LAUSR

We would like to thank Dr Tarantino et al for their interest in our case of “The Three Faces of Takotsubo Cardiomyopathy in a Single Patient”. It was indeed a fascinating presentation of multiple ballooning variants due to varying stressful stimuli. While Dr Tarantino et al propose an intriguing mechanism involving beta-adrenergic receptor (βAR) mismatch to explain the rapid progression of the first two episodes, their hypothesis is largely speculative. We concur with the notion that regional βAR desensitization, G-protein-coupled subtype downregulation, and changes in sympathetic nerve density (components of sympathetic innervation remodeling) contribute to the regional wall motion abnormalities that occur via the canonical pathway of Takotsubo cardiomyopathy. While activation of myocardial βARs is thought to be the primary driver of Takotsubo pathophysiology through the outpouring in catecholamine levels, these catecholamines also interact with many different adrenergic receptors throughout the body. For example, physical and/or mental stress can induce an increase in autonomic tone leading to the release of catecholamines from local sympathetic nerve fibers in the bone marrow that regulate the microenvironment of hematopoietic stem cells.1,2 This surge in inflammatory mediators including macrophages and neutrophils could play a role in Takotsubo pathogenesis although this remains under investigation. A recent study by Scally et al3 demonstrated that myocardial macrophage inflammatory infiltration, changes in monocytes subsets, and increases in systemic pro-inflammatory cytokines are involved in the development of Takotsubo cardiomyopathy. This is supported by another observation by Wilson et al4 who demonstrated an influx of neutrophils followed by pro-inflammatory M1 macrophages and increased inflammatory cytokines. In their state-of-the-art review, de Chazal et al5 discuss the critical role of neuropeptide Y, acting in concert with norepinephrine, in the pathogenesis of microvascular dysfunction and ischemic stunning in Takotsubo cardiomyopathy. Finally, the lack of any strong clinical evidence that beta-blocker therapy reduces recurrences of Takotsubo cardiomyopathy further supports the notion that βAR subtype downregulation is one part of a multifactorial pathogenetic explanation.6 It is very likely that multi-faceted variant presentations of Takotsubo cardiomyopathy are under-recognized, particularly since the midventricular and basal variants may be subtle echocardiographically. Despite the known potential for recurrence, guidelines for timing of follow-up (and the exact role of) echocardiography remains unclear.7 Dobutamine stress echocardiography and/or strain echocardiography may help identify alternative variants in individual patients.8 Numerous case reports and case series have linked the use of dobutamine to the development of regional variants of Takotsubo cardiomyopathy,9,10 and we agree this may have utility in their identification. The patient's past medical history only included a history of melanoma, which was completely excised years prior to admissions, with no known recurrence. Unfortunately, the patient's hemodynamics did not allow for the utility of beta or calcium channel blockers following the coiling of her cerebral artery aneurysms.