Abstract:
Background: Pulmonary hypertension progresses to right heart failure, with evidence of altered cardiomyocyte Ca2+ handling and impaired energetics underlying the contractile dysfunction. However, the early stage of the disease is poorly studied. Aims: To examine Ca2+ handling, t-tubule organization, and energetic sufficiency in a rat model of right ventricular hypertrophy (RVH), prior to the onset of heart failure. Methods: Pulmonary hypertension and RVH were induced in rats (I.P. 60 mg mL−1 monocrotaline) and controls were given an equivalent volume of saline. [Ca2+]i (fura-2/AM) and stress were measured in isolated right ventricular trabeculae. Two energydemanding scenarios were investigated: increased stimulation frequency, and β-adrenergic stimulation. Trabeculaewere subsequently permeabilised and mitochondrial energy sufficiency investigated. Finally, trabeculae were fixed and processed for confocal imaging and analysis (TTpower) of the t-tubular system regularity. Results: Ca2+-transients were 26% smaller in RVH trabeculae, with a 45% slower time-to-peak, but no difference in the decay of the transients. RVH had a negative force-frequency response in comparison to the controls. Beta-adrenergic stimulation altered the time course, but not the amplitude, of Ca2+-transients, and increased spontaneous Ca2+ release. No difference was found in maximum Ca2+-activated stress in trabeculae reliant on mitochondrial ATP production and supply. T-tubular regularity (TTpower) was decreased from 0.11 ± 0.02 a.u. in control trabeculae to 0.07 ± 0.01 a.u. (p = 0.02) in RVH trabeculae. Conclusions: We conclude that impaired Ca2+ handling is present in RVH before mitochondrial energetic deficits occur. This is explained, in part, by t-tubular remodelling which impairs excitation-contraction coupling.
