Alterations in Cardiac Deformation, Timing of Contraction and Relaxation, and Early Myocardial Fibrosis Accompany the Apparent Recovery of Acute Stress-Induced (Takotsubo) Cardiomyopathy: An End to the Concept of Transience

Abstract

Background: Takotsubo syndrome is an increasingly recognized cause of chest pain and occasionally of cardiogenic shock. Despite rapid improvement of the Left Ventricular Ejection Fraction (LV EF), recent registry data raises concerns about long term prognosis. We hypothesized that restoration of normal EF after acute tako-tsubo is not equivalent to full functional recovery. Methods: We prospectively recruited 52 takotsubo patients [according to the Mayo criteria plus cardiac magnetic resonance imaging (CMR) to exclude myocardial infarction] and 44 healthy controls of the same age, gender and cardiovascular co-morbidity distribution. We focused the investigation on takotsubo patients presenting with ST-elevation type ECG or malignant arrhythmias and with LV apical ballooning variant and examined a 4 months recovery end-point. Patients underwent Echocardiography assessment of LV myocardial deformation (Global longitudinal, radial and circumferential strain, LV twist, torsion, untwist, time to peak twist and untwist) and assessment of LV myocardial structure by pre and post contrast-enhanced CMR by T1 mapping acutely and at 4 months follow-up. Controls had a single time-point investigation. Data were analyzed using paired or unpaired tests, as appropriate for their distribution and corrected for multiple comparisons. Results: The patients' mean age was 66 years (range 28-87) and 92% were women. All abnormal echocardiographic indices observed acutely in takotsubo patients improved (but not necessarily normalized) at followup. Significant mechano-temporal alterations characterizing both systole (global longitudinal strain, apical circumferential strain, both p<0.01; left ventricular twist, twist rate and torsion, all p<0.0001) and diastole (untwist rate and time to peak untwisting, all p<0.001) persisted at 4 months follow-up when compared with controls, despite normalization of LV ejection fraction and volumes. Whilst native T1 (which demonstrates edema) normalized at 4 months follow-up only in segments contracting normally during the acute phase [T1=1180± 40.6ms (normally contracting, p=0.2 vs control values of 1189±16 ms) and 1208± 60.3 ms (dysfunctional segments, p<0.05 vs control)], the extracellular volume fraction (ECV, which demonstrates diffuse fibrosis) remained significantly abnormal in all LV segments (whether normally contracting, 0.328±0.043, p<0.001 or ballooning during acute presentation, 0.320±0.044, p<0.001, both vs control values of 0.273±0.045). Conclusion: In patients with the most clinically severe spectrum of takotsubo cardiomyopathy, regional LV systolic and diastolic deformation abnormalities persist beyond the acute event, despite normalization of global LV EF and size. In addition, although myocardial edema partly subsides, a process of global microscopic fibrosis develops in its place, detected as early as 4 months.Suggested Reviewers:Opposed Reviewers: 1 24 th March, 2017 Dear Dr Pearlman, Thank you once again for your comments and those of the associate editors. I think it i...

Acute stress-induced (takotsubo) cardiomyopathy

“…Despite this energetics reduction, upregulation of cardiomyocyte survival pathways (phosphorylated PI3K/Akt) have been clearly documented from human biopsies,31 which is in keeping with the lack of detection of macroscopic fibrosis on CMR in the vast majority of cases. However, CMR imaging of the extracellular compartment shows that this remains expanded,32 and LV biopsies showing an increase in collagen-1 subfraction suggest that microscopic fibrosis may play a part in this expansion 33. Finally, non-invasive indices of systolic and diastolic performance (LV twist, untwist and global longitudinal strain) continue to remain abnormal during this early recovery phase32 34 despite normalisation of LV ejection fraction and volumes.…”

Left ventricular end‐diastolic strain rate recovered in hypothyroidism following levothyroxine replacement therapy: A strain rate imaging study

“…Particularly, average E/e′ has been considered as the most reliable echocardiographic parameter to reflect LV filling pressure . However, the Doppler parameters have been shown to be less sensitive to detect alteration of diastolic performance . E/e′ is subject to angle‐dependence and is restricted in the presence of moderate to severe mitral pathologies, besides extrapolation of global diastolic function by regional measurements also seems problematic, especially in patients with regional wall motion abnormality …”

“…[13][14][15] However, the Doppler parameters have been shown to be less sensitive to detect alteration of diastolic performance. 16,17 E/e′ is subject to angle-dependence and is restricted in the presence of moderate to severe mitral pathologies, besides extrapolation of global diastolic function by regional measurements also seems problematic, especially in patients with regional wall motion abnormality. 17 Diastolic SR has been shown to be useful to detect subclinical myocardial diastolic dysfunction.…”

Takotsubo cardiomyopathy in a man with no trigger and multiple cardioembolic complications—A rare constellation

“…23 Increased platelet reactivity and aggregation, as well as endothelial and cardiomyocyte dysfunction-induced by excess epinephrine and norepinephrine levels-have been postulated to produce intracardiac thrombi. 27 Left ventricular function recovery is variable, 28 with a median time of 12 weeks. 26 Younger age (58 vs 67 years), an identifiable trigger, and anxiety are associated with early recovery (7 days); 29 our patient's recovery time of 7 days in the absence of these characteristics is unusual.…”

“…Increasingly, there is recognition of persistence of subtle abnormalities in myocardial structure, function, and fibrosis even in patients who show clinical recovery challenging the notion that is a fully reversible, transient disease. 28,31 There is only one reported TC case complicated by a large apical LV thrombus which resolved within 3 days. 23 Complete thrombus resolution is exceedingly rare within 7 days, as in our patient.…”