JACC: HEART FAILURE VOL. 6, NO.

2, 2018

ª 2018 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION

PUBLISHED BY ELSEVIER

STATE-OF-THE-ART REVIEWS

Left Ventricular Dysfunction in

Cancer Treatment
Is it Relevant?

Benjamin Kenigsberg, MD,a,b Anton Wellstein, MD, PHD,c Ana Barac, MD, PHDa,b,c

ABSTRACT

Contemporary cancer therapies have dramatically improved cancer-free and overall survival but have been accompanied by
increasing cancer treatment–related cardiovascular toxicity, including left ventricular (LV) systolic dysfunction. Previously,
systemic chemotherapy with anthracyclines and radiation therapy were the only cancer treatments with significant
cardiotoxicity. However, modern targeted cancer therapies, including HER2 inhibitors, tyrosine kinase inhibitors (TKIs),
proteasome inhibitors, and immune checkpoint inhibitors, have all been associated with adverse cardiovascular events. As
cancer treatment paradigms successfully move toward prolonged targeted therapy, cardiologists are increasingly needed to
assess cardiotoxicity risk and manage asymptomatic and symptomatic LV systolic dysfunction. This state of the art review
summarizes the present knowledge about the mechanisms and clinical practices of screening, diagnosis, and management of
LV dysfunction associated with cancer therapeutic regimens. We utilize the framework of the ACCF/AHA stages of heart
failure (HF) to summarize current evidence for risk stratification and modification (Stage A HF), asymptomatic structural
heart disease detection and treatment (Stage B HF), and reduction of HF morbidity and mortality (Stages C and D HF) during
cancer treatment and in survivorship. We also present new clinical practice challenges and opportunities for active
engagement of cardiologists with multidisciplinary cancer treatment teams in order to ensure optimal patient outcomes.
(J Am Coll Cardiol HF 2018;6:87–95) © 2018 by the American College of Cardiology Foundation.

C ontemporary cancer therapy has led to a 23%

decrease in the cancer-related mortality rate
from 1991 to 2012, with an associated rapid
increase in cancer survivorship (1). Patients undergo-
ing cancer treatment and long-term cancer survivors
remain at elevated risk for a variety of cardiovascular
(CV) toxicities, and CV disease (CVD) represents the
main competing cause of death in cancer survivors
across many primary malignancies (2,3). Moreover,
an increasing number of patients are receiving long-
term, including lifelong, cancer therapies with poten-
tial adverse CV effects. Cancer treatment–related CV
complications include, but are not limited to, left
ventricular (LV) dysfunction, heart failure (HF),
coronary artery disease, myocardial infarction, hy-
pertension, arterial and venous thromboembolism,
and arrhythmias (4).
This state-of-the-art review provides a historic
perspective of cancer treatment–associated LV
dysfunction, its impact on clinical oncology and car-
diology practice over time, and the growing impor-
tance of HF prevention and treatment to improve
outcomes in patients with cancer and cancer survi-
vors (Central Illustration). We use the framework of
the American College of Cardiology Foundation/
American Heart Association (ACCF/AHA) stages of HF
(5) to summarize current evidence for risk stratifica-
tion and prevention, asymptomatic structural heart

From the aDivision of Cardiology, Medstar Washington Hospital Center, Washington, DC; bMedstar Heart and Vascular Institute,
Washington, DC; and the cDepartment of Oncology, Georgetown University, Washington, DC. Dr. Barac is the cardiology principal
investigator on the SAFE-HEaRt trial supported by Genentech, Inc., but has received no financial support for this role. All other
authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Manuscript received August 17, 2017; accepted August 31, 2017.

ISSN 2213-1779/$36.00 https://doi.org/10.1016/j.jchf.2017.08.024

88 Kenigsberg et al. JACC: HEART FAILURE VOL. 6, NO. 2, 2018

Left Ventricular Dysfunction in Cancer Treatment FEBRUARY 2018:87–95

ABBREVIATIONS disease detection and treatment, and reduc-
AND ACRONYMS tion of HF morbidity and mortality during
adult cancer treatment and survivorship.
ACCF = American College of
Cardiology Foundation
STAGE A HF
AHA = American Heart
Association
The 2013 ACCF/AHA HF guidelines identify
ASCO = American Society of
Clinical Oncology that cardiotoxic agents, particularly
ASE = American Society of
anthracycline-based chemotherapy and tras-
Echocardiography tuzumab, may lead to or contribute to HF,
cTnI = cardiac troponin I similar to other known risk factors such as
CV = cardiovascular diabetes, obesity, and tobacco use (Class I,
CVD = cardiovascular disease
Level of Evidence: C) (5). Moreover, recent
data demonstrate significantly higher CVD
FDA = Food and Drug
Administration risk among survivors of lung, non-Hodgkin
GLS = global longitudinal lymphoma and breast cancer, compared
strain with noncancer population, with poor overall
HER2 = human epidermal survival in survivors who develop CVD (6),
growth factor receptor 2 providing a rationale for proactive CV risk
HF = heart failure factor screening and treatment. Specific
LV = left ventricular recommendations regarding dose-related
LVEF = left ventricular ejection toxicity, risk stratification, and HF preven-
fraction tion strategies are lacking in the ACCF/AHA
MCS = mechanical circulatory HF guidelines and we here summarize and
support
contrast recent oncology (7,8) and cardiology
PI = proteasome inhibitor
(9,10) professional society statements and
VEGF = vascular endothelial guidelines.
growth factor
ANTHRACYCLINES. Anthracyclines are potent
inhibitors of topoisomerase II, and thus DNA func-
tion, and for decades have been a crucial component
of chemotherapy for many neoplastic conditions
(Online Table 1). Anthracycline therapy is limited by
dose-related cardiotoxicity, presenting as LV systolic
dysfunction with or without clinical HF, with risk
rising significantly after cumulative doxorubicin
doses above 400 mg/m2 (11). Avoidance or dose
reduction of anthracyclines is recommended when-
ever feasible (8–10) and indeed, anthracycline expo-
sure has significantly declined over time, especially in
breast cancer treatment (12). Data regarding incidence
of cardiotoxicity with lower-dose anthracycline
(doxorubicin #250 mg/m 2 or epirubicin #600 mg/m2 )
used in contemporary breast cancer regimens, are
scarce and recommendations about CV evaluation are
inconsistent across existing guidelines (8–10).
LV ejection fraction assessment and risk stratification
before treatment. A comprehensive assessment,
including screening for CV risk factors and an echo-
cardiogram to exclude underlying cardiomyopathy, is
recommended in all patients planned to receive
potentially cardiotoxic therapy (8–10). The cost-
effectiveness of cardiac screening, especially with
lower-dose anthracycline and no trastuzumab ther-
apy, has been recently questioned (13); however,
these recommendations are based on strong epide-
miologic evidence that presence of CV disease before
initiation of cancer therapy importantly determines
the risk of future cardiac dysfunction (8). The most
recent cardiology professional society statements do
not address this patient population (9,10) whereas the
2017 American Society of Clinical Oncology (ASCO)
Cardiac Dysfunction Guideline bases risk stratifica-
tion on concomitant risk factors (increased risk
with lower-dose anthracycline if in combination
with radiation therapy, or in combination with any
of the following: at least 2 CV risk factors, age
>60 years, pre-existing cardiac dysfunction, or
sequential therapy with trastuzumab) (8). In addition,
modifiable CV risk factors (hypertension, smoking,
diabetes, and dyslipidemia) and borderline low left
ventricular ejection fraction (LVEF) are associated
with increased risk of HF with anthracycline admin-
istration and management is recommended (8)
(Online Table 1).
P r e d i c t o r s o f c a r d i o t o x i c i t y b e y o n d L V E F . The
limitation of normal LVEF for risk prediction has been
widely recognized, prompting investigation of serum
and imaging biomarkers in patients receiving car-
diotoxic therapies. In patients receiving high-dose
chemotherapy, early elevations in cardiac troponin I
(cTnI)–predicted cardiac events at 3 years (14), and
troponin-guided initiation of enalapril in a similar
cohort was associated with reduced risk of LVEF
decline (15). Decreases in global longitudinal strain
(GLS), an echocardiographic marker investigated in
breast cancer patients receiving doxorubicin and
trastuzumab, have also been shown to predict subse-
quent LV dysfunction in combination with ultrasen-
sitive cTnI (16). In a systematic review, a 10% to 15%
reduction in GLS predicted subsequent LV systolic
dysfunction (17), supporting the American Society of
Echocardiography (ASE) recommendations to include
GLS and cTnI in risk stratification of patients before
and during treatment with anthracyclines or trastu-
zumab (9). However, routine use of serum and imaging
biomarkers in asymptomatic oncology population re-
mains limited, primarily due to lack of data supporting
improved outcomes. We await the results of the
ongoing SUCCOUR (Strain sUrveillance during
Chemotherapy for improving Cardiovascular OUt-
comes) trial testing the use of GLS in guiding car-
dioprotection (18). The ASCO guidelines recommend
use of biomarkers in conjunction with clinical assess-
ment only in patients with clinical signs or symptoms
concerning for HF (8), emphasizing the need for pro-
spective studies in asymptomatic population.
D u r i n g s u r v i v o r s h i p . Recent oncology guidelines
recommend a single echocardiogram 6 to 12 months
JACC: HEART FAILURE VOL. 6, NO. 2, 2018
FEBRUARY 2018:87–95
after completion of anthracycline therapy in asymp-
tomatic patients only if they meet high-risk criteria
(Online Table 1). Cardiology consensus statements
recommend more frequent (at the completion of
treatment and 6 months after) (9) or longer follow-up
(at 1 and 5 years) (10), albeit recognizing lack of data
regarding frequency and duration of LVEF monitoring
in cancer survivors.
C a r d i o p r o t e c t i v e s t r a t e g i e s d u r i n g anthracycline
treatment. Cardioprotective strategies have been
historically investigated in patients requiring high
doses of anthracyclines. Administration of the intra-
cellular iron chelator dexrazoxane before anthracy-
cline infusion significantly reduced risk of HF in
randomized clinical trials (19); however, clinical use
remains limited. This is in part due to trial design,
which mostly included patients with advanced stage
malignancies after cumulative doxorubicin dose of
>300 mg/m 2 and lack of data on oncology outcomes
in early-stage cancer (20). As a result, the benefit of
dexrazoxane at initiation of therapy, with lower
anthracycline doses or pre-existing cardiomyopathy,
remains unknown. Alterations in administration, such
as slow infusion and liposomal preparation of doxo-
rubicin, also showed benefit in randomized trials (20),
but are infrequently used with exception of patients
with advanced stage malignancies.
Relevant to cardiologists, evidence is growing for
prophylactic use of beta-blockers, angiotensin-
converting enzyme inhibitors, and angiotensin re-
ceptor blockers (Online Table 1). These agents have
been mostly investigated in patients receiving lower
anthracycline doses and overall have demonstrated
feasibility, safety, and varying degree of LVEF decline
attenuation, which has been the most common
endpoint (21,22). Confirmation in larger trials and
improved understanding of the biological effects of
specific agents are needed before routine adoption
into clinical practice.
At the molecular level, new insights into mecha-
nisms of anthracycline-induced cardiotoxicity may
identify pathway-specific risk predictors or targets
for intervention. For example, topoisomerase IIB
inhibition–associated DNA damage (23) and mito-
chondrial iron deposition (24) have been established as
important mechanisms leading to cellular injury, and
further research is needed to translate these findings
into clinical tools for risk stratification and prevention.
HUMAN EPIDERMAL GROWTH FACTOR RECEPTOR 2–
TARGETED THERAPIES. Human epidermal growth
factor receptor 2 (HER2) was first identified in 1985 as
a homolog of avian erythroblastosis retrovirus (v-erb)
and an oncogene in rat brain tumors (neu), hence
Kenigsberg et al. 89
Left Ventricular Dysfunction in Cancer Treatment
the acronyms HER2/ErbB2/neu (25). HER2 inhibitors
block the overexpressed signaling pathway in HER2-
positive malignancies and have dramatically
improved outcomes in patients with HER2-positive
disease (26). However, HER2-targeted therapies are
associated with a risk of cardiomyopathy and existing
discrepancies in recommendations across guidelines
reflect dynamic evolution of their CV safety moni-
toring (Online Table 1) (27).
L V E F a s s e s s m e n t a n d r i s k s t r a t i fi c a t i o n . In the
seminal trial, in patients with metastatic HER2-
positive breast cancer, addition of trastuzumab to
doxorubicin-containing chemotherapy markedly
improved overall survival (26). Trastuzumab was well
tolerated, with the important exception of incident
cardiomyopathy and unexpected HF in almost one-
third (27%) of patients receiving trastuzumab and
doxorubicin (28). To improve cardiac safety, changes
were introduced in the design of subsequent trastu-
zumab trials including: 1) separate administration of
anthracyclines and trastuzumab; 2) strict entry criteria
based on normal LVEF at baseline or following
anthracyclines; and 3) mandated LVEF monitoring
with recommended therapy holds or cessation if
significant (>10%) LVEF decline was identified (27).
These regulations resulted in dramatically reduced
clinical HF (29). Current Food and Drug Administration
(FDA) recommendations for patients receiving trastu-
zumab, pertuzumab, and ado-trastuzumab emtansine
include assessment of cardiac function before initia-
tion of therapy, frequent (routinely every 3 months)
LVEF evaluations during treatment, and LVEF assess-
ments after completion of therapy (Online Table 1).
The ASE and the European Society of Cardiology
recommend similar frequency in LVEF screening dur-
ing and after treatment with trastuzumab (9,10);
however, recent concerns of over-imaging and the
negative impact of HER2 treatment interruptions on
cancer-specific outcomes call for further research (30).
Notably, the ASCO guidelines state that “echocardio-
gram frequency should be determined by health
care providers based on clinical judgement and
patient circumstances” and point to “a risk from
overscreening that curative or palliative therapy will
be inappropriately compromised in some patients” (8).
The cost-effectiveness of routine echocardiograms to
detect subclinical cardiomyopathy in asymptomatic
patients undergoing treatment with HER2 therapies
requires further investigation. Most importantly,
strong evidence of improved overall survival in breast
cancer patients with trastuzumab therapy (30) shifts
the focus from detection of cardiotoxicity to LV
dysfunction management and multidisciplinary
90 Kenigsberg et al. JACC: HEART FAILURE VOL. 6, NO. 2, 2018

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C ENTR A L I LL U ST RA TI ON Current Clinical Practice of Stage A to D HF Related to Cancer Therapeutics

Kenigsberg, B. et al. J Am Coll Cardiol HF. 2018;6(2):87–95.

Continued on the next page

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FEBRUARY 2018:87–95 Left Ventricular Dysfunction in Cancer Treatment

decision making that will assure access to potentially clinical trials, representing a successful example of
life prolonging cancer therapy. reverse translation research bridging oncology and
Cardioprotective strategies with HER2 targeted cardiology.
t h e r a p y . Cardioprotective strategies during trastu-
VASCULAR ENDOTHELIAL GROWTH FACTOR
zumab therapy have been investigated in small ran-
INHIBITORS. The inhibitors of VEGF signaling form a
domized, placebo-controlled studies (Online Table 1).
heterogeneous group of agents (including antibodies,
In the MANTICORE (Multidisciplinary Approach to
and VEGF trap and kinase inhibitors) that share a
Novel Therapies in Cardiology Oncology Research)
principal mechanism of action (Online Table 1).
trial, bisoprolol or perindopril did not affect the pri-
Hypertension, attributed to dysregulation of critical
mary endpoint of cardiac remodeling (defined as
VEGF pathways in the vascular endothelium, is the
change in indexed LV end-diastolic volume) after 1-
most common CV toxicity, with frequency varying
year of trastuzumab treatment (31). However, biso-
from 25% to 70% depending on drug selectivity,
prolol and perindopril were associated with less
dosing, and underlying cancer and regimen. Cardio-
trastuzumab interruptions and with a small attenua-
myopathy events were initially considered rare, but
tion of LVEF decline (bisoprolol), suggesting that they
post hoc analyses found significantly higher risk of LV
may have a role in cardioprotection (31). In the simi-
dysfunction and HF (35). The lack of prospective CV
larly designed PRADA (Prevention of cardiac
data collection and adjudication, as well as varying
dysfunction during adjuvant breast cancer therapy)
definitions of HF and LV dysfunction in the Common
trial, candesartan, but not metoprolol, attenuated
Terminology Criteria for Adverse Events (used for
LVEF decline in patients receiving epirubicin with or
oncology trial reporting), have been proposed as rea-
without trastuzumab (21). There were no symptom-
sons for data discrepancies. At present time, the car-
atic HF events and overall LVEF remained above 50%
diology (ASE and European Society of Cardiology)
in both studies, questioning the choice of primary
guidelines recommend baseline and surveillance
outcome and whether higher HF risk population
echocardiography whereas the ASCO guidelines do not
should be targeted (32). These trials demonstrate
address patients receiving VEGF inhibitors. In
feasibility and safety of primary cardioprevention
oncology clinical practice LVEF is not routinely
strategies and set the stage for further investigations
assessed before or during treatment with VEGF in-
into distinct biologic effects of HF therapies in cancer
hibitors whereas hypertension management has been
treatment–induced LV dysfunction.
recommended, particularly for patients with other CV
Mechanisms of trastuzumab-associated cardiotox-
risk factors (36,37).
icity remain an area of active investigation and are
relevant for the HF field. It is hypothesized today that PROTEASOME INHIBITORS. The proteasome plays a
interruption of HER2/4 heterodimer signaling inhibits fundamental role in cardiomyocyte homeostasis and
prosurvival pathways and renders cardiomyocytes its inhibitors have been associated with a small in-
susceptible to cellular injuries such as the one induced crease in risk of cardiac dysfunction (Online Table 1).
by anthracyclines (33). The HER2/ErbB agonist neu- Proteasome inhibitors (PIs) are mostly used to treat
regulin improves cardiac function following injury in multiple myeloma and the newer, irreversible PI in-
animal studies (34) and is now being investigated in HF hibitor carfilzomib, commonly used for refractory

C ENTR AL I LL U STRA T I O N Continued

(Upper Panel) Key clinical developments (Clinical use [square], recognition of cancer treatment–related cardiotoxicity [star], and introduction of left
ventricular (LV) FUNCTION monitoring [circle]) are symbolically presented on a timeline for 5 classes of cancer therapies. LV monitoring is not currently
routine oncology practice for treatment with vascular endothelial growth factor (VEGF) inhibitors, proteasome inhibitors, or immune checkpoint inhibitors.
Publication of relevant cardiology and oncology professional society statements that address LV dysfunction is marked on the timeline for each class of
cancer treatment therapeutics that is included in the respective guidelines and statements. (Lower Panel) Current clinical practices regarding LV
dysfunction risk, screening, and treatment, across different categories of cancer therapies, are shown using a simplified schema. The checkmark indicates
existing data and statements or guidelines addressing specific cancer treatment category, a checkmark with asterisk indicates major differences in the
recommendations regarding LV dysfunction among guidelines, and O indicates lack of data or recommendations. The following statements were
included: American College of Cardiology Foundation/American Heart Association (ACCF/AHA) Heart Failure (HF) Guideline (5); American Society of
Echocardiography (ASE) Expert Consensus on Multimodality Imaging of Adult Patients During and After Cancer Therapy (8); National Comprehensive
Cancer Network (NCCN) Guidelines on Survivorship: Anthracycline-Induced Cardiac Toxicity (6); European Society of Cardiology (ESC) Position Statement
on Cancer Treatments and Cardiovascular Toxicity (9); and American Society of Clinical Oncology (ASCO) Clinical Practice Guideline on Prevention and
Monitoring of Cardiac Dysfunction in Survivors of Adult Cancers (7). HER-2 ¼ human epidermal growth factor receptor 2; LVEF ¼ left ventricular ejection
fraction.
92 Kenigsberg et al.
Left Ventricular Dysfunction in Cancer Treatment
disease, has a stronger association with HF compared
with bortezomib (38). Currently, routine CV risk or
LVEF assessment are not recommended before or
during treatment with PIs and predictors of LV
dysfunction remain unknown. Of interest, PIs are
important part of the treatment of patients with HF
due to light chain cardiac amyloidosis, a small pro-
portion (w10% to 15%) of whom overlap with multiple
myeloma (39).
IMMUNE CHECKPOINT INHIBITORS. The immune-
checkpoint blocking antibodies (inhibitor
cytotoxic T-lymphocyte associated antigen 4 [ipili-
mumab], programmed death 1 inhibitors [pem-
brolizumab and nivolumab], and programmed death 1
ligand inhibitor [atezolizumab]) act by releasing in-
hibition of the host’s immune response toward cancer
cells. These agents have revolutionized the treatment
of melanoma and are increasingly used for other
advanced stage malignancies (Online Table 1). Recent
reports of fulminant myocarditis, although rare, have
caused major concern because of fatal outcomes
(40,41). Rash and autoimmune phenomena were
common side effects in checkpoint inhibitor clinical
trials; however, only post hoc review identified the
increased risk of myocarditis, particularly with com-
bination ipilimumab and nivolumab (41). The pro-
posed mechanisms, including shared antigens among
tumor and cardiac myocytes, and potential unmask-
ing of cardiac autoimmune predisposition (41), and
risk stratification strategies remain important areas of
future research.
STAGE B HEART FAILURE
Although awareness is growing that multiple cancer
therapies may cause LV dysfunction, at present time
LVEF assessment is only advised by FDA drug labeling
or oncology society guidelines during treatment with
anthracycline and HER2-targeted agents (Online
Table 1). As a result, data about asymptomatic LV
dysfunction are mostly limited to these 2 classes of
agents.
Historically, anthracycline-induced cardiac injury
was believed to develop late after treatment and be
irreversible. More recently, Cardinale et al. (42) used
routine serial echocardiograms in a heterogeneous
population of 2,625 patients with history of cancer
and anthracycline treatment and identified 226 pa-
tients with cardiotoxicity during a median follow-up
of 5.2 years, 221 of which occurred during the first
year of treatment (42). Importantly, 81% of these
patients were asymptomatic or New York Heart As-
sociation functional class I to II, and treatment with
enalapril, and carvedilol or bisoprolol, resulted in
JACC: HEART FAILURE VOL. 6, NO. 2, 2018
FEBRUARY 2018:87–95
partial or full recovery of LV function in 185 (85%)
patients, thus contradicting the prior paradigm.
Adding to these findings, recent work by Narayan
et al. (43) assessing the longitudinal effects of doxo-
rubicin treatment on LV volumes, strain, LVEF
decline, and recovery, provides echocardiographic
phenotyping of Stage B HF related to anthracyclines.
Trastuzumab-related Stage B HF is typically
defined as an absolute LVEF decrease $10% to less
than the lower limit of normal, as was relatively
of arbitrarily defined in trastuzumab clinical trials (28).
Asymptomatic cardiac dysfunction during treatment
is mostly reversible with recovery of function after
holding or discontinuation of trastuzumab (29). The
crucial modern clinical challenge in this population is
minimizing the serious oncologic consequences of
stopping HER2 treatment due to asymptomatic LV
function decline (30). Current FDA recommendations
limit the use of HER2-targeted therapies to patients
with normal LVEF (Online Table 1) and the results of
the ongoing SAFE-HEaRt (Study Investigating Cardiac
SAFEty of HER2 Targeted Therapy in Patients with
HER2-Positive Breast Cancer and Reduced Left Ven-
tricular Function) trial will provide information about
the safety of continuing HER2 therapy with concur-
rent neurohormonal antagonism in patients with mild
LV dysfunction (44). In clinical practice, the decision
about continuation and choice of cancer therapy in
the setting of Stage B HF should be individualized
and include multidisciplinary cardio-oncology
assessment.
STAGE C HEART FAILURE
Incident HF symptoms in patients with cancer and
cancer survivors should trigger prompt comprehen-
sive evaluation by cardiology and oncology teams
with expertise, initiation of HF treatment, and po-
tential modification of cancer treatment plans (5,8,9).
Clinical management of cancer treatment–related HF
prioritizes initiation of guideline-directed medical
therapy, although notably there is a lack of data on
the use of novel HF pharmacotherapy, including
sacubitril or valsartan and ivabradine, in this popu-
lation (45). In addition to the direct myocardial injury
described previously, multimodality cancer treat-
ment may also contribute to HF development via
ischemia, inflammation, pericardial and valvular
disease (associated with radiation), and existing CV
risk factors may act in concert with these processes.
Although radiation therapy has not been included
in this review focused on chemo- and bio-
therapeutics, a recent report by Saiki et al. (46) de-
serves mention. This population-based study
JACC: HEART FAILURE VOL. 6, NO. 2, 2018
FEBRUARY 2018:87–95
identified an increased risk of HF with preserved EF
in breast cancer survivors that correlated with
increasing cardiac radiation exposure. In addition to
novel insight that radiation may lead to HF inde-
pendent from coronary artery disease, these findings
inform clinicians about the risk of HF with preserved
EF among cancer survivors treated with contempo-
rary radiotherapy.
STAGE D HEART FAILURE
Chemotherapy-induced Stage D HF is relatively
infrequent but has unique management challenges.
Recent reports of immune therapy–related acute
myocarditis presenting with fulminant HF
cardiogenic shock highlight the need for expertise in
advanced hemodynamic support and immunosup-
pressive therapy in managing these patients (41,47).
For patients with chronic advanced HF, a recent his-
tory of active malignancy precludes consideration of
cardiac transplant and mechanical circulatory sup-
port (MCS) may be preferential treatment, either as
destination therapy or as a bridge to decision on
transplant. The International Society for Heart Lung
Transplantation guidelines state that MCS should be
considered for patients with potentially treatable
comorbidities including cancer, although notes that
subsequent transplant candidacy depends on indi-
vidual factors predictive of low recurrence risk
including tumor type, response to therapy, and a
negative metastatic work-up (48). As malignancy
survival rates continue to improve (1), close collabo-
ration between oncologists and transplant cardiolo-
gists is needed to revise practice standards based on
patient-specific clinical risks. A recent analysis of
the INTERMACS (Interagency Registry for Mechani-
cally Assisted Circulatory Support) registry identified
75 patients with chemotherapy-induced HF treated
with MCS from 2006 to 2011 and found similar sur-
vival outcomes although with higher rates of right
ventricular support and bleeding (49). Similarly, pa-
tients with chemotherapy-induced HF who receive
orthotopic heart transplantation have similar survival
to patients without history of cancer (50). Although
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Left Ventricular Dysfunction in Cancer Treatment
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The rapid development of novel oncologic therapies
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and
avoidance of cardiac toxicity to a new common goal of
HF risk prediction, prevention, early diagnosis, and
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patient outcomes.
Recent developments summarized in this article
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dysfunction related to cancer therapies and its
increasing relevance for oncologists and cardiologists
(Central Illustration). LVEF monitoring practices with
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an important shift in focus from detection of toxicity
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promise to transform care and improve outcomes.
ACKNOWLEDGMENT The authors would like to thank
Maria Rodrigo, MD, for her critical reading of the
manuscript input and assistance with the Central
Illustration.
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Kenigsberg et al. 95
Left Ventricular Dysfunction in Cancer Treatment
KEY WORDS anthracyclines, cancer
treatment, cardiotoxicity, HER2-targeted
therapy, LV dysfunction
A PP END IX For an expanded References
section as well as a supplemental table please
see the online version of this paper.