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Falcão-Pires I, Gillebert TC, LeiteMoreira AF, Lourenço AP. Afterload-induced diastolic dysfunction contributes to high filling pressures in experimental heart failure with preserved ejection fraction. Am J Physiol Heart Circ Physiol 309: H1648 -H1654, 2015. First published September 25, 2015; doi:10.1152/ajpheart.00397.2015.-Myocardial stiffness and upward-shifted end-diastolic pressure-volume (P-V) relationship (EDPVR) are the key to high filling pressures in heart failure with preserved ejection fraction (HFpEF). Nevertheless, many patients may remain asymptomatic unless hemodynamic stress is imposed on the myocardium. Whether delayed relaxation induced by pressure challenge may contribute to high end-diastolic pressure (EDP) remains unsettled. Our aim was to assess the effect of suddenly imposed isovolumic afterload on relaxation and EDP, exploiting a highly controlled P-V experimental evaluation setup in the ZSF1 obese rat (ZSF1 Ob) model of HFpEF. Twenty-week-old ZSF1 Ob (n ϭ 12), healthy Wistar-Kyoto rats (WKY, n ϭ 11), and hypertensive ZSF1 lean control rats (ZSF1 Ln, n ϭ 10) underwent open-thorax left ventricular (LV) P-V hemodynamic evaluation under anesthesia with sevoflurane. EDPVR was obtained by inferior vena cava occlusions to assess LV ED chamber stiffness constant ␤, and single-beat isovolumic afterload acquisitions were obtained by swift occlusions of the ascending aorta. ZSF1 Ob showed increased ED stiffness, delayed relaxation, as assessed by time constant of isovolumic relaxation (), and elevated EDP with normal ejection fraction. Isovolumic afterload increased EDP without concomitant changes in ED volume or heart rate. In isovolumic beats, relaxation was delayed to the extent that time for complete relaxation as predicted by 3.5 ϫ monoexponentially derived (exp) exceeded effective filling time. EDP elevation correlated with reduced time available to relax, which was the only independent predictor of EDP rise in multiple linear regression. Our results suggest that delayed relaxation during pressure challenge is an important contributor to lung congestion and effort intolerance in HFpEF.afterload; relaxation; diastolic function; heart failure with preserved ejection fraction NEW & NOTEWORTHY In a highly controlled hemodynamic evaluation setup in experimental heart failure with preserved ejection fraction, we demonstrate that delayed relaxation independently explains enddiastolic pressure elevation during suddenly imposed afterload. This is an important contribution to understanding the response to exercise or hypertensive stress in preserved ejection fraction heart failure.HEART FAILURE with preserved ejection fraction (HFpEF) remains a major unsolved health issue and a complex disease in which the contribution of various aspects is still incompletely understood (22,24). Although HFpEF pathophysiology is multifarious and HFpEF patients constitute a heterogeneous group comprising several risk factors (26), most experts would agree upon abnormalities of left ventricular (LV) relaxation and high...

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.