Brain–Heart Axis and Phenotype-Guided Care in Takotsubo Syndrome: A Contemporary Clinical Review
Journal: Journal of Clinical Medicine Research DOI: 10.32629/jcmr.v7i2.5292
Abstract
More and more evidence suggests that Takotsubo syndrome (TTS) is not a one-size-fits-all benign self-limiting condition, but a highly heterogeneous acute heart failure syndrome. Most existing reviews are largely descriptive and fail to truly link brain–heart axis mechanisms, diagnostic refinement, and phenotype-guided care. This review focuses on recent advances since 2019, with emphasis on autonomic imbalance, neurocardiac vulnerability, multimodal imaging, Mayo and InterTAK diagnostic frameworks, and emerging contexts such as COVID-19, immune checkpoint inhibitors, and spontaneous coronary artery dissection. Current evidence points to sympathetic activation, insufficient parasympathetic regulation, coronary microvascular dysfunction, and inflammatory–immune responses jointly contributing to reversible myocardial stunning. Diagnosis cannot rely solely on ruling out obstructive coronary artery disease, because TTS can coexist with coronary artery disease, acute coronary syndrome (ACS), or SCAD. CMR and, in selected stable patients, CCTA provide useful complementary information for differential diagnosis and risk assessment. Management remains largely supportive, but stratifying patients according to hemodynamic status, left ventricular outflow tract obstruction, arrhythmic and thromboembolic risks, trigger context, and extracardiac comorbidities can make acute and long-term care more individualized. Finally, we propose a phenotype-guided clinical framework and highlight priorities for future prospective studies.
Keywords
Takotsubo syndrome; stress-induced cardiomyopathy; brain–heart axis; immune checkpoint inhibitors; COVID-19; spontaneous coronary artery dissection
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[23] Habib M, Aronson D. Thromboembolic complications in takotsubo cardiomyopathy. Seminars in Thrombosis and Hemostasis. 2025;51(4):423-429.
[24] Sethi Y, Murli H, Kaiwan O, et al. Broken heart syndrome: evolving molecular mechanisms and principles of management. Journal of Clinical Medicine. 2023;12(1):125.
[25] Qadri HM, Ismail F, Khawaja M, et al. Takotsubo cardiomyopathy in epilepsy: a systematic insight into the existing literature from 2000-2023. Pakistan Journal of Medical Sciences. 2024;40(12 PINS Suppl):S114-S125.
[26] Cruciani G, Cavicchioli M, Tanzilli G, et al. Heart rate variability alterations in takotsubo syndrome and related association with psychological factors: a systematic review and meta-analysis. Scientific Reports. 2023;13(1):20744.
[27] Prasad A, Lerman A, Rihal CS. Apical ballooning syndrome (Tako-Tsubo or stress cardiomyopathy): a mimic of acute myocardial infarction. American Heart Journal. 2008;155(3):408-417.
[28] Ghadri JR, Wittstein IS, Prasad A, et al. International expert consensus document on takotsubo syndrome (Part I): clinical characteristics, diagnostic criteria, and pathophysiology. European Heart Journal. 2018;39(22):2032-2046.
[29] Ghadri JR, Cammann VL, Jurisic S, et al. A novel clinical score (InterTAK Diagnostic Score) to differentiate takotsubo syndrome from acute coronary syndrome: results from the International Takotsubo Registry. European Journal of Heart Failure. 2017;19(8):1036-1042.
[30] Yalçin F. Stress and heart in remodeling process: multiple stressors at the same time kill. Journal of Clinical Medicine. 2024;13(9):2597.
[2] Scafa-Udriste A, Horodinschi RN, Babos M, Dinu B. Diagnostic challenges between takotsubo cardiomyopathy and acute myocardial infarction: where is the emergency? A literature review. International Journal of Emergency Medicine. 2024;17(1):22.
[3] Salamanca J, Alfonso F. Takotsubo syndrome: unravelling the enigma of the broken heart syndrome? A narrative review. Cardiovascular Diagnosis and Therapy. 2023;13(6):1080-1103.
[4] Kilaru P, Kilaru P, Garikipaty S. The role of cardiac biomarkers in evaluating takotsubo cardiomyopathy: a systematic review. Cureus. 2025;17(6):e86168.
[5] Kato K, Di Vece D, Kitagawa M, et al. Clinical characteristics and outcomes in takotsubo syndrome: review of insights from the InterTAK Registry. Journal of Cardiology. 2025;85(4):263-267.
[6] Lu X, Li P, Teng C, et al. Prognostic factors of takotsubo cardiomyopathy: a systematic review. ESC Heart Failure. 2021;8(5):3663-3689.
[7] Citro R, Radano I, Bellino M, et al. Epidemiology, pathogenesis, and clinical course of takotsubo syndrome. Heart Failure Clinics. 2022;18(1):125-137.
[8] Giubilato S, Rossini R, Gatto L, et al. Takotsubo syndrome and gender differences: exploring pathophysiological mechanisms and clinical differences for a personalized approach in patient management. Journal of Clinical Medicine. 2024;13(16):4925.
[9] Abuelazm M, Saleh O, Ahmad S, et al. Sex difference in clinical and management outcomes in patients with takotsubo syndrome: a systematic review and meta-analysis. Current Problems in Cardiology. 2023;48(4):101545.
[10] Abusnina W, Elhouderi E, Walters RW, et al. Sex differences in the clinical outcomes of patients with takotsubo stress cardiomyopathy: a meta-analysis of observational studies. American Journal of Cardiology. 2024;211:316-325.
[11] Ahmed T, Lodhi SH, Haigh PJ, Sorrell VL. The many faces of takotsubo syndrome: a review. Current Problems in Cardiology. 2024;49(3):102421.
[12] Bairashevskaia AV, Belogubova SY, Kondratiuk MR, et al. Update of takotsubo cardiomyopathy: present experience and outlook for the future. International Journal of Cardiology: Heart & Vasculature. 2022;39:100990.
[13] Alevroudis I, Petridou M, Sakkou A, et al. Restless nights, stressed hearts: the link between sleep disorders and takotsubo syndrome: a comprehensive review. Reviews in Cardiovascular Medicine. 2025;26(5):28244.
[14] Malik S, Ali ZS, Al-Rawi R, et al. Emotions and heart: exploring the impact of negative emotions on cardiovascular health. Current Problems in Cardiology. 2025;50(3):102989.
[15] Y-Hassan S, Falhammar H. Clinical features, complications, and outcomes of exogenous and endogenous catecholamine-triggered takotsubo syndrome: a systematic review and meta-analysis of 156 published cases. Clinical Cardiology. 2020;43(5):459-467.
[16] Ang SP, Chia JE, Krittanawong C, et al. Racial disparities in trend, clinical characteristics and outcomes in takotsubo syndrome. Current Problems in Cardiology. 2024;49(11):102826.
[17] Tsugu T, Nagatomo Y, Nakajima Y, et al. Biventricular takotsubo cardiomyopathy with asymmetrical wall motion abnormality between left and right ventricle: a new case and literature review. Journal of Echocardiography. 2019;17(3):123-128.
[18] Gonuguntla K, Thyagaturu H, Shaik A, et al. Takotsubo cardiomyopathy and psychiatric illness: insight from National Inpatient Sample (NIS) and National Re-admission Database (NRD) 2016 to 2018. Current Problems in Cardiology. 2024;49(4):102429.
[19] Oliveri F, Goud HK, Mohammed L, et al. Role of depression and anxiety disorders in takotsubo syndrome: the psychiatric side of broken heart. Cureus. 2020;12(9):e10400.
[20] Kouhanjani MF, Hosseini SA, Mousavi SM, et al. Takotsubo cardiomyopathy and autoimmune disorders: a systematic scoping review of published cases. International Journal of Clinical Practice. 2024;2024:7259200.
[21] Saito Y, Watanabe T, Ishigaki T, et al. Recurrent takotsubo syndrome presenting with different ballooning patterns and electrocardiographic abnormalities. Internal Medicine. 2023;62(20):2977-2980.
[22] Okura H. Update of takotsubo syndrome in the era of COVID-19. Journal of Cardiology. 2021;77(4):361-369.
[23] Habib M, Aronson D. Thromboembolic complications in takotsubo cardiomyopathy. Seminars in Thrombosis and Hemostasis. 2025;51(4):423-429.
[24] Sethi Y, Murli H, Kaiwan O, et al. Broken heart syndrome: evolving molecular mechanisms and principles of management. Journal of Clinical Medicine. 2023;12(1):125.
[25] Qadri HM, Ismail F, Khawaja M, et al. Takotsubo cardiomyopathy in epilepsy: a systematic insight into the existing literature from 2000-2023. Pakistan Journal of Medical Sciences. 2024;40(12 PINS Suppl):S114-S125.
[26] Cruciani G, Cavicchioli M, Tanzilli G, et al. Heart rate variability alterations in takotsubo syndrome and related association with psychological factors: a systematic review and meta-analysis. Scientific Reports. 2023;13(1):20744.
[27] Prasad A, Lerman A, Rihal CS. Apical ballooning syndrome (Tako-Tsubo or stress cardiomyopathy): a mimic of acute myocardial infarction. American Heart Journal. 2008;155(3):408-417.
[28] Ghadri JR, Wittstein IS, Prasad A, et al. International expert consensus document on takotsubo syndrome (Part I): clinical characteristics, diagnostic criteria, and pathophysiology. European Heart Journal. 2018;39(22):2032-2046.
[29] Ghadri JR, Cammann VL, Jurisic S, et al. A novel clinical score (InterTAK Diagnostic Score) to differentiate takotsubo syndrome from acute coronary syndrome: results from the International Takotsubo Registry. European Journal of Heart Failure. 2017;19(8):1036-1042.
[30] Yalçin F. Stress and heart in remodeling process: multiple stressors at the same time kill. Journal of Clinical Medicine. 2024;13(9):2597.
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