Abstract Body (Do not enter title and authors here): Introduction/Background: Aging is a significant risk factor for cardiac pathologies, such as heart failure, arrhythmias, and myocardial infarction. p38 MAPKs regulate cardiac remodeling and are implicated in age-related cardiac dysfunction. However, the isoform-specific roles of p38 kinases in the heart are not fully understood. While p38β has been shown to provide cardioprotection in models of doxorubicin-induced cardiotoxicity and ischemia/reperfusion injury, its role in cardiac aging remains unclear.
Research Questions/Hypothesis: The systemic genetic deletion of p38β exacerbates age-related cardiac dysfunction.
Methods/Approach: Wild-type and p38β knockout (p38β^-/-) male and female mice on the C57BL/6J genetic background, aged 13.5 to 20 months, were evaluated using echocardiography and electrocardiography to assess cardiac structural, mechanical, and electrical function. Multiparametric optical mapping of transmembrane potential and intracellular calcium was performed, followed by an arrhythmia induction protocol consisting of S1S2, S1S2S3S4, short-burst, and long-burst pacing.
Results/Data (descriptive and inferential statistics): Compared to their wild-type counterparts, p38β^-/- mice displayed an increase in left ventricular (LV) mass (p = 0.0137) and thicker LV anterior walls during both systole (p = 0.0390) and diastole (p = 0.0398). Electrocardiographic alterations included a prolonged P wave (p = 0.0081), QT interval (p = 0.0003), QTc interval duration (p = 0.0003), and a shortened QRS complex duration (p = 0.0012). Optical mapping revealed a prolonged action potential duration at 30% repolarization (p < 0.0001), increased transverse conduction velocity (p = 0.025), and a trend toward slower longitudinal conduction velocity (p = 0.0685). Additionally, optical mapping showed impaired calcium handling, characterized by a prolonged calcium rise time (p = 0.0205) and calcium transient duration at 50% (p = 0.0639) and 80% (p < 0.0001) reuptake. Arrhythmia inducibility studies revealed an increase in non-sustained arrhythmias in p38β^-/- hearts (p = 0.0188).
Conclusion(s): The systemic genetic deletion of p38β exacerbates age-related structural and electrophysiological remodeling of the heart, demonstrating the protective role of p38β in cardiac aging.