Right ventricular end-diastolic stiffness heralds right ventricular failure in monocrotaline-induced pulmonary hypertension

Abstract

Recent studies suggest right ventricular (RV) stiffness is important in pulmonary hypertension (PH) prognosis. Smaller stroke volume (SV) variation after a certain RV end-diastolic pressure (EDP) respiratory variation as assessed by spectral transfer function (STF) may identify RV stiffness. Our aim was to evaluate RV stiffness in monocrotaline (MCT)-induced PH progression and to validate STF gain between EDP and SV as marker of stiffness. Seven-week-old male Wistar rats randomly injected with 60 mg/kg MCT or vehicle were divided into three groups (n = 12 each) according to cardiac index (CI): controls (Ctrl), preserved CI (MCT pCI), and reduced CI (MCT rCI). All underwent RV pressure-volume (PV) evaluation 24-34 days after MCT, under halogenate anesthesia and constant positive-pressure ventilation. End-diastolic stiffness (β), end-systolic elastance (Ees), arterial elastance for indexed volumes (Ea), and preload recruitable stroke work (PRSW) were obtained and beat-to-beat fluctuations during ventilation assessed by STF. Ea was the strongest determinant of CI, alongside β but not PRSW. MCT rCI showed impaired ventricular-vascular coupling (VVC) and higher β, along with low end-diastolic pressure (EDP) and stroke volume index (SV) STF gain, denoting impaired preload reserve. On multivariate analysis β and not Ees correlated with EDP-SV STF gain (P < 0.001). Receiver-operating characteristics (ROC) curve analysis of EDP-SV STF gain showed an area under curve of 0.84 for β prediction (P = 0.002). Afterload, impaired VVC and RV stiffness are major players in RV failure. RV stiffness can be assessed by STF gain analysis of respiratory fluctuations between EDP and SV, which may constitute a prognostic tool in PH.

Transglutaminase 2 in pulmonary and cardiac tissue remodeling in experimental pulmonary hypertension

“…Our results suggest that TG2 plays an important role in hypoxia-induced pulmonary and right ventricular tissue matrix remodeling in the development of PH. pulmonary hypertension; transglutaminase 2; tissue fibrosis; pulmonary remodeling; right ventricular remodeling PRIMARY MANIFESTATIONS of pulmonary hypertension (PH) include decreased compliance (increased stiffness) of both the pulmonary vasculature (40,43) and right ventricle (RV) of the heart (1,32). The decreased compliance of the pulmonary artery (PA) is an important predictor of mortality in heart failure with diastolic dysfunction in patients with PH (2).…”

Diastolic dysfunction in pulmonary artery hypertension: Creatine kinase and the potential therapeutic benefit of beta‐blockers

“…In the monocrotaline rat model of PAH, RV heart failure occurs 3‐4 weeks after a single injection of monocrotaline. The onset of heart failure in this model was associated with diastolic dysfunction . When a reduced dose of monocrotaline was used to induce stable hypertrophy, diastolic function was preserved …”

“…The onset of heart failure in this model was associated with diastolic dysfunction. 11 When a reduced dose of monocrotaline was used to induce stable hypertrophy, diastolic function was preserved. 12 We have used the monocrotaline rat model to study RV failure in PAH.…”

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 .…”