Calcium mishandling impairs contraction in right ventricular hypertrophy prior to overt heart failure

Abstract

Currently, there are no tailored therapies available for the treatment of right ventricular (RV) hypertrophy, and the cellular mechanisms that underlie the disease are poorly understood. We investigated the cellular changes that occur early in the progression of the disease, when RV hypertrophy is evident, but prior to the onset of heart failure. Intracellular Ca ([Ca]) handling was examined in a rat model of monocrotaline (MCT)-induced pulmonary hypertension and subsequent RV hypertrophy. [Ca] and stress production were measured in isolated RV trabeculae under baseline conditions (1-Hz stimulation, 1.5 mM [Ca], 37 °C), and in response to inotropic interventions (5-Hz stimulation or 1-μM isoproterenol). Under baseline conditions, MCT trabeculae had impaired Ca release in response to stimulation with a 45% delay in the time-to-peak Ca, but there was no difference in the amplitude and decay of the Ca transient, or active stress relative to RV trabeculae from normotensive hearts (CON). Increasing stimulation frequency from 1 to 5 Hz increased stress in CON, but not MCT trabeculae. Similarly, β-adrenergic stimulation with isoproterenol increased Ca transient amplitude and active stress in CON, but not in MCT trabeculae, despite accelerating Ca transient decay in trabeculae from both groups. During isoproterenol treatment, MCT trabeculae showed increased diastolic Ca leak, which may explain the blunted inotropic response to β-adrenergic stimulation. Confocal imaging of trabeculae fixed following functional measurements showed that myocytes were on average wider, and transverse-tubule organisation was disrupted in MCT which provides a mechanism to explain the observed slower release of Ca.

Energetics Equivalent of the Cardiac Force-Length End-Systolic Zone: Implications for Contractility and Economy of Contraction

“…The slopes of the isometric heat-stress relations for the control and isoproterenol cases were the same despite an increase in force in the isoproterenol case (Figure 5B). This suggests that isoproterenol has no direct effect on the chemo-mechanical energy transduction of cardiac myofilaments and that the augmentation of contractility arises indirectly from an increase in the peak of the cytosolic Ca 2+ transient (Tamura et al, 1992;Kassiri et al, 2000;Power et al, 2018). Our measurement of a null effect of isoproterenol on economy, but a higher activation heat in the presence of isoproterenol, is consistent with earlier observations reported in the literature (Gibbs, 1967;Gibbs and Gibson, 1972;Barclay et al, 1979).…”

“…The isoproterenol dose-response curve for active force development saturates at concentrations above 0.1 µmol l −1 (Monasky et al, 2008). We chose a concentration of 0.5 µmol l −1 to ensure that the maximum inotropic response is elicited, which is within the typical range, 0.1 µmol l −1 (Barclay et al, 1979) to 1 µmol l −1 (Power et al, 2018), used for cardiac muscle experiments.…”

“…The effect of isoproterenol to increase cardiac contractility has typically been demonstrated in intact isolated tissues contracting at a single fixed muscle length (Kassiri et al, 2000;Layland and Kentish, 2000;Power et al, 2018). Our isometric ESSLR protocol characterizes the peak stress development of twitching trabeculae over a range of muscle lengths in response to isoproterenol (Figure 5).…”

Disruption of Transverse-Tubules Eliminates the Slow Force Response to Stretch in Isolated Rat Trabeculae

“…β2-adrenergic receptors are restricted to the t-tubule SL in ventricular tissue (Schobesberger et al, 2017), and can produce the same effects as β1-adrenergic receptors, although they can couple to both stimulatory and inhibitory G protein coupled receptors (Triposkiadis et al, 2009). We have previously shown that loss of t-tubules in right ventricle hypertrophy coincides with an attenuated inotropic response to β-adrenergic stimulation (Power et al, 2018). However, the results from this study suggest that detubulation per se does not explain the impaired β-adrenergic responsiveness observed in heart failure.…”

“…Disruption and/or loss of myocyte t-tubule structure has been reported in myocytes from human (Crossman et al, 2011) and many animal models (Wei et al, 2010;Ward and Crossman, 2014;Power et al, 2018) of heart disease in which contraction is compromised. The resulting increased t-tubule heterogeneity has been suggested as causing prolonged action potential duration (Beuckelmann et al, 1993;Tomaselli and Marban, 1999), asynchrony of subcellular Ca 2+ release, and reduced force in diseased myocytes (Heinzel et al, 2011).…”