Abstract
Aims
In cancer patients with cardiomyopathy related to anthracyclines and/or trastuzumab, data regarding late gadolinium enhancement (LGE) on cardiovascular magnetic resonance imaging are confusing. The prevalence ranges from 0% to 30% and the patterns are ill-defined. Whether treatment with anthracyclines and/or trastuzumab is associated with LGE is unclear. We aimed to investigate these topics in a large cohort of consecutive cancer patients with suspected cardiotoxicity from anthracyclines and/or trastuzumab.
Methods and results
We studied 298 patients, analysed the prevalence, patterns, and correlates of LGE, and determined their causes. We compared the findings with those from 100 age-matched cancer patients who received neither anthracyclines nor trastuzumab. Amongst those who received anthracyclines and/or trastuzumab, 31 (10.4%) had LGE. It had a wide range of extent (3.9–34.7%) and locations. An ischaemic pattern was present in 20/31 (64.5%) patients. There was an alternative explanation for the non-ischaemic LGE in 7/11 (63.6%) patients. In the age-matched patients who received neither anthracyclines nor trastuzumab, the prevalence of LGE was higher at 27.0%, while the extent of LGE and the proportion with ischaemic pattern were not different.
Conclusion
LGE was present in only a minority. Its patterns and locations did not fit into a single unique profile. It had alternative explanations in virtually all cases. Finally, LGE was also present in cancer patients who received neither anthracyclines nor trastuzumab. Therefore, treatment with anthracyclines and/or trastuzumab is unlikely to be associated with LGE. The absence of LGE can help distinguish anthracycline- and/or trastuzumab-related cardiomyopathy from unrelated cardiomyopathies.
Keywords: magnetic resonance imaging, cardiomyopathy, anthracyclines, trastuzumab, cardiotoxicity, late gadolinium enhancement
Introduction
Anthracyclines are used in the treatment of a wide variety of solid organ tumours and haematologic malignancies, including breast cancer, lymphoma, sarcoma, leukaemia, lung cancer, and multiple myeloma. Trastuzumab is a humanized monoclonal antibody directed against human epidermal growth factor receptor 2 (HER2), which is used to treat HER2-positive breast cancers and metastatic gastric cancer. Both anthracyclines and trastuzumab can affect the cardiovascular system primarily through myocardial damage of varying degrees, which may cause left ventricular (LV) dysfunction and heart failure.1
Cardiovascular magnetic resonance (CMR) is often used to assess patients with known or suspected cardiomyopathy or heart failure. The 2013 ACCF/AHA Guideline for the Management of Heart Failure has a Class IIa (Level of Evidence B) indication for the use of CMR for the evaluation of scar burden in patients with heart failure.2 In patients with newly diagnosed heart failure, CMR can help differentiate between ischaemic and non-ischaemic cardiomyopathies and help identify the cause of the cardiomyopathy based on characteristic profiles of late gadolinium enhancement (LGE) presence, locations, and patterns.3
In patients treated with anthracyclines and/or trastuzumab, data on the prevalence of LGE are conflicting and range from 0%4,5 to 30%,6 and somewhere in between.7,8 These studies have varying designs and relatively small sizes. Some have studied all-comers treated with anthracyclines and/or trastuzumab, while others have only included patients with LV dysfunction. In those with LGE, patterns have been ill-defined. Whether anthracyclines and/or trastuzumab are associated with LGE is unclear. Thus, there is a need to systematically define the prevalence, patterns, and cause of LGE in a large cohort of these patients. This knowledge would help identify the cause of the cardiomyopathy in cancer patients treated with anthracyclines and/or trastuzumab who are suspected to have cardiotoxicity from these drugs. The potential clinical implications are of particular interest since cancer patients are also at high risk for other cardiomyopathies because of their older age and a high burden of cardiovascular risk factors.9
We performed a large cross-sectional study of consecutive cancer patients treated with anthracyclines and/or trastuzumab who underwent CMR for clinical reasons and investigated the prevalence, profiles, correlates, and causes of LGE. We compared the findings with an age-matched group of cancer patients who underwent CMR for similar clinical reasons during the same period but received neither anthracyclines nor trastuzumab.
Methods
Patient selection
Consecutive adult cancer patients treated with anthracyclines and/or trastuzumab and referred for a clinical CMR at the University of Minnesota were identified. Detailed demographic and clinical data were collected by review of the electronic medical record. At our institution, cancer patients are referred for CMR by physician preference primarily for suspected LV systolic dysfunction or, if the patient has poor windows on echocardiography.
An age-matched group of cancer patients, without a history of anthracycline or trastuzumab therapy, who had CMR for cardiomyopathy assessment during the study period was also identified. This group was limited to the four most common types of cancers typically treated with anthracyclines and/or trastuzumab: breast cancer, lymphoma, leukaemia, and sarcoma.
The study was approved by University of Minnesota’s Institutional Review Board with a waiver of signed informed consent.
CMR protocol
CMRs were performed using 1.5 T scanners (Siemens Sonata, Avanto, or Aera, Siemens, Malvern, PA, USA) with phased-array coil systems. The CMR protocol was as follows: first, localizers were acquired to identify the cardiac position. Next, cine CMR images were acquired in short-axis (every 10 mm to cover the entire LV from the mitral valve plane through the apex) and three long-axis views (two-, three-, and four-chamber) using a steady-state free precession sequence. Standard LGE CMR was performed 10–15 min after administration of gadolinium contrast (0.1–0.15 mmol/kg), using a two-dimensional segmented inversion-recovery gradient-echo sequence in identical views as cine CMR. Typical inversion delay times were 280–360 ms.
CMR analyses
CMR analyses were performed for this study by an investigator with expertise in CMR, blinded to all clinical information using Precession (Heart Imaging Technologies, Durham, NC, USA). LV and right ventricular (RV) ejection fractions (EF) were determined by quantitative analysis according to standard recommendations.10 The presence of LGE was determined visually. LGE was noted only if it was seen in two orthogonal planes. LGE was scored on a 17-segment basis, and its distribution pattern was classified as an ischaemic pattern if there was subendocardial and/or transmural involvement in a coronary artery territory, and as a non-ischaemic pattern if there was no subendocardial or transmural involvement in a coronary artery territory. Patients with normal LVEF (55%) and no LGE were defined as having no cardiomyopathy. In those with LGE, the extent was quantified using the full-width-at-half-maximum method and expressed as a percentage of the LV myocardial mass.10–13
Determination of the causes of LGE
After blinded analyses of CMRs for the presence and the extent of LGE, the most likely cause for the LGE and the cardiomyopathy was determined by the consensus of two investigators who reviewed the patient’s medical records to integrate the findings of other diagnostic tests, and the patient’s clinical presentation and course, with their CMR findings.
Statistical analysis
Normally distributed continuous variables were expressed as mean ± SD, and non-normally distributed continuous variables were presented as medians with interquartile range (IQR). Categorical variables were expressed as counts with percentages. Comparison between groups was performed with a two-sample Student’s t-test for continuous, normal variables, and Mann–Whitney rank-sum test for continuous, non-normal data. Pearson χ2 tests were used to compare discrete data between groups; in cases where the expected cell count was <5, Fisher’s exact test was used. All tests were two-tailed. A P-value of <0.05 was used to denote statistical significance. Analyses were performed using R version 3.4 (R Foundation for Statistical Computing).
Results
Overall patient characteristics
Two hundred and ninety-eight patients treated with anthracyclines and/or trastuzumab were included in the study. Patient characteristics are reported in Table 1. The mean age of the cohort was 56.3 years and 36% were men. The most prevalent cancers were breast cancer, lymphoma, and leukaemia. Eighty-three percent had received anthracyclines only, 11% had received both anthracyclines and trastuzumab, and 6% had received trastuzumab only. The prevalence of known coronary artery disease (CAD) was 10%.
Table 1.
Characteristics of cancer patients who received anthracyclines and/or trastuzumab, stratified by the presence or absence of LGE
| All (n = 298) | LGE (n = 31) | No LGE (n = 267) | P-Value | |
|---|---|---|---|---|
| Age (SD) years | 56.3 (14.6) | 61.2 (10.9) | 55.8 (14.9) | 0.049 |
| Men, n (%) | 108 (36.2) | 17 (54.8) | 91 (34.1) | 0.038 |
| BMI (SD) (kg/m2) | 28.4 (6.2) | 28.8 (4.1) | 28.3 (6.4) | 0.70 |
| Type of cancera | 0.37 | |||
| Breast cancer, n (%) | 115 (38.6) | 7 (22.6) | 108 (40.4) | |
| Lymphoma, n (%) | 95 (31.9) | 13 (41.9) | 82 (30.7) | |
| Leukaemia, n (%) | 55 (18.5) | 6 (19.4) | 49 (18.4) | |
| Sarcoma, n (%) | 21 (7.0) | 3 (9.7) | 18 (6.7) | |
| Other cancers, n (%) | 12 (4.0) | 2 (6.5) | 10 (3.7) | |
| Comorbidities | ||||
| Hypertension, n (%) | 136 (45.6) | 20 (64.5) | 116 (43.4) | 0.041 |
| Dyslipidaemia, n (%) | 151 (50.7) | 22 (71.0) | 129 (48.3) | 0.028 |
| Diabetes mellitus, n (%) | 48 (16.1) | 6 (19.4) | 42 (15.7) | 0.79 |
| Former tobacco use, n (%) | 123 (41.3) | 17 (54.8) | 106 (39.7) | 0.15 |
| Current tobacco use, n (%) | 24 (8.1) | 5 (16.1) | 19 (7.1) | 0.16 |
| Coronary artery disease, n (%) | 30 (10.1) | 12 (38.7) | 18 (6.7) | <0.001 |
| Heart failure, n (%) | 81 (27.2) | 13 (41.9) | 68 (25.5) | 0.082 |
| Cancer treatment | ||||
| Anthracyclines only, n (%) | 248 (83.2) | 28 (90.3) | 220 (82.4) | 0.39 |
| Trastuzumab only, n (%) | 17 (5.7) | 3 (9.7) | 14 (5.2) | 0.55 |
| Anthracyclines and trastuzumab, n (%) | 33 (11.1) | 0 (0.0) | 33 (12.4) | 0.033 |
| Chest radiation therapy, n (%) | 117 (39.3) | 9 (29.0) | 108 (40.4) | 0.30 |
| Cumulative anthracycline doseb (IQR) (mg/m2) | 240 (150–300) | 219 (36–262) | 240 (168–300) | 0.10 |
| CMR findings | ||||
| LVEDVI (SD) (mL/m2) | 67.9 (20.9) | 77.7 (29.8) | 66.7 (19.3) | 0.005 |
| LVESVI (SD) (mL/m2) | 35.6 (18.6) | 46.5 (25.8) | 34.3 (17.2) | <0.001 |
| LVEF (SD) (%) | 49.6 (12.5) | 43.1 (12.4) | 50.3 (12.3) | 0.002 |
| LVEF < 55%, n (%) | 189 (63.4) | 27 (87.1) | 162 (60.7) | 0.007 |
| RVEDVI (SD) (mL/m2) | 58.5 (16.5) | 63.6 (22.9) | 57.9 (15.5) | 0.071 |
| RVESVI (SD) (mL/m2) | 25.7 (11.6) | 31.5 (16.6) | 25.0 (10.7) | 0.003 |
| RVEF (SD) (%) | 56.9 (11.1) | 51.9 (11.5) | 57.5 (10.9) | 0.008 |
Three patients received anthracyclines on separate occasions for two different cancers.
The cumulative anthracycline dose was not available for eight patients. P values <0.05 are bolded.
CMR findings
CMRs were done at a median of 2.0 years (IQR 0.6–8.2 years) after cancer treatment. Amongst patients treated with anthracyclines and/or trastuzumab, the median LVEF was 50% and the median RVEF was 57% (Table 1). Sixty-three percent had an abnormal LVEF of <55%. One hundred and five (35.2%) patients had no cardiomyopathy (LVEF 55% and no LGE), 162 (54.3%) patients had an abnormal LVEF with no LGE, and 31 (10.4%) patients had LGE. Of the 31 with LGE, 27 (87.1%) had an abnormal LVEF.
LGE characteristics
The prevalence of LGE was not different amongst patients who received anthracyclines only (28/248; 11.3%) compared with those who received trastuzumab only (3/17; 17.7%); P = 0.43. None of the 33 patients who received both anthracyclines and trastuzumab had LGE.
Amongst those with LGE, ischaemic pattern (subendocardial or transmural) LGE was seen in 20 (64.5%) and non-ischaemic pattern LGE (mid-myocardial or subepicardial) was seen in 11 (35.5%) patients. Supplementary data online, Figure S1 includes patient examples of different LGE patterns.
All 17 LV segments were involved between the 31 patients with LGE. The rates of LGE per segment spanned from 13% to 48%, with relative sparing of the anterior and anterolateral segments, related to myocardial infarctions (MIs) in other segments in most patients with LGE (Figure 1A). In patients with non-ischaemic LGE, all 17 segments were again involved, with segmental rates of LGE ranging widely from 9% to 64%, with the LGE distributed randomly across the segments (Figure 1B).
Figure 1.
Distribution of LGE over the 17 left ventricular segments. (A) The frequency of LGE for each segment, amongst the 31 patients with LGE. (B) The frequency of LGE for each segment, amongst the 11 patients with non-ischaemic LGE.
The extent of LGE ranged widely from 3.9% to 34.7%. The mean was 12.8% and the median was 9.5%. The extent of ischaemic pattern LGE ranged from 3.9% to 34.7%, and the extent of non-ischaemic pattern LGE ranged from 5.9% to 29.7%. The extent of LGE was not different in patients with ischaemic pattern LGE (mean 12.0%; SD 8.9%), compared with those with non-ischaemic pattern LGE (mean 14.2%; SD 6.9%), P = 0.48.
Characteristics of patients with LGE
Patients with LGE were more likely to be older, male, hypertensive, hyperlipidaemic, and have CAD. They were less likely to have received both anthracyclines and trastuzumab. Patients with LGE had lower LVEFs and RVEFs (Table 1).
Causes of LGE
In the 20 patients with ischaemic LGE, the cause of the LGE was determined to be related to ischaemic cardiomyopathy in all, after integration of all available clinical data with the CMR findings, and the absence of other non-ischaemic possibilities. Of these, 12 (60.0%) had a history of CAD, of whom, 10 (50.0%) had a clinical history of MI. Thus, 10/20 (50.0%) were deemed to have an unrecognized MI.
In the 11 patients with non-ischaemic LGE, the cause could be determined in 7 (63.6%) and could not be determined in the remaining 4 (36.4%). Of the 7 with causes identified, 3 were attributed to acute myocarditis, 2 to cardiac sarcoidosis, 1 to acute myocardial calcification,14 and 1 to lymphoma infiltration of the LV. Of the 3 acute myocarditis cases, 1 was attributed to viral myocarditis, 1 to immune check-point inhibitor-associated autoimmune myocarditis, and 1 to eosinophilic myocarditis likely secondary to histoplasmosis.
Findings in age-matched cancer patients who received neither anthracyclines nor trastuzumab
The age-matched group comprised 100 cancer patients with breast cancer, lymphoma, leukaemia, or sarcoma, who were not treated with either anthracyclines or trastuzumab (Table 2). The prevalence of known CAD was 25.0%. The median LVEF was 55% and the median RVEF was 58%. Thirty-eight percent had an abnormal LVEF of <55%. The prevalence of LGE was higher in age-matched cancer patients who received neither anthracyclines nor trastuzumab than in cancer patients who received anthracyclines and/or trastuzumab (27.0% vs. 10.4%; P < 0.001). The extent of LGE was not different between the two groups (9.0% vs. 9.2%; P = 0.71) and the proportion of patients with LGE who had ischaemic cardiomyopathy was also not different (64.5% vs. 66.7%; P = 0.92). In the 9 patients with non-ischaemic LGE, the cause could be determined in 7 (77.8%). Of these, four were attributed to hypertrophic cardiomyopathy, two to eosinophilic myocarditis, and one to cardiac sarcoidosis.
Table 2.
Characteristics of cancer patients who received anthracyclines and/or trastuzumab compared with those of age-matched cancer patients who did not receive either treatment
| Cancer patients who received anthracyclines and/or trastuzumab (n = 298) | Age-matched cancer patients who did not receive either anthracyclines or trastuzumab (n = 100) | P-Value | |
|---|---|---|---|
| Age (SD) (years) | 56.3 (14.6) | 56.9 (11.1) | 0.73 |
| Men, n (%) | 108 (36.2) | 10 (10.0) | <0.001 |
| BMI (SD) (kg/m2) | 28.4 (6.2) | 29.0 (7.3) | 0.42 |
| Type of cancera | <0.001 | ||
| Breast cancer, n (%) | 115 (38.6) | 76 (76.0) | |
| Lymphoma, n (%) | 95 (31.9) | 11 (11.0) | |
| Leukaemia, n (%) | 55 (18.5) | 11 (11.0) | |
| Sarcoma, n (%) | 21 (7.0) | 2 (2.0) | |
| Other cancers, n (%) | 12 (4.0) | 0 (0.0) | |
| Comorbidities | |||
| Hypertension, n (%) | 136 (45.6) | 49 (49.0) | 0.64 |
| Dyslipidaemia, n (%) | 151 (50.7) | 57 (57.0) | 0.33 |
| Diabetes mellitus, n (%) | 48 (16.1) | 12 (12.0) | 0.41 |
| Former tobacco use, n (%) | 123 (41.3) | 36 (36.0) | 0.42 |
| Current tobacco use, n (%) | 24 (8.1) | 19 (19.0) | 0.004 |
| Coronary artery disease, n (%) | 30 (10.1) | 25 (25.0) | <0.001 |
| Heart failure, n (%) | 81 (27.2) | 25 (25.0) | 0.77 |
| Cancer treatment | |||
| Anthracyclines only, n (%) | 248 (83.2) | N/A | – |
| Trastuzumab only, n (%) | 17 (5.7) | N/A | – |
| Anthracyclines and trastuzumab, n (%) | 33 (11.1) | N/A | – |
| Chest radiation therapy, n (%) | 132 (44.4) | 58 (58.0) | 0.002 |
| CMR findings | |||
| LVEDVI (mL/m2) | 67.9 (20.9) | 64.0 (18.5) | 0.11 |
| LVESVI (SD) (mL/m2) | 35.6 (18.6) | 30.2 (17.1) | 0.012 |
| LVEF (SD) (%) | 49.6 (12.5) | 55.1 (12.0) | <0.001 |
| LVEF < 55%, n (%) | 189 (63.4) | 24 (24.0) | <0.001 |
| RVEDVI (SD) (mL/m2) | 58.5 (16.5) | 54.3 (18.4) | 0.034 |
| RVESVI (SD) (mL/m2) | 25.7 (11.6) | 23.8 (15.0) | 0.20 |
| RVEF (SD) (%) | 56.9 (11.1) | 58.4 (11.3) | 0.23 |
| LGE presence, n (%) | 31 (10.4) | 27 (27.0) | <0.001 |
| LGE extent (SD) (%) | 12.7 (9.2) | 11.7 (9.0) | 0.71 |
| Ischaemic LGE, n (%) | 20/31 (64.5) | 18/27 (66.7) | 0.92 |
| Causes of non-ischaemic LGE | 0.24 | ||
| Acute myocardial calcification, n (%) | 1/11 (9.1) | 0/9 (0.0) | |
| Cardiac sarcoidosis, n (%) | 2/11 (18.2) | 1/9 (11.1) | |
| Eosinophilic myocarditis likely due to mediastinal histoplasmosis, n (%) | 1/11 (9.1) | 0/9 (0.0) | |
| Hypertrophic cardiomyopathy, n (%) | 0/11 (0.0) | 4/9 (44.4) | |
| Lymphoma, n (%) | 1/11 (9.1) | 0/9 (0.0) | |
| Myocarditis, n (%) | 1/11 (9.1) | 2/9 (22.2) | |
| Unclear, n (%) | 4/11 (36.4) | 2/9 (22.2) | |
| Viral myocarditis, n (%) | 1/11 (9.1) | 0/9 (0.0) |
Three patients received anthracyclines on separate occasions for two different cancers.
Discussion
Amongst a large cohort of cancer patients treated with anthracyclines and/or trastuzumab, we found that, (i) LGE was present in only a minority of patients (10.4%), (ii) its patterns and locations did not fit into a single unique profile that could be attributed to cancer treatment-related cardiotoxicity; it had a wide range of extent (3.9–34.7%), patterns (64.5% ischaemic, 35.5% non-ischaemic), and locations (amongst the 17 LV segments), (iii) it had alternative explanations in almost all cases, and (iv) LGE was also present in cancer patients not treated with either anthracyclines or trastuzumab. Therefore, it is unlikely that treatment with anthracyclines and/or trastuzumab is associated with LGE.
Comparison with prior studies
Previous studies of cancer patients treated with anthracyclines and/or trastuzumab (Supplementary data online, Table S1) have described rates of LGE ranging from 0% to 30%. Of these, three early studies from the same institution described 94–100% prevalence of LGE in patients with low LVEF after treatment with anthracyclines and trastuzumab, and all were described to be subepicardial linear LGE in the lateral wall.8,15,16 Subsequent studies did not find this prevalence or pattern of LGE. The variation in the prevalence of LGE may reflect the cohort that is referred for CMR. Amongst cancer patients receiving anthracyclines and/or trastuzumab, those with known CAD or other cardiac diseases may be preferentially referred for CMR. Thus, our prevalence of 10.4% reflects the cancer patient cohort referred for clinical CMR at our institution.
Role of CMR in cancer patients treated with anthracyclines and/or trastuzumab and suspected cardiomyopathy
CMR is uniquely suited to help identify the presence of, and the cause of a cardiomyopathy. Cine CMR is the reference standard imaging technique for the assessment of ventricular function17 and LGE CMR allows a direct assessment of cardiomyopathic processes. Cardiomyopathies often manifest with distinct patterns and locations of LGE. A pattern-recognition approach in conjunction with the patient’s clinical information helps in identifying the specific cause in most cases.3 In patients treated with anthracyclines and/or trastuzumab and suspected cardiomyopathy, CMR can confirm the presence of cardiomyopathy (abnormal LV systolic function and/or LGE), and the cause as illustrated in Figure 2.
Figure 2.
Suggested LGE-based algorithm for the workup of suspected cardiomyopathy in cancer patients treated with anthracyclines and/or trastuzumab.
Possible causes of cardiomyopathy in cancer patients treated with anthracyclines and/or trastuzumab
Cancer patients treated with anthracyclines and/or trastuzumab may also have other coexisting cardiac conditions that may be identified based on the LGE location and pattern. CAD is not uncommon amongst cancer patients since both cancer and CAD are associated with older age, smoking, diabetes mellitus, and obesity. CAD may cause unrecognized ischaemic cardiomyopathy, as was seen in 3.3% of our cohort. Unrecognized MI on CMR has been described in clinical18,19 and community-based cohorts20,21 and has been strongly associated with adverse cardiovascular outcomes.19,22–24 Potential non-ischaemic causes of cardiomyopathy that may be more prevalent in cancer patients than in the general population include myocarditis, as a toxic manifestation of cyclophosphamide25 or more recently, of immune checkpoint inhibitors,26 stress cardiomyopathy, and cardiac amyloidosis.
Insights from the age-matched group of cancer patients who received neither anthracyclines nor trastuzumab
If treatment with anthracyclines and/or trastuzumab were to cause LGE, the prevalence of LGE would be expected to be lower in an age-matched group of cancer patients who did not receive these therapies. Interestingly, we observed a higher prevalence of LGE in the age-matched group, supporting our conclusion that treatment with anthracyclines and/or trastuzumab is unlikely to be associated with LGE. The higher prevalence of LGE in the age-matched group is explained by the higher prevalence of CAD compared with cancer patients who received anthracyclines and/or trastuzumab (25.0% vs. 10.1%; P < 0.001). The higher prevalence of CAD in the age-matched group is likely related to the avoidance of anthracyclines and trastuzumab in patients with known CAD because of their higher risk for cancer treatment-related cardiotoxicity.
Clinical implications of our findings
Our study has several important clinical implications. Before treatment with anthracyclines and/or trastuzumab, cancer patients are assessed for their risk for cardiotoxicity. CAD is an important risk factor for heart failure after anthracyclines and/or trastuzumab. Pinder et al.27 identified a hazard ratio of 1.58 (95% CI 1.39–1.79) for the association of CAD with heart failure in older women treated with anthracyclines for breast cancer. Similarly, Ezaz et al.28 identified a hazard ratio of 2.16 (95% CI 1.21–3.86) for the association of CAD with heart failure or cardiomyopathy in older women treated with trastuzumab for breast cancer.28 Patients with CAD are recommended to have a referral to a specialty cardiooncology clinic for treatment and optimization of the CAD prior to cancer treatment, along with a discussion of the risks and benefits of various cancer treatments.29,30 Options to be considered include the selection of alternative non-cardiotoxic cancer treatments, anthracycline preparations with lower cardiotoxicity (e.g. liposomal doxorubicin), reduced-dose schedules, and/or additional cardioprotective drugs (e.g. angiotensin-converting enzyme inhibitors, β-blockers, aldosterone antagonists, or dexrazoxane).29 We show that by detecting unrecognized MIs and undiagnosed CAD, CMR identifies cancer patients with an unrecognized high risk for heart failure after anthracyclines and/or trastuzumab. Thus, there may be a role for CMR in the risk stratification of cancer patients before potentially cardiotoxic treatments, particularly those with risk factors for CAD. The high prevalence of unrecognized MI in patients who received anthracyclines and/or trastuzumab and had ischaemic LGE likely reflects the fact that patients with recognized MI(s) were less likely to receive anthracyclines or trastuzumab.
During or after treatment with anthracyclines and/or trastuzumab, cancer patients undergo periodic imaging for the detection of cancer treatment-related cardiotoxicity. Echocardiography is the most common imaging technique for this purpose. While echocardiography can show abnormal cardiac function (decreased LVEF or global longitudinal strain), it cannot reliably identify the cause of the cardiomyopathy. Using CMR, we show that patients with abnormal cardiac function may have cardiomyopathies from causes other than their potentially cardiotoxic cancer treatment. Knowing the cause of the cardiomyopathy helps guide management with disease-specific therapies.31 For instance, β-blockers may be beneficial in cardiomyopathy related to anthracyclines and/or trastuzumab, but not in cardiac amyloidosis. Identification of ischaemic cardiomyopathy could lead to guideline-directed therapy for CAD, possibly including revascularization. Thus, identifying the correct cause of the cardiomyopathy in these patients could also lead to improved cardiac outcomes. Separately, identification of the correct cause of the cardiomyopathy could prevent unwarranted termination of anthracyclines and/or trastuzumab, which could lead to improved cancer outcomes.
Finally, knowing the cause of the cardiomyopathy allows accurate prognostication because the prognosis varies significantly depending on the cause; patients with ischaemic cardiomyopathy have better survival compared with those with cardiomyopathy related to anthracycline therapy, while those with infiltrative cardiomyopathy have the worst survival.32
These issues could also impact clinical trials of potentially cardiotoxic cancer treatments or cardioprotective drugs. Misidentification of cardiomyopathy unrelated to cancer treatment as cancer treatment-related cardiotoxicity could lead to inaccurate estimates of the cardiotoxic risk of cancer treatments. Similarly, cardiomyopathy unrelated to cancer treatment may respond differently to therapies being tested for the prevention or the treatment of cancer treatment-related cardiotoxicity, and this may lead to inaccurate results.
Limitations
We studied patients who were referred for CMR for clinical reasons based on physician preference, and thus, referral bias is inevitable. This also explains the higher prevalence of CAD and LGE in the age-matched group; they were more likely to be referred for a clinical CMR for evaluation of potentially CAD-related cardiomyopathy, while cancer patients treated with anthracyclines and/or trastuzumab were more likely to be referred for a cardiomyopathy suspected to be related to those treatments. Some causes of non-ischaemic cardiomyopathy such cardiac sarcoidosis may reflect our institutional strengths in these areas, rather than a true prevalence amongst cancer patients treated with anthracyclines and/or trastuzumab. We did not account for the possibility of more than one cause for cardiomyopathy, with anthracyclines and/or trastuzumab as one of them. However, we did not find cases with global LV systolic dysfunction beyond what would be expected from the LGE and the cause of the cardiomyopathy. We did not include data on T1 mapping because they were not available on all patients, and they were not relevant to our study’s objectives. Finally, causality or lack of it cannot be determined from an observational study.
Conclusions
Treatment with anthracyclines and/or trastuzumab is unlikely to be associated with LGE. The absence of LGE can help distinguish anthracycline- and/or trastuzumab-related cardiomyopathy from unrelated cardiomyopathies.
Supplementary data
Supplementary data are available at European Heart Journal - Cardiovascular Imaging online.
Supplementary Material
Acknowledgements
C.S. was supported by National Institutes of Health (NIH) grant K23HL132011. K..M. was supported by the University of Minnesota Clinical and Translational Science Institute (CTSI)’s Advanced Pathways to Research Program (A-PReP). The CTSI is supported through the National Institutes of Health (NIH) Clinical and Translational Science Award (CTSA) program, grant UL1TR002494.
Conflict of interest: none declared.
References
- 1. Armenian SH, Lacchetti C, Barac A, Carver J, Constine LS, Denduluri N. et al. Prevention and monitoring of cardiac dysfunction in survivors of adult cancers: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol 2017;35:893–911. [DOI] [PubMed] [Google Scholar]
- 2. Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Drazner MH. et al. 2013 ACCF/AHA guideline for the management of heart failure: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation 2013;128:1810–52. [DOI] [PubMed] [Google Scholar]
- 3. Senthilkumar A, Majmudar MD, Shenoy C, Kim HW, Kim RJ.. Identifying the etiology: a systematic approach using delayed-enhancement cardiovascular magnetic resonance. Heart Fail Clin 2009;5:349–67, vi. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4. Jordan JH, D’Agostino RB, Hamilton CA, Vasu S, Hall ME, Kitzman DW. et al. Longitudinal assessment of concurrent changes in left ventricular ejection fraction and left ventricular myocardial tissue characteristics after administration of cardiotoxic chemotherapies using T1-weighted and T2-weighted cardiovascular magnetic resonance. Circ Cardiovasc Imaging 2014;7:872–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5. Maestrini V, Cheang MH, Kotwinski P, Rosmini S, Lloyd G, Kellman P. et al. Late anthracycline-related cardiotoxicity in low-risk breast cancer patients. J Am Coll Cardiol 2017;69:2573–5. [DOI] [PubMed] [Google Scholar]
- 6. Lunning MA, Kutty S, Rome ET, Li L, Padiyath A, Loberiza F. et al. Cardiac magnetic resonance imaging for the assessment of the myocardium after doxorubicin-based chemotherapy. Am J Clin Oncol 2015;38:377–81. [DOI] [PubMed] [Google Scholar]
- 7. Harries I, Biglino G, Baritussio A, De Garate E, Dastidar A, Plana JC. et al. Long term cardiovascular magnetic resonance phenotyping of anthracycline cardiomyopathy. Int J Cardiol 2019;292:248–52. [DOI] [PubMed] [Google Scholar]
- 8. Fallah-Rad N, Walker JR, Wassef A, Lytwyn M, Bohonis S, Fang T. et al. The utility of cardiac biomarkers, tissue velocity and strain imaging, and cardiac magnetic resonance imaging in predicting early left ventricular dysfunction in patients with human epidermal growth factor receptor II-positive breast cancer treated with adjuvant trastuzumab therapy. J Am Coll Cardiol 2011;57:2263–70. [DOI] [PubMed] [Google Scholar]
- 9. Shenoy C, Klem I, Crowley AL, Patel MR, Winchester MA, Owusu C. et al. Cardiovascular complications of breast cancer therapy in older adults. Oncologist 2011;16:1138–43. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10. Schulz-Menger J, Bluemke DA, Bremerich J, Flamm SD, Fogel MA, Friedrich MG. et al. Standardized image interpretation and post processing in cardiovascular magnetic resonance: Society for Cardiovascular Magnetic Resonance (SCMR) board of trustees task force on standardized post processing. J Cardiovasc Magn Reson 2013;15:35. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11. Kazmirczak F, Nijjar PS, Zhang L, Hughes A, Chen KA, Okasha O. et al. Safety and prognostic value of regadenoson stress cardiovascular magnetic resonance imaging in heart transplant recipients. J Cardiovasc Magn Reson 2019;21:9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12. Hughes A, Okasha O, Farzaneh-Far A, Kazmirczak F, Nijjar PS, Velangi P. et al. Myocardial fibrosis and prognosis in heart transplant recipients. Circ Cardiovasc Imaging 2019;12:e009060. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13. Shenoy C, Romano S, Hughes A, Okasha O, Nijjar PS, Velangi P. et al. Cardiac magnetic resonance feature tracking global longitudinal strain and prognosis after heart transplantation. JACC Cardiovasc Imaging 2020;13:1934–42. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14. Nijjar PS, Okasha O.. Multiparametric cardiovascular magnetic resonance imaging of acute myocardial calcification. Eur Heart J Cardiovasc Imaging 2019;20:371. [DOI] [PubMed] [Google Scholar]
- 15. Fallah-Rad N, Lytwyn M, Fang T, Kirkpatrick I, Jassal DS.. Delayed contrast enhancement cardiac magnetic resonance imaging in trastuzumab induced cardiomyopathy. J Cardiovasc Magn Reson 2008;10:5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16. Wadhwa D, Fallah-Rad N, Grenier D, Krahn M, Fang T, Ahmadie R. et al. Trastuzumab mediated cardiotoxicity in the setting of adjuvant chemotherapy for breast cancer: a retrospective study. Breast Cancer Res Treat 2009;117:357–64. [DOI] [PubMed] [Google Scholar]
- 17. Huang H, Nijjar PS, Misialek JR, Blaes A, Derrico NP, Kazmirczak F. et al. Accuracy of left ventricular ejection fraction by contemporary multiple gated acquisition scanning in patients with cancer: comparison with cardiovascular magnetic resonance. J Cardiovasc Magn Reson 2017;19:34. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18. Kwong RY, Chan AK, Brown KA, Chan CW, Reynolds HG, Tsang S. et al. Impact of unrecognized myocardial scar detected by cardiac magnetic resonance imaging on event-free survival in patients presenting with signs or symptoms of coronary artery disease. Circulation 2006;113:2733–43. [DOI] [PubMed] [Google Scholar]
- 19. Kim HW, Klem I, Shah DJ, Wu E, Meyers SN, Parker MA. et al. Unrecognized non-Q-wave myocardial infarction: prevalence and prognostic significance in patients with suspected coronary disease. PLoS Med 2009;6:e1000057. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20. Schelbert EB, Cao JJ, Sigurdsson S, Aspelund T, Kellman P, Aletras AH. et al. Prevalence and prognosis of unrecognized myocardial infarction determined by cardiac magnetic resonance in older adults. JAMA 2012;308:890–6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21. Turkbey EB, Nacif MS, Guo M, McClelland RL, Teixeira PB, Bild DE. et al. Prevalence and correlates of myocardial scar in a US cohort. JAMA 2015;314:1945–54. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22. Omori T, Kurita T, Dohi K, Takasaki A, Nakata T, Nakamori S. et al. Prognostic impact of unrecognized myocardial scar in the non-culprit territories by cardiac magnetic resonance imaging in patients with acute myocardial infarction. Eur Heart J Cardiovasc Imaging 2018;19:108–16. [DOI] [PubMed] [Google Scholar]
- 23. Amier RP, Smulders MW, van der Flier WM, Bekkers S, Zweerink A, Allaart CP. et al. Long-term prognostic implications of previous silent myocardial infarction in patients presenting with acute myocardial infarction. JACC Cardiovasc Imaging 2018;11:1773–81. [DOI] [PubMed] [Google Scholar]
- 24. Acharya T, Aspelund T, Jonasson TF, Schelbert EB, Cao JJ, Sathya B. et al. Association of unrecognized myocardial infarction with long-term outcomes in community-dwelling older adults: the ICELAND MI Study. JAMA Cardiol 2018;3:1101–06. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25. Yeh ET, Bickford CL.. Cardiovascular complications of cancer therapy: incidence, pathogenesis, diagnosis, and management. J Am Coll Cardiol 2009;53:2231–47. [DOI] [PubMed] [Google Scholar]
- 26. Johnson DB, Balko JM, Compton ML, Chalkias S, Gorham J, Xu Y. et al. Fulminant myocarditis with combination immune checkpoint blockade. N Engl J Med 2016;375:1749–1755. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27. Pinder MC, Duan Z, Goodwin JS, Hortobagyi GN, Giordano SH.. Congestive heart failure in older women treated with adjuvant anthracycline chemotherapy for breast cancer. J Clin Oncol 2007;25:3808–15. [DOI] [PubMed] [Google Scholar]
- 28. Ezaz G, Long JB, Gross CP, Chen J.. Risk prediction model for heart failure and cardiomyopathy after adjuvant trastuzumab therapy for breast cancer. J Am Heart Assoc 2014;3:e000472. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29. Zamorano JL, Lancellotti P, Rodriguez Munoz D, Aboyans V, Asteggiano R, Galderisi M. et al. 2016 ESC Position Paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines: the Task Force for cancer treatments and cardiovascular toxicity of the European Society of Cardiology (ESC). Eur Heart J 2016;37:2768–2801. [DOI] [PubMed] [Google Scholar]
- 30. Curigliano G, Lenihan D, Fradley M, Ganatra S, Barac A, Blaes A. et al. Management of cardiac disease in cancer patients throughout oncological treatment: ESMO consensus recommendations. Ann Oncol 2020;31:171–190. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31. Bozkurt B, Colvin M, Cook J, Cooper LT, Deswal A, Fonarow GC. et al. Current diagnostic and treatment strategies for specific dilated cardiomyopathies: a scientific statement from the American Heart Association. Circulation 2016;134:e579–646. [DOI] [PubMed] [Google Scholar]
- 32. Felker GM, Thompson RE, Hare JM, Hruban RH, Clemetson DE, Howard DL. et al. Underlying causes and long-term survival in patients with initially unexplained cardiomyopathy. N Engl J Med 2000;342:1077–84. [DOI] [PubMed] [Google Scholar]
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