REVIEW Open Access Takotsubo cardiomyopathy in cancer patients Aakash Desai 1 , Arish Noor 1 , Saurabh Joshi 1,2 and Agnes S. Kim 1,2* Abstract Background: Cancer is a chronic condition that induces significant emotional and physical stress, which may increase the risk for developing Takotsubo cardiomyopathy (TCM). Main body: Takotsubo cardiomyopathy, also known as stress cardiomyopathy, is a clinical syndrome that generally presents as chest pain mimicking acute coronary syndrome or as an acute heart failure characterized by severe left ventricular systolic dysfunction in response to emotional, physical, or medical stress. The potential triggers for Takotsubo syndrome in cancer patients include the emotional turmoil of a cancer diagnosis, the inflammatory state of the cancer itself, and the physical stress of cancer surgery, systemic anti-neoplastic therapy, and radiation treatment. TCM is becoming increasingly recognized among patients with cancer and has been associated with adverse outcomes in this patient population. In this study, we searched the Pubmed database using keywords “Takotsubo cardiomyopathy”, “cancer”, and “anti-neoplastic therapy” to review case reports of Takotsubo syndrome occurring in oncologic patients after systemic anti-neoplastic therapy. Clinical presentation, electrocardiogram, laboratory data, transthoracic echocardiogram and coronary angiogram results, and patient outcomes were collected and analyzed. Conclusion: Patients with cancer are at an elevated risk for developing stress cardiomyopathy, and it is important to know which cancer drugs have been associated with the development of the Takotsubo syndrome. Keywords: Chemotherapy, Takotsubo cardiomyopathy, Stress cardiomyopathy, Cancer Background Patients with cancer who are undergoing systemic therapy for their malignancy often have co-existent cardiovascular illness and/or risk factors. Physicians sometimes face diffi- culty in differentiating chemotherapy-induced cardiotoxi- city from cardiac events unrelated to cancer treatment. Recognition of chemotherapy-induced cardiotoxicity is im- portant since repeated administration of the offending drug can potentially lead to irreversible cardiac damage. On the other hand, premature discontinuation of an effective anti- neoplastic agent due to co-existing cardiac events not dir- ectly related to therapy may increase oncologic morbidity and mortality. One cardiac condition that may be directly caused by chemotherapy or may be completely unrelated to it is Takotsubo cardiomyopathy (TCM). TCM is a clinical syndrome that generally presents as chest pain mimicking acute coronary syndrome (ACS) or as an acute heart failure characterized by severe left ventricular (LV) systolic dysfunction in response to emo- tional, physical, or medical stress. Unlike in ACS, patients generally have a normal coronary angiogram, the LV dysfunction extends beyond a coronary distribu- tion and usually recovers within days or weeks. The most common pattern of LV dysfunction is apical akin- esis or ballooning with hyperdynamic basal segments [1]. The pathophysiology of the syndrome is not well understood; however, catecholamine excess, coronary ar- tery vasospasm, and microvascular dysfunction are thought to be the key mediating processes [2]. These mechanisms can be activated by various stressors, which include emotional or psychological stress, infection, sur- gery, medications, and exacerbation of chronic diseases [3]. Furthermore, a genetic predisposition for TCM has © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. * Correspondence: [email protected] 1 Department of Medicine, University of Connecticut School of Medicine, Farmington, CT, USA 2 Department of Medicine, Division of Cardiology, University of Connecticut School of Medicine, 263 Farmington Avenue, Farmington, CT 06030-2202, USA Desai et al. Cardio-Oncology (2019) 5:7 https://doi.org/10.1186/s40959-019-0042-9
Takotsubo cardiomyopathy in cancer patients
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Takotsubo cardiomyopathy in cancer patientsTakotsubo cardiomyopathy in cancer patients Aakash Desai1, Arish Noor1, Saurabh Joshi1,2 and Agnes S. Kim1,2*
Abstract
Background: Cancer is a chronic condition that induces significant emotional and physical stress, which may increase the risk for developing Takotsubo cardiomyopathy (TCM).
Main body: Takotsubo cardiomyopathy, also known as stress cardiomyopathy, is a clinical syndrome that generally presents as chest pain mimicking acute coronary syndrome or as an acute heart failure characterized by severe left ventricular systolic dysfunction in response to emotional, physical, or medical stress. The potential triggers for Takotsubo syndrome in cancer patients include the emotional turmoil of a cancer diagnosis, the inflammatory state of the cancer itself, and the physical stress of cancer surgery, systemic anti-neoplastic therapy, and radiation treatment. TCM is becoming increasingly recognized among patients with cancer and has been associated with adverse outcomes in this patient population. In this study, we searched the Pubmed database using keywords “Takotsubo cardiomyopathy”, “cancer”, and “anti-neoplastic therapy” to review case reports of Takotsubo syndrome occurring in oncologic patients after systemic anti-neoplastic therapy. Clinical presentation, electrocardiogram, laboratory data, transthoracic echocardiogram and coronary angiogram results, and patient outcomes were collected and analyzed.
Conclusion: Patients with cancer are at an elevated risk for developing stress cardiomyopathy, and it is important to know which cancer drugs have been associated with the development of the Takotsubo syndrome.
Keywords: Chemotherapy, Takotsubo cardiomyopathy, Stress cardiomyopathy, Cancer
Background Patients with cancer who are undergoing systemic therapy for their malignancy often have co-existent cardiovascular illness and/or risk factors. Physicians sometimes face diffi- culty in differentiating chemotherapy-induced cardiotoxi- city from cardiac events unrelated to cancer treatment. Recognition of chemotherapy-induced cardiotoxicity is im- portant since repeated administration of the offending drug can potentially lead to irreversible cardiac damage. On the other hand, premature discontinuation of an effective anti- neoplastic agent due to co-existing cardiac events not dir- ectly related to therapy may increase oncologic morbidity and mortality. One cardiac condition that may be directly
caused by chemotherapy or may be completely unrelated to it is Takotsubo cardiomyopathy (TCM). TCM is a clinical syndrome that generally presents as
chest pain mimicking acute coronary syndrome (ACS) or as an acute heart failure characterized by severe left ventricular (LV) systolic dysfunction in response to emo- tional, physical, or medical stress. Unlike in ACS, patients generally have a normal coronary angiogram, the LV dysfunction extends beyond a coronary distribu- tion and usually recovers within days or weeks. The most common pattern of LV dysfunction is apical akin- esis or ballooning with hyperdynamic basal segments [1]. The pathophysiology of the syndrome is not well understood; however, catecholamine excess, coronary ar- tery vasospasm, and microvascular dysfunction are thought to be the key mediating processes [2]. These mechanisms can be activated by various stressors, which include emotional or psychological stress, infection, sur- gery, medications, and exacerbation of chronic diseases [3]. Furthermore, a genetic predisposition for TCM has
© The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
* Correspondence: [email protected] 1Department of Medicine, University of Connecticut School of Medicine, Farmington, CT, USA 2Department of Medicine, Division of Cardiology, University of Connecticut School of Medicine, 263 Farmington Avenue, Farmington, CT 06030-2202, USA
Desai et al. Cardio-Oncology (2019) 5:7 https://doi.org/10.1186/s40959-019-0042-9
been postulated given the preponderance of familial cases [4]. More recently, anti-neoplastic agents have been associ-
ated with TCM. Certain cancer drugs have been impli- cated in triggering this form of cardiomyopathy. While studies regarding the cardiotoxic effects of chemothera- peutic agents are plentiful, the data on this type of car- diomyopathy induced by cancer treatment are sparse, and no known correlation between dose of chemother- apy and TCM currently exists. Our review explores the possible etiologic link between various cancer drugs and TCM. The cancer therapies that will be discussed in- clude traditional chemotherapeutic agents as well as newer targeted drugs, including immune checkpoint in- hibitors. With this review, we hope to shed light on the association between TCM and cancer as well as TCM and anti-neoplastic agents.
Takotsubo cardiomyopathy TCM was first described in Japan in 1990 by Dote and colleagues [1]. The particular name “Takotsubo” was used to describe the cardiomyopathy due to the charac- teristic apical ballooning on left ventriculography which was similar in shape to a Japanese octopus trap. It is also
referred to as “broken heart”, “apical ballooning syn- drome”, “myocardial stunning”, or “stress cardiomyop- athy”. TCM may occur in the presence of an emotional or physiologic stressor. The syndrome has been observed most frequently in
post-menopausal women who are exposed to major stressors. Patients can experience symptoms varying from chest pain (63%) to dyspnea on exertion (8%) and syncope (3%) [3]. This poses an added diagnostic chal- lenge since this constellation of symptoms can mimic myocardial infarction (MI), pulmonary embolism or cerebrovascular disorders. Patients can present with vari- able ECG changes that affect the ST segment and T wave [5]. ST segment elevation or new LBBB was present in 34.2% of cases, while T wave inversion and non-specific ST-T wave changes were seen in 30.4 and 35.2% respectively [5]. Mild elevation in cardiac enzymes may also be present; however, the degree of elevation is disproportionately low to the area of myocardium af- fected. Coronary angiography does not show obstructive CAD (defined as > 50% narrowing of the coronary artery) [2]. LV dysfunction is observed on imaging modalities like
echocardiography and left ventriculography (Fig. 1).
Fig. 1 Echocardiogram pattern in a patient with TCM demonstrating apical ballooning and diffuse hypokinesis with sparing of the basal myocardial segments. Left ventricle in (a) end-diastole and (b) end-systole is shown; Left Ventriculogram pattern in TCM shown in (c) end-diastole and (d) end-systole
Desai et al. Cardio-Oncology (2019) 5:7 Page 2 of 16
Three different types of contractile abnormality of the LV have been described. The most common pattern is apical akinesis with hyperkinesis of the basal segments. Other less common patterns include: combined akinesis of the mid-LV and apex, isolated akinesis of the mid-LV, and isolated basal akinesis [6]. Typically, LV ejection fraction (LVEF) is severely reduced, with median LVEF of 20%; interquartile range, 15 to 30% (normal LVEF range 55–75%) [2]. In a majority of patients, LVEF im- proves to greater than 50% on follow up. While cardiac recovery usually occurs in 4 to 6 weeks, it can take any- where from 2.5 months to a year for a small proportion of individuals (~ 5%) [2, 7]. The prolonged duration re- quired for normalization of LV systolic function predis- poses individuals to the development thrombus in the LV with increased risk of embolization. Although uncommon, TCM can lead to complications like hemodynamic instability, atrial or ventricular arrhyth- mias, progressive heart failure, cardiogenic shock, and death. To aid in the diagnosis, “Mayo Clinic criteria” [8], can be used (Table 1). Beta blockers along with ACE-inhibitors form the
mainstay of treatment by reducing catecholamine stimu- lation and countering one of the main pathogenetic pathways. In-hospital mortality can be as high as 16% [9]. Given the paucity of lengthy follow-up studies, data regarding long-term prognosis and outcomes are currently lacking.
Pathogenetic mechanisms of Takotsubo cardiomyopathy The exact pathophysiology behind TCM is currently un- known. The rationale behind increased incidence in postmenopausal women or the predilection for the LV apex or mid-cavity are currently unanswered questions. Various postulated mechanisms of TCM include: cat- echolamine excess, coronary artery vasospasm, micro- vascular dysfunction and upregulation of certain cardiac genes (Fig. 2). Catecholamines released during a stressful event play
a significant role in the development of cardiomyopathy. Wittstein et al. [2] found that patients with LV
dysfunction after emotional stress had elevated catechol- amines. The pivotal role of catecholamines is also sup- ported by Abraham et al. [10] where TCM was induced after infusion of norepinephrine and dopamine. The stimulation of cAMP increases the intracellular concen- tration of norepinephrine within the cardiac myocytes, which can lead to damage. The key role of norepineph- rine is also supported by the fact that the use of beta- blockers can significantly reduce damage. The findings of multifocal coronary vasospasm and transient myocar- dial perfusion abnormalities also suggest coronary artery vasospasm as one of the mechanisms inducing TCM. Drugs have been implicated as a cause of TCM, particu- larly in those situations in which no clear emotional or other stress trigger could be identified [11].
Takotsubo cardiomyopathy and cancer Cancer is a chronic condition that induces significant emo- tional and physical stress, increasing the risk of stress car- diomyopathy. The potential triggers for TCM in cancer patients include emotional turmoil of the diagnosis, the in- flammatory state of cancer, and the physical stress of vari- ous cancer treatments, including chemotherapy (Fig. 3) [12, 13]. In addition, it has been hypothesized that the circulat- ing paraneoplastic mediators may modify the adrenorecep- tors in cardiac tissue, leading to contractile dysfunction. The cardiotoxicity of chemotherapeutic agents, such
as anthracyclines and trastuzumab, is a well-known en- tity among cardiologists and oncologists alike [14]. The wide range of potential cardiac side effects rising from cancer therapy include ventricular dysfunction, ischemia, arrhythmia, hypertension, accelerated atherosclerosis, venous thromboembolism, myocarditis and QT pro- longation [15–17]. Several anti-neoplastic agents have been implicated to be associated with TCM. Among these drugs, the most commonly reported is 5- Fluorouracil. Other cancer therapies that have been re- ported to induce this type of cardiomyopathy include capecitabine, combretastatin, rituximab, vascular endo- thelial growth factors inhibitors, other angiogenesis in- hibitors, taxols and others (Tables 2 and 3). TCM is probably an under-recognized and thus under-diagnosed disease entity among cancer patients receiving chemo- therapy [12]. In this study, we searched the Pubmed database using
keywords “Takotsubo cardiomyopathy”, “cancer”, and “anti-neoplastic therapy” to review case reports of Takot- subo syndrome occurring in oncologic patients after sys- temic anti-neoplastic therapy. Clinical presentation, electrocardiogram, laboratory data, transthoracic echo- cardiogram and coronary angiogram results, and patient outcome were collected and analyzed. What follows is a review of the anti-neoplastic drugs that have been re- ported to cause TCM.
Table 1 Mayo Clinic diagnostic criteria for Takotsubo cardiomyopathy [8]
For the diagnosis of TCM, the “Mayo Clinic criteria” must be met, which include [8]:
1. Transient hypokinesis, akinesis or dyskinesis of left ventricular mid segments with/without apical involvement, regional wall motion abnormality extending beyond a single vascular territory, and a stressful trigger is often, but not always, present; 2. Absence of angiographic evidence of obstructive coronary disease or plaque rupture; 3. New ECG abnormalities consisting of ST elevation or T wave inversion with modest elevation in cardiac troponins; 4. Absence of pheochromocytoma and myocarditis
Desai et al. Cardio-Oncology (2019) 5:7 Page 3 of 16
Fig. 2 Proposed Pathogenetic Mechanisms of TCM
Fig. 3 Cancer and Takotsubo cardiomyopathy: Cancer can increase the predisposition to TCM through various pathways. Cancer produces an emotional stress response as well as physical/surgical stressors from the disease. The paraneoplastic mediators along with the chronic inflammatory state is another risk factor. Lastly, the therapeutic regimens including medical therapeutic agents and radiation therapy can trigger the development of TCM
Desai et al. Cardio-Oncology (2019) 5:7 Page 4 of 16
Ta b le
rt s of
ca nc er
o C ar di om
yo pa th y w ith
de ta ils
(c an ce r dr ug
,t yp e of
ca nc er ,p
ce or
ch es t pa in ,a nd
re su lts
Re fe re nc e
N o.
A ge
Re po
rt ed
ca nc er
FO LF O X]
Ye s
Si nu
s Ta ch yc ar di a; ST E in
II, III ,a VF ,V 4, V5 ,V 6
Tr op
Ye s
ad en
FU ,L eu co vo rin
,O xa lip la tin
) Fi rs t cy cl e
N o
N on
sp ec ifi c la te ra lS T ch an ge
s an d po
re ss io n
+ 5- FU
N o
Si nu
s ta ch yc ar di a; LV H w ith
re po
s N /A
ad en
FU ,L eu co vo rin
,O xa lip la tin
) Fi rs t cy cl e
Ye s
w ith
ch an ge
s w ith
in te rm
a of
FU ,L eu co vo rin
,O xa lip la tin
) Fi rs t cy cl e
Ye s
an d TW
I Tr op
FU ,L eu co vo rin
,O xa lip la tin
) Fi rs t cy cl e
Ye s
ST E an d hy pe
ra cu te
s in
Tr op
is pl at in ,5 -F U )
fo llo w ed
,F ol in ic ac id ,
Iri no
N o
Si nu
Ii n V4 ,V 5
Tr op
na so ph
ar yn ge
a
+ 5- FU
N o
Si nu
no ST -T
ch an ge
s N /A
ad en
5 FU
Ye s
r le ad s
ca nc er
itc he
d to
5 cy cl es
C ap ec ita bi ne
Ye s
TW Ii n an te ro se pt al ,i nf er io r, an d
la te ra ll ea ds
Tr op
in va si ve
ca rc in om
Ye s
N on
s, fo llo w ed
by ne
le ad s; ST D an d TW
Ii n le ad s V1
an d V2
a of
C ap ec ita bi ne
Fi rs t cy cl e
Ye s
a of
C ap ec ita bi ne
Fi rs t cy cl e
N o
N /A
[3 0]
39 F
N o
In fla m m at or y br ea st
ca nc er
N o
Si nu
Ii n
Tr op
Desai et al. Cardio-Oncology (2019) 5:7 Page 5 of 16
Ta b le
rt s of
ca nc er
o C ar di om
yo pa th y w ith
de ta ils
(c an ce r dr ug
,t yp e of
ca nc er ,p
ce or
ch es t pa in ,a nd
re su lts
(C on
N o.
A ge
Re po
rt ed
N o
A nt er io r an d in fe rio
r ST E
g ca nc er
Se co nd
cy cl e
w in fe rio
di ffu
th yr oi d
+ D ox or ub
N o
Tr op
th yr oi d
+ D ox or ub
N o
D ee p sy m et ric
TW Ii n pr ec or di al le ad s
N /A
[3 3]
66 M
N o
C LL
+ M et hy lp re dn
is on
N o
Si nu
s ta ch yc ar di a; ST E in
I, II, V4 –6
ca rc in om
a Su ni tin
ca rc in om
a A xi tin
Ye s
Tr op
+ D oc et ax el +
C ar bo
pl at in
El ev en
Tr op
C yt ar ab in e + D au no
ru bi ci n
6) Ye s
s ta ch yc ar di a; ST E in
I, aV L, V5 ,V 6
Tr op
m el an om
ab Fo ur th
s ta ch yc ar di a; 1 m m
ST E in
Desai et al. Cardio-Oncology (2019) 5:7 Page 6 of 16
Ta b le
3 Re po
al lm
ot io n ab no
rm al iti es ,f ol lo w -u p LV EF ,a nd
pa tie nt
ou tc om
N o.
(% )
or m al ity
[1 8]
sy st ol e an d di as to le
no n- ob
55 –6 0%
28 %
Ex te ns iv e ap ic al ak in es is
no rm
ar te rie s
al w al lm
rm al ity
ar te rie s
m id
se gm
en ts ,n or m ok in et ic ba sa lw
al l
N /A
(5 da ys )
no n- ob
68 %
hy pe
m en
ts no
n- ob
50 %
(4 w ee ks )
D ec ea se d (P ro gr es si on
of C an ce r)
[2 5]
w ee ks )
A sy st ol e du
rin g 5t h
cy cl e of
pe ria pi ca la ki ne
si a
70 %
th e an te rio
r an d in fe rio
r w al ls no
t co ns is te nt
w ith
te rr ito
60 %
al lm
rm al ity
no n- ob
55 %
H yp ok in et ic ba sa ls eg
m en
at ou
sl ug
gi sh
bl oo
r w al lh
in co ns is te nt
w ith
ar te ry
te rr ito
55 –6 5%
si s an d a hy pe
rd yn am
m en
Su rv iv ed
Re co ve re d (2 w ee ks )
Su rv iv ed
si s
55 –6 5%
N /A
th e an te rio
r w al l
N /A
(u nr el at ed
to ca rd io m yo pa th y)
[3 4]
ap ic al ba llo on
in g
68 %
Desai et al. Cardio-Oncology (2019) 5:7 Page 7 of 16
Ta b le
3 Re po
al lm
ot io n ab no
rm al iti es ,f ol lo w -u p LV EF ,a nd
pa tie nt
ou tc om
e (C on
tin ue d)
N o.
(% )
or m al ity
O ut co m e
in sy st ol e an d di as to le
[3 5]
in g
50 –5 5%
lg e at
no rm
m en
ts no
ar te rie s
Su rv iv ed
ild an te rio
r, se pt al ,
ap ic al ,i nf er io r an d la te ra lw
al lh
no n- ob
50 %
tic ba se
no n- ob
N /A
Desai et al. Cardio-Oncology (2019) 5:7 Page 8 of 16
Anti-neoplastic drugs and Takotsubo cardiomyopathy 5-fluorouracil (5-FU) 5-Fluorouracil is a pyrimidine analog that inhibits the thymidylate synthase enzyme in malignant cells, causing disruption of DNA synthesis and resulting in cell death [22]. It is administered by intravenous injection as bolus or infusion in the cytostatic treatment of solid tumors, including colorectal, gastric, esophageal, pancreatic, prostate, bladder, and breast cancers. It is the foundation of adjuvant chemotherapy for colorectal cancer and is used in combination with irinotecan or oxaliplatin along with leucovorin as FOLFIRI (5-FU, folinic acid and Iri- notecan) [39] or FOLFOX (5-FU, folinic acid and oxali- platin) [40] regimens. The most common cardiovascular side effect of 5-FU
is chest pain with or without ECG changes. The inci- dence of cardiotoxicity ranges from 1.5–18% [41]. Clin- ical manifestations include signs of acute MI with anginal chest pain and ECG abnormalities, rhythm dis- turbances, heart failure, and…
Abstract
Background: Cancer is a chronic condition that induces significant emotional and physical stress, which may increase the risk for developing Takotsubo cardiomyopathy (TCM).
Main body: Takotsubo cardiomyopathy, also known as stress cardiomyopathy, is a clinical syndrome that generally presents as chest pain mimicking acute coronary syndrome or as an acute heart failure characterized by severe left ventricular systolic dysfunction in response to emotional, physical, or medical stress. The potential triggers for Takotsubo syndrome in cancer patients include the emotional turmoil of a cancer diagnosis, the inflammatory state of the cancer itself, and the physical stress of cancer surgery, systemic anti-neoplastic therapy, and radiation treatment. TCM is becoming increasingly recognized among patients with cancer and has been associated with adverse outcomes in this patient population. In this study, we searched the Pubmed database using keywords “Takotsubo cardiomyopathy”, “cancer”, and “anti-neoplastic therapy” to review case reports of Takotsubo syndrome occurring in oncologic patients after systemic anti-neoplastic therapy. Clinical presentation, electrocardiogram, laboratory data, transthoracic echocardiogram and coronary angiogram results, and patient outcomes were collected and analyzed.
Conclusion: Patients with cancer are at an elevated risk for developing stress cardiomyopathy, and it is important to know which cancer drugs have been associated with the development of the Takotsubo syndrome.
Keywords: Chemotherapy, Takotsubo cardiomyopathy, Stress cardiomyopathy, Cancer
Background Patients with cancer who are undergoing systemic therapy for their malignancy often have co-existent cardiovascular illness and/or risk factors. Physicians sometimes face diffi- culty in differentiating chemotherapy-induced cardiotoxi- city from cardiac events unrelated to cancer treatment. Recognition of chemotherapy-induced cardiotoxicity is im- portant since repeated administration of the offending drug can potentially lead to irreversible cardiac damage. On the other hand, premature discontinuation of an effective anti- neoplastic agent due to co-existing cardiac events not dir- ectly related to therapy may increase oncologic morbidity and mortality. One cardiac condition that may be directly
caused by chemotherapy or may be completely unrelated to it is Takotsubo cardiomyopathy (TCM). TCM is a clinical syndrome that generally presents as
chest pain mimicking acute coronary syndrome (ACS) or as an acute heart failure characterized by severe left ventricular (LV) systolic dysfunction in response to emo- tional, physical, or medical stress. Unlike in ACS, patients generally have a normal coronary angiogram, the LV dysfunction extends beyond a coronary distribu- tion and usually recovers within days or weeks. The most common pattern of LV dysfunction is apical akin- esis or ballooning with hyperdynamic basal segments [1]. The pathophysiology of the syndrome is not well understood; however, catecholamine excess, coronary ar- tery vasospasm, and microvascular dysfunction are thought to be the key mediating processes [2]. These mechanisms can be activated by various stressors, which include emotional or psychological stress, infection, sur- gery, medications, and exacerbation of chronic diseases [3]. Furthermore, a genetic predisposition for TCM has
© The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
* Correspondence: [email protected] 1Department of Medicine, University of Connecticut School of Medicine, Farmington, CT, USA 2Department of Medicine, Division of Cardiology, University of Connecticut School of Medicine, 263 Farmington Avenue, Farmington, CT 06030-2202, USA
Desai et al. Cardio-Oncology (2019) 5:7 https://doi.org/10.1186/s40959-019-0042-9
been postulated given the preponderance of familial cases [4]. More recently, anti-neoplastic agents have been associ-
ated with TCM. Certain cancer drugs have been impli- cated in triggering this form of cardiomyopathy. While studies regarding the cardiotoxic effects of chemothera- peutic agents are plentiful, the data on this type of car- diomyopathy induced by cancer treatment are sparse, and no known correlation between dose of chemother- apy and TCM currently exists. Our review explores the possible etiologic link between various cancer drugs and TCM. The cancer therapies that will be discussed in- clude traditional chemotherapeutic agents as well as newer targeted drugs, including immune checkpoint in- hibitors. With this review, we hope to shed light on the association between TCM and cancer as well as TCM and anti-neoplastic agents.
Takotsubo cardiomyopathy TCM was first described in Japan in 1990 by Dote and colleagues [1]. The particular name “Takotsubo” was used to describe the cardiomyopathy due to the charac- teristic apical ballooning on left ventriculography which was similar in shape to a Japanese octopus trap. It is also
referred to as “broken heart”, “apical ballooning syn- drome”, “myocardial stunning”, or “stress cardiomyop- athy”. TCM may occur in the presence of an emotional or physiologic stressor. The syndrome has been observed most frequently in
post-menopausal women who are exposed to major stressors. Patients can experience symptoms varying from chest pain (63%) to dyspnea on exertion (8%) and syncope (3%) [3]. This poses an added diagnostic chal- lenge since this constellation of symptoms can mimic myocardial infarction (MI), pulmonary embolism or cerebrovascular disorders. Patients can present with vari- able ECG changes that affect the ST segment and T wave [5]. ST segment elevation or new LBBB was present in 34.2% of cases, while T wave inversion and non-specific ST-T wave changes were seen in 30.4 and 35.2% respectively [5]. Mild elevation in cardiac enzymes may also be present; however, the degree of elevation is disproportionately low to the area of myocardium af- fected. Coronary angiography does not show obstructive CAD (defined as > 50% narrowing of the coronary artery) [2]. LV dysfunction is observed on imaging modalities like
echocardiography and left ventriculography (Fig. 1).
Fig. 1 Echocardiogram pattern in a patient with TCM demonstrating apical ballooning and diffuse hypokinesis with sparing of the basal myocardial segments. Left ventricle in (a) end-diastole and (b) end-systole is shown; Left Ventriculogram pattern in TCM shown in (c) end-diastole and (d) end-systole
Desai et al. Cardio-Oncology (2019) 5:7 Page 2 of 16
Three different types of contractile abnormality of the LV have been described. The most common pattern is apical akinesis with hyperkinesis of the basal segments. Other less common patterns include: combined akinesis of the mid-LV and apex, isolated akinesis of the mid-LV, and isolated basal akinesis [6]. Typically, LV ejection fraction (LVEF) is severely reduced, with median LVEF of 20%; interquartile range, 15 to 30% (normal LVEF range 55–75%) [2]. In a majority of patients, LVEF im- proves to greater than 50% on follow up. While cardiac recovery usually occurs in 4 to 6 weeks, it can take any- where from 2.5 months to a year for a small proportion of individuals (~ 5%) [2, 7]. The prolonged duration re- quired for normalization of LV systolic function predis- poses individuals to the development thrombus in the LV with increased risk of embolization. Although uncommon, TCM can lead to complications like hemodynamic instability, atrial or ventricular arrhyth- mias, progressive heart failure, cardiogenic shock, and death. To aid in the diagnosis, “Mayo Clinic criteria” [8], can be used (Table 1). Beta blockers along with ACE-inhibitors form the
mainstay of treatment by reducing catecholamine stimu- lation and countering one of the main pathogenetic pathways. In-hospital mortality can be as high as 16% [9]. Given the paucity of lengthy follow-up studies, data regarding long-term prognosis and outcomes are currently lacking.
Pathogenetic mechanisms of Takotsubo cardiomyopathy The exact pathophysiology behind TCM is currently un- known. The rationale behind increased incidence in postmenopausal women or the predilection for the LV apex or mid-cavity are currently unanswered questions. Various postulated mechanisms of TCM include: cat- echolamine excess, coronary artery vasospasm, micro- vascular dysfunction and upregulation of certain cardiac genes (Fig. 2). Catecholamines released during a stressful event play
a significant role in the development of cardiomyopathy. Wittstein et al. [2] found that patients with LV
dysfunction after emotional stress had elevated catechol- amines. The pivotal role of catecholamines is also sup- ported by Abraham et al. [10] where TCM was induced after infusion of norepinephrine and dopamine. The stimulation of cAMP increases the intracellular concen- tration of norepinephrine within the cardiac myocytes, which can lead to damage. The key role of norepineph- rine is also supported by the fact that the use of beta- blockers can significantly reduce damage. The findings of multifocal coronary vasospasm and transient myocar- dial perfusion abnormalities also suggest coronary artery vasospasm as one of the mechanisms inducing TCM. Drugs have been implicated as a cause of TCM, particu- larly in those situations in which no clear emotional or other stress trigger could be identified [11].
Takotsubo cardiomyopathy and cancer Cancer is a chronic condition that induces significant emo- tional and physical stress, increasing the risk of stress car- diomyopathy. The potential triggers for TCM in cancer patients include emotional turmoil of the diagnosis, the in- flammatory state of cancer, and the physical stress of vari- ous cancer treatments, including chemotherapy (Fig. 3) [12, 13]. In addition, it has been hypothesized that the circulat- ing paraneoplastic mediators may modify the adrenorecep- tors in cardiac tissue, leading to contractile dysfunction. The cardiotoxicity of chemotherapeutic agents, such
as anthracyclines and trastuzumab, is a well-known en- tity among cardiologists and oncologists alike [14]. The wide range of potential cardiac side effects rising from cancer therapy include ventricular dysfunction, ischemia, arrhythmia, hypertension, accelerated atherosclerosis, venous thromboembolism, myocarditis and QT pro- longation [15–17]. Several anti-neoplastic agents have been implicated to be associated with TCM. Among these drugs, the most commonly reported is 5- Fluorouracil. Other cancer therapies that have been re- ported to induce this type of cardiomyopathy include capecitabine, combretastatin, rituximab, vascular endo- thelial growth factors inhibitors, other angiogenesis in- hibitors, taxols and others (Tables 2 and 3). TCM is probably an under-recognized and thus under-diagnosed disease entity among cancer patients receiving chemo- therapy [12]. In this study, we searched the Pubmed database using
keywords “Takotsubo cardiomyopathy”, “cancer”, and “anti-neoplastic therapy” to review case reports of Takot- subo syndrome occurring in oncologic patients after sys- temic anti-neoplastic therapy. Clinical presentation, electrocardiogram, laboratory data, transthoracic echo- cardiogram and coronary angiogram results, and patient outcome were collected and analyzed. What follows is a review of the anti-neoplastic drugs that have been re- ported to cause TCM.
Table 1 Mayo Clinic diagnostic criteria for Takotsubo cardiomyopathy [8]
For the diagnosis of TCM, the “Mayo Clinic criteria” must be met, which include [8]:
1. Transient hypokinesis, akinesis or dyskinesis of left ventricular mid segments with/without apical involvement, regional wall motion abnormality extending beyond a single vascular territory, and a stressful trigger is often, but not always, present; 2. Absence of angiographic evidence of obstructive coronary disease or plaque rupture; 3. New ECG abnormalities consisting of ST elevation or T wave inversion with modest elevation in cardiac troponins; 4. Absence of pheochromocytoma and myocarditis
Desai et al. Cardio-Oncology (2019) 5:7 Page 3 of 16
Fig. 2 Proposed Pathogenetic Mechanisms of TCM
Fig. 3 Cancer and Takotsubo cardiomyopathy: Cancer can increase the predisposition to TCM through various pathways. Cancer produces an emotional stress response as well as physical/surgical stressors from the disease. The paraneoplastic mediators along with the chronic inflammatory state is another risk factor. Lastly, the therapeutic regimens including medical therapeutic agents and radiation therapy can trigger the development of TCM
Desai et al. Cardio-Oncology (2019) 5:7 Page 4 of 16
Ta b le
rt s of
ca nc er
o C ar di om
yo pa th y w ith
de ta ils
(c an ce r dr ug
,t yp e of
ca nc er ,p
ce or
ch es t pa in ,a nd
re su lts
Re fe re nc e
N o.
A ge
Re po
rt ed
ca nc er
FO LF O X]
Ye s
Si nu
s Ta ch yc ar di a; ST E in
II, III ,a VF ,V 4, V5 ,V 6
Tr op
Ye s
ad en
FU ,L eu co vo rin
,O xa lip la tin
) Fi rs t cy cl e
N o
N on
sp ec ifi c la te ra lS T ch an ge
s an d po
re ss io n
+ 5- FU
N o
Si nu
s ta ch yc ar di a; LV H w ith
re po
s N /A
ad en
FU ,L eu co vo rin
,O xa lip la tin
) Fi rs t cy cl e
Ye s
w ith
ch an ge
s w ith
in te rm
a of
FU ,L eu co vo rin
,O xa lip la tin
) Fi rs t cy cl e
Ye s
an d TW
I Tr op
FU ,L eu co vo rin
,O xa lip la tin
) Fi rs t cy cl e
Ye s
ST E an d hy pe
ra cu te
s in
Tr op
is pl at in ,5 -F U )
fo llo w ed
,F ol in ic ac id ,
Iri no
N o
Si nu
Ii n V4 ,V 5
Tr op
na so ph
ar yn ge
a
+ 5- FU
N o
Si nu
no ST -T
ch an ge
s N /A
ad en
5 FU
Ye s
r le ad s
ca nc er
itc he
d to
5 cy cl es
C ap ec ita bi ne
Ye s
TW Ii n an te ro se pt al ,i nf er io r, an d
la te ra ll ea ds
Tr op
in va si ve
ca rc in om
Ye s
N on
s, fo llo w ed
by ne
le ad s; ST D an d TW
Ii n le ad s V1
an d V2
a of
C ap ec ita bi ne
Fi rs t cy cl e
Ye s
a of
C ap ec ita bi ne
Fi rs t cy cl e
N o
N /A
[3 0]
39 F
N o
In fla m m at or y br ea st
ca nc er
N o
Si nu
Ii n
Tr op
Desai et al. Cardio-Oncology (2019) 5:7 Page 5 of 16
Ta b le
rt s of
ca nc er
o C ar di om
yo pa th y w ith
de ta ils
(c an ce r dr ug
,t yp e of
ca nc er ,p
ce or
ch es t pa in ,a nd
re su lts
(C on
N o.
A ge
Re po
rt ed
N o
A nt er io r an d in fe rio
r ST E
g ca nc er
Se co nd
cy cl e
w in fe rio
di ffu
th yr oi d
+ D ox or ub
N o
Tr op
th yr oi d
+ D ox or ub
N o
D ee p sy m et ric
TW Ii n pr ec or di al le ad s
N /A
[3 3]
66 M
N o
C LL
+ M et hy lp re dn
is on
N o
Si nu
s ta ch yc ar di a; ST E in
I, II, V4 –6
ca rc in om
a Su ni tin
ca rc in om
a A xi tin
Ye s
Tr op
+ D oc et ax el +
C ar bo
pl at in
El ev en
Tr op
C yt ar ab in e + D au no
ru bi ci n
6) Ye s
s ta ch yc ar di a; ST E in
I, aV L, V5 ,V 6
Tr op
m el an om
ab Fo ur th
s ta ch yc ar di a; 1 m m
ST E in
Desai et al. Cardio-Oncology (2019) 5:7 Page 6 of 16
Ta b le
3 Re po
al lm
ot io n ab no
rm al iti es ,f ol lo w -u p LV EF ,a nd
pa tie nt
ou tc om
N o.
(% )
or m al ity
[1 8]
sy st ol e an d di as to le
no n- ob
55 –6 0%
28 %
Ex te ns iv e ap ic al ak in es is
no rm
ar te rie s
al w al lm
rm al ity
ar te rie s
m id
se gm
en ts ,n or m ok in et ic ba sa lw
al l
N /A
(5 da ys )
no n- ob
68 %
hy pe
m en
ts no
n- ob
50 %
(4 w ee ks )
D ec ea se d (P ro gr es si on
of C an ce r)
[2 5]
w ee ks )
A sy st ol e du
rin g 5t h
cy cl e of
pe ria pi ca la ki ne
si a
70 %
th e an te rio
r an d in fe rio
r w al ls no
t co ns is te nt
w ith
te rr ito
60 %
al lm
rm al ity
no n- ob
55 %
H yp ok in et ic ba sa ls eg
m en
at ou
sl ug
gi sh
bl oo
r w al lh
in co ns is te nt
w ith
ar te ry
te rr ito
55 –6 5%
si s an d a hy pe
rd yn am
m en
Su rv iv ed
Re co ve re d (2 w ee ks )
Su rv iv ed
si s
55 –6 5%
N /A
th e an te rio
r w al l
N /A
(u nr el at ed
to ca rd io m yo pa th y)
[3 4]
ap ic al ba llo on
in g
68 %
Desai et al. Cardio-Oncology (2019) 5:7 Page 7 of 16
Ta b le
3 Re po
al lm
ot io n ab no
rm al iti es ,f ol lo w -u p LV EF ,a nd
pa tie nt
ou tc om
e (C on
tin ue d)
N o.
(% )
or m al ity
O ut co m e
in sy st ol e an d di as to le
[3 5]
in g
50 –5 5%
lg e at
no rm
m en
ts no
ar te rie s
Su rv iv ed
ild an te rio
r, se pt al ,
ap ic al ,i nf er io r an d la te ra lw
al lh
no n- ob
50 %
tic ba se
no n- ob
N /A
Desai et al. Cardio-Oncology (2019) 5:7 Page 8 of 16
Anti-neoplastic drugs and Takotsubo cardiomyopathy 5-fluorouracil (5-FU) 5-Fluorouracil is a pyrimidine analog that inhibits the thymidylate synthase enzyme in malignant cells, causing disruption of DNA synthesis and resulting in cell death [22]. It is administered by intravenous injection as bolus or infusion in the cytostatic treatment of solid tumors, including colorectal, gastric, esophageal, pancreatic, prostate, bladder, and breast cancers. It is the foundation of adjuvant chemotherapy for colorectal cancer and is used in combination with irinotecan or oxaliplatin along with leucovorin as FOLFIRI (5-FU, folinic acid and Iri- notecan) [39] or FOLFOX (5-FU, folinic acid and oxali- platin) [40] regimens. The most common cardiovascular side effect of 5-FU
is chest pain with or without ECG changes. The inci- dence of cardiotoxicity ranges from 1.5–18% [41]. Clin- ical manifestations include signs of acute MI with anginal chest pain and ECG abnormalities, rhythm dis- turbances, heart failure, and…
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