Cancer therapy–related cardiac dysfunction is a potential side effect of many cancer treatments, including anthracycline chemotherapy, targeted therapies, and chest radiotherapy, as well as many antineoplastic drugs in development.
1
Ten years ago, the multiple-hit hypothesis was proposed, suggesting that pre-existing risk factors coupled with direct and indirect (through associated deconditioning) effects of cancer therapies on the cardiovascular system jointly conspire to increase the risk of heart failure in breast cancer survivors.2
Since then, it has been established that cardiovascular disease is indeed an important competing risk for individuals diagnosed with breast cancer and other curable cancer types.3
, 4
, 5
, 6
In this issue of the Canadian Journal of Cardiology, Tadic et al.7
provide novel data to suggest that there may be another pretreatment “hit” not previously considered as a contributor to this elevated cardiovascular risk in cancer survivors.Tadic et al.
7
evaluated echocardiographically derived cardiac structure and function in 122 patients with solid tumors and no previous cancer therapy as well as 45 controls matched for age, sex, and cardiovascular risk profile. Although there were no differences in left ventricular (LV) ejection fraction, diastolic function, or LV morphologic features, the cancer group had markedly reduced myocardial strain in the longitudinal, circumferential, and radial coordinates. Among the entire cohort, the presence of cancer was a significant predictor of reduced strain even after adjustment for age, sex, and cardiovascular risk factors. Hypertension was also a univariate and multivariate predictor of depressed longitudinal and circumferential strain, as has been previously demonstrated.8
Furthermore, there was no difference in strain between patient groups with differing cancer types, suggesting a common mechanism of pretreatment cardiac dysfunction.Preclinical studies provide supporting evidence that cancer itself is associated with cardiac dysfunction. Compared with controls, various tumor-bearing rodent models demonstrate decreased cardiomyocyte myofibril density, altered gene expression of cardiac contractile proteins, and increased myocardial fibrosis.
9
, 10
, 11
These animal models suggest that cancer-related cardiac dysfunction arises from cancer cachexia, a complex metabolic disorder characterized by a progressive decline in body weight and increased proinflammatory cytokines such as interleukin-6 and tumor necrosis factor-α.9
, 12
To our knowledge, no previous human studies have compared cardiac structure and function in treatment-naive cancer patients and controls. Tadic et al
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found that approximately half of the patients in their cancer cohort had reduced LV strain at baseline before exposure to cancer therapy. Although LV ejection fraction is the primary diagnostic criterion for cardiotoxicity in clinical trials and routine care of oncology patients, a 2014 systematic review found that cancer therapy–related cardiac dysfunction is consistently preceded by alterations in myocardial mechanics.13
Consequently, current guidelines from the Canadian Cardiovascular Society, the American Society of Echocardiography, and the European Association of Cardiovascular Imaging recommend monitoring longitudinal strain for the early detection of LV dysfunction.14
, 15
Pre-existing subclinical cardiac dysfunction could have important implications in cancer care. Clinical studies suggest that anthracycline effects on LV strain are immediate and cumulative with ongoing exposure.
16
, 17
, 18
Therefore, it is reasonable to assume that individuals with abnormal strain at baseline will be more susceptible to overt cardiac dysfunction and adverse outcomes. Indeed, there is evidence linking longitudinal strain to cardiovascular events in individuals with cancer. Patients with hematologic cancer and reduced longitudinal strain before the receipt of anthracycline chemotherapy are more likely to experience symptomatic heart failure or cardiac death.19
Lower longitudinal strain before or during chemotherapy is also predictive of all-cause mortality among individuals with various cancer diagnoses.20
Together, these findings suggest that (1) pretreatment cardiac imaging holds greater clinical utility than as a benchmark for future comparison alone, (2) current strain-based definitions of cancer therapy–related cardiac dysfunction may be inaccurate in patients with abnormal cardiac mechanics at baseline, (3) cancer itself could be contributing to changes in cardiac function during cancer therapy, and (4) there is a stronger rationale for primary prevention treatment with β-blockers and angiotensin-converting enzymes.21
, 22
Finally, these findings on the importance of strain further justify the use of echocardiography over multigated radionuclide scans, a modality that reports only ejection fraction and is the norm for cardiac surveillance across many Canadian institutions.There are important limitations to the study by Tadic et al.
7
The relatively small cohort size and retrospective design may bias the findings on LV strain. Therefore, these results should be confirmed in larger cohorts recruited prospectively and after exclusion of those with conditions known to affect strain (eg, hypertension and diabetes). A prospective design would allow the collection of biofluids to elucidate potential mechanisms of cancer-associated cardiac dysfunction. Although available data from small animal studies suggests a tumour-mediated proinflammatory cause, cardiac metabolism and energetics pathways should also be characterized. Longitudinal studies will also confirm whether patients with abnormal strain are at increased risk of cancer therapy–related cardiac dysfunction. Future investigations will also require collaboration with basic science and translational researchers, given the challenge of evaluating cardiac function during cancer development and progression in a clinical setting.In summary, Tadic et al's
7
findings lead to important questions about the relationship between cancer and cardiac function. Further study of the responsible mechanisms not only will enhance cancer care but also could lead to novel therapies in heart disease.Funding Sources
A.K. holds a Susan G. Komen Postdoctoral Fellowship Grant, a Canadian Institutes of Health Research Postdoctoral Fellowship, and an Alberta Innovates Health Solutions Clinician Fellowship.
Disclosures
The authors have no conflicts of interest to disclose.
References
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- Left ventricular function assessed by two-dimensional speckle tracking echocardiography in long-term survivors of Hodgkin's lymphoma treated by mediastinal radiotherapy with or without anthracycline therapy.Am J Cardiol. 2011; 107: 472-477
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- Incremental prognostic value of echocardiographic strain and its association with mortality in cancer patients.J Am Soc Echocardiogr. 2015; 28: 667-673
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Article info
Publication history
Published online: December 26, 2017
Accepted:
December 19,
2017
Received:
December 19,
2017
Footnotes
See article by Tadic et al., pages 281–287 of this issue.
See page 235 for disclosure information.
Identification
Copyright
© 2018 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.
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- Left Ventricular Strain in Chemotherapy-Naive and Radiotherapy-Naive Patients With CancerCanadian Journal of CardiologyVol. 34Issue 3
