科研之友
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摘要
Editor%26apos;s Highlight: Chemotherapeutics are the epitome of the medical double-edged sword. These agents must be sufficiently toxic to eradicate cancerous cells, but in doing so, non-target tissues are often damaged. One prime example is the damage to the heart tissue after treatment with anthracyclines, such as doxorubicin. Damage to cardiac tissue during treatment leads to an increased rate of heart failure in cancer survivors. As such, it is important to better understand the structural and functional sequelae of treatment on the myocardium. Cove-Smith, Woodhouse, and coworkers employed a battery of cardiac measures along with sophisticated multi-modal cardiac magnetic resonance imaging (CMR) to reveal adverse cardiac consequences after doxorubicin treatment. Key findings include early functional deficits as measured by CMR, as well as subcellular myofibrillar damage and mitochondrial degeneration that occurred well before overt cardiac myocyte degeneration. -Lu Cai and Gary W. Miller.Many efficacious cancer treatments cause significant cardiac morbidity, yet biomarkers or functional indices of early damage, which would allow monitoring and intervention, are lacking. In this study, we have utilized a rat model of progressive doxorubicin (DOX)-induced cardiomyopathy, applying multiple approaches, including cardiac magnetic resonance imaging (MRI), to provide the most comprehensive characterization to date of the timecourse of serological, pathological, and functional events underlying this toxicity. Hannover Wistar rats were dosed with 1.25 mg/kg DOX weekly for 8 weeks followed by a 4 week off-dosing %26quot;recovery%26quot; period. Electron microscopy of the myocardium revealed subcellular degeneration and marked mitochondrial changes after a single dose. Histopathological analysis revealed progressive cardiomyocyte degeneration, hypertrophy/cytomegaly, and extensive vacuolation after two doses. Extensive replacement fibrosis (quantified by Sirius red staining) developed during the off-dosing period. Functional indices assessed by cardiac MRI (including left ventricular ejection fraction (LVEF), cardiac output, and E/A ratio) declined progressively, reaching statistical significance after two doses and culminating in %26quot;clinical%26quot; LV dysfunction by 12 weeks. Significant increases in peak myocardial contrast enhancement and serological cardiac troponin I (cTnI) emerged after eight doses, importantly preceding the LVEF decline to %26lt; 50%. Troponin I levels positively correlated with delayed and peak gadolinium contrast enhancement, histopathological grading, and diastolic dysfunction. In summary, subcellular cardiomyocyte degeneration was the earliest marker, followed by progressive functional decline and histopathological manifestations. Myocardial contrast enhancement and elevations in cTnI occurred later. However, all indices predated %26quot;clinical%26quot; LV dysfunction and thus warrant further evaluation as predictive biomarkers.
- 出版日期2014-7
