Systems approach to the study of stretch and arrhythmias in right ventricular failure induced in rats by monocrotaline

Abstract

We demonstrate the synergistic benefits of using multiple technologies to investigate complex multi-scale biological responses. The combination of reductionist and integrative methodologies can reveal novel insights into mechanisms of action by tracking changes of in vivo phenomena to alterations in protein activity (or vice versa). We have applied this approach to electrical and mechanical remodelling in right ventricular failure caused by monocrotaline-induced pulmonary artery hypertension in rats.We show arrhythmogenic T-wave alternans in the ECG of conscious heart failure animals. Optical mapping of isolated hearts revealed discordant action potential duration (APD) alternans. Potential causes of the arrhythmic substrate; structural remodelling and/or steep APD restitution and dispersion were observed, with specific remodelling of the Right Ventricular Outflow Tract. At the myocyte level, [Ca2+]i transient alternans were observed together with decreased activity, gene and protein expression of the sarcoplasmic reticulum Ca2+-ATPase (SERCA). Computer simulations of the electrical and structural remodelling suggest both contribute to a less stable substrate.Echocardiography was used to estimate increased wall stress in failure, in vivo. Stretch of intact and skinned single myocytes revealed no effect on the Frank-Starling mechanism in failing myocytes. In isolated hearts acute stretch-induced arrhythmias occurred in all preparations. Significant shortening of the early APD was seen in control but not failing hearts. These observations may be linked to changes in the gene expression of candidate mechanosensitive ion channels (MSCs) TREK-1 and TRPC1/6. Computer simulations incorporating MSCs and changes in ion channels with failure, based on altered gene expression, largely reproduced experimental observations.

The length‐dependent activation of contraction is equally impaired in impuberal male and female rats in monocrotaline‐induced right ventricular failure

“…The experimental model of monocrotaline‐induced pulmonary hypertension is used extensively to promote right ventricular failure . The validity of this model has been proven in numerous studies, including characterization of systolic and diastolic right ventricular function . In the present study, severe right ventricular hypertrophy (significant augmentation of right ventricular mass) and symptoms of heart failure (loss of left ventricular mass) were prominent at 23–24 days after treatment with 50 mg/kg MCT.…”

“…This is commonly related to attenuation and/or prolongation of the Ca 2+ transient and to prolongation of the action potential . Depressed sarcoplasmic/endoplasmic reticulum calcium ATPase 2a activity, which has been demonstrated in the failing myocardium, may explain, at least in part, the prolongation of the decline in the Ca 2+ transient. A strong correlation between Ca 2+ transient amplitude and the rate of decline (i.e.…”

Neuregulin‐1 attenuates right ventricular diastolic stiffness in experimental pulmonary hypertension

“…In PAH, RV diastolic stiffening precedes RV failure and it is associated with sarcomeric protein changes, including titin, troponin I, and myosin binding protein C hypophosphorylation, while no significant changes occur in most of the remaining calcium handling proteins . In the experimentally overloaded RV, Serca2a and PLB expression and activity are compromised . However, in our study, just PLB activity seems to be affected.…”

Interactive effect of beta-adrenergic stimulation and mechanical stretch on low-frequency oscillations of ventricular action potential duration in humans

“…Similarly to other electromechanical models published in the literature [28,29], a linear time-independent formulation was used for the current through non-selective cationic SACs:…”

“…where λ is the ratio between SL and the resting SL defined in the model and λmax is set to 1.1 as in [26,28]. The reversal potential ESAC,ns was set to -10 mV based on experimental evidence [30,31].…”