Detection and characterization of early-phase experimental radiation-induced heart disease

• Main Author: Lieblong, Benjamin J
• Format: Dissertation
• Language: English
• Published: ProQuest Dissertations & Theses 01.01.2016
• Subjects: Pharmacology
• ISBN: 1339828324; 9781339828329

Radiation-induced heart disease (RIHD) is a potentially severe side effect of thoracic radiotherapy for malignancies including Hodgkin’s disease and breast, lung, or esophageal cancers. Due to its precarious location in the thoracic cavity, the heart can be irradiated unintentionally when administering radiotherapy for these tumors. As a result, many years after radiotherapy, end-stage manifestations of heart disease may present abruptly following 10 or more years of latency. Unfortunately, very little is known about mechanisms and early biomarkers during the early phase of human or experimental RIHD. We sought to characterize early RIHD in a rat model using local heart irradiation, and to evaluate dobutamine stress testing (DST) as an early diagnostic test to detect RIHD. We reported earlier that the kallikrein-kinin system (KKS), and its best known constituent bradykinin, plays a primarily cardioprotective role by ameliorating inflammation in the irradiated heart at 3 months post-irradiation, but whether the KKS regulates the early inflammatory response to RIHD is largely unknown. To explore this possibility, we subcutaneously administered 0.5 mg/kg/day HOE-140, a bradykinin B2 receptor antagonist, to animals receiving 21 Gy or Sham-irradiation and examined molecular signaling at 1 month post-irradiation. Local heart irradiation caused increased phosphorylation of c-Jun, which was further enhanced by HOE-140 treatment in irradiated rats. This phosphorylation led to a functional consequence; nuclear translocation of c-Jun was increased in irradiated hearts, and further increased in animals treated with HOE-140. Macrophage infiltration was increased in irradiated animals treated with HOE-140, implying that B2 receptors inhibit macrophage infiltration in early-phase RIHD. Cardiac stress tests are used widely in patients to predict the risk of major coronary events. However, despite the fact that patients subjected to thoracic irradiation are susceptible to cardiac ischemia, we lack an early diagnostic test to identify patients at risk for RIHD. Therefore, we explored whether cardiac stress testing using dobutamine, a ?1-adrenoreceptor agonist, could unmask electrocardiographic (ECG) abnormalities of the irradiated heart to provide an early diagnostic test to detect pending RIHD. We showed that T-wave amplitudes on ECGs of resting irradiated rats were elevated at 60 and 90 days post-irradiation. However, DST provoked T-wave elevation in irradiated rats as early as 10 days after 5 x 9 Gy irradiation and as early as 20 days after 5 x 6 Gy irradiation; at these time-points, resting T-wave amplitudes were not significantly different from Sham rats. DST-induced T-wave elevation in irradiated rats preceded functional changes (increased ejection fraction and fractional shortening) and histological changes (myocardial fibrosis), which occurred at 3 months post-irradiation. Because T-wave elevation can indicate myocardial ischemia, we investigated etiologies and indicators of ischemic injury and ECG alterations in the heart. Local heart irradiation caused release of troponin-I at 60 days post-irradiation; a time point associated with elevated T-waves at rest. Systemic hyperkalemia and hypercalcemia can cause T-wave elevation; however, both plasma potassium and calcium concentrations were not altered by irradiation or stress testing at 30 days post-irradiation. Endothelial function, as measured by endothelium-dependent vasodilator responses of isolated coronary septal arteries from irradiated hearts, also was unchanged at 1 month post-IR, which failed to implicate endothelial dysfunction as a contributor to T-wave elevation or myocardial ischemia. Thus, early phase experimental RIHD in our rat model of this pathology is characterized by aberrant bradykinin signaling and ECG disturbances, which may be indicators of myocardial ischemia. DST may be a useful diagnostic tool to provoke T-wave elevation on ECG as an early predictor of latent RIHD.