Fibrotic aortic valve disease after radiotherapy: an immunohistochemical study in breast cancer and lymphoma patients.

BACKGROUND: Radiation-associated aortic valve (AV) stenosis is frequently seen as a late sequela after thoracic radiotherapy (RT). Although the clinical relationship between thoracic radiotherapy and valvular dysfunction has been established, the process leading to accelerated aortic valve stenosis remains unclear. The aim of this study was to determine whether increased inflammatory cell infiltration, fibrosis, and calcification is present in aortic valves after radiotherapy at the time of aortic valve replacement. METHODS: Stenotic aortic valve specimens from 43 patients were obtained after surgical aortic valve replacement. A total 28 patients had previously undergone radiotherapy for breast cancer or malignant lymphoma. A total 15 patients were included as control. The valve leaflets were assessed by (immuno)histochemistry for inflammatory cell composition (CD3, CD20, CD68, and CD163) and extracellular matrix changes (collagen and calcification). RESULTS: Aortic valve cell density after radiotherapy for lymphoma was markedly decreased when compared with other groups. Irradiated aortic valve show similar (low) degrees of late T and B lymphocyte infiltration as control valves, whereas macrophage marker CD68 was decreased after radiotherapy for breast cancer. Collagen content was increased following radiotherapy. Aortic valves of patients with lymphoma contained significantly less calcified tissue when compared with the other groups. CONCLUSION: High-dose radiation at a young age (patients with lymphoma) results in cell loss and premature fibrotic aortic valve stenosis as opposed to the degenerative calcific stenosis observed in patients with breast cancer. Our findings suggest a possible dose-dependent effect of radiotherapy on aortic valve fibrosis. The active presence of inflammatory cells may be limited to the acute phase after radiotherapy.

Electric Polarization of Soft Biological Tissues Induced by Ultrasound Waves.

Ultrasound irradiation makes it possible to generate alternating electric polarization through the electromechanical coupling of materials. It follows that electromagnetic fields are often emitted to the surrounding environment when materials are acoustically stimulated. We investigate the acoustically stimulated electromagnetic (ASEM) response of soft biological tissues. The ASEM signal is detected through a capacitive resonant antenna tuned to the MHz frequency of the irradiated ultrasound waves. The signal is well explained by the stress-induced polarization, which responds linearly to the applied acoustic stress. Induced polarization is clearly observed in the Achilles tendon, aortic wall, and aortic valve samples, whereas it is small in adipose tissue and myocardium samples, indicating that fibrous tissues exhibit electromechanical coupling.

[Successful surgical treatment of aortic heart disease as a complication after combined targeted therapy for cancer]. / Khirurgicheskoe lechenie aortal'nogo poroka serdtsa kak oslozhneniia posle kombinirovannoi targetnoi terapii raka.

Cardiovascular diseases and malignancies are leading causes of mortality in the world. Two categories of advanced age patients with cancer are observed in clinical practice. These are patients with cardiovascular diseases as comorbidities and patients with cardiovascular diseases as a complications of targeted therapy for cancer. Cardiac toxicity of chemotherapeutic drugs results myocardial dysfunction, occurrence or progression of heart valve disease, coronary artery disease, arterial hypertension and thromboembolism. A patient who underwent aortic valve replacement and coronary artery bypass surgery is discussed in the article. Aortic valve disease and coronary artery disease were complications of targeted radio- and chemotherapy for sigmoid colon cancer followed by lung and liver metastases. Questions of timely diagnosis and treatment of advanced age patients in multi-field surgical clinic are also analyzed.

Outcomes of Patients With Severe Symptomatic Aortic Valve Stenosis After Chest Radiation: Transcatheter Versus Surgical Aortic Valve Replacement.

Background Patients with symptomatic severe aortic stenosis and a history of chest radiation therapy represent a complex and challenging cohort. It is unknown how transcatheter aortic valve replacement ( TAVR ) compares with surgical aortic valve replacement in this group of patients, which was the objective of this study. Methods and Results We retrospectively reviewed all patients with severe aortic stenosis who underwent either TAVR or surgical aortic valve replacement at our institution with a history of mediastinal radiation (n=55 per group). End points were echocardiographic and clinical outcomes in-hospital, at 30 days, and at 1 year. Inverse propensity weighting analysis was used to account for intergroup baseline differences. TAVR patients had a higher STS score than surgical aortic valve replacement patients (5.1% [3.2, 7.7] versus 1.6% [0.8, 2.6], P<0.001) and more often ( P<0.01 for all) a history of atrial fibrillation (45.5% versus 12.7%), chronic lung disease (47.3% versus 7.3%), peripheral arterial disease (38.2% versus 7.3%), heart failure (58.2% versus 18.2%), and pacemaker therapy (23.6% versus 1.8%). Postoperative atrial fibrillation was less frequent (1.8% versus 27.3%; P<0.001) and hospital stay was shorter in TAVR patients (4.0 [2.0, 5.0] versus 6.0 [5.0, 8.0] days; P<0.001). The ratio of observed-to-expected 30-day mortality was lower after TAVR as was 30-day mortality in inverse propensity weighting-adjusted Kaplan-Meier analyses. Conclusions In patients with severe aortic stenosis and a history of chest radiation therapy, TAVR performs better than predicted along with less adjusted 30-day all-cause mortality, postoperative atrial fibrillation, and shorter hospitalization compared with surgical aortic valve replacement. These data support further studies on the preferred role of TAVR in this unique patient population.

Rate of Progression of Aortic Stenosis and its Impact on Outcomes in Patients With Radiation-Associated Cardiac Disease: A Matched Cohort Study.

OBJECTIVES: The aim of this study was to study differences in progression of aortic stenosis (AS) in patients with mediastinal radiotherapy (XRT)-associated moderate AS versus a matched cohort during the same time frame, and to ascertain need for aortic valve replacement (AVR) and longer-term survival. BACKGROUND: Rate of progression of XRT-associated moderate AS and its impact on outcomes is not well-described. METHODS: We included 81 patients (age 61 ± 13 years; 57% female) with at least XRT-associated moderate AS (aortic valve area [AVA] 1.05 ± 0.3 cm2; mean gradient 24 ± 10 mm Hg) who had ≥2 transthoracic echocardiograms (TTEs) 1 year apart and matched them in a 1:2 fashion on the basis of age, sex, and AVA with those without prior XRT. Serial aortic valve gradients and AVA were recorded. AVR and longer-term all-cause mortality during follow-up were recorded. RESULTS: A total of 100% of patients had 1, a total of 71% had 2, and 39% had 3 follow-up TTEs. Before AVR, mean AVG and AVA were not significantly different between XRT and comparison groups. At 3.6 ± 2.0 years from baseline TTE, 146 (60%) underwent AVR (16% transcatheter), with significantly more patients in the XRT group undergoing AVR (80% vs. 50%; p < 0.01), at a much shorter time (2.9 ± 1.6 years vs. 4.1 ± 2.4 years; p < 0.01). At 6.6 ± 4.0 years from the initial TTE, 49 (20%) patients died, with a significantly higher mortality in the XRT group (40% vs. 11%; p < 0.01), with prior XRT associated with increased longer-term mortality, whereas AVR was associated with improved longer-term survival. CONCLUSIONS: In patients with moderate AS, those with prior XRT have a similar rate of progression of AS versus a comparison group. A higher proportion of patients in the XRT group were referred for AVR at a shorter time from baseline TTE. Despite that, the XRT patients had significantly higher longer-term mortality, and prior exposure to XRT was associated with significantly increased longer-term mortality.

Reparación del arco aórtico mediante stent XL en Marfan / Aortic arch in Marfan syndrome repaired using the XL-stent

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Long-Term Outcomes of Patients With Mediastinal Radiation-Associated Severe Aortic Stenosis and Subsequent Surgical Aortic Valve Replacement: A Matched Cohort Study.

BACKGROUND: Cardiac disease after mediastinal radiotherapy for thoracic malignancy (chest radiotherapy [XRT]) often manifests as progressive aortic stenosis. In patients with XRT-induced severe aortic stenosis undergoing surgical aortic valve replacement (SAVR), we sought to: (1) study long-term survival and compare these patients with a matched cohort undergoing SAVR during the same time frame; and (2) identify potential predictors of long-term mortality. METHODS AND RESULTS: We studied patients with symptomatic severe aortic stenosis undergoing SAVR at our institution, of which there were 172 mediastinal XRT patients (63±13 years, 62% women) matched in a 1:1 fashion (based on age, sex, time of surgery, and aortic valve area) with 172 non-XRT patients (comparison group). Baseline clinical and postoperative data were obtained. Society of Thoracic Surgeons score was calculated and mortality was recorded. In the XRT group, the median Society of Thoracic Surgeons score was 4% (interquartile range 2-13), while mean left ventricular ejection fraction, left ventricular stroke volume index, and mean aortic valve gradient were 54±11%, 38±14 mL/m2, and 39±11 mm Hg, respectively. In the entire cohort, 27% and 34% of patients underwent concomitant coronary artery bypass grafting and aortic surgery at the time of SAVR, respectively. Thirty-day/in-hospital deaths occurred in 4 (2%) patients in the XRT group and 0 patients in the comparison group. At 6±3 years of follow-up, on matched group analysis, there were 95 (28%) deaths (83 [48%] in the XRT group versus 12 [7%] in the comparison group (log-rank 89, P<0.001). On multivariable Cox survival analysis, in the whole cohort, higher Society of Thoracic Surgeons score (hazard ratio, 1.14; 95% CI, 1.03-1.26) and mediastinal XRT (hazard ratio, 8.12; 95% CI, 4.26-15.64) were associated with increased longer-term mortality (both P<0.01). CONCLUSIONS: In patients with severe aortic stenosis undergoing SAVR, patients with prior mediastinal XRT have significantly worse longer-term survival versus a matched cohort.

Risk of valvular heart disease after treatment for Hodgkin lymphoma.

BACKGROUND: Hodgkin lymphoma (HL) survivors are at increased risk of developing valvular heart disease (VHD). We evaluated the determinants of the risk and the radiation dose-response. METHODS: A case-control study was nested in a cohort of 1852 five-year HL survivors diagnosed at ages 15 to 41 years and treated between 1965 and 1995. Case patients had VHD of at least moderate severity as their first cardiovascular diagnosis following HL treatment. Control patients were matched to case patients for age, gender, and HL diagnosis date. Treatment and follow-up data were abstracted from medical records. Radiation doses to heart valves were estimated by reconstruction of individual treatments on representative computed tomography datasets. All statistical tests were two-sided. RESULTS: Eighty-nine case patients with VHD were identified (66 severe or life-threatening) and 200 control patients. Aortic (n = 63) and mitral valves (n = 42) were most frequently affected. Risks increased more than linearly with radiation dose. For doses to the affected valve(s) of less than or equal to 30, 31-35, 36-40, and more than 40 Gy, VHD rates increased by factors of 1.4, 3.1, 5.4, and 11.8, respectively (P trend < .001). Approximate 30-year cumulative risks were 3.0%, 6.4%, 9.3%, and 12.4% for the same dose categories. VHD rate increased with splenectomy by a factor of 2.3 (P = .02). CONCLUSIONS: Radiation dose to the heart valves can increase the risk of clinically significant VHD, especially at doses above 30 Gy. However, for patients with mediastinal involvement treated today with 20 or 30 Gy, the 30-year risk will be increased by only about 1.4%. These findings may be useful for patients and doctors both before treatment and during follow-up.

Alteration of inflammatory response by shock wave therapy leads to reduced calcification of decellularized aortic xenografts in mice†.

OBJECTIVES: Tissue-engineered xenografts represent a promising treatment option in heart valve disease. However, inflammatory response leading to graft failure and incomplete in vitro repopulation with recipient cells remain challenging. Shock waves (SWs) were shown to modulate inflammation and to enhance re-epithelialization. We therefore aimed to investigate whether SWs could serve as a feasible adjunct to tissue engineering. METHODS: Porcine aortic pieces were decellularized using sodium deoxycholate and sodium dodecylsulphate and implanted subcutaneously into C57BL/6 mice (n = 6 per group). The treatment (shock wave therapy, SWT) group received SWs (0.1 mJ/mm(2), 500 impulses, 5 Hz) for modulation of inflammatory response directly after implantation; control animals remained untreated (CTR). Grafts were harvested 72 h and 3 weeks after implantation and analysed for inflammatory cytokines, macrophage infiltration and polarization, osteoclastic activity and calcification. Transmission electron microscopy (TEM) was performed. Endothelial cells (ECs) were treated with SWs and analysed for macrophage regulatory cytokines. In an ex vivo experimental set-up, decellularized porcine aortic valve conduits were reseeded with ECs with and without SWT (0.1 mJ/mm(2), 300 impulses, 3 Hz), fibroblasts as well as peripheral blood mononuclear cells (all human) and tested in a pulsatile flow perfusion system for cell coverage. RESULTS: Treated ECs showed an increase of macrophage migration inhibitory factor and macrophage inflammatory protein 1ß, whereas CD40 ligand and complement component C5/C5a were decreased. Subcutaneously implanted grafts showed increased mRNA levels of tumour necrosis factor α and interleukin 6 in the treatment group. Enhanced repopulation with recipient cells could be observed after SWT. Augmented macrophage infiltration and increased polarization towards M2 macrophages was observed in treated animals. Enhanced recruitment of osteoclastic cells in proximity to calcified tissue was found after SWT. Consequently, SWT resulted in decreased areas of calcification in treated animals. The reseeding experiment revealed that fibroblasts showed the best coverage compared with other cell types. Moreover, SW-treated ECs exhibited enhanced repopulation compared with untreated controls. CONCLUSIONS: SWs reduce the calcification of subcutaneously implanted decellularized xenografts via the modulation of the acute macrophage-mediated inflammatory response and improves the in vitro repopulation of decellularized grafts. It may therefore serve as a feasible adjunct to heart valve tissue engineering.

Radiation-associated valvular heart disease.

Therapeutic ionizing radiation, such as that used in the treatment of Hodgkin's lymphoma, can cause cardiac valvular damage that may take several years to manifest as radiation-associated valvular heart disease. Treatment can be complicated by comorbid radiation injury to other cardiac and mediastinal structures that lead to traditional surgical valve replacement or repair becoming high-risk. A representative case is presented that demonstrates the complexity of radiation-associated valvular heart disease and its successful treatment with percutaneous transcatheter valve replacement. The prevalence and pathophysiologic mechanism of radiation-associated valvular injury are reviewed. Anthracycline adjuvant therapy appears to increase the risk of valvular fibrosis. Left-sided heart valves are more commonly affected than right-sided heart valves. A particular pattern of calcification has been noted in some patients, and experimental data suggest that radiation induction of an osteogenic phenotype may be responsible. A renewed appreciation of the cardiac valvular effects of therapeutic ionizing radiation for mediastinal malignancies is important, and the treatment of such patients may be assisted by the development of novel, less-invasive approaches.

Radiation induces osteogenesis in human aortic valve interstitial cells.

OBJECTIVE: Irradiation of the chest or chest wall has been shown to cause calcific aortic stenosis. However, the mechanisms are unknown. Aortic valve interstitial cells have been implicated in the pathogenesis of aortic stenosis; they have been shown to change from the phenotype of a myofibroblast to an osteoblastlike cell. We therefore hypothesized that irradiation of human aortic valve interstitial cells induces an osteogenic phenotype. In isolated human aortic valve interstitial cells, our purpose was to determine the effect of irradiation on the production of osteogenic factors: (1) bone morphogenetic protein 2, (2) osteopontin, (3) alkaline phosphatase, and (4) the transcription factor Runx2. METHODS: Human aortic valve interstitial cells were isolated from normal aortic valves obtained from explanted hearts of patients undergoing cardiac transplantation (n = 4) and were grown in culture. The cells were grown to confluence, irradiated with 10 Gy using a cesium-137 irradiator, and then lysed 24 hours after irradiation. Cell lysates were analyzed via immunoblot and densitometry for bone morphogenetic protein 2, osteopontin, alkaline phosphatase, and Runx2. Statistical analysis was performed using analysis of variance, with P < .05 indicating significance. RESULTS: Irradiation induced an osteogenic phenotype in human aortic valve interstitial cells. Irradiation induced a 2-fold increase in bone morphogenetic protein 2, a 7-fold increase in osteopontin, a 3-fold increase in alkaline phosphatase, and a 2-fold increase in Runx2. CONCLUSIONS: Radiation induces an osteogenic phenotype in human aortic valve interstitial cells. The irradiated cells had a significantly increased expression of the osteogenic factors bone morphogenetic protein 2, osteopontin, alkaline phosphatase, and Runx2. These data offer mechanistic insight into the pathogenesis of radiation-induced valvular heart disease.

Redirecting valvular myofibroblasts into dormant fibroblasts through light-mediated reduction in substrate modulus.

Fibroblasts residing in connective tissues throughout the body are responsible for extracellular matrix (ECM) homeostasis and repair. In response to tissue damage, they activate to become myofibroblasts, which have organized contractile cytoskeletons and produce a myriad of proteins for ECM remodeling. However, persistence of myofibroblasts can lead to fibrosis with excessive collagen deposition and tissue stiffening. Thus, understanding which signals regulate de-activation of myofibroblasts during normal tissue repair is critical. Substrate modulus has recently been shown to regulate fibrogenic properties, proliferation and apoptosis of fibroblasts isolated from different organs. However, few studies track the cellular responses of fibroblasts to dynamic changes in the microenvironmental modulus. Here, we utilized a light-responsive hydrogel system to probe the fate of valvular myofibroblasts when the Young's modulus of the substrate was reduced from ~32 kPa, mimicking pre-calcified diseased tissue, to ~7 kPa, mimicking healthy cardiac valve fibrosa. After softening the substrata, valvular myofibroblasts de-activated with decreases in α-smooth muscle actin (α-SMA) stress fibers and proliferation, indicating a dormant fibroblast state. Gene signatures of myofibroblasts (including α-SMA and connective tissue growth factor (CTGF)) were significantly down-regulated to fibroblast levels within 6 hours of in situ substrate elasticity reduction while a general fibroblast gene vimentin was not changed. Additionally, the de-activated fibroblasts were in a reversible state and could be re-activated to enter cell cycle by growth stimulation and to express fibrogenic genes, such as CTGF, collagen 1A1 and fibronectin 1, in response to TGF-ß1. Our data suggest that lowering substrate modulus can serve as a cue to down-regulate the valvular myofibroblast phenotype resulting in a predominantly quiescent fibroblast population. These results provide insight in designing hydrogel substrates with physiologically relevant stiffness to dynamically redirect cell fate in vitro.

Percutaneous valve replacement in a young adult for radiation-induced aortic stenosis.

A 46-year-old woman known with relapsing Hodgkin's lymphoma diagnosed at age 5, treated with repeated cycles of radiotherapy and chemotherapy, presented with severe symptomatic radiation-induced aortic stenosis. She also had other late sequelae of radiotherapy including thyroid cancer, mediastinal fribrosis and left pulmonary fibrosis with severe restrictive lung disease and a newly diagnosed renal carcinoma. Due to the prohibitively high surgical risk and need for urgent treatment, she underwent successful transcatheter aortic valve replacement with transfemoral implantation of a 23 mm Edwards SAPIEN-XT prosthesis, which was performed without valvuloplasty of the noncalcified fibrotic valve. The final result was excellent with reduction of the transaortic gradient and no residual aortic regurgitation.

Simultaneous surgery of the aortic valve and sternal osteomyelitis.

A 64-year-old man was referred for aortic valve replacement due to severe stenosis. He also suffered chronic sternal osteomyelitis with skin fistula subsequent to radiation therapy. Both pathologies were approached simultaneously by sternal resection, omental plasty, and valve replacement, which led to favorable primary and mid-term result.

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.