Reply to Madias

Letter to the EditorReply to MadiasTomohiro Hayashi, Sajal K. Tiwary, Kenji Rowel Q. Lim, Cibele Rocha-Resende, and Douglas L. MannTomohiro HayashiCenter for Cardiovascular Research, Cardiovascular Division, Department of Medicine, Washington University School of Medicine, Saint Louis, Missouri, United States, Sajal K. TiwaryCenter for Cardiovascular Research, Cardiovascular Division, Department of Medicine, Washington University School of Medicine, Saint Louis, Missouri, United States, Kenji Rowel Q. LimCenter for Cardiovascular Research, Cardiovascular Division, Department of Medicine, Washington University School of Medicine, Saint Louis, Missouri, United States, Cibele Rocha-ResendeDepartment of Physiology and Biophysics, Federal University of Minas Gerais, Belo Horizonte, Brazil, and Douglas L. MannCenter for Cardiovascular Research, Cardiovascular Division, Department of Medicine, Washington University School of Medicine, Saint Louis, Missouri, United StatesPublished Online:04 Apr 2023https://doi.org/10.1152/ajpheart.00147.2023MoreSectionsPDF (224 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat reply: We thank Dr. Madias for his thoughtful comments regarding our article entitled “Refining the reproducibility of a murine model of stress-induced reversible cardiomyopathy” (1). Dr. Madias raised some proposals and questions in his letter (2) to which we would like to respond. In commenting on our observation that there were important sexually dimorphic differences in the isoproterenol (Iso)-induced phenotype, he questioned whether the model could be refined either by the inclusion of older mice or ovariectomized mice with or without estrogen replacement. Both questions are certainly important but were not the major focus of the study, which was to provide the scientific community with a methodology to improve the reliability and reproducibility of the Iso-induced, stress-induced, reversible cardiomyopathy model. Both of Dr. Madias’s excellent questions were discussed as limitations of the study. In addition to the well-known cardioprotective effects of estrogen, we would like to point out that it is also possible there were estrogen-independent effects secondary to blunting of β-adrenergic receptor responses in female mouse hearts as compared with male mouse hearts, which has been previously reported (3, 4). Dr. Madias remarked that it would be of interest to determine whether the elevated troponin-I levels correlated with the extent of left ventricular (LV) function as assessed by the two-dimensional (2-D) echocardiography at baseline, 1 h, 6 h, and 7 days after the Iso injection. Although we have not done this exact experiment because the Animal Care And Use Committee would never allow multiple mandibular bleeds in the same mouse to draw serial troponin levels and correlate these levels with serial changes in LV structure and function, based on our prior published experience with this model (5), we are able to detect elevated circulating levels of troponin I as early as 1 h of Iso injection, which corresponds to the onset of LV dilation and decreased LV ejection fraction. However, the normalization of LV structure and function occurs well before troponin-I levels return to baseline. Dr. Madias also questioned whether prior use of β-blockers with both cardioselective and noncardioselective, and/or α1-blockers before the Iso injection might provide more insights about the pathophysiology of the recurrence of the Takotsubo syndrome. This again is an excellent question; however, unlike the spontaneous recurrence of the Takotsubo syndrome that has been observed in some patients, there is no recurrence in the Iso model unless one injects Iso a second time. Thus, we do not believe that pretreating mice with cardiac selective or nonselective β-adrenergic receptors and/or α1-adrenergic receptor blockers would provide useful insights into the pathophysiological mechanisms that underlie the spontaneous recurrence of the Takotsubo syndrome. Finally, Dr. Madias also asked whether inclusion of electrocardiographic (ECG) recordings would be helpful in terms of correlating the changes in ST segments with the increased myocardial edema and changes in 2-D echocardiography. Although this is an interesting question, we avoided performing ECGs in this model insofar as it would have required anesthesia and restraint of the mouse, which would have introduced additional experimental variables that may have decreased the reproducibility of the model, which in our hands can be performed reliably and reproducibly in under 30 s. In closing, we again thank Dr. Madias for his thoughtful comments about our article, which we hope will be of use to the cardiovascular community.DISCLOSURESNo conflicts of interest, financial or otherwise, are declared by the authors.AUTHOR CONTRIBUTIONSD.L.M. drafted manuscript; T.H., S.K.T., K.R.Q.L., and C.R.-R. edited and revised manuscript and approved of the final version of the manuscript.REFERENCES1. Hayashi T, Tiwary SK, Lim KRQ, Rocha-Resende C, Kovacs A, Weinheimer C, Mann DL. Refining the reproducibility of a murine model of stress-induced reversible cardiomyopathy. Am J Physiol Heart Circ Physiol 324: H229–H240, 2023. doi:10.1152/ajpheart.00684.2022. Link | Google Scholar2. Madias JE. Further refining of the murine model of intraperitoneal injection of isoproterenol-induced Takotsubo syndrome. Am J Physiol Heart Circ Physiol 324: TBA, 2023. doi:10.1152/ajpheart.00100.2023.Link | Google Scholar3. Zhu B, Liu K, Yang C, Qiao Y, Li Z. Gender-related differences in β-adrenergic receptor-mediated cardiac remodeling. Can J Physiol Pharmacol 94: 1349–1355, 2016. doi:10.1139/cjpp-2016-0103. Crossref | PubMed | ISI | Google Scholar4. Vizgirda VM, Wahler GM, Sondgeroth KL, Ziolo MT, Schwertz DW. Mechanisms of sex differences in rat cardiac myocyte response to beta-adrenergic stimulation. Am J Physiol Heart Circ Physiol 282: H256–H263, 2002. doi:10.1152/ajpheart.2002.282.1.H256. Link | ISI | Google Scholar5. Hayashi T, Tiwary SK, Lavine KJ, Acharya S, Brent M, Adamo L, Kovacs A, Mann DL. The programmed death 1 signaling axis modulates inflammation and LV structure and function in a stress-induced cardiomyopathy model. JACC Basic Transl Sci 7: 1120–1139, 2022. doi:10.1016/j.jacbts.2022.05.006. Crossref | PubMed | Google ScholarAUTHOR NOTESCorrespondence: D. L. Mann ([email protected]edu). Download PDF Previous Back to Top FiguresReferencesRelatedInformation Related ArticlesFurther refining of the murine model of intraperitoneal injection of isoproterenol-induced takotsubo syndrome 04 Apr 2023American Journal of Physiology-Heart and Circulatory Physiology More from this issue > Volume 324Issue 5May 2023Pages H655-H656 Crossmark Copyright & PermissionsCopyright © 2023 the American Physiological Society.https://doi.org/10.1152/ajpheart.00147.2023PubMed37014082History Received 14 March 2023 Accepted 14 March 2023 Published online 4 April 2023 Published in print 1 May 2023 KeywordsinflammationisoproterenolTakotsubo Metrics