Pulmonary artery pressure-directed therapies in pulmonary arterial hypertension?

Pulmonary arterial hypertension is a rare dyspnea-fatigue syndrome defined by an increase in mean pulmonary artery pressure above 20 mmHg combined with an increase in pulmonary vascular resistance higher than 2 Wood units. The condition is of poor prognosis and still incurable in spite of progress achieved in recent decades. The approach is currently optimized by multi-drug combinations titrated on serial risk assessments using recently validated scores. In this issue of Vascular Pharmacology argument is made based on retrospective registry data from three reference centers in favor of initial multi-drug therapies including a parenteral prostanoid dosed to decrease mPAP to normal. This objective was achieved in only a minority of patients, but improved outcome was demonstrated when mPAP can be brought to below 35 mmHg. This data suggest that pulmonary artery pressure-directed multi-drug therapies in PAH may reverse right heart remodeling and limit progression, or even reverse pulmonary vascular disease. However, further studies are needed to validate mPAP as a primary endpoint in PAH drug trials. In the meantime, aggressive initial prescription of parenteral prostanoids combined with one or two oral drugs targeting the pulmonary circulation under careful clinical, imaging and hemodynamic follow-up may be the best therapeutic strategy.

Magnolol Attenuates Right Ventricular Hypertrophy and Fibrosis in Hypoxia-Induced Pulmonary Arterial Hypertensive Rats Through Inhibition of the JAK2/STAT3 Signaling Pathway.

Right ventricular (RV) remodeling is one of the essential pathological features in pulmonary arterial hypertension (PAH). RV hypertrophy or fibrosis are the leading causes of RV remodeling. Magnolol (6, 6', 7, 12-tetramethoxy-2,2'-dimethyl-1-ß-berbaman, C18H18O2) is a compound isolated from Magnolia Officinalis. It possesses multiple pharmacological activities, such as anti-oxidation and anti-inflammation. This study aims to evaluate the effects and underlying mechanisms of magnolol on RV remodeling in hypoxia-induced PAH. In vivo, male Sprague Dawley rats were exposed to 10% O2 for 4 weeks to establish an RV remodeling model, which showed hypertrophic and fibrotic features (increases of Fulton index, cellular size, hypertrophic and fibrotic marker expression), accompanied by an elevation in phosphorylation levels of JAK2 and STAT3; these changes were attenuated by treating with magnolol. In vitro, the cultured H9c2 cells or cardiac fibroblasts were exposed to 3% O2 for 48 h to induce hypertrophy or fibrosis, which showed hypertrophic (increases in cellular size as well as the expression of ANP and BNP) or fibrotic features (increases in the expression of collagen Ⅰ, collagen Ⅲ, and α-SMA). Administration of magnolol and TG-101348 or JSI-124 (both JAK2 selective inhibitors) could prevent myocardial hypertrophy and fibrosis, accompanied by the decrease in the phosphorylation level of JAK2 and STAT3. Based on these observations, we conclude that magnolol can attenuate RV hypertrophy and fibrosis in hypoxia-induced PAH rats through a mechanism involving inhibition of the JAK2/STAT3 signaling pathway. Magnolol may possess the potential clinical value for PAH therapy.

Magnolol attenuates right ventricular hypertrophy and fibrosis in hypoxia-induced pulmonary arterial hypertensive rats through inhibition of the JAK2/STAT3 signaling pathway / 中国药理学与毒理学杂志

OBJECTIVE Right ventricular (RV) remodeling is one of the essential pathological features in pulmonary arterial hypertension (PAH). RV hypertrophy or fibrosis are the leading causes of RV remodeling. Magnolol is a com?pound isolated from Magnolia officinalis. It possesses multiple pharmacological activities, such as anti-oxidation and anti-inflammation. This study aims to evaluate the effects and underlying mechanisms of magnolol on RV remodeling in hypoxia-induced PAH. METHODS ① Male SD rats (220 g) were randomly divided into 5 groups (n=10): the normoxia group, the hypoxia group, the hypoxia plus Magnolol (10 and 20 mg·kg-1·d-1) group, and the vehicle group. Rats in the normoxia group were kept in a normoxia environment for 4 weeks, while rats in the hypoxia group were kept in a hypoxic chamber (10％ O2). The rats in the hypoxia plus magnolol groups were administered with magnolol at 10 or 20 mg·kg-1 (ip) once a day for 4 weeks. At the end of 4 weeks, the heart function was assessed by Doppler echocardiography, and then the rats were anesthetized with sodium pentobarbital (30 mg·kg-1, ip). The RVSP was measured by the right heart catheterization method. The heart tissues were collected and dissected to calculate the index of RV remodeling (RV/LV+IVS, RV/tibial length, or RV/body weight). Part of the RV samples was fixed with 4％paraformaldehyde for morphological analysis, while other samples were frozen at-80℃for molecular studies (measurements of ANP, BNP,α-SMA, and col?lagen Ⅰ/Ⅲ mRNA expression as well as p-JAK2/JAK2 and p-STAT3/STAT3 protein levels). ② To evaluate the effect of magnolol on hypoxia-induced myocardial hypertrophy and fibrosis, H9c2 or cardiac fibroblasts were divided into 7 groups: the control group, cells were cultured under normal conditions; the hypoxia group, cells were cultured under hypoxic condition (3％ O2);the hypoxia plus magnolol 10 mg·kg-1 group, magnolol10μmol·L-1 was added to the culture medium before the hypoxia treatment;the hypoxia plus magnolol 30 mg·kg-1 group, magnolol 20μmol·L-1 was added to the culture medium before the hypoxia treatment;the hypoxia plus TG-101348 group, TG-101348 (a specific inhibitor of JAK2) 1μmol·L-1 was added to the culture medium before the hypoxia treatment;the hypoxia plus JSI-124 group, JSI-124 (a specific inhibitor of JAK2) 1μmol·L-1 was added to the culture medium before the hypoxia treatment;and the hypoxia plus vehicle group, an equal volume of vehicle (DMSO) was added to the culture medium before the hypoxia treatment. At the end of the experiments, the cells were collected for morphological and molecular analysis. RESULTS In vivo, male Sprang-Daley rats were exposed to 10％ O2 for 4 weeks to establish an RV remodeling model, which showed hypertrophic and fibrotic features (increases of RV remodeling index, cellular size, hypertrophic and fibrotic marker expression), accompanied by an elevation in phosphorylation levels of JAK2 and STAT3;these changes were attenuated by treating rats with magnolol. In vitro, the cultured H9c2 cells or cardiac fibroblasts were exposed to 3％ O2 for 48 h to induce hypertrophy or fibrosis, which showed hypertrophic (increases in cellular size as well as the expression of ANP and BNP) or fibrotic features (increases in the expression of collagenⅠ, collagenⅢandα-SMA). Administration of mag?nolol and TG-101348 or JSI-124 (JAK2 selective inhibitors) could prevent the process of myocardial hypertrophy and fibrosis, accompanied by the decrease in the phosphorylation level of JAK2 and STAT3. CONCLUSION Magnolol can attenuate RV hypertrophy and fibrosis in hypoxia-induced PAH rats through a mechanism involving inhibition of the JAK2/STAT3 signaling pathway.

Epigenetic Regulation of Pulmonary Arterial Hypertension-Induced Vascular and Right Ventricular Remodeling: New Opportunities?

Pulmonary artery hypertension (PAH) is a rare chronic disease with high impact on patients' quality of life and currently no available cure. PAH is characterized by constant remodeling of the pulmonary artery by increased proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs), fibroblasts (FBs) and endothelial cells (ECs). This remodeling eventually leads to increased pressure in the right ventricle (RV) and subsequent right ventricle hypertrophy (RVH) which, when left untreated, progresses into right ventricle failure (RVF). PAH can not only originate from heritable mutations, but also develop as a consequence of congenital heart disease, exposure to drugs or toxins, HIV, connective tissue disease or be idiopathic. While much attention was drawn into investigating and developing therapies related to the most well understood signaling pathways in PAH, in the last decade, a shift towards understanding the epigenetic mechanisms driving the disease occurred. In this review, we reflect on the different epigenetic regulatory factors that are associated with the pathology of RV remodeling, and on their relevance towards a better understanding of the disease and subsequently, the development of new and more efficient therapeutic strategies.

The novel P2X7 receptor antagonist PKT100 improves cardiac function and survival in pulmonary hypertension by direct targeting of the right ventricle.

In pulmonary hypertension (PH) a proinflammatory milieu drives pulmonary vascular remodeling, maladaptive right ventricular (RV) remodeling, and right-sided heart failure. There is an unmet need for RV-targeted pharmaco-therapies to improve mortality. Targeting of the P2X7 receptor (P2X7R) reduces pulmonary pressures; however, its effects on the RV are presently unknown. We investigated the effect of P2X7 receptor (P2X7R) inhibition on the pulmonary vasculature and RV remodeling using the novel P2X7R antagonist PKT100. C57BL/6 mice were administered intratracheal bleomycin or saline and treated with PKT100 (0.2 mg·kg-1·day-1) or DMSO vehicle. RV was assessed by right heart catheterization and echocardiography, 21 days posttreatment. Cytokines in serum and bronchoalveolar lavage fluid (BALF) were analyzed by ELISA and flow cytometry. Lungs and hearts were analyzed histologically for pulmonary vascular and RV remodeling. Focused-PCR using genes involved in RV remodeling was performed. Right ventricular systolic pressure (RVSP) was elevated in bleomycin-treated mice (30.2 ± 1.1; n = 7) compared with control mice (23.5 ± 1.0; n = 10; P = 0.008). PKT100 treatment did not alter RVSP (32.4 ± 1.8; n = 9), but it substantially improved survival (93% vs. 57% DMSO). There were no differences between DMSO and PKT100 bleomycin mice in pulmonary inflammation or remodeling. However, RV hypertrophy was reduced in PKT100 mice. Bleomycin decreased echocardiographic surrogates of RV systolic performance, which were significantly improved with PKT100. Four genes involved in RV remodeling (RPSA, Rplp0, Add2, and Scn7a) were differentially expressed between DMSO and PKT100-treated groups. The novel P2X7R inhibitor, PKT100, attenuates RV hypertrophy and improves RV contractile function and survival in a mouse model of PH independently of effects on the pulmonary vasculature. PKT100 may improve ventricular response to increased afterload and merits further investigation into the potential role of P2X7R antagonists as direct RV-focused therapies in PH.NEW & NOTEWORTHY This study demonstrates the therapeutic potential for right-sided heart failure of a novel inhibitor of the P2X7 receptor (P2X7R). Inflammatory signaling and right ventricular function were improved in a mouse model of pulmonary fibrosis with secondary pulmonary hypertension when treated with this inhibitor. Importantly, survival was also improved, suggesting that this inhibitor, and other P2X7R antagonists, could be uniquely effective in right ventricle (RV)-targeted therapy in pulmonary hypertension. This addresses a major limitation of current treatment options, where the significant improvements in pulmonary pressures ultimately do not prevent mortality due to RV failure.

Impact of right atrium dimension on adverse outcome after pulmonary valve replacement in repaired Tetralogy of Fallot patients.

The hemodynamic impact of residual pulmonary regurgitation (PR) in repaired Tetralogy of Fallot (rTOF) has been well demonstrated. However, markers driving the decision making process to indicate the ideal timing of pulmonary valve replacement (PVR) are still uncertain. Furthermore, very few studies have included the right atrium (RA) dilatation as a preoperative risk factor for post-PVR clinical adverse outcome. The aim of this study was to investigate the impact of pre-PVR right atrial dilation on adverse outcomes in rTOF. We retrospectively reviewed from our CMR database all rTOF patients who underwent CMR study before and after PVR. Detailed clinical and surgical history were collected, in addition to imaging data. The composite primary and secondary post-PVR end points were also recorded. The study cohort consisted of 41 patients (mean age at PVR repair 27.4 ± 10 years). As expected, end-diastolic and end-systolic right ventricle (RV) volumes significantly decreased after PVR (p < 0.001). The RV reverse remodeling, defined by ΔRVEDVi and ΔRVESVi, was associated with both pre-PVR RVEDVi and RVESVi. The higher the pre-PVR RV volumes, more the RV reverse remodeling will be obtained post-surgery. Patients who experienced an adverse outcome were older at pre-PVR, they had a higher Nt-ProBNP, worse VO2/kg/min, more significant tricuspid regurgitation and more dilated RA. The association with the RA dilatation persists and becomes even more significant if we exclude patients who had tricuspid repair beside RVOT surgical reconstruction. Besides RV volumes and function, RA dimensions may play a pivotal role in the decision making of TOF patients.

Distinct right ventricle remodeling in response to pressure overload in the rat.

Pulmonary arterial hypertension (PAH), the most serious chronic disorder of the pulmonary circulation, is characterized by pulmonary vasoconstriction and remodeling, resulting in increased afterload on the right ventricle (RV). In fact, RV function is the main determinant of prognosis in PAH. The most frequently used experimental models of PAH include monocrotaline- and chronic hypoxia-induced PAH, which primarily affect the pulmonary circulation. Alternatively, pulmonary artery banding (PAB) can be performed to achieve RV overload without affecting the pulmonary vasculature, allowing researchers to determine the RV-specific effects of their drugs/interventions. In this work, using two different degrees of pulmonary artery constriction, we characterize, in full detail, PAB-induced adaptive and maladaptive remodeling of the RV at 3 wk after PAB surgery. Our results show that application of a mild constriction resulted in adaptive hypertrophy of the RV, with preserved systolic and diastolic function, while application of a severe constriction resulted in maladaptive hypertrophy, with chamber dilation and systolic and diastolic dysfunction up to the isolated cardiomyocyte level. By applying two different degrees of constriction, we describe, for the first time, a reliable and short-duration PAB model in which RV adaptation can be distinguished at 3 wk after surgery. We characterize, in full detail, structural and functional changes of the RV in its response to moderate and severe constriction, allowing researchers to better study RV physiology and transition to dysfunction and failure, as well as to determine the effects of new therapies.

Right ventricular remodeling, its correlates, and its clinical impact in hypertrophic cardiomyopathy.

BACKGROUND: Structural right ventricular (RV) abnormalities are present in a substantial proportion of patients with hypertrophic cardiomyopathy (HCM), but the trigger for RV hypertrophy remains unclear. The aim of this study was to assess the relationship between RV and left ventricular (LV) remodeling and the impact of biventricular involvement on clinical status in this setting. METHODS: Ninety-nine patients with HCM and 30 normal subjects with a similar age and gender distribution were prospectively enrolled. Comprehensive echocardiography was performed in all, including the assessment of LV and RV function by tissue Doppler and speckle-tracking echocardiography. Measurement of RV free wall thickness (RVWT) was performed at end-diastole, in a zoomed subcostal view, focusing on the RV midwall. RESULTS: Patients with HCM had increased RVWT (6.4 ± 1.9 vs 3.6 ± 0.8 mm, P < .001) and lower values of RV global longitudinal strain (-19.4 ± 4.4% vs -23.8 ± 2.7%, P < .001) compared with control subjects. RVWT was independently related to LV mass and LV global longitudinal strain. Increased RVWT was correlated with New York Heart Association class (r = 0.20, P = .04) and calculated sudden cardiac death risk score (r = 0.52, P < .001) and was independently related to the presence of ventricular arrhythmias (odds ratio, 2.02; 95% CI, 1.28-3.19; P = .002). CONCLUSIONS: In patients with HCM, the presence of RV hypertrophy was associated with increased LV mass and reduced LV longitudinal strain, correlated with increased calculated sudden cardiac death risk score, and independently related to the presence of ventricular arrhythmias. These data suggest more severe disease in patients with biventricular HCM.

Right ventricular remodeling in idiopathic pulmonary arterial hypertension: adaptive versus maladaptive morphology.

BACKGROUND: Although increased pulmonary pressure is caused by changes in the pulmonary vasculature, prognosis in idiopathic pulmonary arterial hypertension (IPAH) is strongly associated with right ventricular (RV) function. The aim of this study was to describe the best RV adaptive remodeling pattern to increased afterload in IPAH. METHODS: In 60 consecutive patients with IPAH, RV morphologic and functional features were evaluated by echocardiography and cardiac magnetic resonance imaging. To address the question of the best RV adaptation pattern, we divided the study population into two groups by the median value of RV mass/volume ratio (0.46) because this parameter allows the distinction between RV eccentric (≤0.46) and concentric hypertrophy (>0.46). The two groups were compared for RV remodeling and systolic function parameters, World Health Organization class, pulmonary hemodynamics, and 6-minute walk test. RESULTS: Despite similar pulmonary vascular resistance, mean pulmonary pressure, and compliance, patients with eccentric hypertrophy had advanced World Health Organization class and worse 6-minute walk test, hemodynamics, RV remodeling, and systolic function parameters compared with patients with concentric hypertrophy. The group with concentric hypertrophy had higher RV to pulmonary arterial coupling compared with the group with eccentric hypertrophy (1.24 ± 0.26 vs 0.83 ± 0.33, p = 0.0001), indicating higher RV efficiency. A significant correlation was found between pulmonary vascular resistance and RV to pulmonary arterial coupling (r = -0.55, r(2) = 0.31, p = 0.0001), with patients with RV mass/volume ratio > 0.46 at the higher part of the scatterplot, confirming more adequate RV function. CONCLUSIONS: Concentric hypertrophy might represent a more favorable RV adaptive remodeling pattern to increased afterload in IPAH because it is associated with more suitable systolic function and mechanical efficiency.