A Murine Model of Pressure Overload-Induced Right Ventricular Hypertrophy and Failure by Pulmonary Trunk Banding.

Right ventricular (RV) failure caused by pressure overload is strongly associated with morbidity and mortality in a number of cardiovascular and pulmonary diseases. The pathogenesis of RV failure is complex and remains inadequately understood. To identify new therapeutic strategies for the treatment of RV failure, robust and reproducible animal models are essential. Models of pulmonary trunk banding (PTB) have gained popularity, as RV function can be assessed independently of changes in the pulmonary vasculature. In this paper, we present a murine model of RV pressure overload induced by PTB in 5-week-old mice. The model can be used to induce different degrees of RV pathology, ranging from mild RV hypertrophy to decompensated RV failure. Detailed protocols for intubation, PTB surgery, and phenotyping by echocardiography are included in the paper. Furthermore, instructions for customizing instruments for intubation and PTB surgery are given, enabling fast and inexpensive reproduction of the PTB model. Titanium ligating clips were used to constrict the pulmonary trunk, ensuring a highly reproducible and operator-independent degree of pulmonary trunk constriction. The severity of PTB was graded by using different inner ligating clip diameters (mild: 450 µm and severe: 250 µm). This resulted in RV pathology ranging from hypertrophy with preserved RV function to decompensated RV failure with reduced cardiac output and extracardiac manifestations. RV function was assessed by echocardiography at 1 week and 3 weeks after surgery. Examples of echocardiographic images and results are presented here. Furthermore, results from right heart catheterization and histological analyses of cardiac tissue are shown.

Nur77 induced by HIF-1α mediates vascular remodeling in hypoxic pulmonary hypertension.

Nur77 is a member of the NR4A subfamily of orphan nuclear receptors that is expressed and has a function within the immune system. This study aimed to investigate the role of Nur77 in hypoxic pulmonary hypertension. SPF male SD rats were exposed in hypobaric chamber simulating 5000 m high altitude for 0, 3, 7, 14, 21 or 28 days. Rat pulmonary artery smooth muscle cells (RPASMCs) were cultured under normoxic conditions (5% CO2-95% ambient air) or hypoxic conditions (5% O2 for 6 h, 12 h, 24 h, 48 h). Hypoxic rats developed pulmonary arterial remodeling and right ventricular hypertrophy with significantly increased pulmonary arterial pressure. The levels of Nur77, HIF-1α and PNCA were upregulated in pulmonary arterial smooth muscle from hypoxic rats. Silencing of either Nur77 or HIF-1α attenuated hypoxia-induced proliferation. Silencing of HIF-1α down-regulated Nur77 protein level, but Nur77 silence did not reduce HIF-1α. Nur77 was not con-immunoprecipitated with HIF-1α. This study demonstrated that Nur77 acted as a downstream regulator of HIF-1α under hypoxia, and plays a critical role in the hypoxia-induced pulmonary vascular remodeling, which is regulated by HIF-1α. Nur77 maybe a novel target of HPH therapy.

Does Cell-Type-Specific Silencing of Monoamine Oxidase B Interfere with the Development of Right Ventricle (RV) Hypertrophy or Right Ventricle Failure in Pulmonary Hypertension?

Increased mitochondrial reactive oxygen species (ROS) formation is important for the development of right ventricular (RV) hypertrophy (RVH) and failure (RVF) during pulmonary hypertension (PH). ROS molecules are produced in different compartments within the cell, with mitochondria known to produce the strongest ROS signal. Among ROS-forming mitochondrial proteins, outer-mitochondrial-membrane-located monoamine oxidases (MAOs, type A or B) are capable of degrading neurotransmitters, thereby producing large amounts of ROS. In mice, MAO-B is the dominant isoform, which is present in almost all cell types within the heart. We analyzed the effect of an inducible cardiomyocyte-specific knockout of MAO-B (cmMAO-B KO) for the development of RVH and RVF in mice. Right ventricular hypertrophy was induced by pulmonary artery banding (PAB). RV dimensions and function were measured through echocardiography. ROS production (dihydroethidium staining), protein kinase activity (PamStation device), and systemic hemodynamics (in vivo catheterization) were assessed. A significant decrease in ROS formation was measured in cmMAO-B KO mice during PAB compared to Cre-negative littermates, which was associated with reduced activity of protein kinases involved in hypertrophic growth. In contrast to littermates in which the RV was dilated and hypertrophied following PAB, RV dimensions were unaffected in response to PAB in cmMAO-B KO mice, and no decline in RV systolic function otherwise seen in littermates during PAB was measured in cmMAO-B KO mice. In conclusion, cmMAO-B KO mice are protected against RV dilatation, hypertrophy, and dysfunction following RV pressure overload compared to littermates. These results support the hypothesis that cmMAO-B is a key player in causing RV hypertrophy and failure during PH.

Preparation of the new peptide drug ACTY116-loaded in situ forming implants and evaluation of its efficacy in pulmonary arterial hypertension and right ventricular hypertrophy induced by SU5416/hypoxia in mice.

There is a lack of effective therapeutic drugs for pulmonary arterial hypertension. Previous studies have demonstrated the positive cardiovascular system protective effects of the new peptide ACTY116. However, its stability in ordinary aqueous solution injections is poor and its half-life in the body is short, which has hindered the development of preparations. This study aimed to prepare in situ forming implants (ISFIs) of the peptide ACTY116 and investigate its impact on pulmonary arterial hypertension. We prepared ISFIs using NMP/TA as a solvent and PLGA as a polymer. These ISFIs exhibited low viscosity, low toxicity and sustained release properties. In a mouse model of pulmonary hypertension induced by SU5416/hypoxia, both ISFIs and ACTY116 peptides effectively reduced pulmonary hypertension, cardiac hypertrophy and pulmonary blood vessel wall thickness. In conclusion, this study highlights the potential of ACTY116 as a treatment for pulmonary arterial hypertension and suggests that incorporating it into an in-situ gel implant could be a promising option.

Mechanisms of cordycepin in the treatment of pulmonary arterial hypertension in rats based on metabonomics and transcriptomics.

Pulmonary arterial hypertension (PAH) is a fatal disease featured by high morbidity and mortality. Although Cordycepin is known for its anti-inflammatory, antioxidant and immune-enhancing effects, its role in PAH treatment and the underlying mechanisms remain unclear. The therapeutic effects of Cordycepin on rats with PAH were investigated using a monocrotaline (MCT)-induced rat model. The metabolic effects of Cordycepin were assessed based on the plasma metabolome. The potential mechanisms of Cordycepin in PAH treatment were investigated through transcriptome sequencing and validated in pulmonary artery smooth muscle cells (PASMC). Evaluations included hematoxylin and eosin staining for pulmonary vascular remodeling, CCK-8 assay, EDU, and TUNEL kits for cell viability, proliferation, and apoptosis, respectively, and western blot for protein expression. Cordycepin significantly reduced right ventricular systolic pressure (RVSP) and right ventricular hypertrophy index (RVHI) in PAH rats, and mitigated pulmonary vascular remodeling. Plasma metabolomics showed that Cordycepin could reverse the metabolic disorders in the lungs of MCT-induced PAH rats, particularly impacting linoleic acid and alpha-linolenic acid metabolism pathways. Transcriptomics revealed that the P53 pathway might be the primary pathway involved, and western blot results showed that Cordycepin significantly increased P53 and P21 protein levels in lung tissues. Integrated analysis of transcriptomics and metabolomics suggested that these pathways were mainly enriched in linoleic acid metabolism and alpha-linolenic acid metabolism pathway. In vitro experiments demonstrated that Cordycepin significantly inhibited the PDGFBB (PD)-induced abnormal proliferation and migration of PASMC and promoted PD-induced apoptosis. Meanwhile, Cordycepin enhanced the expression levels of P53 and P21 proteins in PD-insulted PASMC. However, inhibitors of P53 and P21 eliminated these effects of Cordycepin. Cordycepin may activate the P53-P21 pathway to inhibit abnormal proliferation and migration of PASMC and promote apoptosis, offering a potential approach for PAH treatment.

Bawei Chenxiang Wan ameliorates right ventricular hypertrophy in rats with high altitude heart disease by SIRT3-HIF1α-PDK/PDH signaling pathway improving fatty acid and glucose metabolism.

BACKGROUND: Bawei Chenxiang Wan (BCW) is among the most effective and widely used therapies for coronary heart disease and angina pectoris in Tibet. However, whether it confers protection through a right-ventricle (RV) myocardial metabolic mechanism is unknown. METHODS: Male Sprague-Dawley rats were orally administrated with BCW, which was injected concurrently with a bolus of Sugen5416, and subjected to hypoxia exposure (SuHx; 5000 m altitude) for 4 weeks. Right ventricular hypertrophy (RVH) in high-altitude heart disease (HAHD) was assessed using Fulton's index (FI; ratio of RV to left ventricle + septum weights) and heart-weight-to-body-weight ratio (HW/BW). The effect of therapeutic administration of BCW on the RVH hemodynamics was assessed through catheterization (mean right ventricular pressure and mean pulmonary artery pressure (mRVP and mPAP, respectively)). Tissue samples were used to perform histological staining, and confirmatory analyses of mRNA and protein levels were conducted to detect alterations in the mechanisms of RVH in HAHD. The protective mechanism of BCW was further verified via cell culture. RESULTS: BCW considerably reduced SuHx-associated RVH, as indicated by macro morphology, HW/BW ratio, FI, mPAP, mRVP, hypertrophy markers, heart function, pathological structure, and myocardial enzymes. Moreover, BCW can alleviate the disorder of glucose and fatty acid metabolism through upregulation of carnitine palmitoyltransferase1ɑ, citrate synthase, and acetyl-CoA and downregulation of glucose transport-4, phosphofructokinase, and pyruvate, which resulted in the reduced levels of free fatty acid and lactic acid and increased aerobic oxidation. This process may be mediated via the regulation of sirtuin 3 (SIRT3)-hypoxia-inducible factor 1α (HIF1α)-pyruvate dehydrogenase kinase (PDK)/pyruvate dehydrogenase (PDH) signaling pathway. Subsequently, the inhibition of SIRT3 expression by 3-TYP (a selective inhibitor of SIRT3) can reverse substantially the anti-RVH effect of BCW in HAHD, as indicated by hypertrophy marker and serum myocardial enzyme levels. CONCLUSIONS: BCW prevented SuHx-induced RVH in HAHD via the SIRT3-HIF1ɑ-PDK/PDH signaling pathway to alleviate the disturbance in fatty acid and glucose metabolism. Therefore, BCW can be used as an alternative drug for the treatment of RVH in HAHD.

Echocardiographic features of right ventricle in septic patients with elevated central venous pressure.

BACKGROUND: Elevated central venous pressure (CVP) is deemed as a sign of right ventricular (RV) dysfunction. We aimed to characterize the echocardiographic features of RV in septic patients with elevated CVP, and quantify associations between RV function parameters and 30-day mortality. METHODS: We retrospectively reviewed a cohort of septic patients with CVP ≥ 8 mmHg in a tertiary hospital intensive care unit. General characteristics and echocardiographic parameters including tricuspid annular plane systolic excursion (TAPSE), pulmonary vascular resistance (PVR) as well as prognostic data were collected. Associations between RV function parameters and 30-day mortality were assessed using Cox regression models. RESULTS: Echocardiography was performed in 244 septic patients with CVP ≥ 8 mmHg. Echocardiographic findings revealed that various types of abnormal RV function can occur individually or collectively. Prevalence of RV systolic dysfunction was 46%, prevalence of RV enlargement was 34%, and prevalence of PVR increase was 14%. In addition, we collected haemodynamic consequences and found that prevalence of systemic venous congestion was 16%, prevalence of RV-pulmonary artery decoupling was 34%, and prevalence of low cardiac index (CI) was 23%. The 30-day mortality of the enrolled population was 24.2%. In a Cox regression analysis, TAPSE (HR:0.542, 95% CI:0.302-0.972, p = 0.040) and PVR (HR:1.384, 95% CI:1.007-1.903, p = 0.045) were independently associated with 30-day mortality. CONCLUSIONS: Echocardiographic findings demonstrated a high prevalence of RV-related abnormalities (RV enlargement, RV systolic dysfunction and PVR increase) in septic patients with elevated CVP. Among those echocardiographic parameters, TAPSE and PVR were independently associated with 30-day mortality in these patients.

Effect of free and nanoemulsified ß-caryophyllene on monocrotaline-induced pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is characterized by increased pulmonary vascular resistance (PVR), right ventricular (RV) failure and premature death. Compounds with vasodilatory characteristics, such as ß-caryophyllene, could be promising therapeutics for PAH. This study aimed to determine the effects of free and nanoemulsified ß-caryophyllene in lung oxidative stress and heart function in PAH rats. Male Wistar rats (170 g, n = 6/group) were divided into four groups: control (CO), monocrotaline (MCT), monocrotaline + ß-caryophyllene (MCT-Bcar) and monocrotaline + nanoemulsion with ß-caryophyllene (MCT-Nano). PAH was induced by MCT (60 mg/kg i.p.), and 7 days later, treatment with ß-caryophyllene, either free or in a nanoemulsion (by gavage, 176 mg/kg/day) or vehicle was given for 14 days. Echocardiographic and hemodynamic measurements were performed, and after, the RV was collected for morphometry and the lungs for evaluation of oxidative stress, antioxidant enzymes, total sulfhydryl compounds, nitric oxide synthase (NOS) activity and endothelin-1 receptor expression. RV hypertrophy, increased PVR and RV systolic and diastolic pressures (RVSP and RVEDP, respectively) and increased mean pulmonary arterial pressure (mPAP) were observed in the MCT group. Treatment with both free and nanoemulsified ß-caryophyllene reduced RV hypertrophy, mPAP, RVSP and lipid peroxidation. The reduction in RVSP was more pronounced in the MCT-Nano group. Moreover, RVEDP decreased only in the MCT-Nano group. These treatments also increased superoxide dismutase, catalase and NOS activities and decreased endothelin-1 receptors expression. Both ß-caryophyllene formulations improved mPAP, PVR and oxidative stress parameters. However, ß-caryophyllene in a nanoemulsion was more effective in attenuating the effects of PAH.

Sulforaphane Improves Redox Homeostasis and Right Ventricular Contractility in a Model of Pulmonary Hypertension.

ABSTRACT: Pulmonary arterial hypertension (PAH) is characterized by increased pulmonary vascular resistance (PVR), imposing overload on the right ventricle (RV) and imbalance of the redox state. Our study investigated the influence of treatment with sulforaphane (SFN), found in cruciferous vegetables, on RV remodeling and redox homeostasis in monocrotaline (MCT)-induced PAH. Male Wistar rats were separated into 4 groups: control (CTR); CTR + SFN; MCT; and MCT + SFN. PAH induction was implemented by a single dose of MCT (60 mg/kg intraperitoneally). Treatment with SFN (2.5 mg/kg/day intraperitoneally) started on the seventh day after the MCT injection and persisted for 2 weeks. After 21 days of PAH induction, echocardiographic, hemodynamic, and oxidative stress evaluation was performed. The MCT group showed an increase in RV hypertrophy, RV systolic area, RV systolic, mean pulmonary artery pressure, and PVR and exhibited a decrease in the RV outflow tract acceleration time/ejection time ratio, RV fractional shortening, and tricuspid annular plane systolic excursion compared to CTR ( P < 0.05). SFN-treated PAH attenuated detrimental changes in tricuspid annular plane systolic excursion, mean pulmonary artery pressure, and PVR parameters. Catalase levels and the glutathione/Glutathione disulfide (GSSG) ratio were diminished in the MCT group compared to CTR ( P < 0.05). SFN increased catalase levels and normalized the glutathione/GSSG ratio to control levels ( P < 0.05). Data express the benefit of SFN treatment on the cardiac function of rats with PAH associated with the cellular redox state.

Metabolic changes contribute to maladaptive right ventricular hypertrophy in pulmonary hypertension beyond pressure overload: an integrative imaging and omics investigation.

Right ventricular (RV) failure remains the strongest determinant of survival in pulmonary hypertension (PH). We aimed to identify relevant mechanisms, beyond pressure overload, associated with maladaptive RV hypertrophy in PH. To separate the effect of pressure overload from other potential mechanisms, we developed in pigs two experimental models of PH (M1, by pulmonary vein banding and M2, by aorto-pulmonary shunting) and compared them with a model of pure pressure overload (M3, pulmonary artery banding) and a sham-operated group. Animals were assessed at 1 and 8 months by right heart catheterization, cardiac magnetic resonance and blood sampling, and myocardial tissue was analyzed. Plasma unbiased proteomic and metabolomic data were compared among groups and integrated by an interaction network analysis. A total of 33 pigs completed follow-up (M1, n = 8; M2, n = 6; M3, n = 10; and M0, n = 9). M1 and M2 animals developed PH and reduced RV systolic function, whereas animals in M3 showed increased RV systolic pressure but maintained normal function. Significant plasma arginine and histidine deficiency and complement system activation were observed in both PH models (M1&M2), with additional alterations to taurine and purine pathways in M2. Changes in lipid metabolism were very remarkable, particularly the elevation of free fatty acids in M2. In the integrative analysis, arginine-histidine-purines deficiency, complement activation, and fatty acid accumulation were significantly associated with maladaptive RV hypertrophy. Our study integrating imaging and omics in large-animal experimental models demonstrates that, beyond pressure overload, metabolic alterations play a relevant role in RV dysfunction in PH.

[Effects of human umbilical cord mesenchymal stem cells (MSCs)-derived exosomes on pulmonary vascular remodeling in hypoxic pulmonary hypertension].

The present study aimed to investigate the effect of human umbilical cord mesenchymal stem cells (MSCs)-derived exosomes (MSCs-Exo) on mice with hypoxic pulmonary hypertension (HPH). MSCs were isolated and cultured from human umbilical cords under aseptic conditions, and exosomes were extracted from the supernatants and identified. Healthy SPF C57BL/6 mice were randomly divided into three groups: normoxic group, hypoxic group, and hypoxic+MSCs-Exo group. Mice in the hypoxic group and the hypoxic+MSCs-Exo group were maintained for 28 d at an equivalent altitude of 5 000 m in a hypobaric chamber to establish HPH mouse model. The mice in the hypoxic+MSCs-Exo group were injected with MSCs-Exo via tail vein before hypoxia and on days 1, 3, 5 and 9 of hypoxia, and the mice in the other two groups were injected with PBS. At the end of the experiment, echocardiography was performed to detect pulmonary arterial acceleration time/pulmonary arterial ejection time ratio (PAAT/PET), right ventricular free wall thickness, and right ventricular hypertrophy index RV/(LV+S). HE staining was performed to observe the lung tissue morphology. EVG staining was performed to observe elastic fiber hyperplasia. Immunohistochemistry was performed to detect α smooth muscle actin (α-SMA) expression in lung tissue. Immunofluorescence staining was used to detect macrophage infiltration in lung tissue. qPCR was performed to detect IL-1ß and IL-33 in lung tissue, and cytometric bead array was performed to detect IL-10 secretion. Western blotting was used to detect the M1 macrophage marker iNOS, M2 macrophage marker Arg-1 and IL-33/ST2 pathway proteins in lung tissues. The results showed that hypoxia increased pulmonary artery pressure and pulmonary vascular remodeling, increased macrophage infiltration, IL-1ß and IL-33 expression (P < 0.05) and upregulated the IL-33/ST2 pathway (P < 0.05). Compared with the hypoxic group, MSCs-Exo treatment increased PAAT/PET (P < 0.05), decreased right ventricular free wall thickness (P < 0.05), right ventricular hypertrophy index RV/(LV+S) (P < 0.05), α-SMA expression in small pulmonary vessels (P < 0.05), and inflammatory factors including IL-1ß and IL-33 expression in lung tissue, however increased IL-10 secretion (P < 0.05). In addition, MSCs-Exo treatment upregulated Arg-1 and downregulated iNOS and IL-33/ST2 (P < 0.05). The results suggest that MSC-Exo may alleviate HPH through their immunomodulatory effects.

Forsythoside B Mitigates Monocrotaline-Induced Pulmonary Arterial Hypertension via Blocking the NF-κB Signaling Pathway to Attenuate Vascular Remodeling.

Purpose: Pulmonary arterial hypertension (PAH) is a devastating disease with little effective treatment. The proliferation of pulmonary artery smooth muscle cells (PASMCs) induced by the nuclear factor-κB (NF-κB) signaling activation plays a pivotal role in the pathogenesis of PAH. Forsythoside B (FTS•B) possesses inhibitory effect on NF-κB signaling pathway. The present study aims to explore the effects and mechanisms of FTS•B in PAH. Methods: Sprague-Dawley rats received monocrotaline (MCT) intraperitoneal injection to establish PAH model, and FTS•B was co-treated after MCT injection. Right ventricular hypertrophy and pulmonary artery pressure were measured by echocardiography and right heart catheterization, respectively. Histological alterations were detected by H&E staining and immunohistochemistry. FTS•B's role in PASMC proliferation and migration were evaluated by CCK-8 and wound healing assay. To investigate the underlying mechanisms, Western blotting, immunofluorescence staining and ELISA were conducted. The NF-κB activator PMA was used to investigate the role of NF-κB in FTS•B's protective effects against PAH. Results: FTS•B markedly alleviated MCT-induced vascular remodeling and pulmonary artery pressure, and improved right ventricular hypertrophy and survival. FTS•B also reversed PDGF-BB-induced PASMC proliferation and migration, decreased PCNA and CyclinD1 expression in vitro. The elevated levels of IL-1ß and IL-6 caused by MCT were decreased by FTS•B. Mechanistically, MCT-triggered phosphorylation of p65, IκBα, IKKα and IKKß was blunted by FTS•B. FTS•B also reversed MCT-induced nuclear translocation of p65. However, all these protective effects were blocked by PMA-mediated NF-κB activation. Conclusion: FTS•B effectively attenuates PAH by suppressing the NF-κB signaling pathway to attenuate vascular remodeling. FTS•B might be a promising drug candidate with clinical translational potential for the treatment of PAH.

Cannabidiol may prevent the development of congestive hepatopathy secondary to right ventricular hypertrophy associated with pulmonary hypertension in rats.

BACKGROUND: Pulmonary hypertension (PH) can cause right ventricular (RV) failure and subsequent cardiohepatic syndrome referred to as congestive hepatopathy (CH). Passive blood stasis in the liver can affect inflammation, fibrosis, and ultimately cirrhosis. Cannabidiol (CBD) has many beneficial properties including anti-inflammatory and reduces RV systolic pressure and RV hypertrophy in monocrotaline (MCT)-induced PH in rats. Thus, it suggests that CBD may have the potential to limit CH development secondary to RV failure. The present study aimed to determine whether chronic administration of CBD can inhibit the CH secondary to RV hypertrophy associated with MCT-induced PH. METHODS: The experiments involved rats with and without MCT-induced PH. CBD (10 mg/kg) or its vehicle was administered once daily for 3 weeks after MCT injection (60 mg/kg). RESULTS: Monocrotaline administration increased the liver/body weight ratio. In histology examinations, we observed necrosis and vacuolar degeneration of hepatocytes as well as sinusoidal congestion. In biochemical studies, we observed increased levels of nuclear factor-κappa B (NF-κB), tumour necrosis factor-alpha (TNA-α), interleukin 1 beta (IL-1ß), and interleukin 6 (IL-6). CBD administration to PH rats reduced the liver/body weight ratio, improved the architecture of the liver, and inhibited the formation of necrosis. Cannabidiol also decreased the level of NF-κB, TNF-α, IL-1ß and IL-6. CONCLUSIONS: The studies show that CBD can protect the liver from CH probably through attenuating PH, protective effects on the RV, and possibly direct anti-inflammatory effects on liver tissue through regulation of the NF-κB pathway.

Bariatric surgery mitigated electrocardiographic abnormalities in patients with morbid obesity.

Obesity can lead to cardiovascular dysfunctions and cause electrocardiographic disruptions. Bariatric surgery plays a significant role in weight loss. To assess its benefits, this study investigated electrocardiographic changes before and after bariatric surgery. The present article describes a retrospective cohort study with a 6-month follow-up period. Electrocardiograms were interpreted and compared before and six months after surgery. The relationships between weight loss, type of surgery, and electrocardiographic alterations were analyzed. A total of 200 patients participated in the study, with 34 (17%) men and 166 (83%) women. The mean age of the participants was 44.6 ± 8.6, and their mean body mass index was 43.8 ± 5.5 kg/m2. The mean of QTc decreased after the surgery, while the Sokolow-Lyon scores increased. The statistical analysis showed that QTc dispersion (> 40) (P < 0.001), right ventricular hypertrophy (P < 0.001), abnormal R wave progression (P < 0.001), QTc (P < 0.001) and Sokolow-Lyon criteria (P < 0.001) significantly changed postoperatively. In conclusion, bariatric surgery can reduce QTc, correct poor R wave progression, and resolve right ventricular hypertrophy (RVH) in patients with morbid obesity.

Electrocardiographic Abnormalities and Their Association with Outcomes in Randomized Clinical Trials of Pulmonary Arterial Hypertension.

Rationale: Pulmonary arterial hypertension (PAH) is a progressive disease with manifestations including right atrial enlargement, right ventricular dysfunction, dilation, and hypertrophy. Electrocardiography (ECG) is a noninvasive, inexpensive test that is routinely performed in clinical settings. Prior studies have described separate abnormal findings in the electrocardiograms of patients with PAH. However, the role of composite ECG findings reflective of right heart disease (RHD) for risk stratification, clinical trial enrichment, and management of patients with PAH has not been explored. Objectives: To describe a pattern of RHD on ECG in patients with PAH and to investigate the association of this pattern with clinical measures of disease severity and outcomes. Methods: We harmonized individual participant data from 18 phase III randomized clinical trials of therapies for PAH (1998-2013) submitted to the U.S. Food and Drug Administration. RHD was defined as the presence of right ventricular hypertrophy, right axis deviation, right atrial enlargement, or right bundle branch block on ECG. Random effects linear regression, multilevel ordinal regression (cumulative link model), and Cox proportional hazards models were used to assess the association of RHD by ECG with 6-minute walk distance (6MWD), World Health Organization (WHO) functional class, and clinical worsening after a priori adjustment for age, sex, body mass index, and PAH etiology. Effect modification of treatment and ECG abnormalities was assessed by including an interaction term. Results: A total of 4,439 patients had baseline ECG, and 68% of patients had evidence of RHD. RHD on ECG was associated with higher pulmonary vascular resistance (P < 0.001) and higher mean pulmonary artery pressures (P < 0.001). Patients with RHD on ECG had 10 meters shorter 6MWD (P = 0.005) and worse WHO functional class (P < 0.001) at baseline. RHD on baseline ECG was associated with increased risk of clinical worsening (hazard ratio, 1.42; 95% confidence interval; 1.21, 1.67; P < 0.001). Patients with RHD had greater treatment effect in terms of 6MWD, WHO functional class, and time to clinical worsening than those without (P for interaction = 0.03, 0.001, and 0.03, respectively). Conclusions: RHD by ECG may be associated with worse outcomes and potentially greater treatment effect. Electrocardiograms could be an inexpensive, widely available noninvasive method to enrich clinical trial populations in PAH.

MicroRNA-34a-Dependent Attenuation of Angiogenesis in Right Ventricular Failure.

BACKGROUND: The right ventricle (RV) is at risk in patients with complex congenital heart disease involving right-sided obstructive lesions. We have shown that capillary rarefaction occurs early in the pressure-loaded RV. Here we test the hypothesis that microRNA (miR)-34a, which is induced in RV hypertrophy and RV failure (RVF), blocks the hypoxia-inducible factor-1α-vascular endothelial growth factor (VEGF) axis, leading to the attenuated angiogenic response and increased susceptibility to RV failure. METHODS AND RESULTS: Mice underwent pulmonary artery banding to induce RV hypertrophy and RVF. Capillary rarefaction occurred immediately. Although hypoxia-inducible factor-1α expression increased (0.12±0.01 versus 0.22±0.03, P=0.05), VEGF expression decreased (0.61±0.03 versus 0.22±0.05, P=0.01). miR-34a expression was most upregulated in fibroblasts (4-fold), but also in cardiomyocytes and endothelial cells (2-fold). Overexpression of miR-34a in endothelial cells increased cell senescence (10±3% versus 22±2%, P<0.05) by suppressing sirtulin 1 expression, and decreased tube formation by 50% via suppression of hypoxia-inducible factor-1α, VEGF A, VEGF B, and VEGF receptor 2. miR-34a was induced by stretch, transforming growth factor-ß1, adrenergic stimulation, and hypoxia in cardiac fibroblasts and cardiomyocytes. In mice with RVF, locked nucleic acid-antimiR-34a improved RV shortening fraction and survival half-time and restored capillarity and VEGF expression. In children with congenital heart disease-related RVF, RV capillarity was decreased and miR-34a increased 5-fold. CONCLUSIONS: In summary, miR-34a from fibroblasts, cardiomyocytes, and endothelial cells mediates capillary rarefaction by suppressing the hypoxia-inducible factor-1α-VEGF axis in RV hypertrophy/RVF, raising the potential for anti-miR-34a therapeutics in patients with at-risk RVs.

Right ventricular dilatation: echocardiographic differential diagnosis.

The initial means of detecting right ventricular (RV) dilatation is often transthoracic echocardiography (TTE), and once the presence of RV dilatation is suspected, there is the possibility of RV volume overload, RV pressure overload, RV myocardial disease, and even nonpathological RV dilatation. With respect to congenital heart disease with RV volume overload, defects or valvular abnormalities can be easily detected with TTE, with the exception of some diseases. Volumetric assessment using three-dimensional echocardiography may be useful in determining the intervention timing in these diseases. When the disease progresses in patients with pulmonary hypertension as a result of RV pressure overload, RV dilatation becomes more prominent than hypertrophy, and RV functional parameters predict the prognosis at this stage of maladaptive remodeling. The differential diagnosis of cardiomyopathy or comparison with nonpathological RV dilatation may be difficult in the setting of RV myocardial disease. The characteristics of RV functional parameters such as two-dimensional speckle tracking may help differentiate RV cardiomyopathy from other conditions. We review the diseases presenting with RV dilatation, their characteristics, and echocardiographic findings and parameters that are significant in assessing their status or intervention timing.

Sodium butyrate alleviates right ventricular hypertrophy in pulmonary arterial hypertension by inhibiting H19 and affecting the activation of let-7g-5p/IGF1 receptor/ERK.

Pulmonary arterial hypertension (PAH) is a complex and fatal cardio-pulmonary vascular disease. Decompensated right ventricular hypertrophy (RVH) caused by cardiomyocyte hypertrophy often leads to fatal heart failure, the leading cause of mortality among patients. Sodium butyrate (SB), a compound known to reduce cardiac hypertrophy, was examined for its potential effect and the underlying mechanism of SB on PAH-RVH. The in vivo study showed that SB alleviated RVH and cardiac dysfunction, as well as improved life span and survival rate in MCT-PAH rats. The in vivo and in vitro experiments showed that SB could attenuate cardiomyocyte hypertrophy by reversing the expressions of H19, let-7g-5p, insulin-like growth factor 1 receptor (IGF1 receptor), and pERK. H19 inhibition restored the level of let-7g-5p and prevented the overexpression of IGF1 receptor and pERK in hypertrophic cardiomyocytes. In addition, dual luciferase assay revealed that H19 demonstrated significant binding with let-7g-5p, acting as its endogenous RNA. Briefly, SB attenuated PAH-RVH by inhibiting the H19 overexpression, restoring the level of let-7g-5p, and hindering IGF1 receptor/ERK activation.

Ferrostatin-1 Blunts Right Ventricular Hypertrophy and Dysfunction in Pulmonary Arterial Hypertension by Suppressing the HMOX1/GSH Signaling.

Ferroptosis plays a critical role in pulmonary arterial hypertension (PAH)-induced right ventricular (RV) dysfunction, but key genes remain largely unclear. We here identified HMOX1 as an essential ferroptosis-related differentially expressed gene in PAH by bioinformatic analysis using FerrDb, GSE119754, and GSE3675 datasets, respectively. Notably, there were marked increases in HMOX1 and iron levels in RV of monocrotaline-induced PAH rats with reduced TAPSE levels. More importantly, treatment with ferrostatin-1 effectively attenuated RV hypertrophy, remodeling, myocardial fibrosis, and dysfunction in PAH rats. In cultured H9C2 cells and primary neonatal rat cardiomyocytes, pretreatment with ferrostatin-1 and knockdown HMOX1 by siRNA strikingly blunted hypoxia-induced promotion of lipid peroxidation, ferroptosis, and cardiomyocyte injury by potentiating glutathione (GSH) and nitric oxide signaling, respectively. In summary, ferrostatin-1 attenuates RV hypertrophy, fibrosis, and dysfunction in PAH by suppressing the HMOX1/GSH signaling. Targeting HMOX1 ferroptosis signaling functions as a potential therapeutic strategy for patients with PAH.

Role of Oxygen Starvation in Right Ventricular Decompensation and Failure in Pulmonary Arterial Hypertension.

Right ventricular (RV) function and eventually failure determine outcome in patients with pulmonary arterial hypertension (PAH). Initially, RV responds to an increased load caused by PAH with adaptive hypertrophy; however, eventually RV failure ensues. Unfortunately, it is unclear what causes the transition from compensated RV hypertrophy to decompensated RV failure. Moreover, at present, there are no therapies for RV failure; those for left ventricular (LV) failure are ineffective, and no therapies specifically targeting RV are available. Thus there is a clear need for understanding the biology of RV failure and differences in physiology and pathophysiology between RV and LV that can ultimately lead to development of such therapies. In this paper, we discuss RV adaptation and maladaptation in PAH, with a particular focus of oxygen delivery and hypoxia as the principal drivers of RV hypertrophy and failure, and attempt to pinpoint potential sites for therapy.