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Dr. John D Horowitz
Dr. Thanh H Nguyen
BNP/NT-proBNP elevation, ECG performance, echocardiography, and cardiovascular magnetic resonance, in parallel with cardiac catheterisation might all concur to exclude ischaemia and demonstrate extensive myocardial inflammation both of which are necessary for a diagnosis of Tako-tsubo cardiomyopathy.
Tako-tsubo cardiomyopathy (TTC), also referred to as stress cardiomyopathy, apical ballooning syndrome or “broken heart syndrome” is an acute catecholamine-induced myocardial inflammation occurring mainly in aging women after severe stress. Acute development of segmental - usually periapical - left ventricular systolic dysfunction occurs almost exclusively, and is often precipitated by exposure to severe acute emotional stress. In a cohort study of 136 patients, 96% were female and about 90% were over 50 years of age. Clinically, it typically mimics acute myocardial infarction (MI), with acute onset of severe chest pain, dyspnoea, and ECG changes typical of MI - often with S-T segment elevation initially. Evaluation of left ventricular function by echocardiography usually reveals a periapical zone of akinesis or hypokinesis. Several investigations have shown that left ventricular (LV) wall motion may return to normal within a few weeks and symptoms may subside within a few days, yet severe complications such as LV free wall rupture, pulmonary oedema, heart failure, arrhythmias, dynamic LV outflow tract obstruction, hypotension and even death may occur (1-4).
There is evidence that clinical consequence of TTC is myocardial inflammation initiated by “pulse” exposure to catecholamines in susceptible myocardium. Available mechanistic data from a rat model suggest that the main effects of catecholamines are mediated by β2-aderenoceptor stimulation (5), and we have preliminary evidence to suggest that the coupling of such receptors with synthesis of nitric oxide may also be important (6). Associated with inflammatory activation and nitrosative stress there is probably also myocardial energetic impairment (7). Initial reports suggested that this was a relative rarity, and did not really delineate pathogenesis. Under such circumstances, it became effectively a diagnosis requiring exclusion of ischaemia (8). It is now clear that coronary disease may theoretically co-exist, and that diagnosis ultimately rests on the demonstration of extensive myocardial inflammation yet from a clinical point of view, differentiation from acute MI remains potentially difficult. In table 1, the therapeutic implications of differentiation with AMI/ischaemia are listed. Table 1: Therapeutic implications of differentiation with AMI/ischaemia.
The Mayo clinic requires the presence of all four criteria:
However, we note that these updated criteria (2008) do not mention:
Very elderly, frail patients presenting with prolonged chest pain, especially without S-T elevation, may not undergo cardiac catheterisation, and therefore the diagnosis may easily be missed. All these reasons make it essential to establish consistent diagnostic criteria.
From study results not involving cardiac catheterisation which had thus far dominated, two differences with acute myocardial ischaemia/infarction have been put forward:
Approached according to the mode of presentation and duration of symptoms
The following tests do not enable a clear distinction between TTC and AMI patients.
Individual changes in electrocardiogram vary, but may be similar to changes in MI patients with ST elevation, T-wave inversion, and pathological Q-waves (23).
LV apical ballooning - Changes on echocardiography often show apical and/or midventricular akinesis/hypokinesis and basal hyperkinesis, distorting the shape of the LV, and showing “LV apical ballooning”. Approximately one third of patients also have apical right ventricular hypokinesis (28). The contractile dysfunction of the LV results in a lowered LVEF. Moderate to severe LV systolic/diastolic dysfunction is common but can be absent. Although the wall thickness in the akinetic segments may be reduced in the acute phase, the characteristics of these thinned regions have been reported to be different from the hyperechogenic fibrosis signals of a transmural MI. More importantly, the segmental rather than global wall motion abnormalities, which are not associated with any single coronary artery territory, could be used to distinguish it from AMI (29). Using a speckle tracking echocardiographic methods to quantitate regional LV systolic function, Mansencal et al. (30) reported that there were significant differences in strain, strain rate and systolic peak velocities between acute and chronic phases. Furthermore, in the acute phase, systolic dysfunction was circular with similar velocity among basal, mid ventricle, and apical segments and was different from that of patients with LAD coronary artery obstruction.
Diagnosis is most commonly made by invasive coronary angiography and is rarely the initial diagnosis at hospital admission. In most cases, no significant coronary artery stenoses are found. Left ventriculography is a useful method to diagnose and classify forms, typically demonstrating the distinctive LV shape - similar to a Japanese octopus pot with a round bottom and a narrow neck. Approximately 30% of cases exhibit predominantly mid-ventricular hypokinesis, while there is also a rare basal or “inverted” form (31). Regarding haemodynamics during the acute stages, these are common findings: 1) systemic hypotension or shock (19), 2) mild elevation of pulmonary capillary wedge pressure - although pulmonary oedema is rare (22). Occasionally, patients have haemodynamic evidence of intraventricular pressure gradients and/or severe mitral valve regurgitation. Due to the need for cardiac catheterisation (using the Mayo clinic criteria), the diagnostic process is subject to potential selection bias, as this investigation is more likely to be performed in patients with severe symptoms.
Cardiovascular magnetic resonance (CMR) allows assessment of cardiac function and LV regional wall motion abnormalities with high resolution. Using T2-weighted CMR, periapical oedema is observed in most patients (32). However, careful T2 quantitation reveals oedema throughout the LV (15). Although delayed enhancement is not usually seen in patients with TTC on contrast-enhanced CMR, it has been reported in some cases (due to increase in extracellular matrix content, confirmed with collagen-1 staining) (32).The detection of marked plasma BNP/NT-proBNP elevation as well as a positive troponin T concentration in female patients with prior emotional or physical trauma and presence of ECG showing “multi-regional” changes and no ST segment elevation is suggestive of TTC. Assessments of regional LV wall motion using either echocardiography or coronary angiography followed by detection of myocardial oedema without infarction on CMR (with late gadolinium enhancement and T2-weighted imaging) are the steps which complete the diagnosis.
Therapeutics for TTC have not been firmly established yet they are to:
However, therapeutics for 1) management of shock and 2) accelerating recovery of LV function are still awaiting clinical trial.
TTC is a common differential diagnosis of AMI, irrespective of presence of S-T elevation. Differentiation is important because treatment is also different: while patients presenting with S-T elevation need to undergo cardiac catheterisation as the first diagnostic step, in practice this functions in parallel with clinical assessment, detection of elevated BNP/NT-proBNP levels, ECG performance and echocardiography as initial diagnostic tests and should be followed by the demonstration of extensive myocardial oedema on CMR.
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Thanh H. Nguyen MD, M.Med.Sci, PhD 1,2 John D. Horowitz MBBS, B.Med.Sci (Hons), PhD, FRACP 1,2 1. The Queen Elizabeth Hospital, Department of Cardiology 2. Basil Hetzel Institute, The University of Adelaide, Australia.Authors’ disclosure: None declared.Other ressources:2008 and 2012 e-journal editions on the condition. Upcoming studies: Mayo clinics observations of TTC patient's personality profile, the University of Zurich's registry aiming to include 4,000 subjects and collection of biosamples to identify TTC specific biomarkers and mutations; a Tako tsubo and cancer Registry; a case control study of polymorphisms in the genes involved in the adrenergic pathway that would involve greater catecholamine sensitivity; a pilot study examining central nervous system and hormonal changes In Takotsubo cardiomyopathy, on examining endothelial function and another assessing cardiac sympathetic activity.
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