Description
Myocardial strain refers to the deformation (shortening, lengthening, or thickening) of the myocardium through the cardiac cycle. Myocardial strain can be measured by tissue Doppler imaging or, more recently, speckle-tracking echocardiography. Speckle-tracking echocardiography uses imaging software to assess the movement of specific markers in the myocardium that are detected in standard echocardiograms. It is proposed that a reduction in myocardial strain may indicate sub-clinical impairment of the heart and can be used to inform treatment before development of symptoms and irreversible myocardial dysfunction.

For individuals who have exposure to medications or radiation that could result in cardiotoxicity who receive myocardial strain imaging, the evidence includes a systematic review of observational studies. Relevant outcomes include symptoms, morbid events, quality of life, treatment-related mortality, and treatment-related morbidity. A systematic review of 13 studies with 384 patients treated for cancer suggests that myocardial strain imaging with tissue Doppler imaging or speckle-tracking echocardiography may be able to identify changes in myocardial deformation that precede changes in left ventricle ejection fraction. Although myocardial strain imaging may detect sub-clinical myocardial changes, the value of these changes in predicting clinical outcomes or guiding therapy is uncertain. No studies were identified that compared the diagnostic accuracy of myocardial strain imaging to left ventricle ejection fraction. A study that will compare clinical outcomes when therapy is guided by myocardial strain imaging or left ventricle ejection fraction is in progress and will provide direct evidence on the clinical utility of myocardial strain imaging. The evidence is insufficient to determine the effects of the technology on health outcomes.

Background 
The term strain indicates dimensional or deformational change under force. When used in echocardiography, the term "strain" is used to describe the magnitude of shortening, thickening, and lengthening of the myocardium through the cardiac cycle. The most frequent measure of myocardial strain is the deformation of the left ventricle in the long axis, termed global longitudinal strain. During systole, ventricular myocardial fibers shorten with movement from the base to the apex. Global longitudinal strain is used as a measure of global left ventricle function and provides a quantitative myocardial deformation analysis of each left ventricle segment. Myocardial strain imaging is intended to detect subclinical changes in left ventricle function in patients with a preserved left ventricle ejection fraction, allowing for early detection of systolic dysfunction. Since strain imaging can identify left ventricle dysfunction earlier than standard methods, this raises the possibility of heart failure prophylaxis and primary prevention before the patient develops symptoms and irreversible myocardial dysfunction. Potential applications of speckle-tracking echocardiography are coronary artery disease, ischemic cardiomyopathy, valvular heart disease, dilated cardiomyopathy, hypertrophic cardiomyopathies, stress cardiomyopathy, and chemotherapy-related cardiotoxicity.

Myocardial Strain Imaging 
Myocardial strain can be measured by cardiac magnetic resonance imaging (MRI), tissue Doppler imaging or by speckle-tracking echocardiography. Tissue Doppler strain imaging has been in use since the 1990s but has limitations that include angle dependency and significant noise. In 2016, Smiseth et al. reported that the most widely used method of measuring myocardial strain at the present time is speckle-tracking echocardiography.¹ In speckle-tracking echocardiography, natural acoustic markers generated by the interaction between the ultrasound beam and myocardial fibers form interference patterns (speckles). These markers are stable, and speckle-tracking echocardiography analyzes the spatial dislocation (tracking) of each point (speckle) on routine 2-dimensional sonograms. Echocardiograms are processed using specific acoustic-tracking software on dedicated workstations, with offline semiautomated analysis of myocardial strain. The 2-dimensional displacement is identified by a search with image processing algorithms for similar patterns across two frames. When tracked frame-to-frame, the spatiotemporal displacement of the speckles provides information about myocardial deformation across the cardiac cycle. Global longitudinal strain provides a quantitative analysis of each left ventricle segment, which is expressed as a percentage. In addition to global longitudinal strain, speckle-tracking echocardiography allows evaluation of left ventricle rotational and torsional dynamics.

Regulatory Status 
A number of image analysis systems have been cleared for marketing by the U.S. Food and Drug Administration (FDA) through the 510(k) process. Examples of these are shown in Table 1. For example, the Echolnsight software system (Epsilon Imaging) "enables the production and visualization of 2-dimensional tissue motion measurements (including tissue velocities, strains, strain rates) and cardiac structural measurement information derived from tracking speckle in tissue regions visualized in any B mode (including harmonic) imagery loops as captured by most commercial ultrasound systems" (K110447). The FDA determined that this device was substantially equivalent to existing devices (e.g., syngo US Workplace, Siemens, K091286) for analysis of ultrasound imaging of the human heart.

Table 1. Examples of Software That Have Received FDA Clearance 

FDA: Food and Drug Administration. 

Policy 
Myocardial strain imaging in individuals who have exposure to medications or radiation that could result in cardiotoxicity is considered investigational and/or unproven and therefore considered NOT MEDICALLY NECESSARY.

Myocardial strain imaging is considered investigational and/or unproven and therefore considered NOT MEDICALLY NECESSARY in all other situations.

Policy Guidelines 
Please see the Codes table for details. 

Benefit Application 
BlueCard/National Account Issues
State or federal mandates (e.g., Federal Employee Program) may dictate that certain U.S. Food and Drug Administration approved devices, drugs, or biologics may not be considered investigational, and thus these devices may be assessed only by their medical necessity.

Rationale 
This evidence review was created in March 2019 and updated regularly with searches of the PubMed database. The most recent literature update was performed through March 14, 2022.

Evidence reviews assess whether a medical test is clinically useful. A useful test provides information to make a clinical management decision that improves the net health outcome. That is, the balance of benefits and harms is better when the test is used to manage the condition than when another test or no test is used to manage the condition.

The first step in assessing a medical test is to formulate the clinical context and purpose of the test. The test must be technically reliable, clinically valid, and clinically useful for that purpose. Evidence reviews assess the evidence on whether a test is clinically valid and clinically useful. Technical reliability is outside the scope of these reviews, and credible information on technical reliability is available from other sources.

Myocardial Strain Imaging to Detect Cardiotoxicity
Clinical Context and Test Purpose
The purpose of myocardial strain imaging in patients who have an indication for a transthoracic echocardiogram is to inform a decision whether to modify monitoring and/or treatment before the patient develops symptoms and irreversible myocardial dysfunction.

In 2019, the American College of Cardiology, American Association for Thoracic Surgery, American Heart Association, American Society of Echocardiography, American Society of Nuclear Cardiology, Heart Rhythm Society, Society for Cardiovascular Angiography and Interventions, Society of Cardiovascular Computed Tomography, Society for Cardiovascular Magnetic Resonance, and the Society of Thoracic Surgeons published appropriate use criteria for multimodality imaging in the assessment of cardiac structure and function in nonvalvular heart disease.2, In 2019, the American College of Cardiology et al. considered strain imaging by speckle or tissue Doppler appropriate for the following indications:

• Initial evaluation prior to exposure to medications/radiation that could result in cardiotoxicity/heart failure
• Re-evaluation (1 year) in a patient previously or currently undergoing therapy with potentially cardiotoxic agents
• Periodic re-evaluation in a patient undergoing therapy with cardiotoxic agents with worsening symptoms
• Evaluation of suspected hypertrophic cardiomyopathy

The American College of Cardiology et al. recommended that myocardial strain imaging "may be appropriate" for indications that are described in Table 2, in the Supplemental Information section.

Cardiovascular complications of cancer treatment can be either acute or chronic (early or delayed) and include heart failure, myocardial ischemia or infarction, hypertension, thromboembolism, and arrhythmias. Presymptomatic detection of cardiotoxicity may allow modification of cancer therapy combinations or use of cardioprotective agents. Therefore, this evidence review will focus on clinical outcomes from use of strain imaging by speckle-tracking echocardiography or tissue Doppler imaging for the initial assessment and follow-up for cardiotoxicity.

The question addressed in this evidence review is: Does myocardial strain imaging improve the net health outcome in individuals exposed to cardiotoxic agents?

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is individuals who have been exposed to cardiotoxic medications or radiation.

For patients who are undergoing chemotherapy, current recommendations are to measure ejection fraction prior to chemotherapy, at completion of therapy, and 6 months later. It has been proposed that the measurement of myocardial strain in addition to ejection fraction will be helpful in cases when ejection fraction is in the lower normal range, and in these cases, the finding of subnormal strain should result in closer monitoring of cardiac function, modification of cancer therapy, and/or use of cardioprotective agents.

Interventions
The test being considered is myocardial strain imaging. Strain is a dimensionless measure of tissue deformation (L – L0)/L0, where L is final length and L0 the original length; positive values indicate lengthening, and negative values indicate shortening.³

The most frequent measure of myocardial strain is global longitudinal strain, which averages values over the length of the myocardial wall. Greater deformation is indicated by lower strain values. Cardiac strain in a healthy individual is generally around 20%, indicated in echocardiography by a negative number (-20). In a meta-analysis of 24 studies (2597 healthy volunteers), Yingchoncharoen et al. (2013), reported that global longitudinal strain varied from -15.9% to -22.1% (mean -19.7%, 95% confidence interval [CI] -18.9% to -20.4%).⁴ Shortening of more than 20% is generally considered normal.

Comparators
The following tests are currently being used to make decisions about cardiac function. Tagged magnetic resonance imaging (MRI) is considered the reference standard for myocardial strain imaging. However, its routine use is limited by high cost, limited availability, complexity of acquisition, and time-consuming image analysis. This evidence review will evaluate whether clinical outcomes are improved by myocardial strain imaging in comparison with ejection fraction.

Outcomes
The general outcomes of interest are symptoms and signs of cardiotoxicity. Cardiotoxicity is typically defined as a decline in ejection fraction, but there is little consensus regarding what level of decline in left ventricle ejection fraction constitutes cardiotoxicity.

The beneficial outcome of a true-positive test result would be an increase in monitoring or modification of treatment that would reduce cardiotoxicity.

The beneficial outcome of a true-negative test result would be avoiding unnecessary treatment.

A harmful outcome of a false-positive test result would be unnecessary therapy.

A harmful outcome of a false-negative test result would be failure to diagnose cardiotoxicity or progression of toxicity.

Cardiotoxicity may be measured by clinical symptoms and ejection fraction at 6 months and after 1, 2 and 3 years.

Study Selection Criteria
For the evaluation of clinical validity of myocardial strain imaging, studies that meet the following eligibility criteria were considered:

• Reported on clinical outcomes
• Included a suitable reference standard (ejection fraction)
• Patient/sample clinical characteristics were described
• Patient/sample selection criteria were described

Clinically Valid
A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

Review of Evidence
Systematic Review
Thavendiranathan et al. (2014) conducted a systematic review of myocardial strain imaging for the early detection of cardiotoxicity in patients during and after cancer chemotherapy.⁵ Searches were conducted through November 2013. The reviewers included prospective or retrospective studies of at least 10 patients that used echocardiographic-based myocardial deformation parameters as the primary method to detect cardiotoxicity. Studies had to provide data on changes in deformation parameters and left ventricle ejection fraction during therapy. The authors focused the review on 3 clinical scenarios: 1) detection of early myocardial changes; 2) prediction of subsequent cardiotoxicity; and 3) detection of late consequences of therapy (> 1 year posttreatment).

Detection of early myocardial changes: 13 single-center cohort studies (N = 384) provided information on myocardial strain imaging parameters to detect early myocardial changes in patients treated with anthracycline-containing regimens. The earlier studies (n = 7) used tissue Doppler imaging while more recent studies (n = 6) used speckle-tracking echocardiography. There was heterogeneity regarding patient age, types of cancer, strain techniques, and timing of follow-up, but all of the studies found that changes in myocardial deformation occurred earlier than changes in left ventricle ejection fraction. In addition, reductions in myocardial deformation occurred at doses lower than those historically considered cardiotoxic.

Prognosis for early cardiotoxicity: 8 observational studies (N = 452) included in the systematic review evaluated the prognostic value of myocardial strain imaging for subsequent cardiotoxicity (left ventricle ejection fraction reduction or the development of heart failure). The studies differed in duration of follow-up (6 months, 12 to 15 months), treatment regimens, and other factors but used a similar definition of cardiotoxicity. The researchers found that an early fall in global longitudinal strain of 10% to 15% using speckle-tracking echocardiography predicted subsequent cardiotoxicity.

Prognosis for late cardiotoxicity: 9 case-control studies (N = 436) were identified that compared findings in patients to controls. All of the studies used various myocardial deformation parameters to detect late subclinical cardiac injury, but none provided data on subsequent cardiac events.

The authors identified the following areas for future research:

• Determination of whether strain-based approaches could be reliably implemented in multiple centers, including nonacademic settings
• Evaluate in larger multicenter studies and in cancers other than breast cancer
• Need to determine the optimum sampling (single or multiple)
• Comparison with a traditional left ventricle ejection fraction based approach
• Understanding the long-term effect of strain changes that occur during therapy
• The use of vendor-neutral methods to measure strain
• The prognostic significance of strain abnormalities in survivors of cancer and those receiving radiation therapy
• Whether intervention would change the natural course of the cardiac disease

Clinically Useful
A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, more effective therapy, or avoid unnecessary therapy or testing.

Direct Evidence
Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from randomized controlled trials (RCTs).

In the multicenter, prospective, randomized, controlled, Strain Surveillance of Chemotherapy for Improving Cardiovascular Outcomes (SUCCOUR) trial, anthracycline-treated patients with another heart failure risk factor (N = 331) were randomly assigned to initiation of cardioprotective therapy guided by either a ≥ 12% relative reduction in global longitudinal strain (n = 166) or > 10% absolute reduction in left ventricular ejection fraction (n = 165).⁶ Patients were enrolled at 28 centers from Australia, Asia, Europe, Canada, and the United States between January 2014 and December 2019. Cardioprotective therapy included initiation of an angiotensin converting enzyme (ACE) inhibitor (or an angiotensin receptor blocker [ARB], if the ACE inhibitor was not tolerated) followed by a beta-blocker, with doses titrated every 2 weeks until achievement of the maximal dose or development of intolerable side effects. The primary outcome was a difference in baseline to 1-year follow-up of left ventricular ejection fraction, preferentially based on 3D left ventricular ejection fraction, between the 2 groups. Twenty-four of the 331 randomized patients did not have a 1-year follow-up (2 died; 22 either withdrew consent or did not return for imaging); 307 patients were included in the final analysis (154 in the global longitudinal strain surveillance arm and 153 in the left ventricular ejection fraction surveillance arm). The majority of patients were female (94%) and had breast cancer (91%). Most patients were of European descent (> 60% in each group), followed by East Asian (between 20% to 28% per group), South Asian (3.3% to 7.2%), and African (0.7% in each group).

The primary endpoint was not met as the difference of left ventricular ejection fraction between groups at 1-year follow-up was not statistically significant (global longitudinal strain: 57% ± 6% vs. left ventricular ejection fraction: 55% ± 7%; p = .05).⁶ Of patients in the left ventricular ejection fraction surveillance group, 13.7% met criteria for cancer-therapy-related cardiac dysfunction versus 5.8% in the global longitudinal strain group (p = .02). A subgroup analysis revealed that patients receiving cardioprotective medications in the left ventricular ejection fraction surveillance group had larger reductions in left ventricular ejection fraction at follow-up than in the global longitudinal strain surveillance group (9.1% ± 10.9% vs. 2.9% ± 7.4%; p = .03). More patients in the global longitudinal strain surveillance group received cardioprotective treatment, which may account for this difference in ejection fraction. Limitations of the SUCCOUR trial include the potential for bias in local ejection fraction measurements since the sites were not blinded to study arm, the use of 2D left ventricular ejection fraction (instead of the preferential 3D) in some patients due to image quality, and a general shift toward use of non-anthracycline-based therapies in women with HER2+ breast cancer. With this shift, the focus on anthracycline-treated patients in the SUCCOUR trial may not be generalizable to those who are treated with non-anthracycline-based regimens. Of note, the adoption of global longitudinal strain-guided surveillance in routine practice also requires the commitment of echocardiography laboratories and training of analyzing/reporting clinicians. Additional studies are indicated to better define the threshold for cardioprotective therapy and to assess whether a global longitudinal strain-guided approach to cardioprotective therapy reduces the long-term risk of heart failure and improves clinical outcomes.

Section Summary: Myocardial Strain Imaging to Detect Cardiotoxicity
A systematic review of 13 studies with 384 patients treated for cancer suggests that myocardial strain imaging with tissue Doppler imaging or speckle-tracking echocardiography may be able to identify changes in myocardial deformation that precede changes in left ventricle ejection fraction. Although myocardial strain imaging may detect sub-clinical myocardial changes, the value of these changes in guiding therapy is uncertain. No studies were identified that evaluated the diagnostic accuracy of myocardial strain imaging compared to left ventricle ejection fraction. In the SUCCOUR trial, left ventricle surveillance with global longitudinal strain was associated with an increased use of cardioprotective therapy and a lower incidence of cancer-therapy-related cardiac dysfunction as compared to left ventricular ejection fraction surveillance. However, no difference in the primary endpoint of final left ventricular ejection fraction at 1-year follow-up was observed between the groups and interpretation of findings was limited by important design and relevance limitations.

Summary of Evidence
For individuals who have exposure to medications or radiation that could result in cardiotoxicity who receive myocardial strain imaging, the evidence includes systematic reviews of observational studies and an RCT. Relevant outcomes include symptoms, morbid events, quality of life, treatment-related mortality, and treatment-related morbidity. A systematic review of 13 studies with 384 patients treated for cancer suggests that myocardial strain imaging with tissue Doppler imaging or speckle-tracking echocardiography may be able to identify changes in myocardial deformation that precede changes in left ventricle ejection fraction. Although myocardial strain imaging may detect sub-clinical myocardial changes, the value of these changes in predicting clinical outcomes or guiding therapy is uncertain. In the SUCCOUR RCT, left ventricle surveillance with global longitudinal strain was associated with an increased use of cardioprotective therapy and a lower incidence of cancer-therapy-related cardiac dysfunction as compared to left ventricular ejection fraction surveillance. However, no difference in the primary endpoint of final left ventricular ejection fraction at 1-year follow-up was observed between the groups and interpretation of findings was limited by important design and relevance limitations. Additional studies are indicated to better define the threshold for cardioprotective therapy and assess whether a global longitudinal strain-guided approach to cardioprotective therapy reduces the long-term risk of heart failure and improves clinical outcomes. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Practice Guidelines and Position Statements
Guidelines or position statements will be considered for inclusion in "Supplemental Information" if they were issued by, or jointly by, a U.S. professional society, an international society with U.S. representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

American College of Cardiology et al.
In 2019, the American College of Cardiology, American Association for Thoracic Surgery, American Heart Association, American Society of Echocardiography, American Society of Nuclear Cardiology, Heart Rhythm Society, Society for Cardiovascular Angiography and Interventions, Society of Cardiovascular Computed Tomography, Society for Cardiovascular Magnetic Resonance, and the Society of Thoracic Surgeons published appropriate use criteria for multimodality imaging in the assessment of cardiac structure and function in nonvalvular heart disease (Table 2).²

Using a modified Delphi approach, the panel rated indications as “appropriate”, “may be appropriate”, and “not appropriate."⁷ The specific studies that formed the basis of the American College of Cardiology guidelines are not cited, however, they note that they used American College of Cardiology/American Heart Association clinical practice guidelines whenever possible.

Of 81 indications considered for strain rate imaging, the panel rated only 4 as “appropriate” (Table 2). Three of the 4 concerned evaluation (initial or follow-up) in patients prior to and following exposure to potentially cardiotoxic agents. The other indication was follow-up testing to clarify initial diagnostic testing for patients with suspected hypertrophic cardiomyopathy. The guidelines did not separate out imaging with speckle tracking and tissue Doppler and did not make recommendations related to the comparative effectiveness of these imaging modalities.

The panel rated 14 other indications “may be appropriate” (Table 2). According to the panel, interventions in this category should be performed depending on individual clinical patient circumstances and patient and provider preferences, including shared decision making.⁷

Table 2. Summary of ACC Appropriate Use Criteria for Myocardial Strain Imaging

ACC: American College of Cardiology; CAD: coronary artery disease; CRT: cardiac resynchronization therapy: ECG: electrocardiogram; HF: heart failure; ICD: implantable cardioverter-defibrillator; LBBB: left bundle branch block; VT: ventricular tachycardia.
Source: Adapted from Doherty et al. (2019).²

American Society of Clinical Oncology
In 2017, the American Society of Clinical Oncology noted that measurement of strain has been demonstrated to have some diagnostic and prognostic use in patients with cancer receiving cardiotoxic therapies but that there have been no studies demonstrating that early intervention based on changes in strain alone can result in changes in risk and improved outcomes.⁸ The American Society of Clinical Oncology also notes that screening for asymptomatic cardiac dysfunction using advanced imaging could lead to added distress in cancer survivors.

U.S. Preventive Services Task Force Recommendations
Not applicable.

Ongoing and Unpublished Clinical Trials
Some currently ongoing and unpublished trials that might influence this review are listed in Table 3.

Table 3. Summary of Key Trials

References  

1. Smiseth OA, Torp H, Opdahl A, et al. Myocardial strain imaging: how useful is it in clinical decision making?. Eur Heart J. Apr 14 2016; 37(15): 1196-207. PMID 26508168
2. Doherty JU, Kort S, Mehran R, et al. ACC/AATS/AHA/ASE/ASNC/HRS/SCAI/SCCT/SCMR/STS 2019 Appropriate Use Criteria for Multimodality Imaging in the Assessment of Cardiac Structure and Function in Nonvalvular Heart Disease: A Report of the American College of Cardiology Appropriate Use Criteria Task Force, American Association for Thoracic Surgery, American Heart Association, American Society of Echocardiography, American Society of Nuclear Cardiology, Heart Rhythm Society, Society for Cardiovascular Angiography and Interventions, Society of Cardiovascular Computed Tomography, Society for Cardiovascular Magnetic Resonance, and the Society of Thoracic Surgeons. J Am Soc Echocardiogr. May 2019; 32(5): 553-579. PMID 30744922
3. Trivedi SJ, Altman M, Stanton T, et al. Echocardiographic Strain in Clinical Practice. Heart Lung Circ. Sep 2019; 28(9): 1320-1330. PMID 31064715
4. Yingchoncharoen T, Agarwal S, Popovic ZB, et al. Normal ranges of left ventricular strain: a meta-analysis. J Am Soc Echocardiogr. Feb 2013; 26(2): 185-91. PMID 23218891
5. Thavendiranathan P, Poulin F, Lim KD, et al. Use of myocardial strain imaging by echocardiography for the early detection of cardiotoxicity in patients during and after cancer chemotherapy: a systematic review. J Am Coll Cardiol. Jul 01 2014; 63(25 Pt A): 2751-68. PMID 24703918
6. Thavendiranathan P, Negishi T, Somerset E, et al. Strain-Guided Management of Potentially Cardiotoxic Cancer Therapy. J Am Coll Cardiol. Feb 02 2021; 77(4): 392-401. PMID 33220426
7. Hendel RC, Lindsay BD, Allen JM, et al. ACC Appropriate Use Criteria Methodology: 2018 Update: A Report of the American College of Cardiology Appropriate Use Criteria Task Force. J Am Coll Cardiol. Feb 27 2018; 71(8): 935-948. PMID 29471942
8. Armenian SH, Lacchetti C, Lenihan D. Prevention and Monitoring of Cardiac Dysfunction in Survivors of Adult Cancers: American Society of Clinical Oncology Clinical Practice Guideline Summary. J Oncol Pract. Apr 2017; 13(4): 270-275. PMID 27922796

Coding Section 

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