Transient left ventricular dysfunction syndrome: Patho-physiological bases through nuclear medicine imaging

International Journal of Cardiology 144 (2010) 212–218

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International Journal of Cardiology j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / i j c a r d

Transient left ventricular dysfunction syndrome: Patho-physiological bases through nuclear medicine imaging Sébastien Cimarelli a,⁎, Frédérique Sauer b, Olivier Morel b, Patrick Ohlmann b, André Constantinesco a, Alessio Imperiale a a b

Service de Biophysique et de Médecine Nucléaire, Hôpitaux Universitaires de Strasbourg, Hôpital de Hautepierre, 1 avenue Molière, 67098 Strasbourg Cedex, France Pôle d'activité médico-chirurgicale des Hôpitaux Universitaires de Strasbourg, Nouvel Hôpital Civil, 1 Place de l'Hôpital, 67091 Strasbourg Cedex, France

a r t i c l e

i n f o

Article history: Received 13 October 2008 Received in revised form 27 March 2009 Accepted 11 April 2009 Available online 13 May 2009 Keywords: Transient left ventricular dysfunction Takotsubo Myocardial stunning 123 I-mIBG 18 F-FDG

a b s t r a c t Background: Takotsubo cardiomyopathy (TTC) is a novel heart disease, mimicking acute myocardial infarction. The term “transient left ventricular dysfunction syndrome” (TLVDS) seems to be more appropriate since variant forms of TTC sparing apical segments (mid-ventricular ballooning syndrome (MVBS) and inverted TTC) have been described. Patho-physiological bases of TLVDS remain poorly understood and its optimal management is until now empirical. Our aim was to characterize patho-physiological mechanisms of TLVDS by means of nuclear medicine procedures and to discuss the clinical usefulness of isotopic imaging for a non-invasive diagnosis of TLVDS. Methods and results: During the sub acute phase, eighteen patients with TLVDS (13 TTC and 5 MVBS) underwent myocardial 99mTc-tetrofosmin or 201Thallium Gated Single Photon Emission Computed Tomography (G-SPECT) (n = 11), 123I-mIBG SPECT (n = 8) and 18F-FDG Gated Positron Emission Tomography (G-PET) (n = 15), assessing respectively LV perfusion, sympathetic innervation and glucose metabolism. Hypocontractile LV segments were characterized by normal perfusion but reduced uptake of 18F-FDG and 123I-mIBG. Topography and extent of metabolic defects and innervation abnormalities were largely overlapping. Follow-up 123I-mIBG SPECT and 18F-FDG G-PET were performed in selected patients showing rapid normalization of LV motion and progressive improvement of both glucose metabolism and sympathetic innervation. Discussion: With the hypothesis of neurogenic stunned myocardium as the central causative mechanism of TLVDS, 123I-mIBG SPECT seems to be the most specific diagnostic technique. Sympathetic function and glucose metabolism seem to be strictly correlated in the hypocontractile LV segments. Finally, our results underline the role of nuclear imaging in the setting of patho-physiological mechanisms of TLVDS. © 2009 Elsevier Ireland Ltd. All rights reserved.

1. Introduction Transient apical ballooning syndrome or Takotsubo cardiomyopathy (TTC), represents 1–2% of troponin-positive acute coronary syndromes [1]. TTC affects predominantly postmenopausal women and a stressful event commonly precedes most cases [2]. Symptoms, laboratory and electrocardiographic (ECG) findings mimic closely those of acute myocardial infarction. The acute phase of disease is characterized by akinesis or dyskinesis of left ventricle (LV) apex, which is associated to basal hypercontractility in patients without significant stenoses of epicardial coronary arteries. TTC is transient and wall motion abnormalities are completely reversible in a few

⁎ Corresponding author. Tel.: +33 03 88 11 67 68; fax: +33 03 88 12 83 42. E-mail address: [email protected] (S. Cimarelli). 0167-5273/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2009.04.025

weeks. Nevertheless, complications and death have been reported in 18.9% and 3.2% of patients, respectively [2] and a recurrent episode occurs in 3.5–6% of cases [1,3]. Variant forms of TTC sparing LV apex have been described and called “mid-ventricular ballooning syndrome” (MVBS) and “inverted Takotsubo” [4–7]. Thus, “transient left ventricular dysfunction syndrome” (TLVDS) without coronary artery disease was recently proposed as a new and more appropriate definition for TTC [1]. Patho-physiological bases of TLVDS remain still poorly understood. Neurogenic myocardial stunning that is mediated by stress-induced catecholamine acute release seems to be the most relevant hypothesis. Nevertheless, multivessel coronary spasms [8], impaired coronary microcirculation [9] or inflammatory process [10] have been proposed as causative mechanisms for TLVDS. To improve the knowledge of this interesting myocardial disease, a cohort of patients with TLVDS was investigated by means of nuclear medicine techniques. The clinical usefulness of isotopic imaging for a non-invasive diagnosis of TLVDS was also discussed.

S. Cimarelli et al. / International Journal of Cardiology 144 (2010) 212–218

2. Study population

3. Methods

Between January 2006 and May 2008, we retrospectively included in our study 18 consecutive patients admitted to our Cardiology Department for clinical suspicion of acute myocardial infarction, satisfying the following criteria:

3.1. Non-isotopic procedures

(1) All patients met the Mayo criteria for the clinical diagnosis of TLVDS [11]: a. transient akinesis or dyskinesis of the LV apical and/or midventricular segments with regional wall-motion abnormalities extending beyond a single epicardial vascular distribution; b. absence of obstructive coronary disease or angiographic evidence of plaque rupture; c. new electrocardiographic abnormalities, either ST-segment elevation or T wave inversion; d. absence of recent significant head trauma, intracranial bleeding, pheochromocytoma, obstructive epicardial coronary artery disease or myocarditis; (2) All patients underwent at least one myocardial isotopic procedure 3 to 20 days after the onset of symptomatology (subacute phase), assessing LV perfusion, sympathetic innervation or glucose metabolism. Thirteen out of 18 patients were women (72%). The median age of the studied population was 67 years (age range: 13–87 y). Typical TTC was observed in 13 out of 18 TLVDS patients (72%) as compared to the midventricular pattern assessed in the remaining 5 cases. The onset of symptoms was preceded by manifest acute emotional stress in 5 out of 18 patients (28%). Right arm acute ischemia, acute bupirenorphine withdrawal and acute hyponatremia complicated by confusional syndrome, anticipated TLVDS symptomatology in 3 patients (17%). Potential iatrogenic causative mechanism of TLVDS was suggested in 5 patients (28%). Four of them had an adrenalin IV injection for treating cardiogenic shock secondary to anaphylaxis, sepsis, tricyclic antidepressants abuse for suicidal purpose and general anesthesia. The overdose of β2-mimetic for treating severe asthma exacerbation was probably the cause of TLVDS in the last one. Finally, no identifiable triggering event was identified for the remaining 5 patients (28%). Patient population characteristics are summarized in Table 1.

213

Troponin I and Creatine Phosphokinase (CPK) were measured using standard procedures from blood samples obtained from an antecubital vein at admission and subsequently every 8 h until the recovery of normal values. Two-dimensional transthoracic echocardiography (TTE) was performed on admission and 1 month after the acute phase, using a VIVID 7 (GE Medical System LLC, Waukesha, Wisconsin) with a 2.5-MHz transducer. Emergency coronary angiography was performed by femoral approach in all included patients using Judkins technique with a 4F or 6F catheter. Standard projections were obtained. Coronary artery disease was defined as more than 50% reduction in lumen diameter. LV ejection fraction (LVEF) was calculated by Simpson's method for both TTE and left ventriculography as expressed as mean ± SD. 3.2. Scintigraphic procedures Myocardial perfusion Gated Single Photon Emission Computed Tomography (G-SPECT) began 60 min after 99mTc-tetrofosmin injection (740 MBq) or 10 min after 201Thallium injection (74–111 MBq), using a double-head gamma camera (ECAM, Siemens Medical Systems, Erlangen, Germany) equipped with low-energy, high-resolution parallel-hole collimators, a 180° rotation arc, 32 projections, 30 (99mTc-tetrofosmin) or 40 (201Thallium) s/projection, 8 frames/heart cycle and 64 × 64 matrix. The studies were reconstructed using filtered back-projection without attenuation or scatter correction and realigned along the heart axis. 123 I-metaIodoBenzyl-Guanidine (123I-mIBG) scintigraphy was performed 4 h after IV injection of 220 MBq 123I-mIBG using the same gamma camera. Medical therapy and drugs known to influence 123I-mIBG uptake were discontinued for at least 24 h before tracer injection. Projections data were obtained from a 64 × 64 matrix in 32 views for 60 s each. The studies were reconstructed using ordered-subsets expectation maximization iterative technique without attenuation or scatter correction and realigned along the heart axis. 18 F-Fluorodeoxyglucose (18F-FDG) Gated Positron Emission Tomography (G-PET) was performed after oral glucose loading [12]. G-PET acquisition began 45 min after 18F-FDG injection (250 MBq) using a combined PET/Computed Tomography (CT) technology (Discovery ST; GE Medical Systems, Milwaukee, Wisconsin), at 6–12 frames/heart cycle. A thoracic low-dose CT scan was performed before 15-minute 3-dimensional PET acquisitions. PET data were reconstructed with and without CT-based attenuation correction by use of iterative technique. PET reconstructed images were realigned along the short-axis, vertical and horizontal long-axis and qualitatively interpreted. To facilitate the comparative analysis among perfusion SPECT, 123I-mIBG SPECT and 18F-FDG PET, a 17 segments-model of polar map presentation was obtained from LV short-axis slices. Hence, myocardial uptake defects were quantified as a percentage of the whole LV wall. Two experienced nuclear medicine physicians (CS, IA) interpreted PET and SPECT images, blindly and separately, using QPS-QGS software (Cedars-Sinai, Los Angeles, California). Physicians were uninformed of the results obtained by the conventional diagnostic approach. The final interpretation of images with disagreement was made as a consensus reading.

Table 1 Summary of patient population clinical characteristics. Pt n°

Sex (M/F)

Age (y)

TLVDS type

Trigger event

Symptoms

ECG

Troponin I (Nb 0.14 ng/mL)

CPK (N b 200 IU/L)

LVEF (%) VTG-St

TTE-St

TTE-Fu

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

F F F M F F M F F F F F M M F F M F

83 83 69 17 64 82 84 39 82 87 79 64 13 72 67 60 86 81

TTC TTC TTC TTC TTC MVBS TTC TTC TTC TTC TTC TTC MVBS TTC MVBS MVBS TTC MVBS

Right arm ischemia Unknown Emotional stress Adrenalin injection Adrenalin injection Unknown Hyponatremia Bupirenorphine withdrawal Emotional stress Emotional stress Emotional stress Adrenalin injection Adrenalin injection ß2 mimetic Unknown Emotional stress Unknown Unknown

Chest pain, dyspnea Pulmonary edema Syncope Dyspnea Pulmonary edema Dyspnea Dyspnea Pulmonary edema Chest pain, dyspnea Chest pain, dyspnea Chest pain Chest pain, dyspnea Shock Chest pain, epistaxis Chest pain Chest pain Syncope Syncope

ST elevation T-waves inversion T-waves inversion ST elevation T-waves inversion T-waves inversion ST elevation T-waves inversion ST elevation ST elevation ST elevation T-waves inversion T-waves inversion ST elevation ST elevation ST elevation ST elevation ST elevation

4.6 3.1 4.3 7.1 3.2 6 0.2 4.2 4.9 2.8 1.8 2.6 3.5 0.3 4.1 2.5 4.3 4.8

390 182 230 208 251 100 120 135 246 113 828 150 175 482 302 109 120 153

40 45 50 55 na na 35 20 25 41 20 40 na 32 35 45 na 48

40 40 40 45 30 25 40 20 25 40 25 35 45 30 40 42 40 35

55 55 55 70 50 60 70 55 50 70 50 60 60 60 60 55 55 60

TLVDS: Transient Left Ventricular Dysfunction Syndrome; TTC: Takotsubo Cardiomyopathy; MVBS: Midventricular Ballooning Syndrome; ECG: Electrocardiography; CPK: Creatine Phosphokinase; LVEF: Left Ventricular Ejection Fraction; VTG: ventriculography; TTE: 2D-Transthoracic Echocardiography; St: primary staging; Fu: follow-up; na: not available.

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3.3. Statistical analysis Results are expressed as mean ± SD. The relationships between what were considered the not normally distributed variables were assessed using the Spearman rank test (n N 10) or the Kendall Tau test (n b 10). Comparisons were computed by Mann–Whitney U test. The STATISTICA (STATSOFT; www.statsoft.com) package was used for statistical data analysis and p b 0.05 was considered statistically significant.

.4.3.3. Myocardial glucose metabolism

4. Results 4.1. Clinical, biological and ECG findings Patients presented with dyspnea (39%), chest pain (44%), shock and/or pulmonary edema (44%). Troponin I and total CPK levels increased moderately within 24 h in 18 and 8 patients, respectively and decreased thereafter. On admission, a transient STsegment elevation and T waves inversion were registered in precordial leads in 11 and 7 patients, respectively. No ECG abnormalities were detectable one month after the acute symptomatology and during all the duration of follow-up. Main symptomatology, laboratory results and ECG data obtained at primary staging are summarized in Table 1. 4.2. Echocardiography and cardiac catheterization assessment At admission, TTE revealed akinesis or severe hypokinesis of LV apex with preserved basal function in patients with TTC. Conversely, akinesis or severe hypokinesis of LV mid segments was found in patients with MVBS. A variable degree of LVEF impairment was registered. Full recovery of both LV kinetic and function was observed in all patients one month after the acute phase. Mean LVEF increased from 35 ± 8% to 58 ± 6% (p = 0.0001). Coronary angiography revealed absence of significant organic stenosis in the epicardial arteries in all patients. Left ventriculography data were available in 14 cases and confirmed LV wall motion abnormalities as well as the impaired LVEF (38 ± 11%). Results of TTE and left ventriculography are summarized in Table 1. 4.3. Scintigraphic findings

.4.3.1. Myocardial perfusion In the sub acute phase, 11 out of 18 patients (61%) underwent rest myocardial perfusion SPECT, using 99mTc-tetrofosmin (n = 7) or 201Thallium (n = 4) as radiotracer (Table 2). The mean interval between the onset of acute symptomatology and SPECT was 10.4 days (range: 5–15). Normal myocardial perfusion was observed in all of them. The analysis of LV motion showed apical akinesis or severe hypokinesis in 6 patients with TTC and severe mid ventricular hypokinesis with preserved apical and basal function in 3 patients with MVBS. Wall motion abnormalities were associated to a reduced LVEF in 9 patients. Atrial fibrillation precluded G-SPECT in the 2 remaining patients.

.4.3.2. Myocardial innervation

At staging, 8 out of 18 patients (44%) underwent myocardial 123I-mIBG SPECT revealing absence or severe reduction of tracer uptake in the hypocontractile segments

Table 2 Summary of whole scintigraphic results at primary staging. Pt n° 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

TLVDS TTC TTC TTC TTC TTC MVBS TTC TTC TTC TTC TTC TTC MVBS TTC MVBS MVBS TTC MVBS

of apical or mid-ventricle regions in respectively 7 TTC and 1 MVBS patients (Table 2). The mean interval between the onset of acute symptomatology and SPECT was 11.6 days (range: 4–20). The extent of 123I-mIBG uptake defect was 38% ± 17%. Four TTC patients underwent 123I-mIBG SPECT six months after acute symptomatology showing a dramatic improvement of tracer uptake in apical segments. 123I-mIBG SPECT was repeated one year after diagnosis in 2 patients with persisting moderate abnormalities on the follow-up scintigraphic evaluation. Despite a progressive evolution, no complete recovery of apical 123I-mIBG uptake was obtained (Fig. 1).

123

Perfusion SPECT

I-mIBG SPECT

18

F-FDG PET

P/N

Tracer

Delay⁎

P/N

%

Delay⁎

P/N

%

N N N N N

Tc Tc Tc Tl Tl

10 11 10 7 14

P P P P

50 15 25 30

7 18 20 10

P P

50 10

3 4

N

Tl

10

N

Tc

15

P P P P P P

40 50 40 60 50 25

15 6 10 4 5 15

P P P P P P P

10 20 30 30 40 25 20

12 20 8 5 2 12 12

N

Tl

14

N

Tl

5

N N

Tc Tc

9 9

P P

60 35

4 10

P

60

10

P

30

14

Delay⁎

TLVDS: Transient Left Ventricular Dysfunction Syndrome; TTC: Takotsubo Cardiomyopathy; MVBS: Midventricular Ballooning Syndrome; P: positive; N: negative; %: left ventricle uptake defect extent based on 17 segments polar map; Tc: 99mTc-tetrofosmin; Tl: 201Thallium; delay⁎: days between acute event and scintigraphy.

18 F-FDG G-PET was performed in 15 patients (83%). Severely reduced uptake in LV apex or in mid-segments was showed in 10 TTC and 5 MVBS patients, respectively (Table 2). The mean interval between the onset of acute symptomatology and G-PET was 8.9 days (range: 3–20). The extent of 18F-FDG uptake defect was 33%± 15%. Hypometabolic segments were also characterized by a different degree of hypokinesis largely overlapping with that observed on TTE (Fig. 2). Six patients underwent follow-up G-PET 1 to 12 months after the onset of acute symptomatology showing almost significative improvement of radiotracer uptake defects that were described at primary evaluation (Fig. 1).

.4.3.4.

Relationship among myocardial perfusion, sympathetic innervation and glucose metabolism

a) b) c) d)

At primary staging: 6 patients (33%) underwent both myocardial perfusion SPECT and 123I-mIBG SPECT; 9 patients (50%) underwent both myocardial perfusion SPECT and 18F-FDG G-PET; 5 patients (28%) underwent both 123I-mIBG SPECT and 18F-FDG PET; 4 patients (22%) underwent myocardial perfusion SPECT, 123I-mIBG SPECT and 18FFDG G-PET.

The mean interval between myocardial perfusion SPECT and respectively 123I-mIBG SPECT and 18F-FDG PET was 6.2 days (range: 3–10) and 4.1 days (range: 0–10). The mean interval between 123I-mIBG SPECT and 18F-FDG PET was 8.4 days (range: 0–14). Hypocontractile but normally perfused LV segments were characterized by severe decrease of 123I-mIBG (5 TTC, 1 MVBS) and 18F-FDG (6 TTC, 3 MVBS) uptake (Fig. 3). According to the qualitative analysis of scintigraphic images, the topography of 123ImIBG and 18F-FDG uptake defects was largely overlapping. No statistically significant difference was shown in terms of extent of radiotracer uptake defect in 5 patients who underwent both 123I-mIBG scintigraphy (38% ± 17%; range: 15–60) and 18F-FDG G-PET (40% ± 20%; range: 10–60). The existence of any relationship between sympathetic innervation and glucose metabolism abnormalities was also investigated. A strong significant correlation (t = 0.95; p = 0.02) between the extension of 123I-mIBG and 18FFDG defects was found. Therefore, the severity of 123I-mIBG and 18F-FDG defects was inversely correlated to the time elapsed between the diagnosis and the scintigraphic examination (t = − 0.56; R = − 0.50; p = 0.05). Conversely, no significant correlation was found among the severity of 123I-mIBG or 18F-FDG defects and Troponin I, CPK and echographic LVEF at the time of admission.

5. Discussion Although triggering stress and hormonal disequilibrium have been proposed as potential responsible factors, the pathophysiological mechanisms of TLVDS remain a matter of speculation. Myocardial perfusion defect has been reported in the acute phase of TTC suggesting that disturbance of microcirculation might be the cause of this disease [9,13]. The multivessel spasm may be responsible for a self-limited ischemic event able to generate stunned myocardium but not long enough to cause myocardial necrosis [14]. To support the hypothesis that TTC is caused by severe spasm of many or all of the coronary vessels, Angelini has recently observed the effect of diffuse and reversible vasospasm following a pharmacological provocation in patients with TTC [15]. Diffuse transient microvascular dysfunction could be an associated phenomenon secondary to acute catecholamine release rather than the primary causative mechanism of TLVDS. Triggering stress precedes the majority of reported cases [1,2,16]. In our experience, the onset of symptoms was preceded by manifest acute emotional stress in 5 out of 18 patients (28%). Wittstein et al. [17] reported higher plasma catecholamine levels in 19 patients with acute LV dysfunction after sudden emotional stress supporting the pathogenic role of enhanced catecholamine release secondary to exaggerated sympathetic stimulation in TTC. Catecholamine-induced toxic effect might be the result of cardiocyte overload mediated by cyclic-adenosine monophosphate associated to overproduction of

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Fig. 1. Left ventricle transaxial slices (short axis, vertical long-axis and horizontal long-axis) and polar map presentation (17 segments-model) of respectively cardiac 18F-FDG PET (A) and 123I-mIBG SPECT (B) performed during subacute and chronic phases in two patients with TTC (cases 1 and 3). We found markedly reduced uptake of both 18F-FDG and 123I-mIBG in the apical region of left ventricle in the subacute phase. Despite a great improvement, the uptake of both 18F-FDG and 123I-mIBG in the apex was not completely normalized at about 6 months after the onset of symptomatology.

oxygen-derived free radicals [18]. Contraction-band necrosis is the typical aspect of myocyte injury caused by catecholamine hypersecretion. This phenomenon was illustrated by Takizawa et al. [19] in a case of transient left ventricular ballooning associated to pheochromocytoma hemorrhagic necrosis. Physical stressful condition could be also responsible of TTC. Park et al. [16] assessed the frequency and clinical implications of TTC in 92 patients admitted to the intensive care unit for non-cardiac physical illness. Apical ballooning was observed in 26 patients (28%), suggesting that severe intercurrent medical disease could be a conceivable triggering event for TLVDS. Accordingly, right arm acute ischemia, acute bupirenorphine withdrawal and acute hyponatremia complicated by confusional syndrome, anticipated TLVDS symptomatology in three patients of our cohort (17%). Could the associated emotional stress play a role in TLVDS development in those cases? Further investigations are required to test this hypothesis. Recently, Lyon et al. [20] proposed an exhaustive explanation for TTC considering the direct negative inotropic effects mediated by supraphysiological epinephrine levels on the myocardium via the ß2adrenoceptor, that are particularly abundant in apex. The high levels of epinephrine could trigger a switch in intracellular trafficking in

cardiomyocyte from Gs protein to Gi protein signaling via the ß2adrenoceptor, with consequent negative inotropic effect. However, this switch to ß2adrenoceptor-Gi protein may be considered advantageous by protecting against the proapoptotic effects of intense activation of ß1adrenoceptor. In our experience, adrenalin IV injection or overdose of β2-mimetic preceded the onset of symptoms in five patients (28%) representing a potential iatrogenic causative mechanism of TLVDS. Nevertheless, literature data about the role of exogenous adrenaline in the pathogenesis of TLVDS is scarce [21,22] and further studies are necessary to validate our preliminary observation. TLVDS affects predominantly post menopausal women [2]. Accordingly, elderly women represent 72% of our study population. In postmenopausal period, the physiological reduction of estrogen secretion can increase stress reactivity by deregulation of both autonomic function and cardioprotective substance production [23]. Using an animal model of TTC, Ueyama et al. [24] showed that chronic estrogen supplementation following ovariectomy improves the emotional stress-induced cardiovascular response. 123 I-mIBG is a structural analog of norepinephrine. Increased levels of plasma catecholamine are known to reduce neuronal norepinephrine uptake [25]. Therefore, with the hypothesis of neurogenic stunned

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Fig. 2. Cardiac 18F-FDG Gated PET/CT performed during subacute phase in patient 15 with Mid-ventricular Ballooning Syndrome. (A) Top to bottom: sagital, coronal and transversal slices of CT, PET and PET/CT images. (B) Polar map presentation (17 segments-model) of gated and no gated PET acquisitions. (C) Maximum-intensity projection coronal 18F-FDG PET image. (D) Vertical and horizontal long-axis of 18F-FDG PET. 18F-FDG uptake was severely reduced in all left ventricular hypocontractile mid-segments. Tracer uptake was preserved in the apex and basal region.

Fig. 3. Typical aspect of transient apical ballooning syndrome, also known as Takotsubo cardiomyopathy, in a 64 year-old woman (patient 5) who received adrenalin iv. injection for treating cardiogenic shock caused by general anaesthesia complications during liver transplantation. Cardiac 201Thallium SPECT/CT (A) and 18F-FDG PET/CT (B) were performed respectively 14 and 15 days after acute symptoms (subacute phase). 18F-FDG uptake was severely reduced in a large apical region of the left ventricle, whereas myocardial perfusion was normal.

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myocardium as the central causative mechanism of TLVDS, 123I-mIBG SPECT seems to be the most specific diagnostic imaging tool [26,27]. Starting from the observation that the canine heart has a higher concentration of β-adrenoceptors in the apical segments, it has been suggested that LV apex is more vulnerable to the exaggerated sympathetic stimulation [28]. The description of variant forms of TLVDS, sparing LV apex might be explained by interindividual heterogeneity in the distribution of sympathetic receptors in the LV. Several mechanisms were proposed to justify the reduction of 123I-mIBG myocardial uptake in acute phase. Distal denervation following myocyte permanent damage has been observed in patients with myocardial infarction. In TLVDS, both the normal perfusion and the progressive improvement of 123I-mIBG uptake allow us to discard the hypothesis of myocardial sympathetic denervation. Alternatively, the heterogeneity of 123I-mIBG uptake could be explained by the impairment of the uptake-1 function, which is an ATP-requiring system altered in the failing heart [29]. According to Owa et al. [30], we observed the non-complete normalization of apical myocardial 123I-mIBG uptake after 1-year of follow-up. Patients studied by 123I-mIBG scintigraphy for no-TTC related pathology show a moderate reduction of tracer uptake in left ventricular apex, reflecting the natural basal–apical gradient of sympathetic innervation. Nevertheless, the residual apical defect, which was detected in TTC patients during follow-up was more evident. We can hypothesize a slow recovery process of normal β-adrenoceptors function in the neurogenic stunned myocardium, in particular in the apical region, which is characterized by a higher adrenergic receptor density. At this proposal, further studies including follow-up examinations in patients with transient mid ventricular ballooning syndrome could be interesting and particularly helpful. 18 F-FDG PET is successfully employed for myocardial viability assessment. Discrepancy between normal perfusion and reduced 18FFDG uptake in dysfunctioning LV segments is characteristic of both sub acute and chronic phases of disease [1,6,31,32]. The association between normal perfusion and reduced glucose utilization is commonly known as inverse flow-metabolism mismatch and it is considered as the metabolic state of stunned myocardium [33]. Tsubokawa et al. [14] reported an inverse flow-metabolism mismatch in a patient with acute myocardial infarction successfully treated with intracoronary thrombolytic therapy. One month after the acute event, they observed complete recovery of myocardial perfusion and glucose metabolism while fatty acid metabolism remained impaired. In TLVDS, the altered 18F-FDG uptake in hypokinetic area is probably related to a transient regional metabolic disorder. Catecholamine-mediated myocardial insulin resistance may be responsible for reduced 18F-FDG uptake in the hypocontractile regions [34]. The inhibition of intracellular translocation of glucose transporters (GLUT-4) by calcium overload may also contribute to the decrease of18F-FDG uptake in cardiocyte [35]. The concordance of 123I-mIBG and 18F-FDG uptake abnormalities as well as their common temporal evolution underlined the close relationship between the myocardial sympathetic function and glucose metabolism. Mongillo et al. [36] showed that in the failing human heart, the dysfunctioning LV segments are characterized by reduced presynaptic reuptake as well as reduced myocardial glucose utilization. Ito et al. [9] observed the same discrepancies between perfusion, fatty acid metabolism and sympathetic innervation, suggesting the existence of sympathetic nerve control on cardiac metabolism. In our study, a strong significant correlation between the extension of 123I-mIBG and 18F-FDG defects was found. Therefore, the severity of 123I-mIBG and 18F-FDG defects was inversely correlated to the time elapsed between the diagnosis and the scintigraphic examination, underlining the transient nature of TLVDS. Conversely, no relationship was found among the severity of 123I-mIBG or 18F-FDG defects and Troponin I, CPK and echographic LVEF at the time of admission. The high variability of the time elapsed between the onset of acute symptomatology and the isotopic procedures could explain the lack of significant correlation in our population. Table 3 summarizes the temporal evolution of TLVDS

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Table 3 Potential temporal evolution according to our results and literature data.

Clinical symptomatology laboratory tests, ECG Apex or mid segments of left ventricle motion Perfusion Sympathetic innervation Glucose metabolism

Acute phase

Sub-acute phase (b 21 days)

Altered

Complete recovery

Altered

Complete recovery

Altered Altered

Complete recovery Improvement

Altered

Improvement

Chronic phase (N6 months)

Discrete residual abnormality/Recovery Discrete residual abnormality/Recovery

according to both our results and literature data concerning the acute phase of disease. TLVDS mimes an acute myocardial infarction particularly in women. Thus, most TLVDS patients undergo emergency coronary arteriography and are treated by antithrombotic agents, calcium channels blockers or beta-blockers with high risks of adverse effects in older and fragile patients. TLVDS must be considered in differential diagnosis particularly in patients with preceding stress factor, minimal rise of cardiac enzymes, absence of known cardiovascular disease and typical wall-motion abnormalities at TTE. In this case the need of both coronary angiography and antithrombotic therapy in emergency must be well discussed, because therapeutic approach in TLVDS patients is at present not completely standardized [37]. Furthermore, we draw cardiologists' attention to the possible iatrogenic cause of TLVDS. Inotropic support using exogenous catecholamines may be counterproductive to treat cardiogenic shock [38]. Our study has the inherent limitations of any observational case series focused on a rare condition. Its retrospective character is mainly due to the small studied population. Particularly, the heterogeneous scintigraphic evaluation and the variable interval between the attack and the isotopic procedures make the analysis of results difficult. A prospective study is needed to confirm our observations. In conclusion, neurogenic stunned myocardium mediated by catecholamines over secretion seems to be the central causative mechanism in TLVDS. Diffuse transient coronary microvascular dysfunction may be an associated phenomenon secondary to acute catecholamine release. Acknowledgement The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology [39]. References [1] Kurowski V, Kaiser A, von Hof K, et al. Apical and midventricular transient left ventricular dysfunction syndrome (Tako-tsubo cardiomyopathy): frequency, mechanisms, and prognosis. Chest 2007;132:809–16. [2] Donohue D, Movahed M-R. Clinical characteristics, demographics and prognosis of transient left ventricular apical ballooning syndrome. Heart Fail Rev 2005;10:311–6. [3] Gianni M, Dentali F, Grandi AM, Sumner G, Hiralal R, Lonn E. Apical ballooning syndrome or takotsubo cardiomyopathy: a systematic review. Eur Heart J 2006;27:1523–9. [4] Tamura A, Kawano Y, Watanabe T, et al. A report of 2 cases of transient midventricular ballooning. Int J Cardiol 2007;122:10–2. [5] Yasu T, Tone K, Kubo N, Saito M. Transient mid-ventricular ballooning cardiomyopathy: a new entity of Takotsubo cardiomyopathy. Int J Cardiol 2006;110:100–1. [6] Cimarelli S, Imperiale A, Ben-Sellem D, et al. Nuclear medicine imaging of Takotsubo cardiomyopathy: typical form and mid-ventricular ballooning syndrome. J Nucl Cardiol 2008;15:137–41. [7] Sanchez-Recalde A, Iborra C, Costero O, et al. Isolated left ventricular Basal ballooning in young women: «inverted takotsubo» pattern related to catecholamine-toxicity. Am J Cardiol 2007;100:1496–7. [8] Dote K, Sato H, Tateishi H, Uchida T, Ishihara M. Myocardial stunning due to simultaneous multivessel coronary spasm: a review of 5 cases. J Cardiol 1991;21:203–14. [9] Ito K, Sugihara H, Kinoshita N, Azuma A, Matsubara H. Assessment of Takotsubo cardiomyopathy (transient left ventricular apical ballooning) using 99mTctetrofosmin, 123I-BMIPP, 123I-MIBG and 99mTc-PYP myocardial SPECT. Ann Nucl Med 2005;19:435–45.

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