Prolonged Ca 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 handling by the sarcoplasmic reticulum (SR), in both the SR Ca 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 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 alternans, T-tubule organization, SR Ca uptake, and Ca release refractoriness were measured.

Results: The increased susceptibility of SHR to high-frequency-induced mechanical and Ca alternans appeared when the hypertrophy developed, associated with an adverse remodeling of the T-tubule network (6 mo). At the subcellular level, Ca discordant alternans was also observed. From 6 mo of age, SHR myocytes showed a prolongation of Ca release refractoriness without alterations in the capacity of SR Ca removal, measured by the frequency-dependent acceleration of relaxation. Sensitizing SR Ca release channels (RyR2) by a low dose of caffeine or by an increase in extracellular Ca concentration, shortened refractoriness of SR Ca release, and reduced alternans in SHR hearts.

Conclusions: The tuning of SR Ca release refractoriness is a crucial target to prevent cardiac alternans in a hypertrophic myocardium with an adverse T-tubule remodeling.