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Morphologic Pattern of Late Gadolinium
Enhancement in Tako-Tsubo Syndrome.
“Another Clue to Solve the Enigma."

G. Avegliano(1,2), M. Huguet (4), J.P. Costabel (1), R. Ronderos (1), B. Bijnens (2,3), P. Kuschnir (1), J. Thierer (1), C. Tobón-Gomez (2,4), G Oller Martinez (5), A. Frangi (2,3)

(1) Instituto Cardiovascular de Buenos Aires, Buenos Aires, Argentina.
(2) Center for Computational Imaging & Simulation Technologies in Biomedicine (CISTIB), Universitat Pompeu Fabra (UPF), Networking Biomedical Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Barcelona, Spain.
(3) Institució Catalana de Recerca i Estudis Avançats (ICREA).
(4) Cetir Sant Jordi, Unidad de Cardio-Resonancia, Barcelona, Spain.
(5) Centro Cardiovascular Sant Jordi, Barcelona, Spain.



Abstract
Stress cardiomyopathy (SCM) presents clinically as an acute coronary syndrome. It is characterized by transient dyskinesis–akinesis (generally involving the apex), without significant epicardial coronary lesions, and may occasionally be preceded by emotional or physical stress. Although its etiology remains unknown, many hypotheses have been suggested. Late gadolinium enhancement (LGE) sequences on cardiac magnetic resonance (CMR) allow to clarify the pathophysiology in patients with myocardial infarction and normal coronary arteries, and patients with SCM typically reveal absence of LGE.

Between January 2005 and January 2007, 8 consecutive patients with SCM criteria underwent CMR within the first 72 hours of admission, which was performed on a dedicated cardiovascular scanner (1.5 T GE, Cvi-HDx). Cine, T2-weighted and LGE images were acquired. Patient follow-up included clinical exam and imaging techniques: echocardiogram on days 3, 7, 30 and 60 and CMR at 3 months. 

Symptoms were: chest pain in 8, dyspnea in 3 and heart failure in 3. Five patients had experienced a previous stressful situation, 5 had ST segment elevation; 8 had negative T waves and 6 had elevated Troponin I and CK-MB. No significant lesions were found on coronary angiography, and wall motion improvement was noted at 15 (7-30) days. Median ejection fractions at admission and recovery were 49% and 66.5%, respectively. In 7 cases, dyskinesis was apical and in one case mid-ventricular. Initial CMR showed typical wall motion abnormalities and LGE showed mild hyperenhancement in areas of abnormal wall motion, while normal segments had no contrast enhancement. On follow-up CMR, wall motion was normal without late enhancement. 

In acute SCM, LGE reveals a unique morphologic pattern, which could correspond to edema-inflammation, suggesting diffuse microcirculation damage rather than epicardial vessel involvement.


Introduction:
Stress cardiomyopathy (SCM), described long ago in Japan, was initially called Tako Tsubo syndrome, due to the shape of the left ventricle (LV), which is similar to a vessel used to catch octopi. It is an emerging clinical entity, characterized by transient LV dysfunction with symptoms mimicking an acute myocardial infarction (MI) but without significant coronary lesions on angiography; it may be preceded by emotional or physical stress. Although the pathophysiology remains unclear, the explanation that appears more robust is myocardial stunning mediated by direct catecholamine effect1. Other suggested hypotheses are epicardial or microcirculatory vasospasm, LV outflow obstruction or plaque rupture with spontaneous fibrinolysis [2-7].

Prior studies have shown the usefulness of cardiac magnetic resonance (CMR) with contrast to differentiate small infarcts from myocarditis or SCM
[8-10]. In SCM, although many cases have elevated troponins as a sign of myocardial damage, sequences of late gadolinium enhancement are notably negative. In this study we describe 8 patients with findings consistent with SCM, who on early CMR (i.e., immediately after cardiac catheterization) exhibited a unique morphological pattern of late gadolinium uptake, which has not been described in previous series. 

Methods:
Population and study protocol
Since January 2005 until January 2007, 8 consecutive patients with a diagnosis of SCM were evaluated with CMR performed immediately after cardiac catheterization. Patients were followed with a clinical exam and imaging techniques consisting of an echocardiogram at 3, 7, 15, 30 and 60 days in order to assess the precise moment of LV wall motion recovery. Finally, follow-up with CMR was performed at 90 days post admission.

Imaging Techniques:  
Protocol and assessment with Cardiac Magnetic Resonance
CMR images were acquired on a 1.5 T scanner (Signa CVi-HDx, General Electric) with a dedicated cardiac coil. The protocol included balanced steady-state free precession gradient-echo images (CINE), T2-weighted images (T2) and LGE inversion recovery images (10’after IV administration of 0.2 mmol/kg of gadopentate dimeglumine contrast).  All sequences were acquired in short-axis, two, three and four chamber views. CINE images were used to evaluate LV systolic function. Visual analysis of myocardial LGE was performed, as well as T2 high signal and wall motion assessment of the 17 LV myocardial segments.

Echocardiography
Echocardiograms were performed with a Vivid 3 General Electric with a 3S transducer (1.5 – 3.6 MHz) and a IE33 Philips Medical Systems equipment, with S5-1 and X3-1 transducers; images acquired were stored in digital format. Two patients with a poor window received a 1 ml bolus of SonoVue® (sulfur hexafluoride) echocardiographic contrast injected into a peripheral vein to improve the assessment of the LV endocardium.

Statistical analysis:
Statistical analysis was performed with STATA software (version 10.0 StataCorp LP). The data exhibited a non-parametric distribution; hence they are expressed as medians and their respective interquartile intervals (P25-P75). The comparison of early and recovery ejection fractions was performed with the Wilcoxon test for paired samples. A two-tailed p value < 0.05 was considered significant in all cases.

Results
Demographic, clinical and laboratory data:
The 8 patients were women (median age: 63 years, range: 44-71) and were hospitalized due to SCM. Among them, 40% had coronary risk factors (hypertension in 37%, dyslipidemia in 50% and smoking in 12.5%). At admission, all 8 patients (100%) had chest pain, 3 had dyspnea and 3 had hypertension (37%). A previous stressful situation was identified in 6 pts (64%). The ECG exhibited ST segment elevation in 4 pts (50%) and negative T waves in all cases (100%). Three pts (37%) had signs of heart failure and 6 (75%) had troponin I and CK Mb elevation. No patient had significant coronary stenosis at cardiac catheterization. The data are described in table 1.

 

Variables

Medians (P25-P75)

Age  (years)

62 (44.2 – 71)

Wall motion recovery  (days)

15 (7 – 30)

Chest Pain-CMR  (hours)

60 (48 – 126)

EF1 - %

49 (39.2 – 54.7)

EF2  %

66.5 (59.2 – 71.7)

Troponin I – ng/ml

2.47(0.4 – 3.64)

CK MB – UI/ml

8.4 (1.35 – 15.4)

Table 1. Study patients: selected variables.
EF: Left ventricular ejection fraction; CK: Creatine kinase MB, CMR: Cardiovascular Magnetic Resonance.


Imaging techniques
Echocardiography
Echocardiography, angiographic ventriculography and acute phase CRM showed typical wall motion abnormalities, characterized by akinesis/dyskinesis in the mid-apical segments in 7 pts  and mid-ventricular dyskinesis in 1 patient. Ejection fraction at admission and recovery estimated by echocardiography was 49% (39.2% – 54.7%) and 66.5 % (59.2% – 71.7%), respectively (p= 0.008). Table 1 and Fig. 1.

Fig. 1. EF: left ventricular ejection fraction; ECHO 1: Acute phase echocardiogram; ECHO 2: First echocardiogram with normal wall motion.

Cardiac Magnetic Resonance (CMR)
The CMR exams were performed within 72 hours of the beginning of symptoms in 6 pts. In all of them, the sequence of late gadolinium uptake showed mild LGE in the segments with abnormal contractility, which was clearly different from the absence of signal in segments with normal contractility. In 2 pts referred from other institutions, CMR was performed after 72 hours, and in them LGE was negative. The data are depicted in table 2.

Patient

Chest Pain-CMR

CMR - First Study

CMR - Follow up

Wall motion

LGE

Wall motion - LGE

1

48 hs.

Mid cavity -apical dyskinesis

Transmural Mid cavity- apical

Normal – No LGE

2

48 hs.

Mid cavity-apical dyskinesis

Transmural Mid cavity-apical

Normal – No LGE

3

36 hs.

Mid cavity-apical akinesis

Transmural Mid cavity-apical

Normal – No LGE

4

7 days

Apical  hypokinesis

Negative

Normal – No LGE

5

6 days

Mid cavity-apical akinesis

Negative

Normal – No LGE

6

72 hs.

Mid cavity-apical hypokinesis

Transmural Mid cavity-apical

Normal – No LGE

7

72 hs.

Mid cavity-dyskinesis

Transmural Mid cavity

Normal – No LGE

8

48 hs.

Mid cavity-apical dyskinesis

Transmural mid cavity-apical

Normal – No LGE


Table 2.  Correlation between time to CMR and findings.

CMR: Cardiovascular Magnetic Resonance; LGE: Late Gadolinium Enhancement.

Imaging techniques during follow-up
On echocardiography, improvement in LV wall motion occurred in average at 15 (7-30) days from the beginning of symptoms. A follow-up CMR at 3 months showed a completely normal wall motion, and absence of LGE in all cases, which is shown in the illustrations from patients # 2 and # 7 [Figures 2 and 3].

 

Fig. 2.A. Patient # 2. Contrast 2-D Echo (systolic images).  Left panel: apical 4-chamber view, Center panel: apical 2-chamber view. Right panel: volumes and segmental wall motion assessed with 3D-echo.  Note the mid-apical dyskinesis (full-line arrows) and the normal contractility of the basal segments (dashed line arrows).

 

Fig. 2.B. Contrast 2-D echo (systolic images).  Left panel: apical 4-chamber view of the echo performed the first day, showing mid-apical dyskinesis. Right panel: apical 4-chamber view of the echo performed at 15 days, showing complete wall motion normalization.

 

Fig. 2.C. CMR. Sequence of late myocardial enhancement, showing mild transmural gadolinium enhancement in the mid-apical region (day 1), which disappears completely in the follow-up CMR (day 90).

 

Fig. 3.A. Patient #7. Transient mid-ventricular dyskinesis. A- Contrast echo (systolic image): apical 2-chamber view, showing dyskinesis in the mid segment of the anterior wall (red arrows). B- Angiographic ventriculography, showing similar findings to those described by echo (red arrows). C- CMR. Sequence of 2-chamber late gadolinium enhancement showing hyperintensity in the area of abnormal segmental wall motion (middle segment of the anterior wall) (arrows). D- Coronary angiography without significant lesions of the left coronary artery.

 

Fig. 3.B. CMR. Left panel: Sequence of late gadolinium enhancement in the acute phase, showing abnormal gadolinium washout, expressed as a mild transmural hyperintensity (arrows) and complete normalization after 30 days (right panel).

Discussion
SCM is a syndrome presenting with marked and reversible LV dysfunction, often triggered by an emotional or physical stress. The signs and symptoms mimic an acute myocardial infarction with ECG changes, chest pain and increase in serum markers, without significant coronary artery lesions on angiography[1]. Its pathophysiology remains unknown. It is unclear whether "myocardial stunning" is related to a direct catecholamine-mediated effect on the myocardium or whether the main mechanism affects the coronary circulation via vasospasm or spontaneous lysis of a clot after a plaque accident [2-7]. Wittstein suggests there is a strong correlation between SCM and an excessive activation of catecholamines and plasma neuropeptides [12], while other authors consider that LV outflow tract dynamic obstruction is an essential factor in the etiology of this syndrome [13].
Contrast CMR allows to characterize myocardial tissue [14], therefore, allowing to retrospectively infer the pathophysiological mechanism involved in acute coronary syndromes with normal coronary arteries. As an example, the lesion of an epicardial artery is expressed on CMR by transmural or non-transmural typically subendocardial late enhancement, while, in cases of myocarditis, there is subepicardial or intramyocardial  gadolinium uptake [15-17]. Conversely, the finding of LGE as a sign of myocardial damage is very rarely found in the CMR of patients with SCM. Late gadolinium enhancement has only been found in isolated cases of SCM; an example of this is the large series reported by Sharkey, who among 22 patients described only one with LGE [18]. Of note, LGE was absent in patients who had elevated serum markers of myocardial damage, such as troponins. This finding, i.e., the absence of LGE, could be explained by the fact that imaging studies were not performed early enough or by the spatial resolution of the CMR, which  was insufficient to detect small myocardial lesions that were however detected by the markers of necrosis. As to the duration of the study, most reports in the literature do not clarify exactly when CMR was performed. In a case report, Bruder described a stress cardiomyopathy occurring during a dobutamine-stress CMR [19]. In that case, the LGE sequences were performed very early on, and the images obtained immediately after the event as well as those obtained the third day are identical to the images of patients included in our study.  A similar finding occurred with images obtained during follow-up, with complete disappearance of such findings in the control CMR studies. Hence, the delay in performing the study markedly affects the ability to obtain positive data, and a CMR performed early after the event may reveal a typical pattern of gadolinium uptake in this group of patients.
To our knowledge, this is the first prospective study that has analyzed late gadolinium uptake during the acute phase in a consecutive series of patients with SCM. It shows that when CMR is performed within 72 hours of admission, a characteristic pattern of mild transmural LGE is observed, located in the LV region with the wall motion abnormality. Such findings could be related to a slower gadolinium washout determined by the interstitial edema associated to very small areas of necrosis. As days go by, resorption of edema occurs, contractility improves and late enhancement images become normal. Our findings show that CMR performed  very early on may detect a typical and repeated pattern of LGE in patients with SCM.

Limitations
Several studies with CMR have demonstrated the presence of myocardial edema observed in T2 sequences [20].  In our series, T2 sequences did not provide optimal quality images; hence, they were excluded from the analysis. Only 2 patients with a signal consistent with myocardial edema had images considered adequate for evaluation. Finally, although patients included in the study were consecutive, 2 patients referred from other centers were also included, in whom late gadolinium uptake was negative. It is possible that such finding is related to the delay in performing the study.

Conclusion:
Early CMR in SCM demonstrates a special morphological pattern of late gadolinium uptake that might correspond to localized inflammation and edema in the affected area. Such findings contribute important information; hence we suggest that CMR should not be delayed beyond 72 hours. Finally, the morphological appearance of this pattern suggests that the pathophysiology of this syndrome is related to diffuse damage of the myocardium and the microcirculation, rather than involvement of the coronary epicardial vessels.


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Curriculum del Autor
- Supervisor de Ecocardiografía, Instituto Cardiovascular de Buenos Aires , Agosto de 2007 — Presente
- Investigador Asociado, Grupo de investigación de Imagen Computacional y Tecnologías de Simulación en Biomedicina - CISTIB, Agosto de 2005 — Presente
- Ex Jefe de la Sección de Ecocardiografía, Centro Cardiovascular Sant Jordi, Barcelona, Enero de 2005 — agosto de 2007, España, Barcelona




 

 




Publicación: Septiembre - Noviembre/2009

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