Abstract Introduction Prognosis after ischemic stroke is often worsened by the occurrence of cardiovascular complications collectively termed stroke-heart syndrome (SHS). In addition to inflammatory and neurohormonal disturbances, protein misfolding has emerged as a potential contributor to brain-heart crosstalk due to the presence and physicochemical properties of toxic misfolded proteins (oligomers) provoked by ischemia. However, its biological relevance in SHS remains unclear. Aims This study investigated the systemic cardiac consequences of acute ischemic stroke (AIS) and the involvement of protein misfolding in SHS by assessing oligomer presence, myocardial proteostasis responses after stroke and their direct cellular effects in vitro. Methods AIS was induced via 45-minute transient middle cerebral artery occlusion (tMCAO) in 3 to 4-month-old wild-type male and female C57BL/6J mice, followed by 48 hours of reperfusion. Cardiac function was evaluated by electro- and echocardiography. Oligomer accumulation was assessed in both brain and heart along with cardiac proteostasis responses. To dissect direct effects of oligomers in SHS, rat cardiomyoblasts (H9c2) were exposed for 48 hours to amyloid-β42 (Aβ42)-derived oligomers, a bona fide misfolded protein specie implicated in neurodegeneration, and compared with inflammatory (TNF-α, IFN-γ) and neurohormonal (epinephrine, haloperidol) stimuli. Results AIS induced cardiac dysfunction characterized by bradyarrhythmia, impaired cardiac output and a tendency toward decreased fractional shortening. Systemic alterations were observed including dysregulated inflammatory cytokines, whose pattern was associated with Aβ regulation, along with autonomic imbalance reflected by reduced urinary homovanillic acid, a dopamine catabolite. Oligomers accumulated in both ipsilateral brain hemisphere and myocardium after stroke. Cardiac proteotoxic resistance was impaired evidenced by reduced activating transcription factor-6 (ATF6)-dependent unfolded protein response and the chaperone heat-shock protein 90 (HSP90) expression. Concurrent activation of autophagic and antioxidant defenses was also observed. In vitro, Aβ42-derived oligomers induced transcriptional alterations in unfolded protein responses and endoplasmic reticulum-stress pathways with the Principal Component Analysis showing partial separation from cytokine- and neurohormonal-treated groups. Conclusion AIS exerts systemic effects on the heart in young wild-type mice characterized by cardiac dysfunction, cytokine and autonomic dysregulation. Oligomer accumulation in both brain and heart, indicating their systemic presence and correlation with altered cardiac resistance to proteotoxicity. The proteotoxic response triggered by Aβ42 oligomers in rat cardiomyoblasts suggests that brain-derived misfolded proteins can directly modulate cardiac cellular homeostasis. However, their contribution to cardiac dysfunction warrants further investigation.For image description, please refer to the figure legend and surrounding text. For image description, please refer to the figure legend and surrounding text.
Diteepeng et al. (Fri,) studied this question.