitial collagen III but less myocardial degeneration in hearts from mast cell-deficient rats. These data show that the absence of mast cells accelerates the development of functional changes in the irradiated heart, particularly diastolic dysfunction, and suggest that, in contrast to what has been the prevailing assumption, the role of mast cells in RIHD is predominantly protective.

[Morpho-functional condition of heart in patients with lymphogranulomatosis late after chemoradiotherapy]. / Morfofunktsional'noe sostoianie serdtsa pri limfogranulematoze v otdalennye sroki posle khimioluchevoi terapii.

AIM: The study of clinical and echocardiographic status of the heart in patients with lymphogranulomatosis (LGM) late after chemoradiotherapy. MATERIAL AND METHODS: 44 patients with IIA-IV stage of LGM exposed to irradiation of lymph nodes and polychemotherapy according to the schemes ACOP, ABVD, COPP, CHOP, CVPP were examined. Echocardiography was carried out on the unit Sigma-44 and Toshiba. RESULTS: Some changes in the heart by type of myocardiodystrophy or endomyocardial fibrosis were found. The latter are characterized by diminution of the left and (or) right ventricles due to apex obliteration, hardening and thickening of the endocardium and subvalvular structures, diastolic dysfunction and pulmonary hypertension. The main and additional signs are distinguished. The reasons of endomyocardial fibrosis are discussed: severity of the disease, frequent exacerbations and, consequently, higher doses of specific chemoradiotherapy. CONCLUSION: It is necessary to employ sparing policy in planning radiotherapy after high loading antracycline antibiotics.