Elevated Pulmonary Resistance Research Articles

Pediatric Heart Transplantation in the Context of Severe Pulmonary Hypertension Secondary to Restrictive Cardiomyopathy—Case Report

The aim of this study is to analyze the feasibility of performing an isolated heart transplant in patients with severe pulmonary hypertension as a result of restrictive cardiomyopathy. The results present the clinical course from the diagnosis of restrictive cardiomyopathy at the age of 2 until the heart transplant at 8 years old. Initially, the patient was considered for multiorgan transplantation, heart and lungs, due to extremely high pulmonary resistance. However, due to the prolonged waiting period for a donor and the worsening condition of the child, a decision was made to perforate the atrial septum with the implantation of an atrial flow regulator system. After conducting control hemodynamic measurements, the qualification was changed to an isolated heart transplant, accepting the high operative risk associated with the still elevated pulmonary resistance index of 4.9 Wood units. This study describes the medical problems that occurred during postoperative treatment. The patient underwent an orthotopic heart transplant in her eighth year of life. Postsurgery, complications were observed, including generalized seizures and heart transplant rejection reaction. Immunosuppressive therapies were applied, and efforts were made to combat anemia and electrolyte disorders. While the cardiovascular system and heart parameters improved, there were some difficulties in controlling heart rhythm and stabilizing electrolyte levels.

Approach to hypoxemia in the emergency department in a clinical case of Eisenmenger Syndrome

There is a wide variety of pathologies that can cause hypoxia with different pathophysiological mechanisms, and therefore with different response to treatment with supplemental oxygen, it is essential for emergency care physicians to know the different pathologies causing hypoxia to be able to adequately and direct the treatment , in this paper we discuss the case of a patient with syncope and hypoxia who reaches the emergency department, which mechanism of hypoxia is a consequence of an interatrial short circuit, reaching the conclusion of Eisenmenger syndrome, which is a pulmonary vascular disease, with elevation of pulmonary resistance in patients with a history of heart disease with short circuit from left to right. This pathology is of vital importance that its identification is made in initial stages, with the aim of preventing evolution to the point where medical treatment is insufficient, and as in the case to mention, the only remaining option would be lung and heart transplantation.

Regulatory role of autophagy in development of pulmonary artery hypertension

Pulmonary arterial hypertension (PAH) is a multi-etiological chronic disease characterized by a progressive elevation in pulmonary resistance and vascular remodeling. Its pathogenesis is complicated. Recently, emerging researches suggest that autophagy, as a self-protection mechanism maintaining the intracellular environment homeostasis in eukaryotes, participate in the occurrence and development of various types of PAH. Autophagy can regulate the survival, apoptosis of pulmonary vascular wall cells and secretion of vasoactive substances and inflammatory cytokines, thus influencing pulmonary vascular homeostasis. Some drugs based on regulating autophagy activity can effectively improve the prognosis of PAH. In this article, the regulatory role of autophagy on the development of pulmonary hypertension is reviewed to provide insight into PAH and its treatment.

Vasoactive Drugs and Hemodynamic Monitoring in Pediatric Cardiac Intensive Care: An Italian Survey.

Little is known about practitioner preference, the availability of technology, and variability in practice with respect to hemodynamic monitoring and vasoactive drug use after congenital heart surgery. The aim of this study was to characterize current hospital practices related to the management of low cardiac output syndrome (LCOS) across Italy. We issued a 22-item questionnaire to 14 Italian hospitals performing pediatric cardiac surgery. Electrocardiogram, invasive blood pressure, central venous pressure, pulse oximetry, diuresis, body temperature, arterial lactate, and blood gas analysis were identified as routine in hemodynamic monitoring. With regard to advanced hemodynamic monitoring, pulmonary arterial catheter and transpulmonary thermodilution were available in 43% of the centers, uncalibrated pulse contour methods in 29% of the centers, and transesophageal/transthoracic echocardiograms in all of the centers. Dopamine added to milrinone was the most frequent drug regimen for LCOS prevention after cardiopulmonary bypass. Overall, 86% of centers used milrinone alone as the initial treatment for LCOS with elevated systemic vascular resistances and levosimendan, the second preferred choice. In cases of LCOS with low vascular resistance, epinephrine was the first choice (10 centers), dopamine was the second choice (4 centers), followed by vasopressin and norepinephrine (3 centers). For treatment of LCOS with elevated pulmonary resistances, milrinone was the first choice (eight centers), followed by inhaled nitric oxide (five centers). The survey shows that advanced hemodynamic monitoring is rarely performed. The most commonly used vasoactive drugs are milrinone, levosimendan, dopamine, epinephrine, vasopressin, and norepinephrine. Guidelines on the topic are warranted.

To decipher the hypoxic pulmonary hypertension: Vascular heterogeneity and the hypothesis of hypoxic responsive threshold

Pulmonary hypertension (PH) is a complex and multi-factorial chronic disease characterized by progressively increased pulmonary vascular resistance and vascular remodeling, and it has been recognized as ‘the cancer of cardiovascular diseases’ because of its high morbidity and mortality. Pathophysiological changes of pulmonary arteries, which implicate endothelial dysfunction, smooth muscle cell proliferation, and increased vasoconstriction, decrease the lumen area of the pulmonary microvasculature, optimizing the pulmonary ventilation/perfusion ratio as well as causing fixed elevation of pulmonary resistance. Among various types of PH, hypoxic pulmonary hypertension (HPH) which occurs in patients with cardiopulmonary disease or in residents at high altitude has aroused great interest in researchers. Intriguingly, synchronously exposed to the hypoxic circumstances, the peripheral vessels make responses different from pulmonary arteries, which, besides the effects exerted by nervus and the microenvironment (involving the inflammatory mediators, angiotensin II and other ingredients), has always been expounded as the vascular heterogeneity. Nevertheless, nobody has articulated such heterogeneity and its mechanism to date. Based on our prior experiments, we propound the hypothesis of hypoxic responsive threshold (HRT) for the first time, which means that once the partial pressure of oxygen diminishes to certain degree, vessel in different tissues reacts via the reactive oxygen species (ROS)–potassium channels (Kv)–hypoxia inducible factors (HIF) triangle, resulting in hypoxic vasoconstriction and vascular remodeling. HRT, varying according to different parts of the body, has close relationship with normoxic condition of the vessels. Physiological oxygen-rich milieu determines higher pulmonary vascular HRT, which explains why the pulmonary arterioles are more susceptible to hypoxia.

Restrictive Atrial Septum Defect Becomes a Risk Factor for Norwood Palliation of Hypoplastic Left Heart Syndrome Only When It Is Combined with Mitral or Aortic Atresia

Restrictive atrial septal defect (ASD) is described as risk factor for Norwood procedure because of elevated pulmonary resistance. We hypothesized that it invariably could not cause pulmonary hypertension, unless it was combined with mitral valve or aortic valve atresia. We investigated how restrictive ASD influenced survival of patients with hypoplastic left heart syndrome (HLHS) who underwent Norwood operation. A total of 118 HLHS patients who underwent surgery between January 2005 and December 2012 were grouped into three groups. Group 1 included 31 patients with restrictive ASD combined with mitral or aortic atresia; Group 2 composed of 12 patients with restrictive ASD and mitral and aortic stenosis; Group 3 (n = 75) had no ASD restriction. Survival was determined for each group. Multivariate analysis was conducted to test risk factors for mortality. Mean follow-up was 26.3 ± 24.1 months. Survival was 78.7% ± 4.2% at 30-month interval and onward after Norwood procedure for the whole cohort; it was 43.8% ± 10.0%, 91.7% ± 8.0%, and 77.3% ± 5.0% for Group 1, 2, and 3, respectively. The difference was significant between Group 1 and Group 2 and 3: p < 0.001. Survival was similar for Group 2 and Group 3: p = 0.45. Combination of restrictive ASD and mitral or aortic atresia was found to be the sole risk factor for early and late mortality (odds ratio: 3.5, 95% confidence interval: 1.8-7.1, p < 0.001). Restrictive ASD only affects survival of HLHS patients following Norwood procedure if it is associated with mitral or aortic atresia.

Right Ventricular Assist Device as a Bridge to Recovery Postheart Transplantation for Failed Fontan Circulation

Background: Long-term outcome for children with functionally univentricular hearts has improved. Failure of Fontan circulation and protein loosing enteropathy (PLE) leaves cardiac transplantation as ultimate option. Posttransplantation, these patients are at risk for elevated pulmonary resistance, right ventricular (RV) failure, and early mortality. Supporting the RV with a mechanical circulatory device may allow for recovery of function and hemodynamics.

Performance evaluation of a pediatric viscous impeller pump for Fontan cavopulmonary assist

The anatomic and physiologic constraints for pediatric cavopulmonary assist differ markedly from adult Fontan circulations owing to smaller vessel sizes and risk of elevated pulmonary resistance. In this study, hemodynamic and hemolysis performance of a catheter-based viscous impeller pump (VIP) to power the Fontan circulation is assessed at a pediatric scale (∼15 kg) and performance range (0-30 mm Hg). Computer simulation and mock circulation studies were conducted to assess the hydraulic performance, acute hemodynamic response to different levels VIP support, and the potential for vena caval collapse. Computational fluid dynamics simulations were used to estimate VIP hydraulic performance, shear rates, and potential for hemolysis. Hemolysis was quantified in a mock loop with fresh bovine blood. A VIP augmented 4-way total cavopulmonary connection flow at pediatric scales and restored systemic pressures and flows to biventricular values, without causing flow obstruction or suction. VIP generated flows up to 4.1 L/min and pressure heads of up to 38 mm Hg at 11,000 rpm. Maximal shear rate was 160 Pa, predicting low hemolysis risk. Observed hemolysis was low with plasma free hemoglobin of 11.4 mg · dL(-1) · h(-1). A VIP will augment Fontan cavopulmonary flow in the proper pressure and flow ranges, with low hemolysis risk under more stringent pediatric scale and physiology compared with adult scale. This technology may be developed to simultaneously reduce systemic venous pressure and improve cardiac output after stage 2or 3 Fontan repair. It may serve to compress surgical staging, lessening the pathophysiologic burden of repair.

The outcome of the vertical vein left intact during the surgery for total anomalous venous connection and its effects on ventricular functions

We examined the fate of intact vertical vein during long-term follow-up and its effects on ventricular functions. Eighty one patients with all types of total anomalous pulmonary venous connection (TAPVC) were operated. Thirty-one patients with supracardiac type TAPVC were examined in our retrospective cohort study. Groups were evaluated with respect to left ventricle area, volume, end-systolic, end diastolic diameter, early and late term mortality and properties of pulmonary hypertensive crisis. Vertical vein was left open in 14 patients and it was ligated in 17 patients. Wilcoxon rank and Mann- Whitney U tests were used to compare variables between groups. After mean follow up of 48±36 months, vertical vein closed spontaneously in 3 patients. Two of them were closed surgically due to elevated shunt flow and there was spontaneous closure in one patient who had the highest pulmonary artery pressure amongst others postoperatively. Preoperative left ventricular area, volume, end-systolic diameter and end-diastolic diameter values of the patients increased from 3.5± 0.9 mm(2)-2.9±0.9 mm(3)-14±5 mm-8±4.5 mm to 8±3.3 mm(2)-16±8.7 mm(3)-27±6.7 mm-17±4.8 mm at the postoperative period in Group 1, and from 6.8±3.5 mm(2)-8.4±8.7 mm(3)-15±6.4 mm-9±5.3 mm to 7.4±5.2 mm(2)-16±1.7 mm(3)-21.7±5 mm-13.5±4.1 mm in Group 2, respectively (p=0.02, p=0.039, p=0.054, and p=0.07, respectively). Vertical vein remains intact in most of the patients and may be closed spontaneously in patients with elevated pulmonary resistance. Intact vertical vein both decompresses the left ventricular cavity in patients with decreased left ventricular compliance until the ventricular muscle adapts to new workload and improves ventricular functions on long term follow up. Therefore, we conclude that vertical vein should be left open in selected patients.

Outcomes After Pulmonary Thromboendarterectomy

Pulmonary thromboendarterectomy remains the procedure of choice for appropriate cases of chronic thromboembolic pulmonary hypertension. The acceptance of this strategy is based on comparisons of long-term survival between pertinent natural history studies of nonoperative treatment with that after the development of this surgery. A randomized controlled trial would never be deemed ethically appropriate or feasible at this time due to the tremendous success of surgery in afflicted patients. Aside from the survival advantage, surgery also results in a significant improvement in several quality-of-life factors such as physical, social, energy and general health, and a significant decrease in the need for supplemental oxygen, with many patients returning to work. The degree of improvement may be predicted by preoperative vasoresponsiveness at right heart catheterization as well as measures of upstream resistance. Postoperative elevated pulmonary pressures and resistance are the best predictors of a poor outcome, with the most common cause of death related to persistent pulmonary hypertension. In general, high-volume centres can achieve perioperative mortality rates of 4% to 10%, with a significant predicted improvement in all measures of cardiopulmonary hemodynamics and symptomatology.

Heart transplantation in Vienna: 25 years of experience

Since the beginning of the University of Vienna Cardiac Transplant Program in 1984, 1113 heart transplant procedures have been performed through August of 2008. One- and five-year survival has increased steadily over time (82% and 76%). Ten-year survival is 65%. Over the past 25 years our program has seen dramatic changes in patient selection, accepting now patients with more risk factors (e.g. age, diabetes, elevated pulmonary resistance). Developments in immunosuppression have decreased incidence of infection, rejection and graftarteriosclerosis continuously. Our program continues to pursue novel strategies to improve the survival and quality of life of our heart transplant patients.

Evidence that reduced skeletal muscle recruitment explains the lactate paradox during exercise at high altitude

the studies of Amann et al. ([1][1], [2][2]) provide the final evidence necessary to solve the “lactate paradox” that has haunted the exercise sciences since first described in 1936 ([4][3]) and which was the recent focus of a Point:Counterpoint debate ([25][4], [26][5]). In its simplest form

Pulmonary Responses to Overventilation in Late Multiple Organ Failure

Patients with multiple organ failure (MOF) require mechanical ventilation for several days. The enormous significance of the ventilation strategy for the outcome of these patients is well appreciated. However, most studies have focused on the onset and the early phase of MOF. It was the aim of the current study to investigate the effect of ventilation in the course of MOF. Using a model where mice develop MOF 7-14 days after intraperitoneal injection of zymosan, the authors analyzed lung functions, signaling pathways, and mediator release in response to protective ventilation (end-expiratory pressure -3 cm H2O; end-inspiratory pressure -10 cm H2O) and overventilation (-22.5 cm H2O) in isolated lungs ex vivo. On day 7, pulmonary compliance, pulmonary resistance, and tidal volume were normal, but vascular resistance was elevated compared with untreated animals. During ex vivo ventilation, these lungs showed enhanced nuclear factor-kappaB activation, Akt kinase phosphorylation, and cytokine release, and this was further aggravated by overventilation. After 14 days, zymosan-treated animals were characterized by pulmonary hypertension, reduced tidal volume, elevated pulmonary resistance, and increased mediator production. However, in these lungs, neither nuclear factor-kappaB activation nor cytokine production where enhanced by overventilation. The zymosan model is characterized by pulmonary inflammation, diminished lung functions, and chronic hypertension. Mechanical ventilation with high distending pressures further augmented cytokine production in this chronic model of MOF only if it significantly augmented tidal volume. The authors speculate that these findings may be explained on the basis of different degrees of lung stretch.

Cytochrome P450 Epoxygenase Gene Function in Hypoxic Pulmonary Vasoconstriction and Pulmonary Vascular Remodeling

We assessed pulmonary cytochrome P450 (CYP) epoxygenase expression and activity during hypoxia and explored the effects of modulating epoxygenase activity on pulmonary hypertension. The acute hypoxic vasoconstrictor response was studied in Swiss Webster mice, who express CYP2C29 in their lungs. Animals were pretreated with vehicle, the epoxygenase inhibitor (N-methylsulfonyl-6-[2-propargyloxyphenyl] hexanamide) or an inhibitor of the soluble epoxide hydrolase. Whereas the epoxygenase inhibitor attenuated hypoxic pulmonary constriction (by 52%), the soluble epoxide hydrolase inhibitor enhanced the response (by 39%), indicating that CYP epoxygenase-derived epoxyeicosatrienoic acids elicit pulmonary vasoconstriction. Aerosol gene transfer of recombinant adenovirus containing the human CYP2C9 significantly elevated mean pulmonary artery pressure and total pulmonary resistance indices, both of which were sensitive to the inhibitor sulfaphenazole. The prolonged exposure of mice to hypoxia increased CYP2C29 expression, and transcript levels increased 5-fold after exposure to normobaric hypoxia (FIO2 0.07) for 2 hours. This was followed by a 2-fold increase in protein expression and by a significant increase in epoxyeicosatrienoic acid production after 24 hours. Chronic hypoxia (7 days) elicited pulmonary hypertension and pulmonary vascular remodeling, effects that were significantly attenuated in animals continually treated with N-methylsulfonyl-6-[2-propargyloxyphenyl] hexanamide (-46% and -55%, respectively). Our results indicate that endogenously generated epoxygenase products are associated with hypoxic pulmonary hypertension in mice and that selective epoxygenase inhibition significantly reduces acute hypoxic pulmonary vasoconstriction and chronic hypoxia-induced pulmonary vascular remodeling. These observations indicate potential novel targets for the treatment of pulmonary hypertension and highlight a pivotal role for CYP epoxygenases in pulmonary responses to hypoxia.

HEMODYNAMIC EFFECTS OF IN-PARALLEL ARTIFICIAL LUNG IMPLANTATION IN HEALTHY AND HYPERTENSIVE SHEEP

Chronic lung disease typically results in elevated pulmonary system resistance (PSR) and can cause right ventricular hypertrophy and dysfunction. Thoracic artificial lungs (TALs) may be used with these patients as a bridge to transplantation. To determine the hemodynamic effects, the MC3 Biolung® was attached in-parallel, without pulmonary artery banding, in six sheep with induced chronic pulmonary hypertension (HYP) and three healthy sheep (HEA). Hemodynamic data was acquired just prior and 15 min. after commencing TAL flow. Prior to TAL attachment, the PSR of the healthy and hypertensive sheep were 1.18 ± 0.24 and 3.75 ± 1.25 mmHg/(L/min), respectively. After TAL attachment, HEA PSR decreased significantly to 0.77 ± 0.47 (p=0.03), and HYP PSR decreased significantly (p=0.006) to 1.33 ± 0.48. Prior to TAL attachment, the average HEA and HYP cardiac indices (CIs) were 0.094 ± 0.021 and 0.097 ± 0.015 respectively. After implantation of the TAL, the HEA and HYP CIs were 0.112 ± 0.022 and 0.111 ± 0.019, respectively. Neither group showed a significant difference between pre and post TAL attachment (p=0.25 and 0.86). The CIs were in normal ranges for all situations examined, indicating HYP sheep had compensated for elevated PSR. Thus, TAL attachment had little effect on CI. TAL attachment significantly reduced PSR in both groups, however, suggesting that, in chronic lung disease patients, the TAL might reduce RV hypertrophy, and, in more severe disease states, improve RV function.

Multicenter USA Amplatzer Patent Ductus Arteriosus Occlusion Device Trial: Initial and One-Year Results

We sought to review and report initial and one-year efficacy and safety results of the multicenter USA Amplatzer ductal occluder (ADO) device trial. Transcatheter closure of a moderate to large patent ductus arteriosus (PDA) using conventional techniques is challenging. The ADO can close a PDA up to 12 mm in diameter. From September 1999 to June 2002, 484 patients were enrolled in 25 U.S. centers. Forty-five (9%) of 484 patients did not have ADO implantation, because the PDA was too small or because of elevated pulmonary resistance. The median age of the patients at catheterization was 1.8 years (range 0.2 to 70.7 years), and weight was 11 kg (range 4.5 to 164.5 kg). The median PDA minimal diameter was 2.6 mm (range 0.9 to 11.2 mm); 76 (17%) of 439 were larger than 4.0 mm. Median pulmonary artery mean pressure was 20 mm Hg (range 7 to 80 mm Hg). The ADO was implanted successfully in 435 (99%) of 439 patients, with a median fluoroscopy time of 7.1 min (range 2.9 to 138.4 min). Angiographic demonstration of occlusion was seen in 329 (76%) of 435. This increased to 384 (89%) of 433 on post-catheterization day 1, with occlusion documented in 359 (99.7%) of 360 at one year. At the last evaluation in all patients at any time, PDA closure was documented in 428 (98%) of 435 patients. There have been two cases of partial left pulmonary artery occlusion after ADO implantation and no cases of significant aortic obstruction. Moderate to large PDAs can be effectively and safely closed using the ADO device, with excellent initial and one-year results. This device should obviate the need for multiple coils or surgical intervention for these defects.

Inhaled nitric oxide therapy in the near-term or term neonate with hypoxic respiratory failure.

Inhaled nitric oxide (iNO) has altered the management strategy for treating near-term and term infants with hypoxic respiratory failure (HRF). There is a strong relationship between HRF and persistent pulmonary hypertension of the newborn (PPHN). PPHN is characterized by elevated pulmonary resistance, pulmonary vasoconstriction, and altered vascular reactivity. The resulting high pulmonary pressure may lead to HRF, which is defined as a relative deficiency of oxygen in arterial blood and insufficient minute ventilation. iNO improves oxygenation and decreases the need for extracorporeal membrane oxygenation. Although iNO therapy is effective, its efficacy can depend on the fine points of its use and on other care the infant is receiving. Even in NICUs that do not have iNO available, those who care for term infants with HRF must be familiar with its use and know when and how to transfer these infants and how to help families through this difficult period. Because iNO therapy will probably be used more frequently in nurseries over the next few years, more information on the safety and efficacy of its use in the broader neonatal population needs to be available.

Mortality after partial left ventriculectomy in relation to contraindications for heart transplantation

OBJECTIVE:To analyze the impact of the contraindications for heart transplantation in mortality and survival time after partial left ventriculectomy. METHOD: A prospective clinical study of a cohort of 43 patients submitted to partial left ventriculectomy, in whom there were contraindications for heart transplantation was performed. The following contraindications were analyzed: psychological, sociocultural, age of 65 years of age and older, elevated pulmonary arteriolar resistance and pulmonary arterial hypertension and the refusal or not for transplantation. These variables were tested for association with postoperative mortality and survival time after partial left ventriculectomy. Statistical analysis included the Chi-square test, Kaplan-Meier survival analysis, non-parametric log-rank test, Cox regression model, 95% confidence intervals and p values (significant if less than 0.05). RESULTS: Higher postoperative mortality rates for partial left ventriculectomy were found when the following contraindications of heart transplantation were present preoperatively: poor sociocultural conditions (p = 0.037), psychological disturbances (p = 0.037) and in patients who accepted heart transplantation even when counseled against this procedure (p = 0.017). Survival time was significantly shortened in the presence of psychological disturbances (p = 0.0466), in patients older than 65 years (p = 0.0397) and in those who did not accept heart transplantation (p = 0.0306). Elevated pulmonary arteriolar resistance and pulmonary arterial hypertension were not associated with higher mortality rates or shortened survival time. CONCLUSION: Some of the contraindications for heart transplantation adversely affected the mortality and survival time after partial left ventriculectomy, thus revealing the ineffectiveness of this alternative procedure in this subset of patients.

Effect of Orally Active Prostacyclin Analogue on Survival in Patients With Chronic Thromboembolic Pulmonary Hypertension Without Major Vessel Obstruction

This study investigated whether treatment with beraprost sodium (BPS), an orally active prostacyclin analog, improves hemodynamics and survival in patients with peripheral-vessel chronic thromboembolic pulmonary hypertension (CTEPH), for which there is no surgical option. Oral administration of BPS has been shown to improve the hemodynamics and prognosis in patients with primary pulmonary hypertension; however, whether BPS has beneficial effects in CTEPH remains unknown. Forty-three patients with peripheral-vessel CTEPH were classified into two groups: patients treated with BPS (BPS group, n = 20) and those without BPS (conventional group, n = 23). Baseline demographic and hemodynamic data did not significantly differ between the two groups. BPS therapy improved New York Heart Association functional class in 10 patients (50%) and significantly decreased total pulmonary resistance from 18 +/- 6 to 15 +/- 8 Wood units (p < 0.05) [mean +/- SD]. Sixteen patients died of cardiopulmonary causes in the conventional group during a mean follow-up period of 58 +/- 45 months. In contrast, only three patients died of cardiopulmonary causes in the BPS group during a mean follow-up period of 44 +/- 30 months. The absence of BPS therapy, elevated total pulmonary resistance, heart rate, and age were independently related to the mortality by Cox proportional hazard analysis. The 1-year, 3-year, and 5-year survival rates for the BPS group were 100%, 85%, and 76%, respectively, compared to 87%, 60%, and 46% in the conventional group. This preliminary study suggests that oral administration of BPS may improve hemodynamics and survival in patients with peripheral-vessel CTEPH, for which there is no surgical option.

Chronic postbronchiolitis airway instability induced with anti-IFN-gamma antibody in F344 rats.

Analogous to childhood-onset asthma in humans, rats may develop a chronic asthmalike phenotype, depending on their genetic background and the age at which they experience a viral airway injury. Brown Norway rats develop a postbronchiolitis asthmalike phenotype that may be prevented with supplements of interferon-gamma (IFN-gamma); we hypothesized that the normally resistant F344 rat strain would develop the asthmalike phenotype if the IFN-gamma response were suppressed during viral illness. Weanling F344 rats were pretreated with anti-IFN-gamma or control antibody, and inoculated with Sendai virus or vehicle. Anti-IFN-gamma treatment reduced lung IFN-gamma and increased IL-4 mRNA during the infection. Physiologic studies performed 8 wk later revealed premature airway closure (p = 0.03) and elevated specific pulmonary resistance (p < 0.01) in the postbronchiolitis anti-IFN-gamma group compared with noninfected controls and untreated postbronchiolitis rats. However, unlike the postbronchiolitis asthmalike phenotype in Brown Norway rats, bronchiolar inflammation and fibrosis were absent in the F344 rats. Lung elastic recoil and alveolar surface density also were unchanged compared with noninfected control rats. We conclude that there is an interactive effect of a weak IFN-gamma response and viral bronchiolitis at an early age that may result in persistent postbronchiolitis airway dysfunction. The presence of premature airway closure that is independent of airway wall inflammation or changes in lung elastic recoil suggests peripheral airway instability as a mechanism for the airway obstruction.