In this trial, 261 patients with chronic thromboembolic pulmonary hypertension were assigned to placebo or to the soluble guanylate cyclase stimulator riociguat. At 16 weeks, riociguat had significantly improved the 6-minute walk distance and pulmonary vascular resistance. Chronic thromboembolic pulmonary hypertension is characterized by obstruction of the pulmonary vasculature by residual organized thrombi, 1 leading to increased pulmonary vascular resistance, progressive pulmonary hypertension, and right ventricular failure. 2 , 3 Patients with chronic thromboembolic pulmonary hypertension have a poor prognosis unless they receive treatment early. 4 Pulmonary endarterectomy is the standard treatment for chronic thromboembolic pulmonary hypertension and is the only potentially curative treatment. 5 However, surgery is not an option for all patients; some patients are ineligible for surgery owing to the occlusion of distal vessels or coexisting conditions, some decline surgery, and some do not have access to expert surgical . . .
The number of effective, long-term treatments for pulmonary hypertension is limited. In this double-blind, randomized trial, an aerosolized form of iloprost, a stable analogue of the pulmonary vasodilator prostacyclin, was assessed over a 12-week period. Iloprost had a beneficial effect on the combined end point of the distance walked in six minutes and an improvement in the New York Heart Association functional class. A continuous infusion of prostacyclin was the first therapy shown to reduce mortality in a controlled study of patients with severe pulmonary hypertension. 1 However, its use is associated with a number of serious drawbacks. The lack of pulmonary selectivity results in systemic side effects, tolerance leads to progressive increases in the dose, and there may be recurrent infections of the intravenous catheter. 2 As an alternative, inhaled nitric oxide possesses pulmonary selectivity, but it is less potent than prostacyclin in the pulmonary vasculature. 3 , 4 Moreover, an interruption in the inhalation of continuous nitric oxide may cause rebound pulmonary hypertension. 5 , 6 Designed . . .
Pulmonary hypertension is a common complication of chronic obstructive pulmonary disease (COPD). The increase in pulmonary artery pressures is often mild to moderate, but some patients may suffer from severe pulmonary hypertension, and present with a progressively downhill clinical course because of right-sided heart failure added to ventilatory handicap. The cause of pulmonary hypertension in COPD is generally assumed to be hypoxic pulmonary vasoconstriction leading to permanent medial hypertrophy. However, recent pathological studies point, rather, to extensive remodeling of the pulmonary arterial walls, with prominent intimal changes. These aspects account for minimal reversibility with supplemental oxygen. There may be a case for pharmacological treatment of pulmonary hypertension in selected patients with advanced COPD and right-sided heart failure. Candidate drugs include prostacyclin derivatives, endothelin antagonists and inhaled nitric oxide, all of which have been reported of clinical benefit in primary pulmonary hypertension. However, it will be a challenge for randomized controlled trials to overcome the difficulties of the diagnosis of right ventricular failure and the definition of a relevant primary endpoint in pulmonary hypertensive COPD patients.
Chronic obstructive pulmonary disease (COPD) is one of the most common causes of death worldwide. We report in an emphysema model of mice chronically exposed to tobacco smoke that pulmonary vascular dysfunction, vascular remodeling, and pulmonary hypertension (PH) precede development of alveolar destruction. We provide evidence for a causative role of inducible nitric oxide synthase (iNOS) and peroxynitrite in this context. Mice lacking were protected against emphysema and PH. Treatment of wild-type mice with the iNOS inhibitor N -(1-iminoethyl)-L-lysine (L-NIL) prevented structural and functional alterations of both the lung vasculature and alveoli and also reversed established disease. In chimeric mice lacking in bone marrow (BM)-derived cells, PH was dependent on from BM-derived cells, whereas emphysema development was dependent on from non-BM-derived cells. Similar regulatory and structural alterations as seen in mouse lungs were found in lung tissue from humans with end-stage COPD. ► ( ) loss protects mice from smoke-induced emphysema ► Pulmonary hypertension is dependent on iNOS activity in bone marrow-derived cells ► Emphysema is dependent on iNOS activity in non-BM-derived cells ► The iNOS inhibitor L-N6-(1-iminoethyl)-lysine improves established emphysema in mice Smoking-related damage can be reversed by inhibition of iNOS.
Abstract Pulmonary hypertension (PH) secondary to bronchopulmonary dysplasia (BPD) in infants remains a serious concern and continues to cause significant morbidity despite improvements in both quality of life and survival for patients. One of the potential agents that might help is sildenafil citrate, a phosphodiesterase-V inhibitor used a first line therapy for idiopathic PH. However, only limited evidence exists for its use as either monotherapy or part of a combination approach towards the management of PH in BPD. The evidence and current knowledge is presented for sildenafil alone and in combination with other disease modifying agents to treat PH in the presence of BPD. We have previously suggested that sildenafil appears to be safe and possibly effective in this condition. We present the evidence that if continued until PH resolution, there might be reduced mortality in this debilitating disease.
BACKGROUND: Newborns with anemia are at increased risk of persistent pulmonary hypertension of the newborn (PPHN), yet reports on the association between fetomaternal hemorrhage (FMH) and PPHN are rare. To optimize care for pregnancies complicated by FMH, clinicians should be aware of the risks of FMH and the possible diagnostic and therapeutic options. To increase the current knowledge, the incidence of PPHN and short-term neurologic injury in FMH cases were studied. STUDY DESIGN AND METHODS: We included all FMH cases (>30 mL fetal blood transfused into the maternal circulation) admitted to our neonatal unit between 2006 and 2018. First, we evaluated the incidence of PPHN and short-term neurologic injury. Second, we studied the potential effect of intrauterine transfusion (IUT). RESULTS: PPHN occurred in 37.9% of newborns (11 of 29), respectively, 14.3% (one of seven) and 45.5% (10 of 22) in the IUT group and no-IUT group (p = 0.20). The mortality rate was 13.8% (4 of 29). Severe brain injury occurred in 34.5% (10 of 29), respectively, and 14.3% (one of seven) and 40.9% (nine of 22) in the IUT group and no-IUT group (p = 0.37). CONCLUSION: Awareness should be raised among perinatologists and neonatologists about the possible life-threatening consequences of FMH, as more than one-third of neonates with anemia due to FMH experience PPHN and suffer from severe brain injury. Antenatal treatment with IUT seems to reduce these risks. Specialists should therefore always consider fetal anemia in FMH cases and refer patients to a fetal therapy center. If anemia is present at birth, it should be corrected promptly and neonatologists should be aware of signs of PPHN.
Objective To assess whether maternal use of selective serotonin reuptake inhibitors (SSRIs) increases the risk of persistent pulmonary hypertension in the newborn, and whether such an effect might differ between specific SSRIs.Design Population based cohort study using data from the national health registers.Setting Denmark, Finland, Iceland, Norway, and Sweden, 1996-2007.Participants More than 1.6 million infants born after gestational week 33.Main outcome measures Risks of persistent pulmonary hypertension of the newborn associated with early and late exposure to SSRIs during pregnancy and adjusted for important maternal and pregnancy characteristics. Comparisons were made between infants exposed and not exposed to SSRIs.Results Around 30 000 women had used SSRIs during pregnancy and 11 014 had been dispensed an SSRI later than gestational week 20. Exposure to SSRIs in late pregnancy was associated with an increased risk of persistent pulmonary hypertension in the newborn: 33 of 11 014 exposed infants (absolute risk 3 per 1000 liveborn infants compared with the background incidence of 1.2 per 1000); adjusted odds ratio 2.1 (95% confidence interval 1.5 to 3.0). The increased risks of persistent pulmonary hypertension in the newborn for each of the specific SSRIs (sertraline, citalopram, paroxetine, and fluoxetine) were of similar magnitude. Filling a prescription with SSRIs before gestational week 8 yielded slightly increased risks: adjusted odds ratio 1.4 (95% confidence interval 1.0 to 2.0).Conclusions The risk of persistent pulmonary hypertension of the newborn is low, but use of SSRIs in late pregnancy increases that risk more than twofold. The increased risk seems to be a class effect.
Abstract Background Pulmonary hypertension and associated right ventricular (RV) dysfunction are important determinants of morbidity and mortality, which are optimally characterized by invasive hemodynamic measurements. Objectives This study sought to determine whether metabolite profiling could identify plasma signatures of right ventricular-pulmonary vascular (RV-PV) dysfunction. Methods We measured plasma concentrations of 105 metabolites using targeted mass spectrometry in 71 individuals (discovery cohort) who underwent comprehensive physiological assessment with right-sided heart catheterization and radionuclide ventriculography at rest and during exercise. Our findings were validated in a second cohort undergoing invasive hemodynamic evaluations (n = 71), as well as in an independent cohort with or without known pulmonary arterial (PA) hypertension (n = 30). Results In the discovery cohort, 21 metabolites were associated with 2 or more hemodynamic indicators of RV-PV function (i.e., resting right atrial pressure, mean PA pressure, pulmonary vascular resistance [PVR], and PVR and PA pressure-flow response [ΔPQ] during exercise). We identified novel associations of RV-PV dysfunction with circulating indoleamine 2,3-dioxygenase (IDO)–dependent tryptophan metabolites (TMs), tricarboxylic acid intermediates, and purine metabolites and confirmed previously described associations with arginine–nitric oxide metabolic pathway constituents. IDO-TM levels were inversely related to RV ejection fraction and were particularly well correlated with exercise PVR and ΔPQ. Multisite sampling demonstrated transpulmonary release of IDO-TMs. IDO-TMs also identified RV-PV dysfunction in a validation cohort with known risk factors for pulmonary hypertension and in patients with established PA hypertension. Conclusions Metabolic profiling identified reproducible signatures of RV-PV dysfunction, highlighting both new biomarkers and pathways for further functional characterization.
Background: The nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) signal-transduction pathway is impaired in many cardiovascular diseases, including pulmonary arterial hypertension (PAH). Riociguat (BAY 63-2521) is a stimulator of sGC that works both in synergy with and independently of NO to increase levels of cGMP. The aims of this study were to investigate the role of NO-sGC-cGMP signaling in a model of severe PAH and to evaluate the effects of sGC stimulation by riociguat and PDE5 inhibition by sildenafil on pulmonary hemodynamics and vascular remodeling in severe experimental PAH. Methods and Results: Severe angioproliferative PAH was induced in rats by combined exposure to the vascular endothelial growth factor receptor antagonist SU5416 and hypoxia (SUHx). Twenty-one days thereafter rats were randomized to receive either riociguat (10 mg/kg/day), sildenafil (50 mg/kg/day) or vehicle by oral gavage, for 14 days until the day of the terminal hemodynamic measurements. Administration of riociguat or sildenafil significantly decreased right ventricular systolic pressure (RVSP). Riociguat significantly decreased RV hypertrophy (RVH) (0.55 +/- 0.02, p<0.05), increased cardiac output (60.8 +/-.8 mL/minute, p<0.05) and decreased total pulmonary resistance (4.03 +/- 0.3 mmHg min(-1) ml(-1) 100 g BW, p<0.05), compared with sildenafil and vehicle. Both compounds significantly decreased the RV collagen content and improved RV function, but the effects of riociguat on tricuspid annular plane systolic excursion and RV myocardial performance were significantly better than those of sildenafil (p<0.05). The proportion of occluded arteries was significantly lower in animals receiving riociguat than in those receiving vehicle (p<0.05); furthermore, the neointima/media ratio was significantly lower in those receiving riociguat than in those receiving sildenafil or vehicle (p<0.05). Conclusion: Riociguat and sildenafil significantly reduced RVSP and RVH, and improved RV function compared with vehicle. Riociguat had a greater effect on hemodynamics and RVH than sildenafil.