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Reversible impairment of coronary flow reserve in takotsubo cardiomyopathy: A myocardial PET study
Reversible impairment of coronary flow reserve in takotsubo cardiomyopathy: A myocardial PET study Mauro Feola, MD, FESC,a Stephane Chauvie, PhD,b Gian Luca Rosso, MD,a Alberto Biggi, MD,b Flavio Ribichini, PhD,c and Marco Bobbio, MDa Background. The precise etiology of takotsubo cardiomyopathy remains unclear. The study of myocardial blood flow (MBF) and coronary flow reserve (CFR) by use of positron emission tomography might help in understanding this syndrome. Methods and Results. Three postmenopausal women underwent adenosine/rest perfusion with nitrogen 13 ammonia and metabolism with fluorine 18 fluorodeoxyglucose positron emission tomography, coronary angiography, cardiac magnetic resonance, and echocardiography in the acute phase of takotsubo cardiomyopathy and at 3 months’ follow-up, after normalization of left ventricular function. PET study was performed in 2 parts: the perfusion analysis with nitrogen ammonia and the metabolism of the heart using FDG. MBF and CFR were analyzed quantitatively in the acute phase and at follow-up. The images highlighted the impairment of tissue metabolism in the dysfunctioning left ventricular segments in the acute phase, mainly in the apical segments and progressively less in the medium segments. At the same time, a clear inverse metabolic/perfusion mismatch emerged, which normalized 3 months later. The quantitative analysis of MBF showed a reduction in the acute phase in apical segments in comparison to basal segments without differences between midventricular and basal segments. In the acute phase CFR proved to be reduced in apical versus basal segments. CFR impairment of apical segments recovered completely after 3 months. Conclusion. The acute phase of takotsubo cardiomyopathy is characterized by an inverse perfusion/metabolism mismatch with a reduction in CFR in the apical segments. However, the impairment of CFR and the reduction of metabolism in the apical segments recovered completely after 3 months. (J Nucl Cardiol 2008;15:811-7.) Key Words: Apical ballooning syndrome • takotsubo cardiomyopathy • coronary flow reserve • positron emission tomography Takotsubo cardiomyopathy, also called transient left ventricular (LV) apical ballooning syndrome, is a rare form of transient LV dysfunction that mimics an acute coronary syndrome,1,2 characterized by hypokinesis and dyskinesis of the apical segments and hypercontractility of the basal segments, in total absence of atherothrombotic coronary artery disease. This acute cardiac syndrome was first described in the Japanese population,3 and although it is being reported more frequently, the From the Department of Cardiovascular Diseasesa and Nuclear Medicine Service,b Ospedale Santa Croce-Carle Cuneo, Cuneo, and Division of Cardiology, Università di Verona, Verona,c Italy. Received for publication Feb 14, 2008; final revision accepted April 1, 2008. Reprint requests: Mauro Feola, MD, FESC, Department of Cardiovascular Diseases, Ospedale Santa Croce-Carle Cuneo, Via Coppino 26, 12100 Cuneo, Italy; [email protected]. 1071-3581/$34.00 Copyright © 2008 by the American Society of Nuclear Cardiology. All rights reserved. doi:10.1016/j.nuclcard.2008.06.010
exact cause of the syndrome and its physiopathology remain unknown. Dynamic positron emission tomography (PET) with nitrogen 13 ammonia and tracer kinetic modeling has been used intensively in the past for the noninvasive measurement of myocardial blood flow (MBF) and coronary flow reserve (CFR) in patients with cardiac disorders.4-10 The absolute quantitation of regional MBF is used for the evaluation of the severity of coronary obstructions and for decision making regarding the need for coronary revascularization. PET with fluorine 18 fluorodeoxyglucose (FDG) is used as an indicator of myocardial metabolism.11 In the acute phase this syndrome presents as a transient metabolic disorder at the cellular level, which was recently demonstrated by evidence of the impairment of tissue metabolism in the dysfunctioning left ventricle with preserved MBF at rest.12,13 The aim of this observational study was (1) to analyze changes in MBF and CFR in the acute phase of 811
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takotsubo cardiomyopathy and at follow-up and (2) to investigate whether the flow/metabolism mismatch pattern observed with PET imaging is reversible or permanent. METHODS Patients All patients underwent coronary angiography, transthoracic echocardiography, myocardial PET and cardiac magnetic resonance imaging (MRI) in the acute phase. Except for coronary angiography, all of the noninvasive studies were repeated at 90 days after hospital discharge to evaluate eventual changes from baseline. Takotsubo cardiomyopathy was defined as a syndrome characterized by transient LV dysfunction, electrocardiographic changes and acute onset of chest pain that can mimic acute myocardial infarction, and minimal release of myocardial enzymes in the absence of obstructive coronary artery disease. All of these conditions were necessary to confirm the diagnosis.
Coronary Angiography Selective coronary angiography was performed via the Judkins technique within 1 hour of hospital admission. An experienced angiographer assessed the degree of coronary stenosis. For the purpose of the study, a coronary stenosis greater than 50% on quantitative coronary analysis was considered significant.
Echocardiography Resting transthoracic echocardiograms were obtained in all patients immediately after coronary angiography. Examinations were performed with a wide-angle mechanical scanner (2.5-MHz Sonos 5500; Hewlett-Packard, Palo Alto, Calif). Two-dimensional apical 2- and 4-chamber views were used for ventricular volume measurements. Left ventricular ejection fraction (LVEF) was calculated via a modified Simpson’s method by use of biplane apical (2- and 4-chamber) views. Echocardiography was performed by experienced cardiologists blinded to the results of myocardial PET with an intraobserver variability in LVEF of less than 5%.
Positron Emission Tomography The PET examinations were performed within three days after admission. On 2 consecutive days, 3 PET investigations were performed on each patient including FDG for viability testing and ammonia in both baseline and hyperemic conditions for perfusion. All scans were carried out with the Discovery LS PET/computed tomography (CT) hybrid system (GE Healthcare, Waukesha, Wis). Every PET study was preceded by a CT scan for attenuation correction. To reduce artifacts due to heart movement and breathing, a slow CT helical scan was used that entailed 27.5 seconds to acquire the whole heart field of view. Furthermore, CT and PET images were visually checked for
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potential misregistration. All PET studies were performed in 2-dimensional mode for scatter reduction. Images were reconstructed with an ordered-subset expectation maximization 28subset 3-iteration algorithm with an in-plane image resolution of 4.8-mm full width at half maximum. The reconstruction matrix was 128 ⫻ 128 pixels with a 3.9-mm pixel size.
Determination of CFR On day 1, PET ammonia studies were carried out under rest and hyperemic conditions. PET dynamic acquisition (12 ⫻ 10 seconds, 4 ⫻ 30 seconds, and 1 ⫻ 360 seconds) was started immediately after injection of 550 to 590 MBq of ammonia. Pharmacologic stress testing was performed with an adenosine infusion at 140 g · kg⫺1 · min⫺1 over a period of 6 minutes, starting 3 minutes before and ending 3 minutes after ammonia administration.
FDG PET On day 2, after fasting for 12 hours, patients were injected with 378 to 402 MBq of FDG, and CT acquisition was started 1 hour later. The injection of tracers was preceded by a short hyperinsulinemic-euglycemic clamp that obtained a similar metabolic milieu. (For the first scan, at baseline, the mean glycemic level was 85 mg/dL and mean insulin level was 3.5 U/L; after FDG injection, the mean glycemic level was 68 mg/dL and the mean insulin level was 44 U/L. For the follow-up scan, at baseline, the mean glycemic level was 106 mg/dL and the mean insulin level was 4.7 U/L; after FDG injection, the mean glycemic level was 73 mg/dL and the mean insulin level was 69.4 U/L.) A standard protocol for the hyperinsulinemic-euglycemic clamp was used.14 After an overnight fast, a 20-gauge polyethylene cannula was inserted into a superficial forearm vein for insulin and 20% glucose solution infusion. A second cannula was placed in the other arm after being “arterialized” by heating with an external lamp to a temperature of 45°C to 50°C. Before the insulin clamp was started, the doses of glucose (via a dry chemistry enzymatic method) and insulin (via an immunofluorometric assay [AIA 21 system; Eurogenetics-Tosoh, Saran, France]) (normal range, 4-20 mU/L) were obtained. Approximately 60 minutes before the F-18 FDG injection, a constant insulin infusion at a dose of 40 mU · min⫺1 · m⫺2 of body surface area was performed. “Arterial” blood glucose levels were monitored at 5-minute intervals from the contralateral arm. Glucose infusion was started after 4 minutes of insulin infusion, and the rate was adjusted to maintain baseline glucose levels.9 Steady state was defined as 3 consecutive blood glucose values within ⫾ 5%. When this condition was obtained, F-18 FDG was injected, and the clamp was maintained for the duration of the PET acquisition.
Tracer Kinetic Analysis The reconstructed axial images of all frames were reoriented into short-axis views of the left ventricle. The reorientation parameters were defined on the last frame of the acquisi-
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tion resulting from the best tissue-to-blood pool ratio for easy recognition of myocardial edges. The region of interest was drawn for myocardium and right and left ventricles. The kinetic data have been processed with PMOD Biomedical Image Quantification and Kinetic Modeling Software (PMOD Technologies, Zurich, Switzerland). The compartmental model describes the exchange of the tracer between blood and tissue by a 1-tissue compartment model with the MBF ⫽ K1 and the efflux rate k2.15 The model incorporates 2 geometric spillover terms from blood in the left and right ventricles.
Cardiac MRI The cardiac MRI examinations were performed within three days after admission. Patients underwent cardiac MRI via a clinical 1.5-T Gyroscan ACS-NT MRI scanner (Philips Medical Systems, Eindhoven, The Netherlands). The scan was analyzed according to (1) LV function (balanced-echo sequences on cine MRI) and (2) the presence of scar tissue with delayed-enhancement images. Delayed sequences were obtained approximately 12 minutes after intravenous injection of 0.2-mmol/kg gadolinium diethylenetriamine pentaacetic acid by use of a fast field-echo sequence (slice thickness, 8 mm; field of view, 360 mm; flip angle, 15°; echo time, 1.3 milliseconds; repetition time, 4.1 milliseconds).16 Delayed-enhancement images were displayed in gray scale to optimally show normal myocardium (dark) and the region of delayed-enhancement myocardium (bright).
Figure 1. The transthoracic echocardiogram (long-axis projection) showed the enlargement of the apex and periapical segments in the acute phase. LVEF was 42%.
dexes of myocardial necrosis (mean troponin I level, 1.3 ⫾ 1.6 ng/mL). Acute Phase Images and Perfusion Quantitation
Statistical Analysis Statistical comparisons between variables were made by use of the Student t test, and analysis of variance was used for other continuous variables. All statistical analyses were performed with SPSS software, version 7.5 (SPSS, Chicago, Ill), and P ⬍ .05 was considered statistically significant.
RESULTS Three female patients (aged 65, 74, and 87 years) were studied. All patients were admitted with angina-like chest pain and an electrocardiographic pattern of transmural anterior acute myocardial infarction. In all subjects an extreme emotional stress occurred a few days before admission. In 2 women a history of hypertension and high plasma cholesterol level (low-density lipoprotein level ⬎130 mg/dL) were recorded. None of the patients were active smokers or were diabetic. The transthoracic echocardiogram showed ipo/akinesia in the apical and periapical segments with LVEF lower than 45% (mean, 40.7% ⫾ 5.1%) (Figure 1). Coronary angiography excluded any significant coronary stenosis (Figure 2). The echocardiographic data, according to the coronary angiography results, permitted the diagnosis of takotsubo cardiomyopathy, later confirmed by the enzymatic in-
In all patients a clear inverse mismatch between perfusion and severe reduction of metabolic activity in the apex and periapical segments was observed. In fact, images obtained during hyperinsulinemic-euglycemic clamp showed that FDG uptake was severely reduced in the apex and apical and midventricular segments in all patients. A clear enlargement of the apical region emerged (Figure 3). The perfusion analysis by use of ammonia showed a slight reduction in tracer uptake after adenosine in the apex and apical segments of the left ventricle that normalized at rest. This image pattern of FDG/ammonia uptake was defined as inverse-mismatch flow/metabolism. Mean MBF (without heart rate pressure product correction) in the apical segments was calculated as 0.66 ⫾ 0.07 mL · g⫺1 · min⫺1, 1.02 ⫾ 0.09 mL · g⫺1 · min⫺1, and 1.06 ⫾ 0.15 mL · g⫺1 · min⫺1 (in cases 1, 2, and 3, respectively) (Table 1). MBF was also impaired in the periapical segments (0.87 ⫾ 0.15 mL · g⫺1 · min⫺1, 1.31 ⫾ 0.19 mL · g⫺1 · min⫺1, and 1.24 ⫾ 0.15 mL · g⫺1 · min⫺1, respectively) and in the basal segments (0.77 ⫾ 0.12 mL · g⫺1 · min⫺1, 1.35 ⫾ 0.1 mL · g⫺1 · min⫺1, and 1.42 ⫾ 0.22 mL · g⫺1 · min⫺1, respectively). Baseline MBF was significantly different between the apical and basal segments (P ⫽ .08, P ⫽ .0001, and P ⫽ .008, respectively), but no differences were found between midventricular and basal segments
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Figure 2. Coronary angiogram of patient 1 in acute phase. No significant coronary stenosis was demonstrated. On angiography of the left ventricle, the typical akinesia of the apex and periapical regions emerged.
(P ⫽ .2, P ⫽ .1, and P ⫽ .4, respectively). In all patients CFR was impaired in the apical versus basal segments; in the midventricular segments only in cases 1 and 3 was CFR reduced in comparison to the basal segments (Table 1).
tion either in the acute phase or at 3 months’ follow-up (Figure 6). The LV function recovered completely in all patients at 3 months’ follow-up, and the mean LVEF obtained by echocardiography was calculated as 54%.
Follow-Up Images and Perfusion Quantitation After the normalization of LV kinesis, the enlargement of the apical region disappeared and the FDG uptake normalized (Figure 3). Visual analyses of perfusion imaging at rest and after adenosine stimulation were normal. MBF did not change substantially at rest at 3 months’ follow-up, whereas CFR improved in all cases (Figures 4 and 5). In all cases cardiac MRI demonstrated, in the acute phase, ipo/akinesia in the apex and periapical LV segments determining LV systolic dysfunction (mean LVEF, 35.3% ⫾ 4.2%). In no patient were areas of delayed enhancement observed after gadolinium injec-
DISCUSSION Takotsubo cardiomyopathy is a severe but reversible form of LV dysfunction that mimics acute myocardial infarction in the absence of any obstructive coronary artery disease. A possible explanation might be related to increased reactivity to sympathetic stimulation in apical segments of the left ventricle.17 By use of iodine 123 metaiodobenzylguanidine, regional cardiac denervation has recently been reported in the apex and in the inferior wall of the left ventricle during the acute phase of apical ballooning.18 Malafronte et al19 demonstrated a fixed apical perfusion defect on technetium 99m myocardial
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Figure 3. Scans of patients 1 (left), 2 (middle), and 3 (right) obtained in the acute phase showed an enlargement of the apical region of the left ventricle with a severe reduction in FDG uptake in the apex and in the apical and midventricular segments. The perfusion analysis by use of ammonia (NH3) showed a slight reduction in tracer uptake after adenosine in the apex and apical segments of the left ventricle that normalized at rest. This image pattern of FDG/ammonia uptake was defined as inverse-mismatch flow/metabolism. The follow-up images were obtained at 3 months, after the normalization of LV kinesis: the enlargement of the apical region disappeared, and the FDG uptake normalized. Perfusion images at rest and after adenosine stimulation were normal. The normalization of the FDG/ammonia pattern at the same time of the recovery of cardiac function confirmed the reversibility of the perfusion, metabolic, and functional abnormalities. The images were similar in the 3 patients.
Table 1. Quantification of baseline MBF and CFR in acute phase of takotsubo cardiomyopathy and at 3 months’ follow-up
MBF (mL · minⴚ1 · gⴚ1) Segment Acute phase Apical Mid Basal 3 Months’ follow-up Apical Mid Basal
CFR
Patient 1
Patient 2
Patient 3
Patient 1
Patient 2
Patient 3
0.66 ⫾ 0.07* 0.87 ⫾ 0.15 0.77 ⫾ 0.12
1.02 ⫾ 0.09† 1.31 ⫾ 0.19 1.35 ⫾ 0.10
1.06 ⫾ 0.15† 1.24 ⫾ 0.15 1.42 ⫾ 0.22
1.34 ⫾ 0.18† 1.60 ⫾ 0.17† 1.99 ⫾ 0.20
1.01 ⫾ 0.14* 1.10 ⫾ 0.12 1.21 ⫾ 0.15
0.92 ⫾ 0.13† 1.03 ⫾ 0.10* 1.16 ⫾ 0.07
0.74 ⫾ 0.07 0.87 ⫾ 0.14 0.84 ⫾ 0.10
1.10 ⫾ 0.10† 1.32 ⫾ 0.18 1.33 ⫾ 0.12
0.94 ⫾ 0.12† 1.23 ⫾ 0.16 1.34 ⫾ 0.15
2.71 ⫾ 0.31 2.84 ⫾ 0.33 2.71 ⫾ 0.31
2.45 ⫾ 0.24 2.54 ⫾ 0.20 2.56 ⫾ 0.17
2.20 ⫾ 0.31 2.22 ⫾ 0.25 2.22 ⫾ 0.14
P values compared the mean blood flow of the 6 basal segments with respect to the 6 midventricular segments and 5 apical segments. *P ⬍ .05. † P ⬍ .01.
scintigraphy in the acute phase, which normalized completely after 3 months. The pathophysiology of apical ballooning still remains unclear. Two recent reviews of this syndrome underlined 4 possible causes: epimyocardial vasospasm, microcirculation disturbance, catecholamine-triggered injury, and finally, obstruction of the LV outflow tract.20,21 The microcirculation disturbance was hypothesized by Sadamatsu et al,22 who showed, in the acute phase, only a slight increase in CFR after a bolus of nicorandil
in the left anterior descending coronary artery (LAD) in 2 women admitted for apical ballooning syndrome. The authors used an intracoronary Doppler guidewire to obtain a CFR of 2 to 2.1. More recently, a low CFR (1.3-1.8) in the LAD territory was demonstrated in the acute phase in 2 patients admitted for apical ballooning; in the same study contrast echocardiography performed after 1 month showed a homogeneous visual signal in the myocardium, suggesting the reversibility of the microvascular abnormalities.23 Nevertheless, Abe et al2 did not detect any significant abnormalities in the intracoronary
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Figure 4. Modifications in MBF in the 3 female patients in the acute phase and at follow-up according to the different areas of the left ventricle (P ⫽ not significant for all comparisons).
Figure 6. Cardiac MRI scans obtained in the acute phase 12 minutes after the injection of gadolinium. The absence of delayed enhancement in dysfunctioning LV segments excluded the presence of myocardial necrosis. Cardiac MRI scans after 3 months confirmed the normalization of LV function and the absence of delayed enhancement. L, Left; P, posterior.
Figure 5. Improvement in CFR in the 3 female patients from the acute phase to follow-up according to the different areas of the left ventricle (P ⫽ .0001 for all comparisons).
determination of CFR in the acute phase in 3 patients with apical ballooning syndrome. In our 3 female patients we confirmed the presence of an “inverse metabolic/perfusion mismatch” that represented a transient metabolic disorder at the cellular level, recently demonstrated by evidence of the impairment of tissue metabolism in the dysfunctioning left ventricle with preserved MBF at rest.12,13 This pattern seemed to be reversible after 3 months, according to the normalization of cardiac function. The severe reduction of glucose metabolism in dyskinetic myocardium without signs of necrosis (absence of Q wave on electrocardiogram and absence of area of delayed enhancement on cardiac MRI) suggests that apical ballooning represents a transient metabolic disorder at the cellular level, rather than a structural contractile disease. In the acute phase, quantitative analysis of PET showed a significant reduction in MBF at rest in the apical segments in comparison to the midventricular and basal LV segments (Table 1). Apical rest MBF remained impaired in 2 of 3 patients at
3 months’ follow-up. In the acute phase, after vasodilation with adenosine, CFR proved to be reduced in the apical segments, and in 2 of 3 of cases CFR was reduced in the midventricular segments in comparison to the basal LV segments (Table 1). These data normalized at 3 months’ follow-up, demonstrating the reversibility of the phenomenon. The reduction of CFR in 2 of 3 patients extending into the midventricular segments might be explained by the presence of a perfusion gradient of MBF from the basal segments to the apical ones. A perfusion gradient between the mid and mid-to-apical sections of LV myocardium during dipyridamole hyperemia was demonstrated in patients with coronary risk factors without clinical evidence of coronary artery disease.24 The longitudinal perfusion gradient (base-toapex direction) might justify the presence of the reversible impaired CFR observed in the acute phase not only in the areas of asynergy (apical) but also in the remote areas (midventricular). To our knowledge, this is the first demonstration of the reversibility of the impairment of CFR by use of a precise, validated quantitative method. These results, though obtained in a limited population, demonstrated the presence of a microcirculation disturbance limited to the apical LV segments, which might explain the transient decrease in glucose uptake and the contractile abnormalities as a mechanism of the disease. The reversibility of this CFR modification might
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correlate with the normalization of glucose uptake and LV function. According to the recent review of Camici and Crea25 on coronary microvascular dysfunction, the CFR impairment that emerged in our patients occurred in the absence of obstructive coronary artery and structural myocardial diseases. The excess of circulating catecholamines could well determine a transient microvascular dysfunction extended to apical LV segments. This reduction in CFR was not associated with structural abnormalities and, in fact, soon normalized, as observed in asymptomatic smokers26 or in asymptomatic subjects with hypercholesterolemia27 and normal angiographic coronary arteries. This hypothesis needs to be confirmed in larger future investigations. Study Limitations The major limitation of this study is the small population examined. The elaborate study protocol and the low incidence of the syndrome led to this limitation in our series, which aimed to study a mechanism of the disease but still needs further validation. Moreover, the previously published experiences included a similar number of subjects. Data regarding circulating catecholamines were not provided. Acknowledgment The authors have indicated they have no financial conflicts of interest.
References 1. Bybee KA, Kara T, Prasad A, Lerman A, Barsness GW, Wright RS, et al. Systematic review: Transient left ventricular apical ballooning: A syndrome that mimics ST-segment elevation myocardial infarction. Ann Intern Med 2004;141:858-65. 2. Abe Y, Kondo M, Matsuoka R, Araki M, Dohyama K, Tanio H. Assessment of clinical features in transient left ventricular apical ballooning. J Am Coll Cardiol 2003;41:737-42. 3. Dote K, Sato H, Tateishi H, Uchida T, Ishihara M. Myocardial stunning due to simultaneous multivessel coronary spasms: A review of 5 cases [in Japanese]. J Cardiol 1991;21:203-14. 4. Schelbert HR, Phelps ME, Hoffman EJ, Huang SC, Selin CE, Kuhl DE. Regional myocardial perfusion assessed with N-13 labeled ammonia and positron emission computerized axial tomography. Am J Cardiol 1979;43:209-18. 5. Schelbert HR, Phelps ME, Huang SC, MacDonald NS, Hansen H, Selin C, et al. N-13 ammonia as an indicator of myocardial blood flow. Circulation 1981;63:1259-72. 6. Bellina CR, Parodi O, Camici P, Salvadori PA, Taddei L, Fusani L, et al. Simultaneous in vitro and in vivo validation of nitrogen-13ammonia for the assessment of regional myocardial blood flow. J Nucl Med 1990;31:1335-43. 7. Hutchins GD, Schwaiger M, Rosenspire KC, Krivokapich J, Schelbert H, Kuhl DE. Noninvasive quantification of regional blood flow in the human heart using N-13 ammonia and dynamic positron emission tomographic imaging. J Am Coll Cardiol 1990;15:1032-42.
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8. Krivokapich J, Smith GT, Huang SC, Hoffman EJ, Ratib O, Phelps ME, et al. 13N ammonia myocardial imaging at rest and with exercise in normal volunteers: Quantification of absolute myocardial perfusion with dynamic positron emission tomography. Circulation 1989;80:1328-37. 9. Muzik O, Beanlands RS, Hutchins GD, Manger TJ, Nguyen N, Schwaiger M. Validation of nitrogen-13-ammonia tracer kinetic model for quantification of myocardial blood flow using PET. J Nucl Med 1993;34:83-91. 10. Rimoldi OE, Camici PG. Positron emission tomography for quantitation of myocardial perfusion. J Nucl Cardiol 2004;11: 482-90. 11. Camici PG. Positron emission tomography and myocardial imaging. Heart 2000;83:475-80. 12. Feola M, Rosso GL, Casasso F, Morena L, Biggi A, Chauvie S, et al. “Reversible inverse-mismatch” in transient left ventricular apical ballooning: Perfusion/metabolism positron emission tomography imaging. J Nucl Cardiol 2006;13:587-90. 13. Alexanderson E, Cruz P, Talayero JA, Damas F, Zeron J, Meave A. Transient perfusion and motion abnormalities in takotsubo cardiomyopathy. J Nucl Cardiol 2007;14:129-33. 14. DeFronzo RA, Tobin JD, Andres R. Glucose clamp technique: A method for quantifying insulin secretion and resistance. Am J Physiol 1979;273:E214-23. 15. DeGrado TR, Hanson MW, Turkington TG, Delong DM, Brezinski DA, Vallee JP, et al. Estimation of myocardial blood flow for longitudinal studies with N13-labeled ammonia and positron emission tomography. J Nucl Cardiol 1996;3:494-507. 16. Kim RJ, Wu E, Rafael A, Chen EL, Parker MA, Simonetti O, et al. The use of contrast-enhanced magnetic resonance imaging to identify reversible myocardial dysfunction. N Engl J Med 2000;343:1445-53. 17. Mori H, Ishikawa S, Kojima S, Hayashi J, Watanabe Y, Hoffman JI, et al. Increased responsiveness of left ventricular apical myocardium to adrenergic stimuli. Cardiovasc Res 1993;27:192-8. 18. Scholte AJH, Bax JJ, Stokkel MP, Plokker T, Kaandorp AM, Lamb HJ, et al. Multimodality imaging to diagnose takotsubo cardiomyopathy. J Nucl Cardiol 2006;13:123-6. 19. Malafronte C, Farina A, Tempesta A, Lobiati E, Galbiati R, Cantù E, et al. Tako-tsubo: A transitory impairment of microcirculation? A case report. Ital Heart J 2005;6:933-8. 20. Nef HM, Mollmann H, Elsasser A. Tako-tsubo cardiomyopathy (apical ballooning). Heart 2007;93:1309-15. 21. Gianni M, Dentali F, Grandi AM, Sumner G, Hiralal R, Lonn E. Apical ballooning syndrome or takotsubo cardiomyopathy: A systematic review. Eur Heart J 2007;27:1523-29. 22. Sadamatsu K, Tashiro H, Maehira N, Yamamoto K. Coronary microvascular abnormality in reversible systolic dysfunction observed after noncardiac disease. Jpn Circ 2000;64:789-92. 23. Ako J, Takenaka K, Uno K, Nakamura F, Shoji T, Iijmia K, et al. Reversible left ventricular systolic dysfunction-reversibility of coronary microvascular abnormality. Jpn Heart J 2001;42:355-63. 24. Hernandez-Pampaloni M, Keng FYJ, Kudo T, Sayre JS, Schelbert HR. Abnormal longitudinal, base-to-apex myocardial perfusion gradient by quantitative blood flow measurements in patients with coronary risk factors. Circulation 2001;104:527-32. 25. Camici PG, Crea F. Coronary microvascular dysfunction. N Engl J Med 2007;356:830-40. 26. Kaufmann PA, Gnecchi-Ruscone T, di Terlizzi M, Schafers KP, Lusher TF, Camici PG. Coronary artery disease in smokers: Vitamin C restores coronary microcirculatory function. Circulation 2000;102:1233-8. 27. Kaufmann PA, Gnechhi-Ruscone T, Schafers KP, Lusher TF, Camici PG. LDL and coronary microvascular dysfunction in hypercholesterolemia. J Am Coll Cardiol 2000;36:103-9.
exact cause of the syndrome and its physiopathology remain unknown. Dynamic positron emission tomography (PET) with nitrogen 13 ammonia and tracer kinetic modeling has been used intensively in the past for the noninvasive measurement of myocardial blood flow (MBF) and coronary flow reserve (CFR) in patients with cardiac disorders.4-10 The absolute quantitation of regional MBF is used for the evaluation of the severity of coronary obstructions and for decision making regarding the need for coronary revascularization. PET with fluorine 18 fluorodeoxyglucose (FDG) is used as an indicator of myocardial metabolism.11 In the acute phase this syndrome presents as a transient metabolic disorder at the cellular level, which was recently demonstrated by evidence of the impairment of tissue metabolism in the dysfunctioning left ventricle with preserved MBF at rest.12,13 The aim of this observational study was (1) to analyze changes in MBF and CFR in the acute phase of 811
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takotsubo cardiomyopathy and at follow-up and (2) to investigate whether the flow/metabolism mismatch pattern observed with PET imaging is reversible or permanent. METHODS Patients All patients underwent coronary angiography, transthoracic echocardiography, myocardial PET and cardiac magnetic resonance imaging (MRI) in the acute phase. Except for coronary angiography, all of the noninvasive studies were repeated at 90 days after hospital discharge to evaluate eventual changes from baseline. Takotsubo cardiomyopathy was defined as a syndrome characterized by transient LV dysfunction, electrocardiographic changes and acute onset of chest pain that can mimic acute myocardial infarction, and minimal release of myocardial enzymes in the absence of obstructive coronary artery disease. All of these conditions were necessary to confirm the diagnosis.
Coronary Angiography Selective coronary angiography was performed via the Judkins technique within 1 hour of hospital admission. An experienced angiographer assessed the degree of coronary stenosis. For the purpose of the study, a coronary stenosis greater than 50% on quantitative coronary analysis was considered significant.
Echocardiography Resting transthoracic echocardiograms were obtained in all patients immediately after coronary angiography. Examinations were performed with a wide-angle mechanical scanner (2.5-MHz Sonos 5500; Hewlett-Packard, Palo Alto, Calif). Two-dimensional apical 2- and 4-chamber views were used for ventricular volume measurements. Left ventricular ejection fraction (LVEF) was calculated via a modified Simpson’s method by use of biplane apical (2- and 4-chamber) views. Echocardiography was performed by experienced cardiologists blinded to the results of myocardial PET with an intraobserver variability in LVEF of less than 5%.
Positron Emission Tomography The PET examinations were performed within three days after admission. On 2 consecutive days, 3 PET investigations were performed on each patient including FDG for viability testing and ammonia in both baseline and hyperemic conditions for perfusion. All scans were carried out with the Discovery LS PET/computed tomography (CT) hybrid system (GE Healthcare, Waukesha, Wis). Every PET study was preceded by a CT scan for attenuation correction. To reduce artifacts due to heart movement and breathing, a slow CT helical scan was used that entailed 27.5 seconds to acquire the whole heart field of view. Furthermore, CT and PET images were visually checked for
Journal of Nuclear Cardiology November/December 2008
potential misregistration. All PET studies were performed in 2-dimensional mode for scatter reduction. Images were reconstructed with an ordered-subset expectation maximization 28subset 3-iteration algorithm with an in-plane image resolution of 4.8-mm full width at half maximum. The reconstruction matrix was 128 ⫻ 128 pixels with a 3.9-mm pixel size.
Determination of CFR On day 1, PET ammonia studies were carried out under rest and hyperemic conditions. PET dynamic acquisition (12 ⫻ 10 seconds, 4 ⫻ 30 seconds, and 1 ⫻ 360 seconds) was started immediately after injection of 550 to 590 MBq of ammonia. Pharmacologic stress testing was performed with an adenosine infusion at 140 g · kg⫺1 · min⫺1 over a period of 6 minutes, starting 3 minutes before and ending 3 minutes after ammonia administration.
FDG PET On day 2, after fasting for 12 hours, patients were injected with 378 to 402 MBq of FDG, and CT acquisition was started 1 hour later. The injection of tracers was preceded by a short hyperinsulinemic-euglycemic clamp that obtained a similar metabolic milieu. (For the first scan, at baseline, the mean glycemic level was 85 mg/dL and mean insulin level was 3.5 U/L; after FDG injection, the mean glycemic level was 68 mg/dL and the mean insulin level was 44 U/L. For the follow-up scan, at baseline, the mean glycemic level was 106 mg/dL and the mean insulin level was 4.7 U/L; after FDG injection, the mean glycemic level was 73 mg/dL and the mean insulin level was 69.4 U/L.) A standard protocol for the hyperinsulinemic-euglycemic clamp was used.14 After an overnight fast, a 20-gauge polyethylene cannula was inserted into a superficial forearm vein for insulin and 20% glucose solution infusion. A second cannula was placed in the other arm after being “arterialized” by heating with an external lamp to a temperature of 45°C to 50°C. Before the insulin clamp was started, the doses of glucose (via a dry chemistry enzymatic method) and insulin (via an immunofluorometric assay [AIA 21 system; Eurogenetics-Tosoh, Saran, France]) (normal range, 4-20 mU/L) were obtained. Approximately 60 minutes before the F-18 FDG injection, a constant insulin infusion at a dose of 40 mU · min⫺1 · m⫺2 of body surface area was performed. “Arterial” blood glucose levels were monitored at 5-minute intervals from the contralateral arm. Glucose infusion was started after 4 minutes of insulin infusion, and the rate was adjusted to maintain baseline glucose levels.9 Steady state was defined as 3 consecutive blood glucose values within ⫾ 5%. When this condition was obtained, F-18 FDG was injected, and the clamp was maintained for the duration of the PET acquisition.
Tracer Kinetic Analysis The reconstructed axial images of all frames were reoriented into short-axis views of the left ventricle. The reorientation parameters were defined on the last frame of the acquisi-
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tion resulting from the best tissue-to-blood pool ratio for easy recognition of myocardial edges. The region of interest was drawn for myocardium and right and left ventricles. The kinetic data have been processed with PMOD Biomedical Image Quantification and Kinetic Modeling Software (PMOD Technologies, Zurich, Switzerland). The compartmental model describes the exchange of the tracer between blood and tissue by a 1-tissue compartment model with the MBF ⫽ K1 and the efflux rate k2.15 The model incorporates 2 geometric spillover terms from blood in the left and right ventricles.
Cardiac MRI The cardiac MRI examinations were performed within three days after admission. Patients underwent cardiac MRI via a clinical 1.5-T Gyroscan ACS-NT MRI scanner (Philips Medical Systems, Eindhoven, The Netherlands). The scan was analyzed according to (1) LV function (balanced-echo sequences on cine MRI) and (2) the presence of scar tissue with delayed-enhancement images. Delayed sequences were obtained approximately 12 minutes after intravenous injection of 0.2-mmol/kg gadolinium diethylenetriamine pentaacetic acid by use of a fast field-echo sequence (slice thickness, 8 mm; field of view, 360 mm; flip angle, 15°; echo time, 1.3 milliseconds; repetition time, 4.1 milliseconds).16 Delayed-enhancement images were displayed in gray scale to optimally show normal myocardium (dark) and the region of delayed-enhancement myocardium (bright).
Figure 1. The transthoracic echocardiogram (long-axis projection) showed the enlargement of the apex and periapical segments in the acute phase. LVEF was 42%.
dexes of myocardial necrosis (mean troponin I level, 1.3 ⫾ 1.6 ng/mL). Acute Phase Images and Perfusion Quantitation
Statistical Analysis Statistical comparisons between variables were made by use of the Student t test, and analysis of variance was used for other continuous variables. All statistical analyses were performed with SPSS software, version 7.5 (SPSS, Chicago, Ill), and P ⬍ .05 was considered statistically significant.
RESULTS Three female patients (aged 65, 74, and 87 years) were studied. All patients were admitted with angina-like chest pain and an electrocardiographic pattern of transmural anterior acute myocardial infarction. In all subjects an extreme emotional stress occurred a few days before admission. In 2 women a history of hypertension and high plasma cholesterol level (low-density lipoprotein level ⬎130 mg/dL) were recorded. None of the patients were active smokers or were diabetic. The transthoracic echocardiogram showed ipo/akinesia in the apical and periapical segments with LVEF lower than 45% (mean, 40.7% ⫾ 5.1%) (Figure 1). Coronary angiography excluded any significant coronary stenosis (Figure 2). The echocardiographic data, according to the coronary angiography results, permitted the diagnosis of takotsubo cardiomyopathy, later confirmed by the enzymatic in-
In all patients a clear inverse mismatch between perfusion and severe reduction of metabolic activity in the apex and periapical segments was observed. In fact, images obtained during hyperinsulinemic-euglycemic clamp showed that FDG uptake was severely reduced in the apex and apical and midventricular segments in all patients. A clear enlargement of the apical region emerged (Figure 3). The perfusion analysis by use of ammonia showed a slight reduction in tracer uptake after adenosine in the apex and apical segments of the left ventricle that normalized at rest. This image pattern of FDG/ammonia uptake was defined as inverse-mismatch flow/metabolism. Mean MBF (without heart rate pressure product correction) in the apical segments was calculated as 0.66 ⫾ 0.07 mL · g⫺1 · min⫺1, 1.02 ⫾ 0.09 mL · g⫺1 · min⫺1, and 1.06 ⫾ 0.15 mL · g⫺1 · min⫺1 (in cases 1, 2, and 3, respectively) (Table 1). MBF was also impaired in the periapical segments (0.87 ⫾ 0.15 mL · g⫺1 · min⫺1, 1.31 ⫾ 0.19 mL · g⫺1 · min⫺1, and 1.24 ⫾ 0.15 mL · g⫺1 · min⫺1, respectively) and in the basal segments (0.77 ⫾ 0.12 mL · g⫺1 · min⫺1, 1.35 ⫾ 0.1 mL · g⫺1 · min⫺1, and 1.42 ⫾ 0.22 mL · g⫺1 · min⫺1, respectively). Baseline MBF was significantly different between the apical and basal segments (P ⫽ .08, P ⫽ .0001, and P ⫽ .008, respectively), but no differences were found between midventricular and basal segments
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Figure 2. Coronary angiogram of patient 1 in acute phase. No significant coronary stenosis was demonstrated. On angiography of the left ventricle, the typical akinesia of the apex and periapical regions emerged.
(P ⫽ .2, P ⫽ .1, and P ⫽ .4, respectively). In all patients CFR was impaired in the apical versus basal segments; in the midventricular segments only in cases 1 and 3 was CFR reduced in comparison to the basal segments (Table 1).
tion either in the acute phase or at 3 months’ follow-up (Figure 6). The LV function recovered completely in all patients at 3 months’ follow-up, and the mean LVEF obtained by echocardiography was calculated as 54%.
Follow-Up Images and Perfusion Quantitation After the normalization of LV kinesis, the enlargement of the apical region disappeared and the FDG uptake normalized (Figure 3). Visual analyses of perfusion imaging at rest and after adenosine stimulation were normal. MBF did not change substantially at rest at 3 months’ follow-up, whereas CFR improved in all cases (Figures 4 and 5). In all cases cardiac MRI demonstrated, in the acute phase, ipo/akinesia in the apex and periapical LV segments determining LV systolic dysfunction (mean LVEF, 35.3% ⫾ 4.2%). In no patient were areas of delayed enhancement observed after gadolinium injec-
DISCUSSION Takotsubo cardiomyopathy is a severe but reversible form of LV dysfunction that mimics acute myocardial infarction in the absence of any obstructive coronary artery disease. A possible explanation might be related to increased reactivity to sympathetic stimulation in apical segments of the left ventricle.17 By use of iodine 123 metaiodobenzylguanidine, regional cardiac denervation has recently been reported in the apex and in the inferior wall of the left ventricle during the acute phase of apical ballooning.18 Malafronte et al19 demonstrated a fixed apical perfusion defect on technetium 99m myocardial
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Figure 3. Scans of patients 1 (left), 2 (middle), and 3 (right) obtained in the acute phase showed an enlargement of the apical region of the left ventricle with a severe reduction in FDG uptake in the apex and in the apical and midventricular segments. The perfusion analysis by use of ammonia (NH3) showed a slight reduction in tracer uptake after adenosine in the apex and apical segments of the left ventricle that normalized at rest. This image pattern of FDG/ammonia uptake was defined as inverse-mismatch flow/metabolism. The follow-up images were obtained at 3 months, after the normalization of LV kinesis: the enlargement of the apical region disappeared, and the FDG uptake normalized. Perfusion images at rest and after adenosine stimulation were normal. The normalization of the FDG/ammonia pattern at the same time of the recovery of cardiac function confirmed the reversibility of the perfusion, metabolic, and functional abnormalities. The images were similar in the 3 patients.
Table 1. Quantification of baseline MBF and CFR in acute phase of takotsubo cardiomyopathy and at 3 months’ follow-up
MBF (mL · minⴚ1 · gⴚ1) Segment Acute phase Apical Mid Basal 3 Months’ follow-up Apical Mid Basal
CFR
Patient 1
Patient 2
Patient 3
Patient 1
Patient 2
Patient 3
0.66 ⫾ 0.07* 0.87 ⫾ 0.15 0.77 ⫾ 0.12
1.02 ⫾ 0.09† 1.31 ⫾ 0.19 1.35 ⫾ 0.10
1.06 ⫾ 0.15† 1.24 ⫾ 0.15 1.42 ⫾ 0.22
1.34 ⫾ 0.18† 1.60 ⫾ 0.17† 1.99 ⫾ 0.20
1.01 ⫾ 0.14* 1.10 ⫾ 0.12 1.21 ⫾ 0.15
0.92 ⫾ 0.13† 1.03 ⫾ 0.10* 1.16 ⫾ 0.07
0.74 ⫾ 0.07 0.87 ⫾ 0.14 0.84 ⫾ 0.10
1.10 ⫾ 0.10† 1.32 ⫾ 0.18 1.33 ⫾ 0.12
0.94 ⫾ 0.12† 1.23 ⫾ 0.16 1.34 ⫾ 0.15
2.71 ⫾ 0.31 2.84 ⫾ 0.33 2.71 ⫾ 0.31
2.45 ⫾ 0.24 2.54 ⫾ 0.20 2.56 ⫾ 0.17
2.20 ⫾ 0.31 2.22 ⫾ 0.25 2.22 ⫾ 0.14
P values compared the mean blood flow of the 6 basal segments with respect to the 6 midventricular segments and 5 apical segments. *P ⬍ .05. † P ⬍ .01.
scintigraphy in the acute phase, which normalized completely after 3 months. The pathophysiology of apical ballooning still remains unclear. Two recent reviews of this syndrome underlined 4 possible causes: epimyocardial vasospasm, microcirculation disturbance, catecholamine-triggered injury, and finally, obstruction of the LV outflow tract.20,21 The microcirculation disturbance was hypothesized by Sadamatsu et al,22 who showed, in the acute phase, only a slight increase in CFR after a bolus of nicorandil
in the left anterior descending coronary artery (LAD) in 2 women admitted for apical ballooning syndrome. The authors used an intracoronary Doppler guidewire to obtain a CFR of 2 to 2.1. More recently, a low CFR (1.3-1.8) in the LAD territory was demonstrated in the acute phase in 2 patients admitted for apical ballooning; in the same study contrast echocardiography performed after 1 month showed a homogeneous visual signal in the myocardium, suggesting the reversibility of the microvascular abnormalities.23 Nevertheless, Abe et al2 did not detect any significant abnormalities in the intracoronary
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Figure 4. Modifications in MBF in the 3 female patients in the acute phase and at follow-up according to the different areas of the left ventricle (P ⫽ not significant for all comparisons).
Figure 6. Cardiac MRI scans obtained in the acute phase 12 minutes after the injection of gadolinium. The absence of delayed enhancement in dysfunctioning LV segments excluded the presence of myocardial necrosis. Cardiac MRI scans after 3 months confirmed the normalization of LV function and the absence of delayed enhancement. L, Left; P, posterior.
Figure 5. Improvement in CFR in the 3 female patients from the acute phase to follow-up according to the different areas of the left ventricle (P ⫽ .0001 for all comparisons).
determination of CFR in the acute phase in 3 patients with apical ballooning syndrome. In our 3 female patients we confirmed the presence of an “inverse metabolic/perfusion mismatch” that represented a transient metabolic disorder at the cellular level, recently demonstrated by evidence of the impairment of tissue metabolism in the dysfunctioning left ventricle with preserved MBF at rest.12,13 This pattern seemed to be reversible after 3 months, according to the normalization of cardiac function. The severe reduction of glucose metabolism in dyskinetic myocardium without signs of necrosis (absence of Q wave on electrocardiogram and absence of area of delayed enhancement on cardiac MRI) suggests that apical ballooning represents a transient metabolic disorder at the cellular level, rather than a structural contractile disease. In the acute phase, quantitative analysis of PET showed a significant reduction in MBF at rest in the apical segments in comparison to the midventricular and basal LV segments (Table 1). Apical rest MBF remained impaired in 2 of 3 patients at
3 months’ follow-up. In the acute phase, after vasodilation with adenosine, CFR proved to be reduced in the apical segments, and in 2 of 3 of cases CFR was reduced in the midventricular segments in comparison to the basal LV segments (Table 1). These data normalized at 3 months’ follow-up, demonstrating the reversibility of the phenomenon. The reduction of CFR in 2 of 3 patients extending into the midventricular segments might be explained by the presence of a perfusion gradient of MBF from the basal segments to the apical ones. A perfusion gradient between the mid and mid-to-apical sections of LV myocardium during dipyridamole hyperemia was demonstrated in patients with coronary risk factors without clinical evidence of coronary artery disease.24 The longitudinal perfusion gradient (base-toapex direction) might justify the presence of the reversible impaired CFR observed in the acute phase not only in the areas of asynergy (apical) but also in the remote areas (midventricular). To our knowledge, this is the first demonstration of the reversibility of the impairment of CFR by use of a precise, validated quantitative method. These results, though obtained in a limited population, demonstrated the presence of a microcirculation disturbance limited to the apical LV segments, which might explain the transient decrease in glucose uptake and the contractile abnormalities as a mechanism of the disease. The reversibility of this CFR modification might
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correlate with the normalization of glucose uptake and LV function. According to the recent review of Camici and Crea25 on coronary microvascular dysfunction, the CFR impairment that emerged in our patients occurred in the absence of obstructive coronary artery and structural myocardial diseases. The excess of circulating catecholamines could well determine a transient microvascular dysfunction extended to apical LV segments. This reduction in CFR was not associated with structural abnormalities and, in fact, soon normalized, as observed in asymptomatic smokers26 or in asymptomatic subjects with hypercholesterolemia27 and normal angiographic coronary arteries. This hypothesis needs to be confirmed in larger future investigations. Study Limitations The major limitation of this study is the small population examined. The elaborate study protocol and the low incidence of the syndrome led to this limitation in our series, which aimed to study a mechanism of the disease but still needs further validation. Moreover, the previously published experiences included a similar number of subjects. Data regarding circulating catecholamines were not provided. Acknowledgment The authors have indicated they have no financial conflicts of interest.
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