Key result
Global macrophage depletion or blockade of macrophage infiltration resulted in recovery of cardiac dysfunction in isoproterenol-challenged mice, identifying macrophages as a critical regulator of Takotsubo syndrome pathogenesis.
Why the study?
The molecular basis for Takotsubo syndrome remains unknown, specific therapies are lacking, and the functional importance of myocardial monocyte and macrophage infiltration is poorly understood.
Does macrophage depletion or inhibition improve cardiac dysfunction in an isoproterenol-induced mouse model of Takotsubo-like cardiomyopathy?
Does macrophage depletion or inhibition improve cardiac dysfunction in an isoproterenol-induced mouse model of Takotsubo-like cardiomyopathy?
Answers are grounded in this paper and cite their sources.
Macrophages play a critical role in the pathogenesis of isoproterenol-induced Takotsubo-like cardiomyopathy in mice, suggesting they could be a potential therapeutic target.
Takotsubo syndrome (TTS) is an acute, stress-induced cardiomyopathy that occurs predominantly in women after extreme physical and/or emotional stress. To date, our understanding of the molecular basis for TTS remains unknown and, consequently, specific therapies are lacking. Myocardial infiltration of monocytes and macrophages in TTS has been documented in clinical studies. However, the functional importance of these findings remains poorly understood. Here, we show that a single high dose of isoproterenol (ISO) in mice induced a TTS-like cardiomyopathy phenotype characterized by female predominance, severe cardiac dysfunction, and robust myocardial infiltration of macrophages. Single-cell RNA-Seq studies of myocardial immune cells revealed that TTS-like cardiomyopathy is associated with complex activation of innate and adaptive immune cells in the heart, and macrophages were identified as the dominant immune cells. Global macrophage depletion (via clodronate liposome administration) or blockade of macrophage infiltration (via a CCR2 antagonist or in CCR2-KO mice) resulted in recovery of cardiac dysfunction in ISO-challenged mice. In addition, damping myeloid cell activation by HIF1α deficiency or exposure to the immunomodulatory agent bortezomib ameliorated ISO-induced cardiac dysfunction. Collectively, our findings identify macrophages as a critical regulator of TTS pathogenesis that can be targeted for therapeutic gain.
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Liao et al. (2022) studied Takotsubo-like cardiomyopathy. Macrophage depletion or inhibition (clodronate, CCR2 antagonist, bortezomib) vs. Vehicle (PBS) was evaluated on Left ventricular ejection fraction (LVEF) and macrophage infiltration. Global macrophage depletion or blockade of macrophage infiltration resulted in recovery of cardiac dysfunction in isoproterenol-challenged mice, identifying macrophages as a critical regulator of Takotsubo syndrome pathogenesis.
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