Mitoxantrone, an anthracenedione derivative used in cancer therapy, is a recently approved broad spectrum immunosuppressant for managing multiple sclerosis (MS). Its prolonged use in individual patients, however, is limited due to a known cumulative dose-dependent cardiotoxicity. 1,2 In general, mitoxantrone-related cardiotoxic effects are similar to those previously described for anthracyclines. However, at clinically equivalent doses, these effects have been considered to be significantly less severe than those of doxorubicin. 3
Cardiac events associated with mitoxantrone include complex arrhythmias, decreased left ventricular ejection fraction (LVEF), development of congestive heart failure (CHF), and ECG changes including nonspecific ST-T wave changes or T wave abnormalities. 4,5 Histologic characterization disclosed tubular swelling, degeneration of mitochondria, minimal chromatin clumping, and myofibrillar lysis similar to that seen in doxorubicin-treated myocyts. 1
Mitoxantrone-induced cardiotoxicity is a relatively rare, but potentially severe side effect with a significant impact on patients' overall constitution. In oncological patients the incidence of mitoxantrone-mediated cardiotoxicity increases from less than 3% after a cumulative dose of 120 mg/m2 to up to 10% after a dose of 160 mg/m2. 6 As most MS patients are younger than oncological patients with a rather normal life expectancy, 7 special care is necessary to avoid mitoxantrone-induced cardiac morbidity. Currently, EF measurement by echocardiography is the most frequently used non-invasive diagnostic tool for monitoring cardiotoxicity during mitoxantrone treatment. However, echocardiographic EF measurements rely intrinsically on certain geometric assumptions and are subject to a significant inter- and intra-observer variability. 8
To screen for more sensitive non-invasive diagnostic tools to detect subclinical mitoxantrone-mediated cardiac damage we focused on metabolic and other functional parameters. It has been reported that myocardial high-energy phosphate metabolism was altered in experimental models of acute and chronic adriamycin-induced cardiotoxicity. 9 In addition, it has been shown that 31P-MR spectroscopy can detect early metabolic disturbances even before functional abnormalities were observed. 10 Finally, it is well accepted that LV relaxation is predominantly an energy-requiring process 11 and some histopathologic studies describe anthracycline-induced cardiotoxicity to be a restrictive endomyocardial disease leading to an increase of myocardial stiffness. 12 Therefore, diastolic performance including the dynamic process of early ventricular relaxation and subsequent atrial filling of the left ventricle is assumed to be altered prior to systolic function. As a consequence, focusing on left ventricular diastolic performance, which can be performed with high accuracy by Doppler-echocardiography, might be a particularly well-suited approach to detect early mitoxantrone-mediated cardiotoxicity.
Here, we report on an exploratory case-control study, combining cardiac 31P-MR spectroscopy, MR imaging, and Doppler-echocardiography to assess a putative subclinical mitoxantrone-mediated cardiac damage.
This was a retrospective case-control study of 30 MS patients attending our hospital and outpatient clinic who received immunosuppression with mitoxantrone due to rapid disease progression during the past 5 years. Only patients with a confirmed diagnosis of MS according to established criteria were eligible for the case-control study. The investigation conforms with the principles outlined in the Declaration of Helsinki and was reviewed by the institutional review board. All patients provided written informed consent. As this was regarded as an exploratory pilot study with a novel challenging and time-consuming battery of diagnostic measurements in population of disabled MS patients, no power statistics could be calculated in advance.
Patients were between 17 and 50 years of age and had documented secondary progressive or relapsing progressive MS with Kurzke Expanded Disabilitiy Status Score EDSS between 1.5 and 7.5 at the time point of evaluation. All patients had been on active immunsuppressive treatment with mitoxantrone during the preceding years and had received at least 5 i.v. infusions with a minimum cumulative dosage of 46.7 mg/m2. Mean time to last mitoxantrone treatment was 10 months (± 7 months, range: 5 days to 23 months). Patient demographics and cumulative doses of mitoxantrone are listed in Table 1.
Using a computerized database, each mitoxantrone-treated patient was matched as closely as possible to an otherwise-treated MS control patient regarding gender, date of birth (± 2 years), EDSS (± 1.0), and date of MS onset (± 5 years).
The standard evaluation included a physical examination, 12-lead surface ECG, blood count, blood chemistry tests including serum glucose, kidney and liver function as well as markers of myocardial ischemia including creatine kinase, myoglobin, and Troponin-T.
Two-dimensional, M-mode, and Doppler echocardiography were performed with a high-resolution scanner (System 5, GE-Vingmed, Horten, Norway). The mean wall motion score of each patient was assessed using a 16-segment model. 13 From digitized 2D loops LV ejection fraction was measured using the biplane Simpson's method taking apical 4-chamber and 2-chamber views. 13 Mitral valve plane excursion at the lateral left ventricular wall and at the septum were assessed from the digitized 2D loops of the apical 4-chamber view. In parasternal long axis views, left ventricular diameters (enddiastolic/endsystolic diameter of the cavity and of the posterior left ventricular wall) were measured. The transmitral E/A ratio and the E-wave deceleration time was measured using the pulsed-wave Doppler method, placing the sample volume at the tip of the mitral leaflets. Isovolumic relaxation time was assessed by a continuous-wave Doppler, where the scanline was placed to cross the left ventricular apex and cut the aortic annulus to define aortic valve closure and mitral valve opening. All measurements were done at end-expiratory breathhold. The investigators were unaware whether the patients belonged to the untreated or the mitoxantrone-treated group.
Magnetic Resonance Measurements
Cardiac Magnetic Resonance Imaging
Magnetic resonance imaging (MRI) as well as MR spectroscopy (MRS) were performed with a 1.5 Tesla scanner (Magnetom VISION, Siemens, Erlangen, Germany). For imaging, patients were studied in supine position, using a phased-array body coil. Short- and long-axis cine MRI was performed using an ECG-triggered Cine FLASH-2D sequence as recently described. 14 For functional analysis all short-axis slices from the base to the apex were analyzed using the ARGUS software version VB31B (Siemens AG, Erlangen, Germany). For a valid interindividual comparison of morphologic and functional cardiac parameters independent of body height and mass, these indices were calculated related to body surface area. The following parameters were determined: LV mass index, LV end-diastolic volume, LV end-systolic volume, left ventricular ejection fraction (LV EF), stroke volume (SV), and cardiac output (CO).
31P-Magnetic Resonance Spectroscopy
To perform MRS, patients were positioned in prone position to decrease breathing artifacts. 31P-spectra were acquired using the commercially available double resonant 31P/1H-surface coil (Siemens, Erlangen, Germany). To allow better positioning of the heart above the coil center, the coil system was placed asymmetrically within the magnet. Using a 2D-Turbo-Flash sequence with an FOV of 400 × 400 mm2 (30 neighbored 8-mm slices each, 128 × 256 matrix, 4 acquisitions, dark blood technique) 1H-images were acquired from the short and the two long axes. Then an automatic phase-sensitive map-shim was performed. The mean half-width of the free induction decay in all examinations was below 70 Hz. Thereafter, a 31P-3D-chemical shift imaging (CSI) sequence was started as recently described. 15 To increase the signal to noise ratio (SNR) of the spectra, nuclear Overhauser enhancement (NOE) was applied. Total examination time ranged from 45 to 60 minutes. A SUN Sparc Station 20 (SUN Microsystems) was used for data postprocessing. After positioning of a voxel of 25 ccm within the myocardial septum metabolite ratios were determined using AMARES. 16 Measurement time for cardiac MR imaging and MR spectroscopy was 2 h/patient; data calculation required a further 6 h/patient.
Statistical analysis was performed using StatView (Abacus Corporation, Inc.). All data are presented as mean ± SEM. For statistical analysis, the unpaired T-test and Wilcoxon-matched-pairs test were used to identify differences between volunteers and patients. A value of P < 0.05 was considered statistically significant.
Clinical characteristics of the 15 matched pairs did not differ significantly (Table 1). All completed a 1-page questionnaire that provided information about angina pectoris, hypertension, diabetes mellitus, shortness of breath, or any previous cardiac disease. None of them had reported any signs or symptoms of myocardiac compromise. Mean blood pressure at the time of examination was 114 ± 4 / 76 ± 1 mm Hg for control patients and 107 ± 2 / 69 ± 1 mm Hg for mitoxantrone-treated patients. Mean heart rate was 71 ± 1/min and 72 ± 1/min for control patients and mitoxantrone-treated patients, respectively. All clinical examinations regarding heart functions, laboratory values, and ECGs were within the normal range (data not shown).
Morphologic and Functional Parameters
As shown in Tables 2 and 3, analysis of cardiac function and morphology by MRI did not disclose any significant difference in LV mass index, end-systolic volume index (ESVI), end-diastolic volume index (EDVI), cardiac output, and ejection fraction (EF) between mitoxantrone-treated and untreated MS patients. Furthermore, no signs of systolic LV dysfunction could be detected by echocardiography (Table 3). The independent measurements of LV EF by conventional echocardiography and by MR imaging showed a weak correlation of r = 0.61 (ANOVA). Although there was no difference between both groups with regard to EF there was a weak association between LV EF measured by MRI and cumulative mitoxantrone dosage (r = 0.59, P = 0.0189 ANOVA) but not when LV EF was measured with echocardiography (r = 0.25, P = 0.32 ANOVA). Doppler echocardiographic standard parameters of diastolic performance, including transmitral E/A-ratio, deceleration time (DT) and isovolumetric relaxation time were not different between control and mitoxantrone-treated patients and within normal limits of healthy volunteers (Table 4).
In addition, no association could be detected between the severity of multiple sclerosis (ie, duration of disease, EDSS) or the cumulative mitoxantrone dosage and any functional or morphologic myocardial characteristics (ie, LV volumes, LV EF, data not shown).
Myocardial High-Energy Phosphate Metabolism
In one control patient (a 39-year-old woman without mitoxantrone treatment) the signal-to-noise ratio of the MR spectroscopy was too low to allow accurate quantification. Comparison of 1H-images before and after the acquisition of the spectra revealed a mismatch between single-image slices indicating movement of the patient during data acquisition.
A representative 31P-MR spectrum of a patient with MS after mitoxantrone treatment is shown in Figure 2. The mean phosphocreatine (PCr) to ATP-ratios of MS patients with and without mitoxantrone treatment were 1.48 ± 0.23 and 1.43 ± 0.41, respectively; there was no difference between both groups. Furthermore, no association could be found for PCr/ATP ratios and cumulative mitoxantrone dosage. There was no association between age, EDSS, duration of disease, and PCr/ATP (data not shown).
As mitoxantrone is a recently approved immunosuppressant for managing MS, the number of patients treated will increase in near future. The well-known risk of cardiac side effects for mitoxantrone is lower at clinically equivalent doses than for other anthracyclines. 17 Nevertheless, a dose-dependent cardiotoxicity has been reported; mitoxantrone is therefore limited to doses of less than 140 mg/m2 in the management of MS. 18 Since individual susceptibility for cardiotoxicity varies widely, this precaution may result in premature withdrawal of a beneficial and effective immunosuppressive MS therapy.
Myocardial High-Energy Phosphate Metabolism
Suggested mechanism(s) involved in anthracycline-induced cardiotoxicity include: (1) intercalation of the drug into DNA, 19 (2) inhibition of DNA topoisomerase II, 20 and (3) iron or enzyme-mediated generation of reactive oxygen intermediates (ROI). 21 Several recent experimental in vitro and in vivo data suggested that doxorubicine and mitoxantrone use similar biochemical pathways. It is assumed that the formation of an iron-mitoxantrone complex subsequently induces reactive oxygen intermediates that ultimately damage the heart. 22
Histologic assessment of myocardial tissue samples would be one obvious approach to search for direct evidence of mitoxantrone-induced toxicity. However, the biopsy procedure is costly, uncomfortable, and associated with an inherent procedural risk. Furthermore, putative alterations in myocardial metabolism, constituting a very early, initiating step in mitoxantrone-mediated cardiotoxicity, would be certainly missed by exclusive histologic studies. For instance, it has been suggested that one potential mechanism of anthracycline-induced cardiotoxicity consists of its interaction with cardiolipin, a major phospholipid of the inner mitochondrial membrane, thought to be coupled to mitochondrial creatine kinase and therefore directly affecting myocardial high-energy phosphate metabolism. 23,24 As a consequence, several experimental studies of anthracycline-induced cardiotoxicity have focused on myocardial energetics using 31P MR spectroscopy to non-invasively assess the influence of high-energy phosphates on the development of adriamycin-induced cardiotoxicity. 9,25
To our knowledge the present study is the first study that applies 31P MR spectroscopy in a clinical setting to examine subclinical mitoxantrone-induced cardiotoxicity in MS. Despite the substantial technical challenges inherent in clinical 31P MR spectroscopy this study included 30 patients, one of the largest number of patients studied with MR spectroscopy in the literature. In the MS patient group treated with up to 100 mg/m2 mitoxantrone we found no difference in PCr/ATP ratio compared with control MS patients. Several experimental studies are supporting this finding by showing unchanged PCr/ATP ratios in animal models of acute 25 and chronic 26 anthracycline (adriamycin)-induced cardiotoxicity. Other groups, however, have demonstrated depletion of PCr, unchanged ATP levels, and only mild morphologic and hemodynamic changes in a perfused rat heart model after exposure to adriamycin for 14 days. 27 A possible explanation for the diverging results in these experimental studies might be related to the total adriamycin dose administered, the schedule of administration, and the different animal models used. Unfortunately, no experimental data about myocardial high-energy metabolites are available for mitoxantrone-induced cardiotoxicity.
One might ask whether clinical 31P MR spectroscopy is sensitive enough to detect only subtle changes in myocardial high-energy phosphate concentrations. It has been shown previously (ie, in patients with inherited cardiomyopathy) that MR spectroscopy is able to depict small changes in high-energy phosphates even before functional changes can be detected. 10 The PCr/ATP ratio is, however, only a good measure of myocardial energetics under certain assumptions: A simultaneous decrease of both PCr and ATP can remain undetected when PCr/ATP ratios are used to estimate the energetic state of the heart. The intracellular concentration of ATP is known to be tightly controlled and kept constant by numerous metabolic pathways over a broad range of performances. 28 We and others were able to show that the absolute concentration of ATP remains constant even in severely hypertrophied hearts (due to hypertension or aortic stenosis) as long as LV performance is maintained. 29,30 Only in patients with severe systolic dysfunction (ie, due to ischemic heart disease), significant reduction of ATP was reported. 31 It is therefore unlikely that in our MS patients with preserved systolic and diastolic function, ATP concentration is significantly reduced. Thus, PCr/ATP ratios in this setting is a valid estimate of the energetic status of mitoxantrone-treated MS patients.
Systolic and Diastolic Left Ventricular Performance
Echocardiography has long been used to assess potential cardiac damage during anthracycline and mitoxantrone therapy. In addition to serial measurements of LV EF, currently the standard program to monitor systolic performance during anthracycline treatment, other studies focus on the careful analysis of diastolic parameters for detection of anthracycline-mediated cardiotoxicity. 32–34 In most of these studies, patients were receiving moderate to high doses of mitoxantrone for treatment of malignancies (up to 256 mg/m2). 35 Depending on the cumulative dose of mitoxantrone, the synchronous application of radiotherapy, the additional cardiotoxicity of preceding and concomitant medication, and the time interval after the end of the chemotherapy, the reports of mitoxantrone-induced cardiotoxicity vary from isolated diastolic dysfunction or altered heart rate variability 36 to overt heart failure. 37 It is therefore often impossible to separate the mitoxantrone-induced effects from other confounding factors to estimate the true cardiotoxic impact of mitoxantrone treatment.
So far, altogether 1.378 MS patients in 3 different studies have been evaluated regarding adverse cardiac effects associated with mitoxantrone. 38 Two of these 1.378 experienced congestive heart failure during mitoxantrone therapy. Of 779 patients with normal baseline LV EF, scheduled LV EF testing during follow-up revealed a decreased LV EF (defined as <50%) in 17 patients (2.18%). This asymptomatic decrease in LV EF trended to correlate with a cumulative dose of ≥100mg/m2 as compared with <100mg/m2, but was not significantly related to duration of therapy, age, gender, or application interval. 38 Hartung et al 39 reported in the pivotal prospective, placebo-controlled study of 124 MS patients that 2 of 64 patients receiving a low mitoxantrone dose (mean cumulative dose 37.2 ± 7.7 mg/m2) and 2 of 60 patients receiving a moderate dose (mean cumulative dose 82.6 ± 23.1 mg/m2) developed echocardiographic signs of systolic impairment (LVEF < 50%). No information is available regarding the diastolic performance in these patient groups.
For a comparable dose range in the present study, we did not find any differences for systolic LV function measured by two-dimensional echocardiography. In addition, we did not observe any difference in a large number of diastolic performance indices including two-dimensional echocardiographic evaluation of left ventricular relaxation, Doppler recording of trans-mitral flow velocities, and LV filling patterns in mitoxantrone compared with non-mitoxantrone–treated MS patients. Furthermore, structural and geometric changes were ruled out by MR imaging, currently regarded as gold standard for the assessment of LV volumetric changes.
Measuring LV EF by echocardiography, there was no difference in LV EF between treated and untreated MS patients. Even though there was a statistically significant correlation between the cumulative mitoxantrone dose and LV EF assessed by MRI, echocardiography failed to reproduce that finding. This might be due to the variability of echocardiographic measurements of EF. In addition, in some MS patients without previous mitoxantrone treatment a reduced LV EF has been reported in MR imaging. 40 More patients treated with rather high doses of mitoxantrone studied with both methods are needed to assess whether this association will hold diagnostic information in the future or is an effect of the small study group.
Other Diagnostic Markers
A number of unresolved issues remain to be answered in this context. First, studies using the uptake of indium-111-antimoysin antibody in the myocardium demonstrated an increased uptake in patients treated with mitoxantrone in the absence of functional abnormalities. 41 For practical reasons the indium uptake method, which is available only in specialized centers, is not suited to serve as a screening method for suspected cardiotoxicity. Using a sensitive assay of Troponin T as an established, cardiac specific marker of early myocardial damage, as proposed by others in doxorubicin therapy, 42 we could not find any evidence for minimal alterations in myocardial integrity in our cohort of patients.
Second, although conventional echocardiography disclosed no differences in systolic and diastolic performance in children receiving a mean cumulative anthracycline dose of up to 305 mg/m2, an automatic border detection algorithm revealed a reduced peak filling rate compared with the control group. 43 Since this echocardiographic approach intrinsically relies on accurate endocardial border delineation it remains to be shown whether it is also applicable to adult patients in whom acoustic insonation properties often are limited.
Finally, in patients receiving 210 mg/m2 anthracycline, decreased mitral E/A ratios were demonstrated during low-dose dobutamin stress-echocardiography, but not under resting conditions. 44 It should be pointed out that in these studies high dosages of anthracycline were used and no comparable studies using mitoxantrone are available.
CONCLUSION AND PERSPECTIVES
In this exploratory pilot case-control study of 15 patients with MS treated with an average dose of mitoxantrone of 75 mg/m2 no cardiotoxic effect of mitoxantrone could be detected by analyzing myocardial high-energy phosphate metabolism or by assessing functional and morphometric parameters by MR imaging and Doppler echocardiography. Since we did not perform any exercise testing, no statement can be made regarding possible deterioration of exercise capacity induced by mitoxantrone. However, standard exercise tests are precluded by neurologic disability in most MS patients receiving mitoxantrone.
When treating MS patients with mitoxantrone, a number of questions remain: (1) What maximum dose can be regarded safe in an individual patient and is there a certain threshold for cardiotoxicity? (2) Can we exceed commonly accepted upper-dose limits under close cardiac monitoring? and (3) What are the best screening methods to identify latent or beginning cardiotoxicity? Larger prospective studies including more patients with a broader range of mitoxantrone doses might answer part of the questions. New technologies including MR tagging, Doppler myocardial imaging, or new biochemical markers are under investigation and must be compared against established methodology. Finally, a set of established and sensitive monitoring tools for mitoxantrone cardiotoxicity will be necessary to develop and assess new cardioprotective agents to diminish mitoxantrone-induced cardiotoxicity in daily clinical practice in the future.
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