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Cardiac adaptations to frequent premature ventricular contractions

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conference contribution
posted on 2023-01-13, 21:25 authored by J.M.L. Medina Contreras, Jaime Balderas-Villalobos, Rafael J. Ramirez, Christopher Lynch, Alex Y. Tan, Karoly kaszala, Montserrat Samsó, Jose F. Huizar

 

Frequent premature ventricular contractions (PVCs) are prevalent in adult patients and commonly associated with left ventricular (LV) systolic dysfunction. Animal translational models of PVC- induced cardiomyopathy (PVC-CM) are reproducible and allow for study of specific adaptations resulting from frequent PVCs. Our PVC-CM canine model has shown LV eccentric hypertrophy and downregulation of key Ca2+ handling proteins. We performed subsequent studies to understand cellular and chemical mediators involved in LV remodeling observed in PVC-CM. Animals underwent experimental pacemaker implantation to produce bigeminal PVCs (50% burden at 200-220 ms coupling interval) for 12-week, including a sham group where PVCs were disabled. Cellular hypertrophy (WGA-Alexa Fluor 633 staining), fibrosis (Sirius red/fast green staining), and myofibroblast content (αSMA immunostaining) were studied in sections of LV samples using confocal or optical microscopy. Ultrastructure of LV samples was observed using transmission electron microscopy. Western blot analysis was used to study the expression and/or phosphorylation of proteins involved in Ca2+ handling (SERCA, phospholamban [PLN]) and signaling pathways involved in pathological, or physiological hypertrophy, and fibrosis. Results showed an increased presence of myofibroblast and diffuse fibrosis in PVC-CM tissues. The expression of αSMA, IL-1β was increased, whereas PLN phosphorylation and SERCA expression were reduced with PVC-CM. Cellular hypertrophy was confirmed by microscopy, but biochemical markers of pathological hypertrophy (α-skeletal actin and β-myosin heavy chain) were unchanged. AKT, a marker of physiological hypertrophy, was upregulated in PVC-CM vs sham. At the structural level, the dyadic cleft is altered in PVC-CM samples. All these results suggest that adaptations to PVCs include beneficial factors favoring physiological hypertrophy, maladaptive responses including dyad remodeling, and detrimental cytokine production (i.e., IL-1β) known to promote fibrosis and to downregulate key Ca2+ handling proteins in myocytes.

 

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Grant ID

836430