A mouse model reveals an important role for catecholamine‐induced lipotoxicity in the pathogenesis of stress‐induced cardiomyopathy

Abstract

AimStress-induced cardiomyopathy (SIC), also known as takotsubo cardiomyopathy, is an acute cardiac syndrome with substantial morbidity and mortality. The unique hallmark of SIC is extensive ventricular dysfunction (akinesia) involving apical segments with preserved function in basal segments. Adrenergic overstimulation plays an important role in initiating SIC, but the pathomechanisms involved are unknown. We tested the hypothesis that excessive catecholamines cause perturbation of myocardial lipid metabolism and that cardiac lipotoxicity is responsible for the pathogenesis of SIC. Methods and resultsA single dose injection of isoprenaline (ISO; 400 mg/kg) induced SIC-like regional akinesia in mice. Oil red O staining revealed severe lipid accumulation in the heart 2 h post-ISO. Both intramyocardial lipid accumulation and cardiac function were normalized within 1 week post-ISO and no significant amount of fibrosis was detected. We found that gene expression of lipid importers and exporters (ApoB lipoprotein) was depressed 2 h post-ISO. These results were confirmed by similar findings in SIC patients and in ISO/patient serum-stressed HL-1 cardiomyocytes. Moreover, overexpression of ApoB in the heart was found to protect against the development of ISO-induced cardiac toxicity and cardiac dysfunction. We also found that ISO-induced intramyocardial lipid accumulation caused electrophysiological disturbance and stunning in ISO/patient serum-stressed HL-1 cardiomyocytes. ConclusionsThe present study demonstrates that lipotoxicity is closely associated with catecholamine-induced myocardial dysfunction, including neurogenic stunning, metabolic stunning, and electrophysiological stunning. Cardiac lipotoxicity may originate from direct inhibition of myocardial ApoB lipoprotein and subsequent decreased lipid export, caused by supraphysiological levels of catecholamines.--

Pathophysiology of Takotsubo Syndrome

“…8 This also seems to be the case after intraperitoneal isoproterenol treatment. 26 Clearly, there must be pharmacodynamic differences following intraperitoneal delivery, which prevents accurate temporal comparison between these models. Izumi et al report a profound depression of ejection fraction at this time-point that was only slightly ameliorated by metoprolol.…”

“…11 At this time-point, myocytolysis and the induction of HF-related genes are observed in these primates. Isoproterenol infusion begins to induce lipid peroxidation and accumulation at approximately 2 h. 26 The study by Redfors et al showed that all catecholamines administered were able to induce either inverted or classical TTS by the 90-min time-point. 25 …”

McConnell's sign — An insight into the pathogenesis of Takotsubo syndrome?

“…The pathogenesis underlying Takotsubo syndrome is incompletely understood. Several mechanisms have been proposed for the development of TTS, including overstimulation of the β2-adrenoceptor-Gi pathway [3], acute coronary microvascular and endothelial dysfunction [4], aborted myocardial infarction with spontaneous recanalisation [5], acute metabolic stunning [6], lipotoxicity [1,7], acute left ventricular outflow tract obstruction (LVOTO) and abnormal ventriculo-arterial coupling [8].…”

Are Resident c-Kit + Cardiac Stem Cells Really All That Are Needed to Mend a Broken Heart?

“…This model shows restoration of ejection fraction and fractional shortening 6 days after ISO injection, which is likely too soon for meaningful maturation of newly minted myocytes to restore normal cardiac function. Indeed, the other reference for this injury model in the mouse is a study in which Shao et al 10 normal cardiac function 1 week after the injection. However, Shao et al 10 suggested that the temporary loss of cardiac performance in this model was because of a stunning effect of the drug rather than myocyte death.…”

“…Indeed, the other reference for this injury model in the mouse is a study in which Shao et al 10 normal cardiac function 1 week after the injection. However, Shao et al 10 suggested that the temporary loss of cardiac performance in this model was because of a stunning effect of the drug rather than myocyte death. This issue notwithstanding, the correlation between ISO-induced myocyte death and BrdU-labeled myocytes shown by Nadal-Ginard and Torella and colleagues supports the idea that these hearts have an ability to repair themselves via new myocyte formation.…”