Right Ventricular Function In Pulmonary Hypertension Research Articles

Abstract 14954: Mitochondrial C-Src Regulates Impaired Mitochondrial Bioenergetics in Right Ventricles in Pulmonary Hypertension

Introduction: Pulmonary hypertension (PH) has poor prognosis with presence of right ventricular (RV) dysfunction. However, no RV targeted therapies are available. Mitochondrial (Mito) energy deficiency is detrimental on RV function in PH, but the underlying mechanism remains unclear. Tyrosine kinase phosphorylation (P-Tyr) has been a critical regulatory mechanism in mito. While mito localized c-Src is recognized as the major tyrosine kinase, little is known regarding its role in RV in PH. Hypothesis: We hypothesized that mito c-Src regulates impaired mito bioenergetics in RV in PH. Methods: PH was induced in adult Sprague-Dawley (SD) rats by injecting 20 mg/kg SU5416, followed by 3 wks of hypoxia (10% FiO 2 ) and then 4 wks of normoxia exposure. Control rats injected with vehicle were kept in normoxia. After echocardiography and hemodynamics, RV tissues were collected for mito respiration using high resolution O2K-FluoRespirometer, mito morphology using electron microscopy, and biochemical assays. Cardiomyocytes and H9c2 cells were used for in vitro mechanistic studies. Results: Compared to controls, PH rats show increased RV systolic pressure and RV dysfunction. Mito complex I-coupled oxidative phosphorylation and electron transfer capacity are significantly reduced in RV of PH rats (O 2 flux per mass: 216±21 vs. 90±19 and 209±22 vs. 91±22 pmol·s-1·mg-1, respectively, p <0.01, n=6 each), which is associated with decreased ATP but no changes in mito membrane integrity, mito DNA content, or mito size. Mito c-Src kinase activity and expression are significantly reduced in RV of PH rats and in dysfunctional RV of human patients. Chemical or molecular inhibition of mito c-Src results in a similar reduction of mito respiration in culture as found in RV of PH rats and is associated with decreased ATP production. Mito c-Src phosphorylates NADH dehydrogenase [ubiquinone] flavoprotein 2 (NDUFV2), a critical protein for complex I, and P-Tyr of NDUFV2 is reduced in RV of PH rats. Conclusions: Impaired mito bioenergetics is associated with progression of RV dysfunction. Basal mito c-Src kinase activity is required for mito bioenergetics and mito c-Src-dependent P-Tyr of NDUFV2 may serve as a regulatory mechanism in impaired RV mito bioenergetics in settings of PH.

Predictors and prognosis of RV function in pulmonary hypertension due to heart failure with reduced ejection fraction

Abstract Background and aims Failure of right ventricular (RV) function worsens outcome in pulmonary hypertension (PH). The adaptation of RV contractility to afterload, the RV-pulmonary artery (PA) coupling, is defined by the ratio of RV end-systolic to PA elastances (Ees/Ea). Using pressure volume loop (PV-L) technique we aimed to identify an Ees/Ea cutoff predictive for overall survival and to assess hemodynamic and morphologic conditions for adapted RV function in secondary PH due to Heart Failure with Reduced Ejection Fraction (HFREF). Methods This post hoc analysis is based on 112 patients of the prospective Magdeburger Resynchronization Responder Trial. All patients underwent right and left heart echocardiography, and a baseline PV-L and RV catheter measurement. A subgroup of patients (n=50) without a pre-implanted cardiac device underwent MRI at baseline. Results The analysis revealed that 0.68 is an optimal Ees/Ea cutoff (area under the curve: 0.697, p<0.001) predictive for overall survival (median follow up = 4.7 years, Ees/Ea ≥0.68 vs. <0.68, log-rank 8.9, p=0.003. In patients with PH (n=76, 68%) Multivariate Cox-regression demonstrated the independent prognostic value of RV-Ees/Ea in PH patients (HR 0.2, p<0.038). Patients without PH (n=36, 32%) and those with PH but RV-Ees/Ea ≥0.68 showed comparable RV-Ees/Ea ratios (0.88 vs. 0.9, p=0.39), RV size/function, and survival. In contrast, secondary PH with RV-PA coupling ratio Ees/Ea <0.68 corresponded extremely close to cut-off values that define RV dilatation/remodeling (RVEDV >160ml, RV-mass/volume-ratio <0.37 g/ml) and dysfunction (RVEF <38%, TAPSE <16mm, FAC <42%, and stroke-volume/end-systolic volume ratio <0.59) and is associated with a dramatically increased short and medium-term all-cause mortality. Independent predictors of prognostically unfavorable RV-PA coupling (Ees/Ea <0.68) in secondary PH were a preexistent dilated RV (end-diastolic volume >171ml, odds ratio, OR 0.96, p=0.021), high pulsatile load (PA compliance <2.3 ml/mmHg, OR 8.6, p=0.003), and advanced systolic left heart failure (left ventricular (LV) ejection fraction <30%, OR 1.23, p=0.028). Conclusions The RV-PA coupling ratio Ees/Ea predicts overall survival in PH due to HFREF and is mainly affected by pulsatile load, RV remodeling and LV dysfunction. Prognostically favorable coupling (RV-Ees/Ea ≥0.68) in PH was associated with preserved RV size/function and mid-term survival, comparable to HFREF without PH. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Boston Scientific

Importance of Cx43 for Right Ventricular Function.

In the heart, connexins form gap junctions, hemichannels, and are also present within mitochondria, with connexin 43 (Cx43) being the most prominent connexin in the ventricles. Whereas the role of Cx43 is well established for the healthy and diseased left ventricle, less is known about the importance of Cx43 for the development of right ventricular (RV) dysfunction. The present article focusses on the importance of Cx43 for the developing heart. Furthermore, we discuss the expression and localization of Cx43 in the diseased RV, i.e., in the tetralogy of Fallot and in pulmonary hypertension, in which the RV is affected, and RV hypertrophy and failure occur. We will also introduce other Cx molecules that are expressed in RV and surrounding tissues and have been reported to be involved in RV pathophysiology. Finally, we highlight therapeutic strategies aiming to improve RV function in pulmonary hypertension that are associated with alterations of Cx43 expression and function.

Clinical Significance of Right Ventricular Function in Pulmonary Hypertension.

Pulmonary hypertension (PH) is a progressive disease characterized by increased pulmonary vascular resistance that leads to right ventricular (RV) failure, a condition that determines its prognosis. This review focuses on the clinical value of the evaluation of RV function in PH. First, the pathophysiology of PH, including hemodynamics, RV function, and their interaction (known as ventriculoarterial coupling), are summarized. Next, non-invasive imaging modalities and the parameters of RV function, mainly assessed by echocardiography, are reviewed. Finally, the clinical impacts of RV function in PH are described. This review will compare the techniques that yield comprehensive information on RV function and their roles in the assessment of PH.

Three‐Dimensional Analysis of Right Ventricular Shape and Function in Pulmonary Hypertension

Right ventricular (RV) failure is a key determinant of morbidity and mortality in pulmonary hypertension (PH). The present study aims to add to existing descriptions of RV structural and functional changes in PH through a comprehensive three-dimensional (3D) shape analysis. We performed 3D echocardiography on 53 subjects with PH and 19 normal subjects. Twenty short-axis slices from apex to tricuspid centroid were measured to characterize regional shape: apical angle, basal bulge, eccentricity, and area. Transverse shortening was assessed by fractional area change (FAC) in each short-axis slice, longitudinal contraction was assessed by tricuspid annular plane systolic excursion (TAPSE) and global function by RV ejection fraction. Multivariate logistic analysis was used to compare the association of RV parameters with New York Heart Association (NYHA) class. Compared to normal, RV function in PH is characterized by decreased stroke volume index (SVi), fractional area change and ejection fraction. Increased eccentricity, apical rounding and bulging at the base characterize the shape of the RV in PH. Increased SVi, ejection fraction and mid-ventricular FAC were associated with less severe NYHA class in adjusted analyses. The RV in idiopathic PH (iPAH) was observed to have a larger end-diastolic volume and decreased function compared with connective tissue disease associated PH (ctd-PH). This work describes increased eccentricity and decreased systolic function in subjects with PH. Functional parameters were associated with NYHA class and heterogeneity in the phenotype was noted between subjects with iPAH and ctd-PH.

ACE2 Improves Right Ventricular Function in a Pressure Overload Model

BackgroundRight ventricular (RV) dysfunction is a complication of pulmonary hypertension and portends a poor prognosis. Pharmacological therapies targeting RV function in pulmonary hypertension may reduce symptoms, improve hemodynamics, and potentially increase survival. We hypothesize that recombinant human angiotensin-converting enzyme 2 (rhACE2) will improve RV function in a pressure overload model.ResultsrhACE2 administered at 1.8 mg/kg/day improved RV systolic and diastolic function in pulmonary artery banded mice as measured by in vivo hemodynamics. Specifically, rhACE2 increased RV ejection fraction and decreased RV end diastolic pressure and diastolic time constant (p<0.05). In addition, rhACE2 decreased RV hypertrophy as measured by RV/LV+S ratio (p<0.05). There were no significant negative effects of rhACE2 administration on LV function. rhACE2 had no significant effect on fibrosis as measured by trichrome staining and collagen1α1 expression. In pulmonary artery banded mice, rhACE2 increased Mas receptor expression and normalized connexin 37 expression.ConclusionIn a mouse RV load-stress model of early heart failure, rhACE2 diminished RV hypertrophy and improved RV systolic and diastolic function in association with a marker of intercellular communication. rhACE2 may be a novel treatment for RV failure.

A simple method to predict impaired right ventricular performance and disease severity in chronic pulmonary hypertension using strain rate imaging

The evaluation of right ventricular (RV) function is clinically important in pulmonary hypertension (PH) because of prognostic implications. Conventional echocardiography has been used to predict adverse outcomes in chronic PH, but there were certain limitations arising from the complexity of RV anatomy. We used strain rate imaging (SRI) to evaluate RV function in PH patients. Study population consisted of 50 patients (mean age 46 ± 13 years; 39 females) with chronic PH who underwent echocardiography including SRI within 24h of right heart catheterization. Mean value of peak systolic longitudinal strain obtained from basal and mid RV free wall were calculated. Reduced RV systolic contraction (fractional area change <32%) and cardiac index (CI) <2.0 L/min/m(2) were defined as impaired RV performance. Pulmonary vascular resistance (PVR) averaged 1195 ± 522 dyn · s · cm(-5). RV strain correlated closely with pulmonary artery systolic pressure (r = 0.53; p < 0.001) and PVR (r = 0.68; p < 0.001). RV strain best correlated with CI (r = -0.70; p < 0.001) among the invasive variables. After adjusting for various parameters that could influence the CI, this correlation remained robust (r = -0.63, p < 0.001). In a multivariate model, RV strain (odds ratio 1.65; 95% confidential interval 1.06-2.57; p = 0.028) was independently associated with impairment of RV performance. A cutoff value of -15.5% discriminated cases of impaired RV performance from those of preserved RV performance with a sensitivity of 100%, specificity of 84% and accuracy of 92%. RV strain correlates well with hemodynamic variables indicative of disease severity and help identify the cases of impaired RV performance in PH patients.

Assessment of Right Ventricular Function Using Tissue Doppler Imaging in Infants with Pulmonary Hypertension

Background: In infants with pulmonary hypertension (PHT), right ventricular (RV) function may be altered and contribute to disease severity. Tissue Doppler imaging (TDI) is a new echocardiographic modality which directly measures myocardial velocities and may allow quantitative assessment of systolic and diastolic ventricular function in infants. Objective: To measure and compare RV myocardial velocities in infants with PHT and in normal control infants, using TDI. Methods: This was a prospective case-control study. Twenty-eight control infants and 15 infants with PHT, of whom 11 had congenital diaphragmatic hernia (CDH), were recruited. TDI was used to obtain systolic and diastolic myocardial velocities in the RV and interventricular septum in all infants. Results: There were significant reductions in systolic isovolumic contraction velocity (IVV; 5.3 vs. 6.6 cm/s) and systolic ejection velocity (S; 6.6 vs. 9.2 cm/s) in the PHT group compared to the control group. Early diastolic myocardial velocity, E’, was also significantly reduced in the RV in the PHT infants compared to controls (–4.3 vs. 8.6 cm/s). The same significant reductions in systolic and early diastolic TDI velocities were observed in the subgroup of CDH infants alone. Conclusions: TDI permits non-invasive assessment of RV myocardial velocities in infants. Reduced systolic and diastolic velocities in PHT may represent impaired systolic contraction and early diastolic relaxation. Therapies which target inotropic and lusitropic function may be appropriate in infants with PHT and RV dysfunction. The load-dependency of TDI measures in infants and the effects of specific therapies on RV function in PHT require further investigation.

Magnetic resonance and nuclear imaging of the right ventricle in pulmonary arterial hypertension

Many clinicians have recognized the unique possibilities of magnetic resonance imaging (MRI) for the study of right ventricular (RV) anatomy. Especially for the assessment of the RV in pulmonary hypertension, MRI has been proven to be of clinical importance. It is, however, less well known that if MRI measures of volume and flow are combined with pressure measurements, accurate description of RV function in relation to its afterload is possible. Furthermore, nuclear imaging techniques offer the opportunity to study the altered RV metabolism and to elucidate the possible contribution of ischaemia to RV failure in pulmonary hypertension. Since RV failure in pulmonary hypertension is the result of the complex interaction between geometry, structure, function, perfusion, and metabolism, MRI and nuclear imaging are promising techniques to study these mechanisms and to evaluate the effects of therapy aimed at improving RV function in pulmonary hypertension.