Reduced in vivo high-energy phosphates precede Adriamycin-induced cardiac dysfunction

Abstract

is an established, life-saving antineoplastic agent, the use of which is often limited by cardiotoxicity. ADR-induced cardiomyopathy is often accompanied by depressed myocardial high-energy phosphate (HEP) metabolism. Impaired HEP metabolism has been suggested as a potential mechanism of ADR cardiomyopathy, in which case the bioenergetic decline should precede left ventricular (LV) dysfunction. We tested the hypothesis that murine cardiac energetics decrease before LV dysfunction following ADR (5 mg/kg ip, weekly, 5 injections) in the mouse. As a result, the mean myocardial phosphocreatine-to-ATP ratio (PCr/ATP) by spatially localized 31 P magnetic resonance spectroscopy decreased at 6 wk after first ADR injection (1.79 Ϯ 0.18 vs. 1.39 Ϯ 0.30, means Ϯ SD, control vs. ADR, respectively, P Ͻ 0.05) when indices of systolic and diastolic function by magnetic resonance imaging were unchanged from control values. At 8 wk, lower PCr/ATP was accompanied by a reduction in ejection fraction (67.3 Ϯ 3.9 vs. 55.9 Ϯ 4.2%, control vs. ADR, respectively, P Ͻ 0.002) and peak filling rate (0.56 Ϯ 0.12 vs. 0.30 Ϯ 0.13 l/ms, control vs. ADR, respectively, P Ͻ 0.01). PCr/ATP correlated with peak filling rate and ejection fraction, suggesting a relationship between cardiac energetics and both LV systolic and diastolic dysfunction. In conclusion, myocardial in vivo HEP metabolism is impaired following ADR administration, occurring before systolic or diastolic abnormalities and in proportion to the extent of eventual contractile abnormalities. These observations are consistent with the hypothesis that impaired HEP metabolism contributes to ADRinduced myocardial dysfunction. magnetic resonance imaging; 31 P spectroscopy ADRIAMYCIN (ADR) represents one of the most potent and extensively used anticancer drugs (46); however, its antineoplastic use can be compromised in practice by cardiotoxic side effects (17,35). Although ADR-induced cardiotoxicity is usually subclinical, symptoms of heart failure (HF) can develop acutely during therapy (18, 33) or chronically (25,34). In general, HF with systolic and diastolic abnormalities develops in 18 -36% of patients receiving a cumulative ADR dose of 250 -601 mg/m 2 (17, 35). A spectrum of cardiac metabolic (21, 39) and morphological (2, 6) abnormalities occurs following ADR treatment, but it is unclear which, if any of these, causes ADR cardiotoxicity. One metabolic abnormality that may contribute mechanistically to ADR cardiotoxicity is impaired creatine kinase (CK) energetics.The CK reaction serves as the prime cardiac energy reservoir, quickly and reversibly converting adenosine diphosphate and phosphocreatine (PCr) to ATP and creatine (15,44), where the PCr-to-ATP ratio (PCr/ATP) is commonly used to characterize a high-energy phosphate metabolism. An inhibition of CK impairs cardiac function or contractile reserve in normal hearts (13, 37), and an altered CK metabolism is observed in both experimental and human HF (14,19,23,32,47). In particular, an altered in vitro and in vivo CK energetics ...

Structural correlates of the creatine transporter function regulation: the undiscovered country

“…Studies performed in humans and animal models of cardiac failure demonstrate that a decrease in Cr levels antedates a decrease in ATP levels, the latter which is a hallmark of advanced cardiac failure (Maslov et al 2010;Neubauer 2007).…”

Creatine Kinase-Overexpression Improves Myocardial Energetics, Contractile Dysfunction and Survival in Murine Doxorubicin Cardiotoxicity

“…DOX also inhibits the creatine kinase (CK) reaction, the prime myocardial energy reserve reaction which rapidly and reversibly exchanges a phosphoryl group between ATP and PCr [23-26]. Following chronic DOX administration in a murine model, myocardial energetic changes, indexed by a reduced PCr/ATP ratio, occur relatively early and precede the appearance of contractile dysfunction and predict the subsequent degree of contractile abnormalities [27], suggesting, but not proving, a causal role for impaired energy metabolism in subsequent DOX-induced cardiac dysfunction.…”

Heat Shock Protein 25-Enriched Plasma Transfusion Preconditions the Heart against Doxorubicin-Induced Dilated Cardiomyopathy in Mice

“…Even though several pathways such as mammalian target of rapamycin inhibition (Zhu et al, 2009), phosphodiesterase-5 inhibition (Fisher et al, 2005), reduction in circulating progenitor cells (Huang et al, 2010), activation of Toll-like receptors (Nozaki et al, 2004;Riad et al, 2008), impaired metabolism (Maslov et al, 2010), and triggering autophagy (Kobayashi et al, 2010) have been identified, the precise mechanism of Dox-induced cardiotoxicity still remains unclear. We recently identified a novel pathway: that heat shock factor (HSF-1) is activated because of Dox-induced oxidative stress, and this activation enhanced the expression of heat shock proteins including Hsp25 in Dox-treated mouse hearts (Vedam et al, 2010).…”