Protein misfolding in stroke-heart syndrome: a molecular bridge between brain and heart

Abstract Introduction After ischemic stroke, patient prognosis can be negatively affected by the occurrence of cardiovascular complications grouped nowadays within the term stroke-heart syndrome (SHS). In addition to inflammatory and neurohormonal signals, 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, the biological relevance of protein misfolding in SHS remains elusive. Aims To investigate the systemic effects of acute ischemic stroke (AIS) on cardiac function and assess the involvement of protein misfolding in SHS by evaluating oligomer presence and its biological relevance in the post-stroke myocardium. Methods AIS was induced in 3 to 4 months-old wild-type C57BL/6J male and female mice via 45-minute transient middle cerebral artery occlusion (tMCAO), followed by 48 hours of reperfusion. Cardiac function was evaluated using electro- and echocardiography. Oligomer localization and proteostasis responses were both assessed in the heart. Additionally, the direct effect of oligomers on cardiomyocytes was examined at transcriptional and translational levels in both sexes of human induced-pluripotent stem cell-derived cardiomyocytes (hiCM). Results AIS induced cardiac dysfunction characterized by bradyarrhythmias and reduced cardiac output. Systemic alterations were observed including dysregulated plasma pro-inflammatory cytokines, whose pattern was associated with amyloid-β (Aβ) regulation, a key hallmark in a number of misfolding-related diseases, including vascular dementia. Elevated oligomer accumulation was detected in both the ipsilateral injured brain hemisphere and the heart, along with compromised cardiac proteotoxic resistance, as evidenced by reduced levels of the chaperone heat-shock protein 90 (HSP90) and impairment of activating transcription factor-6 (ATF6)-dependent unfolded protein response in both sexes with a selective increase in ATF4 observed only in males. Concurrent activation of autophagic and antioxidant responses was also observed. In hiCM, Aβ42-derived oligomers broadly disrupted proteotoxic stress responses at the transcription level, with potential sex-specific differences in certain markers. Principal component analysis further revealed distinct vehicle proteomic profiles between sexes while showing a converging transcriptional response to oligomer exposure. Conclusion The findings indicate the systemic effects of AIS on cardiac function in healthy young wild-type mice. The accumulation of oligomers in both injured brain and heart, along with impaired cardiac resistance to proteotoxicity, suggests a potential mechanistic link between post-stroke neurodegeneration and cardiac dysfunction. The complex response of hiCM to Aβ42 oligomers underscores the unique feature of oligomers impact on the human myocardium with potential sex-specific divergence.Figure 1 Figure 2