Central Illustration.

Ibrutinib Increases VA Vulnerability in Old SHRs

In old SHRs, acute exposure of ibrutinib is associated with cytosolic Ca²⁺ dysregulation and aberration in membrane electrophysiology. The components of Ca²⁺ dysregulation include shortening TTP, prolongation of CaTD₅₀, and Ca²⁺ transient alternans. The alteration in membrane electrophysiology is characterized by spatially discordant APD alternans. Shortening of TTP and prolongation of CaTD₅₀ led to the generation of afterdepolarization (early or late), which triggers VA. Calcium transient alternans is also linked to membrane repolarization alternans. Repolarization heterogeneity, as indicated by discordant APD alternans, constitutes the substrate for VA. A combination of triggers and the vulnerable substrate is translated into an increased propensity to VF following ibrutinib treatment. APD = action potential duration; C = control, CaT = calcium transient; CaTD₅₀ = calcium transient duration 50; SERCA2a = sarco/endoplasmic reticulum Ca²⁺-ATPase; SHR = spontaneous hypertensive rat; SR = sarcoplasmic reticulum; RyR2 = Ryanodine Receptor 2; TTP = time to peak; VA = ventricular arrhythmia; VF = ventricular fibrillation.