Takotsubo syndrome is a coronary microvascular disease: experimental evidence

Abstract

Background and aims Takotsubo syndrome (TTS) is a conundrum without consensus about the cause. In a murine model of coronary microvascular dysfunction (CMD), abnormalities in myocardial perfusion played a key role in the development of TTS. Methods and results Vascular Kv1.5 channels connect coronary blood flow to myocardial metabolism and their deletion mimics the phenotype of CMD. To determine if TTS is related to CMD, wild-type (WT), Kv1.5−/−, and TgKv1.5−/− (Kv1.5−/− with smooth muscle-specific expression Kv1.5 channels) mice were studied following transaortic constriction (TAC). Measurements of left ventricular (LV) fractional shortening (FS) in base and apex, and myocardial blood flow (MBF) were completed with standard and contrast echocardiography. Ribonucleic Acid deep sequencing was performed on LV apex and base from WT and Kv1.5−/− (control and TAC). Changes in gene expression were confirmed by real-time-polymerase chain reaction. MBF was increased with chromonar or by smooth muscle expression of Kv1.5 channels in the TgKv1.5−/−. TAC-induced systolic apical ballooning in Kv1.5−/−, shown as negative FS (P < 0.05 vs. base), which was not observed in WT, Kv1.5−/− with chromonar, or TgKv1.5−/−. Following TAC in Kv1.5−/−, MBF was lower in LV apex than in base. Increasing MBF with either chromonar or in TgKv1.5−/− normalized perfusion and function between LV apex and base (P = NS). Some genetic changes during TTS were reversed by chromonar, suggesting these were independent of TAC and more related to TTS. Conclusion Abnormalities in flow regulation between the LV apex and base cause TTS. When perfusion is normalized between the two regions, normal ventricular function is restored.

Case Report: Asymptomatic SARS-COV2 infection triggering recurrent Takotsubo syndrome

“…Indeed, the incidence of TTS during the COVID-19 pandemic increased likely due to the intense emotional stress caused by fear of getting seriously ill, fear for loved ones, changes to lifestyle habits including unemployment, economic crisis, and social distancing (8). On the other hand, in COVID-19 patients, irrespective of the severity of the clinical manifestation, several conditions which may favour TTS onset can occur: like catecholamine-induced myocyte injury and neurogenic myocardial stunning, cytokine storm, immune-mediated damage, direct viral myocyte injury, procoagulant state, microvascular coronary impairment due to endothelial injury, and vasospasm (9,10). The hypothesis is that SARS-COV-2 infection, even asymptomatic, may precipitate TTS onset in predisposed patients, where endothelial dysfunction plays a pivotal role as cause of microvascular impairment (11).…”

Takotsubo syndrome: unravelling the enigma of the broken heart syndrome?—a narrative review

“…Furthermore, Rivero et al assessing the index of microvascular resistance, showed the presence of acute microvascular damage with temporal evolution toward resolution that correlated with myocardial stunning recovery ( 25 ). Recently, in a mouse model of coronary microvascular dysfunction, a study demonstrated the significant role of disruptions in myocardial perfusion in the development of TTS ( 70 ). The impact of vascular Kv1.5 channels, which connect coronary blood flow to myocardial metabolism, in wild-type, Kv1.5 −/− , and TgKv1.5 −/− mice following transaortic constriction, was examined.…”

“…The results revealed that transaortic constriction caused systolic apical ballooning and lower LV apex myocardial blood flow in Kv1.5 −/− mice, while other groups did not exhibit these effects. However, increasing myocardial blood flow through the use of chromonar, or inducing smooth muscle expression of Kv1.5 channels in TgKv1.5 −/− mice, restored perfusion and normalized ventricular function between the apex and base ( 70 ). These interesting findings highlight the contribution of flow regulation abnormalities between the LV apex and base on the pathophysiology of TTS and also emphasize the potential of restoring normal perfusion to recover ventricular function.…”

Animal models of Takotsubo syndrome: bridging the gap to the human condition

“…The IP administration of isoprenaline, which reproduces the RWMA as reported in patients, was first introduced by the Omerovic Lab (Gothenburg, Sweden) in 2013 in mice ( 16 ) and later in rats ( 14 ). The TS-like RWMA has also been reproduced in non-human primates ( 9 ) and rabbits ( 74 ). However, the most commonly used animal for TS research is the naïve rat (no pre-treatment or genetic modification), accounting for 72% of studies.…”