Prolonged Ca ²⁺ release refractoriness and T-tubule disruption as determinants of increased propensity to cardiac alternans in the hypertensive heart disease.

Publisher: Wiley-Blackwell Country of Publication: England NLM ID: 101262545 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1748-1716 (Electronic) Linking ISSN: 17481708 NLM ISO Abbreviation: Acta Physiol (Oxf) Subsets: MEDLINE

Publication: Oxford : Wiley-Blackwell
Original Publication: Oxford : Blackwell Pub., c2006-4

Myocytes, Cardiac*/metabolism ; Hypertension*/metabolism; Rats ; Animals ; Myocardium/metabolism ; Arrhythmias, Cardiac ; Rats, Inbred SHR ; Sarcoplasmic Reticulum/metabolism ; Calcium/metabolism ; Calcium Signaling ; Ryanodine Receptor Calcium Release Channel/metabolism

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.
(© 2023 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.)

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Keywords: T-tubule organization; alternans reversal; calcium release refractoriness; cardiac alternans; hypertensive hypertrophy

SY7Q814VUP (Calcium)
0 (Ryanodine Receptor Calcium Release Channel)

Date Created: 20230327 Date Completed: 20230518 Latest Revision: 20230614

20250114

10.1111/apha.13969

36971744