Prolonged Ca2+ release refractoriness and T‐tubule disruption as determinants of increased propensity to cardiac alternans in the hypertensive heart disease

Abstract

AbstractAimCardiac alternans is a dynamical phenomenon linked to the genesis of severe arrhythmias and sudden cardiac death. It has been proposed that alternans is caused by alterations in Ca2+ handling by the sarcoplasmic reticulum (SR), in both the SR Ca2+ uptake and release processes. The hypertrophic myocardium is particularly prone to alternans, but the precise mechanisms underlying its increased vulnerability are not known.MethodsMechanical alternans (intact hearts) and Ca2+ alternans (cardiac myocytes) were studied in spontaneously hypertensive rats (SHR) during the first year of age after the onset of hypertension and compared with age‐matched normotensive rats. Subcellular Ca2+ alternans, T‐tubule organization, SR Ca2+ uptake, and Ca2+ release refractoriness were measured.ResultsThe increased susceptibility of SHR to high‐frequency‐induced mechanical and Ca2+ alternans appeared when the hypertrophy developed, associated with an adverse remodeling of the T‐tubule network (6 mo). At the subcellular level, Ca2+ discordant alternans was also observed. From 6 mo of age, SHR myocytes showed a prolongation of Ca2+ release refractoriness without alterations in the capacity of SR Ca2+ removal, measured by the frequency‐dependent acceleration of relaxation. Sensitizing SR Ca2+ release channels (RyR2) by a low dose of caffeine or by an increase in extracellular Ca2+ concentration, shortened refractoriness of SR Ca2+ release, and reduced alternans in SHR hearts.ConclusionsThe tuning of SR Ca2+ release refractoriness is a crucial target to prevent cardiac alternans in a hypertrophic myocardium with an adverse T‐tubule remodeling.