Development Of Severe Pulmonary Hypertension Research Articles

Long-Term Erythrocytapheresis Did Not Prevent Development of Severe Pulmonary Hypertension in Sickle Cell Disease

Background The WHO classifies pulmonary hypertension into five different groups based on pathophysiology, clinical presentation, and therapeutic options. The development of pulmonary hypertension (PH) in sickle cell disease (SCD) is multifactorial and can cause devastating complications. Erythrocytapheresis is utilized in patients with SCD who have multiple comorbidities or are unresponsive to first-line treatments like hydroxyurea. It is hypothesized that treatment with long-term erythrocytapheresis (LTE) could slow the progression to pulmonary hypertension by modifying the pathophysiology of the disease process. However, limited clinical data supports this transfusion modality [1]. Case Description The patient is a 17-year-old female with a history of SCD, obstructive sleep apnea (OSA), nocturnal hypoxemia, and recurrent pain crises maintained on LTE every four weeks for the past seven years. She had previously failed hydroxyurea therapy. She underwent a tonsillectomy and adenoidectomy seven years ago to treat OSA. The patient had an echocardiogram five years ago, which showed normal biventricular function and tricuspid regurgitation jet velocity. Recently she presented to the emergency department with cough, shortness of breath, fever, diarrhea, and nausea lasting for three days. Initial assessment revealed elevated liver enzymes, elevated BNP, hyperbilirubinemia, hemoglobin of 9.5 g/dL, and oxygen saturations in the 80's. Echo revealed right ventricular dysfunction and right atrial and ventricular enlargement with a tricuspid regurgitation jet velocity of 4.29 m/s and estimated right ventricular systolic pressure 90% systemic, as seen in figure 1. The patient was admitted to the PICU under concern of pulmonary hypertension crisis. She underwent a right cardiac catheterization three days into her admission and was diagnosed with severe pulmonary hypertension with a mean pulmonary artery pressure of 49 mmHg. Pulmonary capillary wedge pressure was 11 mmHg, and pulmonary vascular resistance was calculated to be 18 wood units x m 2 with 20 PPM of nitric oxide and 80% FiO2 the PVR decreased to 11 woods units x m 2 (figure 2). CTA showed subsegmental thrombosis and vascular surgery was consulted for evaluation for endarterectomy, but they decided she was not a surgical candidate. She was initiated on anticoagulation therapy with enoxaparin, sildenafil, and bosentan. Conclusions The cause of PH in this patient appears to be multifactorial. Possible etiologies include SCD-related, primary pulmonary hypertension, or subsegmental pulmonary embolism. Although LTE is increasingly used in the management of SCD, providers should not assume that a patient receiving this treatment will not progress to develop complications. Some patients on LTE may also develop progressive CNS vasculopathy and are still at risk for developing hypertension. Patients with SCD should be screened for PH if they are symptomatic or have comorbid conditions. This patient had a history of nocturnal hypoxemia and OSA, which some studies indicate are associated with pulmonary hypertension in adolescents with SCD. Screening for nocturnal hypoxemia and OSA is recommended in SCD to identify patients at high risk of PH development [2].

A rare coexistence: Hammock mitral valve and aortopulmonary window.

Congenital mitral stenosis is a broad-spectrum pathology in which blood flow to the left ventricle is obstructed both functionally and anatomically. Hammock mitral valve, also known as anomalous mitral arcade, is a rare congenital anomaly particularly in infants and children. Hammock mitral valve may not be suitable for repair regarding the advanced dysplastic mitral valve structure. Aortopulmonary window is an unusual cardiac anomaly which is defined as a communication between the main pulmonary artery and the ascending aorta. As a result of the excessive left-to-right shunt, early intervention and surgical closure deemed mandatory to avoid development of severe pulmonary hypertension and its consequences. All patients with an aortopulmonary window necessitates prompt repair immediately. In this brief report, mitral valve replacement with a mechanical valve and repair of aortopulmonary window with a Dacron patch were performed simultaneously in a 5-month-old patient with a hammock mitral valve and accompanying aortopulmonary window.

Prevalence and Risk Factors of Pulmonary Arterial Hypertension in Interstitial Lung Diseases: A Cross-sectional Study

Introduction: Interstitial Lung Diseases (ILD) is associated with inflammatory and/or fibrotic changes in the lungs. Pulmonary Arterial Hypertension (PAH) is a complication of many end-stage lung diseases due to the re-modelling of pulmonary vasculature associated with hypoxia leading to pulmonary vascular resistance. The Association of PAH in ILD contributes significantly to high morbidity and mortality. ILD being a progressive disease it is difficult to predict when the PAH will set in. Aim: To assess the clinical and radiological profiles of patients with ILD and to associate these with the severity of PAH. Materials and Methods: The present cross-sectional study was conducted in the Department of Respiratory Medicine at GSL Medical College on 23 patients with ILD from 1st October 2019 to 31st august 2021, in GSL medical college and hospital, Andhra Pradesh. Each patient was subjected to chest X-ray (CXR), Electrocardiogram (ECG), and 2-Dimensional Echocardiogram (2D ECHO). Evidence of PAH in any one investigation was considered. In ECG reports evidence of right ventricular enlargement (R>S in V1/V2 and right axis deviation >110 degrees, R=11 mm) was considered as PAH. CXR showing dilatation of the pulmonary artery with an increased cardiothoracic ratio was considered as PAH. A 2-D ECHO was performed to estimate the right arterial pressure and evidence of pulmonary arterial systemic pressure of >40 mmHg was considered as PAH. All the data were statistically analysed by using IBM Statistical Package for Social Sciences (SPSS) version 20.0. Results: Fifty-two percent of the population constituted females, and the mean age of the whole population was 59.7±14.4 years and the majority of them (65%) belonged to upper lower socioeconomic class. Usual Interstitial Pneumonia (UIP) was the most common pattern observed accounting for 57%. Prevalence of PAH was 65% and a longer duration of symptoms, 57% of the population had grade 3 of Modified Medical Research Council (MMRC) and 52.17% covered less than 200 meters in the 6-Minute Walk Test (6MWT). Oxygen desaturation after 6MWT was observed to be the contributing factor for the development of severe pulmonary hypertension in ILD patients. Conclusion: Factors like delayed seeking of medical care, co-morbidity like hypertension, higher grades of dyspnoea at the time of presentation, shorter 6MWD, and post-walk oxygen saturation were found to be predictors of pulmonary artery hypertension in patients with ILD. Early recognition of these risk factors in patients with ILD and the prompt treatment of the disease can reduce the development of severe PAH.

Abstract 15801: Early and Late Risk of Mortality or Development of Severe Pulmonary Hypertension Following Closure of Ventricular Septal Defects in Children With Severe Pulmonary Hypertension and Elevated Pulmonary Vascular Resistance Using Traditional or Uni-directional Flap Valve Patch Closure

Introduction: Children with large ventricular septal defects, severe pulmonary hypertension (PHT), and elevated pulmonary vascular resistance (PVR) are frequently denied operation in low and middle-income countries secondary to concerns of high mortality and development of severe pulmonary hypertension following operation, early and late. Hypothesis: We hypothesized that closure with a uni-directional flap valve patch (DP) would provide lower mortality and better survival without severe PHT. Methods: From 5/96 - 12/2016 all patients undergoing VSD closure with severe PHT and elevated PVR by either traditional (TP) or DP closure were followed annually. Baseline and O 2 provocation catheterization were performed before operation. Echocardiograms were performed at discharge and follow-up. The decision on TP or DP closure was based upon age and surgeon preference. Beginning in 2005 all patients regardless of technique received sildenafil 3 mgs/kg/day for 3 months before operation. Results: The number of patients receiving operation was 129, of which 40 received the DP. Males were 66/129, age and weight differed significantly for DP group compared to the TP group (7.5 vs 2.6 years, p<0.001 and 20 vs 11.5 kgs, p<0.001).Catheterization baseline data, PVR 9.0 vs 7.4 for DP and TP respectively (p<0.001), negative vasoactive test 32.5% vs 13.5% for DP and TP respectively (p=0.016). Mortality was 1/40 for DP and 9/89 for TP. Pulmonary to Systemic systolic pressure ratio was lower at discharge vs baseline cath (0.38 vs 0.99, p<0.001). Predictors of late severe pulmonary hypertension were PVR/SVR >0.5, p<0.024; and a negative vasoactive test of <10% decrease, p<0.001. PHT at last follow-up, none or mild 86/115 (74.8%), moderate 16/115 (13.9%) or severe 13/115 (11.3%). Conclusions: DP patients had less risk of death and both groups had few patients with severe PHT at late follow-up..

Abstract 14372: Identification of the Genes That Are Involved in Severe Pulmonary Hypertension in Type 2 Diabetic Mice

Pulmonary hypertension (PH) is a progressive disease characterized by increased pulmonary vascular resistance. Increasing evidence shows that diabetes increases the risks of PH, and diabetic priming leads to severe PH. However, the molecular mechanism by which preconditioning of diabetes results in severe PH is still unknown. It has been shown that endothelium serves as a key regulator of vascular tone, and endothelial cell dysfunction is implicated in the development of PH and diabetes-related vascular complications. Therefore, we identified the genes that contribute to the development of severe PH in diabetic mice with a focus on endothelial function. We first determined the effect of chronic hypoxia (10% O 2 , 4 weeks) on hemodynamics in type 2 diabetic (T2D) mice. We used inducible T2D mice (generated by high-fat diet and a low-dose streptozotocin injection) and spontaneous T2D mice (TALLYHO/Jng). Diabetic mice exhibited a slight increase in right ventricular systolic pressure (RVSP), and chronic hypoxia led to a further rise in RVSP in both inducible and spontaneous T2D mice. We isolated pulmonary endothelial cells (MPEC) from normoxia-exposed control mice (CN), hypoxia-exposed control mice (CH), normoxia-exposed diabetic mice (DN), and hypoxia-exposed diabetic mice (DH) to examine the levels of 92 genes using real-time PCR. Nighty two genes were selected based on their functions, which are significantly related to endothelial function. We found that 27 genes were significantly changed among 4 groups. We then examined the protein levels of genes that were related to apoptosis and glycolysis. Western Blot data indicated that the protein level of GAPDH was significantly increased in CH and DH compared to CN and DN. In addition, hypoxic exposure in diabetic mice (DH) significantly increased HK2 protein level compare to hypoxia-exposed control mice (CH). These data suggest that precondition of diabetes increases susceptibility to developing PH due partly to altering gene expression of HK2 and Gapdh in MPECs. Since HK2 and GAPDH are a crucial regulator of glycolysis, alteration of glycolysis is expected in hypoxia-exposed diabetic mice. Our study revealed the key molecules which could be used for treating severe PH in diabetes.

Direct Delivery of MicroRNA96 to the Lungs Reduces Progression of Sugen/Hypoxia-Induced Pulmonary Hypertension in the Rat

The 5HT1B receptor (5HT1BR) contributes to the pathogenic effects of serotonin in pulmonary arterial hypertension. Here, we determine the effect of a microRNA96 (miR96) mimic delivered directly to the lungs on development of severe pulmonary hypertension in rats. Female rats were dosed with sugen (30 mg/kg) and subjected to 3 weeks of hypobaric hypoxia. In normoxia, rats were dosed with either a 5HT1BR antagonist SB216641 (7.5 mg/kg/day for 3 weeks), miR96, or scramble sequence (50 μg per rat), delivered by intratracheal (i.t) administration, once a week for 3 weeks. Cardiac hemodynamics were determined, pulmonary vascular remodeling was assessed, and gene expression was assessed by qRT-PCR, and in situ hybridization and protein expression were assessed by western blot and ELISA. miR96 expression was increased in pulmonary arteries and associated with a downregulation of the 5HT1BR protein in the lung. miR96 reduced progression of right ventricular systolic pressure, pulmonary arterial remodeling, right ventricular hypertrophy, and the occurrence of occlusive pulmonary lesions. Importantly, miR96 had no off-target effects and did not affect fibrotic markers of liver and kidney function. In conclusion, direct delivery of miR96 to the lungs was effective, reducing progression of sugen/hypoxia-induced pulmonary hypertension with no measured off-target effects. miR96 may be a novel therapy for pulmonary arterial hypertension, acting through downregulation of 5HT1BR.

Scimitar syndrome – Uncommon variant with common presentation

Scimitar syndrome, or congenital pulmonary venolobar syndrome, is a rare congenital heart defect characterized by the anomalous venous return from the right lung. A number of cases that lack all the features of a typical syndrome have been described as the scimitar variant, but the incidence is rare. These variants may be difficult to diagnose and, if diagnosed, they may not require surgical correction, instead, can be managed through episodic treatment and yearly monitoring for the development of complications. Herein, we report the case of a 9-month-old male baby with an uncommon variant of scimitar syndrome where the aortopulmonary collateral maintaining the blood supply of the right lung aroused from the right subclavian artery and descending thoracic aorta instead of inferior vena cava. Due to this, the management completely changed from catheterization of the heart to just follow-up monitoring of ventricular function and development of severe pulmonary hypertension.

Multisistemska histiocitoza Langerhansovih ćelija sa dominantnim lezijama u plućnom parenhimu

Langerhans cell histiocytosis (LCH) is a rare disease of unknown aetiology characterized by abnormal monoclonal proliferation of CD1a+/ CD207+ myeloid dendritic cells (Langerhans cells) in various organs, including bones, skin, lymph nodes, liver, lungs, central nervous system (CNS). Pulmonary Langerhans cell histiocytosis (PLCH) may occur as single-system disease or the lungs may be affected within a multisystemic disease. This paper presents cases of two patients with multisystemic LCH, with predominant lung involvement. In the first patient, the disease is in the terminal stage, with chronic respiratory failure requiring long-term oxygen therapy at home and development of severe pulmonary hypertension, so the lung transplantation may be considered as the only potentially effective therapeutic procedure at this moment. The second patient is in the initial stage of the disease, with satisfactory pulmonary function for now, so it could be considered to use some new targeted therapy to prevent the progression of the disease. Thus, it is essential to consistently apply, as soon as possible, all available pharmacological treatments, as well as adequate palliative and health care, to ensure a decent quality of life for these patients.

Aspectos pronósticos de la cirugía aislada de sustitución valvular tricuspídea

BackgroundIsolated tricuspid valve replacement (TVR) is a rarely performed procedure, with controversial indications for performing surgery, mostly due to the poor outcomes reported. Material and methodsAll patients undergoing isolated TVR between 2003 and 2014 were included. We analyzed: a) Perioperative mortality and long-term mortality; b) Prosthetic valves related complications during follow-up (thrombosis and biological valve deterioration). ResultsA total of 40 patients underwent isolated TVR during the study period. 82.5% of these patients where in III-IV/IV NYHA functional class, and 70% of them had at least moderate pulmonary hypertension (mean PAP>40mmHg). Perioperative mortality was 25%. The EuroSCORE I underestimated the mortality associated to this procedure (estimated mortality of 13.89%). Preoperative anemia (OR: 0.52; CI 95%: 0.30-0.89; P=.017) was associated to a higher perioperative mortality. There was a trend towards a higher mortality in patients with previous cardiac surgery (P=.081). Late survival, after 44 months of median follow-up, was 57.50%. Long-term survival was influenced by: 1) Severe pulmonary hypertension (OR: 5,77; CI: 95%: 1.06-31.26; P=.042); 2) NYHA class IV (OR: 8.31; CI: 95%: 1.48-49.06; P=.004). Patients who were operated in NYHA IV had a poor long-term survival (12.5% of one-year survival, log Rank P=.004). ConclusionsIsolated TVR is associated to a high mortality, mostly due to surgery timing, when the patient is already in an advanced heart failure situation.Indication for surgery must be done promptly, before the right ventricle function deterioration or the development of severe pulmonary hypertension. Performing surgery when the patient is in IV NYHA functional class, provides scarce benefit regarding long-term survival.

Endothelial HIF-2α contributes to severe pulmonary hypertension due to endothelial-to-mesenchymal transition.

Pulmonary vascular remodeling characterized by concentric wall thickening and intraluminal obliteration is a major contributor to the elevated pulmonary vascular resistance in patients with idiopathic pulmonary arterial hypertension (IPAH). Here we report that increased hypoxia-inducible factor 2α (HIF-2α) in lung vascular endothelial cells (LVECs) under normoxic conditions is involved in the development of pulmonary hypertension (PH) by inducing endothelial-to-mesenchymal transition (EndMT), which subsequently results in vascular remodeling and occlusive lesions. We observed significant EndMT and markedly increased expression of SNAI, an inducer of EndMT, in LVECs from patients with IPAH and animals with experimental PH compared with normal controls. LVECs isolated from IPAH patients had a higher level of HIF-2α than that from normal subjects, whereas HIF-1α was upregulated in pulmonary arterial smooth muscle cells (PASMCs) from IPAH patients. The increased HIF-2α level, due to downregulated prolyl hydroxylase domain protein 2 (PHD2), a prolyl hydroxylase that promotes HIF-2α degradation, was involved in enhanced EndMT and upregulated SNAI1/2 in LVECs from patients with IPAH. Moreover, knockdown of HIF-2α (but not HIF-1α) with siRNA decreases both SNAI1 and SNAI2 expression in IPAH-LVECs. Mice with endothelial cell (EC)-specific knockout (KO) of the PHD2 gene, egln1 (egln1EC-/-), developed severe PH under normoxic conditions, whereas Snai1/2 and EndMT were increased in LVECs of egln1EC-/- mice. EC-specific KO of the HIF-2α gene, hif2a, prevented mice from developing hypoxia-induced PH, whereas EC-specific deletion of the HIF-1α gene, hif1a, or smooth muscle cell (SMC)-specific deletion of hif2a, negligibly affected the development of PH. Also, exposure to hypoxia for 48-72 h increased protein level of HIF-1α in normal human PASMCs and HIF-2α in normal human LVECs. These data indicate that increased HIF-2α in LVECs plays a pathogenic role in the development of severe PH by upregulating SNAI1/2, inducing EndMT, and causing obliterative pulmonary vascular lesions and vascular remodeling.

Serotonin transporter is not required for the development of severe pulmonary hypertension in the Sugen hypoxia rat model.

Increased serotonin serum levels have been proposed to play a key role in pulmonary arterial hypertension (PAH) by regulating vessel tone and vascular smooth muscle cell proliferation. An intact serotonin system, which critically depends on a normal function of the serotonin transporter (SERT), is required for the development of experimental pulmonary hypertension in rodents exposed to hypoxia or monocrotaline. While these animal models resemble human PAH only with respect to vascular media remodeling, we hypothesized that SERT is likewise required for the presence of lumen-obliterating intima remodeling, a hallmark of human PAH reproduced in the Sugen hypoxia (SuHx) rat model of severe angioproliferative pulmonary hypertension. Therefore, SERT wild-type (WT) and knockout (KO) rats were exposed to the SuHx protocol. SERT KO rats, while completely lacking SERT, were hemodynamically indistinguishable from WT rats. After exposure to SuHx, similar degrees of severe angioproliferative pulmonary hypertension and right ventricular hypertrophy developed in WT and KO rats (right ventricular systolic pressure 60 vs. 55 mmHg, intima thickness 38 vs. 30%, respectively). In conclusion, despite its implicated importance in PAH, SERT does not play an essential role in the pathogenesis of severe angioobliterative pulmonary hypertension in rats exposed to SuHx.

Abstract 11711: Valproic Acid, a Class [[Unable to Display Character: І]] Histone Deacetylase Inhibitor, Suppresses the Development of Severe Pulmonary Hypertension in Rats

Introduction: Pulmonary hypertension (PH) is a progressive vascular remodeling disease characterized by exuberant cell proliferation, apoptosis resistance, and inflammation that contributes to increased pulmonary arterial resistance. Histone deacetylases (HDACs) and histone acetyltransferases shift acetyl groups from histone and non-histone proteins and enhance gene transcription by post-translational modifications. Valproic acid, a class I HDAC inhibitor, is a widely used antiepileptic drug with low toxicity and also shows supportive efficacy in cancer treatment by inhibiting cancer cell proliferation and inflammation. Hypothesis: We assessed the hypothesis that HDAC inhibition may attenuate excessive cell proliferation and inflammation and improve vascular remodeling in a severe PH rat model. Methods: To compare the development of vascular remodeling, we assessed 6 rats that underwent a single monocrotaline injection, chronic hypoxic exposure, or a combination of both treatments. Valproic acid or vehicle was administered in rats with severe PH induced by the combination method to assess whether valproic acid has the ability to prevent severe PH development in the first 3 weeks or to reverse disease progression at 3-5 weeks. Results: The combination method induced PH of greater severity than that induced by any single stimulation in rats after 3 weeks. Compared with the vehicle-treated rats, valproic acid treatment blocked the elevation of right ventricular systolic pressure and right ventricle hypertrophy index (from 57 ± 3 to 49 ± 3 mmHg and from 46 ± 4 to 37 ± 3 %) in both the first 3 weeks and in the late treatment group (from 75 ± 2 to 61 ± 5mmHg and from 61 ± 7 to 48 ± 3 %, respectively; P < 0.01). Valproic acid attenuated the muscularization ratio of peripheral pulmonary vascular, repressed proliferation and inflammation marker expression (PCNA and ED1), and enhanced apoptosis (cleaved caspase 3) in severe PH rats. Conclusions: These data indicate that a selective HDAC inhibitor may be effective in the treatment of PH.

Plasma interleukin-6 adds prognostic information in pulmonary arterial hypertension

To the Editor: Noninvasive biomarkers are needed to aid in making challenging clinical decisions in pulmonary arterial hypertension (PAH). Several biomarkers have been described, but only the natriuretic peptides have gained clinical utility. A key question to answer is whether or not a new biomarker adds independent incremental information [1]. Novel PAH markers may be discovered from new pathobiological pathways, such as inflammation. In particular, interleukin (IL)-6 has been linked with the development of severe pulmonary hypertension in animal models, mimicking the pathology of human disease [2]. IL-6 is a major regulator of the production of C-reactive protein (CRP), a marker of cardiovascular risk [3]. We conducted this study to determine if these inflammatory biomarkers add incremental prognostic information in PAH. This is a cohort study based on a prospective Biobank. We enrolled patients with idiopathic, heritable, connective tissue-associated and congenital heart disease-associated PAH, as defined by current guidelines [4], between March 2005 and June 2011. The study was approved by the Cleveland Clinic Institutional Review Board. We used ELISA (RD Siemens Healthcare Diagnostics, Inc., Tarrytown, NY, USA) Peripheral plasma samples were kept at -80°C until retrieved for the measurement of the biomarkers (September 2011 for hsCRP and BNP, and February 2012 for IL-6). Investigators who performed the biomarker determination were blinded to the study participants’ outcomes. All-cause mortality since the date of study blood sampling was ascertained via manual and automated …

571 Malignant Pertussis in the Young Infant: a Case Report

Infections by bordetella pertussis, has resurged in many countries around the world including developed regions. Where as new vaccination strategies for adolescents, pregnant women and adults have been recommended, mortality...

New-Onset Neonatal Pulmonary Hypertension Associated with a Rhinovirus Infection

A 3.5-week-old male neonate who developed an upper and lower respiratory tract rhinovirus infection that was temporally associated with the development of severe pulmonary hypertension is described. Rhinovirus has not previously been associated with pulmonary hypertension. This child developed severe pulmonary hypertension with right ventricular failure, requiring mechanical ventilation, nitric oxide inhalation and, eventually, extracorporeal membrane oxygenation.

Abstract P141: Gender Differences in the Development of Severe Pulmonary Hypertension and Right Ventricular Dysfunction in Apolipoprotein E--Deficient Mice Are Eliminated with Increasing Age

Apolipoprotein E (ApoE) is a multifunctional protein and its deficiency leads to the development of atherosclerosis in mice. Patients with pulmonary hypertension (PH) have reduced expression of ApoE in lung tissue. ApoE is known to inhibit endothelial and smooth muscle cell proliferation and has anti-inflammatory and anti-platelet aggregation properties. Young ApoE deficient mice have been shown to develop high fat diet-induced PH in a gender specific manner. Estrous cyclicity peaks at 7–8 months and declines by 9 months of age in mice. Here we investigated the effects of monocrotaline (MCT) on young and middle-aged ApoE deficient mice.Middle-Aged (MA) (11–12 month old) male (n=4) and female (n=4) and young (7–8 month old) male (n=5) and female (n=5) ApoE deficient mice were injected with a single intraperitoneal dose of MCT (60 mg/kg). Mice were closely monitored for ∼4 weeks with serial echocardiography for cardiopulmonary hemodynamic assessment. Direct cardiac catheterisation was performed terminally to record peak systolic right ventricular pressure (RVP). RV, LV, IVS and lung tissue was dissected and weighed. Trichrome staining and histochemical analyses were performed. At ∼4 weeks after MCT, MA male and female and young male mice developed severe PH (RVP: MA male=64±5 mmHg, MA female=71±4 mmHg, young male=60±5 mmHg, p=n.s between all the groups) whereas young females developed significantly less severe PH (RVP: 37±5 mmHg, P<0.05 vs. MA male and female, and young male). MA male and female and young male mice developed severe RV dysfunction (RV ejection fraction (RVEF): MA male=31±2%, MA female=28±4%, young male=36±1%, p=n.s between all the groups) whereas young females showed significantly better RV function (RVEF: 43±2%, P<0.05 vs. MA male and female, and young male). MA male and female mice also developed more severe RV hypertrophy (RV/LV+Septum, MA male=0.49, MA female=0.53, young female=0.39). MA male and female mice also manifested increased peripheral pulmonary artery muscularization and pulmonary fibrosis. Interestingly, the gender differences witnessed between young ApoE deficient male and female mice in the development of severe PH and RV dysfunction are abolished as the mice increase in age.

Low dose chronically infused hemoglobin induces pulmonary hypertension or excerbates hypoxia‐induced pulmonary hypertension

Observations from examining past medical records from patients with sickle cell anemia or thalassemia suggest these diseases may be a risk factor for the development of severe pulmonary hypertension (PH). Recently it has been proposed that the chronic exposure to cell free hemoglobin is a major contributor to the development of PH in these patients. Therefore, we hypothesized that chronic infusion (3 and 6 wk) of cell free hemoglobin in rats would either induced or exacerbate PH in rats exposed to room air or hypoxia.MethodsMale, age matched (8–10 wk) Sprague dawley rats were treated with chronically infused free hemoglobin (500 ug/hr) or left untreated and either exposed to chronic hypoxia (18,000 ft; PB ~ 379 mm Hg;) or remained in normoxic conditions (5,280 ft; PB ~ 620 mm Hg). After wards, cardiac output (CO), mean pulmonary artery (Pa) and systemic pressures (MAP) and hemotocrit (Hct) were recorded, and RV/LV+S ratio was determined and lungs were examed as indication of the severity of PH.ResultsOverall, hemoglobin (Hb) infusion increased Pa pressures and lowered Hct compared to untreated cohorts. In the normoxic Hb infused animals MAP and Pa pressures increased between 3 and 6 weeks. Compared to hypoxic control rats, Pa pressures were greater at 3 and 6 wks, whereas MAP was greater only at 3 wk in Hb infused animals.ConclusionChronic infusion of CFH can induce or exacerbate hypoxic‐induced PH. However, whether CFH exerts this effect by oxidative damage, inflammation or NO scavenging is unknown.

Development of Pulmonary Hypertension in an Infant Treated with Diazoxide

Diazoxide is commonly used in the treatment of neonatal hyperinsulinism. We describe a one month-old infant who was treated with diazoxide for prolonged neonatal hyperinsulinism. Shortly after starting diazoxide, she was admitted to the hospital for tachypnea with hypoxemia, and was subsequently diagnosed with laryngomalacia and obstructive apnea. During hospitalization, her clinical course worsened due to the development of severe pulmonary hypertension, presumed due to diazoxide toxicity. Lung biopsy revealed a probable toxic vascular drug reaction. After discontinuing diazoxide, her clinical status improved and eventually returned to baseline.

Obesity Exacerbates the Development of Hypoxia‐induced Pulmonary Hypertension

Obesity is a known risk factor for cardiovascular disease, insulin resistance and premature death. Recent observations from examining past medical records suggest that obesity may be a risk factor for the development of severe pulmonary hypertension. Therefore, we hypothesized that hypoxic pulmonary hypertension (PH) would be exacerbated in the Zucker obese vs. the Zucker lean rats. Methods: Male, age matched (8–10 wk) obese (547 ± 17 g) and lean (345 ± 11g) Zucker rats were exposed to either chronic hypoxia (3 wk; 18,000 ft; PB ~ 379 mm Hg;) or remained at ambient barometric pressure (5,280 ft; PB ~ 620 mm Hg). After wards, cardiac output (CO), mean pulmonary artery (Pa) and mean systemic pressures (MAP) and hemotocrit (Hct) were recorded. Following hemodynamic measurements, rats were euthanized, the lungs perfused with paraformaldehyde (PFA), dissected free of the heart and embedded in paraffin for histological analyses. The heart was removed, the right ventricle (RV) was dissected free from the left ventricle + septum (LV+S) and RV/LV+S ratio was determined as a further indication of the severity of PH. Results: Chronic hypoxia exposure increased Pa pressure, RV/ LV+S and Hct in all rats (P<0.001; P<0.01 and <0.001 vs. normoxia respectively). The Pa pressure, RV/LV+S were 37 ± 10%, 30 ± 12% and 18 ± 3% greater in the Zucker obese rats vs. Zucker lean cohorts (P=0.023; P=0.026 and P<0.01 respectively). Histological analyses revealed increased pulmonary remodeling in the obese vs. lean hypoxic rats. Conclusion: We conclude that obesity exacerbates hypoxia-induced mean Pa pressure, right ventricular hypertrophy and pulmonary vascular remodeling.

Blood Pressure in Mutant Rats Lacking the 5-Hydroxytryptamine Transporter

To the Editor: Although 5-HT uptake inhibitors are widely used as antidepressants, the role of 5-HT in the control of systemic blood pressure is far from clear.1 In a recent issue of Hypertension , Ni et al reported that 5-hydroxytryptamine (5-HT) transporter (SERT) expression was increased, whereas SERT function was decreased in aorta of rats with DOCA salt and Nω-nitro-L-arginine (L-NNA)-induced hypertension.2 We have observed that several 5-HT receptors are induced in leukocytes of hypertensive patients.3 These 2 observations could point at a functional response of the serotonin system …