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Clinical Manifestations, Monitoring, and Prognosis: A Review of Cardiotoxicity After Antitumor Strategy

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The development of various antitumor drugs has significantly improved the survival of patients with cancer. Many first-line chemotherapy drugs are cytotoxic and the cardiotoxicity is one of the most significant effects that could leads to poor prognosis and decreased survival rate. Cancer treatment include traditional anthracycline drugs, as well as some new targeted drugs such as trastuzumab and ICIs. These drugs may directly or indirectly cause cardiovascular injury through different mechanisms, and lead to increasing the risk of cardiovascular disease or accelerating the development of cardiovascular disease. Cardiotoxicity is clinically manifested by arrhythmia, decreased cardiac function, or even sudden death. The cardiotoxicity caused by traditional chemotherapy drugs such as anthracyclines are significantly known. The cardiotoxicity of some new antitumor drugs such like immune checkpoint inhibitors (ICIs) is also relatively clear and requiring further observation and verification. This review is focused on major three drugs with relatively high incidence of cardiotoxicity and poor prognosis and intended to provide an update on the clinical complications and outcomes of these drugs, and we innovatively summarize the monitoring status of survivors using these drugs and discuss the biomarkers and non-invasive imaging features to identify early cardiotoxicity. Finally, we summarize the prevention that decreasing antitumor drugs-induced cardiotoxicity.
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REVIEW
published: 10 June 2022
doi: 10.3389/fcvm.2022.912329
Edited by:
Emanuela Salvatorelli,
Campus Bio-Medico University, Italy
Reviewed by:
Christian Zuppinger,
Bern University Hospital, Switzerland
Mary Branch,
Wake Forest Baptist Medical Center,
United States
*Correspondence:
Yingkun Guo
gykpanda@163.com
Huayan Xu
xuhuayan89@sina.com
Xia Guo
guoxkl@163.com
These authors have contributed
equally to this work and share first
authorship
Specialty section:
This article was submitted to
Cardio-Oncology,
a section of the journal
Frontiers in Cardiovascular Medicine
Received: 05 April 2022
Accepted: 23 May 2022
Published: 10 June 2022
Citation:
Huang W, Xu R, Zhou B, Lin C,
Guo Y, Xu H and Guo X (2022) Clinical
Manifestations, Monitoring,
and Prognosis: A Review
of Cardiotoxicity After Antitumor
Strategy.
Front. Cardiovasc. Med. 9:912329.
doi: 10.3389/fcvm.2022.912329
Clinical Manifestations, Monitoring,
and Prognosis: A Review of
Cardiotoxicity After Antitumor
Strategy
Wei Huang1, Rong Xu1, Bin Zhou2, Chao Lin3, Yingkun Guo1*, Huayan Xu1*and
Xia Guo3*
1Key Laboratory of Birth Defects and Related Diseases of Women and Children of Ministry of Education, Department
of Radiology, West China Second University Hospital, Sichuan University, Chengdu, China, 2Laboratory of Molecular
Translational Medicine, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University),
Center for Translational Medicine, Ministry of Education, Clinical Research Center for Birth Defects of Sichuan Province,
West China Second University Hospital, Sichuan University, Chengdu, China, 3Department of Hematology, West China
Second University Hospital, Sichuan University, Chengdu, China
The development of various antitumor drugs has significantly improved the survival
of patients with cancer. Many first-line chemotherapy drugs are cytotoxic and the
cardiotoxicity is one of the most significant effects that could leads to poor prognosis
and decreased survival rate. Cancer treatment include traditional anthracycline drugs,
as well as some new targeted drugs such as trastuzumab and ICIs. These drugs may
directly or indirectly cause cardiovascular injury through different mechanisms, and lead
to increasing the risk of cardiovascular disease or accelerating the development of
cardiovascular disease. Cardiotoxicity is clinically manifested by arrhythmia, decreased
cardiac function, or even sudden death. The cardiotoxicity caused by traditional
chemotherapy drugs such as anthracyclines are significantly known. The cardiotoxicity
of some new antitumor drugs such like immune checkpoint inhibitors (ICIs) is also
relatively clear and requiring further observation and verification. This review is focused
on major three drugs with relatively high incidence of cardiotoxicity and poor prognosis
and intended to provide an update on the clinical complications and outcomes of
these drugs, and we innovatively summarize the monitoring status of survivors using
these drugs and discuss the biomarkers and non-invasive imaging features to identify
early cardiotoxicity. Finally, we summarize the prevention that decreasing antitumor
drugs-induced cardiotoxicity.
Keywords: cardiotoxicity, chemotherapy, immune checkpoint inhibitors (ICI), treatment measures, monitoring
methods, cardiac magnetic resonance (CMR)
INTRODUCTION
Antitumor drugs are essential for cancer treatment. These drugs, especially various chemotherapy
and immune checkpoint inhibitors (ICIs), have been rapidly developed and used extensively,
resulting in the significant increase in the survival rate of patients with cancer. However, how to
improve the 5-year survival rate and quality of long-term life of these patients after chemotherapy
is a huge challenge that clinicians need to face in the long-term treatment/remission cycle.
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Huang et al. Cardiotoxicity After Antitumor Strategy
Cardiotoxicity is served as one of the main factors that
affected the quality of life and prognosis of cancer patients (1).
Different types of chemotherapeutic drugs and ICIs currently
used in different clinical conditions, cumulative doses, and
treatment options may cause different effects of myocardial
damage (2). Clinically, cardiotoxicity may be asymptomatic for
a long time or manifest various symptoms such as arrhythmia,
decreased systolic function, and/or myocarditis. These symptoms
may occur immediately after drug administration or occur in
months or years later (3). In some patients, cardiotoxicity could
even affect the choice of cancer treatment strategy. Once the
decreased cardiac function or other significant signs occur,
patients can only receive poorly effective alternative drugs, or
the treatment strategy may be terminated (2,4,5). Hence,
cardiotoxicity is apparently severe, causing more uncertainty to
the treatment of cancer.
Cardiotoxic complications are the main cause of mortality,
and childhood cancer survivors have higher risk of cardiotoxicity
(6). Compared with the general population, childhood cancer
survivors have a 15-fold increase in the risk of congestive heart
failure (CHF) and a 7-fold increase in the risk of premature
death (7). Therefore, continuous monitoring of heart function
throughout the entire cancer treatment course contributes to
detecting myocardial damage, and timely intervention measures
can prevent or even reverse cardiac dysfunction progression.
In this manuscript, we will review the clinical complications
and outcomes of several traditional chemotherapy agents and
newer targeted cancer therapies that may cause high incidence of
cardiotoxicity and poor prognosis. We innovatively summarize
the monitoring status of survivors using these drugs and discuss
the biomarkers and non-invasive imaging features to identify
early cardiotoxicity. Finally, we will summarize the prevention
that decreasing antitumor drugs-induced cardiotoxicity.
CLINICAL MANIFESTATIONS AND
PROGNOSIS
Anthracyclines
Anthracyclines are one of the most widely used antitumor
drugs. Approximately 1 million patients with cancer undergo
anthracycline treatment each year. Generally, it is used clinically
in many blood system and solid malignant tumors (3,8).
Anthracyclines include doxorubicin, which is isolated from
the bacteria of the genus Streptomyces. Hence, they possess
antibiotic properties and have become one of the most effective
chemotherapy treatments ever (8).
Myocardial damage caused by anthracyclines have been
confirmed by many studies and are generally recognized and
accepted in clinical practice. From the initial oncology diagnosis,
more than half of patients who received anthracycline therapy
manifested with cardiac abnormalities after 10–20 years later
(9). Of these patients, approximately 5% patients developed with
CHF. Within 20 years after diagnosis, roughly 40% of patients
experienced with arrhythmia (2). The American Society of
Clinical Oncology has reported the high-risk indicators of cardiac
dysfunction in adult cancer survivors, such indicators include
the high-dose use of anthracyclines (doxorubicin 250 mg/m2,
epirubicin 600 mg/m2) or the use of low-dose anthracyclines
(doxorubicin 250 mg/m2and epirubicin 600 mg/m2)
accompanied with smoking, hypertension, diabetes, obesity, age
over 60 years old, and/or other risk factors (1).
For survivors with previous anthracycline therapy, the
asymptomatic stage is usually characterized by left ventricular
(LV) wall thinning, LV diameter increase, and subsequent LV
wall stress increase, which is similar to dilated cardiomyopathy
(7). Anthracycline cardiotoxicity is related to the cumulative dose
(4,7,9,10). Meanwhile, the dose threshold of anthracyclines
causing heart failure (HF) has been confirmed to become lower
in nearly 30 years of research. According to the initial research,
the dose threshold of doxorubicin-induced HF is 400 mg/m2
(11,12). Without other influencing factors, the incidence of HF
increases to 5, 26, and 48% when the cumulative anthracycline
doses are 400, 550, and 700 mg/m2, respectively. However, a
subsequent study suggested that the dose threshold for HF is
lower (13). In a prospective analysis of clinical trials for patients
with breast cancer and lung cancer, 9% of the study participants
with a cumulative doxorubicin dose of 250 mg/m2developed
cardiac dysfunction. When doxorubicin was administered at a
cumulative dose of 350 or 450 mg/m2, the incidence of cardiac
dysfunction increased to 18 and 38%, respectively. According
to a recent cardiomyopathy screening guideline, the high-risk
cumulative anthracycline dose threshold for childhood cancer
survivors is 250 mg/m2(5,7). But in other reports, the
threshold of long-term cardiomyopathy risk with mitoxantrone is
considerably lower than 250 mg/m2in childhood (14). Therefore,
the safe dose of anthracyclines remains unestablished.
Notably, some cases exhibited sudden HF during the course
of cancer treatment. In a case provided by Saro, a 14-year-
old patient with AML underwent three intensive treatments
containing mitoxantrone (12 mg/m2/dose per day; four doses
in total) after two cycles of remission induction. On day 3
of the second intensive treatment phase (the phase containing
mitoxantrone), the patient developed febrile tachycardia and
high oxygen demand. Echocardiogram showed that the LV
was enlarged. Compared with the cardiac function before
chemotherapy (ejection fraction, 60%; fractional shortening,
32%), the LV function was moderately to severely decreased (EF,
28%; SF, 14%) (4). Although the incidence of mitoxantrone-
induced cardiotoxicity is low, symptoms may vary rapidly
over a short period.
Immune Checkpoint Inhibitors
The use of immune checkpoint inhibitor (ICI) was an important
advance in the field of cancer therapy in the past decade. The
anti-CTLA-4 antibody ipilimumab was the first ICI approved
by the US Food and Drug Administration (FDA). Subsequently,
pembrolizumab, durvalumab, and cemiplimab-rwlc have been
approved for clinical treatment (15). ICI exhibits an antitumor
effect by inhibiting the key regulators of immunotolerance
hijacked by tumor cells. ICI is mostly used for treating
various cancers, including melanoma (unresectable or metastatic
disease and adjuvant therapy), metastatic non-small cell and
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small cell lung cancer, and locally advanced or metastatic
squamous cell carcinoma of the skin. In patients with stage III
(unresectable) or stage IV melanoma, treatment with ipilimumab
can increase the median survival from 6.4 to 10.1 months (16).
However, ICI use may cause immune-related adverse events
(IRAEs) affecting multiple organs, such as the colon, lung, liver,
skin, pituitary, thyroid, and heart. Multiple-organ dysfunction
commonly occurs in therapies combined with ICIs (17). Wolchok
et al. reported that ICIs combination therapy is significantly
associated with adverse events (96%), and grade 3 or 4 adverse
events occurred in 59%, treatment-related adverse events that led
to the discontinuation of therapy occurred more frequently with
combination therapy than with either monotherapy (the severity
of adverse events was graded according to the National Cancer
Institute Common Terminology Criteria for Adverse Events,
version 4.0.) (18).
For cardiotoxicity, some research reported the incidence of
cardiac IRAEs is low (<1%), but the prognosis extremely poor
especially life-threatening fulminant myocarditis, and the median
time from the first exposure of ICI to the onset of myocarditis is
30 days (1924). In addition, left ventricular systolic dysfunction
(LVSD) has an incidence rate of approximately 49–79%, which
does not necessarily exist at the same time as ICI myocarditis.
More notably, a previous study reported 16 serious adverse
cardiovascular events related to ICI but 6 (38%) of them
had a normal LVEF, which indicated patients with a normal
ejection fraction may still develop ICI-related myocarditis (21).
Furthermore, ICI-related myocarditis is associated with other
IRAEs. In previous studies, among patients with ICI myocarditis,
25% had concomitant myositis and 10–11% had concomitant
myasthenia gravis, which indicate that patients receiving ICI who
present with myositis or myasthenia gravis should be assessed
for ICI-associated myocarditis (20,22,25). A recent retrospective
study proposed demographic risk factors for ICI cardiotoxicity.
According to review 538 medical records of patients who
underwent immunotherapy, Brumberger et al. found that there
was a significantly higher percentage of women experiencing
cardiac events compared to men (8.1 vs. 2.9%; P = 0.011) as well
as a higher percentage of African Americans with cardiac events
than Caucasians with cardiac events (12 vs. 4%; P = 0.02) (26).
Patients undergoing treatment with Pembrolizumab (n = 243)
had higher cardiac events rates compared to Nivolumab (n = 220)
(7 vs. 4%) (26). The risk of myocarditis and the mortality rate
are higher when ICI is combined with other drugs that also have
cardiotoxic effects or more than two ICIs treatment (20,22,27).
Salem et al. retrospectively analyzed 32 patients with myocarditis
who received ICI combination therapy (anti-CTLA-4 plus anti-
PD-1 or anti-PD-L1 therapy), and 21 (66%) of them had died
(20). Therefore, once ICI-related myocarditis is suspected during
treatment, patients need to terminate ICI treatment immediately
and permanently because of the high mortality risk for the second
treatment (28). In addition, ICI-related cardiotoxicity events also
include pericardial disease, which can occur alone or association
with myocarditis. The pericardial disease mostly affects patients
with lung cancer. The median time from the first exposure of
ICI to the onset of pericardial disease is approximately 30 days,
and the mortality rate is roughly 21% (20). The ICI combination
therapy also reportedly leads to some complex complications,
such as vasculitis, various arrhythmia types, and acute coronary
syndrome (ACS) (27); however, this matter has not yet been
investigated epidemiologically.
Trastuzumab
Currently, breast cancer is the most common malignancy among
women worldwide, with over 2 million new cases diagnosed in
2018 (29). Human epidermal growth factor receptor 2 (HER2)
protein overexpression occurs in approximately 20–25% of breast
cancer cases and is related to aggressive tumor behavior (3,9,
30). Trastuzumab is a recombinant humanized IgG1 monoclonal
antibody that can selectively bind to HER2. It is often used in
breast cancer chemotherapy for HER2 overexpression treatment
and combined with anthracyclines. Trastuzumab combined with
another chemotherapeutic drug yields a significant effect on
HER2-positive breast cancer, but it can also inhibit tumor growth
when used alone.
A study focusing on HER2 overexpression proved that
trastuzumab combination therapy is effective and that its relative
risk of death and the recurrence rate were reduced by 20 and 51%,
respectively (31). However, cardiotoxicity is the main adverse
event after trastuzumab treatment (30). Patients may present
with myocardial injury, resulting in a poor prognosis including
the risk of sudden death, especially when combined with
anthracyclines. The most common clinical manifestation is the
asymptomatic drop of left ventricular ejection fraction (LVEF)
(3,31,32). Dennis et al. showed that the prevalence of New York
Heart Association classification (NYHA) grade III or IV cardiac
dysfunction is about 16% in patients receiving combination
drug therapy comprising anthracyclines, cyclophosphamide, and
trastuzumab, of which 8% of them developed cardiac dysfunction
and stopped trastuzumab (31). Besides, trastuzumab-related
cardiotoxicity is related to a long-term significant damage of the
cardiopulmonary function. Cardiopulmonary function damage
causes an increased risk of delayed cardiovascular disease in
HER2-positive breast cancer survivors. In an 8-year follow-
up study, the LVEF of approximately 40% of patients with
breast cancer was reduced by 10% after 7 years of trastuzumab
discontinuation that indicated these patients with cardiotoxicity.
Otherwise, compared with those without cardiotoxicity evidence,
these patients had a significantly reduced longitudinal strain and
peak oxygen uptake (32).
Cardiotoxicity also been reported when trastuzumab is used
in combination with other drugs even without anthracycline.
A recent study compared two types of neoadjuvant chemotherapy
for HER2 breast cancer and showed that the incidence of cardiac
events was 7.7% among patients who received trastuzumab plus
docetaxel and carboplatin (TCH) after 9 years’ follow-up. During
chemotherapy or up to 1 year after chemotherapy, 4.6% patients
in the TCH group developed early-stage CHF (33).
In animal experiments, Yi et al. revealed that trastuzumab
combined irradiation caused more cardiotoxicity than irradiation
or trastuzumab alone, which suggested that the concurrent
management of trastuzumab and radiotherapy should be
carefully made in clinical practice, and more attention is needed
on cardiac safety (34) (Figure 1).
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FIGURE 1 | Some antitumor drugs and their characteristics of cardiotoxicity.
MONITORING
The diagnosis of cardiotoxicity in patients undergoing cancer
treatment before having clinical manifestations has a very
positive effect on the prognosis. Therefore, patients with
cancer undergoing chemotherapy are strongly recommended to
undergo regular or even lifelong cardiac function monitoring.
Cardiotoxicity monitoring commonly includes serum biological
markers, ECG, echocardiography, cardiac magnetic resonance
(CMR) and other methods such as endomyocardial biopsy (EMB)
and cytokine measurements. Each of these detection methods
has its own advantages and disadvantages. The disadvantages
and the corresponding suggestions for the common methods for
cardiotoxicity monitoring are shown in the Table 1.
Biological Markers
Serum biomarkers are important for the baseline risk assessment
and diagnosis of cardiovascular disease in cancer patients
treated with potentially cardiotoxic drugs. The increase of
cardiac biomarkers, especially cardiac troponin (cTn) and
natriuretic peptide (NPs), can be used to guide the initiate of
cardioprotective therapy during cancer treatment and monitor
the responses of these protective therapy (35).
Antitumor therapy is often accompanied with troponin
increasing, and patients with elevated troponin levels have a
higher risk of left ventricular dysfunction (36). In a study of
204 patients treated with high-dose anthracyclines, 65 patients
showed an increase in cTnI (>400 ng/L) and a continuous
decrease in LVEF as measured consecutively before and after
each treatment cycle (37). cTnI increasing were associated
with progressive decline in LVEF in breast cancer patients
(38). In addition, Auner et al. reported there were 15% of
patients had increased cTnT (0.03 ng/mL) in patients with
hematological malignancies, and the peak levels was observed
on day 21 and was associated with a decrease in LVEF
(39). For trastuzumab and HER2-targeted therapies, HER2-
positive breast cancer (EBC) patients can detect an increase in
hypersensitive troponin at 3 months after initiation of cancer
therapy and could predict the development of left ventricular
heart disease (40).
In addition, the elevation of BNP and NTroBNP during
anthracycline treatment is also associated with the reduction of
LVEF and poor prognosis (41). A cohort of 333 anthracycline-
treated patients with different types of tumors showed that
BNP >100 pg/mL was a predictor of long-term heart failure, but
not a risk factor for all-cause death. When BNP cutoff value was
30 ng/L, the negative predictive value of future development of
heart failure was 98% (42). Among breast cancer patients treated
with anthracyclines, De Iuliis et al. showed a significant increase
in NTroBNP which associated with 1-year mortality (41). The
continued increase of NTroBNP in the early stage after high-
dose chemotherapy is also closely related to the development
of cardiac dysfunction (43). Analysis of 555 cancer patients at
diagnosis and before anticancer treatment also showed that Nt-
proBNP and hs-cTnT were independent predictors of all-cause
mortality (44).
A consensus from the Society for Immunotherapy of Cancer
(SITC) Toxicity Management Working Group suggested that
cardiac troponins screening should be performed in the first
12 weeks of ICI treatment (45). The assessment of creatine
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TABLE 1 | Common methods for monitoring cardiotoxicity.
Methods Advantage Disadvantage Suggestion
Serum biomarkers Cardiac troponin (cTnT and cTnI) and NPs are specific and
sensitive biomarkers of cardiomyocyte damage
Traditional detection kits are less
sensitive
Combine with imaging
ECG Simple, non-invasive and inexpensive
Holter can record changes over 24/48 h
Less specificity As routine inspection
Echocardiography Monitor the overall parameter of LV: EF, SF, LV wall stress,
LV mass, LV thickness-to-size ratio, diastolic function, and
GLS etc.
Quick, easy to operate and good compliance
Without a description of the overall
structure and subclinical myocardial
changes cannot be detected
As routine inspection
CMR Provide comprehensive information about structural,
functional, tissue characteristics and myocardial perfusion
Multiparameter and multisequence
High repeatability
The cost of CMR is highly expensive for
population-based screening
High requirements for compliance
Preferred as far as possible
cTnT, cardiac troponin T; cTnI, cardiac troponin I; NT, natriuretic peptide; ECG, electrocardiograph; CMR, cardiac magnetic resonance; LV, left ventricular; EF, ejection
fraction; SF, fractional shortening; GLS, global longitudinal strain.
phosphokinase (CPK) may be useful because myocarditis
is an inflammatory disease and may be associated with
myositis (46), but this less sensitive marker may not rise
significantly (47). Some novel serological markers such as
myeloperoxidase, high-sensitivity C-reactive protein, SFLT-
1, placental growth factor, Growth differentiation factor-15,
galactose lectin-3, arginine nitric oxide metabolites, cardiac
fatty acid binding proteins, glycogen phosphorylase BB
and topoisomerase 2βare all increased to varying degrees
after treatment with potentially cardiotoxic drugs (48,49).
Multi-marker strategies (combinations of multiple markers)
may also further improve the ability to detect subclinical
cardiotoxicity (35).
Electrocardiogram
Electrocardiogram, as a routine evaluation method, can reflect
the electrophysiological activity of the heart in time before,
during and after tumor treatment. Tumor drugs may induce
arrhythmias through a variety of ways (50). Although there
is no specificity, different kinds of drugs with cardiovascular
toxicity may have different manifestations on electrocardiogram,
including sinus tachycardia, QT prolongation, ST-T segment
changes, conduction block, etc. (51), among which QT
prolongation is considered to be an important manifestation
in the evaluation of cardiovascular duct toxicity. Andreu et al.
conducted a systematic review of the incidence, diagnosis, and
clinical outcomes of QT prolongation associated with tumor
drug therapy and found that the weighted adjusted incidence
of QT prolongation ranged from 0 to 22% in patients receiving
conventional therapy (e.g., anthracyclines) (52).
Premature ventricular beats are the most common type
of arrhythmia in patients treated with anthracyclines, with
ventricular tachycardia occurring in approximately 73.9%
of patients (53). Kilickap’s team conducted dynamic ECG
monitoring for patients after 48 h of doxorubicin infusion, and
the results showed that the rate of paroxysmal atrial fibrillation
was 10.3% (54). The incidence of this arrhythmia was 6% when
ECG monitoring was performed at each follow-up during the
continuation of chemotherapy (55). In addition, arrhythmias
may also occur in children treated with chemotherapy for cancer.
Lipshultz et al.’s study found that 5% of children treated with
doxorubicin developed unsustained ventricular tachycardia (56).
In a study by Mulrooney et al., of 2,715 children survived from
tumor disease, 290 (about 10%) had major ECG changes and
565 (23.3%) had minor changes, including atrial or ventricular
premature beats, non-specific T wave or ST segment changes, low
QRS and ECG axis deviation (57). Therefore, ECG monitoring
is necessary for both adults and children before and after
tumor treatment, especially for patients with high risk factors
because timely detection of arrhythmias may improve the
prognosis of patients.
Echocardiography
Clinically, the most common parameters include EF, SF, LV
wall stress, LV mass, rate of shortening of heart rhythm
correction, LV thickness-to-size ratio, and diastolic function
in the echocardiographic examination (7). In recent years,
series of studies have confirmed myocardial strain abnormal
earlier than cardiac function dysfunction in many cardiovascular
diseases (58). Especially global longitudinal strain (GLS) provides
prognostic information beyond EF among a broad range of
cardiovascular diseases, from postmyocardial infarction (59) to
aortic stenosis (60), as well as HF (61) and myocarditis (62,63).
For example, among patients with HF, each 1% improvement
in GLS is associated with a 5% decreased risk of mortality
(24,61). The assessment of myocardial strain may also help
to early detect cardiotoxicity in cancer patients (58), Ye et al.
demonstrated that myocardial strain based on speckle-tracking
echocardiography can predict further cardiotoxicity in patients
receiving chemotherapy (64). A prospective study on 627 patients
and implied the GLS was an optimal parameter of deformation
for the early detection of subclinical LV dysfunction (64).
A recent Strain Surveillance of Chemotherapy for Improving
Cardiovascular Outcomes (SUCCOUR) randomized controlled
trial (ANZ Clinical Trials ACTRN12614000341628) showed
the patients in the LVEF-guided group who received cardiac
protection had a greater decrease in LVEF at follow-up than
those in the GLS-guided group, which further confirming that
cardiac protection therapy guided by GLS as the main indicator
can effectively delay cardiac function injury (65).
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Cardiac Magnetic Resonance
Although Echo is considered a routine test for cancer patients
to monitor the cardiotoxicity, recent studies have shown that the
LVEF measured by CMR has the highest repeatability compared
to the LVEF measured by two-dimensional echocardiography
(or myocardial deformation measured by both methods) in
patients with cardiomyotoxicity due to cancer therapy (66,67).
The development of CMR fast scanning protocol and post-
processing technology, and the automatic analysis of CMR
images by machine learning algorithm not only improves the
accuracy between observers, but also greatly reduces the image
analysis time (42). Meanwhile, some studies revealed that precise
evaluation by CMR may reduce the frequency of monitoring and
increase the benefit of patients (43). All these studies indicated
that CMR has a greater prospect in the monitor of cancer patients
treatment. Besides, CMR plays an increasingly prominent role in
the diagnosis of cardiotoxicity in multimodal imaging methods
and it can better understand the underlying mechanisms of
cardiovascular damage caused by cancer treatment, as well as
other aspects related to cardiovascular structure and function (7).
Strain
Myocardial strain could be an alternative more sensitive imaging
biomarkers than LVEF to earlier diagnosis and treatment
of cardiotoxicity. The reduction in global longitudinal and
circumferential strain assessed by CMR tissue-feature tracing is
associated with subclinical decline in LVEF in cancer patients
(68). The global circumferential strain (GCS) decreased while
LVESV did not decrease significantly during chemotherapy, and
the GCS was associated with LVEF measured 2 years later
(69). The study by Jolly showed that circumferential strain
assessed by CMR was associated with subclinical LVEF reduction
in cancer patients undergoing cardiotoxic chemotherapy (70).
Therefore, CMR assessment of myocardial strain may provide
a more comprehensive and detailed parameter for patients with
chemotherapy-induced cardiotoxicity.
T1/T2 Mapping
T1 mapping and T2 mapping technology on CMR is a promising
non-invasive tool that can quantify myocardial tissue changes
via changes in longitudinal and transverse relaxation, allowing
for the early detection of cardiotoxicity (10). T2 mapping
detects the production of edema in the myocardium, which
is the earliest sign of anthracycline-induced cardiotoxicity.
These changes occur in the reversible stage of myocardial
disease, indicating that CMR markers can be used in tailor-
made anthracycline therapy to monitoring cardiotoxicity (71).
Elevated T1 mapping values were common in patients with
ICI myocarditis. Thavendiranathan et al. reported that patients
with higher T1 mapping values had signs of greater myocardial
injury and T1 mapping values (for every 1-unit increase in
z-score, hazard ratio: 1.44) were independently associated with
subsequent MACE (72).
Quantitative T1 imaging can be used to calculate the
myocardial extracellular volume fraction (ECV), a measure of
microscopic myocardial remodeling that has been associated with
underlying diffuse fibrosis (73). In recent study, CMR imaging
were performed before and up to three times serially after
cumulative anthracycline treatment in 27 women with breast
cancer. Those patients undergoing anthracycline therapy had
significant reductions in LVEF and LV mass, and mean ECV had
increased by 0.037 to 0.36 ±0.04 (p = 0.004) (74).
Late Gadolinium Enhancement
Myocardial fibrosis can be detected non-invasively by late
gadolinium enhancement (LGE) with CMR, which is the priority
imaging test for the diagnosis and risk prediction in myocarditis
of other etiologies (7581). But Zhang et al. analyzed the
CMR results of 103 patients diagnosed with ICI-associated
myocarditis, and they found that LGE present in more than
80% of patients with non-ICI-related myocarditis but occurs
in less than 50% of patients with ICI-associated myocarditis,
therefore, clinicians should use more CMR indicators to diagnose
or exclude ICI-associated myocarditis rather than use global
LGE only (82). When two or more suspicious indicators, such
as inducible perfusion deficit, regional or global dysfunction,
edema, necrosis, scar, and pericarditis are monitored by CMR,
ICI-related cardiotoxicity may be indicated (83). In a recent
study, although the global LGE was less frequent in patients with
ICI-myocarditis than those with viral myocarditis, septal and
midwall layer LGE was more common. Septal LGE was the only
CMR predictor of MACE at 1 year after adjustment for peak
troponin (84).
Cardiac magnetic resonance are helpful in individuals whose
echocardiographic techniques are not feasible or whose results
are suboptimal, and provide more information about myocardial
perfusion. However, the cost of CMR is extremely expensive
for a population-based screening, and comprehensive multi-
parametric CMR tissue studies are currently unavailable (71). In
recent years, research in the field of CMR is developing rapidly,
and CMR might become the best means to monitor cardiotoxicity
in the future due to its multi-sequence characteristics (Figure 2).
Other Methods
Cytokines, inflammatory factors, and endocardial biopsies can
also be used to monitor myocardial toxicity. The cytokine’s
sensitivity to inflammation makes it useful for monitoring
cardiotoxicity. An animal experiment showed that the cardiac
tissue levels of TNF-α, IL-6, and IL-1βin the DOX-treated group
were significantly increased as compared to the normal group rats
(85). Ahmed et al. also found that administration of trastuzumab
resulted in significant increase in cardiac tissue IL-6 and TGF-
b1 expression compared to the control group (1362.5 ±18.5 vs.
211.2 ±6.4 pg/g tissue; 11.32 ±0.3 vs. 3.42 ±0.12 pg/µg protein,
respectively) in mice (86).
Myocarditis is one of the important manifestations of ICI
related cardiotoxicity. Recently Vincenzo et al. found that
the expression of IL-6 and IL-1 in breast cancer cells and
cardiomyocytes exposed to ipilimumab significantly increased
when in high glucose state, suggesting the protective role of low
glucose in immune-suppression and cardiotoxicity (87).
Endomyocardial biopsy is available to detect tissue damage,
primarily for rejection monitoring after cardiac transplantation
and also have an important complementary role to the
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Huang et al. Cardiotoxicity After Antitumor Strategy
FIGURE 2 | The monitoring of myocardial injury by multi-parameter of cardiac magnetic resonance.
clinical assessment in establishing the diagnosis of diverse
cardiac disorders (88), but the use is declining due to its
invasive and costly (89,90). EMB may be considered if CMR
or 18 F-fluorodeoxyglucose PET-computed tomography yield
uncertain findings and/or the patients cannot undergo non-
invasive assessment due to haemodynamically instability (82).
PREVENTION OF CARDIOTOXICITY
Prevention of Anthracycline
Dexrazoxane (DEX) is an iron chelating agent that minimizes
cardiotoxicity by limiting the production and accumulation of
ROS in myocardium and preventing the interaction between
antitumor drugs and topoisomerase II (91). Dex is mainly
used in advanced and/or metastatic adult breast cancer patients
with cumulative doxorubicin doses up to 300 mg/m2or
epirubicin cumulative doses up to 540 mg/m2. Ganatra et al.
observed clinical outcomes in five patients with preexisting
asymptomatic left ventricular systolic dysfunction who required
chemotherapy with anthracycline, in combination with off-label
treatment with Dexrazoxane 30 min before each anthracycline
dose. All five patients treated with Dex successfully completed
chemotherapy as planned, with mean LVEF decreasing from 39%
at baseline to 34% after chemotherapy, without symptomatic
heart failure or elevated biomarkers (cardiac troponin I or
brain natriuretic peptide). In three patients who were not
treated with Dexrazoxane, the LVEF decreased from 42.5%
at baseline to 18% after treatment. All patients developed
symptomatic heart failure requiring hospitalization and diuretic
therapy, and two died of cardiogenic shock and multiple organ
failure. Therefore, this study suggested that Dex can reduce
the cardiotoxicity induced by anthracyclines in adults with
existing cardiomyopathy and tumors (92). Lisa et al. showed
that dextroimide prevents left ventricular dysfunction and heart
failure in patients with osteosarcoma treated with high doses of
anthracyclines, especially in girls, by post-evaluation in patients
with osteosarcoma treated with dextroimide (93). Dewilde et al.
thought that no matter which healthcare system they receive
treatment in, Dex protection is a cost-effective way to prevent
cardiotoxicity of anthracyclines in children with sarcomas or
hematological malignancies and these benefits persisted when
patients received cumulative doses of anthracyclines greater than
250 mg/m2(94).
Otherwise, various of anti-cardiotoxicity drugs has been
widely investigated. For instance, neurokinin-1 receptor blockers
can reduce adriamycin-induced cardiac fibrosis and to prevent
possible LV damage (95). The ACEi inhibitor administration
improved the impaired heart function in the patient with
cardiotoxicity induced by doxorubicin or mitoxantrone (4,96).
Prevention of Immune Checkpoint
Inhibitors
For the cardiac protection treatment, corticosteroids are
currently the main first-line treatment for ICI-induced
myocarditis. However, considering the lack of evidence,
the suggestion of initial glucocorticoid doses and treatment
strategies are varies greatly. A recent retrospective observational
study emphasized that an increased initial dose (intravenous
methylprednisolone, 1,000 mg/day) and the early use of
corticosteroids are associated with improved cardiac prognosis
in ICI-related myocarditis. This previous study supported that
the initial dose of corticosteroids is inversely related to the
occurrence of major adverse cardiovascular events (MACE),
the rate of MACE are 61.9, 54.6, and 22.0% respectively in
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Huang et al. Cardiotoxicity After Antitumor Strategy
low, medium and high dose initially (97). Patients receiving
corticosteroids within 24 h after admission (7.0%) had a lower
MACE occurrence rate than those who received it between 24 and
72 h (34.3%) and >72 h (85.1%). However, the effect of high-dose
corticosteroids on the outcome of patients with cancer who take
ICI remains controversial. In addition, some studies suggest that
if the symptoms of myocarditis do not immediately respond to
steroids, upgrading to other immunosuppressive drugs, such as
infliximab, mycophenolate mofetil, and anti-thymocyte globulin,
may be necessary (98).
Prevention of Trastuzumab
The specific mechanism of trastuzumab related cardiotoxicity
remains unclear (99,100). There were study reported the
angiotensin-converting enzyme inhibitors (ACEi) and beta-
blockers might prevent trastuzumab cardiotoxicity (99,101,102).
However, the clear curative effects of these drugs still uncertain.
Edith et al. (103). used perindopril and bisoprolol to protect
the myocardium and found that these drugs were well tolerated
by patients with HER2-positive early breast cancer; both drugs
mitigated the LVEF decline associated with trastuzumab but
did not prevent left ventricular remodeling, thus the long-term
significance of LV remodeling in that study is unclear, and
the cardiovascular risk factors in patient cohort are fewer than
clinical practice, which require further investigation to confirm
these drugs’ effects in chemotherapeutic-related cardiotoxicity.
CONCLUSION
Oncological cardiology is an emerging discipline involving
oncology, cardiovascular, imaging, laboratory, and other fields.
With the continuous in-depth research on antitumor drugs,
various chemotherapeutic and new targeted drugs are being
used widely in clinical, and their adverse effects cannot be
ignored. Such adverse events may be the major causes of death.
Cardiotoxicity based on chemotherapy drugs and ICIs is mainly
manifested as various types of cardiac dysfunction, HF and
myocarditis and may be associated with high morbidity and
mortality. Therefore, early detection of cardiotoxicity facilitated
by these monitor methods especially the advanced multimodality
imaging techniques summarized in this review will permit
intervention at an earlier stage, which is crucial for the
improvement of patient’s quality of life and decrease in mortality
risk. The future development of oncological cardiology may
require more attention to high-risk populations, cardiac function
monitoring, and preventive and therapeutic administration.
Furthermore, the mechanism of cardiotoxicity caused by various
traditional chemotherapy agents and newer targeted cancer
therapies should be researched further to determine ways on how
to protect patients with cancer from cardiotoxicity.
AUTHOR CONTRIBUTIONS
WH and RX wrote the manuscript. BZ and CL provided a
detailed guidance throughout the manuscript. HX, XG, and YG
responsibility for the integrity of the work as a whole from
inception to published manuscript. All authors contributed to the
article and approved the submitted version.
FUNDING
This work was supported by the National Natural Science
Foundation of China (Nos. 82071874, 81771887, 81771897,
81971586, and 81901712), Key Project of Sichuan Science
and Technology Department (No. 2020YFS0050), Sichuan
Science and Technology Program (Nos. 2020ZYD007,
2020YFS0050, 2020YJ0029, 2017TD0005, and 21ZDYF1967),
Fundamental Research Funds for the Central Universities
(SCU2020D4132), Clinical Research Finding of Chinese Society
of Cardiovascular Disease (CSC) of 2019 (No. HFCSC2019B01),
1·3·5 Project for Disciplines of Excellence, West China Hospital,
Sichuan University (ZYGD18019 and ZYGD18013), and
Sichuan Province Science and Technology Support Program
(2020YJ0229).
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Background Checkpoint-inhibitor immunotherapies have had a profound effect in the treatment of cancer by inhibiting down-regulation of T-cell response to malignancy. The cardiotoxic potential of these agents was first described in murine models and, more recently, in numerous clinical case reports of pericarditis, myocarditis, pericardial effusion, cardiomyopathy, and new arrhythmias. The objective of our study was to determine the frequency of and associated risk factors for cardiotoxic events in patients treated with immune checkpoint inhibitors. Methods Medical records of patients who underwent immunotherapy with durvalumab, ipilimumab, nivolumab, and pembrolizumab at Wake Forest Baptist Health were reviewed. We collected retrospective data regarding sex, cancer type, age, and cardiovascular disease risk factors and medications. We aimed to identify new diagnoses of heart failure, atrial fibrillation, ventricular fibrillation/tachycardia, myocarditis, and pericarditis after therapy onset. To assess the relationship between CVD risk factors and the number of cardiac events, a multivariate model was applied using generalized linear regression. Incidence rate ratios were calculated for every covariate along with the adjusted P -value. We applied a multivariate model using logistic regression to assess the relationship between CVD risk factors and mortality. Odds ratios were calculated for every covariate along with the adjusted P -value. Adjusted P -values were calculated using multivariable regression adjusting for other covariates. Results Review of 538 medical records revealed the following events: 3 ventricular fibrillation/tachycardia, 12 pericarditis, 11 atrial fibrillation with rapid ventricular rate, 0 myocarditis, 8 heart failure. Significant risk factors included female gender, African American race, and tobacco use with IRR 3.34 (95% CI 1.421, 7.849; P = 0.006), IRR 3.39 (95% CI 1.141, 10.055; P = 0.028), and IRR 4.21 (95% CI 1.289, 13.763; P = 0.017) respectively. Conclusions Our study revealed 34 significant events, most frequent being pericarditis (2.2%) and atrial fibrillation (2.0%) with strongest risk factors being female gender, African American race, and tobacco use. Patients who meet this demographic, particularly those with planned pembrolizumab treatment, may benefit from early referral to a cardio-oncologist. Further investigation is warranted on the relationship between CTLA-4 and PD-L1 expression and cardiac adverse events with ICIs, particularly for these subpopulations.
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Endomyocardial biopsy (EMB) is an invasive procedure, globally most often used for the monitoring of heart transplant (HTx) rejection. In addition, EMB can have an important complementary role to the clinical assessment in establishing the diagnosis of diverse cardiac disorders, including myocarditis, cardiomyopathies, drug-related cardiotoxicity, amyloidosis, other infiltrative and storage disorders, and cardiac tumours. Improvements in EMB equipment and the development of new techniques for the analysis of EMB samples have significantly improved diagnostic precision of EMB. The present document is the result of the Trilateral Cooperation Project between the Heart Failure Association of the European Society of Cardiology, the Heart Failure Society of America, and the Japanese Heart Failure Society. It represents an expert consensus aiming to provide a comprehensive, up-to-date perspective on EMB, with a focus on the following main issues: (i) an overview of the practical approach to EMB, (ii) an update on indications for EMB, (iii) a revised plan for HTx rejection surveillance, (iv) the impact of multimodality imaging on EMB, and (v) the current clinical practice in the worldwide use of EMB.
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Background Myocarditis is a potentially fatal complication of immune checkpoint inhibitor (ICI) therapy. Data on the utility of cardiovascular magnetic resonance (CMR) T1 and T2 mapping in ICI myocarditis are limited. Objectives This study sought to assess the value of CMR T1 and T2 mapping in patients with ICI myocarditis. Methods In this retrospective study from an international registry of patients with ICI myocarditis, clinical and CMR findings (including T1 and T2 maps) were collected. Abnormal T1 and T2 were defined as 2 SD above site (vendor/field strength specific) reference values and a z-score was calculated for each patient. Major adverse cardiovascular events (MACE) were a composite of cardiovascular death, cardiogenic shock, cardiac arrest, and complete heart block. Results Of 136 patients with ICI myocarditis with a CMR, 86 (63%) had T1 maps and 79 (58%) also had T2 maps. Among the 86 patients (66.3 ± 13.1 years of age), 36 (41.9%) had a left ventricular ejection fraction <55%. Across all patients, mean z-scores for T1 and T2 values were 2.9 ± 1.9 (p < 0.001) and 2.2 ± 2.1 (p < 0.001), respectively. On Siemens 1.5-T scanner (n = 67), native T1 (1,079.0 ± 55.5 ms vs. 1,000.3 ± 22.1 ms; p < 0.001) and T2 (56.2 ± 4.9 ms vs. 49.8 ± 2.2 ms; p < 0.001) values were elevated compared with reference values. Abnormal T1 and T2 values were seen in 78% and 43% of the patients, respectively. Applying the modified Lake Louise Criteria, 95% met the nonischemic myocardial injury criteria and 53% met the myocardial edema criteria. Native T1 values had excellent discriminatory value for subsequent MACE, with an area under the curve of 0.91 (95% confidence interval: 0.84 to 0.98). Native T1 values (for every 1-unit increase in z-score, hazard ratio: 1.44; 95% confidence interval: 1.12 to 1.84; p = 0.004) but not T2 values were independently associated with subsequent MACE. Conclusions The use of T1 mapping and application of the modified Lake Louise Criteria provides important diagnostic value, and T1 mapping provides prognostic value in patients with ICI myocarditis.
Article
Background In patients at risk of cancer therapy-related cardiac dysfunction (CTRCD), initiation of cardio-protective therapy (CPT) is constrained by the low sensitivity of EF for minor changes in LV function. Global longitudinal strain (GLS) is a robust and sensitive marker of LV dysfunction, but existing observational data have been insufficient to support a routine GLS-guided strategy for CPT. Objective To identify whether GLS-guided CPT prevents reduction in LVEF in patients undergoing potentially cardiotoxic chemotherapy, compared with usual care. Methods In this international multicenter prospective randomized controlled trial, 331 anthracycline-treated patients with another heart failure risk factor were randomly allocated to CPT initiation guided by either ≥12% relative reduction in GLS (n=166) or >10% absolute reduction of LVEF (n=165). Patients were followed for EF and development of CTRCD (symptomatic EF reduction >5% or >10% asymptomatic to <55%) over 1 year. Results Of 331 randomized patients, 2 died and 22 withdrew consent or were lost to follow-up. Among 307 patients (age 54±12 years, 94% women, baseline LVEF 59±6%, GLS -20.6±2.4%) with a median (IQR) follow-up of 1.02 (0.98-1.07) years, most (n=278) had breast cancer. HF risk factors were prevalent: 29% had hypertension and 13% had diabetes mellitus. At 1-year follow-up, although the primary outcome of change in LVEF was not significantly different between the two arms, there was significantly greater use of CPT, and fewer patients met CTRCD criteria in the GLS-guided than the EF-guided arm (5.8% vs 13.7%, p=0.02), and 1-year EF was 57±6% versus 55±7% (p=0.05). Patients diagnosed with CTRCD in the EF-guided arm had a larger reduction in LVEF at follow-up than in the GLS-guided arm (9.1±10.9% versus 2.9±7.4%, p=0.03). Conclusions Although the change in LVEF was not different between the two arms, GLS-guided CPT significantly reduced a meaningful fall of LVEF to the abnormal range. The results support the use of GLS in surveillance for CTRCD.