Manifestations Of Pulmonary Hypertension Research Articles

Clinical significance of correlation between persistent pulmonary hypertension and 8-hydroxy-2-desoxyguanosine level in premature newborns.

Persistent pulmonary hypertension is a problem that leads to high morbidity and mortality in preterm infants. In clinical studies, oxidative stress (OS) contributes to the development of pulmonary hypertension (PH). The most specific biomarker of OS in preterm infants is urinary 8-hydroxy-2-deoxyguanosine (8-OHdG).The aim of the study was to determine the clinical correlation between the value of 8-OHdG and the level of a mean pressure in the pulmonary artery (mPAP) in premature infants with respiratory distress syndrome (RDS) and asphyxia in the early neonatal period. Determination of the urinary 8-OHdG value and PH in 96 premature infants born at gestational age of 26-32 weeks on the 1st and the 3rd-5th days of life in two groups: group I -52 children with respiratory distress syndrome; II -44 children with RDS associated with perinatal asphyxia. The 2nd group of children had higher average mPAP level, mmHg, both in the 1st and in the 3rd-5th day of life compared with the 1st group. The value of the urinary 8-OHdG correlated with the manifestation of PH that required prolonged respiratory support in group II. Perinatal asphyxia in preterm infants with RDS on the 1st day of life complicates the course of PH, as indicated by a higher level of the urinary 8-OHdG and correlated to mPAP. Gender characteristics of the dynamics of 8-OHdG levels in children with perinatal pathology reveal reduced adaptability and reactivity of boys to OS at birth.

Stress-induced pulmonary hypertension: definition and diagnosis

The first hemodynamic definition of pulmonary hypertension (PH) was given at the World Symposium on PH (WSPH, 1973) in Geneva as an increasebin resting mean pulmonary artery pressure (mPAP) >25 mm Hg by heart chamber catheterization. Since 2004, in the definition of PH, in addition to an increase in resting mPAP, an 'exercise' criterion has also been included: mPAP at the peak of exercise >30 mm Hg. However, at the 4th WSPH Symposium in 2008, due to uncertainty of the relationship between age-related changes in cardiac output (CO) and pulmonary vascular physiology, in particular pulmonary vascular resistance (PVR) under exercise, this criterion was excluded.Resting PH manifests only at the absence of ≥50 % of pulmonary microcirculation, so for the earliest diagnosis of the disease, it’s necessary to use factors that provoke an increase in CO and PVR. Moreover, in clinical practice, manifestations of PH are not uncommon on exercise. In the absence of consensus the definition of stress- induced PH is defined in individuals with normal mPAP (< 25 mm Hg) at rest and elevated mPAP (>30 mm Hg) and PVR> 3 WU at the peak of exercise.

Analysis of Ultrasonic Features Based on Absence of Pulmonary Artery

According to clinical features and ultrasonic imaging features of patients with absence of pulmonary artery, it is necessary to analyze ultrasonic imaging features of absence of pulmonary artery to provide clinical basis for improving the diagnostic value and prognosis. The data and color Doppler echocardiography of 45 patients with absence of pulmonary artery are collected, who are confirmed by cardiac catheterization, CTA and operation, and the clinical features and ultrasonic imaging features are studied. The research results show that 57% of the patients have left absence of pulmonary artery and 91% of them have other cardiovascular malformations, where ASD/PFO is the most common, PDA and VSD are the second. Patients with UAPA have changes of pulmonary artery, the incidence of pulmonary artery abnormalities in multiple malformations, changes of ASD/PFO, PDA and VSD are mainly pulmonary hypertension. The ejection fraction of patients with UAPA is normal. The main manifestation of pulmonary hypertension is the increase of right cardiac volume load, and the main manifestation of pulmonary stenosis is the increase of collateral circulation. Pulmonary hypertension and its associated cardiovascular malformations may be related to the prognosis of patients. Ultrasound doctors should understand such diseases to improve the diagnosis rate and the prognosis.

Pulmonary embolism in a 51-year-old woman with chronic kidney disease

Background Chronic kidney disease (CKD) is a worldwide public health problem both in terms of the number of patients and the cost of treatment. Chronic kidney disease seems to be the main driver of pulmonary embolism (PE) in dialysis patients. The diagnosis of PE is difficult due to its non-specific signs and symptoms, especially in many comorbidities with similar features. Chronic kidney disease plays a role in both the incidence of venous thromboembolism and the manifestations of pulmonary hypertension, resulting in an increased risk of morbidity and mortality. Advances in the management of patients with suspected PE have improved diagnostic accuracy. An approach using several diagnostic tools with different characteristics, such as D-dimer measurement, and imaging tests-predominantly computed tomography pulmonary angiography (CTPA) - can help evaluate the diagnosis. Case DescriptionHere we report the case of a 51-year-old woman with a history of chronic kidney disease, who presented with sudden worsening of dyspnea. Further examination showed signs of right heart failure with a high probability of pulmonary hypertension on echocardiography. Based on the general features it is difficult to distinguish between acute pulmonary embolism and chronic pulmonary hypertension, both of which can be caused by the underlying chronic kidney disease. Nevertheless, gold standard imaging using CTPA confirmed the diagnosis of pulmonary embolism, with underlying pulmonary hypertension from chronic kidney disease. ConclusionsThe diagnosis of pulmonary embolism with comorbidities is challenging. The availability of diagnostic modalities will confer different advantages and particular accuracy to meet the challenges in diagnosis.

Pulmonary Hypertension in Pregnancy: A Review.

Pulmonary hypertension (PH) is a disease, which targets the pulmonary vasculature affecting the heart and the lungs, and is characterized by a vast array of signs and symptoms. These manifestations of PH in pregnancy are highly variable and non-specific hence, it is prudent to have a very keen and high index of suspicion while evaluating these patients. This rare disease can be extremely debilitating and can be associated with a poor overall prognosis. Pregnancy in women with PH puts them at an elevated risk because the physiological changes associated with pregnancy are not well endured leading to even higher morbidity and mortality in these patients. Although there are various modalities for evaluation and workup of PH, right heart catheterization (RHC) remains the gold standard. A mean pulmonary artery pressure (PAP) of more than 20 mm of Hg is considered diagnostic. It is indeed heartening to see that in the past decade many novel therapeutic modalities have emerged and along with a better understanding of the disease process have proved to be promising in terms of reducing the adverse outcomes and preventing death in this population of patients.

Computed tomography appearances of the lung parenchyma in pulmonary hypertension.

Computed tomography (CT) is a valuable tool in the workup of patients under investigation for pulmonary hypertension (PH) and may be the first test to suggest the diagnosis. CT parenchymal lung changes can help to differentiate the aetiology of PH. CT can demonstrate interstitial lung disease, emphysema associated with chronic obstructive pulmonary disease, features of left heart failure (including interstitial oedema), and changes secondary to miscellaneous conditions such as sarcoidosis. CT also demonstrates parenchymal changes secondary to chronic thromboembolic disease and venous diseases such as pulmonary venous occlusive disease (PVOD) and pulmonary capillary haemangiomatosis (PCH). It is important for the radiologist to be aware of the various manifestations of PH in the lung, to help facilitate an accurate and timely diagnosis. This pictorial review illustrates the parenchymal lung changes that can be seen in the various conditions causing PH.

A promising approach for screening pulmonary hypertension based on frontal chest radiographs using deep learning: A retrospective study.

BackgroundTo date, the missed diagnosis rate of pulmonary hypertension (PH) was high, and there has been limited development of a rapid, simple, and effective way to screen the disease. The purpose of this study is to develop a deep learning approach to achieve rapid detection of possible abnormalities in chest radiographs suggesting PH for screening patients suspected of PH.MethodsWe retrospectively collected frontal chest radiographs and the pulmonary artery systolic pressure (PASP) value measured by Doppler transthoracic echocardiography from 762 patients (357 healthy controls and 405 with PH) from three institutes in China from January 2013 to May 2019. The wohle sample comprised 762 images (641 for training, 80 for internal test, and 41 for external test). We firstly performed a 8-fold cross-validation on the 641 images selected for training (561 for pre-training, 80 for validation), then decided to tune learning rate to 0.0008 according to the best score on validation data. Finally, we used all the pre-training and validation data (561+80 = 641) to train our models (Resnet50, Xception, and Inception V3), evaluated them on internal and external test dataset to classify the images as having manifestations of PH or healthy according to the area under the receiver operating characteristic curve (AUC/ROC). After that, the three deep learning models were further used for prediction of PASP using regression algorithm. Moreover, we invited an experienced chest radiologist to classify the images in the test dataset as having PH or not, and compared the prediction accuracy performed by deep learing models with that of manual classification.ResultsThe AUC performed by the best model (Inception V3) achieved 0.970 in the internal test, and slightly declined in the external test (0.967) when using deep learning algorithms to classify PH from normal based on chest X-rays. The mean absolute error (MAE) of the best model for prediction of PASP value was smaller in the internal test (7.45) compared to 9.95 in the external test. Manual classification of PH based on chest X-rays showed much lower AUCs compared to that performed by deep learning models both in the internal and external test.ConclusionsThe present study used deep learning algorithms to classify abnormalities suggesting PH in chest radiographs with high accuracy and good generalizability. Once tested prospectively in clinical settings, the technology could provide a non-invasive and easy-to-use method to screen patients suspected of having PH.

P1596 Pulmonary hypertension in cardiology practice: clinical echocardiographic evaluation

Abstract Purpose To study the clinical echocardiographic features of various variants of pulmonary hypertension (PH). Methods of research. Clinical evaluation and analysis of the results of 45,000 Doppler echocardiographic studies were performed. Moderate PH corresponded to the mean pulmonary artery pressure (MPAP) level up to 50 mm Hg, severe PH was characterized by MPAP above 50 mm Hg. Results Clinically significant moderate and severe PH was established in 283 patients, which was 0.63% of the examined patients. Severe PH was detected in 106 patients, including 30 men and 76 women, whose average age was 43.1 ± 1.7 years in the age range of 14-75 years. Patients with congenital heart disease (CHD) represented the majority of the patients with severe pulmonary arterial hypertension (PAH) - 49 people (10 men and 39 women, mean age 43.0 ± 1.8 years in the age range of 14-69 years), including 16 with ventricular septal defect, 9 with an atrial septal defect, 7 with transposition of the great arteries, 6 with complete common atrioventricular canal defect, 3 with congenitally corrected transposition of the great arteries, 3 with a double outlet right ventricle, 3 with a common arterial trunk, 2 with the Ebstein anomaly. Severe PH was also established in 12 patients with idiopathic PAH, 21 patients with recurrent pulmonary embolism (PE), 10 with acquired valvular heart disease (AVHD) (in 7 cases with severe mitral stenosis, 3 with severe aortic stenosis), in 7 patients with postinfarction left ventricular aneurysm, 4 patients with chronic obstructive pulmonary disease (COPD), 3 with dilated cardiomyopathy. Moderate PH was diagnosed in 177 patients (97 men and 80 women, mean age 60.3 ± 1.3 years in the age range of 21-87 years), including 54 patients with dilated, 26 - ischemic cardiomyopathy, 38 with AVHD, 26 with PE, 17 post-MI patients, 9 with CHD, and 7 with COPD. PAH-specific therapy with bosentan and / or sildenafil was performed in 9 patients with idiopathic PAH and 7 patients with CHD without significant clinical effect; in other cases, nonspecific therapy was continued with diuretics, positive inotropic agents, and anticoagulants. Conclusions The most pronounced manifestations of PH were observed predominantly in CHD patients with advanced left-to-right and right-to-left shunting of blood, idiopathic PAH and thromboembolic PH. For prevailing venous PH, the less pronounced clinical manifestations were observed in patients with ischemic, non-coronary and valvular heart lesions, as well as with COPD accompanied by hypoxemia.

Evolving systems biology approaches to understanding non-coding RNAs in pulmonary hypertension.

Our appreciation of the roles of non-coding RNAs, in particular microRNAs, in the manifestation of pulmonary hypertension (PH) has advanced considerably over the past decade. Comprised of small nucleotide sequences, microRNAs have demonstrated critical and broad regulatory roles in the pathogenesis of PH via the direct binding to messenger RNA transcripts for degradation or inhibition of translation, thereby exerting a profound influence on cellular activity. Yet, as inherently pleiotropic molecules, microRNAs have been difficult to study using traditional, reductionist approaches alone. With the advent of high-throughput -omics technologies and more advanced computational modelling, the study of microRNAs and their multi-faceted and complex functions in human disease serves as a fertile platform for the application of systems biology methodologies in combination with traditional experimental techniques. Here, we offer our viewpoint of past successes of systems biology in elucidating the otherwise hidden actions of microRNAs in PH, as well as areas for future development to integrate these strategies into the discovery of RNA pathobiology in this disease. We contend that such successful applications of systems biology in elucidating the functional architecture of microRNA regulation will further reveal the molecular mechanisms of disease, while simultaneously revealing potential diagnostic and therapeutic strategies in disease amelioration.

A case of successful systemic thrombolysis in massive thromboembolia of pulmonary artery against the background of pregnancy

We present a clinical case of successful systemic thrombolysis in a pregnant patient with massive pulmonary embolism. A 29-year old patient at 28 weeks of pregnancy was hospitalized 2 hours after sudden suffocation in a presyncopal state and hypotension of 90/50 mm Hg. ECG showed the signs of overload of right heart chambers in the form of a typical S1-Q3-T3 (McGinn–White) syndrome, as well as the Kosuge sign. Echocardiography verified pulmonary 3 Grade hypertension (81 mm Hg), enlargement of the right atrium and ventricle, 3 Grade tricuspid regurgitation and paradoxical movement of the interventricular septum. Multislice computed tomography of the chest with contrast of the pulmonary artery revealed a defect of contrast in the right main pulmonary artery, occlusive clearance, and thrombotic mass, extending to the bifurcation of the left main pulmonary artery ("clot - rider"). Thrombolytic therapy was started with recombinant tissue plasminogen activator (alteplase 10 mg bolus, then 90 mg for 2 hours). The patient was daily examined by a gynecologist. The viability of the fetus, monitoring of possible hemorrhagic complications of the placenta were evaluated. After thrombolysis, the patient began to note clinical improvement in the form of a regression of dyspnea. According to echocardioscopy control, the signs of overload of right heart chambers completely regressed. There were no complications both in the mother and in the fetus during the subsequent days until discharge. On 25.05.16 there was uncomplicated delivery vaginally of live full-term girl. Thus, when there is life-threatening massive pulmonary embolism, the application of General principles of diagnosis and treatment of this disease in patients with pregnancy is warranted. The carrying out of thrombolytic therapy in massive pulmonary embolism enables to reduce the manifestations of pulmonary hypertension, right ventricular failure, and to conduct births on time. Used intravenous thrombolytics have no teratogenic effect in the later stages of pregnancy.Received 18 April 2017. Accepted 5 June 2017.Funding: The study did not have sponsorship.Conflict of interest: The authors declare no conflict of interest.

Influence of Pulmonary Hypertension on Patients With Idiopathic Pulmonary Fibrosis Awaiting Lung Transplantation

The influence of varying levels of pulmonary hypertension (PH) on survival in idiopathic pulmonary fibrosis is not well defined. The United Network for Organ Sharing database was queried from 2005 to 2013 to identify first-time lung transplant candidates listed for lung transplantation who were tracked from waitlist entry date until death or censoring to determine the influence of PH on patients with advanced lung disease. Using data for right heart catheterization measurements, mild PH was defined as mean pulmonary artery pressure of 25 mm Hg or more, and severe as 35 mm Hg or more. Of 6,657 idiopathic pulmonary fibrosis patients, 6,651 were used for univariate analysis, 6,126 for Kaplan-Meier survival function, 6,013 for multivariate Cox models, and 5,186 (mild PH) and 2,014 (severe PH) for propensity score matching, respectively. Univariate Cox proportional hazards analysis found significant differences in survival for mild PH (hazard ratio [HR] 1.689, 95% confidence interval [CI]: 1.434 to 1.988, p < 0.001) and severe PH (HR 2.068, 95% CI: 1.715 to 2.493, p < 0.001). Further assessment by multivariate Cox models identified significant risk for death for mild PH (HR 1.433, 95% CI: 1.203 to 1.706, p < 0.001) and severe PH (HR 1.597, 95% CI: 1.308 to 1.949, p < 0.001). Propensity score matching confirmed the risk for death for mild PH (HR 1.530, 95% CI: 1.189 to 1.969, p = 0.001) and severe PH (HR 2.103, 95% CI: 1.436 to 3.078, p < 0.001). The manifestation of PH, even with mild severity, is associated with significantly increased risk for death among patients with idiopathic pulmonary fibrosis awaiting lung transplantation, so referral should be considered early in the disease course.

PSEUDO-THROMBOSIS OF THE SUPERIOR VENA CAVA AS A MANIFESTATION OF PULMONARY HYPERTENSION CRISIS AFTER GLENN PROCEDURE

O bjective. Pulmonary hypertension is one of the typical complications of the congenital heart defects with pulmonary overload circulation. Hemodynamic status of the pulmonary circulation is critically important for the patients with univentricular heart anatomy and determines opportunities and results of the surgical treatment. Case report. We present a case report of superior vena cava syndrome feigning a thrombosis of the anastomosis in a patient after Glenn procedure. Clear clinical picture, hemodynamic instability of the patient and inability to exclude anastomosis dysfunction were an indication for re-operation. There were no signs of anastomosis dysfunction or thrombosis. This clinical situation was assessed as a manifestation of pulmonary hypertension (PH) feigning a thrombosis of the Glenn anastomosis. Applying of pulmonary vasodilation agents gave an opportunity to avoid a PH crisis and promoted stable postoperative period. Conclusions. In consideration of our clinical experience we believe that inclusion of computer tomography scan or magnetic resonance imaging into examination protocol is appropriate for the patients with high risk of PH crisis.

Pulmonary Hypertension in Cystic Fibrosis with Advanced Lung Disease

The impact of pulmonary hypertension (PH) on survival in cystic fibrosis (CF) remains unclear. To determine the influence of PH on survival in the CF population. The United Network for Organ Sharing database was queried from 1987 to 2013 to identify first-time lung transplant candidates who were tracked from wait list entry date until death or censoring to determine influence of PH. Using right heart catheterization measurements, mild PH was defined as mean pulmonary artery pressure greater than or equal to 25 mm Hg and severe greater than or equal to 35 mm Hg. Of 2,781 CF patients, 2,100 were used for univariate analysis, 764 for Kaplan-Meier survival function, 687 for multivariate Cox models, and 576 and 132 for matching on the propensity of mild PH and severe PH, respectively. Univariate Cox analysis found significant differences in survival for mild PH (hazard ratio [HR], 1.747; 95% confidence interval [CI], 1.387-2.201; P < 0.001) and severe PH (HR, 2.299; 95% CI, 1.639-3.225; P < 0.001). Further assessment by multivariate Cox models identified significant risk for death associated with mild PH (HR, 1.757; 95% CI, 1.367-2.258; P < 0.001) and severe PH (HR, 2.284; 95% CI, 1.596-3.268; P < 0.001). Cox regression stratified on matched pairs of PH cases and control subjects confirmed the risk for death for mild PH (HR, 1.919; 95% CI, 1.290-2.85; P = 0.001) and severe PH (HR, 4.167; 95% CI, 1.709-10.157; P = 0.002). The manifestation of PH is associated with significantly increased risk for death in CF patients with advanced lung disease.

Diagnostic value of echocardiography in the diagnosis of pulmonary hypertension.

AimsTo determine the value of echocardiography including tissue Doppler imaging (TDI) and right ventricular (RV) speckle tracking analysis for the diagnosis of pulmonary hypertension (PH) and discrimination between pre- and postcapillary PH.Methods and Results155 consecutive patients (mean age 70.5±13.0 years, 81 [52%] male gender, BMI 27.2±6.1 kg/m2) with PH undergoing right heart catheterization (RHC) and transthoracic echocardiography (TTE) with TDI between January 2008 and December 2009 were retrospectively evaluated including offline speckle tracking analysis of RV contractility. After RHC 23.2% of patients (36) were diagnosed with precapillary PH. Invasive results from RHC were significantly correlated to TTE measurements (E/é, postcapillary wedge pressure [PCWP], r = 0.61, P<0.001; mean, systolic pulmonary arterial pressure [mPAP, sPAP], r = 0.43, P<0.001). Single echocardiographic parameters were of good predictive value for final PH-diagnosis (sPAP, area under the curve [AUC] 0.63, P = 0.025; lateral apical RV longitudinal strain [RVaSl)], AUC 0.76, P = 0.001; E/é, AUC 0.84, P<0.001) which could be increased by combining most predictive parameters after receiver operating curves (ROC) cut off analysis (sPAP>69 mmHg, E/é<12, RVaSl ≥−8.4%). TTE had a sensitivity of 33.33% and a specificity of 100% to identify patients with precapillary PH, and a negative predictive value of 84.72% to rule out precapilary PH.ConclusionEchocardiography allows feasible and reliable estimation of PH and seems helpful to distinguish between pre-and postcapillary PH. Further prospective studies on patients with different manifestations of PH must validate the predictive value of echocardiography in this clinical setting.

Contemporary issues in pulmonary hypertension

In recent years, important contributions to the understanding of pulmonary hypertension (PH) have been published in core clinical journals [1]. Relevant and thought-provoking studies evidencing the high quality of research in the PH field have been carried out by specialists worldwide. We have decided to focus on special issues we believe to be, on the one hand, pertinent to the understanding of what has happened hitherto and, on the other hand, useful to lay the new foundations on which future research will be based. Amongst the articles published in the last couple of years, we believe that the following groups of interest deserve special attention: the summary of the fourth World Symposium on PH; the guidelines on PH (both the American and the European); and the studies that shed new light on the discussion of survival in PH. In June 2009, the results of the discussion of working groups on specific issues of PH were published in 11 articles and one editorial in the Journal of the American College of Cardiology [2–13]. The articles covered a vast array of topics on PH, from basic research (comprising development, pathology, inflammation, genetics, and cellular and molecular basis of PH) to clinical issues, such as classification, diagnosis, the role of surgery and medical treatment in pulmonary arterial hypertension (PAH). Interestingly, there were also papers on end-points and clinical trials, and on future perspectives for the treatment of PAH. The article entitled “Updated clinical classification of pulmonary hypertension” [3] aimed at grouping together different PH manifestations with similar pathophysiological mechanisms, clinical presentation and therapeutic options. In spite of the maintenance of the general architecture of the classification compared to the previous classifications (Second and Third World Symposium on Pulmonary Hypertension in 1998 (Evian, France) and 2003 …

CT imaging of peripheral pulmonary vessel disease

The diseases concerning the small pulmonary vessels are difficult to diagnose. Pathologic findings are rarely limited to the small vessels, and a continuum between the involvement of small and large vessels is frequent. Moreover, small vessels can be affected by various disease entities with overlapping radiologic features and a wide spectrum of clinical manifestations. Nevertheless, these various entities can be easily separated into two different groups by imaging techniques, particularly by computed tomography: obstructive and inflammatory diseases. Radiologic findings of obstructive diseases are relatively constant, dominated by the manifestation of pulmonary hypertension. In contrast, radiologic manifestations of inflammatory diseases are often florid and nonspecific. After a recall of the classification of small vessel diseases and the imaging techniques, we show the computed tomography features of the principal diseases involving the small pulmonary vessels by classifying them in these two principal groups.

CT imaging of peripheral pulmonary vessel disease

The diseases concerning the small pulmonary vessels are difficult to diagnose. Pathologic findings are rarely limited to the small vessels, and a continuum between the involvement of small and large vessels is frequent. Moreover, small vessels can be affected by various disease entities with overlapping radiologic features and a wide spectrum of clinical manifestations. Nevertheless, these various entities can be easily separated into two different groups by imaging techniques, particularly by computed tomography: obstructive and inflammatory diseases. Radiologic findings of obstructive diseases are relatively constant, dominated by the manifestation of pulmonary hypertension. In contrast, radiologic manifestations of inflammatory diseases are often florid and nonspecific. After a recall of the classification of small vessel diseases and the imaging techniques, we show the computed tomography features of the principal diseases involving the small pulmonary vessels by classifying them in these two principal groups.

503. Gene Transfer Strategies for Pulmonary Hypertension

Pulmonary hypertension may be a potential disease target for alveolar gene transfer by luminal delivery. We hypothesize that long-term expression of prostacyclin synthase (PGIS) cDNA can ameliorate the manifestations of pulmonary hypertension in mouse models. To test this hypothesis, we are exploring the utility of alveolar gene transfer mediated by luminal delivery of adenoassociated virus (AAV) and equine infectious anemia virus (EIAV) vectors in comparison to vascular (internal jugular vein) route of delivery in vivo. AAV (serotypes 1 and 5) and EIAV vectors pseudotyped with the vesicular stomatis virus (VSV) glycoprotein (G) were produced containing either reporter genes or the PGIS cDNA under control of the clara cell 10 kd (CC10), beta actin promoter with cytomegalovirus enhancer (CB), or murine U1a promoters. Vector (50 ul of 1012 vector genomes/ml AAV; 109 infectious units (IU)/ml EIAV) was instilled luminally (nasally or intratracheally) and compared to internal jugular vein (IJ) administration of the same dose of vec-tor in mice. The mice were euthanized and transgene expression assessed by biochemical assays and histochemistry. In initial studies, AAV5-CB human placental alkaline phosphatase (hPLAP) vectors and AAV5-U1a green fluorescent protein (GFP) vectors mediated more efficient gene transfer to alveolar epithelia than AAV1 vectors with the same reporter expression cassettes. Transgene expression was detected in multiple cell types by histochemical analysis following transduction with AAV vectors containing the CB and U1a promoters, whereas expression from an AAV vector with a CC10 promoter was more specific to alveolar type II and airway epithelial cells. Luminal gene transfer efficiency was similar to IJ vein administration for AAV1 vectors, but AAV5 vectors provided more efficient gene transfer following luminal (nasal) rather than IJ delivery. Both AAV1 and AAV5 vectors mediated reporter gene expression for more than 3 months following nasal administration when driven by CB and U1a promoters, but AAV1 vector-mediated expression was attenuated by 70% over a 60 day period, whereas AAV5-mediated re-porter gene expression was only attenuated by 30%. Expression from both vectors remained stable from 60–90 days after transduction. With regard to lentivectors, luminal (intratracheal) delivery of a VSV-G pseudotyped EIAV-lacZ vector exhibited inefficient gene transfer. However, in vivo luminal delivery of a VSV-G pseudotyped EIAV-PGIS vector mediated a 1.3 fold increase in 6-keto-PGF1alpha (the nonenzymatic hydrolysis product of prostacyclin) levels in serum and IJ delivery induced a 2.2-fold increase in serum 6-ketoPGF1alpha levels. These data suggest that vectors with potential for long-term expression can mediate reporter gene and therapeutic transgene expression following in vivo delivery by vascular and luminal delivery routes and offer hope for gene transfer approaches to pulmonary hypertension.

Manifestation of Pulmonary Hypertension During REM Sleep in Obstructive Sleep Apnea Syndrome

The effect of sleep stage change on pulmonary circulation has not been well documented in patients with obstructive sleep apnea syndrome (OSAS). We investigated whether or not stage-specific change can affect pulmonary artery pressure (Ppa) in patients with OSAS. Thirty-one patients with OSAS underwent right cardiac catheterization in the daytime and the following night, including 19 patients in whom Ppa could be measured throughout non-rapid eye movement (NREM) and rapid eye movement (REM) sleep. Ten of the 19 patients had daytime pulmonary hypertension (PH) defined by a mean Ppa (Ppa) >/= 20 mm Hg. Then we analyzed Ppa response to hypoxia spontaneously occurring during the period of sleep apnea. The slopes of the regression lines between arterial oxygen saturation measured by pulse oximeter (SpO2) and Ppa curves were almost the same in both NREM and REM patient groups with or without daytime PH, whereas the response curve was significantly shifted upward in REM compared with NREM patients with daytime PH. Furthermore, Ppa was elevated more markedly in association with REM burst, phasic REM, compared with tonic REM. We conclude that vascular tone of pulmonary artery could be elevated in association with REM sleep which is independent of the degree of hypoxia, and that this state-specific change is manifested in patients with daytime PH.

Clinical relevance of endothelial dysfunction in cardiovascular disorders.

The potential role of endothelial dysfunction, defined by an imbalance in the production of endothelium-derived vasodilator and constrictor factors is discussed. Evidence is presented that increased endothelin-1 production plays an important role in the clinical and morphological manifestations of pulmonary hypertension, particularly in primary disease. As well, the potential contribution of a relative decrease in nitric oxide production to inappropriately elevated pulmonary vascular resistance in patients with secondary causes of pulmonary hypertension, particularly those with congestive heart failure is discussed.