Unraveling Pathophysiology of Takotsubo Syndrome: The Emerging Role of the Oxidative Stress's Systemic Status

Abstract

Takotsubo Syndrome (TTS) is usually triggered by emotional or physical stressors, thus suggesting that an increased sympathetic activity, leading to myocardial perfusion abnormalities and ventricular dysfunction, plays a major pathogenetic role. However, it remains to be elucidated why severe emotional and physical stress might trigger TTS in certain individuals but not others. Clinical research has been focused mainly on mechanisms underlying the activation of the sympathetic nervous system and the occurrence of myocardial ischemia in TTS. However, scientific evidence shows that additional factors might play a pathophysiologic role in the condition's occurrence. In this regard, a significant contribution arrived from metabolomics studies that followed the systemic response to TTS. Specifically, preliminary data clearly show that there is an interplay between inflammation, genetics, and oxidative status which might explain susceptibility to the condition. This review aims to sum up the established pathogenetic factors underlying TTS and to appraise emerging mechanisms, with particular emphasis on oxidative status, which might better explain susceptibility to the condition.

Keywords: Takotsubo syndrome; genetics; inflammation; myocardial ischemia; oxidative stress; personalized treatment.

Figure 1

Key pathogenetic aspects in Takotsubo syndrome. The interplay between triggers, pathogenetic factors, mechanisms of cardiac injury, and clinical consequences. ANS indicates autonomic nervous system; CNS, central nervous system; LV, left ventricular; and MVo2, myocardial oxygen consumption. (Reprinted with permission from Aimo A et al. Int J Cardiol. 2021, 333, 45–50).

Figure 2

The pyramid of life and the omics sciences.

Figure 3

The four layers that make up metabolomics research: from studying metabolites to trying to understand pathological states.

Figure 4

Differences in metabolite levels and ratios between CTRL and TTS. Boxes denote IQR, lines denote the median, whiskers denote the 5th and 95th percentile, and x denotes the average. * p < 0.05, ** p < 0.01. Abbreviation used: AcAc: acetoacetate; 3HB: 3-hydroxybutyrate; ALCAR: acetyl-L-carnitine; 2HB: 2-hydroxybutyrate; CAR: L-carnitine; Ala: alanine; Arg: arginine; His: histidine; Met: methionine; Glu: glutamate; Phe: phenylalanine; Tyr: tyrosine. (Reprinted with permission from Vanni D et al. Antioxidants (Basel). 2021, 10, 1982).

Figure 5

Linear correlation between acetoacetate/3-hydroxybutyrate ratio (AcAc/3HB) (A) and total amino acid concentration (B) with LVEF%. Green dots: controls; blue dots: TTS. (Reprinted with permission from Vanni D et al. Antioxidants (Basel). 2021, 10, 1982).

Figure 6

Summary of alteration observed in TTS patients related to oxidative stress. Abbreviation used: AcAc: acetoacetate; 3HB: 3-hydroxybutyrate; ALCAR: acetyl-L-carnitine; 2HB: hydroxybutyrate; ALCAR: acetyl-L-carnitine; CAR: L-carnitine; Ala: alanine; Arg: arginine; His: histidine; Met: methionine; Glu: glutamate; Phe: phenylalanine; Tyr: tyrosine. 2KB: _£HB: 3-ketobutyrate; 2-KG: 2-ketoglutarate; ALT: alanine aminotransferase; Pyr: Pyruvate. (Reprinted with permission from Vanni D et al. Antioxidants (Basel). 2021, 10, 1982).