Takotsubo Cardiomyopathy – Catecholamine-Induced Inflammation
An Editorial published in the March 2012 issue of Expert Review of Cardiovascular Therapy outlines some new insights and research trends related to stress-induced cardiomyopathy.
Stress-induced cardiomyopathy, also known as “Takotsubo” cardiomyopathy, broken heart syndrome and apical ballooning syndrome, was first described in Japan, in 1990, by Sato et al. as tako-tsubo-like left ventricular dysfunction.
The syndrome is characterized by a bulging out of the left ventricular apex with a hyper-contractile base of the left ventricle. The term “Takotsubo” is a Japanese word for a round-bottomed pot with a narrow neck used for trapping octopuses.
Stress-induced cardiomyopathy represents a transient left ventricle systolic dysfunction with electrocardiographic changes that can mimic acute myocardial infarction and minimal release of myocardial enzymes in the absence of obstructive coronary artery disease. This cardiomyopathy is more commonly seen in post-menopausal women and most likely accounts for 1% to 2% of all cases of suspected acute myocardial infarction. In fact, more than 90% of reported cases are in women ages 58 to 75 and up to 5% of women suspected of having a heart attack actually have this disorder.
Features of takotsubo cardiomyopathy include:
- Chest pain and shortness of breath after severe stress (emotional or physical)
- Electrocardiogram abnormalities that mimic those of a heart attack
- No evidence of coronary artery obstruction
- Movement abnormalities in the left ventricle
- Ballooning of the left ventricle
- Recovery within a month
Data from patients who underwent myocardial biopsy indicate interstitial infiltrates consisting primarily of mononuclear lymphocytes, leukocytes, macrophages, myocardial fibrosis; and contraction bands with or without overt myocyte necrosis. Mechanisms suggested being involved in the etiology and pathophysiologies of stress-induced cardiomyopathy include: coronary microcirculatory abnormalities, multi-vessel epicardial spasm and regionally stunned myocardium, high circulating levels of catecholamines (mostly epinephrine/adrenaline) and related catecholamine-mediated cardiotoxicity.
A neurogenic stunned myocardium has also been linked with a much higher concentration of adrenoceptors in the left ventricular apex, and thus, to a pronounced myocardial responsiveness to adrenergic stimulation in the apex. Takotsubo cardiomyopathy might be due to a locally high toxic concentration of catecholamines, not coronary artery or microvascular disease (for review, see Yoshihiro J. et al., Circulation, 2008, 118:2754).
Interestingly, immobilization in rats, a well-established stress model and condition inducing high epinephrine and norepinephrine levels, has also been shown to be associated with characteristic ECG changes, including ST-segment elevation and reversible left ventricular apical ballooning, strikingly reproducing the abnormalities seen in Takotsubo cardiomyopathy.
In the Expert Review of Cardiovascular Therapy editorial Matthias Friedrich and Myra Cocker discuss new advances and studies using cardiovascular magnetic resonance. This method enables a comprehensive analysis of regional and global myocardial function, combined with a multi-parametric myocardial tissue characterization.
The most intriguing finding obtained from these studies indicates that myocardial inflammation is an important component of the pathophysiology behind stress-induced cardiomyopathy. Furthermore, the authors discuss recent evidence suggesting that stress-induced inflammation, and particularly catecholamine-induced inflammation, might represent the driving force leading to the development of acute symptoms and transiently altered ventricular contractility.
The authors conclude that future research will have to identify key determinants of individual susceptibility to stress-induced inflammation, and that cardiovascular magnetic resonance is expected to play a major role in advancing our understanding of myocardial stress.
SOURCE: Expert Rev Cardiovasc Ther, 2012, 10: 271.
Read more: Expert Review of Cardiovascular Therapy
An Update
In 2019, Caroline Scally and colleagues reported in Circulation that takotsubo cardiomyopathy is characterized by a myocardial macrophage inflammatory infiltrate, changes in the distribution of monocyte subsets, and an increase in systemic proinflammatory cytokines. They studied 55 patients with takotsubo cardiomyopathy; patients underwent multiparametric cardiac magnetic resonance imaging, including ultrasmall superparamagnetic particles of iron oxide (USPIO) enhancement for detection of inflammatory macrophages in the myocardium.
The investigators found a macrophage-mediated cellular inflammatory response in the myocardium, superimposed on myocardial edema, associated with systemic peripheral inflammatory responses, which appear to persist for at least 5 months. Thus, as per the authors the localized and systemic inflammatory responses provide a potential explanation for the development of the long-term heart failure phenotype.
The authors demonstrate for the first time, that USPIO-enhanced magnetic resonance imaging suggests a macrophage-driven cellular infiltration within the myocardium. As previously shown, the main cells capable of phagocytosing USPIO that accumulate in the infarcted myocardium are monocyte-derived macrophages.
Of note, the authors have recently reported data from postmortem cases of takotsubo cardiomyopathy where clusters of macrophages (CD68+ staining) in the left ventricular myocardium were predominantly M1 macrophages, supporting the proinflammatory findings in the present study. Thus, most likely the cellular protagonists responsible for the organ-specific inflammatory response observed in the present study (USPIO uptake in the myocardium) are macrophages.
Furthermore, the authors describe for the first time that patients with takotsubo cardiomyopathy exhibit a substantial increase in the proinflammatory, classic monocyte subset (CD14++CD16−) at the expense of a decrease in the other 2 subpopulations: CD14++CD16+ (intermediate) and CD14+CD16++ (nonclassic, patrolling, and reparative). They propose that the increased percentage of CD14++CD16− (classic) monocytes is the result of an immediate release of CD14++CD16− (classic) monocytes from the bone marrow (and spleen) into the circulation or the infiltration of CD14++CD16+ (intermediate) and CD14+CD16++ (nonclassic) monocytes into myocardial tissue.
Finally, the increase in systemic inflammatory cytokines/chemokines IL-6, IL-8, and CXCL1 (growth-regulated protein), reported in the study, correlates with the increase in myocardial inflammation and increase in percentage of blood CD14++CD16− monocytes, highlighting the inflammatory nature of takotsubo cardiomyopathy.
Cover Image (Left panel) Diagram of Takotsubo cardiomyopathy. From: Takotsubo Cardiomyopathy, at www.svhhearthealth.com.au; (Right panel): Left ventriculogram (A, end-diastolic phase; B, end-systolic phase) in the right anterior oblique projection. The extensive area around the apex shows akinesis, and the basal segments display hypercontraction, especially in the end-diastolic phase. C, A picture of a real takotsubo, which has a round bottom and narrow neck to capture octopuses and has been used for a long time in Japan; From: Takotsubo Cardiomyopathy, A New Form of Acute, Reversible Heart Failure by Yoshihiro J. Akashi, David S. Goldstein, Giuseppe Barbaro and Takashi Ueyama, Circulation, 2008 Dec 16;118(25):2754-62. doi: 10.1161/CIRCULATIONAHA.108.767012.
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