Specific Pulmonary Hypertension Therapy Research Articles

Therapeutic approaches for pulmonary hypertension in patients with chronic kidney disease.

Pulmonary hypertension is a common comorbidity in patients with chronic kidney disease (CKD), but therapeutic options are limited. We discuss the epidemiology of pulmonary hypertension in patients with CKD and review therapies for pulmonary hypertension with a focus on emerging treatments for pulmonary arterial hypertension (PAH). The definition of pulmonary hypertension has been updated to a lower threshold of mean pulmonary artery pressures of more than 20 mmHg, potentially leading to more patients with CKD to qualify for the diagnosis of pulmonary hypertension. Endothelin receptor antagonists, a class of medications, which demonstrated efficacy in patients with PAH, have been shown to slow progression of CKD, but their efficacy in lowering pulmonary artery pressures and their effects on reducing cardiovascular mortality in this population remains unproven. Sotatercept, a novel activin signaling inhibitor, which was previously studied in dialysis patients has been shown to increase exercise capacity in patients with PAH. These studies may lead to new specific therapies for pulmonary hypertension in patients with CKD. Pulmonary hypertension is common in patients with CKD. Although our understanding of factors leading to pulmonary hypertension in this population have evolved, evidence supporting disease-specific therapy in CKD is limited arguing for larger, long-term studies.

Pulmonary Hypertension and Survival among Non-Small Cell Lung Cancer Patients: A Retrospective Cohort Study in the U.S. Military Health System.

Background: Lung cancer is one of the most lethal cancers with survival being closely related to stage and influenced by comorbid illness. The survival implications of pulmonary hypertension (PH) on patients with non-small cell lung cancer (NSCLC) have only been evaluated in small cohorts, with limited long-term follow-up. Methods: We conducted a retrospective cohort study of 7946 patients with NSCLC diagnosed in the MHS. This study evaluated the survival impact of PH in patients diagnosed with NSCLC in the MHS. Patients were classified as having and not having PH. We stratified PH into those diagnosed before the diagnosis of NSCLC and those diagnosed after NSCLC diagnosis. Results: Relative to patients without PH, patients with PH diagnosed before NSCLC had an increased risk of death (HR = 1.15 [95% CI, 1.02-1.29]). The increased risk of death was more obvious for patients with PH diagnosed after NSCLC compared with those without PH (HR = 2.74 [95% CI, 2.51-2.99]). The results were similar when stratified by patient demographics. Conclusions: In the MHS, PH is associated with worsened NSCLC survival, regardless of when it is diagnosed. When PH is diagnosed after NSCLC, it is associated with a marked reduction in survival, and this finding may suggest a potential role for monitoring pulmonary pressures in NSCLC patients. Furthermore, as specific PH therapy exists, some NSCLC patients with PH may be candidates for therapy.

Idiopathic Pulmonary Hypertension and in Situ Thromboembolism: A Difficult Case in Clinical Practice

Pulmonary hypertension is a complex syndrome for differential diagnosis, which is the outcome of various pathological conditions. With the exclusion of the two most common causes of pulmonary hypertension, such as pathology of the left heart chambers and pulmonary embolism, further search for etiology often becomes problematic. Despite the emergence of a number of international and domestic recommendations, as well as certain successes in drug therapy, the long-term prognosis in patients with pulmonary arterial hypertension remains unfavorable. In the description of this clinical case in a 39-year-old woman suffering from idiopathic pulmonary arterial hypertension, the main complaint of the patient was very non-specific. The woman could not bear the child, all her attempts, lasting more than 19 years, remained unsuccessful. Even in absolutely healthy women, pregnancy is associated with the highest risks and is a powerful “test” of the body, not to mention patients suffering from rare diseases. The patient has a “subacute” course and a fairly rapid progression of the disease with a significant deterioration in the quality of life, which led to the impossibility of carrying a pregnancy. There were also signs that aggravated the prognosis, such as increased dyspnea, loss of consciousness, a significant decrease in working capacity and a high degree of pulmonary hypertension (according to echocardiography, systolic pressure in the pulmonary artery > 128 mm Hg). Due to the ineffectiveness of standard therapy with a selective inhibitor of cycloguanosine monophosphate — specific phosphodiesterase type 5 — sildenafil; the option of specific therapy for pulmonary hypertension was considered, which made it possible to change the situation and bring the patient into a stable state and draw conclusions about the pregnancy.

Specific therapies of pulmonary hypertension and prognosis in COVID-19: 18-months analysis of BNP-PL national database

Abstract Introduction The SARS-CoV-2 pandemic had a significant impact on mortality in the group of patients (pts) with pulmonary hypertension (PH). Specific therapies offer the potential to improve COVID-19 survival in this vulnerable population, but data on COVID-19 mortality according to specific PH therapies are scarce. Aim To assess mortality in the course of COVID-19 among pts diagnosed with PH, treated under the Polish ministry therapeutic program and registered in the national BNP-PL database, according to the intensity of specific PH therapy used in Poland. Methods We analyzed the records of the complete population of Polish pts treated under the National Drug Program of PH (PAH and CTEPH) and registered in the national database of BNP-PL from 01 March 2020 to 31 August 2022. The clinical severity of COVID-19 course and mortality were reviewed. Clinical characteristics of infected and deceased patients were compared in relation to the specific therapy used. Results The analysis included 188 pts with SARS-CoV-2 infection (mean age 59 ± 17,7 years; 61% female). 45 patients (24%) required hospitalization. Mortality rate was 18% (34/188, including 15 out-of-hospital deaths) vs. 2,6% for estimated in the general population. Those who died due to COVID-19 were slightly older (mean age 63 ± 18.4 vs. 58 ± 17.5 yrs; p=0,13). There was no significant difference in mortality in subsets receiving monotherapy (13.8%), 2 drugs (25.4%) or 3 drugs(15%)- p=0.18. There was a trend towards higher mortality in pts on double regimen. Pts treated with prostacyclin analogues had significantly higher risk of dying from COVID-19 (30% vs 11.4% in others, p=0.002). Conclusions COVID-19 infection in pulmonary hypertension pts was related to high mortality and prostacyclin analogues users are at highest risk. Considering that this analysis suggests that COVID-19 mortality was equalized between less sick patients suitable for monotherapy and those qualified for double/triple regimens. The finding of numerically highest risk in double therapy users might signify needs for earlier escalation to triple regimen.Characteristics of pts with PH and Covid

Right-Sided Heart Failure and Cor Pulmonale in the Pediatric Patient.

Right-Sided Heart Failure and Cor Pulmonale in the Pediatric Patient.

Алгоритми діагностики та лікування ідіопатичної легеневої артеріальної гіпертензії

Визначення. Легенева гіпертензія (ЛГ) — це гемодинамічний та патофізіологічний стан, що характеризується підвищенням середнього тиску в легеневій артерії > 20 мм рт.ст. та оцінюється за даними катетеризації правих відділів серця (КПС). У більшості випадків ЛГ не самостійне захворювання, а є проявом інших хвороб. Ідіопатична легенева артеріальна гіпертензія (ІЛАГ) — діагноз, який встановлюється методом виключення усіх інших причин ЛГ (ураження лівих відділів серця, захворювання сполучної тканини, ВІЛ-інфекція, захворювання легень, портальна гіпертензія, вроджені вади серця, легенева тромбоемболія в анамнезі та ін.). При ІЛАГ етіологія захворювання невідома. Патогенез та симптоми ЛГ. Вазоконстрикція, мікротромбоз та ремоделювання судин — три основні патофізіологічні елементи при ЛГ. Симптоми ЛГ неспецифічні: задишка, швидка втомлюваність, біль у грудях при фізичному навантаженні, іноді спостерігаються синкопальні стани. У декомпенсованих пацієнтів наявні ознаки правосторонньої серцевої недостатності (нябряки, асцит, здуття живота, пульсація яремних вен). Діагностика. Діагностичний алгорим при ЛГ складається з двох етапів. Перший — поза межами експертного центру, другий — безпосередньо в експертному центрі ЛГ. При підозрі на це захворювання та за наявності типових симптомів та ознак усім хворим проводиться ехокардіографічне обстеження (ЕхоКГ). Далі, за певних умов (наприклад, відсутність основної причини ЛГ), хворий направляється до експертного центру ЛГ, де можливе проведення КПС. Оцінка прогнозу. Оцінка хворих з ІЛАГ необхідна для покращення контролю захворювання та переходу з більш високого ризику до більш низького. Оцінка прогнозу є комплексною та визначається на основі: клінічного статусу, прогресування симптомів, наявності синкопе, результатів тесту 6-хвилинної ходьби та NT-proBNP, результатів методів обстеження (кардіопульмональний тест із фізичним навантаженням, ЕхоКГ або МРТ серця, оцінка гемодинаміки). Лікування. Основними завданнями лікування ІЛАГ є зменшення вираженості симптомів, уповільнення прогресування захворювання, поліпшення якості та збільшення тривалості життя хворих. У першу чергу це загальні заходи (фізична активність, запобігання та ведення вагітності), запобігання інфекційним захворюванням, соціально-психологічна допомога, контроль дотримання режиму, рекомендації щодо подорожей/поїздок, підтримуюча терапія (пероральні антикоагулянти, діуретики, дигоксин, оксигенотерапія). Хворим із позитивним вазореактивним тестом призначаються блокатори кальцієвих каналів. У всіх інших хворих специфічна терапія ЛГ може включати простагландини (інгаляційна, внутрішньовенна та підшкірна форма), антагоністи простациклінових рецепторів, антагоністи рецепторів ендотеліну, інгібітори фосфодіестерази-5, стимулятори розчинної гуанілатциклази. Хірургічне лікування. Одним із варіантів хірургічного лікування ІЛАГ є передсердна септостомія — створення перфорації в міжпередсердній перегородці. Це призводить до декомпресії правих камер серця і збільшує перед-навантаження на лівий шлуночок, що веде до збільшення серцевого викиду. У разі неефективності всіх вищеописаних методів лікування та значного прогресування захворювання пацієнтам показана трансплантація легень або комплексу серце — легені.

Impact of COVID-19 pandemics upon pulmonary hypertension patients: insights from BNP-PL national database

Abstract Introduction COVID-19 pandemic has caused not only an increase in overall and cardiovascular mortality, but also hindered access to health care, diagnosis and treatment of diseases other than coronavirus infection. Aim Assessment of the impact of the SARS-CoV-2 pandemic on the rate of diagnosis and therapy of pulmonary hypertension (PH) in Poland, along with an analysis of the incidence and course of COVID-19 among patients (pts) diagnosed with PH, treated under the National Health Fund program, registered in the national BNP-PL database. Methods The records of the complete population of Polish pts treated under the National Drug Program of PH (PAH and CTEPH), registered in the national database of BNP-PL, updated on an ongoing basis by all PH centers, were analyzed. The frequency of SARS-CoV-2 infections, the clinical severity of their course and the mortality were reviewed, taking into account the specific therapies used. The basic clinical characteristics of the group of sick and deceased patients were compared to the remaining patients registered in the BNP-PL database. The rate of increase of new diagnoses ended with inclusion in the Drug Program between March and December 2020, compared to the corresponding periods of the previous year, and the change in the treatment profile were compared. Results The analysis included 1704 pts (PAH 1134, CTEPH 570). The incidence of SARS-CoV-2 infections was 3.8% (n=65), including PAH 2.7% (n=46) and CTEPH 3,2% (n=18). 32 patients (49%) required hospitalization. Mortality rate was 28% (18/65) – including 7/18 outside of hospital. Those who died due to COVID-19 were older (mean age 68.4±15.8 vs. 50.8±18.8 yrs; p<0,001), had higher WHO class and more cardiovascular comorbidities (4±2,06 vs. 2,66±1,8; p=0,01) (Table 1). During the pandemic the number of new diagnoses of PH markedly decreased compared to the corresponding period in 2019 (total 150 vs. 203, PAH 90 vs. 123, CTEPH 60 vs. 80, respectively). A significant increase in total mortality was also observed in the PH group (9,72 vs. 5,85%). Moreover, escalation of specific PH therapy decreased significantly (14,7% vs. 21,6%). Incidence of COVID-19 study group was lower than estimated for general Polish adult population (3,8% vs. 6,5%). Conclusions COVID-19 pandemic deeply influenced the diagnostic and therapeutic process of pulmonary hypertension by reducing the number of new diagnoses, escalation therapy and increased overall mortality in this population. This may be due in part to the conversion of some PAH centers into hospitals treating patients infected with SARS-CoV-2, as well as to patients' fear of admitting to hospital despite clinical deterioration. Pulmonary hypertension is linked to markedly increased mortality in COVID-19, similarly for PAH and CTEPH. Intriguing finding of lower infection rate may be linked to protective lifestyle or specific therapies. Funding Acknowledgement Type of funding sources: None.

Optimization of specific therapy for pulmonary hypertension: the possibilities of riociguat

Pulmonary hypertension (PH) is a severe and often rapidly progressive disease with fatal outcome. Endothelial dysfunction in PH is associated with decreased nitric oxide production. After reviewing the mechanisms of action and the evidence base for specific therapy with phosphodiesterase 5 inhibitors (PDE-5) and soluble guanylate cyclase stimulators, a reseach review on switching from PDE-5 to riociguat is conducted. A potential advantage of riociguat is its independence from endogenous nitric oxide and from the other (besides PDE-5) isoenzymes of phosphodiesterases. The favorable efficacy profile of sildenafil has been proven for the main forms of pulmonary arterial hypertension, of riociguat for the main forms of pulmonary arterial hypertension and chronic thromboembolic PH. The clinical efficacy of replacing PDE-5 with riociguat has been demonstrated in uncontrolled trials and in the randomized controlled study REPLACE. The possibility of therapy optimization by switching from IFDE-5 to riociguat is fixed in the Russian (class and level of evidence B-3) and Eurasian (class and level of evidence IIb-B) clinical guidelines, as well as in the materials of the Cologne Expert Consensus. An additional argument for switching is the lower cost as compared to combination therapy in the Russian Federation. According to the Russian and Eurasian guidelines for PH and the Russian instructions for the use of riociguat, the drug should be taken at least 24 hours after sildenafil discontinuation.

Klippel-Trenaunay syndrome as a rare cause of chronic thromboemboembolic pulmonary hypertension

Klippel-Trenaunay syndrome (KTS) is a congenital disorder characterized by cutaneous capillary malformations, soft tissue and bone hypertrophy, and multiple capillary, venous or lymphatic malformations. KTS is associated with recurrent thromboembolic events. We reported herein five cases of chronic thromboembolic pulmonary hypertension (CTEPH) associated with KTS (age minimum–maximum 26–50 years old, 3 males/2 females). Hemodynamics showed severe pulmonary hypertension (PH) with pulmonary vascular resistance ranging from 5.6 to 18.3 Wood units (WU), associated with marked clinical impairment (NYHA functional class III or IV in 4 patients). Computed tomography (CT) of the chest and pulmonary angiography confirmed proximal CTEPH accessible to surgical intervention in one patient and distal forms of CTEPH in 4 patients. Evolution after pulmonary endarterectomy showed hemodynamic normalization, while the patients with distal CTEPH had severe outcomes with 2 early deaths after PH diagnosis (44 and 35 months respectively). One patient with distal CTEPH was still alive 16 years after diagnosis on specific PH therapy and one was transplanted after 15 years because of right heart failure (death after 12 months). Histological analysis of the lung explants showed typical chronic thromboembolic material specific for CTEPH. In conclusion, KTS may be complicated by severe CTEPH requiring careful anticoagulation and multidisciplinary follow-up in expert centers to screen for disease potentially accessible to endarterectomy. In the modern management era of CTEPH, balloon pulmonary angioplasty will certainly be an interesting option in patients with inoperable disease.

Right heart catheterization for hemodynamic evaluation of pulmonary hypertension

Objective description of clinical characteristics of patients, their physiological and hemodynamic parameters during right heart catheterization in the center of pulmonary hypertension in Ukraine.Material and methods. The procedure fof the right heart catheterization according to national and international protocols was performed in 108 patients with intermediate or high probability of pulmonary hypertension according to expert echocardiography. Physiological evaluation at the time of diagnosis includes a 6-minute walk test, a NTpro-BNP level, and an expert echocardiography with expanded protocol and an assessment of the right ventricular function.Results. We confirmed the presence of pulmonary hypertension in 94 patients (90.4%). During the diagnosis, 67% of patients with pulmonary hypertension had functional class III and 8% — functional class IV, 75% of patients had functional class III or IV. 67 patients underwent right heart catheterization before administering specific therapy for pulmonary hypertension, and the remaining 27 patients had already received specific therapy without confirmation of diagnosis. Our experience has shown that the lack of accurate hemodynamic measurements leads to a misleading diagnosis or inappropriate use of drugs specific to pulmonary hypertension, which can lead the patient to seek alternative treatments that have no proven efficacy.Conclusions. Catheterization of the right heart is the only way to reliable diagnosis of pulmonary hypertension and the risk of serious complications. It is necessary for the diagnosis of pulmonary hypertension, assessment of pulmonary hemodynamic condition and estimation of further prognosis.

Anesthesia for pregnant women with pulmonary hypertension.

Purpose of review is to summarize and highlight recent advances in the management of pregnant patients with pulmonary hypertension. Despite recent advances in the therapy of pulmonary hypertension, prognosis for pregnant patients with pulmonary hypertension remains poor with high maternal mortality. Pregnancy is still considered contraindicated in these patients. If pregnancy occurs, referral to a tertiary hospital and a multidisciplinary approach ensure the best possible outcome. All pregnant patients with pulmonary hypertension should be counseled for a termination of pregnancy. If the patient wants to continue the pregnancy despite strong recommendations for therapeutic interruption, specific pulmonary hypertension therapy has to be initiated, adjusted, and/or augmented. A close clinical follow-up of the mother throughout the entire pregnancy is of utmost importance. Elective caesarean section in week 34-36 is recommended as preferred mode of delivery, preferentially under epidural or low-dose combined spinal-epidural anesthesia. Because of an acute increase in pulmonary vascular resistance and delivery-associated acute volume overload, the immediate postpartum period carries the highest risk for acute right ventricular failure necessitating close monitoring and treatment on an ICU. Anesthesiologists involved in the management of pregnant patients with pulmonary hypertension must have detailed knowledge of pathophysiological alterations in pregnancy and during birth, cardiac (patho)physiology, cardiovascular and obstetric pharmacology, hemodynamic monitoring, and echocardiography. Both regional and general anesthesia have typical adverse effects that can severely jeopardize the cardiovascular system in patients with pulmonary hypertension, and should therefore be anticipated/prevented/rapidly treated by the attending anesthesiologist.

Hemodynamic assessment and acute pulmonary vasoreactivity testing in the evaluation of children with pulmonary vascular disease. Expert consensus statement on the diagnosis and treatment of paediatric pulmonary hypertension. The European Paediatric Pulmonary Vascular Disease Network, endorsed by ISHLT and DGPK

Invasive assessment of haemodynamics (ventricular, pulmonary) and testing of acute vasoreactivity in the catheterisation laboratory remain the gold standard for the diagnosis of pulmonary hypertension (PH) and pulmonary hypertensive vascular...

Recommendations for the Use of Inhaled Nitric Oxide Therapy in Premature Newborns with Severe Pulmonary Hypertension

Recommendations for the Use of Inhaled Nitric Oxide Therapy in Premature Newborns with Severe Pulmonary Hypertension

Pulmonary Arterial Hypertension-Specific Drug Therapy in COPD Patients with Severe Pulmonary Hypertension and Mild-to-Moderate Airflow Limitation

Background: Patients with severe pulmonary hypertension (PH) associated with chronic obstructive pulmonary disease (COPD) present a poor outcome. Specific PH treatment could improve the clinical and hemodynamic status of these patients but may worsen arterial blood gases. Objectives: Our study retrospectively included 28 patients with severe precapillary PH (mean pulmonary arterial pressure >35 mm Hg) associated with mild-to-moderate COPD [forced expiratory volume in 1 s (FEV₁) >50% predicted]. All patients underwent specific pulmonary arterial hypertension (PAH) treatment as mono-, bi- or triple therapy. Methods: Our single-center study was conducted based on retrospective data of 537 right heart catheterizations (RHCs) performed on patients with COPD from January 2004 to June 2014. An echocardiography, comprehensive blood tests, pulmonary function tests, and a high-resolution computed tomography were performed before the RHCs. All patients underwent RHC with a Swan-Ganz catheter. Results: Compared to baseline, patients treated with specific PAH drugs showed a significant increase in cardiac index at long term (2.5 ± 0.7 liters/min/m² at baseline vs. 3.2 ± 0.6 liters/min/m² at 6/12 months; p = 0.003) as well as a decrease in pulmonary vascular resistance in the long term (8.4 ± 4.2 Wood units at baseline vs. 5 ± 1.7 Wood units at 6/12 months; p = 0.008). There was a slight decrease in arterial oxygen tension (Pa<smlcap>O</smlcap>₂) after 3 months of treatment (-2.4 ± 7.21 mm Hg; p = 0.066). During a median follow-up of 3 years, 12 patients (42.8%) died (including all causes of death). Conclusions: This preliminary report suggests that the use of specific PH therapy in severe PH associated with mild-to-moderate COPD can improve pulmonary hemodynamic parameters, with worsening of Pa<smlcap>O</smlcap>₂, which had no clinical significance and did not lead to specific PAH therapy withdrawal in any patient.

Sarcoidosis-associated pulmonary hypertension

Pulmonary hypertension is a serious complication of sarcoidosis. This review discusses clinical characteristics of patients with sarcoid-associated pulmonary hypertension (SAPH) and pitfalls in the diagnosis, and highlights potential therapies. SAPH is common in patients with advanced disease, but it can occur in patients with minimal disease burden. Risk factors for SAPH include restrictive lung physiology, hypoxemia, advanced Scadding chest X-ray stage, and low carbon monoxide diffusion capacity. Echocardiogram is a good initial screening tool in the diagnosis of pulmonary hypertension, but right heart catheterization is necessary to confirm the diagnosis. Treatment with pulmonary vasodilators, including endothelin antagonists, can lead to improvements in pulmonary hemodynamics in some patients but may not improve their exercise capacity. Forced vital capacity is an important predictor of exercise performance in patients with SAPH. Clinical observations and response to specific therapies for pulmonary hypertension suggest the presence of different SAPH phenotypes. Patients who complain of persistent dyspnea should be screened for the presence of pulmonary hypertension. The prognosis of SAPH is poor and it is prudent to consider referral of these patients for lung transplantation. In some patients with SAPH, treatment with anti-inflammatory agents and pulmonary vasodilators can lower pulmonary arterial pressures, improve dyspnea and functionality, and enhance overall quality of life.

Pulmonary hypertension in sarcoidosis: A review

Pulmonary hypertension (PH) is a well-recognized complication of sarcoidosis. Patients with sarcoidosis-associated PH (SAPH) have poorer functional status and greater supplemental oxygen requirements than sarcoidosis patients without PH, and are more likely to be listed for lung transplantation. PH is an independent risk factor for mortality in sarcoidosis patients awaiting lung transplantation. The pathophysiology of SAPH is complex, with multiple mechanisms contributing to pathogenesis, including the fibrous destruction of the pulmonary vascular bed, extrinsic compression of the central pulmonary vessels and an intrinsic vasculopathy. Recognition of SAPH may be delayed as it can be masked by the clinical picture of underlying pulmonary sarcoidosis, and right heart catheter remains the gold-standard for diagnosis. Management of SAPH is based on reversal of resting hypoxaemia, treatment of comorbidities and treatment of the underlying sarcoidosis. The use of corticosteroids in SAPH is controversial. Specific PH therapy is not routinely recommended in SAPH as there are no successful placebo-controlled trials, although there is limited data to suggest that endothelin receptor antagonists and phosphodiesterase-5 inhibitors may be useful.

Pulmonary hypertension in interstitial lung disease: Fig. 1—

In the lungs, parenchymal and vascular remodelling share pathomechanisms that may explain the relatively high prevalence (30-40%) of pulmonary hypertension (PH) in interstitial lung disease (ILD) patients. Notably, PH significantly contributes to exercise limitation and dismal prognosis of ILD patients. The absence of specific clinical symptoms commonly leads to delayed diagnosis. Besides clinical judgment and out-of-proportion reduction in diffusing capacity, severe hypoxaemia or exercise oxygen desaturation, echocardiography and biomarkers such as B-type natriuretic peptide (BNP) and N-terminal pro-hormone BNP are potentially helpful tools in identifying PH. However, right heart catheterisation is still necessary to confirm the diagnosis. Management of PH in ILD comprises treatment of the underlying disease process and long-term oxygen therapy. Affected patients should be listed for lung transplantation without delay, when appropriate. However, due to age and comorbidities only a minority of ILD patients will be eligible for lung transplantation. In the absence of satisfactory therapies for many ILDs, and considering the clinical burden of PH in affected patients, specific vasomodulatory therapies presently approved for PAH may be promising options for ILD patients. Consequently, there is an urgent need for adequately designed clinical trials to assess the effectiveness of specific PH therapy in the context of ILDs.

Hypoxia- and non-hypoxia-related pulmonary hypertension — Established and new therapies

Pulmonary hypertension can occur as an isolated disease affecting the lung vessels only, in association with underlying hypoxic lung disorders, or due to chronic thromboembolic disease. Pulmonary hypertension caused by pulmonary venous congestion will not be focused on in this review. Regardless of the underlying disease, chronic cor pulmonale is associated with progressive clinical deterioration and a poor prognosis in most cases. The aim of specific therapies for pulmonary hypertension is to reduce pulmonary vascular resistance and thereby improve right ventricular function. Currently, three classes of drugs (prostanoids, endothelin receptor antagonists, and phosphodiesterase-5 inhibitors) are approved for the treatment of pulmonary arterial hypertension (PAH) in a defined patient population (group I according to the recent WHO classification). However, these medications may also lower pulmonary vascular resistance in patients with associated lung diseases (e.g. chronic obstructive pulmonary disease or lung fibrosis) and significant pulmonary hypertension, for whom these drugs are not yet approved. As non-selective vasodilators may induce gas-exchange disturbances, which preclude their long term use in these patients, such substances should be avoided in the hypoxemic patient. In this article we provide an update of the current understanding of hypoxia- and non-hypoxia-related pulmonary hypertension, addressing both the pathophysiological understanding of different disease aetiologies as well as the therapeutic options currently available.

Pulmonary Hypertension in Sickle Cell Disease: Cardiopulmonary Evaluation and Response to Chronic Phosphodiesterase 5 Inhibitor Therapy.

Pulmonary hypertension (PH) is a risk factor for mortality in Sickle Cell Disease, but it is unclear whether pulmonary hypertension is a marker or a direct cause of mortality. To better understand the pathophysiology of pulmonary hypertension in patients with sickle cell disease we performed evaluations of cardiopulmonary function in sickle cell disease patients with pulmonary hypertension (n= 15, mean age = 41 ± 2.4 years, males = 7, HbSS = 15, mean Hb = 8.3 ± 0.2 g/dl, mean tricuspid regurgitant jet velocity = 3.2 ± 0.11 m/s) compared to matched controls with sickle cell disease without pulmonary hypertension (n=11, mean age=40.2 ± 2.5 years, males=4, HbSS=11, mean Hb=8.5 ± 0.3 g/dl, mean tricuspid regurgitant jet velocity = 2.28 ± 0.07 m/s). To evaluate if specific therapy for pulmonary hypertension has any impact on systolic pulmonary artery pressure (PAP), estimated by tricuspid regurgitant jet velocity (TRJ), and functional capacity, measured by six-minute walk test (a well validated surrogate of functional capacity and response to therapy in patients with other causes of pulmonary hypertension), we treated 14 patients with sickle cell disease and pulmonary hypertension (mean age = 40 ± 2.5 years, males = 3, HbSS = 14, mean Hb = 8.8 ± 0.6 g/dl, mean TRJ = 3.4 ± 0.1 m/s) with sildenafil for at least three months. When compared to controls pulmonary hypertension patients had lower maximal oxygen consumption (VO2 max (% predicted), +PH: 44 ± 4, −PH: 55 ± 4; P=0.41), walked shorter six-minute walk distance (meters, +PH: 308.5 ± 53.8, −PH: 427.1 ± 44.6; P=0.03), demonstrated greater degree of interstitial lung disease by chest CT (P < 0.05), and more perfusion impairments measured by ventilation perfusion scan (P < 0.05). Six-minute walk distance correlated directly with maximal oxygen consumption (R=0.6; P=0.01), and inversely with mean pulmonary arterial pressure (R= −0.5; P=0.03) and tricuspid regurgitant jet velocity (R= −0.6;P=0.002), suggesting that the test is an adequate surrogate of functional capacity and response to therapy in pulmonary hypertension patients with sickle cell disease. Chronic treatment with sildenafil (up to 100 mg TID) decreased pulmonary arterial pressure (PAP mmHg, baseline: 50 ± 4.4, sildenafil: 41 ± 2.5; P=0.04) and increased six-minute walk distance (meters, baseline: 394 ± 31, sildenafil: 476 ± 26: P= 0.02). Sildenafil was well tolerated with only 2 patients stopping the drug due to headaches. We also observed 3 episodes of transient eyelid edema not requiring discontinuation of drug. Priapism was not observed in the 3 males treated (2 on exchange transfusion therapy, 1 with erectile dysfunction).In conclusion, we find that in patients with sickle cell disease, 1) pulmonary hypertension, though relatively mild, is associated with severe impairments in cardiopulmonary function, 2) traditional markers of functional capacity such as six-minute walk test can be utilized in this population as a therapeutic endpoint for clinical trials, 3) and therapy with sildenafil seems to have a favorable impact on pulmonary pressures and functional capacity.