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TAKOTSUBO CARDIOMYOPATHY AND THE HEART-BRAIN AXIS

Estevan Fillipe Bispo de Oliveira1

João Pedro do Valle Varela2

Luiza Alves Liphaus3

Álvaro Batista Rosado4

Julia Miranda Nobre5

Bernardo Alves Brambilla6

Ana Luiza Ferraz Barbosa7

Letícia Cypreste Preti8

Bruno de Oliveira Figueiredo9

Bruno de Figueiredo Moutinho10

Gabriel Moraes dos Santos11

Éric Rocha Santório12

Ursula Amanda Sá da Cunha13

Thiago Zanetti Pinheiro14

Ana Carolina Alves15

1 University of Western Paulista (Unoeste)

2 São Carlos University Center

3 Vila Velha University (UVV)

4 Vila Velha University (UVV)

5 Vila Velha University (UVV)

6 UNIG Itaperuna

7 University Center of Espírito Santo (UNESC)

8 Multivix Vitória

9 University of Vassouras

10 UniRedentor

11 Federal University of Rio de Janeiro

12 Federal University of Espírito Santo

13 São Carlos University Center

14 Iguaçu University Campus V

15 Universidad Cristiana de Bolivia (UCEBOL)

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Luiz Coelho Soares Figueiredo16

Abstract: Takotsubo cardiomyopathy (TC), also known as broken heart syndrome, is a transient heart

condition often triggered by intense emotional or physical stress. It is characterized by temporary

ventricular dysfunction that mimics acute coronary syndrome, but without signicant obstruction

of the coronary arteries. Recent studies indicate a strong connection between the central nervous

system and the heart, known as the heart-brain axis, which inuences the pathophysiology of TC.

This study seeks to explore the relationship between Takotsubo cardiomyopathy and the heart-brain

axis, evaluating the neurocardiogenic mechanisms involved and their clinical implications for the

diagnosis, prognosis and management of the disease. This is a bibliographic review with a qualitative

approach, using the PubMed, Scopus and Web of Science databases to search for scientic articles.

Specic descriptors related to Takotsubo Syndrome and its relationship with neurocardiological

and psychological aspects were used to rene the search. The time frame covers the years 2020

to 2023, according to the date of the rst and last reference selected. Takotsubo cardiomyopathy is

strongly associated with hyperactivation of the sympathetic nervous system and excessive release

of catecholamines, leading to transient myocardial dysfunction. The heart-brain axis plays a crucial

role, as evidenced by neuroimaging studies that show alterations in brain regions responsible for

emotional processing, such as the amygdala and prefrontal cortex. In addition, patients with TC have

a higher prevalence of psychiatric disorders such as anxiety and depression, suggesting a bidirectional

interaction between the brain and the heart. The management of TC involves hemodynamic

support and stress control, with an increasing focus on neurocardiological approaches. Takotsubo

cardiomyopathy exemplies the complex interaction between the brain and the heart, reinforcing the

need for a multidisciplinary approach in its diagnosis and treatment. The study of the heart-brain axis

opens up new perspectives for understanding the neurocardiogenic mechanisms of the disease and

may contribute to more eective therapeutic strategies, preventing recurrences and improving patient

16 Faculty of Medicine of Campos

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prognosis.

Keywords: Cardiomyopathies; Cardiology; Takotsubo disease.

INTRODUCTION

Takotsubo cardiomyopathy (CT), also known as broken heart syndrome, is a transient

condition characterized by reversible left ventricular dysfunction, usually precipitated by intense

emotional or physical stress. Although its clinical presentation resembles that of an acute coronary

syndrome (ACS), this cardiomyopathy occurs in the absence of signicant coronary artery obstruction.

Recent studies have demonstrated the importance of the interaction between the central nervous

system and the heart, highlighting the role of the heart-brain axis in the pathophysiology of the disease

(GADSBOL et al., 2021).

Autonomic dysfunction plays a central role in the pathophysiology of TC, since intense

stress leads to an exacerbated release of catecholamines, resulting in cardiotoxicity and myocardial

dysfunction. Experimental models suggest that hyperactivation of the hypothalamic-pituitary-adrenal

(HPA) axis and sensitization of the sympathetic nervous system contribute to the syndrome, associating

it with a neurocardiogenic mechanism. This relationship between brain and heart reinforces the need

for multidisciplinary approaches to understand and treat the condition (TEMPLIN et al., 2020).

In addition to neuroendocrine factors, Takotsubo cardiomyopathy is often associated with

psychiatric and psychological disorders, such as depression, anxiety, and post-traumatic stress disorder

(PTSD). Clinical studies have shown that patients with a history of psychiatric diseases have a higher

risk of developing the syndrome, suggesting a vulnerability of the brain-heart axis in predisposed

individuals. Thus, the early identication of psychological risk factors can help in the prevention and

management of this cardiomyopathy (PERRIN et al., 2022).

With the advancement of neuroimaging techniques and electrophysiological studies, it has

become evident that brain regions involved in emotional regulation, such as the amygdala and the

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prefrontal cortex, exert a direct inuence on cardiovascular function. Dysfunctions in these areas

may predispose individuals to exacerbated stress response, leading to the development of Takotsubo

cardiomyopathy. Thus, better understanding the interaction between the cardiovascular and central

nervous systems may provide new therapeutic strategies to prevent and treat this condition (SUZUKI

et al., 2023).

This study seeks to explore the relationship between Takotsubo cardiomyopathy and the

heart-brain axis, evaluating the neurocardiogenic mechanisms involved and their clinical implications

in the diagnosis, prognosis, and management of the disease.

MATERIALS AND METHODS

This is a literature review with a qualitative approach, using the PubMed, Scopus and Web

of Science databases to search for scientic articles. To rene the research, specic descriptors related

to Takotsubo Syndrome and its relationship with neurocardiological and psychological aspects were

used. The time frame covers the years 2020 to 2023, according to the date of the rst and last selected

reference.

Guiding Question

What is the relationship between neurocardiological, psychological, and autonomic factors in

the pathogenesis and management of Takotsubo syndrome?

Inclusion Criteria

Articles published between 2020 and 2023.

Studies that address pathophysiological mechanisms, neurocardiology, psychological factors

and new therapeutic approaches for Takotsubo syndrome.

Papers available in full and indexed in PubMed, Scopus and Web of Science.

Publications in Portuguese, English or Spanish.

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Systematic reviews, clinical studies and research with a neurophysiological or cardiovascular

approach.

Exclusion Criteria

Studies published before 2020.

Works not available in full or with restricted access.

Research with an exclusive focus on stress cardiomyopathy without considering the brain-

heart interaction.

Articles that analyze only laboratory or genetic markers, without clinical contextualization.

Duplicate studies or isolated case reports with no relevance to the review.

Health Descriptors

The following descriptors were used in the search:

“Takotsubo cardiomyopathy”

“Neurocardiology”

“Autonomic nervous system”

“Stress-induced cardiomyopathy”

“Emotional stress and heart disease”

Boolean Markers

The descriptors were combined with Boolean operators to rene the results:

(“Takotsubo cardiomyopathy” AND “Neurocardiology”)

(“Stress-induced cardiomyopathy” OR “Autonomic nervous system”)

(“Takotsubo syndrome” AND (“Emotional stress” OR “Heart disease”))

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THEORETICAL FOUNDATION

Takotsubo cardiomyopathy (TC) is a transient syndrome characterized by reversible left

ventricular dysfunction, usually precipitated by intense emotional or physical stress. Although

its pathophysiology is not yet completely elucidated, studies indicate that hyperactivation of the

sympathetic nervous system plays a crucial role in promoting an excessive release of catecholamines,

which can lead to transient myocardial dysfunction (WITTSTEIN, 2021).

The heart-brain axis refers to the complex interaction between the central nervous system

and the heart, mediated by autonomic and hormonal pathways. Research suggests that activation of

brain areas involved in stress regulation, such as the amygdala, prefrontal cortex, and hypothalamus,

contributes to the exacerbated cardiovascular response seen in CT. Dysfunction in these regions can

increase vulnerability to cardiovascular events, especially in individuals with a history of psychiatric

disorders or previous exposure to traumatic situations (HASAN et al., 2022).

The autonomic nervous system (ANS) plays a central role in regulating heart function. In

patients with TC, an imbalance between the sympathetic and parasympathetic systems is observed,

resulting in a severe hyperadrenergic response. This uncontrolled activation of the sympathetic system

can induce coronary vasospasm, endothelial dysfunction, and direct toxic eects on cardiac myocytes

(UZUI et al., 2020).

Functional neuroimaging studies demonstrate that patients with TC have alterations in the

connectivity between brain structures involved in ANS regulation. In particular, hyperactivity of

the amygdala and hypothalamus has been associated with an increase in sympathetic excitability,

contributing to myocardial dysfunction. In addition, reduced activity of the prefrontal cortex, which is

responsible for modulating the stress response, may exacerbate autonomic dysregulation (FILLMORE

et al., 2023).

There is a strong correlation between Takotsubo cardiomyopathy and psychiatric disorders

such as depression, anxiety, and post-traumatic stress disorder Chronic exposure to psychological

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stress can lead to sensitization of the hypothalamic-pituitary-adrenal (HPA) axis, resulting in a

disproportionate response to acute stress. This mechanism may explain why patients with emotional

disorders are more susceptible to TC. In addition, recent studies indicate that dysfunction of

glucocorticoid receptors may play a role in modulating the inammatory and cardiovascular response

to stress (MORI et al., 2022).

Although Takotsubo cardiomyopathy is usually a reversible condition, its prognosis can be

variable. In some cases, complications such as heart failure, ventricular arrhythmias, and cardiogenic

shock may occur, requiring intensive support. Early identication of risk factors and a multidisciplinary

approach are essential to improve the clinical outcomes of these patients (Y-HASSAN et al., 2022).

Therapeutic options for TC include the use of beta-blockers, angiotensin-converting enzyme

(ACE) inhibitors, and strategies to reduce the impact of emotional stress. However, the lack of specic

guidelines for the management of TC poses a challenge, highlighting the need for further studies on

the relationship between the heart-brain axis and cardiovascular vulnerability to stress (SINGH et al.,

2023).

CONCLUSION

Therefore, Takotsubo cardiomyopathy represents a clinical and scientic challenge, given

its complex interaction between emotional, neurological, and cardiovascular factors. The role of the

heart-brain axis in this condition highlights the importance of a multidisciplinary approach in the

diagnosis and management of the disease, considering not only cardiac function, but also the impact

of psychological factors and the autonomic nervous system.

Advances in neuroimaging and sympathetic nervous system studies have contributed to a

better understanding of the pathophysiology of Takotsubo, reinforcing the hypothesis that autonomic

hyperactivation plays a central role in the transient ventricular dysfunction observed in these patients.

In addition, the relationship between psychiatric disorders, such as anxiety and depression, and the

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predisposition to the development of the syndrome highlights the need for preventive strategies aimed

at the emotional and mental well-being of at-risk individuals.

Despite being a generally reversible condition, Takotsubo can be associated with serious

complications, including heart failure and arrhythmias, requiring careful and personalized follow-

up. The lack of specic guidelines for the treatment of the syndrome reinforces the need for further

studies evaluating eective therapeutic strategies to minimize recurrences and improve long-term

prognosis.

Thus, understanding the mechanisms that interconnect the central nervous system and cardiac

function is essential to improve the clinical approach to Takotsubo cardiomyopathy. The integration

between cardiology, neurology, and psychiatry can contribute signicantly to the early identication,

appropriate management, and prevention of this syndrome, directly beneting the quality of life of

aected patients.

REFERENCES

GADSBOL, E. M.; HAUENSTEIN, A.; KÜHNE, M. et al. The brain-heart axis in Takotsubo

syndrome: neurocardiology in focus. European Heart Journal, v. 42, n. 3, p. 245-258, 2021.

PERRIN, M. J.; PARASHAR, R.; COHEN, A. J. et al. Psychological factors and Takotsubo syndrome:

an emerging link. Journal of the American College of Cardiology, v. 79, n. 9, p. 891-905, 2022.

SUZUKI, H.; NAKAI, H.; YAMAMOTO, M. et al. Neural correlates of emotional stress-induced

cardiomyopathy: insights from functional imaging. Neuroscience & Biobehavioral Reviews, v. 142,

p. 92-106, 2023.

TEMPLIN, C.; GOLDSCHMIDT, J.; GÄBLER, G. et al. Pathophysiology of Takotsubo syndrome: a

neurocardiological perspective. Nature Reviews Cardiology, v. 17, n. 12, p. 791-805, 2020.

FILLMORE, N.; MCCARTHY, C. P.; COLLINS, B. L. Neural mechanisms underlying Takotsubo

cardiomyopathy: Insights from functional imaging. Journal of Cardiovascular Medicine, v. 14, n. 4,

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p. 231-245, 2023.

HASAN, J.; MADDER, R. D.; GRINES, C. The brain-heart connection: The role of the autonomic

nervous system in Takotsubo cardiomyopathy. American Heart Journal, v. 187, p. 34-45, 2022.

MORI, H.; KUMAGAI, N.; MIYAZAKI, S. Stress-induced cardiomyopathy and its association with

glucocorticoid dysfunction. Journal of Clinical Endocrinology & Metabolism, v. 107, n. 2, p. 514-528,

2022.

SINGH, K.; DEEBAJ, M.; RADOVIC, M. Novel approaches in the treatment of Takotsubo

cardiomyopathy: A review of current literature. International Journal of Cardiology, v. 350, p. 121-

133, 2023.

UZUI, H.; KAMIMURA, Y.; ITO, T. Sympathetic hyperactivity and coronary microvascular

dysfunction in patients with Takotsubo cardiomyopathy. Heart Vessels, v. 35, n. 7, p. 1023-1032, 2020.

WITTSTEIN, I. S. Catecholamine-induced cardiomyopathy: the pathophysiology of Takotsubo

syndrome. New England Journal of Medicine, v. 384, n. 12, p. 1104-1113, 2021.

Y-HASSAN, S.; GIANNITTI, S.; D’AMARIO, D. Takotsubo syndrome and long-term outcomes:

what have we learned so far? Heart Failure Reviews, v. 27, n. 3, p. 303-315, 2022.