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

Aim Cardiac 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 Ca 2+ handling by the sarcoplasmic reticulum (SR), in both the SR Ca 2+ uptake and release processes. The hypertrophic myocardium is particularly prone to alternans, but the precise mechanisms underlying its increased vulnerability are not known. Methods Mechanical alternans (intact hearts) and Ca 2+ 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 Ca 2+ alternans, T‐tubule organization, SR Ca 2+ uptake, and Ca 2+ release refractoriness were measured. Results The increased susceptibility of SHR to high‐frequency‐induced mechanical and Ca 2+ alternans appeared when the hypertrophy developed, associated with an adverse remodeling of the T‐tubule network (6 mo). At the subcellular level, Ca 2+ discordant alternans was also observed. From 6 mo of age, SHR myocytes showed a prolongation of Ca 2+ release refractoriness without alterations in the capacity of SR Ca 2+ removal, measured by the frequency‐dependent acceleration of relaxation. Sensitizing SR Ca 2+ release channels (RyR2) by a low dose of caffeine or by an increase in extracellular Ca 2+ concentration, shortened refractoriness of SR Ca 2+ release, and reduced alternans in SHR hearts. Conclusions The tuning of SR Ca 2+ release refractoriness is a crucial target to prevent cardiac alternans in a hypertrophic myocardium with an adverse T‐tubule remodeling.