Pattern of Right Ventricular Changes in Patients with Uncomplicated Systemic Hypertension at a Tertiary Centre in Southwest Nigeria.

BACKGROUND AND AIMS: Hypertension is an independent risk factor for cardiovascular complications. The effect of systemic hypertension on the right ventricle (RV) has received less attention probably due to its complex structure and location. The aim of the study was to assess the effect of systemic hypertension on the structure and function of the right ventricle using transthoracic echocardiography. METHOD: One hundred hypertensives and 100 healthy controls were recruited into the study. Transthoracic echocardiography was used to measure RV wall thickness (RVWT) in diastole, RV internal dimensions in diastole, tricuspid annular plane systolic excursion (TAPSE), right ventricular filling velocities (TE and TA), and RV systolic excursion velocity (RVSm). These measurements were repeated on the left ventricle. RESULTS: There was significantly thicker RV wall (0.51 + 0.08cm vs 0.44+0.08cm; p=0.001) in the hypertensive group and higher frequency of RV hypertrophy (48.45% vs 18.75%; p<0.001). Tricuspid annular plane systolic excursion (TAPSE) and the tricuspid annular peak systolic excursion velocity (TSm) were significantly lower in the hypertensive group (2.34+0.45cm vs 2.50+0.36cm; p=0.008, and 11.70+3.03cm/s vs 12.60+2.93cm/s p=0.039, respectively), though no participant had abnormal TAPSE. Tricuspid E/A ratio was lower in the hypertensive group (1.13+ 0.33 vs 1.24+0.27; p=0.011). The tricuspid E/A ratio had positive correlation with mitral E/A ratio. CONCLUSION: Right ventricular structural and functional changes are found in systemic hypertension, even in the absence of other systemic complications. These changes could have been mediated by ventricular interdependence and altered humoral factors.

CONTEXTES ET OBJECTIFS: L'hypertension artérielle est un facteur de risque indépendant pour les complications cardiovasculaires. L'effet de l'hypertension artérielle systémique sur le ventricule droit (VD) a reçu moins d'attention probablement en raison de sa structure complexe et de son emplacement. L'objectif de l'étude était d'évaluer l'effet de l'hypertension artérielle systémique sur la structure et la fonction du ventricule droit en utilisant l'échocardiographie transthoracique. MÉTHODE: Cent hypertendus et 100 témoins en bonne santé ont été recrutés dans l'étude. L'échocardiographie transthoracique a été utilisée pour mesurer l'épaisseur de la paroi du VD (EPVD) en diastole, les dimensions internes du VD en diastole, l'excursion plane systolique annulaire tricuspide (TAPSE), les vitesses de remplissage ventriculaire droit (TE et TA), et la vitesse d'excursion systolique ventriculaire droit (RVSm). Ces mesures ont été répétées sur le ventricule gauche. RÉSULTATS: Il y avait une paroi du VD significativement plus épaisse (0,51 ± 0,08 cm vs 0,44 ± 0,08 cm ; p=0,001) dans le groupe hypertendu et une fréquence plus élevée d'hypertrophie ventriculaire droite (48,45% vs 18,75% ; p<0,001). L'excursion plane systolique annulaire tricuspide (TAPSE) et la vitesse maximale systolique annulaire tricuspide (TSm) étaient significativement plus basses dans le groupe hypertendu (2,34 ± 0,45 cm vs 2,50 ± 0,36 cm ; p=0,008, et 11,70 ± 3,03 cm/s vs 12,60 ± 2,93 cm/s p=0,039, respectivement), bien qu'aucun participant n'ait eu de TAPSE anormal. Le rapport E/A tricuspide était plus bas dans le groupe hypertendu (1,13 ± 0,33 vs 1,24 ± 0,27 ; p=0,011). Le rapport E/A tricuspide avait une corrélation positive avec le rapport E/A mitral. CONCLUSION: Des modifications structurales et fonctionnelles du ventricule droit sont retrouvées dans l'hypertension artérielle systémique, même en l'absence d'autres complications systémiques. Ces changements pourraient avoir été médiés par l'interdépendance ventriculaire et des facteurs humoraux modifiés. MOTS-CLÉS: Hypertension ; Échocardiographie ; Hypertrophie ventriculaire droite ; Dysfonction diastolique ventriculaire droit.

Evaluation of cardiac index and right ventricular hypertrophy index in rats under a chronic hypoxic environment at high altitude.

High-altitude areas are characterized by low pressure and hypoxia, which have a significant impact on various body systems. This study aimed to investigate the alterations in cardiac index and right ventricular hypertrophy index(RVHI) in rats at different altitudes.Twenty-one male Sprague-Dawley (SD) rats aged 4 weeks were randomly divided into three groups based on altitude. The rats were raised for 28 weeks and then transferred to Qinghai University Plateau Medicine Laboratory. Body weight was measured, heart organs were isolated and weighed, and cardiac index and right ventricular hypertrophy index were determined. Statistical analysis was performed on the data from the three groups. Compared with the plain group, the body weight of the middle-altitude group was significantly decreased (P < 0.05), and cardiac index, RVHI-1, RVHI-2 increased significantly ((P < 0.05). The body weight, whole heart mass, right ventricular mass were significantly decreased in high-altitude group (P < 0.05), RVHI-1 and RVHI-2 were significantly increased (P < 0.05). Compared with the middle-altitude group, the body weight, whole heart mass and right ventricular mass of the high-altitude group were significantly decreased (P < 0.05), and RVHI-1 and RVHI-2 were significantly increased (P < 0.05). Increasing altitude led to a decrease in body weight, whole heart mass, and right ventricular mass in rats, indicating structural changes in the right heart. Additionally, the proportion of right heart to body weight and whole heart increased with altitude.

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.

Electrocardiographic Z-axis QRS-T voltage-time-integral in patients with typical right bundle branch block - Correlation with echocardiographic right ventricular size and function.

BACKGROUND: Right bundle branch block (RBBB) can be benign or associated with right ventricular (RV) functional and structural abnormalities. Our aim was to evaluate QRS-T voltage-time-integral (VTI) compared to QRS duration and lead V1 R' as markers for RV abnormalities. METHODS: We included adults with an ECG demonstrating RBBB and echocardiogram obtained within 3 months of each other, between 2010 and 2020. VTIQRS and VTIQRST were obtained for 12 standard ECG leads, reconstructed vectorcardiographic X, Y, Z leads and root-mean-squared (3D) ECG. Age, sex and BSA-adjusted linear regressions were used to assess associations of QRS duration, amplitudes, VTIs and lead V1 R' duration/VTI with echocardiographic tricuspid annular plane systolic excursion (TAPSE), RV tissue Doppler imaging S', basal and mid diameter, and systolic pressure (RVSP). RESULTS: Among 782 patients (33% women, age 71 ± 14 years) with RBBB, R' duration in lead V1 was modestly associated with RV S', RV diameters and RVSP (all p ≤ 0.03). QRS duration was more strongly associated with RV diameters (both p < 0.0001). AmplitudeQRS-Z was modestly correlated with all 5 RV echocardiographic variables (all p ≤ 0.02). VTIR'-V1 was more strongly associated with TAPSE, RV S' and RVSP (all p ≤ 0.0003). VTIQRS-Z and VTIQRST-Z were among the strongest correlates of the 5 RV variables (all p < 0.0001). VTIQRST-Z.√BSA cutoff of ≥62 µVsm had sensitivity 62.7% and specificity 65.7% for predicting ≥3 of 5 abnormal RV variables (AUC 0.66; men 0.71, women 0.60). CONCLUSION: In patients with RBBB, VTIQRST-Z is a stronger predictor of RV dysfunction and adverse remodeling than QRS duration and lead V1 R'.

ECG patterns to predict pulmonary arterial hypertension in patients with severe tricuspid regurgitation.

INTRODUCTION: Echocardiographic evaluation of tricuspid regurgitation (TR) velocity is a key measure in screening for pulmonary hypertension. Based on its value and additional features of right ventricle overload patients are classified into low, intermediate or high probability of pulmonary hypertension which transfers into decisions of further invasive evaluation. However, in the presence of severe TR echocardiography underestimates pulmonary artery pressure and therefore pulmonary hypertension may be overlooked in some patients. Accordingly, in the present study we aimed to assess the role of electrocardiography in predicting the presence of pulmonary arterial hypertension (PAH) in patients with severe TR. RESULTS: We analysed 83 consecutive patients with severe TR who were diagnosed in our centre between February 2008 and 2021 and who underwent right heart catheterization. Of them 58 had PAH while 25 had isolated TR (iTR). We found that the following ECG criteria supported the diagnosis of PAH as opposed to the diagnosis of iTR: R:SV1 > 1.0, max RV1 or 2 + max S I or aVL -SV1 > 6 mm, SI/RI > 1 in I. For these parameters using ROC analysis we found that the optimal thresholds suggesting the presence of pulmonary hypertension were: R:SV1 > 1.5 (AUC = 0.74, p = 0.0004, sensitivity 57.1%,specificity of 85%), max RV1 or 2 + max S I or aVL - SV1 > 3 mm (AUC = 0.76, p < 0.0001, sensitivity 91.4%, specificity of 60%) and for SI:RI > 0.71 (AUC = 0.79, p < 0.0001, sensitivity 82.5%,specificity of 70.8%). Presence of atrial fibrillation predicted iTR with 76% sensitivity and 81% specificity. CONCLUSIONS: ECG analysis can improve the diagnostic process for patients with severe TR. The presence of atrial fibrillation facilitates the diagnosis of isolated tricuspid regurgitation (iTR), while increased values of R:SV1, R:SI, and increased max RV1 or 2 + max SI or aVL - SV1 favor the diagnosis of TR secondary to PAH.

Superoxide-Mediated Upregulation of MMP9 Participates in BMPR2 Destabilization and Pulmonary Hypertension Development.

BACKGROUND AND AIMS: we previously reported in studies on organoid-cultured bovine pulmonary arteries that pulmonary hypertension (PH) conditions of exposure to hypoxia or endothelin-1 caused a loss of a cartilage oligomeric matrix protein (COMP) stabilization of bone morphogenetic protein receptor-2 (BMPR2) function, a known key process contributing to pulmonary hypertension development. Based on subsequent findings, these conditions were associated with an extracellular superoxide-mediated increase in matrix metalloproteinase 9 (MMP-9) expression. We investigated if this contributed to PH development using mice deficient in MMP9. RESULTS: wild-type (WT) mice exposed to Sugen/Hypoxia (SuHx) to induce PH had increased levels of MMP9 in their lungs. Hemodynamic measures from MMP9 knockout mice (MMP9 KO) indicated they had attenuated PH parameters compared to WT mice based on an ECHO assessment of pulmonary artery pressure, right ventricular systolic pressure, and Fulton index hypertrophy measurements. In vitro vascular reactivity studies showed impaired endothelium-dependent and endothelium-independent NO-associated vasodilatory responses in the pulmonary arteries of SuHx mice and decreased lung levels of COMP and BMPR2 expression. These changes were attenuated in MMP9 KO mice potentially through preserving COMP-dependent stabilization of BMPR2. INNOVATION: this study supports a new function of superoxide in increasing MMP9 and the associated impairment of BMPR2 in promoting PH development which could be a target for future therapies. CONCLUSION: superoxide, through promoting increases in MMP9, mediates BMPR2 depletion and its consequent control of vascular function in response to PH mediators and the SuHx mouse model of PH.

Right ventricular global strain in patients with hypertrophic cardiomyopathy with and without right ventricular hypertrophy.

PURPOSE: Regardless of whether there are morphological abnormalities of right ventricle in hypertrophic cardiomyopathy (HCM) patients, the exact contribution of right ventricular (RV) global strains remains unresolved. We aimed to study the prognostic value of RV global strains in HCM patients with and without RV hypertrophy (RVH). METHOD: A total of 358 HCM patients who underwent the CMR examination and carried out the follow-up were finally included in this retrospective study. The endpoint was a composite of all-cause mortality, aborted SCD, and heart failure readmission. RV hypertrophy (RVH) was defined as maximal RVWT ≥ 5 mm at end-diastole. RV global strains (RV global longitudinal strain (GLS) and RV global circumferential strain (GCS) were measured in HCM patients by cardiac MRI feature tracking technique. The intraobserver and interobserver reproducibility were evaluated. Receiver-operating characteristic curves and Kaplan-Meier curves, cox proportional hazards regression, Likelihood ratio test and Integrated Discrimination Improvement (IDI) analysis were performed. P-value were corrected for multiple testing when using many covariables by a false discovery rate adjustment. RESULTS: Over a median follow-up of 25 (range 3-54) months, 49 patients reached the composite endpoints. HCM patients were divided into the RVH group and non-RVH groups. In the multivariate cox proportional hazards regression, after adjusting multiple clinical and imaging variables, RV GLS and RV GCS were independently associated with the composite endpoints in the RVH group (HR: 1.123; 95 % CI: 1.048-1.205; P = 0.002) and non-RVH group (HR: 1.174; 95 % CI: 1.031-1.337; P = 0.015), respectively. And The IDI index of models improved when adding RV GLS (IDI = 0.030, p < 0.001) and RV GLS (IDI = 0.056, p = 0.020), respectively. CONCLUSIONS: RV GLS and RV GCS are independent predictors of HCM with RVH and without RVH, respectively. RV GLS in the RVH group and RV GCS in the non-RVH group provide additional values for predicting the risk of adverse events.

A neonatal rat model of pulmonary vein stenosis.

OBJECTIVES: Pulmonary vein stenosis (PVS), one of the most challenging clinical problems in congenital heart disease, leads to secondary pulmonary arterial hypertension (PAH) and right ventricular (RV) hypertrophy. Due to the lack of a rodent model, the mechanisms underlying PVS and its associated secondary effects are largely unknown, and treatments are minimally successful. This study developed a neonatal rat PVS model with the aim of increasing our understanding of the mechanisms and developing possible treatments for PVS. METHODS: PVS was created at postnatal day 1 (P1) by banding pulmonary veins that receive blood from the right anterior and mid lobes. The condition was confirmed using echocardiography, computed tomography (CT), gross anatomic examination, hematoxylin and eosin (H&E) staining, fibrosis staining, and immunofluorescence. Lung and RV remodeling under the condition of PVS were evaluated using H&E staining, fibrosis staining, and immunofluorescence. RESULTS: At P21, echocardiography revealed a change in wave form and a decrease in pulmonary artery acceleration time-indicators of PAH-at the transpulmonary valve site in the PVS group. CT at P21 showed a decrease in pulmonary vein diameter in the PVS group. At P30 in the PVS group, gross anatomic examination showed pulmonary congestion, H&E staining showed wall thickening and lumen narrowing in the upstream pulmonary veins, and immunofluorescence showed an increase in the smooth muscle layers in the upstream pulmonary veins. In addition, at P30 in the PVS group, lung remodeling was evidenced by hyperemia, thickening of pulmonary small vessel walls and smooth muscle layers, and reduction of the number of alveoli. RV remodeling was evidenced by an increase in RV free wall thickness. CONCLUSIONS: A neonatal rat model of PVS was successfully established, showing secondary lung and RV remodeling. This model may serve as a useful platform for understanding the mechanisms and treatments for PVS.

Circ-Ntrk2 acts as a miR-296-5p sponge to activate the TGF-ß1/p38 MAPK pathway and promote pulmonary hypertension and vascular remodelling.

BACKGROUND: Circular RNAs (circRNAs), a novel class of non-coding RNAs, play an important regulatory role in pulmonary arterial hypertension (PAH); however, the specific mechanism is rarely studied. In this study, we aimed to discover functional circRNAs and investigate their effects and mechanisms in hypoxia-induced pulmonary vascular remodelling, a core pathological change in PAH. METHODS: RNA sequencing was used to illustrate the expression profile of circRNAs in hypoxic PAH. Bioinformatics, Sanger sequencing, and quantitative real-time PCR were used to identify the ring-forming characteristics of RNA and analyse its expression. Then, we established a hypoxia-induced PAH mouse model to evaluate circRNA function in PAH by echocardiography and hemodynamic measurements. Moreover, microRNA target gene database screening, fluorescence in situ hybridisation, luciferase reporter gene detection, and western blotting were used to explore the mechanism of circRNAs. RESULTS: RNA sequencing identified 432 differentially expressed circRNAs in mouse hypoxic lung tissues. Our results indicated that circ-Ntrk2 is a stable cytoplasmic circRNA derived from Ntrk2 mRNA and frequently upregulated in hypoxic lung tissue. We further found that circ-Ntrk2 sponges miR-296-5p and miR-296-5p can bind to the 3'-untranslated region of transforming growth factor-ß1 (TGF-ß1) mRNA, thereby attenuating TGF-ß1 translation. Through gene knockout or exogenous expression, we demonstrated that circ-Ntrk2 could promote PAH and vascular remodelling. Moreover, we verified that miR-296-5p overexpression alleviated pulmonary vascular remodelling and improved PAH through the TGF-ß1/p38 MAPK pathway. CONCLUSIONS: We identified a new circRNA (circ-Ntrk2) and explored its function and mechanism in PAH, thereby establishing potential targets for the diagnosis and treatment of PAH. Furthermore, our study contributes to the understanding of circRNA in relation to PAH.

Right Heart Failure in Mice Upon Pressure Overload Is Promoted by Mitochondrial Oxidative Stress.

We sought to unravel pathomechanisms of the transition of maladaptive right ventricular (RV) remodeling to right heart failure (RHF) upon pressure overload. Exposure of C57BL/6J and C57BL/6N mice to pulmonary artery banding disclosed a tight relation of structural remodeling with afterload, but a dissociation from RV systolic function. Reduced release of mitochondrial reactive oxygen species in C57BL/6J mice prevented the development of RHF. In patients with left heart failure, increased oxidative damage in RV sections was associated with severely impaired RV function. In conclusion, reactive oxygen species are involved in the transition of maladaptive RV remodeling to RHF.

Kallikrein-related peptidase-8 (KLK8) aggravated hypoxia-induced right ventricular hypertrophy by targeting P38 MAPK/P53 signaling pathway.

Right ventricular (RV) hypertrophy and further heart failure are major co-morbidities, resulting in the premature death of patients with hypoxic pulmonary hypertension (HPH). The regulatory effects of kallikrein-related peptidase (KLK) family members on cardiac function have been extensively studied. However, to the best of the authors' knowledge, the regulatory effects of KLK8 on RV hypertrophy caused by HPH have yet to be reported. The aim of the present study was to assess KLK8 expression in the RV tissue of HPH-modeled rats, and to further explore the effects and underlying mechanism of KLK8 in regulating the hypertrophy of hypoxia-induced H9c2 cardiomyocytes. In HPH model rats, increases in the right ventricle hypertrophy index, the right ventricular systolic pressure, cardiac output, as well as pulmonary artery wall thickness were observed. Western blot analysis revealed that KLK8 expression and MAPK/p53 signaling activity were enhanced in the RVs of rats in an RV HPH rat model. In hypoxia-induced H9c2 cardiomyocytes, KLK8 overexpression promoted cardiomyocyte hypertrophy, whereas KLK8 silencing showed the opposite results. KLK8 overexpression increased the expression levels of ventricular hypertrophy markers, including atrial natriuretic peptide, brain natriuretic peptide and myosin heavy chain 7, which were blocked upon addition of the p38 MAPK inhibitor, SB202190. Conversely, KLK8 silencing caused a decrease in the expression levels of the ventricular hypertrophy markers, which were further reduced via inhibition of the p38 MAPK/p53 signaling pathway. Taken together, the results of the present study have shown that KLK8 may subtly regulate RV hypertrophy, and therefore KLK8 may be a promising therapeutic target for treating HPH-induced RV hypertrophy.

Novel and robust treatment of pulmonary hypertension with netrin-1 and netrin-1-derived small peptides.

Limited medical therapies have been implemented for the treatment of the devastating cardiorespiratory disease of pulmonary hypertension (PH) while none of which is sufficiently effective to stop or regress development of PH. We have previously shown that netrin-1, an axon-guiding protein during development, protects against ischemia reperfusion injury induced myocardial infarction via modest and stable production of nitric oxide (NO) and attenuation of oxidative stress. Since NO deficiency and oxidative stress-mediated vascular remodeling play important roles in the pathogenesis of PH, our present study investigated therapeutic effects on PH of netrin-1 and its derived small peptides. Infused into mice for 3 weeks during exposure to hypoxia, netrin-1 and netrin-1 derived small peptides V1, V2 or V3 substantially alleviated pathophysiological and molecular features of PH, as indicated by abrogated increases in mean pulmonary artery pressure (mPAP) and right ventricular systolic pressure (RVSP), attenuated right ventricular hypertrophy, diminished vascular remodeling of medial thickening and upregulation in smooth muscle alpha-actin (SMA) and proliferative cell nuclear antigen (PCNA), and alleviated perivascular and peribronchial fibrosis reflected by collagen deposition. NO bioavailability was substantially improved by treatment with netrin-1 and netrin-1 derived small peptides, while hypoxia induced increases in total superoxide production and eNOS uncoupling activity were all attenuated. These dual mechanisms of increasing NO bioavailability and decreasing oxidative stress at the same time, underlie robust protective effects on PH of netrin-1 and its derived small peptides, which are different from existing medications that primarily target NO signaling alone. Our data for the first time demonstrate intriguing findings that netrin-1 and netrin-1 derived small peptides can be used as novel and robust therapeutics for the treatment of PH.

EGR1 Is Implicated in Right Ventricular Cardiac Remodeling Associated with Pulmonary Hypertension.

BACKGROUND: Pulmonary hypertension (PH) is a vasoconstrictive disease characterized by elevated mean pulmonary arterial pressure (mPAP) at rest. Idiopathic pulmonary arterial hypertension (iPAH) and chronic thromboembolic pulmonary hypertension (CTEPH) represent two distinct subtypes of PH. Persisting PH leads to right ventricular (RV) hypertrophy, heart failure, and death. RV performance predicts survival and surgical interventions re-establishing physiological mPAP reverse cardiac remodeling. Nonetheless, a considerable number of PH patients are deemed inoperable. The underlying mechanism(s) governing cardiac regeneration, however, remain largely elusive. METHODS: In a longitudinal approach, we profiled the transcriptional landscapes of hypertrophic RVs and recovered hearts 3 months after surgery of iPAH and CTEPH patients. RESULTS: Genes associated with cellular responses to inflammatory stimuli and metal ions were downregulated, and cardiac muscle tissue development was induced in iPAH after recovery. In CTEPH patients, genes related to muscle cell development were decreased, and genes governing cardiac conduction were upregulated in RVs following regeneration. Intriguingly, early growth response 1 (EGR1), a profibrotic regulator, was identified as a major transcription factor of hypertrophic RVs in iPAH and CTEPH. A histological assessment confirmed our biocomputational results, and suggested a pivotal role for EGR1 in RV vasculopathy. CONCLUSION: Our findings improved our understanding of the molecular events driving reverse cardiac remodeling following surgery. EGR1 might represent a promising candidate for targeted therapy of PH patients not eligible for surgical treatment.

Lack of right ventricular hypertrophy is associated with right heart failure in patients with left ventricular failure.

Presence of right heart failure (RHF) is associated with a worse prognosis in patients with left ventricular failure (LVF). While the cause of RHF secondary to LVF is multifactorial, an increased right ventricular (RV) afterload is believed as the major cause of RHF. However, data are scarce on the adaptive responses of the RV in patients with LVF. Our aim was to understand the relationship of right ventricular hypertrophy (RVH) with RHF and RV systolic and diastolic properties in patients with LVF. 55 patients with a left ventricular ejection fraction of 40% or less were included in the present study. A comprehensive two-dimensional transthoracic echocardiographic examination was done to all participants. 12 patients (21.8%) had RHF, and patients with RHF had a significantly lower right ventricular free wall thickness (RVFWT) as compared to patients without RHF (5.3 ± 1.7 mm vs. 6.6 ± 0.9 mm, p = 0.02) and the difference remained statistically significant after adjusting for confounders (Δx̅:1.34 mm, p = 0.002). RVFWT had a statistically significant correlation with tricuspid annular plane systolic excursion (r = 0.479, p < 0.001) and tricuspid annular lateral systolic velocity (r = 0.360, p = 0.007), but not with the indices of the RV diastolic function. None of the patients with concentric RVH had RHF, while 22.2% of patients with eccentric RVH and 66.7% of patients without RVH had RHF (p < 0.01 as compared to patients with concentric RVH). In patients with left ventricular systolic dysfunction, absence of RVH was associated with worse RV systolic performance and a significantly higher incidence of RHF.

MSC Transplantation Attenuates Inflammation, Prevents Endothelial Damage and Enhances the Angiogenic Potency of Endogenous MSCs in a Model of Pulmonary Arterial Hypertension.

Purpose: Pulmonary arterial hypertension (PAH) is a progressive and fatal pulmonary vascular disease initiated by endothelial dysfunction. Mesenchymal stromal cells (MSCs) have been shown to ameliorate PAH in various rodent models; however, these models do not recapitulate all the histopathological alterations observed in human PAH. Broiler chickens (Gallus gallus) can develop PAH spontaneously with neointimal and plexogenic arteriopathy strikingly similar to that in human patients. Herein, we examined the protective effects of MSC transplantation on the development of PAH in this avian model. Methods: Mixed-sex broilers at 15 d of age were received 2×106 MSCs or PBS intravenously. One day later, birds were exposed to cool temperature with excessive salt in their drinking water to induce PAH. Cumulative morbidity from PAH and right-to-left ventricle ratio were recorded. Lung histologic features were evaluated for the presence of endothelial damage, endothelial proliferation and plexiform lesions. Expression of proinflammatory mediators and angiogenic factors in the lung was detected. Matrigel tube formation assay was performed to determine the angiogenic potential of endogenous MSCs. Results: MSC administration reduced cumulative PAH morbidity and attenuated endothelial damage, plexiform lesions and production of inflammatory mediators in the lungs. No significant difference in the expression of paracrine angiogenic factors including VEGF-A and TGF-ß was determined between groups, suggesting that they are not essential for the beneficial effect of MSC transplantation. Interestingly, the endogenous MSCs from birds receiving MSC transplantation demonstrated endothelial differentiatial capacity in vitro whereas those from the mock birds did not. Conclusion: Our results support the therapeutic use of MSC transplantation for PAH treatment and suggest that exogenous MSCs produce beneficial effects through modulating inflammation and endogenous MSC-mediated vascular repair.

Sildenafil prevents right ventricular hypertrophy and improves heart rate variability in rats with pulmonary hypertension secondary to experimental diabetes.

Chronic treatment with sildenafil (SILD) is an effective protector on the development of cardiovascular complications of pulmonary hypertension (PH) and diabetes. However, to date, no studies have evaluated the effect of SILD on cardiopulmonary pathophysiology during PH secondary to type 1 diabetes. AIM: The present study aimed to evaluate the beneficial effects of chronic SILD treatment on pulmonary arterial pressure, right ventricular hypertrophy (RVH) and cardiac autonomic dysfunction in rats with PH secondary to diabetes. METODOLOGY: Male Sprague Dawley rats were randomly distributed into the control group (saline), diabetic group (60 mg/kg with streptozotocin), SILD-treated control group (20 mg/kg) and SILD-treated diabetic group. RESULTS: After 8 weeks the type 1 diabetic animals presented PH, endothelial dysfunction of the pulmonary arteries, electrocardiographic alterations, RVH and overexpression of phosphodiesterase type 5 in the heart. In type 1 diabetic animals, SILD treatment prevented the development of PH, endothelial dysfunction and RVH. SILD treatment also prevented alterations in the corrected QT period and heart rate variability and prevented overexpression of phosphodiesterase type 5. CONCLUSION: Our results indicate for the first time that SILD treatment prevents pulmonary arterial endothelial dysfunction, pulmonary hypertension, right ventricular hypertrophy and improves heart rate variability in type 1 diabetic rats.

Association of Electrocardiographic Signs of Right Ventricular Hypertrophy and Clot Localization in Chronic Thromboembolic Pulmonary Hypertension.

The role of electrocardiography (ECG) in chronic thromboembolic pulmonary hypertension (CTEPH) diagnosis and prognosticating has not been yet established. We aimed to assess the relationships of the recommended ECG criteria of right ventricular hypertrophy (RVH) with clot localization in CTEPH patients. ECG patterns of RVH according to the American College of Cardiology Foundation were assessed in patients with newly diagnosed CTEPH. We enrolled 58 (45.3%) patients with proximal and 70 (54.7%) with distal CTEPH. Receiver-operating characteristics curves analysis indicated that the following ECG abnormalities predicted proximal CTEPH localization: RV1 > 6 mm-AUC 0.75 (CI: 0.66-0.84, p < 0.00001); SV6 > 3 mm-AUC 0.70 (CI: 0.60-0.79, p < 0.00001); SI > RI wave-AUC 0.67 (CI: 0.58-0.77, p = 0.0004); RV1:SV1 > 1.0-AUC 0.66 (CI: 0.56-0.76, p = 0.0009); RV1 peak > 0.035 s (QRS < 120 ms)-AUC 0.66 (CI: 0.56-0.75, p = 0.0016); RV1:SV1 > RV3(V4):SV3(V4)-AUC-0.65 (CI: 0.54-0.75, p = 0.0081); RaVR > 4 mm-AUC 0.62 (CI: 0.52-0.71, p = 0.002) and PII > 2.5 mm-AUC 0.62 (CI: 0.52-0.72, p = 0.00162). Pulmonary vascular resistance significantly correlated with amplitudes of RV1 (r = 0.34, p = 0.008), SV6 (r = 0.53, p = 0.000027) and PII (r = 0.44, p = 0.00007). In patients with CTEPH, only 8 out of 23 ECG RVH criteria were useful for differentiating between proximal and distal CTEPH localization and we found that RV1 and SV6 may contribute as potential discriminators.

Inhibiting pyruvate kinase muscle isoform 2 regresses group 2 pulmonary hypertension induced by supra-coronary aortic banding.

INTRODUCTION: Group 2 pulmonary hypertension (PH) has no approved PH-targeted therapy. Metabolic remodelling, specifically a biventricular increase in pyruvate kinase muscle (PKM) isozyme 2 to 1 ratio, occurs in rats with group 2 PH induced by supra-coronary aortic banding (SAB). We hypothesize that increased PKM2/PKM1 is maladaptive and inhibiting PKM2 would improve right ventricular (RV) function. METHODS: Male, Sprague-Dawley SAB rats were confirmed to have PH by echocardiography and then randomized to treatment with a PKM2 inhibitor (intraperitoneal shikonin, 2 mg/kg/day) versus 5% DMSO (n = 5/group) or small interfering RNA-targeting PKM2 (siPKM2) versus siRNA controls (n = 7/group) by airway nebulization. RESULTS: Shikonin-treated SAB rats had milder PH (PAAT 32.1 ± 1.3 vs 22.1 ± 1.2 ms, P = .0009) and lower RV systolic pressure (RVSP) (31.5 ± 0.9 vs 55.7 ± 1.9 mm Hg, P < .0001) versus DMSO-SAB rats. siPKM2 nebulization reduced PKM2 expression in the RV, increased PAAT (31.7 ± 0.7 vs 28.0 ± 1.3 ms, P = .025), lowered RVSP (30.6 ± 2.6 vs 42.0 ± 4.0 mm Hg, P = .032) and reduced diastolic RVFW thickness (0.69 ± 0.04 vs 0.85 ± 0.06 mm, P = .046). Both shikonin and siPKM2 regressed PH-induced medial hypertrophy of small pulmonary arteries. CONCLUSION: Increases in PKM2/PKM1 in the RV contribute to RV dysfunction in group 2 PH. Chemical or molecular inhibition of PKM2 restores the normal PKM2/PKM1 ratio, reduces PH, RVSP and RVH and regresses adverse PA remodelling. PKM2 merits consideration as a therapeutic cardiac target for group 2 PH.

Perk heterozygosity ameliorates chronic hypoxia-induced pulmonary hypertension and right ventricular hypertrophy in male rats.

BACKGROUND: Pulmonary hypertension (PH) is a rare and deadly disease characterized by remodeling of the pulmonary vasculature and increased pulmonary artery pressure. hypobaric pulmonary hypertension (HPH) is clinically classified as group 4 of pulmonary hypertension and has a poor prognosis . Previous reports showed that HPH was associated with increased endoplasmic reticulum (ER) stress. The protein kinase R-like endoplasmic reticulum kinase (PERK) is an ER-associated stress protein. However, to date, its physiological effects on HPH and RVF development remains unknown. This study aimed to assess PERK's role in HPH and RV function using in vivo experimental model. METHODS: Perk-knockout male Sprague-Dawley rats were generated and were housed in either a hypobaric chamber or in a normoxic environment. After stimulation for 4 weeks, the hemodynamic parameters of the rats were measured. The heart and lungs were harvested for pathological observation. Blood was collected for the detection of inflammatory indexes. The right ventricle tissue was collected to assess phosphorylated-AKT, ROCK1, ET1, and MMP2 protein expression. RESULTS: WE FIRSTLY GENERATED PERK+/− RATS,: Under normal conditions, Perk+/- rats showed no changes in mPAP(mean pulmonary artery pressure), RVHI(Right ventricular hypertrophy index), cardiomyocyte size and interstitial fibrosis, and pulmonary vascular remodeling. However, in response to chronic hypoxia, Perk+/- rats exhibited decreased in mPAP, RVHI, ventricular fibrosis, and lung remodeling compared to wild-type rats. Perk+/- rats also showed lower expression of phosphor-AKT, ROCK1, ET1, and MMP2 protein in response to chronic hypoxia. CONCLUSIONS: These findings suggest that Perk heterozygosity protects against HPH and Perk may be a suitable target for treating HPH.