Clinical Evidence Of Pulmonary Hypertension Research Articles

High Prevalence of Pulmonary Hypertension Complicates the Care of Infants with Omphalocele

Background: Omphalocele is one of the most common abdominal wall defects. Many newborn infants born with omphalocele present with significant respiratory distress at birth, requiring mechanical ventilatory support, and have clinical evidence of pulmonary hypertension. Little information exists on the prevalence of and risk factors associated with pulmonary hypertension in this cohort of infants. Objectives: To describe the prevalence of and risk factors associated with pulmonary hypertension among infants with omphalocele. Methods: This is a multicenter retrospective chart review of demographic data and clinical characteristics of infants with omphalocele admitted to the neonatal intensive care units of Loma Linda University Children's Hospital and Children's Mercy Hospital between 1994 and 2011. Echocardiogram images were reviewed for pulmonary hypertension, and statistical analyses were performed to identify risk factors associated with the presence of pulmonary hypertension. Results: Pulmonary hypertension was diagnosed in 32/56 (57%) infants with omphalocele. Compared to infants without pulmonary hypertension, infants with pulmonary hypertension were more likely to have a liver-containing defect (16/32 [50%] vs. 5/24 [21%], p = 0.03), require intubation at birth (18/32 [56%] vs. 6/24 [17%], p = 0.03), and die during initial hospitalization (12/32 [38%] vs. 2/24 [8%], p = 0.01). Conclusion: The majority of infants with omphalocele have evidence of pulmonary hypertension which is associated with increased mortality. Echocardiograms to screen for pulmonary hypertension should be obtained at ≥2 days of life in infants with omphalocele, especially in those with liver within the omphalocele sac and/or in those infants who require intubation at birth to screen for pulmonary hypertension.

Computed tomography, radiology and echocardiography in cats naturally infected with Aelurostrongylus abstrusus.

Objectives The aims of the study were to describe the radiographic and computed tomographic features in cats naturally infected with Aelurostrongylus abstrusus, and to identify signs of pulmonary hypertension with echocardiography. Methods Fourteen cats positive on Baermann test for A abstrusus were included in the study. All cats underwent thoracic radiography, CT and echocardiography. Results The most common clinical signs were coughing (10/14) and dyspnoea (5/14). Radiographic findings included a generalised unstructured interstitial pulmonary pattern (8/14), mixed bronchointerstitioalveolar pattern (3/14) and bronchointerstitial pattern with bronchial wall thickening (3/14). Sternal lymphadenopathy was detected on thoracic radiographs in six cats. On CT, features were mixed bronchointerstitioalveolar pattern with ground-glass appearance in six cats, interstitioalveolar with multiple pulmonary nodules in five, interstitial ground-glass infiltrates in three, regional lymph node enlargement in 11 (10 sternal, three cranial mediastinal and three tracheobronchial lymph nodes) and subpleural thickening in four. None of the thoracic radiographs revealed subpleural thickening. In all cases, pulmonary vessels were normal in terms of size, shape and attenuation on both radiography and CT. Pulmonary hypertension and cardiac abnormalities were not observed in any cat during echocardiography. Conclusions and relevance CT provided a more thorough characterisation of pulmonary and mediastinal lesions compared with thoracic radiographs in cats naturally infected with A abstrusus. Although feline aelurostrongylosis has been previously associated with histopathological lesions in lung arteries, in this cohort clinical evidence of pulmonary hypertension was not documented.

Relaxation of human pulmonary arteries by PPARγ agonists

It has been suggested that activation of nuclear peroxisome proliferator-activated receptors γ (PPARγ) may represent a new strategy for the treatment of pulmonary arterial hypertension. It has been demonstrated that PPARγ activation relaxed the isolated mouse pulmonary artery. The aims of the present study were to examine whether and to which extent the two PPARγ agonists rosiglitazone and pioglitazone relax the isolated human pulmonary artery and to investigate the underlying mechanism(s). Isolated human pulmonary arteries were obtained from patients without clinical evidence of pulmonary hypertension during resection of lung carcinoma. Vasodilatory effects of PPARγ agonists were examined on endothelium-intact or endothelium-denuded vessels preconstricted with the thromboxane prostanoid receptor agonist U-46619. Rosiglitazone and pioglitazone (0.01–100 μM) caused a concentration- and/or time-dependent full relaxation of U-46619-preconstricted vessels. The rosiglitazone-induced relaxation was attenuated by the PPARγ antagonist GW9662 1 μM, endothelium denudation, the nitric oxide synthase inhibitor L-NAME 300 μM, the cyclooxygenase inhibitor indomethacin 10 μM, and the KATP channel blocker glibenclamide 10 μM. The prostacyclin IP receptor antagonist RO1138452 1 μM shifted the concentration–response curve for rosiglitazone to the right. The PPARγ agonists pioglitazone and rosiglitazone relax human pulmonary arteries. The rosiglitazone-induced vasorelaxation is partially endothelium-dependent and involves PPARγ receptors, arachidonic acid degradation products, nitric oxide, and KATP channels. Thus, the relaxant effect of PPARγ agonists in human pulmonary arteries may represent a new therapeutic target in pulmonary arterial hypertension.

The sFLT-1 to PlGF Ratio is Impaired in Patients with Thalassemia and Sickle Cell Disease.

Abstract 2010Poster Board I-1032 Background:Placental growth factor (PlGF) is a member of the vascular endothelial growth factor family and is associated with inflammation and with pathologic angiogenesis. PlGF is released from marrow erythroid cells. Serum PlGF concentrations have been reported to be elevated in patients with sickle cell disease. The fms-like tyrosine kinase-1 or sFlt-1 is a soluble form of vascular endothelial growth factor receptor-1 (VEGF-R1), which binds to and sequesters circulating free vascular endothelial growth factor (VEGF) and free PlGF, thereby neutralizing their pro-angiogenic effects. PlGF and VEGFR-1 are key molecules in regulating the angiogenic switch during pathological conditions maintaining the proangio-and anti-angiogenic balance. Perturbations of this balance leads to various degree of endothelial dysfunction, a common pathology in patients with hemoglobinopathies and specifically induce pulmonary hypertension (PHT). In this study we assessed the PlGF and sFLT-1 levels in patients with hemoglobinopathies at steady state. Patients and Methods:One hundred twenty three patients with hemoglobinopathies and 20 apparently healthy individuals were included in the study divided in groups as follows: Group A: 38 patients with thalassemia intermedia; Group B: 41 patients with transfusion-dependent beta-thalassemia; Group C: 33 patients with beta-thallassemia/sickle cell disease (SCD) Group D: 11 patients with beta-thallassemia and clinical evidence of PHT, and; Group E: 20 individuals served as control group In patients and controls we performed measurements of PlGF and sFLT-1 with fully automated electrochemiluminescence assays using the immunochemistry autoanalyzer Roche cobas e411. This method provides rapid and reliable assessments and follow-up of patients any time in the day compared to immunoenzymatic assays. Results:We found that: a) serum PlGF levels were increased in all groups of patients compared to controls (42.7±19.9 pg/mL, 49.9±23.4 pg/mL, 27.5±9.4 pg/mL, 58.1±27.6 pg/mL for group A, B, C and D, respectively vs 17.1±3.9 pg/mL for control group, p<0.001), b) serum sFLT-1 levels were also increased in all groups of patients compared to controls (89.3±18.3 pg/mL, 90.2±24.0 pg/mL, 89.4±15.3 pg/mL, 117.2±43.5 pg/mL, respectively vs 76.7±11.1 pg/mL, p<0.001 for control group and c) sFLT-1 to PlGF ratio was decreased in all groups of patients compared to controls (2.4±0.9, 2.2±1.2, 3.5±1.0, 2.2±0.8, respectively vs 4.7±1.1 for control group, p<0.001. The most significant changes were found in patients with PHT. Conclusions:These findings indicate that patients with thalassemia syndromes and SCD appear to have increased degree of angiogenesis, which is more pronounced in patients with thalassemia compared to patients with SCD and markedly increased in patients with PHT. The decreased sFLT-1/PlGF ratio in almost all patients suggest that the proangio-and anti-angiogenic system is shifted towards to proangiogenic state, providing evidence that patients with hemoglobinopathies even in the steady phase have altered angiogenic state and low-grade inflammation. The results are in accordance to those published earlier for SCD (Blood, 2008;112:856-865.), where the authors demonstrated that PlGF levels were intrinsically elevated due to the increased red cell turnover and may contribute to inflammation and PHT seen in the disease. Disclosures:No relevant conflicts of interest to declare.

Identification of the vasodilatory endothelial cannabinoid receptor in the human pulmonary artery

The endocannabinoid anandamide is implicated in the pathogenesis of hypotension in haemorrhagic, endotoxic, and cardiogenic shock. It has been demonstrated in animal, but not in human, vessels that the vasodilatory effects of anandamide and abnormal cannabidiol are partially mediated by an as yet unidentified endothelial cannabinoid receptor. Our study was performed to examine the influence of abnormal cannabidiol on the human pulmonary artery. Isolated human pulmonary arteries were obtained from patients without clinical evidence of pulmonary hypertension during resection of lung carcinoma. Vasodilatory effects of abnormal cannabidiol were examined on endothelium-intact vessels preconstricted with serotonin or potassium chloride. Anandamide and abnormal cannabidiol relaxed serotonin-preconstricted vessels concentration-dependently. The effect of abnormal cannabidiol was reduced by endothelium denudation, pertussis toxin and two antagonists of the novel endothelial receptor, cannabidiol and O-1918, but not by the nitric oxide synthase inhibitor L-NAME given together with the cyclooxygenase inhibitor indomethacin. It was also diminished by blockade of calcium-activated potassium channels by the nonselective blocker tetraethylammonium or by combination of selective blockers of small (apamin) and intermediate and large (charybdotoxin) conductance calcium-activated potassium channels. The potency of abnormal cannabidiol to relax vessels was lower in potassium chloride than in serotonin-preconstriced preparations. Abnormal cannabidiol relaxes human pulmonary arteries in an endothelium-independent and endothelium-dependent manner. The latter component is probably mediated via the putative endothelial cannabinoid receptor, activation of which may release endothelium-derived hyperpolarizing factor, which in turn acts via calcium-activated potassium channels. Abnormal cannabidiol is behaviourally inactive; it may have a therapeutic implication in vascular diseases, especially in the treatment of pulmonary hypertension.

Neonatal thoracoscopic repair of congenital diaphragmatic hernia: selection criteria for successful outcome

Background/Purpose Complications of open conversion, hypercarbia, and intestinal injury have plagued minimally invasive approaches to congenital diaphragmatic hernia (CDH) repair in neonates. To safely begin using minimally invasive techniques for neonatal CDH repair, we formulated preoperative selection criteria and operative techniques that would enhance chances for successful thoracoscopic primary diaphragm repair and uncomplicated outcome. Methods During the period from January 2003 to October 2004, neonates were selected for thoracoscopic CDH repair using anatomic and physiologic criteria. Anatomically, all patients were required to have stomach in the abdomen by radiography. Physiologically, all patients were required to be on minimal ventilator support with preoperative ventilator peak inspiratory pressures in the low 20s mm Hg. No patient could have clinical evidence of pulmonary hypertension at the time of surgery. Thoracoscopic CDH repair was performed using 3 trocars (3 and 5 mm). The hernia contents were reduced into the abdomen using 5–mm Hg insufflation, and the diaphragms were repaired primarily using interrupted 3-0 Ethibond simple sutures (Ethicon, Inc, Piscataway, NJ). Posterolateral diaphragm stitches were passed around the posterolateral ribs and tied extracorporeally. Results Thirty neonates with CDH were admitted to Children's Hospital Boston and Vanderbilt Children's Hospital during the study period. Eight patients (27%) met selection criteria and 7 underwent thoracoscopic CDH repair. Primary diaphragmatic repair was successfully accomplished thoracoscopically in all neonates without perioperative complication. Preoperative anatomic criteria correlated accurately with intact esophageal hiatus and primary diaphragm repair. Physiologically, each patient tolerated intrathoracic insufflation and CDH repair without clinical pulmonary hypertension or blood pressure lability. Three patients had intraoperative respiratory acidosis that was reversed with ventilator changes. Operative times averaged 152 minutes and ranged from 212 to 106 minutes. Postoperative mechanical ventilation ranged from 0 to 7 days, and the length of hospitalization ranged from 5 to 32 days. Longest follow-up has been 17 months. One patient required reoperation for recurrent CDH at 10 months after repair, but there have been no other long-term complications. Conclusions Neonatal thoracoscopic CDH repair is safe in selected patients who have good preoperative pulmonary function and anatomy amenable to primary diaphragmatic repair. A wider range of neonates may be acceptable for thoracoscopic CDH repair with increasing surgical experience.

Pulmonary Hypertension in the Setting of Acquired Systemic Arteriovenous Fistulas

We describe 2 patients who presented with symptoms and clinical evidence of pulmonary hypertension. The first patient, who had severe pulmonary hypertension, underwent correction of an acquired arteriovenous (AV) fistula, which led to improvement according to clinical and noninvasive hemodynamic criteria. The second patient had severely symptomatic pulmonary hypertension associated with a large, previously unrecognized, superior mesenteric AV fistula after intra-abdominal surgery. Surgical correction of the fistula resulted in normalization of pulmonary hemodynamics assessed by right heart catheterization. Truly reversible substrates of pulmonary hypertension are rare. Acquired systemic AV fistulas are a less recognized cause of secondary pulmonary hypertension. It is unknown whether high blood flow peripheral AV shunts ultimately lead to endothelial proliferation, vascular smooth muscle hypertrophy, plexiform lesions, and other histopathologic changes that are seen in patients with left-to-right shunts due to atrial septal defects, ventricular septal defects, and patent ductus arteriosus.

An imbalance between the excretion of thromboxane and prostacyclin metabolites in pulmonary hypertension.

Constriction of small pulmonary arteries and arterioles and focal vascular injury are features of pulmonary hypertension. Because thromboxane A2 is both a vasoconstrictor and a potent stimulus for platelet aggregation, it may be an important mediator of pulmonary hypertension. Its effects are antagonized by prostacyclin, which is released by vascular endothelial cells. We tested the hypothesis that there may be an imbalance between the release of thromboxane A2 and prostacyclin in pulmonary hypertension, reflecting platelet activation and an abnormal response of the pulmonary vascular endothelium. We used radioimmunoassays to measure the 24-hour urinary excretion of two stable metabolites of thromboxane A2 and a metabolite of prostacyclin in 20 patients with primary pulmonary hypertension, 14 with secondary pulmonary hypertension, 9 with severe chronic obstructive pulmonary disease (COPD) but no clinical evidence of pulmonary hypertension, and 23 normal controls. The 24-hour excretion of 11-dehydro-thromboxane B2 (a stable metabolite of thromboxane A2) was increased in patients with primary pulmonary hypertension and patients with secondary pulmonary hypertension, as compared with normal controls (3224 +/- 482, 5392 +/- 1640, and 1145 +/- 221 pg per milligram of creatinine, respectively; P less than 0.05), whereas the 24-hour excretion of 2,3-dinor-6-keto-prostaglandin F1 alpha (a stable metabolite of prostacyclin) was decreased (369 +/- 106, 304 +/- 76, and 644 +/- 124 pg per milligram of creatinine, respectively; P less than 0.05). The rate of excretion of all metabolites in the patients with COPD but no clinical evidence of pulmonary hypertension was similar to that in the normal controls. An increase in the release of the vasoconstrictor thromboxane A2, suggesting the activation of platelets, occurs in both the primary and secondary forms of pulmonary hypertension. By contrast, the release of prostacyclin is depressed in these patients. Whether the imbalance in the release of these mediators is a cause or a result of pulmonary hypertension is unknown, but it may play a part in the development and maintenance of both forms of the disorder.

Respiratory failure due to choriocarcinoma: A study of 103 dyspneic patients

Treatment of choriocarcinoma is mostly successful but there is still appreciable mortality from early respiratory failure. A series of 135 patients with choriocarcinoma presenting with dyspnea between 1960 and 1988 was studied to find prognostic factors for early respiratory death and to identify how mortality may be further reduced. Mortality with respect to early respiratory death (ERD) was 11% and was significantly associated with WHO prognostic score, chest X-ray appearance, central cyanosis, tachycardia, anemia, and clinical evidence of pulmonary hypertension. Indicators on chest X ray of high risk of ERD were the presence of more than 10 opacities, extensive opacification of lung fields, size of metastases, and hazy background obscuring the vascular pattern. Intensity of initial treatment was not correlated with this outcome. A set of criteria has been derived which will predict ERD with 100% sensitivity and 38% positive predictive value. These are opacification of lung fields on chest X ray of more than 50%, OR initial plasma hCG level greater than 10 5 when there is anemia and a history of chest pain. Patients presenting with choriocarcinoma and dyspnea who fulfill these criteria should be considered for extracorporeal perfusion techniques. As respiratory failure in this condition is characterized by hypoxemia and right-to-left shunting, extracorporeal perfusion should be effective. Ventilation should be avoided as no patient survived mechanical ventilation.

The Clinical Profile of Unresolved Pulmonary Embolism

Nearly all patients with pulmonary embolism (PE) have complete clinical and hemodynamic and at least near complete roentgenographic and angiographic resolution within four to six weeks of the acute event. To classify the syndrome of unresolved pulmonary embolism we reviewed our experience and that of the English literature to extract 30 well-described cases. The mean age at presentation was 45 years, and most patients were less than 60 years old. Almost all complained of dyspnea, and the majority had at least one clinical event suggestive of PE. Most had clinical evidence of pulmonary hypertension. Roentgenographic, arterial blood gas and electrocardiographic findings were nonspecific, though the perfusion lung scan was always abnormal. Most patients exhibited mild-to-moderate pulmonary hypertension. The severity of pulmonary artery obstruction was quite variable and did not correlate with the magnitude of arterial hypoxemia or pulmonary hypertension. Most patients did not improve with long-term anticoagulation therapy and underwent pulmonary embolectomy with acceptable mortality. Postoperative improvement correlated with improved arterial blood gas levels, abatement of pulmonary hypertension, and more satisfactory pulmonary perfusion.

Increased systemic vascular resistance in neonates with pulmonary hypertension

The time necessary for aortic diastolic pressure to decrease to 50 percent of an initially selected value after dissipation of the dicrotic notch ( T 1 2 ) was determined in newborn infants with and without pulmonary hypertension. The mean T 1 2 was 671 ± 167 msec in seven infants with clinical evidence of pulmonary hypertension and documented right to left ductus arteriosus shunting; 849 ± 243 msec in nine infants with clinical evidence of pulmonary hypertension but no documented right to left ductus arteriosus shunting; and 457 ± 66 msec in eight infants with hyaline membrane disease and no clinical evidence of pulmonary hypertension or a patent ductus arteriosus. The mean T 1 2 values in the former two groups were significantly different from that in the group with no pulmonary hypertension ( P < 0.01). An evaluation of factors affecting T 1 2 leads to the conclusion that the patients with pulmonary hypertension had increased systemic vascular resistance as well. This finding has important diagnostic, etiologic and therapeutic implications.

Unexplained pulmonary hypertension with pulmonary arteritis in rheumatoid disease

The case is described of a 24-year-old woman who died after suffering from rheumatoid arthritis for eight years. During the last four months of her life there was clinical evidence of pulmonary hypertension. At necropsy the heart showed right ventricular hypertrophy but no congenital defect. Microscopic examination of the lungs disclosed evidence of hypertensive pulmonary vascular disease with medial hypertrophy and intimal fibrosis of muscular pulmonary arteries together with hypertensive changes in the pulmonary arterioles. Some of the muscular pulmonary arteries also showed fibrinoid necrosis of their media and acute arteritis. It was concluded that the fibrinoid necrosis was a manifestation of severe hypertensive pulmonary vascular disease rather than being a primary rheumatoid arteritis of the lung.

Pulmonary hypertension associated with cirrhosis of the liver and with portacaval shunts.

Pulmonary hemodynamics were studied in 11 patients with hepatic cirrhosis who had undergone surgical portal decompression several years earlier. Four of the patients had both clinical and physiological evidence of pulmonary hypertension; two others had mild, subclinical pulmonary hypertension. Autopsy examination of two patients who had clinical evidence of pulmonary hypertension revealed thickening of the small pulmonary arteries and multiple small pulmonary emboli. Before the portosystemic venous anastomosis was created, all of the patients had had normal cardiorespiratory performance. These studies suggest that emboli from the portal vein may have been involved in the genesis of the pulmonary hypertension in these patients. The role of surgical portal decompression is unclear. Retrospective studies of 70 clinical records and of 17 autopsy protocols in a similar group of patients did not clarify the role of the surgical decompression in the genesis of the pulmonary hypertension.

Early diagnosis of chronic pulmonary vascular obstruction: Value of pulmonary function tests

Eight patients were studied to determine the origin of their dyspnea. They had no clinical evidence of pulmonary hypertension and the pulmonary artery pressures were normal at rest. Special tests of pulmonary function showed that pulmonary vascular obstruction was present; the diagnosis was confirmed anatomically in five patients and by roentgenologic studies in two patients. In three patients pulmonary hypertension did not develop even during exercise; results of pulmonary angiograms and radioisotope scanning of the lungs in these patients were within normal limits. The discrepancy is explained by the presence of scattered lesions narrowing small pulmonary arteries and arterioles in these patients. The abnormal responses during pulmonary function studies included (1) increased V{inD}: V{InT}, which was present at rest in only two patients, but increased abnormally during exercise in all the patients in whom it was normal at rest; (2) decreased singlebreath diffusing capacity in every patient and decreased pulmonary capillary blood volume in every patient in whom the measurement was made; (3) partially compensated respiratory alkalosis at rest and during exercise in six of eight patients; and (4) significantly decreased arterial O 2 tensions during exercise in two patients (in one the hypoxemia was mainly due to right to left “shunting” of blood, and in one who exercised to high levels it was probably due to a diffusion defect). The abnormalities in pulmonary function not only allowed us to make the diagnosis but also were useful in following the course of the disease. Any patient with dyspnea during exertion who is suspected of having occlusive pulmonary vascular disease deserves detailed pulmonary function studies of the pulmonary circulation, including exercise tests, especially when pulmonary hypertension is absent and roentgenologic methods fail to demonstrate areas of large vessel obstruction.

Cor triatriatum: Successful diagnosis and surgical correction in a three year old girl

Successful diagnosis and surgical repair of a cor triatriatum defect (stenosis of common pulmonary vein) in a three year old girl is described. Prior to surgery severe pulmonary hypertension was found at right heart catheterization, with a mean pulmonary artery wedge pressure of 35 mm. Hg. Nine months after surgery there was a normal mean pulmonary artery wedge pressure of 6 mm. Hg. Except for a transient but severe episode of cardiac failure in the immediate postoperative period, the patient showed an excellent response to surgery. This case illustrates the typical clinical features of cor triatriatum as seen in young children. The symptoms and signs are those of pulmonary venous and arterial hypertension, and are related to the size of the stenotic orifice. Dyspnea is a central feature in persons of all ages. The majority of patients die within the first two years of life, often after a relatively short period of symptoms. In such cases differentiation from congenital mitral stenosis, endocardial fibroelastosis, anomalous pulmonary venous connection or primary pulmonary disease may be difficult. However, at any age, clinical evidence of pulmonary hypertension and the finding of an elevated pulmonary artery wedge pressure are highly suggestive; and if associated with normal left atrial pressure, are pathognomonic for this anomaly. Although comparatively rare, cor triatriatum is easily and completely corrected by surgery and therefore deserves particular emphasis. Surgical exploration for this defect is justified in patients with high pulmonary artery wedge pressure and near normal size of the left atrium.