T-wave alternans (TWA)—the beat-to-beat alternation of T-wave morphology on the electrocardiogram—arises from repolarization instability and is strongly linked to ventricular arrhythmias and sudden cardiac death. β-adrenergic (β-AR) stimulation is a key regulator of TWA, but its effects are context-dependent and may reflect different underlying pathologies. While many studies show that β-AR stimulation can suppress alternans, others suggest that heightened β-AR activation may promote arrhythmogenesis, particularly in disease states such as heart failure. Importantly, the contribution of tissue-level heterogeneities in β-AR signaling, including regional differences in innervation, catecholamine concentration, receptor density, cyclic adenosine monophosphate (cAMP), and phosphodiesterase (PDE) activity, remains incompletely defined. We addressed this gap using biophysically detailed computational models of human ventricular excitation-contraction coupling, incorporating β-AR signaling and sex- and region-specific parameterizations (epicardium vs. endocardium; apex vs. base). One-dimensional strands with transmural or apico-basal variation were paced dynamically, and pseudo electrocardiograms were computed. Alternans were calcium-driven, originating from mismatches between sarcoplasmic reticulum (SR) uptake and release, and gave rise to action potential duration alternans that manifested as TWA. Uniform β-AR stimulation across the strand with isoproterenol suppressed alternans by enhancing SR uptake and stabilizing repolarization. In contrast, introducing heterogeneities in isoproterenol concentration or PDE activity produced localized alternans, resulting in TWA. These findings demonstrate that nonuniform β-AR signaling can destabilize repolarization and promote alternans. Ongoing work extends this framework to two-dimensional tissue simulations to quantify how β-AR heterogeneity and sex differences interact to shape TWA dynamics and arrhythmia vulnerability.
Shetty et al. (Sun,) studied this question.