European Heart Journal

European Heart Journal Advance Access originally published online on May 22, 2006
European Heart Journal 2006 27(15):1868-1875; doi:10.1093/eurheartj/ehl013

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Tissue Doppler imaging predicts left ventricular dysfunction and mortality in a murine model of cardiac injury

Tomas G. Neilan^1,2, Davinder S. Jassal¹, Teresa M. Perez-Sanz¹, Michael J. Raher², Aruna D. Pradhan⁴, Emmanuel S. Buys², Fumito Ichinose², David B. Bayne², Elkan F. Halpern³, Arthur E. Weyman¹, Geneviéve Derumeaux⁵, Kenneth D. Bloch², Michael H. Picard¹ and Marielle Scherrer-Crosbie^1,2,*

¹ Cardiac Ultrasound Laboratory
² Cardiovascular Research Center, Cardiology Division of the Department of Medicine, Harvard Medical School USA
³ Institute for Technology Assessment, Massachusetts General Hospital USA
⁴ Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, USA
⁵ Department of Cardiology, Hospital Louis Pradel, Lyon, France

Received 17 October 2005; revised 7 April 2006; accepted 13 April 2006; online publish-ahead-of-print 22 May 2006.

^* Corresponding author. Tel: +1 617 7267686; fax: +1 617 7268383. E-mail address: marielle{at}crosbie.com

See page 1771 for the editorial comment on this article (doi:10.1093/eurheartj/ehl144)

	Abstract

Top Abstract Introduction Methods Results Acute experiment Chronic experiment Discussion Supplementary material Acknowledgements References

 
Aims Currently available non-invasive imaging methods frequently fail to detect alterations in left ventricular (LV) function despite histological evidence of injury. Tissue Doppler imaging (TDI) can detect subtle LV dysfunction. The aim of this study was to investigate whether TDI indices can predict LV systolic dysfunction and mortality following exposure to doxorubicin (DOX) in mice.

Methods and results TDI-derived peak endocardial systolic velocity (V_ENDO) and strain rate (SR), as well as M-mode and two-dimensional indices of LV systolic function, were measured serially in mice after receiving DOX as a single dose (20 mg/kg). Haemodynamic measurements were obtained invasively before and at 1, 2, 4, and 5 days after the single DOX dose. Cardiac apoptosis was measured before and at 1 day after DOX. V_ENDO and SR decreased after 1 and 2 days, respectively, whereas changes in fractional shortening (FS) and LV ejection fraction (LVEF) were not detected before 5 days. The reduction in both V_ENDO and SR correlated with the decrease in dP/dt_MAX, and the change in V_ENDO correlated with the early increase in cardiac cell apoptosis. In a subsequent experiment, DOX was administered at 4 mg/kg/week for 5 weeks, and LV function was followed serially for 16 weeks. In this chronic experiment, TDI indices decreased before FS and LVEF, correlated with late LV dysfunction, and predicted DOX-induced mortality.

Conclusion In a murine model of DOX-induced cardiac injury, TDI detects LV dysfunction prior to alterations in conventional echocardiographic indices and predicts mortality. This study suggests that TDI may be a reliable tool to detect early subtle changes in DOX-induced cardiac dysfunction.

Key Words: Echocardiography • Tissue Doppler imaging • Doxorubicin • Apoptosis • Heart failure

	Introduction

Top Abstract Introduction Methods Results Acute experiment Chronic experiment Discussion Supplementary material Acknowledgements References

 
Doxorubicin (DOX; Adriamycin) is an anthracycline antibiotic with a broad spectrum of activity in oncological practice. The use of DOX, however, is limited by its dose-dependent cardiotoxicity.¹ The aetiology of DOX-induced cardiac dysfunction is incompletely understood, but likely involves a free radical-mediated increase in oxidative stress with resultant cardiomyocyte apoptosis.² DOX cardiotoxicity manifests itself as a dilated cardiomyopathy presenting either acutely or often years after therapy. Once symptomatic, recovery from DOX-induced cardiac dysfunction rarely occurs. Importantly, DOX administration is associated with subtle early cardiac injury³ at a stage when detection and appropriate intervention may limit morbidity and mortality.⁴ Routine screening for DOX-induced cardiac dysfunction usually involves assessment of left ventricular (LV) function and volumes both before and after chemotherapy. However, early screening is limited by the subtle nature of the initial injury and the insensitivity of the available methods.^3,5

Murine models are frequently used to characterize the mechanisms involved in the cardiac dysfunction that occurs after a variety of insults, including DOX.⁶ Tissue Doppler imaging (TDI) allows non-invasive measurement of myocardial velocities and strain rate (SR); these measurement have been shown to be sensitive indices of LV systolic function⁷ and have recently been validated in mice.⁸ The aim of the present study was to determine whether or not TDI-derived indices could detect myocardial dysfunction before conventional echocardiographic parameters in a murine model of DOX-induced cardiac dysfunction and, thus, could potentially serve as an early screening measure.

	Methods

Top Abstract Introduction Methods Results Acute experiment Chronic experiment Discussion Supplementary material Acknowledgements References

 
Study design
All experiments were approved by the Massachusetts General Hospital Subcommittee on Research Animal Care. Male C57BL/6 mice (8–10 weeks) were used for all studies. To evaluate the acute cardiac effects of DOX on echocardiographic indices, we randomly assigned mice to either DOX HCL or saline prior to treatment. DOX (20 mg/kg) was administered via intraperitoneal (ip) injection (2 mg/mL). The acute experiments are summarized in Figure 1. Control animals were used in the initial acute experiment and received equal volumes of 0.9% saline. In this first experiment, mice injected with DOX (n=10) or saline (n=10) were followed serially by echocardiography for 5 days. On the basis of results of this first study group, a second acute experiment studied additional mice either at baseline (n=10) or after treatment with DOX for 1, 2, 4, and 5 days (n=5 at each time point). In this experiment, no saline group was studied and mice were randomly pre-assigned to receive no treatment or DOX for a pre-specified amount of time (1, 2, 4, or 5 days). These mice underwent both echocardiography and invasive haemodynamic assessment. After performing invasive haemodynamics, hearts from mice at baseline (n=10) and 24 h after treatment with 20 mg/kg DOX (n=5) were harvested for measurement of cardiac apoptosis.

View larger version (4K): [in this window] [in a new window]   Figure 1 Flow diagram detailing the protocol for the acute DOX study. For group 1, n=10 DOX, n=10 saline; for group 2, n=10; for the DOX-treated groups 3–6, n=5.

 
To evaluate the chronic effects of DOX, C57BL/6 mice (n=20) received DOX (4 mg/kg, ip) once a week for 5 weeks. Mice underwent echocardiography at baseline and 6 weeks (day 42), 12 weeks (day 84), and 16 weeks (day 112) after initiation of chemotherapy. Surviving animals were sacrificed after 16 weeks.

Echocardiographic measurements
Echocardiography was performed using a 13 MHz linear array ultrasound probe (Vivid 7, GE Medical Systems, Milwaukee, WI, USA) in lightly sedated mice (ketamine, 0.05 mg/g, ip). LV dimensions and posterior wall thickness (PWT) were measured from the M-mode tracings, and the fractional shortening (FS) was derived.⁹ LV volumes were calculated using the single-plane prolate ellipsoid geometric model from the parasternal long axis view and the LV ejection fraction (LVEF) was calculated.¹⁰ TDI images were acquired and analysed as previously described.⁸ Briefly, parasternal short-axis views were obtained at the mid-ventricular level (483 frames per second). For peak systolic endocardial velocity (V_ENDO), a region of interest (0.2x0.2 mm) was manually positioned in the PW. For radial SR, a region of interest (0.6x0.6 mm) was measured (Echopac PC, GE Medical). The temporal smoothing filters were turned off for all measurements. The values obtained in five consecutive cardiac cycles were averaged.

Haemodynamic measurements
Mice were anaesthetized with an intraperitoneal injection of morphine (2.0 mg/kg), etomidate (20 mg/kg), and urethane (800 mg/kg). Thoracotomy was performed after tracheostomy, venous catheterization, and mechanical ventilation. A Millar catheter (1.4 Fr, SPR 839, Millar Instruments Inc., Houston, TX, USA) was inserted through the cardiac apex. Pvan software was used to analyse all pressure–volume loop data (Conductance Technologies Inc., San Antonio, TX, USA and Millar Instruments Inc., Houston, TX, USA).

Apoptosis assay
Cardiac apoptosis was measured on paraffin-embedded sections using the terminal deoxynucleotidyltransferase-mediated dUTP nick-end labelling technique (TUNEL) (DeadEnd^TM Fluorometric TUNEL System, Promega Corporation, Madison, WI, USA) and counterstained with DAPI. The percentage apoptosis was calculated by dividing the number of apoptotic cells by the total number of cardiac cells viewed in the section.

Statistical analysis
Data are expressed as mean±SEM. All statistical analysis was done using the JMP statistical package (SAS Institute Inc., Cary, NC, USA). To assess the inter-study variability of the TDI-derived indices, V_ENDO and SR were measured in 20 healthy mice, 24 h apart. The error between the two measurements and its standard deviation are reported. The two measurements were compared using a two-sided paired t-test. P<0.05 was considered significant. On the basis of preliminary data, we hypothesized that DOX would induce a decrease in the EF of 10% over 5 days. Therefore, allowing for a common standard deviation of 5.4% (from previous studies in our group), a significance level of 0.05, and a power of 0.85, we estimated that we would require 10 sham and 10 DOX-treated mice for the initial acute study. For analysis of the initial acute study group, initial comparisons were made between the saline-treated and DOX-treated mice over time using an ANOVA for repeated measurements. The fixed effect was treatment (DOX or saline). The effect of interest is the interaction between time and treatment. If the interaction between time and treatment was significant, DOX-treated animals were compared to saline-treated controls at the same time points using Student's t-tests. To correct for the experiment-wise Type I error (effects of interest FS, EF, V_ENDO, and SR), we considered the effect to be significant if the interaction between time and treatment had a P-value of <0.0125. For comparison of the haemodynamic parameters (effect of interest dP/dt_MAX), results were analysed by means of one-way ANOVA. If the ANOVA showed an overall difference between groups, post hoc comparisons were performed with the Dunnett's test as appropriate. Pearson correlation coefficients were calculated using standard methods. Kaplan–Meier survival curves were derived and differences in event-free survival according to TDI measures assessed using the log-rank test. In the study assessing the chronic effects of DOX, we used a 25% reduction in V_ENDO and a 33% reduction in SR at 6 weeks to separate the mice into relatively equally populated groups.

	Results

Top Abstract Introduction Methods Results Acute experiment Chronic experiment Discussion Supplementary material Acknowledgements References

 
Inter-study variability
The inter-study variability for V_ENDO and SR was 0.2±0.1 cm/s (3±2%) and 1±0.5 s^–1 (3±2%), respectively. There was no significant difference between measurements obtained in healthy mice 24 h apart (P=0.72 for V_ENDO and P=0.53 for SR).

	Acute experiment

Top Abstract Introduction Methods Results Acute experiment Chronic experiment Discussion Supplementary material Acknowledgements References

 
Echocardiography
When compared with baseline, all echocardiographic parameters remained unchanged over time in saline-treated animals (data not shown). In the 10 mice treated with a single dose of DOX (20 mg/kg) and followed serially by echocardiography, FS and EF, when compared with both saline-treated contemporaneous controls and baseline mice, did not change until 5 days after DOX administration when the FS and EF decreased by 17±1 and 13±1%, respectively (Table 1). Figure 2 shows representative examples of V_ENDO and SR obtained in a mouse at baseline and 5 days after treatment with DOX. Although conventional indices remained unchanged acutely after DOX, V_ENDO decreased within 24 h (Table 1) and SR decreased within 48 h (P<0.05; Table 1). Both indices remained decreased throughout the remainder of the experiment. In mice undergoing echocardiography and haemodynamic measurements, V_ENDO and SR correlated closely with dP/dt_MAX before and at 1, 2, 4, and 5 days after receiving DOX (Figure 3). There was a negative correlation noted between the degree of apoptosis and the measured V_ENDO 24 h after DOX (r²=0.72, P<0.001).

View this table: [in this window] [in a new window]   Table 1 Echocardiographic analysis in the initial group of mice treated acutely with 20 mg/kg DOX (n=10)

 

View larger version (85K): [in this window] [in a new window]   Figure 2 TDI measurements before and after DOX administration. Representative parasternal short-axis tracing showing the peak endocardial systolic velocity (VENDO) and SR in a mouse at baseline (A and C) and 5 days after treatment with 20 mg/kg DOX (B and D). The region of interest (circle) is manually positioned along the PW. VENDO and SR were decreased after DOX. See online Supplementary material for a colour version of this figure.

 

View larger version (12K): [in this window] [in a new window]   Figure 3 Correlation between TDI-derived variables and invasive measures of LV systolic function in mice treated acutely with 20 mg/kg DOX. VENDO (A) and maximal systolic SR (B) before and after DOX injection correlated closely with dP/dtMAX measured at all time points.

 
Haemodynamic measurements
LV systolic function, as measured by dP/dt_MAX, decreased 1 day following administration of DOX (20 mg/kg) (P<0.05; Table 2). An early decrease in stroke work was also noted. Diastolic function, as measured by dP/dt_MIN and (tau), and LV end-systolic pressure did not change until 5 days after DOX injection.

View this table: [in this window] [in a new window]   Table 2 Invasive haemodynamics in mice treated acutely with 20 mg/kg DOX

 
Apoptosis
At baseline, there was minimal detectable apoptosis (9/100 000 cardiac cells viewed). There was a 75-fold increase in cardiac cell apoptosis 24 h after a single injection of 20 mg/kg of DOX (P<0.001; Figure 4).

View larger version (45K): [in this window] [in a new window]   Figure 4 DOX induces cardiac apoptosis. Apoptosis in representative myocardial sections from mice at baseline (A) or 24 h after DOX (B) using the TUNEL assay (200x magnification). Fluorescent-labelled apoptotic nuclei stain green and are indicated by arrows. Administration of DOX was associated with an increase in cardiac cell apoptosis after 1 day (C). The percentage of apoptosis represents the number of TUNEL-positive cells expressed as a percentage of the total number of cardiac cells viewed (200 000 cardiac cells in total n=15 mice). *P<0.001 vs. baseline. See online Supplementary material for a colour version of this figure.

 

	Chronic experiment

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Of the 20 mice that were treated with multiple DOX doses (4 mg/kg weekly for 5 weeks), 100, 95, and 35% remained alive at 6, 12, and 16 weeks, respectively, after the first dose. Chronic administration of DOX resulted in mild early LV dilatation, but preservation of systolic function (FS baseline 57±1 vs. 55±1%, 6 weeks after the first dose, P>0.05; Table 3). Reductions in FS and EF were first detected 12 weeks after initiation of DOX (P<0.001 for both). When animals that survived were compared with those that died, there was no difference in LV dimensions, FS, or EF 6 weeks after DOX initiation (Table 4). Moreover, the FS, EF, and the LV dimensions 6 weeks after initiation of DOX did not correlate with the late systolic dysfunction after DOX (r²=0.01, P=0.68, FS 6 weeks vs. FS at 12 weeks). However, both V_ENDO and SR were reduced at 6 weeks after the first dose (Table 3). This early reduction in both TDI-derived variables correlated with the reduction in FS at 12 weeks (Figure 5). Moreover, a 25% decrease in V_ENDO or a 33% decrease in SR at 6 weeks predicted DOX-induced mortality (Figure 6).

View this table: [in this window] [in a new window]   Table 3 Echocardiographic analysis after chronic administration of DOX (n=20)

 

View this table: [in this window] [in a new window]   Table 4 Early (6 weeks) echocardiographic parameters in animals separated according to survival at termination of study (n=20)

 

View larger version (11K): [in this window] [in a new window]   Figure 5 Correlation between the early reduction in the TDI-derived endocardial velocities and SR and the late decrease in FS. VENDO (A) and SR (B) at 6 weeks after commencement of DOX (4 mg/kg weekly for 5 weeks) correlated closely with the FS measured at 12 weeks.

 

View larger version (11K): [in this window] [in a new window]   Figure 6 Reduction in TDI-derived indices 42 days after DOX administration predicts DOX-induced mortality. A 25% reduction VENDO (A) and a 33% reduction in SR (B) at 6 weeks predicted DOX-induced mortality. We defined a 25% reduction in VENDO and a 33% reduction in SR at 6 weeks to separate the mice into relatively equally populated groups.

 

	Discussion

Top Abstract Introduction Methods Results Acute experiment Chronic experiment Discussion Supplementary material Acknowledgements References

 
In this study, we report that TDI-derived indices of LV systolic function accurately detect subtle myocardial injury, prior to alterations in conventional echocardiographic markers in a murine model of LV dysfunction. The TDI-derived indices correlated with invasive haemodynamics and histological evidence of cardiac apoptosis. Early alterations in TDI-derived parameters predicted the development of late cardiac dysfunction and mortality after treatment with DOX.

Until recently, non-invasive assessment of murine cardiac function was limited to M-mode measurements of FS and two-dimensional evaluation of EF. TDI indices have been validated as sensitive measures of myocardial function, both in large animals and rats, in conditions such as ischaemia,¹¹ pressure-overload,¹² and Duchenne's cardiomyopathy.¹³ In mice, Doppler-derived annular diastolic velocities have been used to detect abnormal diastolic function in models of fatty acid-induced cardiac injury¹⁴ and transverse aortic constriction.¹⁵ Recently, TDI-derived systolic and diastolic endocardial velocities in mice challenged with DOX have been reported to reflect changes detected by conventional echocardiographic measurements¹⁶ and to precede the reduction in conventional indices of LV systolic function in mice acutely after endotoxin injection.⁸ In the present study, alterations in V_ENDO and SR preceded the reduction in conventional echocardiographic markers, both in an acute and in a chronic model of LV dysfunction. FS and LVEF were unchanged at a time when there was significant histological and invasive haemodynamic evidence of cardiac injury. The reduction in V_ENDO and SR occurred before any change in heart rate, LV end-diastolic pressure, or blood pressure could be appreciated, suggesting that these indices may non-invasively detect subtle cardiac injury in this model.

LV function is a strong predictor of cardiac morbidity and mortality in patients. Several M-mode and two-dimensional echocardiographic measures have been shown to predict survival after the development of overt ventricular dysfunction.^17–19 Furthermore, asymptomatic subjects with mild echocardiographic LV dysfunction have elevated risk of congestive heart failure (CHF) and death rate, underscoring the importance of detecting and monitoring subtle changes in cardiac function.²⁰ In patients free from overt cardiovascular disease, TDI-derived variables have previously been shown to be abnormal in the presence of histological abnormalities and normal conventional indices of LV systolic function.^21,22 It is unknown whether TDI-derived indices are more sensitive than conventional echocardiographic indices in predicting LV dysfunction and its associated morbidity and mortality in patients. The present study, in mice, suggests that abnormal TDI indices, obtained when conventional echocardiography is still normal, may predict late cardiac dysfunction and death. It is, as yet, unclear whether intervention in the presence of early subtle cardiac injury would limit morbidity and mortality.

Sensitive indices of cardiac injury may also be of use in the assessment of patients treated with DOX. Long-term follow-up studies of paediatric patients who received anthracyclines for various cancers have demonstrated abnormalities of global LV function in up to 50% of survivors.²³ Current guidelines for patients receiving DOX treatment recommend serial measurements of LV function beginning 10–14 days after the most recent cycle of chemotherapy and avoidance of further therapy with DOX if LV function becomes subnormal.²⁴ However, currently employed measures of LV dimensions and systolic function correlate poorly with biochemical evidence of cardiac cell damage,³ biopsy evidence of cardiac injury,²⁵ and progression to heart failure.²⁶ Although conventional diastolic indices have previously been shown to detect LV dysfunction early after treatment with DOX,^27,28 they are not routinely used to make clinically relevant decisions. Owing to the lack of a sensitive early indicator of cardiac toxicity and, therefore, an appropriate prospective study to determine the effects of dose modification based on cardiac test results, the current guidelines for cardiac monitoring of patients receiving DOX are not universally accepted.²⁹ Whether or not TDI provides such an early and sensitive index in DOX-induced cardiomyopathy is, as yet, unclear. TDI has previously been reported to detect DOX-induced cardiac dysfunction in both adults^30,31 and children,³² and transient regional diastolic abnormalities during and shortly after DOX treatment have been reported.³³ Although these studies are limited, in part, by the numbers of participating patients, the varying length of follow-up, and the lack of outcome data, they, along with this present work, suggest that additional research and larger trials into a role for TDI in the early detection of anthracycline-induced LV dysfunction are warranted.

Our study has several limitations. Although the acute and chronic models we used are well validated for research into the mechanisms involved in DOX-induced cardiac injury, they may not be completely representative of the chronic cardiotoxicity seen clinically. In addition, owing to the lack of reproducible apical four-chamber views in mice, we only analysed the radial component of myocardial velocities and SR. In mice, the EKG is difficult to obtain without adequate anaesthesia which maintains the animal immobile. Obtaining the EKG significantly lengthens the procedure and may result in less physiological heart rates. Owing to the absence of an EKG in the present study, strain cannot be easily measured and therefore was not assessed. The TDI tracings derived from the anterior wall are more susceptible to artifact and were not reported. Also, at physiological murine heart rates, there is fusion of diastolic waves, thus prohibiting accurate analysis of diastolic function by Doppler echocardiography.

In summary, we have shown in a murine model of LV dysfunction that maximal systolic endocardial velocities and radial SR measured non-invasively with TDI accurately detect subtle myocardial dysfunction before conventional non-invasive measures and predict late cardiac dysfunction and mortality. This in vivo work suggests that TDI may be a reliable tool to detect early or subtle changes in other murine models of LV dysfunction and in patients at risk for development of CHF. It may also promote further research into the application of TDI in the early cardiac assessment of patients undergoing treatment with anthracyclines, with early detection of abnormalities helping to guide tailoring of dosage regimens.

	Supplementary material

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Supplementary material is available at European Heart Journal online.

	Acknowledgements

Top Abstract Introduction Methods Results Acute experiment Chronic experiment Discussion Supplementary material Acknowledgements References

 
This study was supported by an American Heart Association Post-Doctoral Fellowship Grant (TGN) and a Scientist Development Grant (MSC), an Irish Board for Training in Cardiovascular Medicine and Department of Health and Children Cardiovascular Health Strategy Travelling Fellowship 2004 (TGN), and an American Society of Echocardiography Research Fellowship Award 2004 (TGN), as well as grants from the National Heart, Lung, and Blood Institute Public Health Service grants HL-42397, HL-70896, and HL-71987.

Conflict of interest: none declared.

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Top Abstract Introduction Methods Results Acute experiment Chronic experiment Discussion Supplementary material Acknowledgements References

 

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