Analysis of QRS complex morphology in children and adolescents with obstructive sleep apnea syndrome.

Obstructive sleep apnea syndrome (OSAS) leads to many cardiovascular, neurologic, metabolic, and neurocognitive consequences. Conduction deficits, deviations in electrical axis, and changes in QRS morphology reflect the impairments in cardiac muscle activity and underlie the cardiovascular complications of OSAS. Here we aimed to determine the relationship between OSAS and changes in the cardiac conduction system in children and adolescents. During the 6-month duration of the study, all children having the diagnosis of OSAS in Sleep and Disorders Unit following a full-night polysomnography (PSG) were consecutively evaluated. ECGs were performed and analyzed in the Division of Pediatric Cardiology, Department of Pediatrics. The maximum spatial vector size (QRSmax), QRS electrical axis (EA), left and right ventricular hypertrophy, and the presence of fragmented QRS (fQRS) or prolonged R or S wave were examined in detail. A total of 17 boys with OSAS and 13 healthy boys participated in the study. The mean QRSmax and the QRSmax on V5 derivative were significantly lower in the patient group compared to those in the control group (p = 0.011 and p = 0.017, respectively). EA was similar between the two groups. While none of the patients with OSAS nor the control group had left ventricular hypertrophy, only one boy with OSAS had right ventricular hypertrophy according to ECG-derived analysis. The percentage of fQRS or notched R or S waves was significantly higher in patients with OSAS compared to healthy controls (p = 0.035), especially in children below the age of 5 years (p = 0.036).  Conclusion: This study demonstrated that male children and adolescents with OSAS have a combination of QRS complex changes characterized by low QRS voltages, and increased frequency of fragmented QRS. These findings reflect that the electrical remodeling and structural remodeling of the myocardium are considerably affected by OSAS in children and adolescents, leading to ventricular changes and intraventricular conduction problems. What is Known: • Pediatric obstructive sleep apnea syndrome (OSAS) characterized by recurrent intermittent hypoxemia, hypercapnia, and sleep fragmentation results in sympathetic nervous system activation, increased inflammation, and hypoxic endothelial dysfunction. When left untreated, OSAS leads to many cardiovascular, neurologic, metabolic and neurocognitive consequences, and also to sudden infant death syndrome in young children, probably due to the involvement of the cardiac conduction system. What is New: • This study demonstrated that mean QRSmax was significantly lower in male children and adolescents with OSAS, reflecting the structural and electrical remodeling of the myocardium, and one boy with OSAS had RVH according to ECG-derived analysis. The percentage of fQRS or notched R or S waves was much higher in boys with OSAS, especially in children below the age of five years. These finding showed that myocardium was considerably affected to impair the intraventricular conduction in younger children with OSAS.

Comparison of hypoxia-induced pulmonary hypertension rat models caused by different hypoxia protocols.

Background and aim: Pulmonary hypertension (PH) is a serious and even fatal disorder with limited treatment strategies. The hypoxia-induced pulmonary hypertension (HPH) rat model is commonly used in this field. While the HPH rat model has strong predictability and repeatability, the model is a chronic model, making it time-consuming, costly, and complicated and limiting the progress of the experiments. Currently, there is no uniform international standard for the HPH model. Our study aimed to find a relatively effective and efficient HPH modeling protocol. Methods: We established HPH rat models with different total hypoxia periods and different daily hypoxia times, and assessed different hypoxia modeling modes in multiple dimensions, such as haemodynamics, right ventricular (RV) hypertrophy, pulmonary arterial remodeling, muscularization, inflammation, and collagen deposition. Results: Longer daily hypoxia time resulted in higher mean pulmonary arterial pressure (mPAP)/right ventricular systolic pressure (RVSP) and more obvious RV hypertrophy, as well as more severe pulmonary arterial remodeling and muscularization, regardless of the total period of hypoxia (3- or 4-week). Moreover, pulmonary perivascular macrophages and collagen deposition showed daily hypoxia time-dependent increases, both in 3- and 4-week hypoxia groups. Conclusion: Our findings showed that the 3-week continuous hypoxia mode was a relatively efficient way to reduce the time needed to induce significant disease phenotypes, which offered methodological evidence for future studies in building HPH models.

Effect of the number of parity on right heart chamber quantification.

INTRODUCTION: Pregnancy is a process that can cause several physiologic changes to the cardiovascular system such as ventricular hypertrophy and dilation of cardiac chambers. Although there are studies about pregnancy-related changes in echocardiographic examination; there is no data about the long-term effects of parity on these alterations. Therefore, we evaluated the long-term effect of pregnancy on right ventricular (RV) dilation and RV hypertrophy and their relation to the parity number. METHODS: This prospective study included a total of 600 women (200 consecutive women who had no parity, 200 women who had a parity number of 1 to 4 and 200 women who had a parity number of more than 4). Right chambers' measurements were compared between the groups. RESULTS: In echocardiographic analysis, RV and right atrial dimensions and areas and RV wall thickness were higher in parous women. On the other hand, RV systolic function parameters were significantly lower in parous women. These significant changes showed a gradual increase or decrease by increasing parity number. By multivariate hierarchical logistic regression analysis, the four independent factors that increased the risk of RV dilation were age (OR: 1.16 CI: 1.10-1.20), body mass index (OR: 1.05, CI: 1.02-1.08), smoking (OR: 1.87, CI: 1.28-4.02), and giving a birth (OR: 3.94 CI: 1.82-8.81). There was also independent relationship between the number of parity and RV hypertrophy even after adjustment for several confounders. CONCLUSION: Pregnancy-related physiological changes mostly resolve after delivery. This study about long-term effects of pregnancy on RV has demonstrated that there is a significant relation between the number of parity and either RV dilation or RV hypertrophy. Each parity had also additive effect on these changes.

Reversal of Right Ventricular Hypertrophy and Dysfunction by Prostacyclin in a Rat Model of Severe Pulmonary Arterial Hypertension.

Prostacyclin analogs are among the most effective and widely used therapies for pulmonary arterial hypertension (PAH). However, it is unknown whether they also confer protection through right ventricle (RV) myocardio-specific mechanisms. Moreover, the use of prostacyclin analogs in severe models of PAH has not been adequately tested. To further identify underlying responses to prostacyclin, a prostacyclin analogue, treprostinil, was used in a preclinical rat Sugen-chronic hypoxia (SuCH) model of severe PAH that closely resembles the human disease. Male Sprague-Dawley rats were implanted with osmotic pumps containing vehicle or treprostinil, injected concurrently with a bolus of Sugen (SU5416) and exposed to 3-week hypoxia followed by 3-week normoxia. RV function was assessed using pressure-volume loops and hypertrophy by weight assessed. To identify altered mechanisms within the RV, tissue samples were used to perform a custom RNA array analysis, histological staining, and protein and transcript level confirmatory analyses. Treprostinil significantly reduced SuCH-associated RV hypertrophy and decreased the rise in RV systolic pressure, mean pulmonary arterial (mPAP), and right atrial (RAP) pressure. Prostacyclin treatment was associated with improvements in RV stroke work, maximum rate of ventricular pressure change (max dP/dt) and the contractile index, and almost a complete reversal of SuCH-associated increase in RV end-systolic elastance, suggesting the involvement of load-independent improvements in intrinsic RV systolic contractility by prostacyclin treatment. An analysis of the RV tissues showed no changes in cardiac mitochondrial respiration and ATP generation. However, custom RNA array analysis revealed amelioration of SuCH-associated increases in newly identified TBX20 as well as the fibrotic markers collagen1α1 and collagen 3α1 upon treprostinil treatment. Taken together, our data support decreased afterload and load-independent improvements in RV function following prostacyclin administration in severe PAH, and these changes appear to associate with improvements in RV fibrotic responses.

Increased MAO-A Activity Promotes Progression of Pulmonary Arterial Hypertension.

Monoamine oxidases (MAOs), a class of enzymes bound to the outer mitochondrial membrane, are important sources of reactive oxygen species. Increased MAO-A activity in endothelial cells and cardiomyocytes contributes to vascular dysfunction and progression of left heart failure. We hypothesized that inhibition of MAO-A can be used to treat pulmonary arterial hypertension (PAH) and right ventricular (RV) failure. MAO-A levels in lung and RV samples from patients with PAH were compared with levels in samples from donors without PAH. Experimental PAH was induced in male Sprague-Dawley rats by using Sugen 5416 and hypoxia (SuHx), and RV failure was induced in male Wistar rats by using pulmonary trunk banding (PTB). Animals were randomized to receive either saline or the MAO-A inhibitor clorgyline at 10 mg/kg. Echocardiography and RV catheterization were performed, and heart and lung tissues were collected for further analysis. We found increased MAO-A expression in the pulmonary vasculature of patients with PAH and in experimental experimental PAH induced by SuHx. Cardiac MAO-A expression and activity was increased in SuHx- and PTB-induced RV failure. Clorgyline treatment reduced RV afterload and pulmonary vascular remodeling in SuHx rats through reduced pulmonary vascular proliferation and oxidative stress. Moreover, clorgyline improved RV stiffness and relaxation and reversed RV hypertrophy in SuHx rats. In PTB rats, clorgyline had no direct clorgyline had no direct effect on the right ventricle effect. Our study reveals the role of MAO-A in the progression of PAH. Collectively, these findings indicated that MAO-A may be involved in pulmonary vascular remodeling and consecutive RV failure.

Perillyl alcohol suppresses monocrotaline-induced pulmonary arterial hypertension in rats via anti-remodeling, anti-oxidant, and anti-inflammatory effects.

Background: Pulmonary arterial hypertension (PAH) is a disastrous disease that current treatments cannot prevent its progression. The present study investigated the effects of perillyl alcohol (PA), a natural monoterpene, on the experimental PAH in male Wistar rats. Methods: Rats divided into eight groups of control, Monocrotaline (MCT), MCT+vehicle, and MCT+PA with doses of 20, 30, 40, 50, and 60 mg/kg. PAH was induced by a single injection of monocrotaline (60 mg/kg) on day 0. The animals in the groups of MCT+vehicle and MCT+PA received the vehicle or PA from day 22 to 42 once a day. On day 43, under general anesthesia, right ventricular systolic pressure (RVSP), as an index of pulmonary artery systolic pressure, and the ratio of the right ventricle to the left ventricle plus septum weight, as the right ventricular hypertrophy index (RVHI), were measured. Also, some histological and biochemical indices were assessed in the lung tissue. Results: MCT significantly (p < .001) enhanced the RVSP and RVHI compared to the control group (89.4 ± 8.2 vs 23 ± 3.3 mmHg & 0.63 ± 0.08 vs 0.26 ± 0.04 respectively). It also increased oxidative stress and inflammatory cytokines and reduced Bax/Bcl2 ratio. Treatment with PA significantly recovered RVSP and hypertrophy index and suppressed vascular cell proliferation, oxidant production, and inflammatory processes. Conclusion: PA exerted noticeable protective and curative effects against MCT-induced PAH and pulmonary vascular remodeling through inhibiting cellular proliferation, oxidative stress, and inflammation. Therefore, PA can be considered as a new therapeutic goal for the treatment of PAH.

Congestive Hepatopathy Secondary to Right Ventricular Hypertrophy Related to Monocrotaline-Induced Pulmonary Arterial Hypertension.

Heart dysfunction and liver disease often coexist. Among the types of cardiohepatic syndrome, Type 2 is characterized by the chronic impairment of cardiac function, leading to chronic liver injury, referred to as congestive hepatopathy (CH). In this study, we aimed to establish a rat model of CH secondary to right ventricular hypertrophy (RVH) related to monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH). Fifty male Wistar rats were divided into four groups and randomly assigned to control and experimental groups. Three experimental groups were submitted to intraperitoneal MCT inoculation (60 mg/kg) and were under its effect for 15, 30 and 37 days. The animals were then sacrificed, obtaining cardiac and hepatic tissues for anatomopathological and morphometric analysis. At macroscopic examination, the livers in the MCT groups presented a nutmeg-like appearance. PAH produced marked RVH and dilatation in the MCT groups, characterized by a significant increase in right ventricular free wall thickness (RVFWT) and chamber area. At histological evaluation, centrilobular congestion was the earliest manifestation, with preservation of the hepatocytes. Centrilobular hemorrhagic necrosis was observed in the groups exposed to prolonged MCT. Sinusoidal dilatation was markedly increased in the MCT groups, quantified by the Sinusoidal Lumen Ratio (SLR). The Congestive Hepatic Fibrosis Score and the Centrilobular Fibrosis Ratio (CFR) were also significantly increased in the MCT30 group. Hepatic atrophy, steatosis, apoptotic bodies and, rarely, hydropic swelling were also observed. SLR correlated strongly with CFR and RVFWT, and CFR correlated moderately with RVFWT. Our rat model was able to cause CH, related to monocrotaline-induced PAH and RVH; it was feasible, reproducible, and safe.

The Short-Chain Fatty Acid Butyrate Attenuates Pulmonary Vascular Remodeling and Inflammation in Hypoxia-Induced Pulmonary Hypertension.

Pulmonary hypertension (PH) is a progressive cardiovascular disorder in which local vascular inflammation leads to increased pulmonary vascular remodeling and ultimately to right heart failure. The HDAC inhibitor butyrate, a product of microbial fermentation, is protective in inflammatory intestinal diseases, but little is known regarding its effect on extraintestinal diseases, such as PH. In this study, we tested the hypothesis that butyrate is protective in a Sprague-Dawley (SD) rat model of hypoxic PH. Treatment with butyrate (220 mg/kg intake) prevented hypoxia-induced right ventricular hypertrophy (RVH), hypoxia-induced increases in right ventricular systolic pressure (RVSP), pulmonary vascular remodeling, and permeability. A reversal effect of butyrate (2200 mg/kg intake) was observed on elevated RVH. Butyrate treatment also increased the acetylation of histone H3, 25-34 kDa, and 34-50 kDa proteins in the total lung lysates of butyrate-treated animals. In addition, butyrate decreased hypoxia-induced accumulation of alveolar (mostly CD68+) and interstitial (CD68+ and CD163+) lung macrophages. Analysis of cytokine profiles in lung tissue lysates showed a hypoxia-induced upregulation of TIMP-1, CINC-1, and Fractalkine and downregulation of soluble ICAM (sICAM). The expression of Fractalkine and VEGFα, but not CINC-1, TIMP-1, and sICAM was downregulated by butyrate. In rat microvascular endothelial cells (RMVEC), butyrate (1 mM, 2 and 24 h) exhibited a protective effect against TNFα- and LPS-induced barrier disruption. Butyrate (1 mM, 24 h) also upregulated tight junctional proteins (occludin, cingulin, claudin-1) and increased the acetylation of histone H3 but not α-tubulin. These findings provide evidence of the protective effect of butyrate on hypoxic PH and suggest its potential use as a complementary treatment for PH and other cardiovascular diseases.

Eicosapentaenoic acid ameliorates pulmonary hypertension via inhibition of tyrosine kinase Fyn.

Pulmonary arterial hypertension (PAH) is a multifactorial disease characterized by pulmonary arterial vasoconstriction and remodeling. Src family tyrosine kinases, including Fyn, play critical roles in vascular remodeling via the inhibition of STAT3 signaling. EPA is known to inhibit Fyn kinase activity. This study investigated the therapeutic potential and underlying mechanisms of EPA and its metabolite, resolvin E1 (RvE1), to treat PAH using monocrotaline-induced PAH model rats (MCT-PAH), human pulmonary artery endothelial cells (HPAECs), and human pulmonary artery smooth muscle cells (HPASMCs). Administration of EPA 1 and 2 weeks after MCT injection both ameliorated right ventricular hypertrophy, remodeling and dysfunction, and medial wall thickening of the pulmonary arteries and prolonged survival in MCT-PAH rats. EPA attenuated the enhanced contractile response to 5-hydroxytryptamine in isolated pulmonary arteries of MCT-PAH rats. Mechanistically, the treatment with EPA and RvE1 or the introduction of dominant-negative Fyn prevented TGF-ß2-induced endothelial-to-mesenchymal transition and IL-6-induced phosphorylation of STAT3 in cultured HPAECs. EPA and RvE1 suppressed Src family kinases' activity as evaluated by their phosphorylation status in cultured HPAECs and HPASMCs. EPA and RvE1 suppressed vasocontraction of rat and human PA. Furthermore, EPA and RvE1 inhibited the enhanced proliferation and activity of Src family kinases in HPASMCs derived from patients with idiopathic PAH. EPA ameliorated PAH's pathophysiology by mitigating vascular remodeling and vasoconstriction, probably inhibiting Src family kinases, especially Fyn. Thus, EPA is considered a potent therapeutic agent for the treatment of PAH.

Involvement of fatty acid synthase in right ventricle dysfunction in pulmonary hypertension.

Apart from pulmonary vascular resistance and right ventricle (RV) hypertrophy, metabolic dysfunction also plays a major role in pathophysiology of pulmonary hypertension (PH). Recently, we have shown that fatty acid synthase (FAS), an enzyme involved in de novo fatty acid synthesis, plays a pivotal role in PH as its inhibition was protective and decreased pulmonary vascular remodelling, RV pressure and hypertrophy and improved endothelial functions. However, the precise mechanism behind protective effect of FAS inhibition on right ventricle dysfunction associated with PH is not completely understood. Therefore, the present study delineated the mechanism of protective effect of FAS inhibition on RV dysfunction associated with PH. siRNA mediated inhibition of FAS reduced FAS expression, hypertrophy, inflammation, apoptosis, autophagy and improved the glucose oxidation, mitochondrial membrane potential and ATP level in hypoxic cardiomyocytes. In monocrotaline (MCT) treated rats, FAS inhibition by C75 (2 mg/kg, i.p., once a week from 21 to 35 days) decreased the expression and activity of FAS and palmitate level. C75 also improved cardiac functions and mitochondrial membrane potential leading to decreased apoptosis in RV of MCT treated rats. In conclusion, our study reveals that inhibition of FAS decreases RV hypertrophy and improves cardiac function associated with PH by perking up metabolic functions.

Is the cardioprotective effect of the ACE2 activator diminazene aceturate more potent than the ACE inhibitor enalapril on acute myocardial infarction in rats?

Myocardial infarction is a major cause of cardiac dysfunction. All components of the cardiac renin-angiotensin system (RAS) are upregulated in myocardial infarction. Angiotensin-converting enzyme (ACE) and ACE2 are key enzymes involved in synthesis of components of RAS and provide a counter-regulatory mechanism within RAS. We compared the cardioprotective effect of the ACE2 activator diminazene aceturate (DIZE) versus the ACE inhibitor enalapril on post acute myocardial infarction (AMI) ventricular dysfunction in rats. Adult male rats received subcutaneous injections of either saline (control) or isoproterenol (85 mg/kg) to induce AMI. Rats with AMI confirmed biochemically and by ECG, were either left untreated (AMI) or administered DIZE (AMI + DIZE) or enalapril (AMI + enalapril) daily for 4 weeks. DIZE caused a significant activation of cardiac ACE2 compared with enalapril. DIZE caused a significantly greater enhancement of cardiac hemodynamics. DIZE also caused greater reductions in heart-type fatty acid binding protein (H-FABP), ß-myosin heavy chain (ß-MYH), and in heart mass to total body mass ratio. These results indicated that activation of cardiac ACE2 by DIZE enhanced the protective axis of RAS and improved myocardial function following AMI, whereas enalapril was not sufficient to restore all cardiac parameters back to normal.

Characteristics of Pulmonary Vascular Remodeling in a Novel Model of Shunt-Associated Pulmonary Arterial Hypertension.

BACKGROUND Establishing a shunt-induced pulmonary arterial hypertension (PAH) model in mice would be of great scientific value, but no such models have been reported to date. Here, we established a shunt-associated PAH in mice to investigate the characteristics of pulmonary vascular remodeling, which provides a new platform for the in-depth study of PAH associated with congenital heart disease (CHD). MATERIAL AND METHODS Eighty mice were randomly divided into the heavy shunt group (n=32), the small shunt group (n=32), the sham operation group (n=8), and the control group (n=8). The septum of the abdominal aorta and inferior vena cava was cut directly to create a heavy abdominal aortocaval shunt. Pulmonary artery pressure, right ventricular hypertrophy index, and lung tissue morphology were evaluated in the 4th, 6th, 8th, and 12th weeks in the shunt groups. RESULTS Shunt-associated PAH by abdominal aortocaval shunt in mice was successfully established. The shunt patency rate was significantly higher in the heavy shunt group. Significant differences were observed between the heavy shunt group and other groups in terms of pulmonary artery pressure and the right ventricular hypertrophy index. Tissue sections revealed a thickened pulmonary intimal layer and muscular layer and stenosis of the lumen in the shunt groups. Immunofluorescent assay results showed significant proliferations of PAH smooth muscle cells and endothelial cells, consistent with the clinical pulmonary vascular remodeling seen in human patients with severe PAH. CONCLUSIONS Shunt-associated PAH established by directly cutting the septum between the abdominal aorta and inferior vena cava is a stable and reliable model for research on PAH associated with CHD.

Peroxisome Proliferator-Activated Receptor γ Regulates the V-Ets Avian Erythroblastosis Virus E26 Oncogene Homolog 1/microRNA-27a Axis to Reduce Endothelin-1 and Endothelial Dysfunction in the Sickle Cell Mouse Lung.

Pulmonary hypertension (PH), a serious complication of sickle cell disease (SCD), causes significant morbidity and mortality. Although a recent study determined that hemin release during hemolysis triggers endothelial dysfunction in SCD, the pathogenesis of SCD-PH remains incompletely defined. This study examines peroxisome proliferator-activated receptor γ (PPARγ) regulation in SCD-PH and endothelial dysfunction. PH and right ventricular hypertrophy were studied in Townes humanized sickle cell (SS) and littermate control (AA) mice. In parallel studies, SS or AA mice were gavaged with the PPARγ agonist, rosiglitazone (RSG), 10 mg/kg/day, or vehicle for 10 days. In vitro, human pulmonary artery endothelial cells (HPAECs) were treated with vehicle or hemin for 72 hours, and selected HPAECs were treated with RSG. SS mice developed PH and right ventricular hypertrophy associated with reduced lung levels of PPARγ and increased levels of microRNA-27a (miR-27a), v-ets avian erythroblastosis virus E26 oncogene homolog 1 (ETS1), endothelin-1 (ET-1), and markers of endothelial dysfunction (platelet/endothelial cell adhesion molecule 1 and E selectin). HPAECs treated with hemin had increased ETS1, miR-27a, ET-1, and endothelial dysfunction and decreased PPARγ levels. These derangements were attenuated by ETS1 knockdown, inhibition of miR-27a, or PPARγ overexpression. In SS mouse lung or in hemin-treated HPAECs, activation of PPARγ with RSG attenuated reductions in PPARγ and increases in miR-27a, ET-1, and markers of endothelial dysfunction. In SCD-PH pathogenesis, ETS1 stimulates increases in miR-27a levels that reduce PPARγ and increase ET-1 and endothelial dysfunction. PPARγ activation attenuated SCD-associated signaling derangements, suggesting a novel therapeutic approach to attenuate SCD-PH pathogenesis.

Effect of α7 nicotinic acetylcholine receptor activation on cardiac fibroblasts: a mechanism underlying RV fibrosis associated with cigarette smoke exposure.

Right ventricular (RV) dysfunction is associated with numerous smoking-related illnesses, including chronic obstructive pulmonary disease (COPD), in which it is present even in the absence of pulmonary hypertension. It is unknown whether exposure to cigarette smoke (CS) has direct effects on RV function and cardiac fibroblast (CF) proliferation or collagen synthesis. In this study, we evaluated cardiac function and fibrosis in mice exposed to CS and determined mechanisms of smoke-induced changes in CF signaling and fibrosis. AKR mice were exposed to CS for 6 wk followed by echocardiography and evaluation of cardiac hypertrophy, collagen content, and pulmonary muscularization. Proliferation and collagen content were evaluated in primary isolated rat CFs exposed to CS extract (CSE) or nicotine. Markers of cell proliferation, fibrosis, and proliferative signaling were determined by immunoblot or Sircol collagen assay. Mice exposed to CS had significantly decreased RV function, as determined by tricuspid annular plane systolic excursion. There were no changes in left ventricular parameters. RV collagen content was significantly elevated, but there was no change in RV hypertrophy or pulmonary vascular muscularization. CSE directly increased CF proliferation and collagen content in CF. Nicotine alone reproduced these effects. CSE and nicotine-induced fibroblast proliferation and collagen content were mediated through α7 nicotinic acetylcholine receptors and were dependent on PKC-α, PKC-δ, and reduced p38-MAPK phosphorylation. CS and nicotine have direct effects on CFs to induce proliferation and fibrosis, which may negatively affect right heart function.

Easily measurable, noninvasive, and novel finding for pulmonary hypertension: Hypertrophy of the basal segment of septomarginal trabeculation of right ventricle.

BACKGROUND: Effect of pulmonary hypertension (PH) on right ventricular (RV) geometry constitutes an ideal target to assess both pulmonary artery pressure (PAP) and its physiological importance. In this study, we evaluated the diagnostic power of the basal segment of septomarginal trabeculation (SMT) in predicting the PH and RV hypertrophy by cardiovascular magnetic resonance (CMR) in patients with idiopathic pulmonary arterial hypertension (IPAH) and Eisenmenger's syndrome (ES). METHODS: Eleven patients with IPAH, seven patients with ES, and 20 healthy controls were enrolled. CMR was used to measure the area and the thickness of the basal segment of SMT and right ventricular free wall (RVFW). Pulmonary artery systolic pressures (PASPs) were estimated by transthoracic echocardiography (TTE) with continuous-wave Doppler analysis measuring maximal tricuspid regurgitation (TR) velocity. Late gadolinium enhancement (LGE) findings of CMR and brain natriuretic peptide (BNP) levels were also obtained in all patients and control group. RESULTS: The area and the thickness of the basal segment of SMT were higher in patients with IPAH and ES than control group (P<.001). Pulmonary artery dimension, end-diastolic diameter of RV, RVFW thickness, and BNP levels were found to be significantly correlated with PAP (P<.001). LGE was present at the insertion point of RV only in patients group (P<.001). CONCLUSIONS: Increased area and thickness of the basal segment of SMT are easily measurable noninvasive markers of PH in patients with IPAH and ES.

Coconut Oil Aggravates Pressure Overload-Induced Cardiomyopathy without Inducing Obesity, Systemic Insulin Resistance, or Cardiac Steatosis.

Studies evaluating the effects of high-saturated fat diets on cardiac function are most often confounded by diet-induced obesity and by systemic insulin resistance. We evaluated whether coconut oil, containing C12:0 and C14:0 as main fatty acids, aggravates pressure overload-induced cardiomyopathy induced by transverse aortic constriction (TAC) in C57BL/6 mice. Mortality rate after TAC was higher (p < 0.05) in 0.2% cholesterol 10% coconut oil diet-fed mice than in standard chow-fed mice (hazard ratio 2.32, 95% confidence interval 1.16 to 4.64) during eight weeks of follow-up. The effects of coconut oil on cardiac remodeling occurred in the absence of weight gain and of systemic insulin resistance. Wet lung weight was 1.76-fold (p < 0.01) higher in coconut oil mice than in standard chow mice. Myocardial capillary density (p < 0.001) was decreased, interstitial fibrosis was 1.88-fold (p < 0.001) higher, and systolic and diastolic function was worse in coconut oil mice than in standard chow mice. Myocardial glucose uptake was 1.86-fold (p < 0.001) higher in coconut oil mice and was accompanied by higher myocardial pyruvate dehydrogenase levels and higher acetyl-CoA carboxylase levels. The coconut oil diet increased oxidative stress. Myocardial triglycerides and free fatty acids were lower (p < 0.05) in coconut oil mice. In conclusion, coconut oil aggravates pressure overload-induced cardiomyopathy.

[INFLUENCE OF THE FEMALE SEX HORMONE 17-BETA-ESTRADIOL ON THE DEGREE OF HYPOXIC PULMONARY HYPERTENSION IN MALE AND FEMALE WISTAR RATS.]

The influence of endogenous and exogenous 17-beta-estradiol on the degree of hypoxic pulmonary hypertension (HPH) in male and female Wistar rats has been studied. Endogenous estradiol reduced the right ventricular systolic pressure (RVSP) in normal female rats, but not in male rats. Exogenous estradiol (15 pg/kg for 4 weeks) caused the same effect. The HPH was induced by exposure to intermittent hypobaric hypoxia (10 h a day, 02 = 10%). Two weeks after hypoxia exposure, increased RVSP was more developed in females as compared to males. Comparison of RVSP between hypertensive and normotensive fet'a- le groups showed that the pathology in hypertensive females with retained ovaries is developed more than in ovariectomized ones. Exogenous estradiol exhibi- ted no protective effect in hypoxic ovariectomized female rats. In males, the ovariectomy did not influence the RVSP level, but caused hypertrophy of the right ventricle. In this case, exogenous estradiol led to an increase in RVSP. Thus, endogenous 17-beta-estradiol has a protective effect on the pulmonary blood flow in normal females. In the case of hypoxic pulmonary hypertension, endogenous estradiol enhances the development of this pathology in females and ovariecto- mized males.

Inhibition of Regulatory-Associated Protein of Mechanistic Target of Rapamycin Prevents Hyperoxia-Induced Lung Injury by Enhancing Autophagy and Reducing Apoptosis in Neonatal Mice.

Administration of supplemental oxygen remains a critical clinical intervention for survival of preterm infants with respiratory failure. However, prolonged exposure to hyperoxia can augment pulmonary damage, resulting in developmental lung diseases embodied as hyperoxia-induced acute lung injury and bronchopulmonary dysplasia (BPD). We sought to investigate the role of autophagy in hyperoxia-induced apoptotic cell death in developing lungs. We identified increased autophagy signaling in hyperoxia-exposed mouse lung epithelial-12 cells, freshly isolated fetal type II alveolar epithelial cells, lungs of newborn wild-type mice, and human newborns with respiratory distress syndrome and evolving and established BPD. We found that hyperoxia exposure induces autophagy in a Trp53-dependent manner in mouse lung epithelial-12 cells and in neonatal mouse lungs. Using pharmacological inhibitors and gene silencing techniques, we found that the activation of autophagy, upon hyperoxia exposure, demonstrated a protective role with an antiapoptotic response. Specifically, inhibiting regulatory-associated protein of mechanistic target of rapamycin (RPTOR) in hyperoxia settings, as evidenced by wild-type mice treated with torin2 or mice administered (Rptor) silencing RNA via intranasal delivery or Rptor+/-, limited lung injury by increased autophagy, decreased apoptosis, improved lung architecture, and increased survival. Furthermore, we identified increased protein expression of phospho-beclin1, light chain-3-II and lysosomal-associated membrane protein 1, suggesting altered autophagic flux in the lungs of human neonates with established BPD. Collectively, our study unveils a novel demonstration of enhancing autophagy and antiapoptotic effects, specifically through the inhibition of RPTOR as a potentially useful therapeutic target for the treatment of hyperoxia-induced acute lung injury and BPD in developing lungs.

The right ventricle in pulmonary arterial hypertension: disorders of metabolism, angiogenesis and adrenergic signaling in right ventricular failure.

The right ventricle (RV) is the major determinant of functional state and prognosis in pulmonary arterial hypertension. RV hypertrophy (RVH) triggered by pressure overload is initially compensatory but often leads to RV failure. Despite similar RV afterload and mass some patients develop adaptive RVH (concentric with retained RV function), while others develop maladaptive RVH, characterized by dilatation, fibrosis, and RV failure. The differentiation of adaptive versus maladaptive RVH is imprecise, but adaptive RVH is associated with better functional capacity and survival. At the molecular level, maladaptive RVH displays greater impairment of angiogenesis, adrenergic signaling, and metabolism than adaptive RVH, and these derangements often involve the left ventricle. Clinically, maladaptive RVH is characterized by increased N-terminal pro-brain natriuretic peptide levels, troponin release, elevated catecholamine levels, RV dilatation, and late gadolinium enhancement on MRI, increased (18)fluorodeoxyglucose uptake on positron emission tomography, and QTc prolongation on the ECG. In maladaptive RVH there is reduced inotrope responsiveness because of G-protein receptor kinase-mediated downregulation, desensitization, and uncoupling of ß-adrenoreceptors. RV ischemia may result from capillary rarefaction or decreased right coronary artery perfusion pressure. Maladaptive RVH shares metabolic abnormalities with cancer including aerobic glycolysis (resulting from a forkhead box protein O1-mediated transcriptional upregulation of pyruvate dehydrogenase kinase), and glutaminolysis (reflecting ischemia-induced cMyc activation). Augmentation of glucose oxidation is beneficial in experimental RVH and can be achieved by inhibition of pyruvate dehydrogenase kinase, fatty acid oxidation, or glutaminolysis. Therapeutic targets in RV failure include chamber-specific abnormalities of metabolism, angiogenesis, adrenergic signaling, and phosphodiesterase-5 expression. The ability to restore RV function in experimental models challenges the dogma that RV failure is irreversible without regression of pulmonary vascular disease.

Use of triple ultra-high-pressure balloons for obstructed right ventricular outflow conduits in adults can be safe and effective.

To date, no transcatheter valve has been approved for placement in the pulmonary position in Japan. Consequently, percutaneous balloon dilatation may be advised for stenotic right ventricular outflow lesions; however, technical difficulties persist, particularly in adults. We describe the acute haemodynamic changes and outcome of balloon dilatation of right ventricular outflow obstruction using triple ultra-high pressure balloons. This is the first report of such a technical development, which seems to be safe and effective. A total of three adult patients, aged 25, 29, and 37 years, with severe conduit obstruction were referred for balloon dilatation. A triple ultra-high-pressure balloon technique was used in the three patients after unsuccessful double-balloon dilatation, or for highly calcified lesions, which were expected to require ultra-high pressure for effective relief. Following balloon dilatation, the pressure gradient decreased from 24, 30, 65 to 3, 25, 30 mmHg, respectively. There were no procedural complications except slightly increased pulmonary regurgitation. Balloon dilatation using a triple ultra-high pressure balloon technique can be a safe and effective palliative procedure for conduit obstruction in adult patients.