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European Journal of Echocardiography 2007 8(2):144-150; doi:10.1016/j.euje.2006.02.009
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Copyright © 2006, The European Society of Cardiology

Evaluation of the myocardial performance index for early detection of mitoxantrone-induced cardiotoxicity in patients with multiple sclerosis

Paolo Pattoneria,*, Giovanna Pelàa, Enrico Montanarib, Ilaria Pescib, Paolo Moruzzic and Alberico Borghettia

aDepartment of Internal Medicine, Nephrology and Health Sciences, University of Parma, Via Gramsci 14, 43100 Parma, Italy
bOperative Unit of Neurology, Hospital of Fidenza, Parma, Italy
cOperative Unit of Cardiology, Hospital of Fidenza Parma, Italy

Received 28 November 2005; received in revised form 10 February 2006; accepted after revision 28 February 2006.

* Corresponding author. Tel.: +39 052 103 3192; fax: +39 052 103 3185. pattopaolo{at}libero.it


   Abstract
Top
 Abstract
Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Aims Multiple sclerosis is the most common cause of neurological disability in young adults. Mitoxantrone is a synthetic anthracenedione, recently approved for the treatment of worsening multiple sclerosis, which is known to induce cardiotoxicity. This study was designed to evaluate the early alterations in left ventricular function in patients with multiple sclerosis receiving mitoxantrone, by the use of the myocardial performance index, a new parameter of global (systolic and diastolic) ventricular function.

Methods and results The study included 29 Caucasian patients with multiple sclerosis (mean age 41.8±9.3years, 12 males and 17 females) treated with mitoxantrone (mean cumulative dose 30.8±18.2mg/m2) who were compared with 28 healthy subjects (mean age 37.8±11.8years, 13 males and 15 females). Both groups underwent a complete two-dimensional and Doppler echocardiography including assessment of the mitral inflow and left ventricular outflow patterns for estimation of the Doppler-derived myocardial performance index. This parameter is defined as the sum of isovolumic contraction time and isovolumic relaxation time, divided by ventricular ejection time.

No differences were observed in blood pressure, heart rate, left ventricular diameters, mass and ejection fraction in multiple sclerosis patients compared to the controls. The mitral flow pattern showed a significant decrease of E wave calculated as peak velocity (Epv) (63.3±13.4 vs. 77.2±17.2, P<0.002) and time velocity integral (Etvi) (8.8±1.9 vs. 10.3±2.4, P<0.02), with a significant decrease of Epv/Apv ratio and a non-significant decrease of Etvi/Atvi ratio in the patients. In addition, E-wave deceleration time was significantly increased in multiple sclerosis patients compared to controls (178.2±30.2 vs. 137.9±14.7, P<0.0001). The mean value of myocardial performance index was 0.55±0.1 in patients compared to 0.37±0.06 in the controls (P<0.0001). A significant correlation between the given cumulative dose of mitoxantrone and myocardial performance index (r=0.67, P<0.001) and E-wave deceleration time (r=0.45, P<0.001) respectively were demonstrated.

Conclusion The myocardial performance index represents a parameter of combined systolic and diastolic myocardial performance strongly correlated with the given cumulative dose of mitoxantrone. The myocardial performance index may be an adjunctive parameter to conventional echocardiography for detecting sub-clinical cardiotoxicity of mitoxantrone in the clinical management of the multiple sclerosis patients.

Keywords: Multiple sclerosis; Myocardial performance index; Echocardiography; Mitoxantrone; Diastolic function


   Introduction
Top
 Abstract
 Introduction
Subjects and methods
 Results
 Discussion
 References
 
Multiple sclerosis (MS) is a neurological disorder that typically results in significant disability and has a negative impact on the patient's quality of life. Treatment options, recently approved by the FDA, specifically target the inflammatory phase of MS and include immunomodulators and an immunosuppressant, mitoxantrone. Mitoxantrone hydrochloride is an anthracenedione that has been used as one of the latest in a long line of general immunosuppressive agents studied in worsening MS. Although there is increasing evidence for the beneficial effects of mitoxantrone in the treatment of patients with MS, there is controversy concerning the potential cardiotoxicity effects of this therapy.1,2 The potential for myocardial damage resulting in congestive heart failure is the factor limiting the total dose in MS patients. The risk for chronic cardiomyopathy limits the approved cumulative dose of mitoxantrone for treatment of worsening MS to 140mg/m2. The drug is taken up by myocardial cells, in which it chelates with iron and forms complexes. Cardiomyopathy is thought to result from intracellular generation of reactive oxygen intermediates via iron or enzyme-mediated oxidation–reduction reactions. Cardiac myocytes appear to be selectively susceptible to mitoxantrone-induced damage due to their relative lack of defence mechanisms such as catalase and superoxide dismutase.3,4

A relatively new Doppler-derived index, able to assess the global left ventricular function including components from both systole and diastole, was proposed by Tei and co-workers.5,6 This myocardial performance index (MPI, also denoted the TEI-Doppler index), which is defined as the sum of isovolumic contraction time and isovolumic relaxation time divided by the ejection time, was reported to be simple, non-invasive, reproducible and independent of the heart rate and blood pressure.5 The MPI has been shown to have significant clinical utility. It is prolonged in many cardiac diseases even in the absence of clinical signs. Studies have demonstrated that MPI correlates well with invasive measures of both systolic and diastolic function in adults7 and provides prognostic information about morbidity and mortality in patients with ischemic heart disease,8 cardiac amyloidosis,9 dilated cardiomyopathy,10 and primary pulmonary hypertension.11 The aim of the present study was to investigate whether conventional two-dimensional and Doppler echocardiography can detect early alterations in left ventricular function induced by mitoxantrone therapy and, in particular, whether MPI can contribute to the assessment of subtle changes of myocardial function.


   Subjects and methods
Top
 Abstract
 Introduction
 Subjects and methods
Results
 Discussion
 References
 
Subjects
We examined 29 Caucasian patients (12 males and 17 females, mean age 41.8±9.8, range 24–58years), 12 with relapsing-remitting MS and 17 with secondary progressive MS, treated with mitoxantrone in the Operative Unit of Neurology, Hospital of Fidenza, during the period from September 2004 to June 2005.

A control group of 28 healthy subjects matched for age and gender were included. All subjects enrolled in the study underwent a 12-lead standard electrocardiogram, a clinical examination and blood pressure evaluation before the echocardiogram. No subject was a smoker or had a history of arterial hypertension, heart disease or clinical symptoms of heart failure. The comparison of both groups is summarized in Table 1.


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  		Table 1 Clinical data

 
Echocardiography
An experienced sonographer examined the subjects in the left lateral decubitus position utilizing Acuson Sequoia (Acuson Corp., Mountain View, CA) ultrasound imaging systems, equipped with a multi-hertz sector probe (2–4MHz).

The systolic and diastolic thickness of the septum and posterior wall, systolic and diastolic left ventricle short-axis dimensions were measured according to the Penn-convention in the parasternal view.12 Left ventricular mass was calculated using the Penn-convention and indexed to the body surface area.12 Left ventricle end-diastolic and end-systolic volume as well as the ejection fraction were calculated according to the biplane Simpson's rule. Endocardial border detection was enhanced by use of Coded second harmonic imaging.13

The blood flow across the mitral valve was monitored by the pulse-Doppler technique in the apical four-chamber view. The sample volume of 3–5mm was placed at the tip of the valve leaflets with the Doppler beam aligned perpendicular to the plane of the mitral annulus. The blood flow profile contains a diastolic early filling (E) wave and atrial contraction (A) wave in diastole. For each wave the peak velocity and its time integral were measured. In the text and Table 3, peak velocities and time velocity integrals are often abbreviated with the subscripts pv and tvi, respectively (e.g. Epv, Atvi).


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  		Table 3 Summary of Doppler time intervals and mitral flow patterns

 
Deceleration time was measured as the time from E-wave peak velocity to the intercept of the deceleration of flow with the baseline.14

Doppler time intervals were measured from mitral inflow and left ventricle outflow Doppler tracings, as described by Tei et al.5 Specific time intervals measured to derive MPI are shown in Fig. 1. MPI is defined as the sum of isovolumic contraction time (ICT) and isovolumic relaxation time (IRT) divided by ventricular ejection time (ET). To obtain the sum of ICT and IRT, the left ventricular ET (interval b), measured from the apical five-chamber view in the left ventricle outflow tract, was subtracted from the interval from cessation to onset of mitral valve inflow (interval a) obtained from the apical four-chamber view. This difference was then divided by the ET to derive the MPI. IRT was measured by subtracting the interval d, between the R wave and cessation of left ventricle outflow, from the interval c, between the R wave and the onset of mitral inflow. ICT was calculated by subtracting the IRT from a–b interval. Three consecutive beats were measured and averaged for each parameter. Twenty random Doppler recordings were analysed to determine the inter- and intra-observer variability in measurement of MPI. The mean inter-observer difference in the measurement of MPI was 3.9%, whereas the mean intra-observer variability was 3.2%.


Figure 1
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  		Figure 1 Schema for measurements of Doppler time intervals. The index is derived as (a–b/b), where a is the interval between cessation and onset of the mitral inflow, and b is the ejection time (ET) of left ventricular outflow. Isovolumic relaxation time (IRT) is measured by subtracting the interval c, between the R wave and the cessation of left ventricular outflow, from the interval d, between the R wave and the onset of mitral inflow. Isovolumic contraction time (ICT) is obtained by subtracting IRT from a–b.

 
Statistics
Data were expressed as mean+standard deviation. The statistical analysis was based on the paired two-tailed Student's t-test. The relationship between parameters was evaluated by means of linear regression data analysis. Values were considered significantly different at P<0.05. We used the statistical program Microsoft Excel Win Office XP for the purpose of statistical data analysis.


   Results
Top
 Abstract
 Introduction
 Subjects and methods
 Results
Discussion
 References
 
Baseline characteristics of patients
As Table 1 shows, MS patients and controls did not differ significantly with respect to age, body surface area (BSA), body mass index (BMI), heart rate and systolic and diastolic blood pressure. ECG tracings did not indicate any pathological pattern in all subjects. The MS patients received a mean cumulative dose of mitoxantrone of 30.81±18.17mg/m2 (range 3–68mg/m2).

Standard echocardiography study
In terms of basic echocardiography, no significant differences were observed in the cavity dimensions of left ventricle. The thickness of septum and posterior wall as well as the relative wall thickness and LVM/BSA were similar in MS patients and controls. The left ventricular systolic function, evaluated as ejection fraction (range 55–70%) and fractional shortening, were superimposable in the two groups (Table 2). In seven patients a mild mitral insufficiency was detected whilst in four a very slight aortic insufficiency was found. In the control group, a mild mitral insufficiency was found in three subjects.


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  		Table 2 Comparison of basic echocardiographic parameters between controls and patients

 
Doppler measurements
The left ventricular diastolic function, assessed by mitral inflow, showed a significant decrease of Epv and Etvi, with a significant decrease of the Epv/Apv ratio and a non-significant decrease of Etvi/Atvi ratio (Table 3). However, all these parameters were within the normal limits in both groups. The E-wave deceleration time was significantly increased in MS patients compared to controls (Table 3).

MPI was easily obtained in all study subjects. MPI was significantly increased in MS patients treated with mitoxantrone (0.55±0.1 vs. 0.37±0.06). This was due to a significant prolongation of IRT and ICT and a shortening of the ET in MS group (Table 3).

Correlations
In all patients MPI significantly correlated with the cumulative dose of mitoxantrone (r=0.67, P<0.001) (Fig. 2, top left) and with E-wave deceleration time (r=0.39, P<0.01) (Fig. 2, bottom right). In addition, a significant correlation was found between E-wave deceleration time and cumulative dose of mitoxantrone (r=0.45, P<0.001) (Fig. 2, top right) and IRT and cumulative dose of mitoxantrone (r=0.70, P<0.001) (Fig. 2, bottom left).


Figure 2
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  		Figure 2 Relations between MPI and cumulative dose of mitoxantrone (top left), E-wave deceleration time and cumulative dose of mitoxantrone (top right), IRT and cumulative dose of mitoxantrone (bottom left) and E-wave deceleration time and MPI (bottom right).

 
MPI correlated inversely with Epv (r=–0.42, P<0.001) and Etvi (r=–0.34, P<0.05). No significant correlation was detected between MPI and Epv/Apv and Etvi/Atvi ratios. MPI did not correlate with age, BSA, heart rate, blood pressure and the systolic function parameters.


   Discussion
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
References
 
Few systematic echocardiographic reports are available in patients with MS receiving mitoxantrone. Some studies suggest no adverse cardiac effects, but others have documented a decrease in the left ventricular systolic function estimated by either shortening fraction or ejection fraction in patients receiving mitoxantrone.15,16 In a previous paper Spindler and co-workers found that all the echo parameters of systolic and diastolic performance (E/A-ratio, isovolumic relaxation time, and E-wave deceleration time) were not different in 15 MS patients treated with mitoxantrone compared with 15 matched control MS patients.17 On the other hand, a number of studies have shown that the diastolic parameters of left ventricular function were affected before systolic indexes.18–21 The risk for myocardial toxicity increases with cumulative doses >100mg/m2, and the total approved dose for use in worsening MS is 140mg/m2. Consequently, cardiac function monitoring is required periodically and is recommended before every infusion once a cumulative dose of 100mg/m2 has been reached. In spite of the fact that the incidence of early cardiotoxicity when the doses of mitoxantrone are under 100mg/m2 is small, there is the problem of subclinical consequences of this treatment. There is a growing interest in detecting the early signs of left ventricular damage. In this study we tested if MPI was able to identify an initial myocardial involvement in a group of MS patients treated with low cumulative dose of mitoxantrone who were asymptomatic for cardiac disease. In one preliminary study, MPI appeared to be a more sensitive non-invasive parameter for detecting subclinical left ventricle dysfunction than current standard echocardiographic measurements.22 Our data support these suggestions. In the current investigation, we report for the first time that a significant increase in the left ventricular MPI occurred before changes in other conventional echocardiographic measures of left ventricular function in MS patients receiving mitoxantrone, and we proved the good correlation between this index and the given cumulative dose of mitoxantrone. These changes occurred at mean cumulative doses as low as 40mg/m2. Our data agree with previously mentioned studies that demonstrated left ventricular diastolic function to be mainly impaired before systolic function after mitoxantrone therapy. In fact, we have found an impaired left ventricular relaxation characterized by an increase of the isovolumic relaxation time and the deceleration time and decreasing Epv and Etvi, with a significant decrease of the Epv/Apv ratio, when compared with the control group. Furthermore, we have found a significant increase of ICT in MS patients, but without significant correlations with echocardiographic conventional indexes of systolic function.

Our study had several limitations. For the evaluation of diastolic function only the mitral valve inflow parameters were determined. The mitral valve inflow represents the cornerstone of the conventional echocardiographic assessment of diastolic function but is now clear that it is indeed limited. Also, our study was observational. Longitudinal follow-up of these patients is essential to define outcomes. Future research could evaluate whether MPI can be used to monitor the impact of treatment in MS patients receiving mitoxantrone.

In conclusion, MPI appears to be a sensitive non-invasive technique for detecting significant subclinical left ventricular dysfunction, occurring at a substantially low dose of mitoxantrone, than current standard echocardiographic measurements. We expect that MPI may be an adjunctive parameter to conventional echocardiography for detecting subclinical cardiotoxicity of mitoxantrone.


   References
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

  1. Noseworthy J.H., Gold R., Hartung H.P. Treatment of multiple sclerosis: recent trials and future perspectives. Curr Opin Neurol (1999) 12:179–193.
  2. Millefiorini E., Gasperini C., Pozzilli C., D'Andrea F., Bastianello S., Trojano M., et al. Randomized placebo-controlled trial of mitoxantrone in relapsing-remitting multiple sclerosis: 24-month clinical and MRI outcome. J Neurol (1997) 244:153–159.[CrossRef][Web of Science][Medline]
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