Cardiovascular Imaging in Cardio-Oncology: The Role of Echocardiography and Cardiac MRI in Modern Cardio-Oncology

Introduction

The constant evolution of cancer treatment has led to improved outcomes in numerous malignancies¹. With improved cancer survivorship and the introduction of novel therapies such as biologic agents and immunotherapeutics, the prevalence of systemic toxicities, in particular cardiotoxicity has grown². As cardiovascular (CV) disease remains the leading non-cancer cause of death in cancer survivors, the field of cardio-oncology strives to understand and improve CV health in cancer patients^3,4.

CV imaging is crucial in recognizing, understanding, monitoring, and treating cancer treatment-related cardiotoxicities (CTRCT)⁵. Structural and functional imaging modalities provide important information in the management of cardio-oncologic pathologies. Echocardiography continues to be highly utilized for assessment of cardiac structure and function due to its low cost, accessibility, and effectiveness. Newer echocardiographic applications, such as strain imaging, are increasingly used in evaluation of CTRCT, especially to detect subclinical disease^6,7. Similarly, cardiac magnetic resonance (CMR) has become a crucial imaging modality in the field of cardio-oncology. Though less accessible, CMR offers accurate functional and structural assessment due to excellent reproducibility, high signal-to-noise ratio in addition to fine tissue characterization that is particularly helpful when echo is insufficient or suboptimal^6,8. This review will discuss current evidence for use of echocardiography and CMR in cardio-oncology and practical clinical uses for each.

Traditional 2D Echocardiography

Due to availability, low cost, short acquisition time, and safety, echocardiography is the first line imaging modality for CTRCT screening by all published cardio-oncology guidelines and expert consensus statements⁵. Figure 1 illustrates the relative utility of echocardiography considering various parameters. While left ventricular ejection fraction (LVEF) as measured by Simpson’s biplane method is the most cited parameter in strict definitions of cardiotoxicity (definitions range from reduction in LVEF by 5–10% to absolute LVEF of <50–55%)⁹, LVEF assessment via 2D echocardiography lacks the sensitivity and reproducibility for primary CTRCT screening¹⁰. Thus, newer echocardiographic applications such as strain imaging, 3D echocardiography, and contrast echocardiography have growing roles in screening for CTRCT.

Figure 1:

Comparison of value of echocardiography and cardiac MRI. One filled in black circle represents minimal value, two represents limited value, three represents good value and four represents gold standard.

Echocardiographic Strain Imaging

Myocardial strain, or deformation, is the measure of percent change in the length of a myocardial segment over a given timeframe. This parameter is helpful in quantifying myocardial function directly rather than indirectly via 2D LVEF with Simpson’s biplane method. Speckle-tracking echocardiography (STE) is the preferred method of strain imaging. STE tracks the artifactual “speckles” created by reflected and scattered ultrasound beams through cardiac tissue. Strain can be calculated for the three major orientations of myocardial fibers (longitudinal, radial, and circumferential) and as global longitudinal strain (GLS) which uses data from multiple segments, all of which show promise in early detection CTRCT before changes in LVEF occur^7,11. A decrease in GLS of less than or equal to 15% from baseline is considered abnormal and has been most extensively studied¹².

Several studies have assessed the prognostic value of GLS in early prediction of CTRCT prior to LVEF changes. A 2019 systematic review¹³ evaluated twenty-one such studies of patients treated with anthracyclines with or without trastuzumab for a variety of cancers. Summary odds ratios (ORs) for prediction of CTRCT based on threshold GLS values and percent change of GLS after treatment initiation were 12.27 and 15.82, respectively. Since the publication of this systematic review, newer studies have shown similar findings^14–18, some incorporating several biomarkers for additional predictive value with mixed utility^19–21. GLS has been studied in pediatric populations as well. Though less robust, the studies use strain-imaging to evaluate subclinical cardiac dysfunction in varying follow up periods after anthracycline therapy or radiation^22–27. As in adults, GLS in pediatric patients detects myocardial dysfunction prior to changes in LVEF. Future studies in all populations should focus on both early and long-term predictive value of strain imaging with and without biomarkers for the development of CTRCT.

Echocardiography in Anthracyclines

Anthracyclines are anti-tumor antibiotics that play a major role in the treatment of a wide range of cancers. Both anti-tumor action and cardiotoxicity are thought to be due to activation of apoptotic pathways triggered by a combination of three separate mechanisms: direct DNA damage via intercalation into DNA strands, transcription interference via inhibition of topoisomerase enzymes, and DNA and cellular damage via generation of free radicals^28,29. Cardiotoxicity manifests primarily in the form of myocardial dysfunction, usually within one year³⁰ of therapy initiation, and it can progress to irreversible heart failure, characterized by diffuse fibrosis³¹. Risk factors for cardiotoxicity include cumulative anthracycline exposure, age >65 years or <18 years, female sex, pre-existing cardiac risk factors, kidney disease, and exposure to other cardiotoxic therapies³². Patients can be categorized into low, intermediate and high risk for cardiotoxicity based on these risk factors (Table 1). Echocardiography is the primary screening tool for anthracycline cardiotoxicity, with GLS emerging as the most sensitive measure of early myocardial dysfunction¹³.

Table 1:

Low, intermediate, and high-risk features for development of CTRCT. A patient should be grouped with their highest individual risk factor.

Risk Factor Categories for CTRCT
Low Risk	Age 18–50 years Cumulative dose <200 mg/m2 doxorubicin (or equivalent) No pre-existing or new CVD risk factors* Cumulative RT dose <30 Gy without chest involvement
Intermediate Risk	Age 50–65 years Cumulative dose 200–400 mg/m2 doxorubicin (or equivalent) 1–2 pre-existing or new CVD risk factors* Cumulative RT dose >30 Gy without chest involvement Single-agent targeted therapy or immunotherapy
High Risk	Age <18 or >65 years Cumulative dose >400 mg/m2 doxorubicin (or equivalent) Any RT involving the chest Any combination of cardiotoxic cancer therapies, even within same class >2 pre-existing or new CVD risk factors* Underlying CVD (CAD, HF, PAD, etc.) History of CTRCT

^*CVD risk factors include, but are not limited to, hypertension, insulin resistance, diabetes mellitus, smoking, obesity, and dyslipidemia.

Abbreviations: CAD, coronary artery disease; CTRCT, cancer therapy-related cardiotoxicity; CVD, cardiovascular disease; Gy, Gray unit(s); HF, heart failure; PAD, peripheral artery disease; RT, radiation therapy

Echocardiography in Her2/Neu Therapy

Trastuzumab is a monoclonal antibody used mostly in the treatment of HER2 positive breast cancer that targets HER2/neu receptors, epidermal growth factor receptor tyrosine kinases important in cell proliferation. Cardiotoxicity is the major adverse effect attributed to trastuzumab, primarily manifesting as potentially severe, reversible left ventricular (LV) dysfunction while on therapy³³ as well as right ventricular (RV) dysfunction³⁴. Myocardial dysfunction has been reported in up to 30% of patients¹⁹ with a 3% risk of severe cardiotoxicity³⁵. Women treated with both anthracyclines and trastuzumab are at higher risk of cardiotoxicity than those treated with either alone³⁶. Toxicity is thought to be due to inhibition of cardioprotective mechanisms (sarcomere maintenance, pro-apoptotic molecule scavenging) initiated by neoreguline-1 mediated activation of HER2. Subsequent oxidative stress and upregulation of angiotensin II is thought to further promote toxicity³³. As with anthracyclines, GLS detects subclinical myocardial dysfunction prior to LVEF changes and should be implemented in any echocardiographic assessment of patients treated with trastuzumab^13,18.

Echocardiography in Targeted Therapies and Immunotherapy

While anthracyclines and trastuzumab represent the classic culprits of CTRCT, emerging therapies also cause cardiotoxicities that can be assessed via echocardiography and strain imaging. These include targeted therapies (e.g. proteasome inhibitors [PIs], vascular endothelial growth factor inhibitors [VEGF-Is], tyrosine kinase inhibitors [TKIs]) and immunotherapies (e.g. immune checkpoint inhibitors [ICIs], chimeric antigen receptor T cell [CAR-T] therapy).

Echocardiography in Proteasome Inhibitors

PIs, such as bortezomib and carfilzomib, are used in the treatment of multiple myeloma and are known to cause cardiotoxicity in the form of myocardial dysfunction and heart failure³⁷. Proposed mechanisms include interference of production of nitric oxide in the endothelium leading to vasoconstriction and inhibition of the ubiquitin-proteasome system leading to protein misfolding and cell death. Cardiomyocytes are particularly vulnerable to this second mechanism as they are non-proliferative and express elevated proteasome levels³⁸. Meta-analyses of carfilzomib and bortezomib showed ORs of 2.03 and 1.74, respectively, for development of cardiotoxicity and a cumulative incidence of cardiotoxicity in nearly 10% of those on carfilzomib^39,40. PI use is associated with decreased GLS without change in LVEF, indicating subclinical cardiac dysfunction⁴¹ and early detection of CTRCT³⁸, but the amount of published data is minimal.

Echocardiography in Vascular Endothelial Growth Factor Inhibitors

VEGF-Is are used to treat a variety of malignancies by inhibiting tumor angiogenesis. Numerous VEGF-Is are cardiotoxic, causing hypertension and myocardial dysfunction⁴². Hypertension is thought to be driven via inhibition of endothelial nitric oxide production. The myocardial dysfunction is less well understood but thought to include a multitude of effects leading to inhibition of cardioprotective cellular mechanisms, coronary microvasculature destabilization, and decreased density of myocardial capillaries⁴³. Although LVEF effects have been inconsistent, STE monitoring in patients receiving various VEGF-Is showed significant decrease in GLS from baseline both during treatment⁴⁴ and up to six months following treatment^45,46.

Echocardiography in Tyrosine Kinase Inhibitors

TKIs are a diverse group of agents that target tyrosine kinase (TK) molecules in various cellular functions. By targeting specific pathways, TKIs can be tailored for specific types of malignancies. Because TKs are so widely utilized in cellular biology, there is much cross-reactivity with other TKs leading to “off target” effects, including cardiotoxicity in the form of cardiomyopathy and heart failure^47,48. Sunitinib and pazopanib, VEGF-Is acting via TKI mechanism, are associated with myocardial dysfunction and demonstrate significant decrease in GLS⁴⁵. Newer generation Bcr-abl-targeting TKIs cause significantly lower GLS compared to first generation, but the absolute value difference is minimal with no comparison to baseline, limiting the clinical relevance of this finding⁴⁹. Another subset of TKIs, BRAF and MEK inhibitors, are used in the treatment of melanoma and are known to be cardiotoxic, most commonly in the form of LVEF reduction (seen in 13% of patients⁵⁰) and hypertension. Combination BRAF/MEK therapy poses higher risk for LVEF reduction, hypertension, and thromboembolic phenomena compared to BRAF therapy alone^51,52. In TKI CTRCT, heart failure tends to present in the first six months of therapy. However, no published studies address predictive value of GLS or other parameters.

Echocardiography in Immunotherapies

Immunotherapies such as ICIs and CAR-T therapy are used in a wide range of cancers. ICIs work by targeting molecules that inhibit immune destruction by T-cells. Not surprisingly, this general approach can lead to unintended inflammatory cascade throughout the body, including cardiac manifestations⁵³ including myocarditis, pericarditis, arrhythmia, cardiomyopathy, or myocardial ischemia. The most apparent risk factor for ICI-cardiotoxicity is combination therapy with another cardiotoxic agent (including another ICI)⁵⁴. With increasing recognition of the immune phenomena associated with immunotherapy, retrospective studies estimate myocarditis occurs in up to 1% of patients taking ICIs^55–57. In patients that develop ICI myocarditis, GLS is reduced even if LVEF is not and is associated with future major adverse cardiac events (MACE)⁵⁸. There is evidence of STE-detected RV dysfunction that correlates with duration of ICI use, suggesting a role of CTRCT monitoring⁵⁹.

In contrast to ICIs, CAR-T therapy works by using T cells that have been harvested from the host, reprogramming them to target tumor cells, and reintroducing them into the host. CAR-T cardiotoxicity manifests primarily as arrhythmia, cardiomyopathy, or ischemic events. LVEF reduction has been demonstrated in 5–10% of patients on CAR-T therapy^60–62. To our knowledge, there are no published studies evaluating strain imaging in patients receiving CAR-T therapy. Thus, the rate of cardiac toxicity is likely underestimated.

Echocardiography in Radiation Therapy

Radiation has long been used as a cancer therapy. Cardiotoxicity arises from direct cellular damage of the myocardium and endothelial tissue of the heart and vasculature within the field of radiation. Cardiotoxicity can manifest as hypertension, coronary artery disease (CAD), valvular disease, pericarditis, myocarditis, cardiomyopathy, or arrhythmia⁶³. Cardiotoxicity risk is increased in patients with total exposure of >15Gy and increases with increasing doses⁶⁴. Strain imaging, GLS mostly, has been used to evaluate CTRCT following radiotherapy (RT) to the chest. Numerous studies show subclinical cardiac dysfunction after initiation of chest RT (in the absence of other cardiotoxic therapies) for treatment of breast cancer in both acute and follow up periods of up to three years^65–71. Higher radiation doses^{66–68,70,71} and left-sided breast radiation^67,68 are associated with larger decreases in GLS. The apical region⁷² and subendocardial region of the heart receiving the most radiation⁶⁵ have demonstrated earlier detection of strain reduction, suggesting higher sensitivity for detection of CTRCT by assessing these regions.

3D Echocardiography

3D echocardiography is a modality that has emerging potential in the field of cardio-oncology. While not as ubiquitous as 2D echocardiography, it offers superior capability in assessment of LVEF^4,73, providing values that agree with CMR⁷⁴. Compared to 2D echocardiography, 3D echocardiography offers more reproducible LVEF¹⁰, faster and earlier strain assessment^75,76, and more detailed structural and anatomic characteristics of cardiac masses.

Echocardiography and Cardiac Masses

Echocardiography plays a pivotal role in the detection and diagnosis of cardiac masses. Although rare, neoplastic cardiac masses carry significant morbidity and mortality⁷⁷. Benign cardiac tumors are more common than malignant ones. Metastatic cardiac tumors, seen in 10–12% of patients with a known primary cancer⁷⁸, are more common than primary cardiac malignancy. 2D echocardiography can delineate cardiac masses and certain characteristics (size, shape, mobility, relative density, associated effusions) quite well for initial evaluation (Figure 2, Panel A). However, there is limited ability to distinguish right-sided masses, left atrial appendage masses, extra-cardiac masses, tissue characteristics, and type of mass⁷⁹. 3D echocardiography better evaluates size and anatomical associations of cardiac masses, adding benefit in surgical planning⁷⁶. Perfusion contrast with 2D echocardiography enhances diagnostic utility and has sensitivity and specificity of 93–100% in differentiating thrombi vs. benign tumor vs. malignant tumor^80–82. Transesophageal echocardiography (TEE) has shown high diagnostic accuracy⁸² with better anatomic resolution of right-sided and posterior structures⁸³, but it is an invasive procedure associated with risk including that of sedation and expense.

Figure 2:

(A) Mass identified in the RV outflow tract on echocardiography. Suspected to be a metastatic lesion from an unknown primary source. (B) Two masses identified on CMR (horizontal long axis view). The LV mass is a metastatic melanoma. The RA mass is a thrombus. (C) One RV mass on CMR (short axis view), diagnosed as metastatic melanoma with surrounding thrombus. (D) One LV mass identified on CMR (vertical long axis view), diagnosed as a poorly differentiated synovial sarcoma.

Echocardiography in Tamponade and Pericardiocentesis

Pericardial effusions can be due to infection, autoimmune inflammation, direct effect of malignancy, adverse effect of cancer therapy (radiation-induced pericardial disease, ICI inflammation, volume overload), post-surgical, or idiopathic. Pericardial effusions are readily identified on traditional 2D echocardiography, though may require multiple views if the effusion is loculated. If posterior, TEE may be required to adequately view the effusion.

Pericardiocentesis, drainage of a pericardial effusion, is generally indicated for asymptomatic and large effusions, hemodynamically significant effusions (i.e. impending or active tamponade), or fluid biopsy to aid diagnosis. While overt tamponade implies active hemodynamic consequences such as hypotension, tachycardia, dyspnea, or pulses paradoxus from compression of the heart, effusions at high risk for developing tamponade cannot be readily identified on physical exam alone. Echocardiography, viewed as the gold-standard for diagnosis, can identify signs of compression before the presence of symptoms. These include RA or RV collapse during diastole, abnormal septal motion indicative of interventricular dependence, dilated inferior vena cava without inspiratory collapse, swinging heart, or decreased mitral early filling velocity on doppler⁸⁴. Echocardiography-guided pericardiocentesis, which has been used for decades, is safe and effective in cancer patients, and should be the utilized before surgical drainage when possible^85–87.

Echocardiography in Cardiac Amyloidosis

Cardiac amyloidosis is a group of conditions that result in the infiltration and expansion of myocardial extracellular space with amyloid protein deposits. Though various proteins can misfold and deposit as amyloid, transthyretin (ATTR) and immunoglobulin light chains (AL) account for 95% of cases. Cardiac amyloidosis usually manifests clinically as heart failure (preserved ejection fraction more often than reduced ejection fraction), restrictive cardiomyopathy, and dysrhythmias. Typical 2D echocardiographic findings include ventricular wall hypertrophy (concentric more common in AL, asymmetric more common in ATTR), diastolic and/or systolic dysfunction, restrictive LV filling, bi-atrial enlargement, valvular thickening, and a “sparkling” texture of the myocardium^9,88. Two-dimensional STE often reveals a characteristic pattern of reduced GLS with apical sparing, due to segmental differences in total amyloid mass distribution⁸⁹, with a reported sensitivity of 93% and specificity of 82% for cardiac amyloid when compared to LV hypertrophy controls⁹⁰. The combination of GLS values with apical sparing and serum T-troponin offers better sensitivity and specificity⁹¹. One recent study⁹² found a GLS/EF ratio >4.1 to be a strong predictor of cardiac amyloidosis, with an OR of 35.57. While echocardiography is the universal initial imaging modality when suspicious for cardiac amyloid, it cannot reliably distinguish between amyloid and other causes of hypertrophy. Thus, echocardiography alone is not sufficient for diagnosis.

Practical Use of Echocardiography in Everyday Clinical Practice

Each institution and case will have varying protocols for which views and data are obtained on echocardiogram. The following has been suggested for comprehensive initial echocardiographic assessment in screening for CTRCT: 2D LVEF via Simpson’s biplane method or 3D LVEF, 2D or 3D GLS, 2D or 3D LV systolic volume, RV function markers (such as tricuspid annular plane systolic excursion (TAPSE), RV fractional area change, RVEF, RF free wall strain), velocity of tricuspid regurgitation⁹. Suggested echocardiographic surveillance protocols for patients on anthracycline therapy and trastuzumab therapy can be found in Figures 2 and 3, respectively. Suggested echocardiographic surveillance protocols for patients on radiation therapy, targeted therapy, or immunotherapy can be found in Table 2.

Figure 3:

Suggested echocardiographic surveillance protocol of cardiotoxicity in patients on anthracycline therapy. Low risk features include age 18–50 years, cumulative dose <200 mg/m² doxorubicin (or equivalent), no pre-existing or new CVD risk factors. Intermediate features include age 50–65 years, cumulative dose 200–400 mg/m² doxorubicin (or equivalent), 1–2 pre-existing or new CVD risk factors. High risk features include age <18 or >65 years, cumulative dose >400 mg/m² doxorubicin (or equivalent), any combination of cardiotoxic cancer therapies, underlying CVD, history of CTRCT.

Abbreviations: CAD coronary artery disease; CMR, cardiovascular magnetic resonance imaging; CTRCT, cancer therapy-related cardiotoxicity; CVD, cardiovascular disease; Echo, echocardiography.

Table 2:

Suggested echocardiographic and CMR surveillance protocols of cardiotoxicity for patients undergoing targeted therapy, immunotherapy, or radiation therapy.

Suggested Clinical Imaging Surveillance Protocols for CTRCT in Various Cancer Therapies
Class	Echocardiography	Cardiac MRI
All Classes	Consider baseline for all intermediate and high risk patients prior to initiation of therapy Any time there are signs or symptoms concerning for possible CTRCT	Consider with abnormal echo or poor visualization Consider if clinical suspicion for CTRCT persists despite normal/equivocal echo Unexplained CVD
Proteasome inhibitors	Periodically if history of other cardiotoxic cancer therapy, personal CVD or risk factors, or specifically taking carfilzomib	Consider with abnormal echo or poor windows/visualization Unexplained CVD
VEGF-I and TKI (including BRAF, MEK, and VEGF inhibitors with TKI mechanism)	High risk patients on TKI: Consider screening echo every 1–3 months during therapy Intermediate risk patients on TKI: consider every 6–12 months during therapy Intermediate or greater risk of CAD prior to initiation of TKI: consider stress All patients on VEGFI, high risk in particular: consider echo every 3–6 months during therapy High risk patients on combination BRAF/MEK therapy: consider echo every 1–3 months during therapy Low or Intermediate risk patients on BRAF or BRAF/MEK therapy: consider echo at 6 months, then every 6–12 months while on therapy.	Consider in those with potential unexplained cardiomyopathy. Consider in evaluation of ischemic disease Unexplained CVD
Immunotherapies (ex. ICIs, CAR-T cell therapies, allogeneic stem transplantation)	High risk or taking other cardiotoxic therapy (including 2nd ICI): serial echo reasonable In high risk patients, first echo should be obtained within 1–2 months after initiation of therapy If LV function abnormal prior to initiation of ICI, every 3–6 months for duration of therapy Consider anytime screening ECG or serum biomarkers are abnormal	Low threshold to move to CMR after echo With any cardiac symptoms, suspicious elevation in troponin, or ECG change Consider if concern for ischemic cardiotoxicity Unexplained CVD
Radiotherapy	High risk patients: 1–2 years after completion of therapy and every 5–10 years following Intermediate risk or lower: every 5–10 years after therapy completion	If concern for radiation-induced myocardial or pericardial disease despite normal or equivocal echo Unexplained CVD

Abbreviations: BRAF, B-Raf proto-oncogene; CAD, coronary artery disease; CAR-T, chimeric antigen T-cell therapy; CTRCT, cancer therapy-related cardiotoxicity; CMR, cardiovascular magnetic resonance imaging; CVD, cardiovascular disease; ECG, electrocardiogram; Echo, echocardiography; ICI, immune checkpoint inhibitor; LV, left ventricular; MEK, mitogenactivated protein kinase kinase; RV, right ventricular; TKI, tyrosine kinase inhibitor; VEGF-I, vascular endothelial growth factor inhibitor.

Recommendations for targeted therapies and immunotherapy are less defined due to the relative dearth of data in novel agents. Individual risk assessment and joint decision making is paramount in developing a patient-centered screening plan. Regardless of therapy, baseline echocardiography prior to initiation of therapy should be obtained in all intermediate and high-risk patients and can be considered in low-risk patients. Additionally, any time there are signs or symptoms of cardiotoxicity, echocardiography should be obtained and referral to a cardio-oncologist should be considered.

Cardiac MRI

CMR and LVEF

Although CMR is not deployed for routine screening in cardio-oncology, it offers superior imaging in tissue characterization, volume assessments, spatial resolution, and potentially strain imaging. Table 1 illustrates the relative utility of CMR in various parameters. CMR can investigate most adverse cardiac effects from cancer therapies and allows the specific assessment of RV and LV function, ventricular and atrial volumes, ventricular and left atrial deformation, myocardial mass, pericardial disease, fibrosis, infiltrative tissue, edema, and inflammation^9,93. Measurement of LVEF is considered the gold standard due to excellent accuracy and precision^6,94. CMR is utilized for LVEF measurement when there are poor echocardiographic windows or echocardiography is equivocal or unreliable. Given the poor agreement of 2D echocardiography with CMR-derived LVEF, CMR should be used any time highly accurate LVEF quantification is needed, especially if 3D echocardiography is not available^5,95.

CMR Strain Imaging

Like echocardiography, CMR-derived LVEF lacks the sensitivity to detect early myocardial dysfunction in CTRCT. Cardiac deformation quantification via strain imaging techniques is available in some clinical CMR labs and useful in detection of subclinical myocardial dysfunction. Techniques include CMR reference tagging, phase velocity mapping, displacement encoding with stimulated echoes (DENSE), strain encoded (SENC) imaging (Figure 4), and feature tracking (FT). CMR reference tagging is the most validated and considered gold standard for CMR strain imaging, however CMR-FT is gaining traction due to ease of clinical use^93,96,97. Analogous to STE but with better resolution⁹⁸, CMR-FT is a post-acquisition processing method that can be applied to images obtained for LVEF assessment, requiring no extra scanner time⁹⁶. CMR-FT shows good reproducibility in global strain measurements, provided the same software package is used^99,100. The potential for early detection and prognostication in CTRCT by CMR strain has been demonstrated in patients receiving various cardiotoxic chemotherapies^101,102, and is discussed further below. CMR-FT has even shown promise in evaluation of left atrial (LA) strain, which, along with MRI measured LA volume, could represent an important marker for potential development of atrial arrhythmias and clot formation^98,103.

Figure 4:

Suggested echocardiographic surveillance protocol of cardiotoxicity in patients on trastuzumab therapy. Low risk features include age 18–50 years, no pre-existing or new CVD risk factors. Intermediate features include age 50–65 years, 1–2 pre-existing or new CVD risk factors. High risk features include age <18 or >65 years, any combination of cardiotoxic cancer therapies, underlying CVD, history of CTRCT.

Abbreviations: CAD coronary artery disease; CMR, cardiovascular magnetic resonance imaging; CTRCT, cancer therapy-related cardiotoxicity; CVD, cardiovascular disease; Echo, echocardiography.

CMR T1 and T2 Mapping

T1-weighted imaging (Figure 5) reflects the inherent intracellular and extracellular makeup of tissue. Unitless values of intensity (compared to a reference “region of interest” within the same image) are assigned to each pixel but are only comparable within the same image. T1 is lengthened (brightened) by water, edema, and inflammation; it is shortened (darkened) by iron, fat, and contrast¹⁰⁴. T1 mapping is a relatively new CMR application that allows for creation of color maps, where each colored pixel represents a quantified, parametric, tissue-specific T1 value of the corresponding voxel that is comparable across images¹⁰⁵. This allows sensitive detection of subtle T1 changes within the myocardium, often representing early stages of disease. T1 mapping reliably distinguishes regional and diffuse fibrosis (scar)¹⁰⁶, edema¹⁰⁷, and infarction¹⁰⁸. It has shown promise in detecting numerous cardiac disease states^98,109,110. Late gadolinium enhancement (LGE) (Figure 5), conversely, only visualizes regional fibrosis well⁹⁸. T1 mapping solves this limitation while providing a contrast-free alternative for fibrosis detection. T1 mapping is primarily utilized for evaluation of the LV, but there are sequences that can evaluate fibrosis of the LA, with possible application in therapies causing atrial arrhythmias¹¹¹. Contrast T1 imaging is useful, however, in quantifying extracellular volume (ECV), which correlates histologically¹¹² with the excess collagen deposition of fibrosis.

Figure 5:

Representative images of (A) late gadolinium enhancement, and elevated (B) myocardial native T1, and (C) myocardial T2 in a patient with suspected targeted cancer therapy (TKI) cardiotoxicity, as visualized by cardiac magnetic resonance imaging. Red arrows in panels (B) and (C) indicate areas of elevated T1 and T2, respectively; the pink outline in panel (B) denotes a region of interest (ROI) in the septum.

T2-weighted imaging (Figure 5), like T1, is reflective of the intracellular and extracellular makeup of tissue. T2 time is increased by free water and most helpful in distinguishing edema and inflammation, proving to be comparable to Lake Louise criteria for diagnosis of myocarditis¹¹³. T2 mapping can now be created, just as T1 mapping can¹⁰⁴, with good reproducibility¹¹⁴. However, it has not been as thoroughly studied in CTRCT as has T1 mapping.

CMR in Anthracyclines

Anthracycline cardiotoxicity is characterized by myocardial dysfunction that in its most severe presentation manifests as heart failure with reduced ejection²⁸. Although CMR is more sensitive and accurate in LVEF assessment than echocardiography, it is not sensitive enough for CTRCT screening¹⁰⁹. CMR strain imaging, while not as extensively studied or as readily available as echocardiographic strain imaging, shows a similar promise in early detection and prediction of CTRCT⁹⁶ via both systolic^115–119 and diastolic¹²⁰ measurements. Because anthracycline CTRCT is characterized by diffuse fibrosis³¹, LGE is seen in just 6% of patients¹²¹. Numerous studies have demonstrated that T1 mapping and ECV quantification detect fibrosis after anthracycline therapy, representing an avenue for early diagnosis of CTRCT^{118,122–125}. One prospective study¹¹⁸ showed elevated T1 and T2 mapping values in patients on anthracycline therapy compared to controls three months after therapy initiation, but only elevated T1 more than 12 months after therapy initiation. This suggests that initial edema/inflammation eventually progresses to fibrosis. The authors created criteria for detection of cardiotoxicity in these patients which led to diagnostic accuracy of 84% for detection of CTRCT, outperforming both GLS and troponin alone. More studies are needed to elucidate ideal threshold values for optimum diagnostic and prognostic ability. Published data on T2 mapping in anthracyclines, though minimal, shows early edema and inflammation^118,126 after administration indicating early signs of CTRCT with excellent sensitivty¹²⁷. There is encouraging data for the utility of T2 mapping in CTRCT in various animal models^128–130, but human studies remain relatively sparse. Other CMR-derived measurements have been studied in anthracycline use. LA enlargement has been associated with increasing anthracycline doses, potentially offering a marker of diastolic dysfunction¹³¹. Decrease in myocardial mass after anthracycline therapy has been repeatedly demonstrated^{95,121,132,133}, which is associated with increased risk of MACE¹²¹ and HF symptoms¹³³.

CMR in HER2/Neu Therapy

CMR strain parameters have shown promising ability to predict the development of CTRCT in patients on Trastuzumab therapy. One prospective study demonstrated that a 15% relative decrease in tagged-CMR GLS, tagged-CMR GCS, and CMR-FT correspond to increased odds of CTRCT of 47%, 50%, and 87% respectively¹³⁴. Multiple other studies have shown a decrease in various CMR-measured strain parameters, often with persistence up to twelve months. Recovery by eighteen months is frequently seen, highlighting the reversibility of trastuzumab cardiotoxicity^135–137. Diastolic function has been assessed with both strain and LV diastolic filling rates, but these data are inconsistent^137,138. CMR evaluation of LGE highlights a key difference in the pathogenesis of trastuzumab from anthracyclines. While LGE is uncommon in anthracycline cardiotoxicity due to diffuse fibrosis, LV lateral wall LGE enhancement is seen in 94–100%^139,140 of patients treated with trastuzumab who had reduced LVEF. This parallels the knowledge that trastuzumab cardiotoxicity primarily affects the LV. There is CMR evidence to add to echocardiographic evidence³⁴ that RV myocardial dysfunction is also seen, though more subtle than LV dysfunction¹⁴¹. Animal studies show increased T1 and T2 values in subjects receiving trastuzumab with eventual recovery^142–144. Human data show similar findings¹⁴⁵ but clinical utility in early detection and prediction of CTRCT is limited due to temporal variability^101,146.

CMR in Proteasome Inhibitors

Case reports represent the bulk of literature covering the heterogeneous CMR findings in PI cardiotoxicity. Fibrosis indicated by LGE is the most common finding, seen mostly at the basal and inferior portions of the septum^147–149. Conversely, two patients receiving both carfilzomib and bortezomib developed significant but reversible LVEF reduction with wall motion abnormalities without LGE³⁷. The only prospective study we are aware of studied eleven patients with cardiovascular risk factors but no pre-existing cardiovascular disease for up to six months after bortezomib therapy with echocardiography and CMR. All imaging parameters, including echocardiographic GLS and CMR LGE, were normal¹⁵⁰. More data is needed for proper understanding of CMR findings in PI-associated CTRCT.

CMR in TKIs and VEGF-Is

There is scant published data on CMR findings in VEGF-Is and TKIs, mostly in the form of case reports. Many overlap as they involve TKIs that inhibit VEGF pathways. One prospective study evaluated cardiotoxicity of 90 patients in phase I trials of a VEGF-I monoclonal antibody, VEGF-I TKI, or a kinesin inhibitor¹⁵¹. Out of 90 patients, 10 developed cardiotoxicity. Of these ten, two were taking the VEGF-I TKI, and six were taking the VEGF-I monoclonal antibody. The only patient with a reduced EF was taking the VEGF-I TKI. None of the 10 patients had LGE on CMR. One case report of sunitinib-induced cardiomyopathy included CMR evaluation that showed no LGE or resting perfusion defects¹⁵². We are not aware of any published data pertaining to CMR strain, T1 mapping, or T2 mapping in relation to cardiotoxicity of TKIs or VEGF-Is. Because of the propensity of some TKIs to invoke atrial arrhythmias, such as ibrutinib, LA evaluation with LGE, T1 and T2 mapping, and CMR strain could be beneficial and warrants further study. Hypertension and vascular effects of therapies that inhibit VEGF pathways make CAD and myocardial ischemia an important adverse effect to monitor for. Along with stress and perfusion imaging, CMR offers techniques with ability to quantify myocardial viability^6,98.

CMR in Immunotherapy

CMR is the gold-standard non-invasive diagnostic tool for myocarditis, the most important cardiotoxic effect of immunotherapy. The Lake Louise Criteria (LLC), introduced in 2009 for the diagnosis of non-ICI myocarditis, requires clinical suspicion of myocarditis plus two of the following: regional or global myocardial increase in T2-weighted images, increased global myocardial early T1 gadolinium enhancement, or ≥ 1 focal lesion with non-ischemic regional LGE¹⁵³. The emergence of T1 and T2 mapping and ECV quantification has outdated the original criteria, leading some groups to use modified LLC to incorporate these parameters to increase diagnostic accuracy^55,154,155. One study found 100% of ICI myocarditis cases met original LLC or had abnormal T1 or T2 imaging¹⁵⁵. A meta-analysis of non-ICI myocarditis patients found native T1 and T2 mapping and ECV provide comparable diagnostic performance to LLC with native T1 having higher sensitivity than LLC for non-ICI myocarditis. It is important to note the underlying inflammatory mechanisms of ICI myocarditis are not necessarily comparable to non-ICI myocarditis. Additionally, diagnostic specificity is challenging in ICI myocarditis due to inherent heterogeneity, stemming from varying levels of inflammation in varying cardiac structures¹⁵⁶. This heterogeneity is reflected in the literature in both clinical presentations and imaging findings^157–159.

Reduced LVEF on CMR is not a sensitive finding for ICI myocarditis, reported in just 39%−50% of patients^{155,158–160}. Strain imaging via CMR-FT has demonstrated significant reduction of LV-GLS in all ICI myocarditis patients, with even larger reduction in those with reduced LVEF¹⁵⁸. While LA strain has demonstrated additional prognostic value when combined with LV strain and LLC¹⁶¹ in non-ICI myocarditis, this was not seen in ICI myocarditis. In ICI myocarditis, LGE has been reported in 48–80% of patients^56,157–159. LGE occurs in non-coronary distributions, but location varies by case¹⁵⁹. Presence of LGE is an independent predictor of mortality in ICI myocarditis¹⁵⁸ but has not been associated with MACE¹⁵⁹. Interestingly, in one study¹⁵⁹, LGE was seen in 21.6% of patients when CMR was obtained prior to day four of admission and 72% when obtained on or after that. Thus, LGE prognostic value might differ depending on the timing of CMR acquisition.

Qualitative T1 and T2 lack adequate sensitivity compared to quantitative mapping^155,158,162. A retrospective¹⁵⁵ study that evaluated T1 and T2 mapping in patients with ICI myocarditis found elevated values compared to controls in 78% and 43% of the patients, respectively. Elevated T1 values were independently associated with MACE and lower MACE-free survival. No patients with normal T1 values had MACE, suggesting a clinically important negative predictive value. While abnormal T2-mapping has been associated with MACE in non-ICI myocarditis¹⁶³, this is not reflected in ICI myocarditis^155,159. Increased ECV is also associated with MACE and death in non-ICI myocarditis^164,165, though no published data addresses this in ICI myocarditis.

CMR in Radiation Therapy

Cardiotoxicity from RT has a wide spectrum of manifestations, all stemming from direct macrovascular and microvascular damage. Literature surrounding radiation can be difficult to interpret, as most studies involve patients who in addition to radiotherapy have received anthracyclines and/or trastuzumab. Radiation cardiotoxicity can lead to reduction in LVEF detectable by CMR. This is seen transiently at 6 months with resolution at 2 years¹⁶⁶, and, in survivors, many years after therapy¹⁶⁷. LA volume assessment reveals an association between LA size and radiation dose, suggesting a possible early marker of diastolic dysfunction¹³¹. CMR strain imaging for the detection of subclinical cardiac dysfunction in patients who received radiation is not as well studied. In one study there is a transient decrease in CMR-derived strain at 6 and 12 months that recovers by 24 months¹⁶⁶. Other studies in humans and rats have similar findings, but it is unclear if there is a correlation between GLS reduction and radiation dose^168,169. Fibrosis indicated by LGE has been well-documented following radiotherapy, however, studies are vastly heterogeneous, reporting LGE incidence of 0%−100%^{168,170–173}. Multiple studies demonstrate LGE presence in areas that received the highest radiation doses^170,172,173. Studies of T1 mapping post-RT are sparse and inconsistent. Some show elevated T1 mapping values in areas of higher radiation^172,174, while others found either no elevation of T1 values¹⁶⁸ or no correlation with radiation dose¹⁷¹. There is minimal published data on T2 mapping post-RT.

CMR offers sensitive and detailed structural and tissue characterization of pericardial toxicity and its associated hemodynamic consequences. LGE of the pericardium is indicative of active pericarditis, while chronic constrictive pericarditis will not enhance. CMR tagging can identify pericardial adhesions. Real-time cine imaging during respiration can reveal hemodynamic consequences of constrictive pericarditis, such as ventricular interdependence. Real-time phase contrast imaging can be useful in detecting effects of respiration on flow through the mitral and tricuspid valves^6,63,104. CMR can also be helpful in evaluation of valvular pathology induced by radiation toxicity, generally not seen for 10–20 years after therapy. CMR is particularly useful in visualizing the pulmonary valve, which can be challenging via echocardiography. CAD and ischemic heart disease secondary to radiation therapy are also assessable by CMR via perfusion imaging and coronary artery visualization^6,63,98,104. CMR can even play a role in prevention of cardiotoxicity. Through various techniques under investigation, CMR shows promise in preparatory and real-time imaging to improve safety and precision of radiotherapy¹⁷⁵ and radiosurgery¹⁷⁶, reducing total radiation exposure.

Potential Role of Stress Perfusion and Other Cardiac MRI Imaging Techniques

Numerous cancer therapies increase risk of vascular disease, as does malignancy itself. Contrast-enhanced myocardial stress perfusion has excellent diagnostic performance in detection of ischemic disease¹⁷⁷. However, screening via stress-perfusion CMR without symptoms does not provide additional benefit in cardiotoxicity diagnosis or management¹⁷⁸. Pulse wave velocity, an MRI method of quantifying arterial stiffness, is elevated during and after breast cancer treatment with various anti-cancer therapies^179,180 and could represent a method of risk stratification. 4-dimensional flow MRI can provide flow and pressure parameters of the vasculature. Its role in risk stratification is still under exploration¹⁸¹. Real-time CMR has shown benefit in enhancing precision of radiation targeting to reduce total radiation exposure^175,176 and increasing diagnostic yield of endomyocardial biopsy¹⁸².

CMR and Cardiac Masses

The superior tissue characterization and spatial resolution of CMR makes it the preferred method of imaging for intra-cardiac and pericardial masses (Figure 2, Panels B–D). CMR is particularly helpful in confirmation and further characterization when echocardiography is not sufficient¹⁸³. Balanced steady-state free precession (SSFP) is the primary method for detailed anatomic description. T1- or T2-weighted double inversion recovery (DIR) imaging with or without fat saturation is useful in tissue characterization of masses. Gadolinium enhancement is helpful in assessing tumor vascularity and associated myocardial fibrosis¹⁸⁴. CMR performs well at distinguishing non-tumors from tumors, and benign tumors from malignant ones^185,186. With a wider field of view, CMR can catch pericardial and extra-cardiac masses missed by echocardiography. Additionally, CMR outperforms echocardiography in predicting ultimate tumor diagnosis as confirmed by pathology. CMR has fewer false positives and can eliminate the need for biopsy by ruling out a mass seen on echocardiography¹⁸³.

CMR in Tamponade and Pericardiocentesis

While echocardiography is generally sufficient to diagnose pericardial effusion and tamponade, CMR can offer further details in the assessment of pericardial disease. CMR can identify loculated or posterior effusions, pericardial thickening, and pericardial masses where echocardiography often cannot. As described above, CMR is certainly capable of detecting signs of tamponade^6,63,104, however, it is generally unnecessary unless echocardiography is unavailable or CMR is to be obtained for another reason. One of the more helpful applications of CMR in pericardial disease is the ability to distinguish constrictive pericarditis (thickened pericardium, interventricular dependence) from restrictive cardiomyopathy (diastolic dysfunction, large but normally contoured atria, thickened myocardium, normal pericardium)^187,188. CMR does not play a role in percutaneous pericardiocentesis but can aid in planning for surgical drainage of a pericardial effusion.

CMR in Cardiac Amyloidosis

CMR, with its fine tissue characterization, plays an important role in cardiac amyloidosis screening, diagnosis, and surveillance of disease burden. LGE is almost invariably seen in cardiac amyloidosis, with the typical patterns being diffuse subendocardial (representing earlier stages) and diffuse transmural (representing later stages). RV LGE is also seen in >90% of patients. Transmural LGE is more common in ATTR than AL¹⁸⁹ and also carries prognostic value¹⁹⁰. Native T1 values are markedly elevated in cardiac amyloid, and T1 mapping is particularly helpful when amyloid renal disease precludes the use of gadolinium¹⁶². ECV quantification is a valuable tool given the underlying pathologic mechanisms of amyloidosis¹⁹¹. ECV values are markedly elevated in cardiac amyloidosis, often indicating >40% ECV. Serial measurement of ECV is reliable¹⁹², prognostic¹⁹³, and indicative of disease progression or response to therapy^194–196. T2 mapping, of which there is little published data in regards to amyloid, shows higher values in amyloidosis compared to controls. However, there is little difference in AL and ATTR¹⁹⁷. Although LGE, T1 mapping, and ECV all provide valuable roles in cardiac amyloidosis, a recent meta-analysis suggests that ECV provides the highest diagnostic and prognostic capability of the three¹⁹⁸. Regardless, all should be included in any cardiac amyloidosis evaluation.

Practical Use in Everyday Clinical Practice

Guidelines do not recommend routine screening for CTRCT via CMR unless echocardiography is not feasible due to poor windows or CMR is needed for other indications⁵. Additionally, if echocardiography is normal or equivocal, but clinical suspicion for cardiotoxicity remains high, CMR should be obtained. CMR protocols for CTRCT evaluation differ between institutions and individual cases. Commonly used sequences include cine balanced SSFP, strain imaging through myocardial tagging or other methods, phase contrast flow, native T1 and T2 sequences with respective parametric mapping, post contrast T1 ECV mapping, first pass arterial perfusion, inversion recovery, and 4D flow^93,199. Suggested CMR surveillance protocols for patients on anthracyclines and trastuzumab can be found in Figure 3 and Figure 4, respectively. Suggested CMR surveillance protocols for patients on radiation therapy, targeted therapy, and immunotherapy can be found in Table 2. Again, individual risk assessment and joint decision making is a crucial part in developing a patient-centered surveillance plan. Patients should be referred to a cardio-oncologist any time there are signs or symptoms of cardiotoxicity.

Future Directions and Ongoing Clinical Trials

The field of cardio-oncology has seen a boom in research over the past ten years. The more we learn, the more our gaps in knowledge become evident. Strain imaging via echocardiography represents our best early imaging biomarker for CTRCT, and the addition of serum biomarkers can increase diagnostic and prognostic value. The majority of the available data, however, is in observational studies of patients exposed to anthracyclines, trastuzumab, or radiation. More prospective studies with larger cohorts are needed in patients exposed to all groups of cardiotoxic cancer therapies, especially novel therapies. The LATER CARDS study will provide a large prospective dataset of echocardiographic findings and serum biomarkers in the under-studied pediatric population²⁰⁰.

CMR, though offering better imaging sensitivity and specificity for most cardiac pathologies, is more difficult to clinically implement and has not been as robustly studied as echocardiography. Future research should aim for larger, prospective studies evaluating traditional and emerging CMR protocols. Patients on targeted and immunotherapies are under-studied compared to anthracyclines, trastuzumab, and radiation and should be a major focus of research as well. The CARTIER study is a prospective study of elderly patients on cardiotoxic chemotherapy who will receive serial CMR before each cycle of treatment and with follow up after treatment completion¹²⁷. The CareBest prospective study, currently underway, will enroll >2000 breast cancer patients and study various CMR parameters in a short CMR protocol²⁰¹. Similarly, other CMR-based trials across various cancer drug-classes are underway, which should illuminate the role of trackable subclinical disease in the development of limiting CVD.

Machine learning is a growing research tool with much potential in cardio-oncology. It allows for identification of similar groups buried within the noise of highly heterogenous populations. Machine learning has been used to identify potentially cardioprotective variants in cardiac injury pathway genes among pediatric cancer survivors with anthracycline-induced CTRCT²⁰². It has also been used to identify unique asymptomatic diastolic dysfunction phenotypes based on echocardiographic parameters, each with distinct long-term outcomes risks²⁰³. It is natural to foresee the incredible value of machine learning to sift and organize the vast amount of hard data collected with echocardiography and CMR into clinically useful CTRCT prediction tools⁶. Some combination of serum biomarkers and echocardiographic strain parameters is the intuitive place to start given our current knowledge.

Finally, research should also focus on our ability to implement CTRCT screening protocols. Only 30–40% of patients receive optimal screening via echocardiography²⁰⁴. Implementing user-friendly guidelines, development of dedicated cardio-oncology programs and multidisciplinary clinics, improved patient and provider education of CTRCT, and development of quicker and cheaper imaging protocols could increase patient participation in CTRCT. Continued improvement of CTRCT screening protocols has the potential to positively impact survival and outcomes in the ever-growing cancer patient population.

Figure 6:

(A) Representative screenshot of CMR (SENC) image in short axis view with overlying endocardial (yellow) and epicardial (green) borders. (B) MyoStrain LV and RV longitudinal strain with corresponding heat map, and absolute values of each individual segment. (C) MyoStrain LV and RV circumferential strain with corresponding heat map, and absolute values of each individual segment.

Abbreviations: CMR, cardiovascular magnetic resonance imaging; LV, left ventricular; RV, right ventricular; SENC, strain encoded.

Key Points.

• Echocardiography is the first line imaging modality for cancer therapy related cardiotoxicity (CTRCT) screening and investigation.

• Echocardiographic strain imaging can detect subclinical cardiac dysfunction and is a promising tool for prediction and prognostication of CTRCT.

• Cardiac MRI (CMR) should be obtained if echocardiography is insufficient or suboptimal, highly accurate volume assessments are needed, or myocarditis is suspected.

• CMR is the gold standard for ventricular volume and functional assessment.

• T1 mapping can identify and quantify edema, infarction, and fibrosis. T2 mapping can identify and quantify edema and inflammation. Both should be included in CMR protocols as they offer invaluable tissue characterization for the diagnosis of various CTRCT manifestations, including myocarditis.

• Surveillance protocols for CTRCT via echocardiography and/or CMR vary based on the patient’s individual risk and cancer therapy.

• Baseline echocardiography should be obtained prior to initiation of any cancer therapy in all intermediate and high-risk patients and considered in low-risk patients.

• Echocardiography should be obtained any time there are signs or symptoms of cardiac involvement in a patient with history of exposure to cardiotoxic cancer therapy. Referral to a cardio-oncologist should also be considered at that time.

Synopsis:

Cardiovascular (CV) events are an increasingly common limitation of effective anticancer therapy. Over the last decade imaging has become essential to patients receiving contemporary cancer therapy. Herein we discuss the current state of CV imaging in cardio-oncology. We also provide a practical apparatus for the use of imaging in everyday cardiovascular care of oncology patients to improve outcomes for those at risk for cardiotoxicity, or with established cardiovascular disease. Finally, we consider future directions in the field given the wave of new anticancer therapies.

Clinics Care Points.

Echocardiography

• When using echocardiography to measure LVEF, remember there is limited precision. Values can vary up to 10% between studies.

• A normal EF does not rule out the possibility of CTRCT.

• When interpreting deformation values, remember that threshold numbers and strict normal ranges have not been widely agreed upon. Relative change from baseline is a better datapoint to follow.

• Multidisciplinary clinics can minimize patient stress, enhance communication, and increase patient access to guideline and evidence-based screening/treatment.

• Echocardiography alone is not sufficient to diagnose myocarditis. CMR should be obtained anytime there is a question of myocarditis.

• Normal EF and lack of LGE do not rule out myocarditis

• While appropriate surveillance practices allow us to catch and treat CTRCT early, optimizing modifiable risk factors (diet, exercise, smoking, hypertension, etc.) is equally important.

• Educating patients on signs and symptoms of CTRCT is important for patient empowerment and home monitoring of symptoms.

• Consult with an imaging or cardio-oncology specialist prior to obtaining echocardiography and/or CMR to ensure all needed parameters/sequences are acquired. This can prevent repeated scans and optimize available clinical data.