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The Oncologist, Vol. 12, No. 9, 1124-1133, September 2007; doi:10.1634/theoncologist.12-9-1124
© 2007 AlphaMed Press

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 Early Epirubicin-Induced Myocardial Dysfunction Revealed by Serial Tissue D...
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Prevention

Early Epirubicin-Induced Myocardial Dysfunction Revealed by Serial Tissue Doppler Echocardiography: Correlation with Inflammatory and Oxidative Stress Markers

Giuseppe Mercuroa, Christian Cadeddua, Alessandra Pirasa, Mariele Dessìb, Clelia Madeddub, Martino Deiddaa, Roberto Serpeb, Elena Massab, Giovanni Mantovanib

Department of aCardiovascular and Neurological Sciences and bMedical Oncology, University of Cagliari, Cagliari, Italy

Key Words. Epirubicin • Myocardial dysfunction • TDI • Inflammatory markers • Oxidative stress markers

Correspondence: Giovanni Mantovani, M.D., Cattedra e Divisione di Oncologia Medica, Università di Cagliari, Policlinico Universitario, Presidio di Monserrato, Strada Statale 554, Km 4.500, 09042 Monserrato (Cagliari), Italy. Telephone: 0039-070-5109-6253; Fax: 0039-070-5109-6253; e-mail: mantovan{at}pacs.unica.it

Received March 13, 2007; accepted for publication July 19, 2007.

Disclosure: No potential conflicts of interest were reported by the authors, planners, reviewers, or staff managers of this article.


   Learning Objectives
Top
 Learning Objectives
Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 Acknowledgments
 References
 
After completing this course, the reader will be able to:

  1. Interpret modern techniques to detect early instrumental and biochemical signs of epirubicin-induced myocardial dysfunction.
  2. Evaluate the correlation between instrumental signs and biochemical/biological variables with the aim of defining more exhaustively the clinical effects of drugs.
  3. Discuss the effectiveness and safety of an important antineoplastic drug such as epirubicin.

Access and take the CME test online and receive 1 AMA PRA Category 1 CreditTM at CME.TheOncologist.com


   ABSTRACT
Top
 Learning Objectives
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 Acknowledgments
 References
 
A phase II, open, nonrandomized trial was carried out in a group of epirubicin-treated patients with cancer at different sites with the aim of detecting early preclinical changes that are predictive of the risk for heart failure. All patients underwent conventional echocardiography, as well as tissue Doppler imaging (TDI) with strain ({Sigma}) and strain rate (SR), a very accurate technique for detecting minimal changes in cardiac left ventricular (LV) function. Moreover, echocardiographic changes identified during epirubicin treatment were compared with those of a series of biochemical markers of both myocardial damage and inflammation/oxidative stress. Sixteen patients (male-to-female ratio, 3:13; mean age ± standard deviation, 56 ±3 years; range, 27–75 years) with histologically confirmed tumors at different sites, scheduled to be treated with an epirubicin-based chemotherapy regimen, were enrolled in the study. A significant impairment in systolic LV function was observed after 200 mg/m2 of epirubicin; this was shown by a lower SR peak compared with baseline (1.82 ± 0.57/second versus 1.45 ± 0.44/second), whereas {Sigma} remained unchanged. The following significant changes in LV diastolic function occurred only after 300 mg/m2 of epirubicin: a decrease in conventional early/late diastolic (E/A) velocities (1.16 ± 0.31 versus 0.93 ± 0.24) and a reduction in both the Em wave in the basal portion of the interventricular septum (8.86 ± 1.73 cm/second versus 7.51 ± 2.30 cm/second) and in the Em/Am ratio (1.09 ± 0.51 versus 0.83 ± 0.51), as measured using the TDI technique. No significant changes in LV ejection fraction were observed. Baseline values of brain natriuretic peptide, troponin I, myoglobin, and creatine kinase-myocardial subfraction were within the normal range and no significant changes were observed throughout the study. Levels of interleukin (IL)-6 and its soluble receptor (sIL-6R) and reactive oxygen species increased significantly, whereas glutathione peroxidase (GPx) levels decreased significantly, after 200 mg/m2 of epirubicin. Significant correlations between the reduction in the SR peak ({Delta}SR) after 200 mg/m2 of epirubicin and the increase in IL-6 and ROS and decrease in GPx were observed. The multiple regression analysis showed that the only independent predictive variable for {Delta}SR was ROS level. Our data show that: (a) subtle cardiac abnormalities may occur at epirubicin doses significantly below those known to be potentially clinically harmful and (b) the earliest myocardial impairment affects LV systolic rather than diastolic function. Early contractility impairment during epirubicin treatment was associated with high levels of ROS and markers of inflammation. The clinical meaningfulness of our findings warrants further investigations in a larger number of patients for a longer period of follow-up.


   INTRODUCTION
Top
 Learning Objectives
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 Acknowledgments
 References
 
Anthracycline antibiotics are potent antitumor agents used in a wide spectrum of malignancies both in the adjuvant and metastatic settings. The successful use of anthracyclines is, however, limited by the risk for developing life-threatening congestive heart failure, whose structural-functional left ventricular (LV) changes and mortality rate resemble those produced by idiopathic cardiomyopathy [1].

Anthracycline-induced cardiotoxicity is potentially fatal and can significantly impair patient quality of life. It increases exponentially with cumulative dose, and is further augmented by the addition of other drugs in combination regimens (i.e., trastuzumab in breast cancer patients). The susceptibility of patients to anthracycline-induced cardiotoxicity varies widely, increasing significantly with advancing age [2].

The two most commonly used anthracyclines are doxorubicin and epirubicin, which, at similar doses, provide similar response rates; however, their toxicity profiles differ somewhat. The equimolar dose ratio of doxorubicin to epirubicin for cardiotoxicity is 1:1.7–2.0 [3]. A recent meta-analysis showed no evidence for a significant difference between epirubicin and doxorubicin in the occurrence of clinical heart failure [4]; however, there is some suggestion of a lower rate of this complication in patients treated with epirubicin [5].

Epirubicin is used in an extensive range of solid and hematologic tumors such as breast cancer [6], sarcomas, lymphomas, and leukemias.

Evidence that 10%–26% of patients administered cumulative anthracycline doses above those recommended (>450 mg/m2 for doxorubicin and >900 mg/m2 for epirubicin) develop heart failure has compelled clinicians to set empirical dose limits, above which the cardiotoxic risk is deemed unacceptable. However, anthracycline cardiotoxicity does not develop abruptly, but it results from slowly progressive impairment in cardiac function [7].

A major hypothesis regarding the pathophysiology of anthracycline-induced cardiotoxicity is that cardiac damage is caused by oxidative stress through the generation of reactive oxygen species (ROS). Reduction of doxorubicin by several NADPH-dependent microsomial enzymes results in ROS generation. Cardiac cells, by means of a mitochondrial NADH dehydrogenase, which is absent in other types of cells, generate very high levels of free radicals in the presence of doxorubicin [8]. Moreover, it has been suggested that proinflammatory cytokines may contribute to the pathophysiology of dilatative cardiomyopathy [9]. Interleukin (IL)-6 and its soluble receptor (sIL-6R) are elevated in patients with heart failure, particularly those with cardiac cachexia and edematous decompensation [10]. Previous studies have consistently shown a direct relationship between levels of these cytokines and an impairment in functional New York Heart Association classes of heart failure [11].

The early detection of anthracycline-induced cardiotoxicity is crucial because it may be useful in the prevention of heart failure. Currently, the most commonly used methods to detect anthracycline-induced cardiotoxicity are the evaluation of functional parameters including the left ventricular ejection fraction (LVEF) and fractional shortening by echocardiography (ECG) and radionuclide imaging. Unfortunately, impairment in these parameters is often detected only after considerable cell loss has taken place [12]. For detection and prevention of cardiotoxicity at an earlier phase, the use of biochemical markers, such as brain natriuretic peptide (BNP), endothelin-1, as well as cardiac troponin T and troponin I (TnI), have also been investigated [13–15]. Indeed, BNP levels increased significantly during high doses of anthracycline-based chemotherapy [16] and were correlated with diastolic, more than systolic, dysfunction [17]. Also TnI, creatine kinase-myocardial subfraction (CK-MB), and myoglobin (Myo) are relevant markers of myocardial damage and were found to be associated with systolic and diastolic functional impairment in patients undergoing anthracycline treatment [14].

Tissue Doppler imaging (TDI) allows measurement of diastolic and systolic velocities of the ventricular walls and of the mitral annulus. In the evaluation of LV diastolic performance, TDI is more reliable than conventional Doppler, because it is less influenced by loading conditions. TDI may also demonstrate changes in regional function, which are not revealed by global LVEF, thus improving the evaluation of cardiac function changes during anthracycline therapy [18]. An ultrasonic method of quantifying regional deformation based on principles derived from mechanical engineering called strain ({Sigma}) and strain rate (SR) imaging was introduced recently. {Sigma} and SR may be more accurate than TDI velocities alone in detecting early changes in systolic function because they tend to be less affected by translational motion. SR was demonstrated to be a reliable index of LV contractility [19]. Thus, this newly developed technique may improve the evaluation of cardiac function changes during anthracycline therapy, enabling either the timely interruption of anthracycline-based therapy or, alternatively, the initiation of specific potentially cardioprotective treatment.

The aim of the present study was to detect early preclinical changes that are predictive of the risk for heart failure in a group of epirubicin-treated patients with cancer at different sites by means of TDI, {Sigma}, and SR imaging. Additionally, we compared ECG changes during epirubicin treatment with those of biochemical markers of both myocardial-endothelial damage and inflammation/oxidative stress.


   PATIENTS AND METHODS
Top
 Learning Objectives
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 Acknowledgments
 References
 
The study was a phase II, open, nonrandomized trial; it was approved by the Institutional Ethics Committee (Policlinico Universitario, University of Cagliari) and written informed consent was obtained from all included patients. The study was performed in accordance with the Declaration of Helsinki.

Inclusion criteria were the following: age 18–70 years with a histologically confirmed diagnosis of cancer at any site, previously untreated, and candidates for treatment with an epirubicin-based chemotherapy regimen according to international standardized protocols for their specific tumors; an ECG LVEF value ≥55%; an Eastern Cooperative Oncology Group (ECOG) performance status score of 0–2 [20]; and normal hepatic (bilirubin ≤1.5 mg/dl) and renal (creatinine ≤2.0 mg/dl) function. Patients with a history of cardiac disease, hypertension, or diabetes mellitus, and/or who were previously treated with mediastinal irradiation were excluded from the study.

At enrollment, prior to starting chemotherapy treatment, all patients underwent a physical examination, blood pressure measurement, 12-lead ECG and ECG analysis (conventional and TDI technique). In all patients, a blood sample was obtained from venipuncture of the antecubital vein at 8 a.m., after overnight fasting. Blood samples were collected in tubes with clot activating factor and centrifuged immediately after collection, and serum was stored at –20°C until assayed. In each serum sample, the levels of the proinflammatory cytokines IL-6, sIL-6R, tumor necrosis factor (TNF)-{alpha} and its soluble type 1 receptor (sTNF-{alpha}R1)- and IL-1ß were analyzed. ROS and the antioxidant enzymes glutathione peroxidase (GPx) and superoxide dismutase (SOD) were assessed on fresh heparinized blood samples. A blood sample collected in an EDTA tube was immediately processed for assessment of biochemical markers of myocardial-endothelial damage (TnI, CK-MB, BNP, and Myo).

The instrumental and laboratory variables were assessed at baseline and at 24 hours and 7 days after reaching an epirubicin dose of 100, 200, 300, and 400 mg/m2. Reported doses of epirubicin are always cumulative.

Conventional ECG and TDI
ECG images were recorded using a commercially available system equipped with TDI and {Sigma} and SR imaging (Toshiba APLIO CV ultrasound system-SSA 770A/CV; Toshiba Corp., Tochigi, Japan). LVEF was obtained from the apical four- and two-chamber views according to Simpson's rule and was considered abnormal under 55%. We performed a pulsed wave Doppler examination of the LV inflow from the four-chamber view with the sample volume placed between the mitral leaflet tips, and the early (E) and late diastolic (A) peak velocities and E deceleration time were measured and then the E/A ratio was derived [21]. We evaluated longitudinal function using pulsed TDI at the mitral annulus, placing the sample volume in the basal segment of the interventricular septum (IVS) from the apical four-chamber view: peak velocities in systole (Sm) and early (Em) and late (Am) diastole were measured. For more accurate measurements, the TDI curves were obtained from raw data analysis. The longitudinal function of the LV was evaluated from raw data, and the {Sigma} and SR of the myocardium in the IVS were also quantified. The same experienced echocardiographer, unaware of the patient's clinical status and therapeutic regimens administered, carried out all examinations. A simultaneous ECG tracing was also obtained. To reduce interobserver variability, all ECG data were randomly read by a second, blinded, experienced observer, and an average value for each measurement was calculated. Reproducibility of TDI parameters in our laboratory has been previously documented [22].

Assessment of Biochemical Markers of Myocardial-Endothelial Damage
Plasma levels of the myocardial functional and structural damage markers BNP, TnI, Myo, and CK-MB were assessed at the above scheduled epirubicin doses using noncompetitive immunofluorimetric tests with high specificity—Triage® BNP Test (Biosite Inc., San Diego, CA) for BNP (normal value, <100 pg/ml; sensitivity, 5–5,000 pg/ml) and Triage® Cardiac Panel (Biosite Inc.) for TnI, Myo, and CK-MB (normal values: Myo, <170 ng/ml; sensitivity, 5–500 ng/ml; CK-MB, <10 ng/ml; sensitivity, 1–80 ng/ml; TnI, <0.1 ng/ml; sensitivity, 0.05–30 ng/ml). The quantitative analysis was performed using a fluorescence gauge Triage MeterPlus (Biosite Inc.).

Assessment of Inflammatory and Oxidative Stress Markers
Serum levels of IL-6, sIL-6R, TNF-{alpha}, sTNF-{alpha}R1, and IL-1ß were determined by enzyme-linked immunosorbent assay (Immunotech, Marseille, France). Results are expressed in pg/ml for IL-6, TNF-{alpha}, and IL-1ß and in ng/ml for sIL-6R and sTNF-{alpha}R1. Blood levels of ROS were determined using the free oxygen radicals test (FORt)—the radical species produced by the reaction that are directly proportional to the quantity of lipid peroxides present in the sample interact with an additive (phenylenediamine derivative) that forms a radical molecule evaluable by spectrophotometer at 505 nm (Form CR 2000, Callegari, Parma, Italy). Results are expressed as FORT units, where 1 FORT unit corresponds to 0.26 mg/l of H2O2. The erythrocyte antioxidant enzymes GPx and SOD were measured by photometer using a commercially available kit (Ransod, Randox Lab, Crumlin, United Kingdom) and expressed as U/l and U/ml, respectively.

Statistical Analysis
Data are reported as mean ± standard deviation (SD). Differences between values measured at baseline and at different epirubicin doses were assessed by the Student's two-tailed t-test for paired data. Correlation between instrumental (SR peak) and laboratory variables was assessed by Pearson's t-test (or Spearman's t-test for nonparametric variables). Significant relationships were then examined by multivariate linear regression analysis against the SR peak (dependent variable). p-values were considered significant when ≤.05.


   RESULTS
Top
 Learning Objectives
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 Acknowledgments
 References
 
Patients
From May 2005 to October 2006, 16 patients (male-to-female ratio, 3:13; mean age ± SD, 56 ± 3 years; range, 27–75 years) with histologically confirmed tumors at different sites scheduled to be treated with an epirubicin-based chemotherapy regimen were enrolled. The majority of patients (13 of 16 patients) had an ECOG performance status score of 0. Patient clinical characteristics are reported in Table 1. In accordance with the eligibility criteria, enrolled patients underwent chemotherapy treatment with epirubicin in combination with other antineoplastic drugs. The regimens used and doses administered are reported in Table 2. All patients completed the planned treatment. Thirteen of 16 patients reached a cumulative epirubicin dose of 400 mg/m2 and three patients reached a cumulative epirubicin dose of 300 mg/m2. Overall, the treatment was well tolerated. The main toxicities observed were grade 3–4 neutropenia (one patient) at the 400-mg/m2 epirubicin dose, anemia (two patients) at the 300-mg/m2 epirubicin dose, and nausea (five patients) at the 200-mg/m2 epirubicin dose. One patient with carcinoma of the endometrium suffered a massive pulmonary embolism 1 week after reaching the 300-mg/m2 dose of epirubicin, and she was immediately treated with anticoagulant therapy (i.v. heparin followed by an oral anticoagulant). The patient had already completed epirubicin treatment and thereafter she recovered.


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  		Table 1. Patient clinical characteristics

 


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  		Table 2. Chemotherapy regimens administered

 
In March 2007, 13 patients were still alive, whereas three patients died 3 months after completion of epirubicin treatment, as a result of disease progression.

ECG Monitoring
This test, carried out throughout the treatment, showed normal ECG morphology in 14 patients and widespread and unspecified modifications during the ventricular repolarization phase concomitant with the 300-mg/m2 epirubicin dose in two patients, with complete normalization 24 hours after drug administration.

Conventional ECG and TDI
A significant impairment in systolic LV function was observed after 200 mg/m2 of epirubicin. This abnormality was shown by a lower SR peak compared with baseline (1.82 ± 0.57/second versus 1.45 ± 0.44/second; p < .001); the SR peak did not decrease further after 300 mg/m2 of epirubicin (Fig. 1). The {Sigma} peak was not different after epirubicin compared with baseline (21.15 ± 5.43% versus 21.45 ± 8.18%; p = .84). The other TDI parameters and all conventional ECG variables were not appreciably different after treatment with 200 mg/m2 of epirubicin, when compared with the respective values at enrollment (Table 3).


Figure 1
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  		Figure 1. Strain pate peak (per second) at different epirubicin doses (mg/m2).

 


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  		Table 3. Variables of systolic/diastolic function with conventional and TDI ECG

 
Regarding diastolic function, the following significant changes occurred 1 week after the 300-mg/m2 dose of epirubicin: a decrease in E/A at conventional ECG (measured with pulsed wave Doppler of the transmitralic flow) (1.16 ± 0.31 versus 0.93 ± 0.24; p = .02); and a reduction in Em wave measured in the basal portion of the IVS (8.86 ± 1.73 cm/second versus 7.51 ± 2.30 cm/second; p = .03) and a reduction in the Em/Am ratio (1.09 ± 0.51 versus 0.83 ± 0.51; p = .002) with the TDI technique. No significant differences in LVEF were observed at the epirubicin doses of 200 mg/m2 (67 ± 6%), 300 mg/m2 (65 ± 5%), and 400 mg/m2 (66 ± 6%) as compared with baseline (65 ± 5%) (Table 3).

Biochemical Markers of Myocardial-Endothelial Damage
Baseline values of BNP, TnI, CK-MB, and Myo were within the normal range (data not shown). No significant changes were observed throughout the study.

Inflammatory and Oxidative Stress Markers
Serum levels of IL-6 and sIL-6R increased significantly (p = .05 and p = .0259, respectively), whereas serum levels of TNF-{alpha}, sTNF-{alpha}R1, and IL-1ß did not change significantly after 200 mg/m2 of epirubicin. ROS levels increased significantly (p = .04), whereas GPx levels decreased (p < .0001) after 200 mg/m2 of epirubicin. No significant changes were observed after 300 mg/m2 and 400 mg/m2 of epirubicin, except for sIL-6R, which further increased (Table 4).


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  		Table 4. Assessment of inflammatory cytokines and oxidative stress markers at baseline and after epirubicin cumulative dose of 100, 200, 300, and 400 mg/m2

 
Correlations Between Changes in SR Peak and Inflammatory and Oxidative Stress Markers
We found significant correlations between {Delta}SR (calculated by subtracting the value after 200 mg/m2 of epirubicin from the baseline value) and an increase in IL-6 and ROS and a decrease in GPx (Table 5). The multiple regression analysis showed that the only independent predictive variable of {Delta}SR was ROS (p = .0167).


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  		Table 5. Correlations between {Delta}SR and inflammatory/oxidative stress markers

 

   DISCUSSION
Top
 Learning Objectives
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
Acknowledgments
 References
 
Our data show an impairment in cardiac contractility as the earliest sign of cardiotoxicity induced by epirubicin, a potent chemotherapeutic agent used in a wide spectrum of malignancies. This event occurred, unexpectedly, at the 200 mg/m2 level of epirubicin, a dose believed to be very low by oncologists [23]. This early cardiac abnormality was not associated with significant increases in biochemical markers such as BNP and cardiac necrosis enzymes. A reduction in the SR peak, currently regarded as the earliest sign of subclinical cardiotoxicity and associated with low rates of cardiotoxicity by oncologists, preceded the signs of diastolic dysfunction; the latter were observed, both with conventional ECG examination and TDI, only after administration of 300 mg/m2 of epirubicin. In accordance with these findings, a significant increase in the inflammatory and oxidative stress markers together with a significant decrease in the antioxidant enzymatic potential was observed at the same epirubicin dose of 200 mg/m2.

Studies have reported that >50% of patients administered cumulative epirubicin doses above those recommended (>900 mg/m2) experience measurable functional impairment months to years after the end of therapy and that 10%–26% of them suffer congestive heart failure [2]. The relative risk is even higher in children, because of the increasing number of long-term survivors and high probability of developing long-term cardiac damage [24], and in the elderly [2].

A prospective, long-term, observational study illustrated a dose-dependent evolution of the cardiotoxic effect of doxorubicin leading to the development of cardiomyopathy [25]. More precisely, recent evidence demonstrated that a "subcritical dose" (356–388 mg/m2) accounted for LV diastolic dysfunction and that at a cumulative dose of 533 mg/m2 anthracycline-induced dilatative cardiomyopathy develops, with a clinical pattern of heart failure including systolic and diastolic dysfunction [26].

The results of the present study provide further evidence that a subtle impairment in cardiac function during the systolic phase may be detected in epirubicin-treated patients long before clinical manifestation of congestive heart failure is seen [23], and they additionally show that measurable systolic dysfunction may appear even at a dose level of 200 mg/m2 of epirubicin, a dose so far not regarded as sufficient to induce clinically meaningful cardiac injury.

As an additional finding, we documented the progression through which acute cardiac injury induced by epirubicin becomes manifest. Actually, the TDI technique allowed us to recognize that, at the lowest dose level of the drug, the earliest initial dysfunction concerns the inotropic state of the myocardium; the diastolic function is involved in a subsequent functional step. Finally, we documented that the global myocardial (dys)function assessed at dose of 200 mg/m2 remained unmodified throughout the entire period of cumulative drug administration. It is important to note that conventional ECG, which we used in comparison with TDI, {Sigma}, and SR, did not show any significant derangement in systolic indexes of our patients, thus explaining the negative or unconvincing results acquired in previous studies carried out with this technique.

BNP acts as a two-way natriuretic system in the regulation of blood pressure and fluid balance [27]. The heart is the main source of circulating BNP, which is released to counteract the increase in ventricular volume and pressure overload [28]. BNP is a hormonal sensitive marker of systolic and diastolic ventricular function [29], and its concentration is strictly correlated with the seriousness of the signs and symptoms of heart failure [30, 31]. Concordant studies suggest that BNP is useful in the detection of subclinical LV dysfunction in patients receiving doxorubicin therapy and that it is more closely associated with impairment in LV diastolic filling than LV systolic function [14, 17]. In the present study, plasma BNP values were not modified by epirubicin administration at a cumulative dose within the recommended range. This observation suggests that the observed cardiac TDI dysfunction was not induced by an early altered loading condition, but was strictly dependent on the myocardial functional status.

The assessment of cardiac Tn represents the gold standard test for myocardial cell necrosis [32]. Changes in membrane permeability and subsequent cardiomyocyte destruction are the final common steps of cell damage. Thus, Tn is currently being used as a very sensitive biomarker of drug-induced cardiac toxicity, and mild increases in Tn above the detection limits of the currently available assays confer a poor prognosis and predict rapid progression of cardiovascular disease [33, 34]. In the present study, serum levels of TnI did not show significant differences after epirubicin administration in comparison with baseline values. This finding suggests that the myocardial dysfunction revealed in our patients by TDI and SR is not the result of cell disruption sufficient to elevate troponin levels.

The cardiotoxic effect of epirubicin leading to the development of dilatative cardiomyopathy has been attributed to irreversible damage of heart cell mitochondria, which express a unique enzyme on the inner membrane able to reduce anthracyclines to their semiquinone derivatives. This specific cellular pathway results in severe oxidative stress, disruption of mitochondrial energetic machinery, and irreversible damage of mitochondrial DNA. The compromised regenerative capability of the organelles ultimately leads to apoptosis or necrosis of myocytes [8]. It has been shown that ROS and nitric oxide species might interact to develop highly toxic products, which negatively affect cellular calcium and iron homeostasis [35]. Our data clearly support the involvement of oxidative stress in the early, functional impairment of cardiac contractility. Moreover, increasing evidence suggests a primary role for inflammatory factors as a clinically useful predictor of cardiovascular morbidity and mortality [36]. Specific cytokines, such as IL-6 and TNF-{alpha}, are sensitive systemic markers of tissue damage, predictive of the development of unstable cardiovascular diseases [37]. A correlation between apoptosis of cardiomyocytes in the failing human heart and an increase in the plasma concentration of IL-6 and sIL-6R, as well as TNF-{alpha} and sTNF-{alpha}R1 has been found [10, 38]. Recently, it was reported that a negative inotropic effect induced by inflammatory cytokines is involved in the pathophysiology of human dilatative cardiomyopathy [9].

In several of our previous studies, carried out on different populations of cancer patients, high levels of inflammatory cytokines and oxidative stress markers correlated with an advanced stage of disease, poor ECOG performance status, and symptoms such as cachexia and fatigue [39–42], regardless of heart disease. Half of the patients enrolled in the present study had early-stage cancer and no patient had cardiovascular disease. Baseline values of inflammatory and oxidative stress markers were almost within the range of normal individuals, and therefore their subsequent changes could be attributed to the chemotherapy, that is, epirubicin-based treatment, or, alternatively, to disease progression; however, the latter was not the case. This finding suggests that inflammatory and oxidative stress parameters may also have a role as useful markers of early cardiotoxicity: their sensitivity may be considered comparable with that of TDI measurements.

In the present study, the significant increase in IL-6 and sIL-6R at a level of epirubicin as low as 200 mg/m2 appears as a biological equivalent of the TDI evidence of initial cell deterioration. In addition, the correlation found in our patients between the reduction in {Delta}SR and the increase in IL-6 confirms the role of inflammatory markers in the early identification of cardiac damage induced by epirubicin, provides a biological explanation to the instrumental data supplied by TDI and SR, and suggests the usefulness of TDI in association with inflammatory markers in the monitoring of cardiomyopathy.

A further finding of the present study was that the early changes in TDI parameters and circulating IL-6 and sIL-6R observed after 200 mg/m2 of epirubicin were paralleled by a significant increase in serum levels of ROS and a significant decrease in GPx. An explanatory mechanism through which inflammation may induce cardiac dysfunction is the close relationship among cytokines, ROS, mitochondrial DNA damage, and defects in electron transport function, which in turn may lead to an additional generation of ROS. Accordingly, a relationship was found between TNF-{alpha} release and ROS increase in the failing hearts of patients with dilatative cardiomyopathy [43]. Moreover, exposure of rat cardiomyocytes to different concentrations of TNF-{alpha} resulted in a significant reduction in SOD, GPx, and catalase synthesis, and increase in oxidative stress, lipoperoxidation, and cell damage confirmed by myocardial CK-MB increase [44].

This slight and premature contractility dysfunction is probably attributable to an impairment in intracellular processes of cardiomyocytes, as the association between SR peak reduction and high levels of circulating inflammatory and oxidative stress markers seems to suggest.

In conclusion, because of anthracycline-induced cardiotoxicity, empirical dose limits have been set. However, our data support the hypothesis that mild cardiac abnormalities may occur at cumulative dose levels significantly below these empirical doses, revealing early progressive myocardial dysfunction even at the lowest doses of epirubicin. Thus, new methods of early identification of patients at risk for congestive heart failure at the lowest doses of anthracyclines are needed to optimize the use of chemotherapy and reduce cardiac damage. Although two major consensus guidelines recommended radionuclide LVEF estimations for monitoring anthracycline cardiotoxicity during therapy [45, 46], doubts have been raised about the reliability of this technique to predict the development of heart failure [25]. The combination of TDI parameters and inflammatory/oxidative stress markers introduced in the present study seems to address this issue. We are confident that this approach, providing an earlier and more accurate evaluation of cardiac function changes during anthracycline therapy, may enable either the timely interruption of anthracycline-based therapy, or alternatively, the initiation of specific potentially cardioprotective treatment. The clinical meaningfulness of our findings warrants further investigations in a higher number of patients for a longer period of follow-up.


   ACKNOWLEDGMENTS
Top
 Learning Objectives
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 Acknowledgments
References
 
We thank Ms. Anna Rita Succa for her excellent technical assistance in editing the article.


   REFERENCES
Top
 Learning Objectives
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 Acknowledgments
 References
 

  1. Fuster V, Gersh BJ, Giuliani ER et al. The natural history of idiopathic dilated cardiomyopathy. Am J Cardiol 1981;47:525–531.[CrossRef][Medline]
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  4. van Dalen EC, van der Pal HJ, Caron HN, Kremer LC. Different dosage schedules for reducing cardiotoxicity in cancer patients receiving anthracycline chemotherapy. Cochrane Database Syst Rev 2006;(4):CD005008.
  5. Esposito M, Venturini M, Vannozzi MO et al. Comparative effects of paclitaxel and docetaxel on the metabolism and pharmacokinetics of epirubicin in breast cancer patients. J Clin Oncol 1999;17:1132–1140.[Abstract/Free Full Text]
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  8. Conklin KA. Coenzyme q10 for prevention of anthracycline-induced cardiotoxicity. Integr Cancer Ther 2005;4:110–130.[Abstract]
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G. Mantovani, C. Madeddu, C. Cadeddu, M. Dessi, A. Piras, E. Massa, R. Serpe, G. Antoni, and G. Mercuro
Persistence, Up to 18 Months of Follow-Up, of Epirubicin-Induced Myocardial Dysfunction Detected Early by Serial Tissue Doppler Echocardiography: Correlation with Inflammatory and Oxidative Stress Markers
Oncologist, December 1, 2008; 13(12): 1296 - 1305.
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