Increased propensity to cardiac alternans in spontaneously hypertensive rats at early stages is associated to prolonged sarcoplasmic reticulum Ca release refractoriness and t-tubule remodeling

MARIÁNGELO JIE ; GONANO L.; VITTONE L.; MUNDIÑA - WEILENMNANN C.; SAID M.

Berlín

Congreso; XXIV World Congress of the International Society for Heart Research; 2022

International Society for Heart Research (ISHR)

Introduction: Cardiac alternans is considered an arrhythmogenic substrate. At the cellular level, this periodic beat-to-beat fluctuation is typically linked to defects in intracellular Ca handling. The hypertrophied myocardium of spontaneously hypertensive rats (SHR) shows an increased susceptibility to cardiac alternans, but the underlying mechanism is not fully understood.Objectives: We examined if sarcoplasmic reticulum (SR) Ca uptake and/or release and/or t-tubule (TT) loss, predispose the SHR myocardium to alternans, early after the onset of hypertension.Materials & methods: Frequency-induced mechanical alternans were measured in isolatedhearts from 3 and 6 mo-old SHR and compared with age-matched normotensive rats (W). By epifluorescence/confocal microscopy, using Fura-2/Fluo-4 Ca dyes, we assessed cellular/subcellular Ca alternans in myocytes isolated from the same group of hearts. TT distribution was studied by confocal laser scanning using di-8-ANEPPS.Results: Propensity to mechanical and Ca alternans increased only in the myocardium of SHR at 6 mo (threshold for Ca alternans was 3.91 ± 0.07 and 5.10 ± 0.02 Hz in SHR and W 6 mo myocytes, respectively, p b 0.05). This change was associated to a slowed recovery rate of SR Ca release (time interval to 50% recovery, EC50: 338.7 ± 2.63 SHR vs. 291.2 ± 2.77 msec W, p < 0.05), a significantly disrupted periodicity of the TT (TT power index: 57.37 ± 0.84 SHR vs. 63.11 ± 1.96 A.U. W, p b 0.05) and the appearance of heterogeneity in subcellular Ca release. The frequency-dependent acceleration of relaxation, indicative of SR Ca uptake, was similar in heartsand myocytes from all the groups studied. A low dose of caffeine (caff, 100 μM), which enhances Ca sensitivity of the ryanodine receptor (RyR2), the SR Ca release channel, suppressed pacing-induced Ca alternans and prevents the shift in the restitution curve of SR Ca release in SHR myocytes at 6 mo (EC50: 297.9 ± 4.24 msec) (Figure).Conclusion: Our data indicates that the increased susceptibility to alternans in the SHR myocardium at early stages of the hypertensive disease (6 mo of age) is associated to a lengthened Ca release refractoriness and an adverse remodeling of cardiomyocyte TT network, without alterations in the capacity of SR Ca removal.doi:10.1016/j.yjmcc.2022.08.059