CORRESPONDENCE: RESEARCH CORRESPONDENCE
Takotsubo Cardiomyopathy Induced by Treadmill Exercise TestingAn Insight Into the Pathophysiology of Transient Left Ventricular Apical (or Midventricular) Ballooning in the Absence of Obstructive Coronary Artery Disease
Todd Dorfman, MD*,
Raed Aqel, MD, FACC,
James Allred, MD,
Ryan Woodham, MD and
Ami E. Iskandrian, MD, FACC, FAHA
* Division of Cardiovascular Diseases, The University of Alabama–Birmingham, LHRB 306, 1530 3rd Avenue South, Birmingham, Alabama 35294-0007 (Email: Tdorfman{at}cardmail.dom.uab.edu).
To the Editor: Although the pathogenesis of Takotsubo cardiomyopathy (TC) remains unclear, physical or emotional stress is common in the majority of reported cases (1–3). The central role for sympathetic stimulation in TC is suggested by elevations in plasma catecholamines (1–3), neuronal imaging (2,4), and animal studies (1,3). Takotsubo cardiomyopathy in rats as a result of sympathetic stimulation was not reproducible following pretreatment with beta-adrenergic blockade (1,3).
We present a patient with TC following exercise treadmill testing, a situation known to have sympathetic overdrive. To our knowledge, this is the first report during exercise and the only one with perfusion imaging at the onset of the event. The perfusion data are helpful to the understanding of the pathophysiology of TC, and the presence of normal perfusion despite characteristic wall motion abnormalities makes a strong point to the primary role of metabolic changes rather than vascular abnormalities.
A 71-year-old Caucasian woman underwent exercise sestamibi imaging for evaluation of chest pain (CP). The physical examination and electrocardiogram were normal (Fig. 1). The patient achieved target heart rate, and Tc-99m sestamibi was injected at 5 min when the patient began experiencing substernal CP with ST-segment depression (Fig. 1). She was given 1 spray of nitroglycerin, and the ST-segment changes resolved completely. Gated single-photon emission computed tomography images obtained 1 h later were normal (Fig. 1C), but there was dyskinesia of the apex (Fig. 1); the left ventricular ejection fraction (LVEF) was 51%.
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Figure 1 Exercise-Gated SPECT Imaging Results
(A) The patient’s baseline electrocardiogram in leads V5 and V6 reveals normal sinus rhythm without ST-segment changes suggestive of ischemia. (B) Electrocardiogram during peak exercise and at the onset of substernal chest pressure shows 3 mm of ST-segment depression in V6. (C) The post-exercise single-photon emission computed tomography (SPECT) sestamibi perfusion images demonstrates normal perfusion pattern. Three-dimensional gated SPECT images at end-diastole (D) and end-systole (E), revealing apical dyskinesis (arrows).
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The patient’s CP subsided but did not disappear completely. Coronary angiography was performed 3 h later and revealed no obstructive coronary artery disease. The left ventriculogram was abnormal (Fig. 2), and the LVEF was 55%. She did well at follow-up 1 month later, and a 2-dimensional echocardiography revealed normal LVEF with no regional wall motion abnormality.
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Figure 2 Contrast Left Ventriculography in the Right Anterior Oblique Projection
The left ventriculogram at end-diastole (A) and end-systole (B), showing apical ballooning and basal hyperkinesis.
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The unique features in this patient are the temporal relationship between TC and exercise and the normal perfusion pattern at the onset of her event.
Perhaps TC results from stunning of the myocardium in the setting of excess catecholamines, but whether this stunning is due to ischemia and decreased perfusion on the basis of microvascular vasoconstriction or due to a primary metabolic abnormality is unknown (1–4). One report showed a flow-metabolism mismatch pattern; however, unlike that in coronary artery disease, the pattern seen in TC showed relatively preserved flow but reduced glucose uptake (1). The perfusion defects could be explained by a partial volume effect attributable to stunning. Furthermore, this study could be faulted by the fact that the imaging was obtained  3 days after the initial event, but our patient showed normal perfusion even when the tracer was injected at time zero.
A reduction in glucose uptake with normal perfusion has been shown in humans and animals to be a feature of repetitive stunning (1,4). Possible mechanisms include a decrease in the activity of key enzymes of the glycolytic pathway or reduced sensitivity to calcium in stunned myocardium with inhibition of translocation of glucose transporter-4 from the intracellular pool to the sarcolemma, thus reducing glucose uptake. Also, excess catecholamines could lead to insulin resistance, which may lead to impaired glucose uptake (1).
Other studies have shown a greater impairment in fatty acid metabolism than perfusion in the mid and apical LV regions in TC (4,5). The myocardium depends on a significant amount (70% to 80%) of energy from fatty acid oxidation during aerobic conditions, and there is a marked reduction in beta-oxidation of fatty acids in the post-ischemic myocardium (5).
It seems that large-vessel spasm is an unlikely explanation of TC in the vast majority of patients (1), and provocative coronary vasospasm was induced in only 1 of 7 patients (6). Abnormal Thrombolysis In Myocardial Infarction (TIMI) frame counts have been described in all 3 major coronary arteries in patients with TC, consistent with microvascular rather than macrovascular impairment (3,5). Decreased coronary flow velocity reserve and a reduction in deceleration time of diastolic velocity of all 3 coronary arteries were demonstrated in patients within 24 h of presentation. At 3-week follow-up, these measurements improved, providing further evidence that reversible microvascular dysfunction contributes to transient LV dysfunction (3).
Other perfusion studies have shown moderate to severe reductions in tracer uptake in affected LV segments in the presence of normal angiographic coronary arteries (1,4–6). Thus, while myocardial stunning is seen in TC, it remains poorly understood whether the catecholamine excess leads to microvascular spasm, direct myocyte toxicity secondary to cyclic adenosine monophosphate-mediated calcium overload, or a primary metabolic abnormality (1,2).
Perhaps the most enigmatic finding in patients with TC is the predilection for dysfunction in the mid and apical segments of the LV with basal sparing (1,2). This characteristic finding is likely due to basal-to-apical gradients in both perfusion and sympathetic distribution (1–3). Sympathetic nerves and the density of receptors are not uniformly distributed in the LV myocardium of dogs and cats (3).
Finally, the most puzzling part of this syndrome is the very high predilection in women and the rarity of recurrences, despite the fact that stresses in life are rarely isolated. The role of hormones and the possibility of misdiagnosis or inappropriate diagnosis must be considered in future research projects. Although metabolic changes or vascular abnormalities appear to be the central causes of TC, the precise pathophysiology remains uncertain.
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1. Bybee KA, Murphy J, Prasad A, et al. Acute impairment of regional myocardial glucose uptake in the apical ballooning (takotsubo) syndrome J Nucl Cardiol 2006;13:244-250.[CrossRef][Web of Science][Medline]2. Scholte A, Bax JJ, Stokkel MP, et al. Multimodality imaging to diagnose takotsubo cardiomyopathy J Nucl Cardiol 2006;13:123-126.[CrossRef][Web of Science][Medline] 3. Kume T, Akasaka T, Kawamoto T, et al. Assessment of coronary microcirculation in patients with takotsubo-like left ventricular dysfunction Circ J 2005;69:934-939.[CrossRef][Web of Science][Medline] 4. Ito K, Sugihara H, Kinoshita N, et al. Assessment of takotsubo cardiomyopathy (transient left ventricular apical ballooning) using 99mTc-tetrofosmin, 123I-BMIPP, 123I-MIBG and 99mTc-PYP myocardial SPECT Ann Nucl Med 2005;19:435-445.[Web of Science][Medline] 5. Kurisu S, Inoue I, Kawagoe T, et al. Myocardial perfusion and fatty acid metabolism in patients with takotsubo-like left ventricular dysfunction J Am Coll Cardiol 2003;41:743-748.[Abstract/Free Full Text] 6. Abe Y, Kondo M, Matsuoka R, et al. Assessment of clinical features in transient left ventricular apical ballooning J Am Coll Cardiol 2003;41:737-742.[Abstract/Free Full Text]
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