Myocardial Strain and Strain Rate in Monitoring Subclinical Heart Failure in Asymptomatic Long-Term Survivors of Childhood Cancer

doi:10.1016/j.ultrasmedbio.2010.08.001

Ultrasound in Medicine & Biology

Volume 36, Issue 11, November 2010, Pages 1783-1791

https://doi.org/10.1016/j.ultrasmedbio.2010.08.001 Get rights and content

Abstract

We studied the role of global myocardial strain and strain rate in monitoring subclinical heart failure in a large group of asymptomatic long-term survivors of childhood cancer. Global strain (rate) parameters of survivors were compared with those in healthy controls and were related to conventional echocardiographic parameters, N-terminal-pro-natriuretic peptide (NT-pro-BNP) levels and clinical parameters. Two-dimensional (2-D) echocardiography was performed in 111 survivors and 107 healthy controls. Blood samples were taken from survivors to determine NT-pro-BNP levels. We showed that global myocardial strain, strain rate and time to peak systolic strain in asymptomatic survivors of childhood cancer were significantly lower compared with healthy controls (p values <0.0001) and were significantly related to several systolic and diastolic left ventricular parameters. Whether myocardial strain and strain rate are superior to conventional echocardiography in the early detection of subclinical heart failure needs to be explored in further longitudinal prospective studies. (E-mail: [email protected])

Introduction

Late onset anthracycline-induced cardiotoxicity is a well-known late effect of treatment of childhood cancer. Subclinical heart failure occurs in up to 65% of asymptomatic survivors of childhood cancer (Wouters et al. 2005). Newer techniques, such as myocardial strain imaging and biomarkers still have to prove their prognostic value in the early detection of anthracycline-induced cardiotoxicity (Marwick, 2006, Gianni et al., 2008).

Myocardial strain imaging with two-dimensional (2-D) echocardiography is a relatively new noninvasive method to assess myocardial deformation (Reisner et al. 2004). Strain is the change in size relative to its original size, i.e., the relative deformation. Myocardial strain imaging is now increasingly used in clinical studies (Leitman et al., 2004, Korinek et al., 2005, Jurcut et al., 2008, Ng et al., 2009, Nesbitt and Mankad, 2009). Recently, we showed that in a group of asymptomatic survivors of childhood cancer, myocardial strain imaging with 2-D echocardiography can produce scores with high interobserver, intraobserver and intrapatient reliability (Mavinkurve-Groothuis et al., 2009a, Mavinkurve-Groothuis et al., 2009b). Two studies so far have demonstrated that myocardial longitudinal strain and strain rate are decreased directly after anthracycline therapy for childhood malignancies and in asymptomatic survivors of childhood cancer (Ganame et al., 2007a, Ganame et al., 2007b). Two studies in adults showed reduction in myocardial strain and strain rate directly after anthracyline therapy and after a short follow-up of 18 months (Jurcut et al., 2008, Mantovani et al., 2008). However, the long-term effect of anthracycline-induced cardiotoxicity was not investigated using myocardial strain (rate) imaging.

The role of biomarkers in the early detection of anthracycline-induced cardiotoxicity in children was recently reviewed, showing that brain natriuretic peptide (BNP), NT-pro-BNP and cardiac troponin T (cTnT) might be useful markers in the early detection of anthracyline-induced cardiotoxicity (Mavinkurve-Groothuis et al., 2008, Germanakis et al., 2008). In a large cohort study, we showed that cTnT did not contribute to the early detection of late onset anthracyline-induced cardiotoxicity in asymptomatic survivors of childhood cancer. On the other hand, abnormal levels of NT-pro-BNP were detected in 13% of 122 asymptomatic long-term survivors of childhood cancer and were related to left ventricular internal diameter in end-diastole indexed by body surface area (LIVDd/BSA) (Mavinkurve-Groothuis et al., 2009a, Mavinkurve-Groothuis et al., 2009b).

In this present study, we aim to determine the role of global myocardial strain and strain rate in monitoring subclinical heart failure in a large group of asymptomatic long-term survivors of childhood cancer. Myocardial global strain and strain rate parameters of survivors are compared with healthy controls and related to conventional echocardiographic parameters, N-terminal-pro-natriuretic peptide (NT-pro-BNP) levels and clinical parameters in the survivors.

Section snippets

Study population

All consecutive survivors of childhood cancer, who visited the Late Effects Clinic from May 2006 till October 2008 and who received anthracyclines as part of their therapy for various kinds of malignancies more than 5 years earlier, were included in our study if adequate gray-scale images were available from their echocardiographic study. We considered the sum of doxorubicin and daunorubicin as cumulative anthracycline dosage. Survivors were excluded if they had clinical heart failure, as

Characteristics of the study population

One hundred and eleven asymptomatic survivors of childhood cancer met our inclusion criteria and were included in this study. None of the survivors had a history of acute cardiotoxicity immediately following an anthracycline dosage. One hundred and seven healthy controls were included. Table 1 shows the characteristics of the study population. Both survivors and healthy controls are comparable regarding demographic parameters.

Feasibility

In the survivors group, we were able to measure global SL and SrL in

Discussion

This is the first study of monitoring late-onset subclinical heart failure by strain and strain rate in a large group of asymptomatic long-term survivors of childhood cancer, approximately 15 years after the last anthracycline therapy. This study shows that both conventional echocardiographic parameters and global myocardial strain, strain rate and time to peak systolic strain in asymptomatic survivors of childhood cancer were significantly lower compared with healthy controls (p values

Conclusion

This study showed that global myocardial strain, strain rate and time to peak systolic strain in asymptomatic survivors of childhood cancer were significantly lower compared with healthy controls and were significantly related to several systolic and diastolic left ventricular parameters. Whether myocardial strain and strain rate are superior to conventional echocardiography in the early detection of subclinical heart failure needs to be explored in further longitudinal prospective studies.

Acknowledgments

The authors kindly thank Milanthy Pourier, Gert Weijers, Bob Rijk, Imke Tomasouw-Janssen, Marian Zwartjes and Romana d’Ancona for their help in obtaining the strain data. This study was supported by the Foundation of Childhood Cancer Nijmegen (“Stichting Vrienden KOC”).

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Cardiac Imaging in Childhood Cancer Survivors: A State-of-the-Art Review
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Citation Excerpt :
Scientific societies recommend the use of LV Global Longitudinal Strain (GLS) for early detection of subclinical myocardial dysfunction in adults undergoing cardiotoxic therapies during and after chemotherapy administrations.11,31 With some unavoidable inconsistencies, evidence for the value of GLS in CCS is increasing (Table 1).32–42 Prevalence of altered GLS is variable among studies and seems to range from about 10% to as much as 30% when longer term follow-up durations and higher cumulative anthracycline doses are considered.
Childhood cancer survival has improved significantly in the past few decades, reaching rates of 80% or more at 5 years. However, with improved survival, early- and late-occurring complications of chemotherapy and radiotherapy exposure are becoming progressively more evident. Cardiovascular diseases represent the leading cause of non-oncological morbidity and mortality in this highly vulnerable population. Therefore, the necessity of reliable, noninvasive screening tools able to early identify cardiac complications early is now pre-eminent in order to implement prevention strategies and mitigate disease progression. Echocardiography, may allow identification of myocardial dysfunction, pericardial complications, and valvular heart diseases. However, additional imaging modalities may be necessary in selected cases. This manuscript provides an in-depth review of noninvasive imaging parameters studied in childhood cancer survivors. Furthermore, we will illustrate brief surveillance recommendations according to available evidence and future perspectives in this expanding field.
Myocardial Deformation Imaging by Speckle-Tracking Echocardiography for Assessment of Cardiotoxicity in Children during and after Chemotherapy: A Systematic Review and Meta-Analysis
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Citation Excerpt :
Impairment of LV deformation has been associated with alteration with other indices of cardiac function and injury. First, impaired LV deformation was associated with reduced LV ejection fraction29,34,45,49,52 and fractional shortening.29 The changes of LV ejection and/or shortening fraction with parameters of LV systolic deformation, however, were not consistent.
Children with cancer and childhood cancer survivors (CCS) are at risk for developing chemotherapy-induced cardiomyopathy. Myocardial deformation imaging has shown potential in the early detection of subclinical myocardial damage with implications on therapeutic interventions and improvement of outcomes. The aim of this study was to perform a systemic review and meta-analysis of literature on the assessment of left ventricular and right ventricular myocardial deformation by speckle-tracking echocardiography at rest and during stress in children with cancer during and in survivors after chemotherapy.
A systematic review was performed through searching MEDLINE, Embase, the Cumulative Index to Nursing and Allied Health Literature, the Cochrane Central Register of Controlled Trials, and Scopus. Search hedges were created to cover the concepts of childhood cancer, chemotherapy, radiotherapy, anthracycline, cardiotoxicity, speckle-tracking, myocardial strain, and myocardial deformation. Two independent investigators reviewed the eligibility of articles for inclusion. The weighted mean difference in ventricular strain between pre- and postchemotherapy treatment and that between long-term CCS and healthy subjects were estimated using random-effect models with 95% CIs. Heterogeneity and publication bias were assessed using I² statistics and the Egger test, respectively.
Of the total of 8,703 records initially identified, 42 studies with a total of 5,430 children with cancer were included. Of these 42 studies that showed heterogeneities, nine assessed early myocardial injury during chemotherapy, 30 assessed late myocardial injury after chemotherapy with no publication bias, and three studied myocardial mechanics during stress. The main findings were as follows: (1) left ventricular systolic deformation is impaired in children with cancer during the initial treatment phase and among long-term CCS, while data on changes in right ventricular deformation are limited and inconclusive; (2) the predictive value of early reduction of myocardial strain imaging in forecasting subsequent development of cardiotoxicity is unknown, as it has not been studied; (3) limited data suggest the possibility of impaired left ventricular contractile mechanics during stress in CCS; and (4) cumulative anthracycline dose and chest-directed radiotherapy are consistently identified as factors associated with impaired myocardial deformation.
Myocardial strain imaging by speckle-tracking echocardiography unveils early evidence of myocardial injury in children with cancer and long-term CCS. To support its adoption for clinical use, more data are required for the better understating of myocardial deformation parameters in the risk stratification of children with cancer and prediction of development of cardiomyopathy among CCS.
Refining the 10-Year Prediction of Left Ventricular Systolic Dysfunction in Long-Term Survivors of Childhood Cancer
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In childhood cancer survivors (CCS) at risk for heart failure, echocardiographic surveillance recommendations are currently based on anthracyclines and chest-directed radiotherapy dose. Whether the ejection fraction (EF) measured at an initial surveillance echocardiogram can refine these recommendations is unknown.
The purpose of this study was to assess the added predictive value of EF at >5 years after cancer diagnosis to anthracyclines and chest-directed radiotherapy dose in CCS, for the development of left ventricular dysfunction with an ejection fraction <40% (LVD40).
Echocardiographic surveillance was performed in 299 CCS from the Emma Children’s Hospital in the Netherlands. Cox regression models were built including cardiotoxic cancer treatment exposures with and without EF to estimate the probability of LVD40 at 10-year follow-up. Calibration, discrimination, and reclassification were assessed. Results were externally validated in 218 CCS.
Cumulative incidences of LVD40 at 10-year follow-up were 3.7% and 3.6% in the derivation and validation cohort, respectively. The addition of EF resulted in an integrated area under the curve increase from 0.74 to 0.87 in the derivation cohort and from 0.72 to 0.86 in the validation cohort (likelihood ratio p < 0.001). Reclassification of CCS without LVD40 improved significantly (noncase continuous net reclassification improvement 0.50; 95% confidence interval [CI]: 0.40 to 0.60). A predicted LVD40 probability ≤3%, representing 75% of the CCS, had a negative predictive value of 99% (95% CI: 98% to 100%) for LVD40 within 10 years. However, patients with midrange EF (40% to 49%) at initial screening had an incidence of LVD40 of 11% and a 7.81-fold (95% CI: 2.07- to 29.50-fold) increased risk of LV40 at follow-up.
In CCS, an initial surveillance EF, in addition to anthracyclines and chest-directed radiotherapy dose, improves the 10-year prediction for LVD40. Through this strategy, both the identification of low-risk survivors in whom the surveillance frequency may be reduced and a group of survivors at increased risk of LVD40 could be identified.
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Identification of subclinical cardiomyopathy in patients with various systemic diseases provides an opportunity for early intervention and prevention of advanced heart failure. Although left ventricular ejection fraction is commonly used to identify subclinical cardiomyopathy, it often identifies late stages of myocardial dysfunction. Myocardial strain may be an ideal measure to identify early subclinical cardiomyopathy and discriminate patients at risk of subsequent advanced heart failure. In this review, we summarize the use of strain for diagnosis and prognosis in patients receiving cancer therapy, as well as those with hypertension, and diabetes.
Cardiac Disease in Childhood Cancer Survivors: Risk Prediction, Prevention, and Surveillance
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Cardiac diseases in the growing population of childhood cancer survivors are of major concern. Cardiotoxicity as a consequence of anthracyclines and chest radiotherapy continues to be relevant in the modern treatment era. Mitoxantrone has emerged as an important treatment-related risk factor and evidence on traditional cardiovascular risk factors in childhood cancer survivors is accumulating. International surveillance guidelines have been developed with the aim to detect and manage cardiac diseases early and prevent symptomatic disease. There is growing interest in risk prediction models to individualize prevention and surveillance. This State-of-the-Art Review summarizes literature from a systematic PubMed search focused on cardiac diseases after treatment for childhood cancer. Here, we discuss the prevalence, risk factors, prevention, risk prediction, and surveillance of cardiac diseases in survivors of childhood cancer.
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Original ContributionMyocardial Strain and Strain Rate in Monitoring Subclinical Heart Failure in Asymptomatic Long-Term Survivors of Childhood Cancer

Abstract

Introduction

Section snippets

Study population

Characteristics of the study population

Feasibility

Discussion

Conclusion

Acknowledgments

J Am Coll Cardiol

J Am Coll Cardiol

J Am Soc Echocardiogr

Am J Cardiol

J Am Soc Echocardiogr

J Am Soc Echocardiogr

J Am Soc Echocardiogr

J Am Soc Echocardiogr

J Am Soc Echocardiogr

J Am Coll Cardiol

Ultrasound Med Biol

J Am Coll Cardiol

Am J Cardiol

Mayo Clin Proc

J Am Soc Echocardiogr

Am J Cardiol

Am J Cardiol

Original Contribution
Myocardial Strain and Strain Rate in Monitoring Subclinical Heart Failure in Asymptomatic Long-Term Survivors of Childhood Cancer