Clinical manifestations of noncoronary atherosclerotic vascular disease after moderate dose irradiation.

BACKGROUND: Accelerated atherosclerosis and carotid stenosis are well-established risks occurring after high radiation doses that are used to treat cancers of the head and neck. Noncoronary vascular disease has been observed and may relate to more moderate dose irradiation. METHODS: A search of patients treated for Hodgkin disease, non-Hodgkin lymphoma, or seminoma was performed to identify cases with noncoronary vascular complications after irradiation. These three groups were chosen because of the use of intermediate dose radiation and prevalence of long-term survivors. Individual patient records were reviewed to document the type and presentation of the stenosis and the clinical factors that may have contributed to this risk. RESULTS: Twenty-one patients were identified who developed disease in noncoronary arteries after treatment. The median time from irradiation to diagnosis of vascular stenosis was 15 years. Antecedent risk factors for vascular disease were prevalent. Five patients had disease identified by auscultation of bruits before an adverse clinical event occurred. Five patients died from complications related to their vascular disease, which included three deaths after stroke and two after small bowel infarction. CONCLUSION: Twelve cases arose at an atypically young age for atherosclerotic vascular disease and featured unusual clinical presentations. Nine cases identified occurred at an advanced aged and at a shorter median interval, making a causal relation to irradiation uncertain. Incorporating careful auscultation for bruits in followup evaluation of irradiated patients may identify individuals who are at risk for adverse vascular events. The potential for early vasculopathy in individuals exposed to intermediate dose irradiation suggests a need to manage dyslipidemia and reduce vascular risk factors throughout the posttreatment period.

Radiation-associated cardiovascular disease: manifestations and management.

Irradiation of the heart incidental to the treatment of malignancies can cause a spectrum of cardiovascular complications. These include pericarditis, myocardial fibrosis, muscular dysfunction, valvular abnormalities, and conduction disturbances. Survivors of Hodgkin's disease and breast cancer survivors treated with radiotherapy after mastectomy appear to be the groups at highest risk for radiation-associated cardiovascular disease. Although modern techniques of chest radiotherapy have decreased its frequency by reducing the dose and volume of radiation exposure to the heart, survivors treated with radiation remain at increased risk of cardiovascular disease. The risk of fatal cardiovascular disease increases with younger age at treatment, longer follow-up, and higher dose volumes of exposure to the heart. Certain chemotherapeutic agents, such as anthracyclines, also increase the risk of damage to the heart. Cardiac damage associated with radiotherapy may be progressive. Screening of survivors may help identify those at highest risk for serious cardiovascular disease. The broad range of radiation-associated cardiovascular disease makes it necessary for survivors to be examined with multiple screening modalities, although data do not exist to support definitive recommendations on test frequency.

Clinical significance of increased gelatinolytic activity in the rectal mucosa during external beam radiation therapy of prostate cancer.

PURPOSE: Rectal toxicity (proctitis) is a dose-limiting factor in pelvic radiation therapy. Mucosal atrophy, i.e., net extracellular matrix degradation, is a prominent feature of radiation proctitis, but the underlying mechanisms are not known. We prospectively examined changes in matrix metalloproteinase (MMP)-2 and MMP-9 (gelatinase A and B) in the rectal mucosa during radiation therapy of prostate cancer, as well as the relationships of these changes with symptomatic, structural, and cellular evidence of radiation proctitis. METHODS AND MATERIALS: Seventeen patients scheduled for external beam radiation therapy for prostate cancer were prospectively enrolled. Symptoms of gastrointestinal toxicity were recorded, and endoscopy with biopsy of the rectal mucosa was performed before radiation therapy, as well as 2 and 6 weeks into the treatment course. Radiation proctitis was assessed by endoscopic scoring, quantitative histology, and quantitative immunohistochemistry. MMP-2 and MMP-9 were localized immunohistochemically, and activities were determined by gelatin zymography. RESULTS: Symptoms, endoscopic scores, histologic injury, and mucosal macrophages and neutrophils increased from baseline to 2 weeks. Symptoms increased further from 2 weeks to 6 weeks, whereas endoscopic and cellular evidence of proctitis did not. Compared to pretreatment values, there was increased total gelatinolytic activity of MMP-2 and MMP-9 at 2 weeks (p = 0.02 and p = 0.004, respectively) and 6 weeks (p = 0.006 and p = 0.001, respectively). Active MMP-2 was increased at both time points (p = 0.0001 and p = 0.002). Increased MMP-9 and MMP-2 at 6 weeks was associated with radiation-induced diarrhea (p = 0.007 and p = 0.02, respectively) and with mucosal neutrophil infiltration (rho = 0.62). CONCLUSIONS: Pelvic radiation therapy causes increased MMP-2 and MMP-9 activity in the rectal mucosa. These changes correlate with radiation-induced diarrhea and granulocyte infiltration and may contribute to abnormal connective tissue remodeling in radiation proctitis.

Nicotine accelerates angiogenesis and wound healing in genetically diabetic mice.

Recently, we have discovered an endogenous cholinergic pathway for angiogenesis mediated by endothelial nicotinic acetylcholine receptors (nAChRs). Since angiogenesis plays a major role in wound repair, we hypothesized that activation of nAChRs with nicotine would accelerate wound healing in a murine excisional wound model. In genetically diabetic and control mice full-thickness skin wounds (0.8 cm) were created on the dorsum and topically treated over 7 days with either vehicle (phosphate-buffered saline, PBS) or nicotine (10(-8) mol/L, 10(-9) mol/L; each, n = 5). Wound size was measured over 14 days followed by resection, histological analysis, and quantitation of vascularity. In diabetic animals an agonist (epibatidine, 10(-10) mol/L) or antagonist (hexamethonium, 10(-4) mol/L) of nAChRs as well as the positive control basic fibroblast growth factor (bFGF, 25 microg/kg) were also tested. To further study the role of endothelial nAChRs in angiogenesis, we used an ex vivo vascular explant model. In diabetic mice wound healing was markedly impaired. Nicotine significantly accelerated wound healing as assessed by closure rate and histological score. The effects of nicotine were equal to bFGF and were mimicked by epibatidine and blocked by hexamethonium. Histomorphometry revealed increased neovascularization in animals treated with nicotine. Furthermore, capillary-like sprouting from vascular explants was significantly enhanced by nicotine. In conclusion, agonist-induced stimulation of nAChRs accelerates wound healing in diabetic mice by promoting angiogenesis. We have discovered a cholinergic pathway for angiogenesis that is involved in wound healing, and which is a potential target for therapeutic angiogenesis.