Contractile Failure in Chronic Doxorubicin-induced Cardiomyopathy

doi:10.1006/jmcc.1997.0494

Journal of Molecular and Cellular Cardiology

Volume 29, Issue 10, October 1997, Pages 2631-2640

https://doi.org/10.1006/jmcc.1997.0494 Get rights and content

Abstract

The mechanisms for the progression of the anthracycline-induced cardiomyopathy to contractile failure has not been defined.In vitro, doxorubicin (DOX) appears to modify calcium-mediated excitation–contraction coupling, which depresses cardiac contractility. This study characterizes the onset of contractile failure associated with the development of DOX-induced cardiomyopathy. Rabbits were treated with DOX (1 mg/kg i.v. twice weekly, 12–18 doses; DOX-treated group) and compared with a pair-fed Control group infuse with saline vehicle. The severity of the cardiomyopathy was determined by numerically-scored histopathology. Myocardial contractility was determined in thin fiber bundles from right ventricular (RV) papillary muscles and left atria that were removed and mounted on a force transducer in oxygenated Krebs-bicarbonate buffer (pH=7.4 at 30°C) to record the amplitude (DT) and maximum rate (+dT/dt) of isometric tension. Myofibrillar and calcium loading properties were determined by the calcium and caffeine-activated tension responses respectively in chemically-permeabilized fibers. With the onset of the cardiomyopathy (score <2) DT at low frequency (0.5 Hz) was depressed (0.61±0.01 mN/mg;n=14) compared to Control (0.93±0.09 mN/mg;n=15). Contractility at higher rates (1 Hz) was not different in this DOX-treated and Control groups. Maximum calcium and caffeine-activated force and the pCa to half-maximum force of permeabilized fibers were comparable in DOX-treated and Control groups. The loss of contractility of the DOX-treated group was related to reduction in sacroplasmic reticulum calcium release channel density, as determined by B_maxfor³H-ryanodine binding in cardiac microsomal membrane fraction. Post-rest potentiation of contractility, as well as frequency-dependent (0.25–1.5 Hz) and post-extrasystolic potentiation of contractility were preserved in the DOX-treated group.In vitro, DOX depressed post-rest potentiation of contractility. Thus, the onset of contractile failure of the DOX-induced cardiomyopathy is characterized by effects consistent with disordered calcium-mediated excitation–contraction coupling and these effects are qualitatively different thanin vitroeffects of DOX.

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Cited by (44)

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Citation Excerpt :
Oncology drugs illustrate the broad range of molecules with cardiotoxicity liabilities. Small molecules such as doxorubicin (an anthracycline) are well known to induce a progressive cardiomyopathy (Chatterjee et al., 2010) and/or direct effects on calcium homeostasis regulation and function (Boucek et al., 1997; Olson et al., 2005). Beyond chemotherapeutic drugs, biologics such as trastuzumab (Herceptin; a monoclonal antibody) have also been associated with cardiac dysfunction and decreased contractility (McNeil, 1998; Yeh and Bickford, 2009) but the relevance of the rat model to assess cardiac safety of biologics is often limited due to limited binding affinity.
Cardiovascular effects are considered frequent during drug safety testing. This investigation aimed to characterize the pharmacological response of the conscious telemetered rat in vivo model to known cardiovascular active agents. These effects were analyzed using statistical analysis and cloud representation with marginal distribution curves for the contractility index and heart rate as to assess the effect relationship between cardiac variables. Arterial blood pressure, left ventricular pressure, electrocardiogram and body temperature were monitored. The application of data cloud with marginal distribution curves to heart rate and contractility index provided an interesting tactic during the interpretation of drug-induced changes particularly during selective time resolution (i.e. marginal distribution curves restricted to T_max). Taken together, the present data suggests that marginal distribution curves can be a valuable interpretation strategy when using the rat cardiovascular telemetry model to detect drug-induced cardiovascular effects. Marginal distribution curves could also be considered during the interpretation of other inter-dependent parameters in safety pharmacology studies.
Investigation into the cardiotoxic effects of doxorubicin on contractile function and the protection afforded by cyclosporin A using the work-loop assay
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Calcium in the cytosol is free to bind to cardiac troponin C, which initiates the contractile process of the cardiac cells (Stehle and Iorga, 2010). Previous studies have shown that treatment with doxorubicin can lead to changes affecting the contractile response and properties of cardiac myocytes (Boucek et al., 1997; de Beer et al., 2000). Although the main cause of doxorubicin-induced cardiotoxicity is thought to be due to build of reactive oxygen species, there is ample evidence to suggest a role for doxorubicin-induced imbalance of calcium homeostasis (Arai et al., 1998, 2000; Boucek et al., 1997; Dodd et al., 1993; Olson et al., 1988; Wang et al., 2001).
Doxorubicin is known to cause cardiotoxicity through multiple routes including the build-up of reactive oxygen species and disruption of the calcium homeostasis in cardiac myocytes, but the effect of drug treatment on the associated biomechanics of cardiac injury remains unclear. Detecting and understanding the adverse effects of drugs on cardiac contractility is becoming a priority in non-clinical safety pharmacology assessment. The work-loop technique enables the assessment of force–length work-loop contractions, which mimic those of the pressure–volume work-loops experienced by the heart in vivo.
During this study we evaluated whether the work-loop technique could potentially provide improved insight into the biomechanics associated with drug-induced cardiac dysfunction. In order to do this we investigated the cardiotoxic effects of doxorubicin and characterised the protection afforded by the co-administration of cyclosporin A (CsA).
This study provides detailed biomechanical in vitro insight into the cardiac dysfunction associated with Doxorubicin treatment, including reduction in peak force, force during shortening and power output. These effects were significantly abrogated in doxorubicin-CsA co-treatment studies.
Closely mimicking the in vivo pressure–volume muscle mechanics, this assay provides a quick and easy technique to gain a better understanding of the detailed biomechanics of drug-induced cardiac dysfunction.
Enalaprilat increases PPARβ/δ expression, without influence on PPARα and PPARγ, and modulate cardiac function in sub-acute model of daunorubicin-induced cardiomyopathy
2013, European Journal of Pharmacology
Citation Excerpt :
Importantly, all biochemical parameters remained unaffected by co-treatment of enalaprilat. Chronic anthracycline-induced cardiomyopathy is known to depress the myocardial contractility (Boucek et al., 1997). To address this issue in sub-acute stage we measured a cell shortening of isolated cardiomyocytes.
Anthracycline therapy is limited by a cardiotoxicity that may eventually lead to chronic heart failure which is thought to be prevented by ACE inhibitors (ACEi). However, the protective effect of ACEi in early stages of this specific injury remains elusive. Activated nuclear transcription factors peroxisome proliferator-activated receptors (PPAR) regulate cellular metabolism, but their involvement in anthracycline cardiomyopathy has not been investigated yet. For this purpose, Wistar rats were administered with daunorubicin (i.p., 3 mg/kg, in 48 h intervals) or co-administered with daunorubicine and enalaprilat (i.p., 5 mg/kg in 12 h intervals). Control animals received vehicle. Left ventricular function was measured invasively under anesthesia. Cell-shortening was measured by videomicroscopy in isolated cardiomyocytes. Expression of PPARs mRNA in cardiac tissue was measured by Real-Time PCR. Although the hemodynamic parameters of daunorubicin-treated rats remained altered upon ACEi co-administration, ACEi normalized daunorubicin-induced QT prolongation. On cellular level, ACEi normalized altered basal and isoproterenol-stimulated cardiac cell shortening in daunorubicine-treated group. Moreover, anthracycline administration significantly up-regulated heart PPARα mRNA and its expression remained increased after ACEi co-administration. On the other hand, the expression of cardiac PPARβ/δ was not altered in anthracycline-treated animals, whereas co-administration of ACEi increased its expression. Conclusively, effect of ACEi can be already detected in sub-acute phase of anthracycline-induced cardiotoxicity. Altered expression of heart PPARs may suggest these nuclear receptors as a novel target in anthracycline cardiomyopathy.
The modulatory effect of lithium on doxorubicin-induced cardiotoxicity in rat
2010, European Journal of Pharmacology
Doxorubicin is an effective anti-neoplastic agent application of which has been limited due to its cardiotoxic side effects. Lithium is widely used for treatment of neuropsychiatric symptoms in bipolar disorders. Lines of evidence point to the cardioprotective effects of lithium against heart injuries. The current study aims to investigate the protective effects of lithium against doxorubicin-induced cardiotoxicity in rat model. Male Wistar rats were treated with 300 mg/kg p.o. lithium in their water supply and/or doxorubicin (1.25 mg/kg, i.p.), four times per week for four weeks. General conditions, mortality rate and body weight were measured during the experiment. At the end of the experiment, ECG parameters and papillary muscle contractility force were assessed. Serum samples were collected to measure the lithium concentrations as well as cardiac troponin T level (cTNT, a biomarker of cardiac injury). In addition, heart weight was measured and the cardiac tissues were evaluated both macroscopically and microscopically. The results of the present study indicate that lithium might diminish mortality rate, general toxicity (edema, alopecia and cachexia), improve S_α–T segment and QT interval prolongations as well as heart contractility force. Application of lithium could inhibit the increase of cardiac troponin T and formation of myocardial lesions. These outcomes show the protective effects of lithium against doxorubicin-induced cardiotoxicity in rat. On the whole, the results of the present study suggest that lithium might be considered as a new indication for the prevention of doxorubicin-induced cardiotoxicity.
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^☆: Please address all correspondence to: Robert J. Boucek Jr, University of South Florida College of Medicine, Division of Pediatric Cardiology, 880 Sixth St. So., St Petersburg, FL 33701-4827, USA.

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Regular ArticleContractile Failure in Chronic Doxorubicin-induced Cardiomyopathy☆

Abstract

Regular Article
Contractile Failure in Chronic Doxorubicin-induced Cardiomyopathy☆