The role of thrombosis in severe pulmonary hypertension.

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BackgroundLittle is known about in vivo alterations at bronchial and vascular levels in severe pulmonary hypertension (PH) of different etiologies. We aimed to compare quantitative computed tomography (CT) data from the following three groups of severe precapillary PH patients: COPD, idiopathic pulmonary arterial hypertension (iPAH), and chronic thromboembolic PH (CTEPH).Patients and methodsThis study was approved by the institutional review board. Severe PH patients (mean pulmonary arterial pressure [mPAP] ≥35 mmHg) with COPD, iPAH, or CTEPH (n=24, 16, or 16, respectively) were included retrospectively between January 2008 and January 2017. Univariate analysis of mPAP was performed in each severe PH group. Bronchial wall thickness (WT) and percentage of cross sectional area of pulmonary vessels less than 5 mm2 normalized by lung area (%CSA<5) were measured and compared using CT, and then combined to arterial partial pressure of oxygen (PaO2) to generate a “paw score” compared within the three groups using Kruskal–Wallis and its sensitivity using Fisher’s exact test.ResultsWT was higher and %CSA<5 was lower in the COPD group compared to iPAH and CTEPH groups. Mosaic pattern was higher in CTEPH group than in others. In severe PH patients secondary to COPD, mPAP was positively correlated to %CSA<5. By contrast, in severe iPAH, this correlation was negative, or not correlated in severe CTEPH groups. In the COPD group, “paw score” showed higher sensitivity than in the other two groups.ConclusionUnlike in severe iPAH and CTEPH, severe PH with COPD can be predicted by “paw score” reflecting bronchial and vascular morphological differential alterations.

Since the last World Symposium on Pulmonary Hypertension in 2008, we have witnessed numerous and exciting developments in chronic thromboembolic pulmonary hypertension (CTEPH). Emerging clinical data and advances in technology have led to reinforcing and updated guidance on diagnostic approaches to pulmonary hypertension, guidelines that we hope will lead to better recognition and more timely diagnosis of CTEPH. We have new data on treatment practices across international boundaries as well as long-term outcomes for CTEPH patients treated with or without pulmonary endarterectomy. Furthermore, we have expanded data on alternative treatment options for select CTEPH patients, including data from multiple clinical trials of medical therapy, including 1 recent pivotal trial, and compelling case series of percutaneous pulmonary angioplasty. Lastly, we have garnered more experience, and on a larger international scale, with pulmonary endarterectomy, which is the treatment of choice for operable CTEPH. This report overviews and highlights these important interval developments as deliberated among our task force of CTEPH experts and presented at the 2013 World Symposium on Pulmonary Hypertension in Nice, France.

The pathophysiology of primary pulmonary hypertension (PPH) involves alterations in vascular reactivity, vascular structure, and interactions of the vessel wall with circulating blood elements.1 An imbalance of vasodilator and vasoconstrictor influences is likely to be an early derangement. Progressive intimal and medial thickening, due to proliferation and migration of vascular smooth muscle cells and fibroblasts, reduces the cross-sectional area of the pulmonary microvasculature, causing fixed alterations in pulmonary resistance. Contributing to the progressive increase in pulmonary resistance is thrombosis of the small pulmonary vessels, which explains the benefit of anticoagulation in these patients. In advanced disease, “plexiform arteriopathy” of the small pulmonary vessels is observed. These lesions proliferate into the lumen, creating high-resistance, convoluted endoluminal channels. There is some controversy regarding the nature of the cells constituting these lesions, one group suggesting they are of endothelial origin, whereas more recent evidence indicates that they are myofibroblasts.2,3 See p 1493 The normal pulmonary endothelium maintains a low vascular resistance, suppresses vascular smooth muscle growth, inhibits platelet adherence and aggregation, and stems inflammation. In patients with PPH, the endothelium has lost these vasoprotective functions.1 The endothelium of the PPH patient is characterized by the increased elaboration of vasoconstrictors, mitogens, and prothrombotic and proinflammatory mediators (such as thromboxane, endothelin, plasminogen activator inhibitor, and 5-lipooxygenase). These endothelial alterations promote the pathophysiology of PPH. Furthermore, there is less influence of the countervailing factors prostacyclin and NO. Endothelium-derived NO plays a critical role in pulmonary …

See related article, pages 1109–1114 Idiopathic pulmonary artery hypertension (IPH) is a rare illness with a poor prognosis. Whereas chronic intravenous prostacyclin relieves some of the symptoms of progressive dyspnea and prolongs survival, most patients ultimately require a lung transplant.1 Newer therapies such as nonintravenously administered prostacyclin derivatives,2,3,4 endothelin receptor blockers,5,6 and, to some extent, phosphodiesterase inhibitors,7 hold some promise as alternatives for intravenous prostacyclin, but current expectation is that, like prostacyclin, they will, at best, retard disease progression, serving as a bridge to transplant rather than as an alternative. The pathological features of IPH are loss of small distal precapillary pulmonary arteries, obliterative changes (plexogenic lesions) in more proximal pulmonary arteries associated with migration and proliferation of smooth muscle cells, and increased extracellular matrix deposition. There is also dysregulation of endothelial cells associated with increased proliferation.8 The mechanism underlying the evolution of these changes is unknown, so there was great interest when 2 groups independently identified a mutation in bone morphogenetic protein receptor 11 (BMP-RII) in 60% of families with IPH.9,10 A BMP-RII mutation also occurs in 20% of sporadic cases of IPH,11 but the biological connection between the mutation and the pathobiology of IPH has been relatively elusive. Recent studies using pulmonary artery smooth muscle cells from patients with IPH, including those with and without a BMP-RII mutation, showed similar abnormal proliferation in response to agents such as transforming growth factor-β (TGF-β) or BMP-2.12 In other studies, pulmonary artery smooth muscle cells were transfected with constructs encoding different mutant forms of BMP-RII expressing aberrant kinase or cytoplasmic domains, and impaired signaling was observed related to alterations in the induction of Smads and p38.13 Specifically, suppression of Smad1/5 and activation of p38 were related to smooth muscle cell proliferation. It …

Riociguat, an oral soluble guanylate cyclase stimulator, has been approved for use in adults with pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension. However, there is limited data on its therapeutic use in children. We report the case of two infants with severe suprasystemic pulmonary hypertension who were successfully treated with riociguat after failure to wean off inhaled nitric oxide (iNO) despite combination PAH therapy. Case 1 is a 6-month-old term male with TBX4 deletion who presented with severe hypoxemic respiratory failure and severe PAH immediately after birth. Initial cardiac catheterization showed PVRi 15.5 WU*m2. Marked hypoxemia and PAH persisted despite aggressive therapy with sildenafil, bosentan, intravenous treprostinil, and milrinone. The infant required high doses of inhaled nitric oxide (60 ppm) and manifested significant post-ductal hypoxemia and hemodynamic instability with any attempt at weaning. After discontinuation of sildenafil, initiation, and very slow uptitration of riociguat, the patient was able to maintain hemodynamic stability and wean from nitric oxide over 6 weeks with persistently severe but not worsened pulmonary hypertension. Case 2 is a 4-month-old term male with compound heterozygous SLC25A26 mutation and severe pulmonary hypertension. Initial cardiac catheterization showed PVRi 28.2 WU*m2. After uptitration of sildenafil, bosentan, and IV treprostinil, serial echocardiograms continued to demonstrate near-systemic pulmonary hypertension. He failed multiple attempts to wean off typical doses of iNO (10-20 ppm) over the following weeks with tachypnea, hypoxemia, and worsening pulmonary hypertension on echocardiogram despite continued aggressive combination targeted therapy. After a 24-h sildenafil washout, he was initiated and uptitrated on riociguat with concomitant, successful wean of nitric oxide over one week that was well tolerated. No serious adverse effects in the titration period were observed. Riociguat may be considered as an adjuvant therapeutic agent in selected children with severe PAH who are poorly responsive to sildenafil therapy and unable to wean from iNO.

Aim:Long standing mitral valve disease is usually associated with severe pulmonary hypertension. Perioperative pulmonary hypertension is a risk factor for right ventricular (RV) failure and a cause for morbidity and mortality in patients undergoing mitral valve replacement. Phosphodiesterase 5 inhibitor-sildenafil citrate is widely used to treat primary pulmonary hypertension. There is a lack of evidence of effects of oral sildenafil on secondary pulmonary hypertension due to mitral valve disease. The study aims to assess the effectiveness of preoperative oral sildenafil on severe pulmonary hypertension and incidence of RV failure in patients undergoing mitral valve replacement surgery.Materials and Methods:A total of 40 patients scheduled for mitral valve replacement with severe pulmonary hypertension (RV systolic pressure (RVSP) ≥60 mmHg) on preoperative transthoracic echo were randomly treated with oral sildenafil 25 mg (N = 20) or placebo (N = 20) eight hourly for 24 h before surgery. Hemodynamic variables were measured 20 min after insertion of pulmonary artery catheter (PAC) under anesthesia (T1), 20 min at weaning from cardiopulmonary bypass (CPB) (T2) and after 1,2, and 6 h (T3, T4, T5, respectively) during the postoperative period.Results:Systolic and mean pulmonary artery pressure (MPAP) and pulmonary vascular resistance index (PVRI) were significantly lower (P < 0.0001) in sildenafil group at all times. Ventilation time and postoperative recovery room stay were significantly lower (P < 0.001) in sildenafil group.Conclusion:Sildenafil produces significant pulmonary vasodilatory effect as compared with placebo in mitral valve replacement patients with severe pulmonary hypertension. It also reduces ventilation time and intensive care unit (ICU) stay time as compared with placebo. It is concluded that sildenafil is effective in reducing pulmonary hypertension when administered preoperatively in patients with severe pulmonary hypertension undergoing mitral valve replacement surgery.

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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.

Objective Investigate the clinical features, diagnosis and treatments of the scimitar syndrome, and different forms of treatment to alleviate pulmonary hypertension. Methods A retrospective analysis of clinical data of 14 children with scimitar syndrome from 2013 to 2017, including clinical symptoms and signs, chest X ray, echocardiography, chest CT and cardiac catheterization, treatment outcome and follow-up. Assess embolization of systemic pulmonary collateral and pulmonary venous drainage correction surgery, which is better for lowering pulmonary blood flow. Results 14 patients with scimitar syndrome were diagnosed from 2013 to 2017. There were 5 boys and 9 girls; 3 cases<7 kg in weight. Scimitar syndrome was suspected because of extroversion, and diagnosed by color Doppler echocardiography and 13 of them confirmed by cadiac CT scan when ascimitar vein was detected entering the inferior vena cava. 11 patiens had right lung dysplasia and 4 had horseshoe lung. Three patients had severe pulmonary arterial hypertension, 3 had moderate to severe pulmonary arterial hypertension, and 2 had moderate pulmonary arterial hypertension, the left had slight pulmonary arterial hypertension. 4 patients had pulmonary venous drainage correction surgery, after that 2 of them had systemic pulmonary collateral embolism. 6 patients systemic pulmonary collateral embolism first, then 4 of them had surgical repair, 1 case of 13 years old asymptomatic child without surgery. 1 patient with heart failure, severe pulmonary hypertension, pulmonary infection, died before surgery, while another died after surgical repair. At last 1 patient was lost for follow-up visits. Systemic pulmonary collateral embolism and pulmonary venous drainage correction surgery could all reduce blood flow of pulmonary. After systemic pulmonary collateral embolism, patients had slight pulmonary arterial hypertension just need follow-up visits. Conclusion Clinically, found children with heart of dextrocardia position, growth retardation, recurrent lung infections, unexplained right heart failure, pulmonary hypertension, should consider the possibility scimitar syndrome. Whether pulmonary vascular embolization or surgical repair, can significantly reduce pulmonary artery’s blood flow and alleviate pulmonary hypertension to protect pulmonary, even reduced the incidence of pneumonia and mortality. So we suppose ealy pulmonary hypertension in scimitar syndrome patients maybe dynamic pulmonary hypertension. Key words: Congenital heart defect; Scimitar syndrome; Pulmonary vein; Pulmonary hypertension; Systemic pulmonary collateral circulation

Pulmonary angiography is the gold standard for the diagnosis of chronic thromboembolic pulmonary hypertension; however, major complications have been reported. This study evaluates the hemodynamic effects of direct pulmonary nonionic contrast bolus injection and oxygen inhalation in patients with chronic thromboembolic pulmonary hypertension. In 33 patients, hemodynamic parameters were measured after oxygen inhalation and during bolus injection of nonionic contrast medium in a control group (group 1. n = 11), in a group of patients with moderately severe pulmonary hypertension (group 2, n = 9), and in a group with severe pulmonary hypertension (group 3, n = 13). Oxygen inhalation significantly improved oxygen supply. Pulmonary artery pressure and heart rate were reduced, but pulmonary vascular resistance and total pulmonary resistance were not significantly affected. One hundred ninety-eight angiograms were performed selectively on both pulmonary arteries in the posterior-anterior, oblique, and lateral views. Before contrast bolus injection, RAP and PAP significantly increased because of initial inspiration. Contrast bolus injection caused only a minor pressure increase (delta PA systolic, 2.3 +/- 1.4, 2.5 +/- 1.8, and 5.0 +/- 5.2 mm Hg, groups 1, 2, and 3, respectively) without significance between the groups. After the angiography, pulmonary artery pressure was moderately increased, predominantly in group 3, but pulmonary vascular resistance was not significantly changed. Systemic vascular resistance was decreased. Cardiac index increased in groups 1 and 2 but was unchanged in group 3. Systemic pressure therefore decreased in group 3. We concluded that bolus injection of nonionic contrast medium causes no major hemodynamic effects even in patients with severe chronic thromboembolic pulmonary hypertension. Oxygen contributes to safety during the procedure.