José Oliveira-Pinto

Afterload-induced diastolic dysfunction contributes to high filling pressures in experimental heart failure with preserved ejection fraction.

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 = 12), healthy Wistar-Kyoto rats (WKY, n = 11), and hypertensive ZSF1 lean control rats (ZSF1 Ln, n = 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 β, 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 (τ), 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 × monoexponentially derived τ (τexp) 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.

Myocardial and anti‐inflammatory effects of chronic bosentan therapy in monocrotaline‐induced pulmonary hypertension

INTRODUCTION AND OBJECTIVES Endothelin-1 antagonists are increasingly used in the treatment of pulmonary hypertension despite the lack of knowledge of their myocardial and systemic effects. We assessed the right ventricular myocardial and systemic effects of endothelin-1 antagonists in monocrotaline-induced pulmonary hypertension. METHODS Male Wistar rats (180-200 g, n=57) randomly received 60 mg/kg monocrotaline or vehicle subcutaneously. Two days later, bosentan was randomly started (300 mg/kg/day) by oral route in a subgroup of monocrotaline-injected rats, while the other monocrotaline-injected and control rats received vehicle. At 25-30 days, invasive hemodynamic assessment was performed under anesthesia, arterial blood samples were collected for gas analysis and plasma was extracted for quantification of endothelin-1, cytokines, nitrates and 6-keto-prostaglandin F1α. Right ventricular myocardium was collected for assessment of cyclooxygenase and nitric oxide synthase activity and gene expression. RESULTS The monocrotaline group developed pulmonary hypertension, low cardiac output, right ventricular hypertrophy and dilation, changes in gene expression and inflammatory activation that were attenuated in the group treated with bosentan. From a functional point of view, this group had improved right ventricular function and preserved ventriculo-vascular coupling, without deterioration in arterial gas parameters or systemic hypotension. In molecular terms, they showed reduced endothelin-1 and cytokine levels, decreased right ventricular inducible nitric oxide synthase and cyclooxygenase-2 activity and increased nitrate plasma levels compared with the non-treated group. CONCLUSIONS In this study we demonstrate that besides attenuating pulmonary hypertension, bosentan has beneficial hemodynamic, myocardial and anti-inflammatory effects.

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

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 (βi), end-systolic elastance (Eesi), arterial elastance for indexed volumes (Eai), and preload recruitable stroke work (PRSW) were obtained and beat-to-beat fluctuations during ventilation assessed by STF. Eai was the strongest determinant of CI, alongside βi but not PRSW. MCT rCI showed impaired ventricular-vascular coupling (VVC) and higher βi, along with low end-diastolic pressure (EDP) and stroke volume index (SVi) STF gain, denoting impaired preload reserve. On multivariate analysis βi and not Eesi correlated with EDP-SVi STF gain (P < 0.001). Receiver-operating characteristics (ROC) curve analysis of EDP-SVi STF gain showed an area under curve of 0.84 for βi 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 SVi, which may constitute a prognostic tool in PH.

Spectral transfer function analysis of respiratory hemodynamic fluctuations predicts end-diastolic stiffness in preserved ejection fraction heart failure

Preserved ejection fraction heart failure (HFpEF) diagnosis remains controversial, and invasive left ventricular (LV) hemodynamic evaluation and/or exercise testing is advocated by many. The stiffer HFpEF myocardium may show impaired stroke volume (SV) variation induced by fluctuating LV filling pressure during ventilation. Our aim was to investigate spectral transfer function (STF) gain from end-diastolic pressure (EDP) to indexed SV (SVi) in experimental HFpEF. Eighteen-week-old Wistar-Kyoto (WKY) and ZSF1 lean (ZSF1 Ln) and obese rats (ZSF1 Ob) randomly underwent LV open-chest (OC, n = 8 each group) or closed-chest hemodynamic evaluation (CC, n = 6 each group) under halogenate anesthesia and positive-pressure ventilation at constant inspiratory pressure. Beat-to-beat fluctuations in hemodynamic parameters during ventilation were assessed by STF. End-diastolic stiffness (βi) and end-systolic elastance (Eesi) for indexed volumes were obtained by inferior vena cava occlusion in OC (multibeat) or single-beat method estimates in CC. ZSF1 Ob showed higher EDP spectrum (P < 0.001), higher STF gain between end-diastolic volume and EDP, and impaired STF gain between EDP and SVi compared with both hypertensive ZSF1 Ln and normotensive WKY controls (P < 0.001). Likewise βi was only higher in ZSF1 Ob while Eesi was raised in both ZSF1 groups. On multivariate analysis βi and not Eesi correlated with impaired STF gain from EDP to SVi (P < 0.001), and receiver-operating characteristics analysis showed an area under curve of 0.89 for higher βi prediction (P < 0.001). Results support further clinical testing of STF analysis from right heart catheterization-derived EDP surrogates to noninvasively determined SV as screening/diagnostic tool to assess myocardial stiffness in HFpEF.

Levosimendan: The current situation and new prospects

Levosimendan is a pyridazinone-dinitrile derivative with positive inotropic and vasodilatory effects that has beneficial effects on myocardial performance. In previous randomized studies levosimendan improved hemodynamics and clinical course, but its effect on prognosis is still unclear. This important issue has limited its use. Although primarily used in the management of acute heart failure syndromes, this new inotropic agent may play a role in other clinical conditions. This review aims to summarize current knowledge on levosimendan and to present future prospects for the use of this drug.

PC014. Comparison of Long-term Results for the Endurant and Excluder Stent Graft

Objectives: Because endovascular aneurysm repair has become a predominant alternative, it has a high profile how to train young vascular surgeons in open surgery. The objective was to analyze the learning curve and determine the number needed to treat to establish sufficient surgical skills of open surgery for intact abdominal aortic aneurysm. Methods: This was a retrospective study of a prospectively accumulated database at Asahi General Hospital in Japan between 2003 and 2017. A total of 562 consecutive patients who underwent open repair for intact abdominal aortic aneurysm or iliac artery aneurysms either by an attending surgeon or by six young vascular surgeons (>20 experiences) were included. All young vascular surgeons had accomplished general surgery training. Analysis was conducted by every 10-cases experience performed by young vascular surgeons (Y group) to investigate the learning

Dose–Response Head-to-Head Comparison of Inodilators Dobutamine, Milrinone, and Levosimendan in Chronic Experimental Pulmonary Hypertension:

The choice of inodilator drug in the acute management of patients with pulmonary hypertension (PH) having right ventricular (RV) failure remains unsettled and challenging. Comprehensive experimental evaluations may provide further insight and fundamental translational research clues to support inodilator selection and clinical trial design. Our aim was to compare acute dose–response hemodynamic effects of inodilators dobutamine (DOB), milrinone (MIL), and levosimendan (LEV) in chronic experimental PH. Seven-week-old male Wistar rats were randomly injected with 60 mg·kg−1 monocrotaline (MCT) or vehicle (Ctrl, n = 7) and underwent systemic and pulmonary artery (PA) pressure and RV pressure–volume (PV) hemodynamic evaluation under halogenate anesthesia 24 to 30 days after injection. The MCT-injected animals (n = 7 each) randomly received dose–response infusions of DOB (1, 3, 6 and 12 μg·kg−1·min−1), MIL (MIL: 1, 3, 6 and 12 μg·kg−1·min−1), or LEV (0.3, 0.6, 1.2 and 2.4 μg·kg−1·min−1). Load-independent indexes were obtained by inferior vena cava occlusion at baseline and after the last dose. All inodilators increased RV ejection fraction, preload recruitable stroke work, and ventricular–vascular coupling without jeopardizing perfusion pressure. Dobutamine raised heart rate and PA pressure. Only LEV increased cardiac index and decreased PA elastance and pulmonary vascular resistance (PVR). Moreover, only LEV downward-shifted the end-diastolic PV relationship, thereby improving RV compliance. Adding sildenafil to LEV further decreased PVR. Levosimendan had beneficial acute systolic and diastolic functional effects in experimental chronic PH and RV afterload compared to DOB and MIL. It should be further tested in clinical trials enrolling patients with PH in the perioperative and critical care settings.