Is high-dose catecholamine administration in small animals an appropriate model for takotsubo syndrome?

LETTER TO THE EDITOR Circulation Journal Official Journal of the Japanese Circulation Society http://www. j-circ.or.jp Is High-Dose Catecholamine Administration in Small Animals an Appropriate Model for Takotsubo Syndrome? To the Editor: The recent review article by Wright and colleagues 1 of the takotsubo syndrome (TTS) provides an opportunity to discuss a complex and persistently perplexing clinical entity. It is laud- able that these investigators are working to devise an experi- mental animal model of TTS that could explain the mechanism and clinical manifestations of this mysterious disease. The project appears to be based on the assumption that TTS is a “normal” pathophysiological response to certain noxious pharmacologic agents and that this response is experimentally reproducible in any animal. We would argue that this has not yet been proven, for 2 main reasons. 1. The authors’ model of TTS (and similar experimental mod- els 1–4 ) do not share certain essential aspects of clinical human TTS. (a) Whereas there are multiple predisposing and/or precipi- tating factors in human TTS, a single, essential common initi- ating factor has never been substantiated, including high catecholamine levels. Although the catecholamine “surge” is frequently claimed to be fundamentally important, no clinical guideline has ever required clinicians to measure catecholamine levels routinely, nor are they empirically reported in most pub- lished clinical studies. Furthermore, no large-scale study has ever correlated the development of TTS with catecholamine blood levels in non-TTS patients who present with any critical clinical conditions (and, presumably, high catecholamine lev- els). Catecholamines could be a factor, but they are not the only one at play in TTS. (b) The reproducibility of TTS has never been tested in patients who receive drug regimens presumed to precipitate TTS, such as dobutamine testing, therapeutic administration of other catecholamine vasopressors, and chemotherapy. If an animal model of TTS caused by catecholamines is to be con- sidered valid, one should be able to demonstrate the typical disappearance of the same response inducibility after its first occurrence. The catecholamine theory as currently stated suf- fers from a fundamental contradiction: It assumes that catechol- amine overloading results in a TTS-like response, but it does not explain why TTS does not recur in patients whose stress or catecholamine levels usually remain high or increase after the initial presentation. (c) Severe hypertension is very rarely reported in patients during the initial phase of TTS. This is surprising, because pheochromocytoma and subdural hematoma (which are typi- cally accompanied by hypertension and occasionally by genu- ine forms of TTS, on phenotypic grounds) have been excluded from inclusion in the definition of TTS. The incidence of TTS is reported to be only approximately 5% in clinical pheochro- mocytoma patients. 5 (d) The mortality associated with experimental TTS induced with high-dose catecholamine administration in small animals (rats and mice) has been in the range of 15–40%. 1–3 This is not comparable to the mortality rate in human patients with TTS (1–3%). This difference suggests that the doses used experi- mentally are in the toxic range. (e) Experimental models may have some echocardiographic and/or electrocardiographic resemblance to TTS, but it is dif- ficult to assess those features (apical ballooning) in a small ani- mal heart, beating at more than 300 beats/min (see Figure 1 1 ). 2. The review article 1 concludes that clinical TTS must be a product of catecholamine overload, but TTS more closely resembles “stunned myocardium” (severe, localized reversible dysfunction). The authors quickly dismiss coronary spasm, the usual explanation for stunning, as an explanation for TTS; how- ever, there is recent human evidence (although only from pilot studies) to suggest that endothelial dysfunction with coronary spasm may indeed play an essential, causal role in TTS. Recent studies even show the experimental reproduction of TTS in recovering patients, as assessed by acetylcholine (ACh) test- ing of endothelial function. 6,7 Systematic use of ACh testing in the recovery phase of TTS has shown repeatedly that ACh induces intense spasm of the related territories, accompanied by reproduction of TTS in the myocardial segments originally affected. 6 This spasm (and left ventricular dysfunction) is promptly and consistently eliminated by intracoronary admin- istration of nitroglycerine. An appropriate experimental animal model of TTS must address these important features of TTS. Toxic doses of cate- cholamines are not likely to be helpful in creating such a model, as they seem to cause more sustained and profound myocar- dial changes than those associated with TTS. References 1. Wright PT, Tranter MH, Morley-Smith AC, Lyon AR. Pathophysiology of takotsubo syndrome: Temporal phases of cardiovascular responses to extreme stress. Circ J 2014; 78: 1550 – 1558. 2. Redfors B, Ali A, Shao Y, Lundgren J, Gan LM, Omerovic E. Differ- ent catecholamines induce different patterns of takotsubo-like cardiac dysfunction in an apparently afterload dependent manner. Int J Car- diol 2014; 174: 330 – 336. 3. Sachdeva J, Dai W, Kloner RA. Functional and histological assess- ment of an experimental model of Takotsubo’s cardiomyopathy. J Am Heart Assoc 2014; 3: e000921, doi:10.1161/JAHA.114.000921. 4. Willis BC, Salazar-Cantu A, Silva-Platas C, Fernandez-Sada E, Villegas CA, Rios-Argaiz E, et al. Impaired oxidative metabolism and calcium mishandling underlie cardiac dysfunction in a rat model of post acute isoproterenol-induced cardiomyopathy. Am J Physiol Heart Circ Physiol 2015; 308: H467 – H477. 5. Giavarini A, Chedid A, Bobrie G, Plouin PF, Hagege A, Amar L. Acute catecholamine cardiomyopathy in patients with phaeochromocytoma or functional paraganglioma. Heart 2013; 99: 1438 – 1444. 6. Angelini P. Transient left ventricular apical ballooning: A unifying pathophysiologic theory at the edge of Prinzmetal angina. Catheter Cardiovasc Interv 2008; 71: 342 – 352. 7. Angelini P, Monge J, Simpson L. Biventricular takotsubo cardiomy- opathy: Case report and general discussion. Tex Heart Inst J 2013; Circulation Journal Vol.79, April 2015 Paolo Angelini, MD Texas Heart Institute, Houston, TX, USA Jonathan M. Tobis, MD University of California, Los Angeles, CA, USA (Released online March 5, 2015)