Tako-Tsubo (stress) cardiomyopathy: pathophysiology and natural history.

Abstract

Introduction. Tako-Tsubo cardiomyopathy (TTC), also known as apical ballooning syndrome, is a recently described form of acute cardiac dysfunction of uncertain pathogenesis, which occurs with greatest frequency among post-menopausal women. Presentation generally mimics that of an acute myocardial infarction (AMI) but is independent of the presence of fixed coronary artery disease and is classically preceded by severe stress. While patients with TTC with ST elevation are typically diagnosed at emergent cardiac catheterization, the majority does not exhibit initial ST elevation. It is not known whether TTC can be reliably distinguished for AMI non-invasively on the basis of clinical and laboratory tests. Although there is considerable uncertainty about the pathogenesis of TTC, pronounced catecholamine release and an acute inflammatory process are implicated. Systolic dysfunction most commonly affects the apex of the left ventricle and has generally been considered self-limiting and fully reversible. Although obvious hypokinesis resolves and left ventricular ejection fraction tends to return to normal, data that challenge this view include abnormal elevation of natriuretic peptide concentrations, 3 months from the index event, together with the late persistence of some inflammatory cells on LV biopsy. Methods. In three experimental chapters, this thesis examines aspects of (a) diagnosis (b) pathogenesis and (c) recovery, in a cohort of 125 TTC patients (mean age 67 years; 95% female). As regards diagnosis, it was hypothesized that an arbitrarily derived ‘TTC score’, incorporating NT-proBNP levels, might facilitate early differentiation from a cohort of females with AMI (n = 56; mean age 70 years). The primary comparison was based on data available at 24 hours post-admission. In a subset of 49 TTC patients, acute multisequential cardiac magnetic resonance imaging was performed and repeated at 3 months. Pathogenetic investigations:- Extent of oedema was quantified both regionally and globally from T₂ weighted images, with comparison to data from 10 age-matched female controls. Correlations were sought between oedema and the extent of hypokinesis, catecholamine release, N-terminal proBNP release and markers of systemic inflammatory activation. Functional recovery was assessed via 2D speckle-tracking echocardiography (n = 36) and 15 patients, ≥1 year from their index TTC admission, underwent T₁ mapping via CMR in order to address the question of whether residual fibrosis is present after TTC. Results. A. Diagnosis: TTC scores were significantly different (TTC group median was 4, vs. 2 in the ACS group; P < 0.0001). Receiver operator curve analysis demonstrated an area under the curve (AUC) of 0.74 (P < 0.0001), with 62% sensitivity and 75% specificity for a score ≥4; when stressor exposure was scored in both groups, AUC was 0.89 (P<0.0001), with 78% sensitivity and 82% specificity (TTC score ≥4). The TTC score separated groups when haemodynamic compromise was absent (AUC 0.80, P<0.0001), but not when hypotension or heart failure were evident (P = NS). B. Pathogenesis: 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 three months, T₂-weighted signal decreased substantially but remained abnormally elevated (P = 0.02). Regional extent of edema correlated inversely with radial myocardial strain. There were also direct correlations between global T₂-weighted signal and plasma normetanephrine (r=0.33, p=0.028), peak NT-proBNP (r=0.40, p=0.0045), C-reactive protein (r=0.34, p=0.023) and troponin T release (r=0.29, p=0.045). C. Recovery: Patients exhibited lower global longitudinal strain than controls [mean 17.9 ± 3.1 (SD)%, versus 20.3 ± 1.6; P = 0.0057], but did not differ significantly from controls in values of apical twist. Three month global longitudinal strain correlated with the extent of residual NT-pro-BNP elevation (r=0.38, P=0.027), but did not correlate with markers of the acute severity of the TTC attack. Finally, patients with a remote history of TTC, demonstrated significant intramyocardial fibrosis (Vₑ = 0.24), versus controls (Vₑ = 0.21, P = 0.013), but extent of which was not correlated with global longitudinal strain. Conclusions. (1) The TTC score, while not of itself diagnostic, may facilitate the differentiation of TTC in patients with presumed ACS, but with diminished efficacy in the presence of haemodynamic compromise. (2) TTC is associated with slowly resolving global myocardial edema, the acute extent of which is correlated with regional contractile disturbance and acute release of both catecholamines and NT-proBNP. (3) Imaging data after TTC indicate that, at 3 months, recovery is substantial, but not complete; at ≥1 year there is evidence of diffuse interstitial myocardial fibrosis. Further efforts to expedite diagnosis, delineate pathogenesis and evaluate residual disability may assist in the development of appropriate treatment regimens.