Novel approach to early detection of doxorubicin cardiotoxicity by gadolinium-enhanced cardiovascular magnetic resonance imaging in an experimental model
James C Lightfoot, Ralph B D'Agostino Jr, Craig A Hamilton, Jennifer Jordan, Frank M Torti, Nancy D Kock, James Jordan, Susan Workman, W Gregory Hundley, James C Lightfoot, Ralph B D'Agostino Jr, Craig A Hamilton, Jennifer Jordan, Frank M Torti, Nancy D Kock, James Jordan, Susan Workman, W Gregory Hundley
Abstract
Background: We sought to determine whether cardiovascular magnetic resonance measures of gadolinium (Gd) signal intensity (SI) within the left ventricular myocardium are associated with future changes in left ventricular ejection fraction (LVEF) after receipt of doxorubicin (DOX).
Methods and results: Forty Sprague-Dawley rats were divided into 3 groups scheduled to receive weekly intravenous doses of normal saline (n = 7), 1.5 mg/kg DOX (n = 19), or 2.5 mg/kg DOX (n = 14). Magnetic resonance determinations of LVEF and myocardial Gd-SI were performed before and at 2, 4, 7, and 10 weeks after DOX initiation. During treatment, animals were euthanized at different time points so that histopathologic assessments of the left ventricular myocardium could be obtained. Within-group analyses were performed to examine time-dependent relations between Gd-SI and primary events (deterioration in LVEF or an unanticipated death). Six of 19 animals receiving 1.5 mg/kg DOX and 10 of 14 animals receiving 2.5 mg/kg DOX experienced a primary event; no normal saline animals experienced a primary event. In animals with a primary event, histopathologic evidence of myocellular vacuolization occurred (P = 0.04), and the Gd-SI was elevated relative to baseline at the time of the event (P < 0.0001) and during the measurement period before the event (P = 0.0001). In all animals (including normal saline) without an event, measures of Gd-SI did not differ from baseline.
Conclusions: After DOX, low serial measures of Gd-SI predict an absence of an LVEF drop or unanticipated death. An increase in Gd-SI after DOX forecasts a subsequent drop in LVEF as well as histopathologic evidence of intracellular vacuolization consistent with DOX cardiotoxicity.
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References
- Hortobagyi GN. Treatment of breast cancer. N Eng J Med. 1998;339:974–984.
- Leandro J, Dyck J, Poppe D, Shore R, Airhart C, Greenberg M, Gilday D, Smallhorn J, Benson L. Cardiac dysfunction late after cardiotoxic therapy for childhood cancer. Am J Cardiol. 1994;74:1152–6.
- Gottdiener JS, Mathisen DJ, Borer JS, Bonow RO, Myers CE, Barr LH, Schwartz DE, Bacharach SL, Green MV, Rosenberg SA. Doxorubicin cardiotoxicity: assessment of late left ventricular dysfunction by radionuclide cineangiography. Ann Intern Med. 1981;94:430–5.
- Doyle JJ, Neugut AI, Jacobson JS, Grann VR, Hershman DL. Chemotherapy and cardiotoxicity in older breast cancer patients: A population-based study. J Clin Oncol. 2005;23:8597–605.
- DeVita V,T. 4th ed Lippincott; Philadelphia, Pennsylvania: 1993. Cancer Principles and Practice of Oncology.
- Kim RJ, Wu E, Rafael A, Chen EL, Parker MA, Simonetti O, Klocke FJ, Bonow RO, Judd RM. The use of contrast-enhanced magnetic resonance imaging to identify reversible myocardial dysfunction. N Engl J Med. 2000;343:1445–53.
- Hundley WG, Kizilbash AM, Afridi I, Franco F, Peshock RM, Grayburn PA. Administration of an intravenous perfluorocarbon contrast agent improves echocardiographic determination of left ventricular volumes and ejection fraction: comparison with cine magnetic resonance imaging. J Am Coll Cardiol. 1998;32:1426–32.
- Chuang ML, Hibberd MG, Salton CJ, Beaudin RA, Riley MF, Parker RA, Douglas PS, Manning WJ. Importance of imaging method over imaging modality in noninvasive determination of left ventricular volumes and ejection fraction: assessment by two- and three-dimensional echocardiography and magnetic resonance imaging. J Am Coll Cardiol. 2000;35:477–84.
- Hundley WG, Li HF, Willard JE, Landau C, Lange RA, Meshack BM, Hillis LD, Peshock RM. Magnetic resonance imaging assessment of the severity of mitral regurgitation. Comparison with invasive techniques. Circulation. 1995;92:1151–8.
- Martin ET, Fuisz AR, Pohost GM. Imaging cardiac structure and pump function. Cardiol Clin. 1998;16:135–60.
- Gerber BL, Rochitte CE, Bluemke DA, Melin JA, Crosille P, Becker LC, Lima JA. Relation between Gd-DTPA contrast enhancement and regional inotropic response in the periphery and center of myocardial infarction. Circulation. 2001;104:998–1004.
- Olson HM, Young DM, Prieur DJ, LeRoy AF, Reagan RL. Electrolyte and morphologic alterations of myocardium in adriamycin-treated rabbits. Am J Pathol. 1974;77:439–54.
- Choi KM, Kim RJ, Gubernikoff G, Vargas JD, Parker M, Judd RM. Transmural extent of acute myocardial infarction predicts long-term improvement in contractile function. Circulation. 2001;104:1101–7.
- Ferrans VJ. Overview of cardiac pathology in relation to anthracycline cardiotoxicity. Cancer Treat Rep. 1978;62:955–61.
- Messroghli DR, Niendorf T, Schulz-Menger J, Dietz R, Friedrich MG. T1 mapping in patients with acute myocardial infarction. J Cardiovasc Magn Reson. 2003;5:353–9.
- Thompson RC, Canby RC, Lojeski EW, Ratner AV, Fallon JT, Pohost GM. Adriamycin cardiotoxicity and proton nuclear magnetic resonance relaxation properties. Am Heart J. 1987;113:1444–9.
- Cottin Y, Ribuot C, Maupoil V, Godin D, Arnould L, Brunotte F, Rochette L. Early incidence of adriamycin treatment on cardiac parameters in the rat. Can J Physiol Pharmacol. 1994;72:140–5.
- Wassmuth R, Lentzsch S, Erdbruegger U, Schulz-Menger J, Doerken B, Dietz R, Friedrich MG. Subclinical cardiotoxic effects of anthracyclines as assessed by magnetic resonance imaging-a pilot study. Am Heart J. 2001;141:1007–13.
- Yilmaz S, Atessahin A, Sahna E, Karahan I, Ozer S. Protective effect of lycopene on adriamycin-induced cardiotoxicity and nephrotoxicity. Toxicology. 2006;218:164–71.
- Herman EH, Ferrans VJ. Animal models of anthracycline cardiotoxicity: Basic mechanisms and cardioprotective activity. Progress in Pediatric Cardiology. 1998;8:49–58.
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