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Slowly resolving global myocardial inflammation/oedema in Tako-Tsubo cardiomyopathy: Evidence from T2-weighted cardiac MRI
Abstract
Tako-Tsubo cardiomyopathy (TTC) is associated with regional left ventricular dysfunction, independent of the presence of fixed coronary artery disease. Previous studies have used T2-weighted cardiac MRI to demonstrate the presence of periapical oedema. The authors sought to determine the distribution, resolution and correlates of oedema in TTC.
32 patients with TTC were evaluated at a median of 2 days after presentation, along with 10 age-matched female controls. Extent of oedema was quantified both regionally and globally; scanning was repeated in patients with TTC after 3 months. Correlations were sought between oedema and the extent of hypokinesis, catecholamine release, release of N-terminal prohormone of B-type natriuretic peptide (NT-proBNP), and markers of systemic inflammatory activation (high-sensitivity C-reactive protein and platelet response to nitric oxide).
In the acute phase of TTC, T2-weighted signal intensity was greater at the apex than at the base (p<0.0001) but was nevertheless significantly elevated at the base (p<0.0001), relative to control values. Over 3 months, T2-weighted signal decreased substantially, but remained abnormally elevated (p<0.02). The regional extent of oedema correlated inversely with radial myocardial strain (except at the apex). There were also direct correlations between global T2-weighted signal and (1) plasma normetanephrine (r=0.39, p=0.04) and (2) peak NT-proBNP (r=0.39, p=0.03), but not with systemic inflammatory markers.
TTC is associated with slowly resolving global myocardial oedema, the acute extent of which correlates with regional contractile disturbance and acute release of both catecholamines and NT-proBNP.
... These changes were observed to persist for a minimum of 5 months, suggesting the presence of a low-grade chronic inflammatory condition (93). Moreover, postmortem analysis of hearts from acute phase TTS patients revealed that the present macrophages were predominantly of the proinflammatory M1 type, rather than the reparative M2 type (98). Furthermore, the presence of M1 macrophages and the continued existence of the intermediate (CD14 ++ CD16 + ) monocyte subset during a 5-month observation period firmly suggest a more proinflammatory and less regenerative state, in contrast to comparable stages seen in AMI patients (99). ...
... This phenotype is characterized by a preserved LV ejection fraction, compromised cardiac energy status, limitations in physical activity (lower peak Vo2 and an elevated Ve/Vco2 slope during cardiopulmonary exercise testing), diminished counterclockwise rotation of the apical myocardium during systole along with changes in torsion and twist, and potentially microscopic fibrosis (93,97). Furthermore, long-term elevation of cardiac biomarkers such as B-type natriuretic peptide persists at a mild level (98). The enduring myocardial abnormalities over time prompt the question of whether these issues predated the initial TTS episode. ...
Background and Objective
Takotsubo syndrome (TTS) is a condition characterized by transient ventricular regional wall motion abnormalities, without causative coronary artery disease, typically triggered by emotional or physical stress. TTS is more common in post-menopausal women, closely resembling acute coronary syndrome (ACS) in its clinical presentation, with multiple proposed underlying pathophysiological mechanisms and no evidence-based treatments. This review aims to provide a comprehensive summary of the latest research, encompassing the pathophysiology, diagnostic findings, prognosis, and treatment options for TTS patients.
Methods
Relevant literature from 1990 to June 2023 on TTS epidemiology, physiopathology, diagnosis, clinical manifestations, treatment, and prognosis was retrieved through PubMed research. Only English publications were included.
Key Content and Findings
TTS is an increasingly recognized cardiovascular disorder, a significant release of catecholamines is thought to be a key contributing element, yet its exact mechanism remains unclear. Notably, TTS poses significant short and long-term risks akin to ACS. Initial treatment should focus on ruling out ACS and providing standard care for subsequent left ventricular dysfunction and complications. Research hints at a potential role for Angiotensin-converting enzyme inhibitors and Angiotensin II receptor blockers in improving long-term prognosis in TTS patients.
Conclusions
Significant knowledge gaps still exist in our understanding of the pathophysiology, treatment options, and areas for improvement in diagnosing and prognosticating this intriguing condition. Further research is therefore needed.
... In terms of cardiac inflammation, insights have been gained from cardiac magnetic resonance (CMR) imaging. Increased myocardial edema was found acutely in TTS patients, as evaluated by T2-weighted or native T1 imaging (6,7,22,36,37). Some reports indicate that the edema was regional in nature, being higher in dysfunctional areas of the LV, whereas others found the edema to broadly affect the entire LV and right ventricle (RV). Myocardial edema does gradually resolve in patients, but it can take time to completely normalize. ...
... Myocardial edema does gradually resolve in patients, but it can take time to completely normalize. For instance, myocardial edema can persist for 3 months and even up to 20 months after the index event in TTS patients, albeit at lower levels compared to those found acutely (35,36). Using CMR imaging enhanced with ultrasmall superparamagnetic particles of iron oxide (USPIO), which are preferentially phagocytosed by macrophages, a study showed that TTS patients had significantly increased T2* values post-USPIO acutely, which resolved 5 months later (22), suggesting that inflammation in TTS could be macrophage-driven. ...
Takotsubo syndrome (TTS) is a disorder characterized by transient cardiac dysfunction with ventricular regional wall motion abnormalities, primarily thought to be caused by the effects of a sudden catecholamine surge on the heart. Although the majority of patients exhibit prompt recovery of their cardiac dysfunction, TTS remains associated with increased mortality rates acutely and at long-term, and there is currently no cure for TTS. Inflammation has been shown to play a key role in determining outcomes in TTS patients, as well as in the early pathogenesis of the disorder. There are also cases of TTS patients that have been successfully treated with anti-inflammatory therapies, supporting the importance of the inflammatory response in TTS. In this article, we provide a comprehensive review of the available clinical and pre-clinical literature on the immune response in TTS, in an effort to not only better understand the pathophysiology of TTS but also to generate insights on the treatment of patients with this disorder.
... Additionally, despite the recovery of LVEF and wall motion, persistence of microscopic changes at the cellular level and diastolic dysfunction were indicated [4,20]. T2-weighted signal intensity on CMR imaging suggesting myocardial edema and inflammation in TTS also persists even after the improvement of wall motion abnormalities [21]. Recent studies have reported the persistence of symptoms and elevated brain-type natriuretic peptide release well beyond this period, even after the improvement of LV dysfunction in TTS [22,23], suggesting an association with these residual cardiac dysfunctions. ...
Background: Although takotsubo syndrome (TTS) is characterized by transient systolic dysfunction of the left ventricle (LV), the time course and mechanism of LV function recovery remain elusive. The aim of this study is to evaluate cardiac functional recovery in TTS via serial cardiac magnetic resonance feature tracking (CMR-FT). Methods: In this Japanese multicenter registry, patients with newly diagnosed TTS were prospectively enrolled. In patients who underwent serial cardiovascular magnetic resonance (CMR) imaging at 1 month and 1 year after the onset, CMR-FT was performed to determine the global circumferential strain (GCS), global radial strain (GRS) and global longitudinal strain (GLS). We compared LV ejection fraction, GCS, GRS and GLS at 1 month and 1 year after the onset of TTS. Results: Eighteen patients underwent CMR imaging in one month and one year after the onset in the present study. LV ejection fraction had already normalized at 1 month after the onset, with no significant difference between 1 month and 1 year (55.8 ± 9.2% vs. 58.9 ± 7.3%, p = 0.09). CMR-FT demonstrated significant improvement in GCS from 1 month to 1 year (−16.7 ± 3.4% vs. −18.5 ± 3.2%, p < 0.01), while there was no significant difference in GRS and GLS between 1 month and year (GRS: 59.6 ± 24.2% vs. 59.4 ± 17.3%, p = 0.95, GLS: −12.8 ± 5.9% vs. −13.8 ± 4.9%, p = 0.42). Conclusions: Serial CMR-FT analysis revealed delayed improvement of GCS compared to GRS and GLS despite of rapid recovery of LV ejection fraction. CMR-FT can detect subtle impairment of LV systolic function during the recovery process in patients with TTS.
... While these mechanisms appear to be the major contributors to the pathogenesis of SCM, some studies have highlighted a significant role of local and systemic inflammation in the disease's development. Ultrasound superparamagnetic iron-oxide (USPIO) enhanced magnetic resonance imaging (MRI) has shown increased pro-inflammatory macrophage activity in patients with SCM, affecting both the left and right ventricles and likely contributing to the observed myocardial edema in this disease [18,19]. Myocardial edema is thought to be a consequence of an increase in the systemic release of interleukin (IL)-6, IL-8, and C-X-C motif chemokine ligand 1 (CXCL1) [20]. ...
Takotsubo cardiomyopathy or stress cardiomyopathy (SCM), was first described in 1990 and initially, it was thought to be only associated with short-term complications and mortality with a benign long-term prognosis comparable to a healthy population. However recent investigations have proven otherwise and have shown SCM patients might have comparable long-term morbidity and mortality to ST-elevation myocardial infarction (STEMI) patients. Many emotional, or physical stressors can trigger SCM, and have been able to describe an interplay of neurohormonal and inflammatory mechanisms as the pathophysiology of this disease. Additionally, given the significantly higher prevalence of SCM in post-menopausal women, estrogen levels have been thought to play a role in the pathogenesis of this disease. Furthermore, there is an elusive disparity in prognosis depending upon different triggers. Currently, many questions remain unanswered regarding the long-term management of these patients to reduce morbidity, mortality, and improve quality of life, such as the need for long-term anticoagulation. In this paper, we review the findings of most recent published investigations regarding etiologies, patho-physiology, diagnostic criteria, prognosis, short-term and in more detail, long-term complications of SCM. Finally, we will discuss what future research is needed to learn more about this disease to improve the long-term prognosis, even though as of now, data for long-term management is still lacking.
... In the early stages, stress cardiomyopathy patients have increased LV stiffness and end-diastolic pressure associated with an upward shift in the diastolic pressure-volume relation [4]. Recent studies suggest that stress cardiomyopathy may present with slowly recovering myocardial inflammation [5,6]. Moreover, some degree of diastolic dysfunction may persist in many patients despite recovered global LV ejection fraction and chamber size [7]. ...
In acute sympathetic stress, catecholamine overload can lead to stress cardiomyopathy. We tested the hypothesis that cardiomyocyte NOX4 (NADPH oxidase 4)-dependent mitochondrial oxidative stress mediates inflammation and diastolic dysfunction in stress cardiomyopathy. Isoproterenol (ISO; 5 mg/kg) injection induced sympathetic stress in wild-type and cardiomyocyte (CM)-specific Nox4 knockout (Nox4CM−/−) mice. Wild-type mice treated with ISO showed higher CM NOX4 expression, H2O2 levels, inflammasome activation, and IL18, IL6, CCL2, and TNFα levels than Nox4CM−/− mice. Spectral flow cytometry and t-SNE analysis of cardiac cell suspensions showed significant increases in pro-inflammatory and pro-fibrotic embryonic-derived resident (CCR2⁻MHCIIhiCX3CR1hi) macrophages in wild-type mice 3 days after ISO treatment, whereas Nox4CM−/− mice had a higher proportion of embryonic-derived resident tissue-repair (CCR2⁻MHCIIloCX3CR1lo) macrophages. A significant increase in cardiac fibroblast activation and interstitial collagen deposition and a restrictive pattern of diastolic dysfunction with increased filling pressure was observed in wild-type hearts compared with Nox4CM−/− 7 days post-ISO. A selective NOX4 inhibitor, GKT137831, reduced myocardial mitochondrial ROS, macrophage infiltration, and fibrosis in ISO-injected wild-type mice, and preserved diastolic function. Our data suggest sympathetic overstimulation induces resident macrophage (CCR2⁻MHCII⁺) activation and myocardial inflammation, resulting in fibrosis and impaired diastolic function mediated by CM NOX4-dependent ROS.
Backgrounds
Takotsubo syndrome (TTS) is an intriguing clinical entity characterized by transient myocardial dysfunction. The precise pathophysiological mechanism of TTS is still unknown, but recent evidence suggests a central role of systemic inflammation associated with adrenergic discharge. Although initially considered benign, TTS has shown several potential short-term and long-term complications and adverse outcomes. To improve understanding and management, advanced cardiovascular magnetic resonance (CMR) techniques, such as feature tracking (FT) and parametric mapping, have gained attention.
Purpose of Review
The purpose of this review is to summarize the current literature on the clinical applications of CMR-FT and mapping in TTS. Additionally, the most significant and recent findings will be discussed.
Recent Findings
FT-CMR enables the parametric quantification of myocardial deformation, allowing a comprehensive evaluation of left ventricular, right ventricular, and atrial function. It provides an accurate definition of areas of myocardial dysfunction and potentially serves as a superior prognostic tool compared to ejection fraction. Tissue mapping techniques enable precise and comprehensive tissue characterization by quantifying areas of oedema, and myocardial fibrosis.
Summary
FT-CMR and mapping techniques serve as valuable prognostic tools both in the acute and chronic phases of TTS. They can detect subtle alterations and pan-cardiac involvement, while also providing important insights into the complex underlying mechanisms of the syndrome.
Background: Takotsubo Syndrome (TTS) generally presents like a form of acute coronary syndrome, with variable extents of coronary flow retardation and concomitant release of markers from damaged endothelial glycocalyx (eGC). Whilst systemic hypotension often develops early, there is also rapid emergence and slow resolution of left ventricular (LV) dysfunction. It remains uncertain whether these hypotensive and LV functional complications reflect severity of early coronary vasculitis.
Methods: 284 patients admitted to 3 South Australian hospitals from May 2008 to May 2021 with a diagnosis of TTS were evaluated. Coronary flow velocity was measured using the corrected TIMI frame count. Putative correlations between extent of acute coronary flow retardation and that of acute impairment of LV systolic function, as measured on global longitudinal strain (GLS: primary hypothesis), were determined. Other parameters of acute disturbance of homeostasis, including extent of eGC shedding and of myocardial edema, and residual impairment in GLS and quality of life at 3-months' follow-up, were correlated with extent of flow retardation. We also evaluated correlates of extent of acute systemic hypotension. Results were analysed via univariate followed by multivariate analyses.
Results: The patients studied exhibited mild coronary flow retardation relative to previously described norms at early angiography. On univariate analyses, corrected TIMI frame count correlated with extent of acute impairment of GLS (r=0.31, p=0.003) and this association persisted on backwards stepwise multiple logistic regression (β=0.52, p=0.03). Flow retardation also correlated with preservation of renal function (β=0.50, p=0.02), but tended to vary inversely with C-reactive protein (CRP) concentrations (β=-0.44, p=0.06). There were no significant associations between acute TIMI frame count and other acute or 3-months' parameters. Neither TIMI frame count nor acute GLS predicted minimal systolic blood pressure.
Conclusions: The data demonstrated a strong association between extent of early coronary flow reduction in TTS and that of LV functional impairment, thus establishing some commonality of causation of the coronary and acute myocardial manifestations of TTS. However, neither extent of coronary vasculitis nor that of acute LV systolic dysfunction predict acute hypotensive changes in TTS.
T2-Weighted (T2W) magnetic resonance imaging (MRI) pulse sequences have been used to detect edema in patients with acute myocardial infarction and differentiate acute from chronic infarction. T2W sequences have suffered from several problems including (i) signal intensity variability caused by phased array coils, (ii) high signal from slow moving ventricular chamber blood that can mimic and mask elevated T2 in sub-endocardial myocardium, (iii) motion artifacts, and (iv) the subjective nature of T2W image interpretation. In this work we demonstrate the advantages of a quantitative T2 mapping technique to accurately and reliably detect regions of edematous myocardial tissue without the limitations of qualitative T2W imaging.
Methods of T2 mapping were evaluated on phantoms; the best of these protocols was then optimized for in vivo imaging. The optimized protocol was used to study the spatial, view-dependent, and inter-subject variability and motion sensitivity in healthy subjects. Using the insights gained from this, the utility of T2 mapping was demonstrated in a porcine model of acute myocardial infarction (AMI) and in three patients with AMI.
T2-prepared SSFP demonstrated greater accuracy in estimating the T2 of phantoms than multi-echo turbo spin echo. The T2 of human myocardium was found to be 52.18 +/- 3.4 ms (range: 48.96 ms to 55.67 ms), with variability between subjects unrelated to heart rate. Unlike T2W images, T2 maps did not show any signal variation due to the variable sensitivity of phased array coils and were insensitive to cardiac motion. In the three pigs and three patients with AMI, the T2 of the infarcted region was significantly higher than that of remote myocardium.
Quantitative T2 mapping addresses the well-known problems associated with T2W imaging of the heart and offers the potential for increased accuracy in the detection of myocardial edema.
Takotsubo cardiomyopathy (TTC) is an increasingly recognised acute cardiac syndrome, whose underlying pathophysiological mechanisms remain unknown. Inflammation might play a role as this has been shown in endomyocardial biopsies. The aim of this study was to assess inflammatory parameters in patients with TTC using a comprehensive cardiovascular magnetic resonance imaging (CMR) approach.
Thirty-seven patients with the suspected diagnosis of TTC underwent CMR. T2-weighted imaging to calculate the oedema ratio, T1-weighted imaging before and after contrast agent administration to calculate the global relative enhancement (gRE), and late gadolinium enhancement (LGE) imaging were performed.
In 11 patients CMR revealed the diagnosis of myocardial infarction (n = 7; 19%) or myocarditis (n = 4; 11%) with typical patterns of LGE. In all other patients (n = 26; 70%), no LGE was detected consistent with the diagnosis of TTC. Of these, in 16 patients (62%) both inflammatory markers (oedema ratio and gRE) were elevated with concomitant pericardial effusion, indicating acute inflammation. Follow-up CMR after 3 months showed complete normalisation of left ventricular function and inflammatory parameters in the absence of LGE and pericardial effusion.
This CMR study provides further insights into the pathophysiological mechanisms in TTC, supporting the contribution of an inflammatory process in the acute setting.
To investigate whether and how cold pressor test (CPT) could affect myocardial perfusion and left ventricular (LV) function in patients with previous LV ballooning syndrome (LVBS).
Cold pressor test (3 min hand immersion in ice-water) was performed in 17 women with previous LVBS and in 7 age- and risk factor-matched women with chest pain and normal coronary arteries. At baseline and peak CPT, global and regional LV function, and myocardial perfusion were quantitatively assessed by real-time three-dimensional echocardiography (RT3DE) and myocardial contrast (SonoVue, Bracco) 2D echocardiography (MCE), respectively (Philips iE33 machine, X3-1 and S5-1 probes). Data were analysed off-line (QLab 6.0 software). Peripheral venous catecholamines were assayed by high performance liquid chromatography with electrochemical detection. Cold pressor test induced similar haemodynamic changes and catecholamine increase in controls and LVBS patients. Left ventricular ejection fraction decreased and transient new mid-ventricular and apical motion abnormalities developed in LVBS patients only (quantitative RT3D analysis), without corresponding perfusion defects (MCE). At peak CPT, coronary blood flow and velocity increased (quantitative MCE analysis) in control subjects only.
Cold pressor test induced LV wall motion abnormalities unmatched to regional coronary flow reduction in LVBS patients only. The reduced coronary reserve in response to CPT suggests microvascular dysfunction in LVBS patients.
Nuclear cardiology, echocardiography, cardiovascular magnetic resonance (CMR), cardiac computed tomography (CT), positron emission computed tomography (PET), and coronary angiography are imaging modalities that have been used to measure myocardial perfusion, left ventricular function, and coronary anatomy for clinical management and research. Although there are technical differences between these modalities, all of them image the myocardium and the adjacent cavity. However, the orientation of the heart, angle selection for cardiac planes, number of segments, slice display and thickness, nomenclature for segments, and assignment of segments to coronary arterial territories have evolved independently within each field. This evolution has been based on the inherent strengths and weaknesses of the technique and the practical clinical application of these modalities as they are used for patient management. This independent evolution has resulted in a lack of standardization and has made accurate intra- and cross-modality comparisons for clinical patient management and research very difficult, if not, at times, impossible.
Attempts to standardize these options for all cardiac imaging modalities should be based on the sound principles that have evolved from cardiac anatomy and clinical needs.1–3⇓⇓ Selection of standardized methods must be based on the following criteria:
An earlier special report from the American Heart Association, American College of Cardiology, and Society of Nuclear Medicine4 defined standards for plane selection and display orientation for serial …
We investigated B-type natriuretic peptide (BNP) levels in 10 consecutive patients (all women, mean age 60.4+/-7.8 years) with apical ballooning syndrome. Mean baseline plasma BNP level was 272.6+/-170.4 pg/ml and exceeded the normal range in 8 (80%) patients. When normal levels were adjusted for age and gender, all 10 patients had elevated BNP. Two patients with the highest BNP levels (630 and 423 pg/ml) presented with significant hemodynamic compromise. BNP levels correlated negatively with left ventricular ejection fraction. Increase in BNP levels in apical ballooning syndrome may support the neurohormonal etiology in these patients and requires further studies.
The diagnosis of stress-induced cardiomyopathy requires wall motion abnormality, most typically apical ballooning. The authors report 3 cases of transient global left ventricular systolic dysfunction that developed over the course of severe medical illnesses. The cardiomyopathy that developed in each patient had all the features of takotsubo cardiomyopathy, including reversibility, mild troponin elevation, nonspecific electrocardiographic abnormalities, and a negative work-up for ischemia. The only difference was the absence of regional wall motion abnormalities. No patients developed sepsis or myocarditis. Stress-induced cardiomyopathy may present in different forms, including regional or global left ventricular dysfunction. Classic takotsubo syndrome may represent only part of the spectrum of this reversible condition.
Tako-Tsubo cardiomyopathy (TTC) is a reversible cardiomyopathy with a clinical presentation indistinguishable from myocardial infarction. TTC is estimated to represent 1%-2% of patients presenting with acute myocardial infarction. It most commonly occurs in postmenopausal women and is frequently precipitated by a stressful event. Chest pain and dyspnea are the typical presenting symptoms. Transient ST-segment elevation on ECG and a small rise in cardiac biomarkers are common. Characteristic wall motion abnormalities extend beyond the territory of a single epicardial coronary artery in the absence of obstructive coronary lesions. Supportive treatment leads to spontaneous rapid recovery in nearly all patients. The prognosis is excellent, and recurrence occurs in < 10% of patients. In this article, we review the clinical features of TTC that form the basis of the Mayo Clinic diagnostic criteria, as well as the long-term prognosis for this type of cardiomyopathy.
Plasma BNP and NT-proBNP are often regarded as interchangeable parameters in assessing heart failure (HF) severity and prognosis. Renal failure results in disproportionate increases of NT-proBNP and an increased NT-proBNP/BNP ratio. Low kidney function is therefore considered particularly when NT-proBNP is used to assess HF. The purpose of this study was to identify other conditions affecting the NT-proBNP/BNP ratio. We examined the NT-proBNP/BNP ratio, 26 other lab parameters, and clinical factors in 218 patients admitted to the HF ward. In addition to renal function, we also found significant correlations between the NT-proBNP/BNP ratio and inflammation as measured by orosomucoid (r = 0.525, p < 0.0001), CRP (r = 0.333, p < 0.0001), haptoglobulin (r = 0.201, p = 0.02), and alpha1-antitrypsin (r = 0.223, p = 0.01). Reverse correlation was found with transferrin (r = -0.323, p < 0.0001), albumin (r = -0.251, p = 0.003), and S-Fe (r = -0.205, p = 0.02), parameters known to decrease during inflammation. Inflammation increased levels of NT-proBNP more than BNP, resulting in an increased NT-proBNP/BNP ratio. Our findings indicate that NT-proBNP should be evaluated concomitantly with inflammatory status to avoid overestimation of HF severity.
Stress cardiomyopathy, also referred to as Takotsubo cardiomyopathy, transient apical ballooning or broken heart syndrome, is a disorder associated with transient left ventricular dysfunction. Symptoms include acute chest pain and dyspnea accompanied by electrocardiographic changes, such as ST-segment elevation and T-wave inversions, minimal elevation of cardiac enzyme levels and transient wall-motion abnormalities in the absence of substantial coronary artery obstruction. Complete recovery of contractile function has been documented in nearly all cases, but the mechanisms of disease remain unclear and the cause has not been established. Coronary artery vasospasm, microcirculation dysfunction, and transient obstruction of the left ventricular outflow tract have been proposed as possible causes of this disorder. An excessive release of catecholamines also seems to have a pivotal role in the development of stress cardiomyopathy. This Review summarizes published data on stress cardiomyopathy, focusing primarily on the most likely causes of this cardiac entity.