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Review Articles

Cardiovascular Magnetic Resonance Imaging

Identifying the Effects of Cancer Therapy

Houbois, Christian P. MD*,†; Thavendiranathan, Paaladinesh MSc, MD, SM*,‡,§; Wintersperger, Bernd J. MD, EBCR, FAHA*,†

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doi: 10.1097/RTI.0000000000000430
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Abstract

As a result of evolving treatment options and growing prevention strategies, cancer mortality has declined over the past decades.1–4 In general, cancer therapy may be based on surgery, systemic therapies, and radiation therapy or any combination thereof. With an improved subdifferentiation of tumor biology, specifically systemic tumor therapies have further advanced, either using standard chemotherapy agents or newly developed immunomodulatory agents.5 Despite such a targeted personalized medicine approach, a multitude of applied agents, old or new, may result in adverse effects to the cardiovascular system and particularly the heart. While such effects may culminate in heart failure (HF) symptoms already during the course of the therapy or shortly thereafter, the detrimental effects may also only become noticeable in the long term. As a result, patients may survive their malignancy but suffer from increased morbidity and mortality related to cardiac side effects of employed therapeutic strategies.4

Noninvasive cardiovascular imaging modalities, especially cardiovascular magnetic resonance imaging (MRI), have shown promise in the identification of such side effects. While early identification of functional deterioration may help guide additional therapy to prevent tumor therapy–related HF, identification or exclusion of rare but severe side effects in specific therapies (eg, autoimmune pericarditis/myocarditis) support decisions for urgently mandated add-on therapy or therapy regimen change.

While the details of modern tumor therapy are beyond the scope of this review, we will provide basic general concepts. We will specifically highlight the applications of cardiovascular MRI in the assessment of cancer therapy–related cardiac and vascular toxicity.

CARDIOVASCULAR TOXICITY: DEFINITIONS AND EPIDEMIOLOGY

Cancer survivors are generally at an increased risk of developing cardiovascular disease (including HF, pericardial disease, myocardial infarction) during or after cancer treatment.3,6 While long-term therapy effects and risk of cardiovascular disease are relatively unknown in adults, childhood cancer survivors seem to have a 7-fold higher mortality from therapy-associated cardiovascular disease then the general population.7

Definition

The current definition of cardiotoxicity is predominately based on the assessment of left ventricular ejection fraction (LVEF). LVEF can be derived from multigated acquisition (MUGA) radionuclide angiocardiography, echocardiography, or cardiovascular MRI. Over time, various LVEF-based definitions of cardiotoxicity have been proposed, and, in today’s clinical patient care, their use is often inconsistent. Besides relying on objective measures, some definitions also include patient symptoms and clinical manifestations to categorize different subgroups for left ventricular (LV) dysfunction.

In the current oncology guidelines, cardiotoxicity is defined as a drop in LVEF of ≥10% to <50%, as assessed by MUGA.8 This is also reflected by the still fairly common use of MUGA in the longitudinal follow-up of patients undergoing chemotherapy.

On the basis of the review of initial clinical trials for trastuzumab, the Cardiac Review and Evaluation Committee (CREC) defined cardiotoxicity with a more sophisticated approach including possible patient symptoms as the criteria. In asymptomatic patients, cardiotoxicity is defined as a drop in LVEF of ≥10% to <55% while in patients with symptoms of HF, cardiotoxicity is considered when LVEF drops ≥5% to <55%.9

In 2014, the American Society of Echocardiography (ASE) and the European Association of Cardiovascular Imaging (EACVI) published an expert consensus on imaging in cancer therapy.10 This represents the most recent approach for an imaging-based definition of cardiotoxicity and also embraces the use of possibly more sensitive markers for functional abnormalities. According to this consensus, a reduction in LVEF of ≥10% to <53% on echocardiography was defined as cardiotoxicity.10 As an add-on criterion, a relative decrease from baseline in global longitudinal strain of >15%, as assessed by echocardiography, is considered as subclinical cardiotoxicity.10

It is important to highlight that all these definitions require baseline assessment before therapy induction. As MUGA and echocardiography also demonstrate differences in functional LV parameters,11,12 baseline and follow-up imaging modalities cannot be used in an interchanging manner.

As of today, it is unknown which definition provides the most efficient and reliable approach for the prediction of future HF development and guidance in clinical care.13 In part, this also relates to the definition of HF symptoms within the clinical assessment. Furthermore, currently, there neither exists a specific definition for early cardiac injury nor are any other imaging biomarkers incorporated that reach beyond functional assessment. Cardiovascular MRI may add additional biomarkers that could facilitate a more sensitive and specific identification of cardiotoxicity.

Epidemiology

Cardiotoxicity

In general, “conventional” systemic cancer drugs can lead to a wide spectrum of cardiovascular effects including cardiac dysfunction, myocardial inflammation, and arrhythmias.14–20 Anthracyclines (AC) are known to potentially cause irreversible myocardial damage; the effect is dose dependent, and congestive HF occurs in 0.9% to 26% of patients who receive AC therapy depending on the specific drug administered.14 In the vast majority (73% to 98%) of patients, AC-related HF develops either during or within 1 year after the end of the systemic cancer therapy.21,22 However, even low AC doses do not eliminate potential myocardial damage and may also result in late complications.6,23

It is important to mention that there are known risk factors for the development of AC-induced cardiotoxicity, which include age (above 65 y), female sex, hypertension, existing cardiac disease, other potentially cardiotoxic agents, and mediastinal irradiation therapy.24 In ~30% to 50% of patients who develop AC therapy–related cardiotoxicity, cardiac function does not fully recover after initiation of HF therapy.21,22 After the development of HF, mortality rate reaches as high as 60% within 2 years.16,25–27

In general, targeted therapies like monoclonal antibodies (MAB), tyrosine kinase inhibitors (TKI), and angiogenesis inhibitors seem less toxic. However, specific agents, such as immune checkpoint inhibitors (ICI), carry the potential risk of excessive inflammation and autoimmune responses with rare, but severe cardiotoxic effects despite generally transient and reversible impact.28,29 While myocardial dysfunction appears in only ~7% of patients undergoing trastuzumab monotherapy (MAB; HER-2 inhibitor), in the setting of a combination therapy (eg, AC/trastuzumab), different cardiotoxic effects may overlap, with myocardial dysfunction affecting up to 30% of patients.17,30–32

Currently, other HER-2 inhibitors are being developed or are undergoing clinical evaluation and may, at least partially, overcome the risk of cardiotoxicity.

While ICI may potentially induce (Takotsubo syndrome-like) LV dysfunction during therapy, they are known to possibly cause severe autoimmune myocarditis.33 Recent reports demonstrate an incidence of ~1%, much higher than initially suspected (0.09%), and even a single dose of ICI may result in the development of this rare complication.29,34–36 In the case of appearance, ICI-induced autoimmune myocarditis resulted in a mortality of ∼27%.33

Vascular Toxicity

Negative arterial remodeling due to chemotherapy may induce vascular toxicity. The incidence of hypertension during TKI therapy reaches ∼30%.37 While TKI may also result in the development/progression of peripheral vascular disease, in 4% of patients treated with TKI, arterial thrombosis occurs.38,39 Early atherosclerotic changes may also occur as a result of proteosome inhibitor therapy.40 An important aspect of AC treatment–related vascular toxicity is the early change in aortic stiffness with increased pulse wave velocity (PWV) and a decline in aortic distensibility (AD). Changes are commonly reversible 1 year after chemotherapy.41 Increased aortic stiffness is an independent predictor of mortality in patients with hypertension, and hence it might influence morbidity in cancer patients as well.42

Effects of radiation therapy usually appear many years after therapy.14,17,43,44 After direct exposure within the radiation field, 20% of adult cancer survivors develop significant CAD and ~25% develop valvular or pericardial disease.45 Ten years after chest radiation therapy, the risk for acute cardiac events is ~3%.46

MECHANISMS OF CARDIOTOXIC EFFECTS IN CANCER THERAPY

Biochemical mechanisms of anticancer drug–related cardiac injury and consequently resulting dysfunction are well known, but not fully understood.41,47,48 Cardiotoxicity often develops as a reaction of oxidative stress induced by reactive oxygen species or reactive nitrogen species. Systemic chemotherapeutic agents such as AC may change the equilibrium state either with increased production of both compounds or inhibition of antioxidant enzymes. As a result, high levels of reactive oxygen species lead to an imbalance of redox hemostasis.

MAB, however, are designed to target surface proteins on specific cancer cells. In the case of trastuzumab, the targeted transmembrane (HER-2), which initializes several cellular responses, is not only overexpressed in 30% of breast cancers but is often also expressed on cardiomyocytes.49 Trastuzumab binding to HER-2 receptors inhibits the protective mechanisms of cardiomyocytes resulting from increased oxidative damage caused by prior AC therapy, ultimately leading to contractile dysfunction.47

ICI aim at the activation of the patient’s immune system to conquer cancer cells. Because of potential ligand interaction and expression of similar ligands on cancer cells and immune cells, ICI side effects may result in autoimmune reactions with rare, but severe inflammatory disorders like myocarditis or pericarditis.36

TKI-based interruption of specific signal pathways may result in the activation of the endothelin system, changes in vasomotor tone, and changes of the microvasculature.50–52 As a result of these predominately vascular parameters, increased arterial wall stiffness and changes in blood coagulation may occur.

CARDIOVASCULAR CANCER THERAPY EFFECTS: APPROACHES IN MRI

Given the described potential changes at the tissue level that may relate to cancer therapy and its sequelae, cardiovascular MRI offers a variety of imaging techniques that may be applied. Such techniques generally do not differ from techniques commonly used in other types of nonischemic cardiomyopathies, inflammatory diseases, or vascular abnormalities. However, some imaging approaches and techniques may reach beyond today’s standard of care. Furthermore, especially techniques aiming at tissue characterization have not yet been considered in clinical guidelines aiming at the definition of cardiotoxicity. As a key aspect in diagnosing cancer therapy–related changes of the cardiovascular system, it is of utmost importance to relate potential imaging findings to the patient’s clinical history. MRI findings may not be specific to cardiotoxicity and may also mimic other nonischemic cardiomyopathies findings. Therefore, the temporal relationship to a previous or ongoing systemic tumor therapy is of major importance.

Functional Imaging of the Heart

Ventricular Function and Size

As outlined in the definitions of cardiotoxicity, LVEF has long been established as the parameter of choice in monitoring patients undergoing potential cardiotoxic tumor therapy. In clinical routine settings, the assessment of cardiac function is typically achieved using echocardiography (2D, 3D) or nuclear cardiology using MUGA.10 In the setting of abnormal results or potential discrepancies between modalities, cardiovascular MRI today is clinically being applied as an add-on test (Fig. 1).10,53 MRI has been established as the reference standard for determination of cardiac function and volumes due to its accuracy and high reproducibility.54 In recent years, MRI and echocardiography are increasingly used in cancer therapy monitoring, while the use of MUGA has declined (Fig. 1).55 With respect to the use of cardiovascular MRI for assessment of cardiac function, please refer to the published society guidelines.56,57 Given the possibility of ventricular dysfunction late after tumor therapy, surveillance with these modalities may be required over the patient’s lifetime.

FIGURE 1
FIGURE 1:
A 48-year-old female patient with breast cancer: serial functional bSSFP imaging during and after anthracycline and trastuzumab combination therapy in a patient with HER-2-positive breast cancer. As indicated by end-diastolic time frames (upper row) and results of ventricular quantification, there is no indication of potential relevant lower preload, while end-systolic time frames (lower row) already visually indicate deterioration of global LVEF 12 months after the end of trastuzumab therapy. LVEF quantification confirms a drop in LVEF as a result of cancer therapy.

Animal studies have shown that LVEF, cardiac output, and stroke volume continuously declined until day 78 during doxorubicin-based therapy, with initial LVEF changes occurring as early as 14 days after therapy onset.58 Other studies have demonstrated that a significant LVEF drop may occur as late as after 16 weeks of doxorubicin therapy.59

In general, functional cardiovascular MRI results in a higher diagnostic accuracy in cardiotoxicity identification, as compared with echocardiography, a fact that is likely based on its overall superior reproducibility. Armstrong and colleagues have demonstrated that 2D/3D echocardiography techniques overestimate MRI-derived LVEF (5%), resulting in a higher false-negative rate compared with MRI in patients with LVEF <50%. While MRI identified an LVEF of <50% in 14% of patients, in 11% (2D) and 6% (3D) of these patients, echocardiography incorrectly reported an LVEF >50%. In the same study of survivors with previous undiagnosed cardiotoxicity, ~30% were found with a decreased LVEF >2 SD below the reported normal MRI values. On the basis of these results, consideration of cardiovascular MRI in patients with an LVEF of 50% to 59% was recommended.53 The presence of potential cardiotoxicity may specifically be missed by echocardiography in asymptomatic patients, and cardiovascular MRI may help to better identify patients with undetected cardiomyopathy accompanied by subclinical dysfunction.

Other studies have specifically highlighted the benefit of cardiac MR as a potential add-on in cases of echocardiography-based LVEF of <53% or in cases of insufficient echocardiogram quality.60

Beyond LV deterioration, early studies have also demonstrated right ventricular (RV) AC effects with an RVEF drop in >25% of patients.61,62 Moreover, trastuzumab has been shown to temporarily affect RV function and structure.63

Ventricular EF is based on the evaluation of end-diastolic volume (EDV) and end-systolic volume (ESV), and changes in EF may either relate to changes in myocardial contraction or changes in ventricular preload (filling). As such, it is important to track respective measures such as EDV. Some evidence exists that a drop in LVEF may in part relate to a decrease in ventricular preload potentially incorrectly suggesting cardiotoxic effects.64 Such evidence points to a potential transient effect in the early phase after chemotherapy with AC or trastuzumab, which should not play a relevant role in the longer term. However, the majority of data supports an increase in LVEDV 3 to 4 months after AC therapy, while the effects of trastuzumab may occur even slightly later.65,66 Furthermore, RVEF effects have been reported to initially relate to increased RVEDV with a simultaneous enlargement at end-systole (eg, increased RVESV).63

Myocardial Deformation (Strain)

Beyond the assessment of the ventricular size and global ventricular function, characterization of myocardial mechanics and deformation has continuously evolved over recent years. With respect to cardiotoxicity identification, myocardial strain, a measure of myocardial deformation, has already partially been incorporated into some of the respective criteria (also see above).10

Cardiovascular MRI offers a variety of dedicated strain imaging techniques such as myocardial tagging, SENC (strain-encoded), or DENSE (displacement encoding with stimulated echoes) MRI that have been applied for study purposes in a quest for earlier identification of cardiotoxicity.

In a recent study, myocardial tagging (HARP=harmonic phase) has demonstrated an ~3% relative decrease in global circumferential strain 3 months after AC-based chemotherapy (Table 1).72 With a focus on the midmyocardial layer only, the relative drop in circumferential strain after AC therapy may even reach almost 9%, accompanied by a drop in global LVEF (Table 1).68 Similar findings have been also reported for global longitudinal strain using SENC techniques (Table 1).70 With respect to potential cumulative effects, AC cancer therapy–related changes in circumferential strain are dose-dependent (Table 1).67

TABLE 1
TABLE 1:
Overview of Various Patient Study Results Focusing on LV Strain, as Assessed by Cardiovascular MRI Techniques

Beyond the ability of MRI to assess changes over time, which requires pretherapy/posttherapy examinations, various studies have also embarked on comparison with normal cohorts. Compared with normal controls, ≥75% of patients undergoing AC therapy had a significantly lower magnitude in midwall peak circumferential and longitudinal strain (Table 1).71 Focusing only on patients with reduced LVEF (<55%), abnormal circumferential and longitudinal strain values demonstrated sensitivities of 83% and 79%, respectively (Table 1).71

Besides the use of dedicated imaging techniques for myocardial strain evaluation, more recently, postprocessing algorithms for derivation of strain results from standard bSSFP have become available. Such algorithms, most commonly referred to as feature tracking or deformable registration-based analysis/heart deformation analysis, can simply be applied on routinely acquired functional image data (Figs. 2A, B). Similar to the above-stated dedicated approaches, initial experience in cancer therapy–related cardiotoxicity demonstrated a decline in longitudinal and circumferential strain parameters during therapy, and also showed differences to normal controls (Table 1 and Figs. 2A, B).66,69,73

FIGURE 2
FIGURE 2:
A 48-year-old female patient with breast cancer: Myocardial strain assessment using bSSFP data sets in the same patient, as shown in Figure 1. A, Baseline (left) and 12 months’ posttrastuzumab (right) midventricular short-axis slices at peak systolic strain with color overlay of circumferential strain results. B, Corresponding frames with overlay of longitudinal strain on a 4-chamber view long axis.

Despite the promising results in the use of MRI-derived strain data in the assessment of cardiotoxicity, it has to be taken into account that different techniques and algorithms may result in different ranges of normal values similar to speckle-tracking echocardiography.74,75 Furthermore, reference standards such as myocardial tagging have a higher interobserver variability compared with feature tracking software algorithms.76 More automated approaches using motion correction–based algorithms (deformable registration-based analysis/heart deformation analysis) for the derivation of deformation maps may further reduce interobserver variability (Figs. 2A, B). Initial experiences have already demonstrated promising results in volunteers and patients.72,77,78 The highly important aspect of interstudy reproducibility, which may be influenced by slightly varying settings, may also hamper its widespread standardized clinical use. Various ongoing studies currently investigate the interstudy reproducibility of such cardiovascular MRI biomarkers.

Tissue Characterization

Cardiovascular MRI has been applied for tissue characterization in a broad spectrum of cardiac diseases over >2 decades and plays a major clinical role in the differentiation of various cardiomyopathies, myocardial infiltration, and inflammatory changes.79

With recent developments in techniques, not only qualitative techniques for tissue level differentiation are at hand but also quantitative approaches.

Late Gadolinium Enhancement (LGE)

By far, the most common technique for the purpose of tissue characterization in cardiovascular MRI is late LGE.80 The technique has initially been advocated for the assessment of ischemic myocardial damage/myocardial infarction, but use has then been extended for the assessment of nonischemic cardiomyopathies and inflammation (Fig. 3).81,82 Its basic contrast mechanism relates to the difference in the concentration of an extracellular Gd-based contrast agent (GBCA) caused by variations in contrast kinetics (in-outflow) as well as the amount of extracellular space determining the contrast agent’s distribution volume. Resulting differences in tissue GBCA concentrations are subsequently highlighted by highly T1-weighted inversion recovery techniques based on the nulling of normal appearing myocardium.80

FIGURE 3
FIGURE 3:
A 21-year-old male patient with lymphoma: patient undergoing ICI tumor therapy clinically presenting with chest pain and confirmed elevated troponin in blood samples. Short-axis (A) T2-weighted SPAIR demonstrates fairly homogenous unremarkably low myocardial signal while the pericardium is mildly thickened and of elevated signal (small arrows). The corresponding (B) LGE images demonstrate normally nulled LV myocardium with the prominent enhancement of the pericardium (large arrows) consistent with pericarditis. LV indicates left ventricle; RV, right ventricle.

Animal experiments have demonstrated increased myocardial enhancement and LGE at ~6 weeks of AC treatment.58 However, clinical studies have demonstrated that the vast majority of patients with confirmed cardiotoxicity during/after AC cancer therapy do not demonstrate myocardial LGE61,67,68,70,83–87; in cases where LGE has been reported, locations were in the area of the inferior RV hinge point and in the midmyocardial segments.63,69 Similarly, also in cases of trastuzumab-related cardiotoxicity, LGE is a rare finding.88,89

While LGE imaging may play an important role in the routine assessment of patients with myocarditis, the imaging of autoimmune myocarditis/pericarditis induced by novel personalized medicine treatments with ICI seems much more challenging (Fig. 3). In a cohort analysis, the majority of patients with ICI-associated myocarditis did show a typical LGE pattern,33 but no edema. The presence of a myocarditis-like LGE pattern did not help in predicting future MACE.29

Early Gadolinium Enhancement (EGE)

EGE is considered a marker of hyperemia due to vasodilatation, increased blood volume, and higher blood flow by inflammatory myocardial tissue, and it has been included into the Lake Louise criteria for the diagnosis of myocarditis in cardiac MRI.90,91 Such changes are in general visualized by the use of precontrast and postcontrast T1-weighted fast spin-echo techniques using body coil signal reception92,93 (Fig. 4). Other than LGE imaging, postcontrast data are acquired within 120 seconds after injection. The use of built-in body coils for signal reception is of utmost importance, as the quantification of precontrast/postcontrast changes is not only performed within the myocardium but also the skeletal muscle within the chest wall. With the use of dedicated surface coils, the lack of a homogenous signal behavior would render ratios between both locations unreliable. In patients with myocarditis, Friedrich et al92 reported an elevated EGE ratio of ≥4.0, or an absolute myocardial enhancement of >45%, with a skeletal muscle enhancement ≥25% as indicative of inflammation. Very few data exist in the assessment of cancer therapy impact. Wassmuth et al93 found an increased EGE ratio ≥4.0 in patients with cardiotoxicity after AC therapy. No further published studies have explored the use of EGE in the assessment of cancer therapy effects to the myocardium. A highly important aspect to consider is the likely systemic impact of cancer therapies with resulting hyperemia and as such EGE being affected not only within the myocardium but also within the skeletal muscle. In such a case, the absolute myocardial enhancement may be the parameter of interest, although other influencing factors such as contrast agent dosing and relaxivity of the contrast agent in use need to be taken into account.

FIGURE 4
FIGURE 4:
A 61-year-old female patient with breast cancer: standard EGE imaging in midventricular short-axis orientation acquired with inbuilt body coil to ensure signal homogeneity. In both, precontrast (A) and postcontrast (B) (90 to 120 s) T1-weighted fast-spin echo acquisitions, saturation bands (*) are placed on either side of the heart. For calculation of the EGE ratio, signal intensity, in precontrastand postcontrast acquisitions, is assessed within the myocardium (dotted region of interest) and skeletal muscle (dashed line).

T2-weighted Imaging

Myocardial injury/inflammation may change tissue water content by the higher permeability of cardiomyocyte cell membranes with resulting intracellular edema and by higher vascular permeability resulting in interstitial edema.94 High signal intensity in T2-weighted images is suggestive of edema (Fig. 3A). In various heart diseases, for example, myocarditis, short-tau inversion recovery T2-weighted sequences (STIR) demonstrated increased myocardial water content with high sensitivity and specificity.91

In cardiotoxicity, T2-weighted STIR was not found to demonstrate high signal intensity directly after AC therapy,70 while studies focusing on the SI ratio between the myocardium and skeletal muscle indicated edematous changes in >50% of patients.95 In direct comparison with quantitative cardiac relaxometry techniques, T2-weighted techniques seem to be inferior in the detection of tissue-level changes.96

Cardiac Relaxometry (T1/T2 Mapping)

In contrast to the emphasis of highlighting T1/T2 weighting in MRI, cardiac relaxometry techniques aim to quantify myocardial relaxation times.97,98 Such techniques have shown promise in providing further insight into various cardiomyopathies, with the potential of further differentiation. T2 mapping has primarily been used to detect inflammatory changes with prolonged T2 relaxation times in the presence of edematous changes99,100 (Fig. 5). While T1 mapping has also been proven beneficial in the assessment of myocardial edema,96,101 these techniques are primarily used in the assessment of potential diffuse fibrotic changes (eg, hypertrophic cardiomyopathy) or myocardial/interstitial deposits (Amyloid, Fabrys et.)102,103 (Fig. 5). In the presence of fibrosis or nonlipid/noniron deposits, native (precontrast) myocardial T1 times are increased compared with normal,104 while a higher extracellular concentration of an injected GBCA results in a more prominent T1 shortening.105

FIGURE 5
FIGURE 5:
A 49-year-old female patient with metastatic breast cancer: patient under ICI cancer therapy presenting with suspected myocarditis (elevated troponins). A, Native (precontrast) T1 mapping (1.5 T) exhibits diffusely elevated T1 values of >1100 ms across the entire myocardium on the midventricular short-axis slice (>1170 ms within the septum), while (B) T2 mapping demonstrates T2 values of >55 ms indicative of diffuse myocarditis changes. LV indicates left ventricle; RV, right ventricle.

In recent years, T1 and T2 mapping techniques have demonstrated promising results with regard to the detection of subclinical changes during/after chemotherapy with AC and trastuzumab. Various recent studies have demonstrated that native (precontrast) T1 values are generally elevated during and/or after chemotherapy (Table 2). However, Muehlberg and co-workers reported that, in patients experiencing AC-induced cardiotoxicity at 6 months, native T1 relaxation times acutely decreased within 48 hours of AC therapy, while T1 values after the end of the AC therapy were not significantly different from baseline. While the pathophysiology of such early changes remains unclear, the authors have suggested a possible temporary increase of intracellular lipid contents (Table 2).107 In experimental settings, elevated native T1 values (over baseline) have been demonstrated at 6 weeks after AC therapy (Table 3),108 while similar changes have been described in patients in the midterm and long-term follow-up starting 2 years after AC therapy (Table 2).67,85,87,106 In long-term cancer survivors, postcontrast T1 values at 20 minutes after GBCA injection are lower compared with healthy controls (458±6 vs. 487±44 ms) and correlated with low LV mass and female sex (Table 2).67 Furthermore, the degree of T1 changes seems to relate to cumulative AC dose and gender (Table 2).85

TABLE 2
TABLE 2:
Overview Table Showing the Results of Various Patient Studies with Respect to the Effect of Anthracycline Therapy (and Variations as Indicated) on Myocardial T1 Times and ECV
TABLE 3
TABLE 3:
Overview Table Showing the Results of Various Experimental Animal Studies with Respect to the Effect of Anthracycline Therapy on Myocardial T1 Times and ECV

Interestingly, Jordan et al106 reported that native T1 values in cancer patients are already elevated compared with patients without cancer before chemotherapy. Contradictory to other studies, Kimball et al87 reported native T1 values being in the normal range 5 years after a combined AC/trastuzumab therapy.

Ultimately, T1 mapping has been proposed as a possible reliable technique for the detection and monitoring of cardiotoxicity (Table 3).65,108 Furthermore, changes of T1 relaxation times during and after therapy may be an early marker of ventricular remodeling.85

Similarly to T1-related changes, an early increase of T2 relaxation times has been reported 5 weeks after AC therapy in an animal model when compared with healthy controls. Subsequently, an increase in myocardial fibrosis has been observed.65 These sequelae of acute myocardial edema with subacute fibrosis are related, and both were predictive of the doxorubicin-induced animal mortality.65

Jordan and colleagues demonstrated that 3 years after the conclusion of an AC chemotherapy, T2 relaxation times are within normal ranges. Similarly to the above-described animal findings, T1 relaxation times remain elevated compared with normal controls.106

While T1 and T2 relaxation times are dependent on the external field strength (B0) and the specific sequence technique in use, postcontrast T1 values are also heavily related to GBCA dosing, GBCA relaxivity, and timing after GBCA injection. To overcome this limitation, additional quantitative parameters such as the myocardial distribution constant λ and the extracellular volume fraction (ECV) have been introduced. Both parameters are based on the assessment of changes before/after GBCA application within the myocardium and the LV blood pool. As an expansion to λ, ECV is reflecting λ multiplied by (1-hematocrit) in order to describe the distribution volume of GBCA.109–111 It has been demonstrated that, in cancer patients, ECV is normal before chemotherapy and increases significantly after treatment (27.8±0.7% vs. 30.4±0.7%).106 Currently, no cut-off values for the definition of cardiotoxicity exist, but, in patients with dilated cardiomyopathy, it has been demonstrated that an ECV of 26% could differentiate between normal and diseased myocardium.105 It has also been concluded that ECV has a higher diagnostic value than native T1 mapping or LVEF alone and correlates well with histopathologic findings (Table 3).108

There are limited data available with respect to the reproducibility of quantitative cardiac relaxometry. T1 mapping results have shown high interstudy agreement in short-interval repeated measurements.112 Besides cardiac volume changes, tissue-specific properties like magnetization transfer and B1 inhomogeneities may change quantitative imaging parameters. Especially, T1 values may be dependent on these properties in vivo compared with phantom studies.113 T2 mapping also demonstrated a high level of reproducibility, with a CoV of 7.6% for 2 repeated measurements in healthy volunteers.114

Vascular Toxicity Imaging

Besides dedicated imaging of the heart, the assessment of different vascular territories also is commonly performed by means of cardiovascular MRI.

Today’s delineation of the vasculature and imaging of luminal morphology is most commonly performed using contrast-enhanced MR angiography.115 Beyond vascular morphology assessment, various techniques are available for the assessment of vascular flow dynamics. Phase contrast flow imaging is typically being used, enabling the assessment and quantification of flow velocity, flow volumes, flow direction, and other parameters by implementation of flow-sensitive gradients.116

Changes in flow dynamics may be based on altered aortic wall properties leading to/including changes in stiffness. Increased aortic stiffness is an independent predictor of mortality in patients with hypertension and is associated with future cardiovascular events.42,117,118 PWV and AD are possible measures to assess aortic stiffness (Fig. 6).

FIGURE 6
FIGURE 6:
Principles of aortic PWV assessment on cardiovascular MR: on the basis of high temporal resolution phase contrast flow measurements (A) located in the ascending aorta and at the hiatus level (B), derived flow curves allow the assessment of the delay ([INCREMENT]t) in onset of the upslope and, in combination with the distance ([INCREMENT]d) of the 2 measurement locations (dashed lines in A), allow the calculation of the PWV. AA indicates ascending aorta; DA, descending aorta.

Although not yet extensively explored, systemic anticancer therapies may not only influence quantitative cardiac tissue parameters but may also result in alteration of aortic stiffness. AC therapy, for example, can lead to negative arterial remodeling and result in increased aortic stiffness. PWV significantly increases by ~30% after 4 months of AC therapy and slightly decreases after 14 months of therapy.41 However, the available data in cancer survivors and the resulting discussion remain controversial. Twelve months after completion of an AC therapy, it appears that PWV is still elevated as an expression of possible long-term vascular damage.119 However, in the same time period, AD at the level of the aortic arch decreases 1 month after therapy initiation by 25% and starts to recover after 14 months.41

GENERAL CONSIDERATIONS

As outlined above, cardiovascular MRI provides a variety of techniques generally well suited for assessment and monitoring of cardiotoxic effects related to cancer therapy.

However, decision-making based on the sole value of biomarkers or application of thresholds might be inappropriate, as values are likely subject to variation among different patients. As such, it seems more reasonable to evaluate biomarkers during the course of therapy and monitor whether they rise or fall. Given the need for longitudinal surveillance and comparison, the following aspects are of high importance and require consideration in the decision process for a test:

  • Differentiation between physiological variation and true pathologic myocardial tissue-level changes.
  • General changes of hemodynamics (eg. blood pressure, etc.) possibly also influencing variation of biomarkers.
  • Scanning-related variations such as exact positioning, breath-holding, selection of field strength, and detailed imaging technique, etc.
  • Intraobserver and interobserver variability in postprocessing and potential differences between postprocessing algorithms.

All of the above specifically affect modern quantitative tissue-level biomarkers such as T1, T2, and ECV mapping as relatively minor differences in absolute values may lead to different conclusions. With the field of MRI generally striving for continuous development and improvement, changes in technologies may also affect accuracy and precision of quantitative imaging biomarkers. While quantitative myocardial tissue-level changes are on the verge of entering clinical use in daily routine cardiovascular MRI, recent society position statements outline in detail how to do so carefully.120

CONCLUSIONS

Despite the various qualitative and quantitative techniques available, assessment of global ventricular function such as LVEF currently remains the most common indicator of cardiotoxicity in cardiovascular MRI. A large body of evidence highlights the potential availability of various quantitative biomarkers that may allow a much earlier diagnosis of myocardial changes. Implementation of such techniques in a clinical setting would further require adoption of new biomarkers in society guidelines and cardiotoxicity definitions. However, overcoming vendor and technique-related variations and the standardization of approaches remain important tasks of such processes.

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Keywords:

cardiac function; heart failure; magnetic resonance imaging; chemotherapy; cardiotoxicity; malignancy; oncology

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