Marked Pulmonary Hypertension Research Articles

Microtubules distinctly contribute to the performance of the healthy and pressure-overloaded RV

Introduction: Microtubules (MT) are a key contributor to cardiomyocyte contractility and mechanics. Recently, our group reported that acute depolymerization of MT reduces viscosity and elasticity and alters anisotropy of healthy and pressure-overloaded right ventricular (RV) tissues. While RV free wall viscosity and elasticity are distinctly upregulated with chronic pressure overload, how organ function is affected by viscoelastic contribution of the MT remains unknown. Our aim was to investigate the role of MT polymerization in RV function from its effect on RV tissue viscoelasticity. We hypothesized that the MT differentially contributes to healthy and pressure-overloaded RV function. Methods: All procedures and methods were approved by Colorado State University IACUC. Pulmonary hypertension (PH) was induced in 6-week-old male rats via 3-week monocrotaline treatment. Healthy age- and sex-matched rats served as control. Pressure-volume (PV) relationships were obtained by RV catheterization before and after intramyocardial injections of 0.3mM colchicine (COL) to acutely depolymerize the MT network and reduce tissue viscoelasticity. Functional impacts were evaluated by monitoring changes in RV end-systolic pressure (ESP), cardiac output (CO), stroke volume (SV), ejection fraction (EF), dP/dt max and min, cardiac effciency (CE), and the end-systolic pressure-volume relation (ESPVR). Results: As expected, monocrotaline treatment induced marked PH and RV contractile dysfunction, indicated by a significant elevation of RV ESP with reduced CO and ESPVR. In the healthy RV, COL treatment led to marked reductions in all functional parameters, indicating that the MT network is critical to maintain RV performance and contractile function in the healthy heart. In the pressure-overloaded RV, COL treatment similarly reduced SV, CO, EF, and dP/dt max and min, but increased CE and ESPVR, indicating that MT depolymerization improved mechanical effciency and contractility. To rule out effects caused by bolus injections alone, we administered a similar quantity of saline and observed no effects on the PV parameters in healthy RV. Discussion: Our study is the first to investigate the acute effect of MT depolymerization on RV function in healthy and diseased states. We found distinct contributions of MT to the contractile function and mechanical effciency of healthy and pressure-overloaded RVs. These findings reveal a critical influence of tissue viscoelasticity on RV physiology and dysfunction, emphasizing the importance of considering myocardial viscoelastic behavior in future studies investigating cardiac remodeling and heart failure pathophysiology. This work is partially supported by the National Science Foundation (NSF) grant 2244994. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Histone deacetylase inhibitors synergize with sildenafil to suppress purine metabolism and proliferation in pulmonary hypertension

RationaleSildenafil, a well-known vasodilator known to interfere with purinergic signaling through effects on cGMP, is a mainstay in the treatment of pulmonary hypertension (PH). However, little is known regarding its effects on the metabolic reprogramming of vascular cells, which is a hallmark of PH. Purine metabolism, especially intracellular de novo purine biosynthesis is essential for vascular cell proliferation. Since adventitial fibroblasts are critical contributors to proliferative vascular remodeling in PH, in this study we aimed to investigate if sildenafil, beyond its well-known vasodilator role in smooth muscle cells, impacts intracellular purine metabolism and proliferation of fibroblasts derived from human PH patients. MethodsIntegrated omics approaches (plasma and cell metabolomics) and pharmacological inhibitor approaches were employed in plasma samples and cultured pulmonary artery fibroblasts from PH patients. Measurements and main resultsPlasma metabolome analysis of 27 PH patients before and after treatment with sildenafil, demonstrated a partial, but specific effect of sildenafil on purine metabolites, especially adenosine, adenine, and xanthine. However, circulating markers of cell stress, including lactate, succinate, and hypoxanthine were only decreased in a small subset of sildenafil-treated patients. To better understand potential effects of sildenafil on pathological changes in purine metabolism (especially purine synthesis) in PH, we performed studies on pulmonary fibroblasts from PAH patients (PH-Fibs) and corresponding controls (CO-Fibs), since these cells have previously been shown to demonstrate stable and marked PH associated phenotypic and metabolic changes. We found that PH-Fibs exhibited significantly increased purine synthesis. Treatment of PH-Fibs with sildenafil was insufficient to normalize cellular metabolic phenotype and only modestly attenuated the proliferation. However, we observed that treatments which have been shown to normalize glycolysis and mitochondrial abnormalities including a PKM2 activator (TEPP-46), and the histone deacetylase inhibitors (HDACi), SAHA and Apicidin, had significant inhibitory effects on purine synthesis. Importantly, combined treatment with HDACi and sildenafil exhibited synergistic inhibitory effects on proliferation and metabolic reprogramming in PH-Fibs. ConclusionsWhile sildenafil alone partially rescues metabolic alterations associated with PH, treatment with HDACi, in combination with sildenafil, represent a promising and potentially more effective strategy for targeting vasoconstriction, metabolic derangement and pathological vascular remodeling in PH.

Severe Right Heart Failure in a Patient with Chronic Obstructive Lung Disease: A Diagnostic Challenge

A 55-year-old male was admitted for evaluation of severe dyspnoea and hypoxaemia. Physical examination upon admission showed elevated jugular venous pressure and an accentuated second heart sound. Chest radiograph showed cardiomegaly with increased bibasilar markings. Arterial blood gas analysis while breathing room air showed marked hypoxaemia. High resolution computed tomography angiography of the chest showed modestly enlarged mediastinal lymph nodes with discrete diffuse ground-glass attenuation especially at the lower lung zones. Positron emission tomography using 18F labelled 2-deoxy-D-glucose (FDG) demonstrated the mediastinal lymph nodes were FDG-avid. Transthoracic echocardiography showed dilated hypokinetic right heart chambers with bulging of the interventricular septum to the left, compatible with acute cor-pulmonale. From the tricuspid regurgitation jet measurement a systolic pulmonary artery pressure (PAP) of 48 mmHg was estimated. Patent foramen ovale was suspected on bubble test. Right heart catheterisation confirmed pulmonary arterial hypertension: mPAP 47 mmHg, pulmonary artery occlusion pressure 5 mmHg, cardiac index 1.1 L/min/m2, pulmonary vascular resistance (PVR) 959 dyne.sec.cm(-5). Pulmonary function tests showed a marked diffusing capacity for carbon monoxide (DLCO) decrease of 32% predicted but no obstructive lung deficit. Before an open lung biopsy could be scheduled the patient developed acute cardiogenic shock. At autopsy pulmonary veno-occlusive disease with marked pulmonary hypertension was diagnosed.

Mitral Stenosis: Making the diagnosis

The case of a 60-year-old man illustrates a number of important features of rheumatic heart disease (RHD). The patient’s age of presentation was late (>50 yo) and he had no history of predisposing condition for RHD but served in the South Pacific when he was in the US Navy. RHD was limited to mitral stenosis in this patient and his presentation of heart failure was late. His ECG revealed ample evidence of right ventricular enlargement, and echocardiography demonstrated severe mitral stenosis, enlarged right ventricle and right atrium and marked pulmonary hypertension. Because percutaneous balloon mitral valve commissurotomy was precluded by the degree of mitral valve calcification, he underwent successful surgical valve replacement with relief of symptoms. Although RHD is rarely encountered in North America and Europe, it remains a major cause of mortality in the developing nations.

PH Grand Rounds: A Case of Pulmonary Hypertension Associated With High Cardiac Output State from Arteriovenous Fistula–Or Is It?

PH Grand Rounds: A Case of Pulmonary Hypertension Associated With High Cardiac Output State from Arteriovenous Fistula–Or Is It?

Interleukin-6 displays lung anti-inflammatory properties and exerts protective hemodynamic effects in a double-hit murine acute lung injury

BackgroundInterleukin 6 (IL-6) is a predictive factor of poor prognosis in patients with acute respiratory distress syndrome (ARDS). However, its acute pulmonary hemodynamic effects and role in lung injury have not been investigated in a clinically relevant murine model of ARDS.MethodsWe used adult C57Bl6 wild-type (WT) and IL-6 knock-out (IL-6KO) mice. The animals received intravenous recombinant human IL-6 (rHuIL-6) or vehicle followed by intratracheal lipopolysaccharide (LPS) or saline before undergoing low tidal volume mechanical ventilation (MV) for 5 h. Before sacrifice, right ventricular systolic pressure and cardiac output were measured and total pulmonary resistance was calculated. After sacrifice, lung inflammation, edema and injury were assessed with bronchoalveolar lavage (BAL) and histology. In other experiments, right ventricular systolic pressure was recorded during hypoxic challenges in uninjured WT mice pretreated with rHuIL-6 or rHuIL-6 + non-selective nitric oxide synthase inhibitor L-NAME or vehicle.ResultsIL-6KO(LPS+MV) mice showed a faster deterioration of lung elastic properties and more severe bronchoalveolar cellular inflammation as compared to WT(LPS+MV). Treatment with rHuIL-6 partially prevented this lung deterioration. Total pulmonary resistance was higher in IL-6KO(LPS+MV) mice and this increase was abolished in rHuIL-6-treated IL-6KO mice. Finally, rHuIL-6 reduced hypoxic pulmonary vasoconstriction in uninjured WT mice, an effect that was abolished by co-treatment with L-NAME.ConclusionsIn a double-hit murine model of ARDS, IL-6 deficient mice experienced more severe bronchoalveolar cellular inflammation as compared to wild-type littermates. Furthermore, IL-6 deficiency caused marked acute pulmonary hypertension, which may be, at least partially, due to vasoactive mechanisms. A dysregulation of nitric oxide synthase may account for this observation, a hypothesis that will need to be investigated in future studies.

Indications for intervention in asymptomatic children with chronic mitral regurgitation.

Based on outcome data, surgery is recommended for asymptomatic adults with chronic mitral regurgitation (MR) and systolic dysfunction, marked left ventricular (LV) dilation, pulmonary hypertension, atrial fibrillation, or high likelihood of successful repair; but indications for children are poorly defined. We sought to determine predictors of postoperative LV dysfunction in asymptomatic children with chronic MR. The surgical database was searched for all children who underwent mitral valve surgery for chronic MR (2000-2012). Exclusion criteria were preoperative symptoms, acute MR, cardiomyopathy, or other defects affecting LV size. Preoperative and latest follow-up clinical and echocardiographic data were obtained. LV dysfunction was defined as ejection fraction (EF) ≤55% or shortening fraction (SF) ≤28%. Associations between preoperative factors and late LV dysfunction were determined using univariate Poisson regression. For the 25 children who met criteria, preoperative median LV end systolic Z score (LVESZ) was 5.3, EF was 65%, and SF was 34%. At follow-up (median 3.9 years), nine patients (36%) had LV dysfunction. Lower preoperative SF (OR 0.6, p < 0.001) and higher LVESZ (OR 1.7, p < 0.01) were associated with late LV dysfunction. LVESZ ≥ 5 combined with SF ≤ 33% had a sensitivity of 89%, specificity of 88%, and negative predictive value of 93% for late LV dysfunction. Only 1/14 patients with preoperative SF > 33% had late LV dysfunction. For asymptomatic children with chronic MR, surgery should be considered before LVESZ exceeds five and SF falls below 33%. Patients with SF > 33% may be followed with serial echocardiographic measurements.

Inhaled nitric oxide as a salvage therapy in patients with severe ARDS

IntroductionInhaled nitric oxide (iNO) has been shown to preferentially dilate pulmonary vasculature within well ventilated regions of lung without causing systemic hypotension. Patients with severe ARDS may develop marked ventilation perfusion mismatch, severe hypoxemia, pulmonary hypertension, and right heart failure. Use of iNO may help mitigate these pathologic changes. So we used iNO to assess it as a salvage therapy in patients with severe ARDS. MethodsWe describe 4 cases of pneumonia with severe ARDS with right heart failure in which iNO was used as salvage therapy to improve right heart failure and oxygenation when they did not respond to conventional measures. iNO was delivered in inspiratory limb of ventilator circuit by NOxBOX mobile system. Dose of iNO was titrated between 5 and10 ppm. In each of these patients, we monitored hemodynamic status (pulse rate, intra-arterial blood pressure, vasopressor requirements), central venous pressure (CVP), serum lactate, methemoglobin (MetHb) levels, arterial blood gases (ABG) and PaO2/FiO2 (p/f) ratios every 6 h till first 24 h and then every 12 h till 24 h of stopping iNO. 2D Echo was done by a trained cardiologist before initiation of iNO and then every 24 h till 24 h of stopping NO and pulmonary artery systolic pressure (PASP) recorded. ResultsiNO was used for duration ranging from 30 to 120 h. In all patients hemodynamics, oxygenation and PASP showed improvement that persisted even after 24 h of discontinuing iNO. None of the 4 patients had methemoglobinemia or other serious side effects. ConclusioniNO may be used as a salvage therapy for refractory hypoxemia and right heart failure in severe ARDS.

Isolated Pulmonary Ttakayasu’s aArteritis: Report of Two Cases

A 40-year-old female, with progressive exertional dyspnea presented to our emergency room. Chest computed tomography (CT) revealed severe stenosis of the bilateral main pulmonary arteries. Catheterization and angiography confirmed the stenoses and marked pulmonary hypertension (85mmHg). The C-reactive protein (CRP) was 2.17mg/dl. Human leucocyte antigens (HLA) were B52 and B39. We diagnosed the patient as having Takayasu’s arteritis (TA) based on her age, sex, laboratory findings, and the isolated pulmonary artery lesions. Treatment was started with glucocorticoid initially 40mg per day. Pulmonary artery pressure estimated by echocardiography decreased from 85mmHg to 35mmHg. During 2-year follow-up period, her functional status was improved to WHO class 1 and no signs of exacerbation were observed.

Stress Echocardiography in Regurgitant Valve Disease

Because of its wide availability, low cost, versatility, and clinical use, stress echocardiography has become increasingly recognized as a valuable tool in the assessment of patients with regurgitant valvular heart disease. Exercise testing is favored compared with pharmacological stress testing for risk stratification in asymptomatic patients and can identify what might otherwise be considered as a moderate valve disease. It has been shown to provide insights into exertional symptoms disproportionate to resting hemodynamics in these patients and to facilitate individual risk stratification. Aggravation of valvular regurgitation severity, exercise-induced pulmonary hypertension (PHT), impaired left ventricular (LV) contractile reserve, inducible ischemia, dynamic LV dyssynchrony, and altered exercise capacity, together with the development of symptoms during exercise echocardiography, provide the clinician with straightforward prognostic information, therefore enabling a more accurate definition of the optimal timing of intervention in patients with valvular regurgitation.1,2 In contrast, dobutamine stress echocardiography has little value in cases of valvular regurgitation. Dobutamine infusion is almost systematically associated with a decrease in the severity of regurgitation; however, it might be of interest in the detection of LV contractile reserve and inducible ischemia. The most common form of exercise used in conjunction with echocardiography is immediate postexercise imaging on a treadmill or upright bicycle ergometer. However, semisupine exercise testing on an appropriate tilted table allows continuous echocardiographic monitoring, which represents an advantageous tool for quantifying changes in valvular regurgitation severity, LV function, and pulmonary pressure (Table). This exercise stress echocardiography modality (ie, per-exercise echocardiography) is the most used in Europe, and we strongly suggest this approach in the setting of valvular heart disease to detect evanescent changes. A symptom-limited graded exercise test is recommended, and ≥80% of the age-predicted upper heart rate should be reached in the absence of symptoms. The test is adapted to the clinical conditions …

A Case Report of Pulmonary Thromboendarterectomy for Chronic Thromboembolism in a Patient with Protein C Deficiency

The patient was a 41-year-old female with chronic thromboembolism. She was admitted to an affiliated hospital with exertional dyspnea, leg swelling, and hemoptysis, and she was treated medically with tissue plasminogen activator and warfarin therapy. When transferred to our hospital, she was oxygen-dependent with severe dyspnea. A pulmonary arteriogram showed occlusion and stenosis of the pulmonary arteries. Cardiac catheterization revealed marked pulmonary hypertension. The lung perfusion scintigram showedmultiple defects in the right and left lungs. Preoperative laboratory data showed a markedly decreased protein C antigen level. Magnetic resonance angiography showed that a myoma uteri compressed the pelvic vein and that she had deep vein occlusion of the left leg. After the administration of an epoprostenol infusion and the insertion of an inferior vena cava filter, she underwent an operation. Under deep hypothermia, the bilateral pulmonary artery was opened and an endarterectomy was performed during intermittent circulatory arrest. After surgery, her pulmonary vascular resistance was in the normal range. Her New York Heart Association functional classification changed from class IV to class I. She has been in good condition for 7 years since the surgery.

Pulmonary hypertension and the right ventricle in hypoxia

Hypoxia causes pulmonary vasoconstriction. Regional hypoxic vasoconstriction improves the matching of perfusion to alveolar ventilation. Global hypoxic vasoconstriction increases right ventricular afterload. The hypoxic pulmonary pressor response is universal in mammals and in birds, but with considerable interspecies and interindividual variability. Chronic hypoxia induces pulmonary hypertension in proportion to initial vasoconstriction. Prolonged hypoxic exposure is also associated with an increase in red blood cell mass, which aggravates pulmonary hypertension by an increase in blood viscosity. Hypoxic pulmonary hypertension in humans is usually mild to moderate, but pulmonary vascular pressure-flow relationships are steep, which corresponds to a substantial afterload on the right ventricle during exercise. A partial recovery of 10-25% of the hypoxia-induced decrease in maximal oxygen uptake has been reported with intake-specific pulmonary vasodilating interventions. Hypoxia has been reported to decrease myocardial fibre contractility in vitro. However, the acutely hypoxic right ventricle remains able to preserve the coupling of its contractility to increased afterload in intact animals. Echocardiographic studies of the right ventricle in healthy hypoxic human subjects show altered diastolic function, but systolic function that is preserved or even increased acutely and slightly depressed chronically. These findings are more pronounced in patients with chronic mountain sickness. Their clinical significance remains incompletely understood. Almost no imaging studies of right ventricular function have been reported in a minority of subjects who develop severe pulmonary hypertension and clinical right ventricular failure in hypoxia. No imaging studies of right ventricular function during hypoxic exercise in normal subjects are yet available. Thus, while it is plausible that the right ventricle limits exercise capacity in hypoxia, this still needs to be firmly established.

A Case of Locally Advanced Breast Cancer Complicated by Pulmonary Tumor Thrombotic Microangiopathy

Pulmonary tumor thrombotic microangiopathy (PTTM) is a rare, malignancy-related complication that causes marked pulmonary hypertension, right heart failure, and death. We report on a patient with locally advanced breast cancer whose course was complicated by fatal PTTM based on clinical and laboratory findings.

A successful surgical repair of pulmonary stenosis caused by isolated pulmonary Takayasu’s arteritis

A 48-year-old man underwent surgery to treat pulmonary stenoses of unknown origin. The right main pulmonary artery was severely stenotic, and the orifice of the left pulmonary artery was focally constricted. The patient was nearly asymptomatic, despite marked pulmonary hypertension and right heart strain. The pressure gradients beyond the stenotic regions were 88 mmHg bilaterally. The cause of the stenoses could not be established before operation. The right main pulmonary artery and ascending aorta were successfully replaced. It was suspected that the ascending aorta was involved because it was markedly thickened and adhered tightly to the right pulmonary artery. It was therefore also replaced. However, only the transected right pulmonary artery showed histological evidence consistent with a diagnosis of Takayasu's arteritis. The postoperative course was uneventful. The patient was completely free of symptoms six months after the operation. To our knowledge, this is the thirteenth surgically treated case of isolated pulmonary Takayasu's arteritis to be reported.

Inhaled Nitrite Reverses Hemolysis-Induced Pulmonary Vasoconstriction in Newborn Lambs Without Blood Participation

Nitrite can be converted to nitric oxide (NO) by a number of different biochemical pathways. In newborn lambs, an aerosol of inhaled nitrite has been found to reduce pulmonary blood pressure, possibly acting via conversion to NO by reaction with intraerythrocytic deoxyhemoglobin. If so, the vasodilating effects of nitrite would be attenuated by free hemoglobin in plasma that would rapidly scavenge NO. Pulmonary vascular pressures and resistances to flow were measured in anesthetized newborn lambs. Plasma hemoglobin concentrations were then elevated, resulting in marked pulmonary hypertension. This effect was attenuated if infused hemoglobin was first oxidized to methemoglobin, which does not scavenge NO. These results further implicate NO as a tonic pulmonary vasodilator. Next, while free hemoglobin continued to be infused, the lambs were given inhaled NO gas (20 ppm), inhaled sodium nitrite aerosol (0.87 mol/L), or an intravascular nitrite infusion (3 mg/h bolus, 5 mg · kg⁻¹ · h⁻¹ infusion). Inhaled NO and inhaled nitrite aerosol both resulted in pulmonary vasodilation. Intravascular infusion of nitrite, however, did not. Increases in exhaled NO gas were observed in lambs while breathing the nitrite aerosol (≈ 20 ppb NO) but not during intravascular infusion of nitrite. We conclude that the pulmonary vasodilating effect of inhaled nitrite results from its conversion to NO in airway and parenchymal lung tissue and is not dependent on reactions with deoxyhemoglobin in the pulmonary circulation. Inhaled nitrite aerosol remains a promising candidate to reduce pulmonary hypertension in clinical application.

Res-Erection of Viagra as a Heart Drug

In 1998, the world was formally introduced to Viagra (sildenafil), the first oral agent to be approved in the United States for the treatment of erectile dysfunction. Developed by Pfizer chemists, sildenafil inhibited phosphodiesterase type 5 (PDE5), one of the 11-member superfamily of enzymes that hydrolyze cyclic nucleotide monophosphates and among the first discovered that was selective for cGMP. PDE5 had been identified more than 2 decades earlier, first as a protein that bound cGMP and later as one that hydrolyzed it (the binding function turning out to be a mechanism to regulate activity).1 Sildenafil induces vasorelaxation by blocking PDE5-cGMP hydrolysis, raising cGMP levels in smooth muscle to activate protein kinase G (also known as cGK). In platelets, this blunts thrombosis; together, the effects suggested a potential use for coronary vascular disease and hypertension. Pfizer initiated trials targeting coronary ischemia, but, although antianginal effects were disappointing, the study gave a whole new meaning to the term “side effect,” effectively hijacking sildenafil from cardiovascular development to a rather different indication. Article see p 8 There were still some cardiovascular studies performed, but essentially all were limited assessments of volunteer populations, mostly normal and at rest and some with cardiovascular disease; the results were interpreted to support safety for patients taking the drug. In particular, blood pressure changes were slight if present at all, and cardiac function appeared unaltered. Well into the mid 2000s, PDE5 was thought to be expressed in selective vascular beds, lung and corpus cavernosum being dominant, and to have a minor cardiovascular profile elsewhere, with a negligible role in the heart. Sildenafil reemergence as …

Exaggerated Pulmonary Hypertension During Mild Exercise in Chronic Mountain Sickness

Chronic mountain sickness (CMS) is an important public health problem and is characterized by exaggerated hypoxemia, erythrocytosis, and pulmonary hypertension. While pulmonary hypertension is a leading cause of morbidity and mortality in patients with CMS, it is relatively mild and its underlying mechanisms are not known. We speculated that during mild exercise associated with daily activities, pulmonary hypertension in CMS is much more pronounced. We estimated pulmonary artery pressure by using echocardiography at rest and during mild bicycle exercise at 50 W in 30 male patients with CMS and 32 age-matched, healthy control subjects who were born and living at an altitude of 3,600 m. The modest, albeit significant difference of the systolic right-ventricular-to-right-atrial pressure gradient between patients with CMS and controls at rest (30.3 +/- 8.0 vs 25.4 +/- 4.5 mm Hg, P 5 .002) became more than three times larger during mild bicycle exercise (56.4 +/- 19.0 vs 39.8 +/- 8.0 mm Hg, P < .001). Measurements of pulmonary artery pressure at rest greatly underestimate pulmonary artery pressure during daily activity in patients with CMS. The marked pulmonary hypertension during mild exercise associated with daily activity may explain why this problem is a leading cause of morbidity and mortality in patients with CMS.

Chronic NOS inhibition prevents adverse lung remodeling and pulmonary arterial hypertension in caveolin-1 knockout mice

Recently generated caveolin-1 deficient mice (cav-1 ko) suffer from severe lung fibrosis with marked pulmonary hypertension and arterial hypoxemia and may therefore serve as an useful animal model of this devastating human disorder. Accumulating evidence strongly supports the negative regulatory influence of caveolin-1 on endothelial nitric oxide synthase resulting in a constitutive hyperactivation of the nitric oxide (NO) pathway in cav-1 ko. We therefore hypothesized that a disturbed NO signaling is implicated in the evolution of the adverse lung phenotype of cav-1 ko. For this purpose, cav-1 ko of 2 months age were compared with knockout counterparts experiencing 2-month postnatal NO synthase inhibition by N G-nitro- l-arginine methyl ester ( l-NAME) treatment. Chronic l-NAME administration prevented adverse lung remodeling in cav-1 ko. Furthermore, l-NAME donation led to a normalized oxygen saturation (91.5±1.8% vs. 98.5±2.3%, P<0.01, n=10–12), a marked decrease in right ventricular hypertrophy (LV/RV ratio: 4.0±0.3 vs. 2.7±0.3, P<0.01, n=10–12) and reductions of the elevated pulmonary artery pressure (40.2±3.1 mmHg vs. 26.3±4.6 mmHg, P<0.01, n=6). Collectively, these improvements resulted in an enhanced exercise capacity of l-NAME-treated cav-1 ko. Finally, we found evidence for enhanced oxidative stress in untreated cav-1 ko which was substantially reduced by chronic l-NAME administration to cav-1 ko. In view of these data, we speculate that a perturbation of NO signaling, together with enhanced O 2 − production originating from NO synthases, may play a pivotal role in the pathogenesis of the adverse pulmonary phenotype seen in cav-1 ko.

EFFECT OF BAY 41‐2272 IN THE PULMONARY HYPERTENSION INDUCED BY HEPARIN–PROTAMINE COMPLEX IN ANAESTHETIZED DOGS

1. BAY 41-2272 is a potent activator of the nitric oxide-independent site of soluble guanylate cyclase and has been recently introduced as a new therapeutic agent to treat chronic pulmonary hypertension (PH) in neonatal sheep. Because the in vivo heparin-protamine interaction may lead to severe PH, the aim of the present study was to evaluate the effects of BAY 41-2272 in the PH induced by heparin-protamine interaction in anaesthetized dogs. 2. Sixteen male dogs (10 mongrel dogs and six Beagles) were anaesthetized and instrumented for acquisition of mean arterial blood pressure (MABP), mean pulmonary arterial pressure (MPAP), heart rate (HR), pulmonary capillary wedge pressure (PCWP), cardiac index (CI) and indices of systemic and pulmonary vascular resistance (ISVR and IPVR, respectively). Plasma cGMP levels and S(p)o(2) were evaluated. 3. Intravenous administration of heparin (500 IU/kg) followed 3 min later by protamine (10 mg/kg) caused marked PH, as evaluated by the increase in MPAP, PCWP and IPVR. This was accompanied by a significant fall in MABP and a transient increase in HR. Infusion of BAY 41-2272 (10 microg/kg per h, starting 10 min before heparin administration) augmented plasma cGMP levels and slightly and significantly increased HR and CI, without affecting the other cardiovascular parameters. The elevation in IPVR, MPAP and PCWP triggered by the heparin-protamine interaction was significantly reduced in animals exposed to BAY 41-2272. 4. In vehicle-treated dogs, the S(p)o(2) values decreased significantly at the peak of the PH and this was significantly attenuated by treatment with BAY 41-2272. In addition, BAY 41-2272 (10 micromol/L) had no effect on the activated partial thromboplastin time of citrated plasma after the addition of heparin-protamine. 5. In conclusion, BAY 41-2272 was effective in reducing canine PH induced in vivo by the heparin-protamine interaction, thus indicating its potential in the treatment of this type of disorder.

Pulmonary thromboendarterectomy for chronic pulmonary thromboembolism in protein C deficiency

Pulmonary thromboendarterectomy was performed on a patient with chronic pulmonary thromboembolism showing thrombophilia. The patient was a 56-year-old female with the above condition complicated by congenital protein C deficiency. She was admitted to our hospital with severe dyspnea accompanied by right ventricular failure. A pulmonary arteriogram showed occlusion and stenosis from lobar to segmental arteries. Cardiac catheterization showed marked pulmonary hypertension. A lung perfusion scintigram revealed multiple defects in the right and left lungs. After the insertion of an inferior vena cava filter, she was operated on. Following a median sternotomy, thromboendarterectomy of the bilateral pulmonary arteries was performed using deep hypothermia and intermittent circulatory arrest. Circulatory arrest was employed in three periods totaling up to 36 minutes. After surgery, she had improvements in pulmonary hypertension and pulmonary vascular resistance. She maintained improved lung functions, and remained in the New York Heart Association functional class I for more than two years and eight months after surgery.