Right Ventricular Dysfunction In Pulmonary Hypertension Research Articles

Identification of Celastrol as a Novel Therapeutic Agent for Pulmonary Arterial Hypertension and Right Ventricular Failure Through Suppression of Bsg (Basigin)/CyPA (Cyclophilin A).

Pulmonary arterial hypertension is characterized by abnormal proliferation of pulmonary artery smooth muscle cells and vascular remodeling, which leads to right ventricular (RV) failure. Bsg (Basigin) is a transmembrane glycoprotein that promotes myofibroblast differentiation, cell proliferation, and matrix metalloproteinase activation. CyPA (cyclophilin A) binds to its receptor Bsg and promotes pulmonary artery smooth muscle cell proliferation and inflammatory cell recruitment. We previously reported that Bsg promotes cardiac fibrosis and failure in the left ventricle in response to pressure-overload in mice. However, the roles of Bsg and CyPA in RV failure remain to be elucidated. Approach and Results: First, we found that protein levels of Bsg and CyPA were upregulated in the heart of hypoxia-induced pulmonary hypertension (PH) in mice and monocrotaline-induced PH in rats. Furthermore, cardiomyocyte-specific Bsg-overexpressing mice showed exacerbated RV hypertrophy, fibrosis, and dysfunction compared with their littermates under chronic hypoxia and pulmonary artery banding. Treatment with celastrol, which we identified as a suppressor of Bsg and CyPA by drug screening, decreased proliferation, reactive oxygen species, and inflammatory cytokines in pulmonary artery smooth muscle cells. Furthermore, celastrol treatment ameliorated RV systolic pressure, hypertrophy, fibrosis, and dysfunction in hypoxia-induced PH in mice and SU5416/hypoxia-induced PH in rats with reduced Bsg, CyPA, and inflammatory cytokines in the hearts and lungs. These results indicate that elevated Bsg in pressure-overloaded RV exacerbates RV dysfunction and that celastrol ameliorates RV dysfunction in PH model animals by suppressing Bsg and its ligand CyPA. Thus, celastrol can be a novel drug for PH and RV failure that targets Bsg and CyPA. Graphic Abstract: A graphic abstract is available for this article.

Sex Differences in Right Ventricular Dysfunction: Insights From the Bench to Bedside.

There are inherent distinctions in right ventricular (RV) performance based on sex as females have better RV function than males. These differences are magnified and have very important prognostic implications in two RV-centric diseases, pulmonary hypertension (PH), and arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D). In both PH and ARVC/D, RV dysfunction results in poor patient outcomes. However, there are no currently approved therapies specifically targeting the failing RV, an important unmet need for these two life-threatening disorders. In this review, we highlight human data demonstrating divergent RV phenotypes in healthy, PH, and ARVC/D patients based on sex. Furthermore, we discuss the links between estrogen (the female predominant sex hormone), testosterone (the male predominant sex hormone), and dehydroepiandrosterone (a precursor hormone for multiple sex hormones in males and females) and RV function in both disorders. To provide potential mechanistic insights into sex differences in RV function, we review data that investigate how sex hormones combat or contribute to pathophysiological changes in the RV. Finally, we highlight the ongoing clinical trials in pulmonary arterial hypertension targeting estrogen and dehydroepiandrosterone signaling. Hopefully, a greater understanding of the factors that promote superior RV function in females will lead to novel therapeutic approaches to combat RV dysfunction in PH and ARVC/D.

Accuracy and Reproducibility of Right Ventricular Quantification in Patients with Pressure and Volume Overload Using Single-Beat Three-Dimensional Echocardiography

BackgroundThe right ventricle is a complex structure that is challenging to quantify by two-dimensional (2D) echocardiography. Unlike disk summation three-dimensional (3D) echocardiography (3DE), single-beat 3DE can acquire large volumes at high volume rates in one cardiac cycle, avoiding stitching artifacts or long breath-holds. The aim of this study was to assess the accuracy and test-retest reproducibility of single-beat 3DE for quantifying right ventricular (RV) volumes in adult populations of acquired RV pressure or volume overload, namely, pulmonary hypertension (PH) and carcinoid heart disease, respectively. Three-dimensional and 2D echocardiographic indices were also compared for identifying RV dysfunction in PH.MethodsA prospective cross-sectional study was performed in 100 individuals who underwent 2D echocardiography, 3DE, and cardiac magnetic resonance imaging: 49 patients with PH, 20 with carcinoid heart disease, 11 with metastatic carcinoid tumors without cardiac involvement, and 20 healthy volunteers. Two operators performed test-retest acquisition and postprocessing for inter- and intraobserver reproducibility in 20 subjects.Results:RV single-beat 3DE was attainable in 96% of cases, with mean volume rates of 32 to 45 volumes/sec. Bland-Altman analysis of all subjects (presented as mean bias ± 95% limits of agreement) revealed good agreement for end-diastolic volume (−2.3 ± 27.4 mL) and end-systolic volume (5.2 ± 19.0 mL) measured by 3DE and cardiac magnetic resonance imaging, with a tendency to underestimate stroke volume (−7.5 ± 23.6 mL) and ejection fraction (−4.6 ± 13.8%) by 3DE. Subgroup analysis demonstrated a greater bias for volumetric underestimation, particularly in healthy volunteers (end-diastolic volume, −11.9 ± 18.0 mL; stroke volume, −11.2 ± 20.2 mL). Receiver operating characteristic curve analysis showed that 3DE-derived ejection fraction was significantly superior to 2D echocardiographic parameters for identifying RV dysfunction in PH (sensitivity, 94%; specificity, 88%; area under the curve, 0.95; P = .031). There was significant interobserver test-retest bias for RV volume underestimation (end-diastolic volume, −12.5 ± 28.1 mL; stroke volume, −10.6 ± 23.2 mL).ConclusionsSingle-beat 3DE is feasible and clinically applicable for volumetric quantification in acquired RV pressure or volume overload. It has improved limits of agreement compared with previous disk summation 3D echocardiographic studies and has incremental value over standard 2D echocardiographic measures for identifying RV dysfunction. Despite the ability to obtain and postprocess a full-volume 3D echocardiographic RV data set, the quality of the raw data did influence the accuracy of the data obtained. The technique performs better with dilated rather than nondilated RV cavities, with a learning curve that might affect the test-retest reproducibility for serial RV studies.

Global and Regional Right Ventricular Dysfunction in Pulmonary Hypertension

Pulmonary hypertension (PH) is known to affect the right ventricular (RV) function. To assess the extent of global and regional RV dysfunction in PH patients. We performed a cross-sectional study on 20 controls (age 62 ± 15 years, 7 males) and 35 patients (age 67 ± 12 years, 13 males) with PH of mixed etiologies and assessed RV inflow and outflow tracts (OTs) function, using speckle tracking echocardiography (STE) based myocardial deformation and its time relations. RV inlet and OT dimensions (2D), inlet myocardial velocities (TDI), myocardial strain and strain rate (SR), TAPSE (M-mode), ejection and filling times (pulsed-wave [PW] Doppler), and pulmonary artery acceleration (PAc) were measured. RV inlet and OT were dilated (P < 0.001 for both) and TAPSE (P < 0.001), inlet velocities (P < 0.001), basal and mid-cavity strain, SR and longitudinal displacement reduced (P < 0.001 for all). The time to peak systolic SR at basal, mid-cavity (P < 0.001 for both), and RVOT (P = 0.007) was short as was that to peak displacement (P < 0.001 for all). The time to peak pulmonary ejection correlated with time to peak SR at RVOT (r = 0.7, P < 0.001) in controls, but with that of the mid-cavity in patients (r = 0.71, P < 0.001). PAc was faster (P = 0.001) and RV filling time shorter in patients (P = 0.03) with respect to controls. PH has drastic effects on RV structure and intrinsic myocardial function, significantly disturbing its ejection time relations and overall pump performance. Increased RV afterload results in RV configuration changes with the inflow tract determining peak ejection rather than OT.

RV Dysfunction In Pulmonary Hypertension Is Independently Related To Pulmonary Artery Stiffness

This study investigated whether right ventricular (RV) adaptation to chronic pressure overload is associated with pulmonary artery (PA) stiffness beyond the degree of severity of pulmonary hypertension (PH). Increased PA stiffness has been associated with reduced survival in PH. The mechanisms for this association remain unclear. Right heart catheterization and cardiac magnetic resonance were performed within 1 week in 124 patients with known or suspected chronic PH. Pulmonary vascular resistance index (PVRI) and PA pressures were quantified from right heart catheterization. Cardiac magnetic resonance included standard biventricular cine sequences and main PA flow quantification with phase-contrast imaging. Indexes of PA stiffness (elasticity, distensibility, capacitance, stiffness index beta, and pulse pressure) were quantified combining right heart catheterization and cardiac magnetic resonance data. RV performance and adaptation were measured by RV ejection fraction, right ventricular mass index (RVMI), RV end-systolic volume index, and right ventricular stroke work index (RVSWI). All indexes of PA stiffness were significantly correlated with measures of RV performance (Spearman rho coefficients ranging from -0.20 to 0.61, p < 0.05). Using multivariate regression analysis, PA elasticity, distensibility, and index beta were independently associated with all measures of RV performance after adjusting PVRI (p ≤ 0.024). PA capacitance was independently associated with RV ejection fraction, RVMI, and RVSWI (p < 0.05), whereas PA pulse pressure was associated with RVMI and RVSWI (p ≤ 0.027). Compared with PVRI, PA elasticity, distensibility, capacitance, and index beta explained 15% to 68% of the variability in RV ejection fraction, RVMI, and RV end-systolic volume index. Relative contributions of PA stiffness for RVSWI were 1.2× to 18.0× higher than those of PVRI. PA stiffness is independently associated with the degree of RV dysfunction, dilation, and hypertrophy in PH. RV adaptation to chronic pressure overload is related not only to the levels of vascular resistance (steady afterload), but also to PA stiffness (pulsatile load).

Use of the Myocardial Performance Index to Assess Right Ventricular Function in Infants with Pulmonary Hypertension

This study aimed to measure and compare right ventricular (RV) function in normal infants and those with pulmonary hypertension (PHT) using the myocardial performance index (RVMPI) and to investigate the relationship between RV function and pulmonary artery pressure. A case-control study measured RVMPI in 16 infants with PHT (9 of whom had congenital diaphragmatic hernia) and 28 normal control infants. For the PHT infants, 43 paired measures of RVMPI and pulmonary artery pressure (estimated from tricuspid regurgitation jet velocity) were taken to allow investigation of the relationship between RVMPI and pulmonary artery pressure. The mean RVMPI for the control infants was 0.24+/-0.09. The RVMPI was significantly elevated in the PHT group (0.55+/-0.17; p<0.0001), including a subgroup of infants with PHT secondary to congenital diaphragmatic hernia (0.58+/-0.18; p<0.0001). The correlation between RVMPI and pulmonary artery pressure in the infants with PHT (R2=0.05; p=0.17) was poor. In infants, RVMPI allows quantification of right ventricular function and detection of RV dysfunction in PHT. No linear relationship exists between RVMPI pulmonary artery pressure. Use of RVMPI in the clinical setting must take into account the global and load-dependent nature of this measure.

Plasma Brain Natriuretic Peptide Levels Increase in Proportion to the Extent of Right Ventricular Dysfunction in Pulmonary Hypertension

Objectives. This study sought to investigate the influence of right ventricular (RV) hemodynamic variables and function on the secretion of brain natriuretic peptide (BNP) in patients with isolated RV overload.Background. Plasma BNP is known to increase in proportion to the degree of left ventricular (LV) overload. However, whether BNP secretion is also regulated in the presence of RV overload remains unknown.Methods. Plasma BNP and atrial natriuretic peptide (ANP) levels in the pulmonary artery were measured in 44 patients with RV overload: 18 with RV volume overload (RVVO) due to atrial septal defect and 26 with RV pressure overload (RVPO) due to primary or thromboembolic pulmonary hypertension. Right heart catheterization was performed in all patients. RV and LV ejection fraction, myocardial mass and volume of the four chambers were determined by using electron beam computed tomography.Results. Although both plasma BNP and ANP levels were significantly elevated in patients with RV overload compared with values in control subjects, plasma BNP and the BNP/ANP ratio were significantly higher in patients with RVPO than with RVVO (BNP 294 ± 72 vs. 48 ± 14 pg/ml; BNP/ANP 1.6 ± 0.2 vs. 0.8 ± 0.2, both p < 0.05). Plasma BNP correlated positively with mean pulmonary artery pressure (r = 0.73), total pulmonary resistance (r = 0.79), mean right atrial pressure (r = 0.79), RV end-diastolic pressure (r = 0.76) and RV myocardial mass (r = 0.71); it correlated negatively with cardiac output (r = −0.33) and RV ejection fraction (r = −0.71). Plasma BNP significantly decreased from 315 ± 120 to 144 ± 54 pg/ml with long-term vasodilator therapy (total pulmonary resistance decreased from 23 ± 4 to 15 ± 3 Wood U).Conclusions. Plasma BNP increases in proportion to the extent of RV dysfunction in pulmonary hypertension.