The Critical Role of Pulmonary Arterial Compliance in Pulmonary Hypertension

Abstract Background and aim In this study we evaluated the impact of the updated pulmonary hypertension (PH) definitive criteria proposed in 6th World PH Symposium (WSPH) on numbers and frequencies of and pre- versus post-capillary PH as compared to those in European Society of Cardiology (ESC) 2015 PH Guidelines. Methods Study group comprised the retrospectively evaluated 1299 patients (pts) (age 53.1±18.8 years, female 807, 62.1%) who underwent right heart catheterisation (RHC) with different indications between 2006 and 2018. For ESC and WSPH PH definitions, pulmonary arterial mean pressure (PAMP) ≥25 mmHg (definition-A) and PAMP >20 mmHg (definition-B) RHC criteria were used, respectively. For pre-capillary PH definitions, pulmonary artery wedge pressure (PAWP) ≤15 mmHg and pulmonary vascular resistance (PVR) ≥3 Wood units criteria were included in the both definitions. Results In RHC assessments, PAMP ≥25 mmHg and >20 mmHg were noted in 891 (68.6%) and 1051 (80.9%) of overall pts, respectively. Moreover, pre-capillary PH was diagnosed in 284 (21.8%) and 298 (22.9%) with definition-A and B, respectively. Although updated WSPH definition was associated with a net 12.3% and a relative 18% increase in the overall PH diagnosis, net and relative changes in the frequency of the pre-capillary PH were only 1% and 4.9%. Increase in the overall PH with updated WSPH criterias compared to previous ESC definitions was associated with increase in the number of pre-capillary PH (n=298, 22.9%) but not in the overall frequency of post-capillary PH (688, 52.9%). Because PVR was the product of the transpulmonary gradient (PAMP minus PAWP) divided by cardiac output, this measure was found to keep specificity for distinction between pre- versus post-capillary PH even after lowering thetreshold diagnostic for PAMP from 25 to 20 mmHg. Conclusions Although updated WSPH definition was associated with net 12.3% and relative 18% increase in the overall PH diagnosis, its impact on frequencies of pre- versus post-capillary PH within overall PH population was negligible.These seem to be due to critical role of PVR ensuring specificity in pre-capillary PH diagnosis even after lowering the definitive PAMP treshold to 20 mmHg.

Download Full-text

55th Bowditch Lecture: Effects of chronic hypoxia on the pulmonary circulation: Role of HIF-1

Journal of Applied Physiology ◽

10.1152/japplphysiol.00843.2012 ◽

2012 ◽

Vol 113 (9) ◽

pp. 1343-1352 ◽

Cited By ~ 17

Author(s):

Larissa A. Shimoda

Keyword(s):

Pulmonary Hypertension ◽

Pulmonary Circulation ◽

Vascular Remodeling ◽

Chronic Hypoxia ◽

Critical Role ◽

Hypoxia Inducible Factor ◽

Hypoxia Inducible Factor 1 ◽

Pulmonary Arterial ◽

Expression And Activity

When exposed to chronic hypoxia (CH), the pulmonary circulation responds with enhanced contraction and vascular remodeling, resulting in elevated pulmonary arterial pressures. Our work has identified CH-induced alterations in the expression and activity of several ion channels and transporters in pulmonary vascular smooth muscle that contribute to the development of hypoxic pulmonary hypertension and uncovered a critical role for the transcription factor hypoxia-inducible factor-1 (HIF-1) in mediating these responses. Current work is focused on the regulation of HIF in the chronically hypoxic lung and evaluation of the potential for pharmacological inhibitors of HIF to prevent, reverse, or slow the progression of pulmonary hypertension.

Download Full-text

Decreased time constant of the pulmonary circulation in chronic thromboembolic pulmonary hypertension

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00128.2013 ◽

2013 ◽

Vol 305 (2) ◽

pp. H259-H264 ◽

Cited By ~ 45

Author(s):

Robert V. MacKenzie Ross ◽

Mark R. Toshner ◽

Elaine Soon ◽

Robert Naeije ◽

Joanna Pepke-Zaba

Keyword(s):

Pulmonary Hypertension ◽

Time Constant ◽

Pulmonary Circulation ◽

Wave Reflection ◽

Arterial Compliance ◽

Chronic Thromboembolic Pulmonary Hypertension ◽

Left Heart Failure ◽

Thromboembolic Pulmonary Hypertension ◽

Pulmonary Arterial ◽

Rc Time Constant

This study analyzed the relationship between pulmonary vascular resistance (PVR) and pulmonary arterial compliance ( Ca) in patients with idiopathic pulmonary arterial hypertension (IPAH) and proximal chronic thromboembolic pulmonary hypertension (CTEPH). It has recently been shown that the time constant of the pulmonary circulation (RC time constant), or PVR × Ca, remains unaltered in various forms and severities of pulmonary hypertension, with the exception of left heart failure. We reasoned that increased wave reflection in proximal CTEPH would be another cause of the decreased RC time constant. We conducted a retrospective analysis of invasive pulmonary hemodynamic measurements in IPAH ( n = 78), proximal CTEPH ( n = 91) before (pre) and after (post) pulmonary endarterectomy (PEA), and distal CTEPH ( n = 53). Proximal CTEPH was defined by a postoperative mean pulmonary artery pressure (PAP) of ≤25 mmHg. Outcome measures were the RC time constant, PVR, Ca, and relationship between systolic and mean PAPs. The RC time constant for pre-PEA CTEPH was 0.49 ± 0.11 s compared with post-PEA-CTEPH (0.37 ± 0.11 s, P < 0.0001), IPAH (0.63 ± 0.14 s, P < 0.001), and distal CTEPH (0.55 ± 0.12 s, P < 0.05). A shorter RC time constant was associated with a disproportionate decrease in systolic PAP with respect to mean PAP. We concluded that the pulmonary RC time constant is decreased in proximal CTEPH compared with IPAH, pre- and post-PEA, which may be explained by increased wave reflection but also, importantly, by persistent structural changes after the removal of proximal obstructions. A reduced RC time constant in CTEPH is in accord with a wider pulse pressure and hence greater right ventricular work for a given mean PAP.

Download Full-text

EXPRESS: Pulmonary Hypertension Associated With Neurofibromatosis Type 2

Pulmonary Circulation ◽

10.1177/20458940211029550 ◽

2021 ◽

pp. 204589402110295

Author(s):

Hirohisa Taniguchi ◽

Tomoya Takashima ◽

Ly Tu ◽

RaphaÃ«l Thuillet ◽

Asuka Furukawa ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Neurofibromatosis Type ◽

Pulmonary Vascular Remodeling ◽

Life Threatening ◽

History Of ◽

Pulmonary Arterial ◽

First Time

Although precapillary pulmonary hypertension (PH) is a rare but severe complication of patients with neurofibromatosis type 1 (NF1), its association with NF2 remains unknown. Herein, we report a case of a 44-year-old woman who was initially diagnosed with idiopathic pulmonary arterial hypertension (IPAH) and treated with PAH-specific combination therapy. However, a careful assessment for a relevant family history of the disease and genetic testing reveal that this patient had a mutation in the NF2 gene. Using immunofluorescence and Western blotting, we demonstrated a decrease in endothelial NF2 protein in lungs from IPAH patients compared to control lungs, suggesting a potential role of NF2 in PAH development. To our knowledge, this is the first time that precapillary PH has been described in a patient with NF2. The altered endothelial NF2 expression pattern in PAH lungs should stimulate work to better understand how NF2 is contributing to the pulmonary vascular remodeling associated to these severe life-threatening conditions.

Download Full-text

Persistent Pulmonary Hypertension of the Newborn: Role of Nitric Oxide

Journal of Intensive Care Medicine ◽

10.1177/088506669501000602 ◽

1995 ◽

Vol 10 (6) ◽

pp. 270-282

Author(s):

Stella Kourembanas

Keyword(s):

Nitric Oxide ◽

Pulmonary Hypertension ◽

Structural Changes ◽

Critical Role ◽

Persistent Pulmonary Hypertension ◽

Cell Contractility ◽

Vasoactive Mediators ◽

Nitric Oxide Therapy

Persistent pulmonary hypertension of the newborn (PPHN) is a common cause of respiratory failure in the full-term neonate. Molecular and cellular studies in vascular biology have revealed that endothelial-derived mediators play a critical role in the pathogenesis and treatment of PPHN. Endothelial-derived vasoconstrictors, like endothelin, may increase smooth muscle cell contractility and growth, leading to the physiologic and structural changes observed in the pulmonary arterioles of infants with this disease. On the other hand, decreased production of the endothelial-derived relaxing factor, nitric oxide, may exacerbate pulmonary vasoreactivity and lead to more severe pulmonary hypertension. Exogenous (inhaled) nitric oxide therapy reduces pulmonary vascular resistance and improves oxygenation. The safety and efficacy of this therapy in reducing the need for extracorporeal membrane oxygenation and decreasing long-term morbidity is being tested in several trials nationally and abroad. Understanding the basic mechanisms that regulate the gene expression and production of these vasoactive mediators will lead to improved preventive and therapeutic strategies for PPHN.

Download Full-text

Role of Ambrisentan in the Management of Pulmonary Hypertension

Annals of Pharmacotherapy ◽

10.1345/aph.1l014 ◽

2008 ◽

Vol 42 (11) ◽

pp. 1653-1659 ◽

Cited By ~ 15

Author(s):

Sandra L Hrometz ◽

Kelly M Shields

Keyword(s):

Pulmonary Hypertension ◽

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

English Language ◽

Data Extraction ◽

Information Service ◽

Study Selection ◽

Pulmonary Arterial ◽

Improve Exercise Capacity

Objective: To review the role of ambrisentan in the treatment of pulmonary arterial hypertension (PAH). Data Sources: Literature was accessed through MEDLINE (1950-June 2008), Iowa Drug Information Service (1966–March 2008), EMBASE (1966-June 2008), bibliographies of pertinent articles, and unpublished data provided by the manufacturer and the Food and Drug Administration (FDA). Search terms included ambrisentan, endothelin antagonist, pulmonary hypertension, and pulmonary arterial hypertension. Due to limited literature available, additional criteria to limit searches were not used. Study Selection and Data Extraction: Abstracts and original preclinical and clinical research reports available in the English language were Identified for review. All manufacturer-provided data were also evaluated. Literature related to ambrisentan, endothelin antagonists, pulmonary hypertension, and pulmonary arterial hypertension were included. Four clinical trials evaluated the efficacy of ambrisentan in adults with symptomatic PAH. Data Synthesis: Ambrisentan is the latest endothelin-receptor antagonist (ERA) to obtain FDA approval for the treatment of PAH. It joins the first FDA-approved ERA, bosentan. Like bosentan, ambrisentan is available orally (with once-daily dosing compared with bosentan's twice-daily dosing) and has been shown to improve exercise capacity and delay clinical worsening. As with bosentan, the most significant safety concerns with ambrisentan relate to potential liver injury and a contraindication in pregnancy. Although ambrisentan has higher affinity for the endothelin type A receptor than for the endothelin type B receptor, specific advantages of this selectivity, in terms of efficacy compared with bosentan, a nonselective agent, have not been demonstrated. Conclusions: Ambrisentan has been shown to be an effective ERA in patients with PAH. A significant advantage of ambrisentan is the lack of any clinically important drug interactions with warfarin and sildenafil, which are frequently used by patients being treated for PAH.

Download Full-text

Right heart catheterisation: best practice and pitfalls in pulmonary hypertension

European Respiratory Review ◽

10.1183/16000617.0062-2015 ◽

2015 ◽

Vol 24 (138) ◽

pp. 642-652 ◽

Cited By ~ 51

Author(s):

Stephan Rosenkranz ◽

Ioana R. Preston

Keyword(s):

Pulmonary Hypertension ◽

Clinical Practice ◽

Best Practice ◽

Data Interpretation ◽

Volume Measurement ◽

Right Heart ◽

Heart Catheterisation ◽

Right Heart Catheterisation ◽

Pulmonary Arterial

Right heart catheterisation (RHC) plays a central role in identifying pulmonary hypertension (PH) disorders, and is required to definitively diagnose pulmonary arterial hypertension (PAH). Despite widespread acceptance, there is a lack of guidance regarding the best practice for performing RHC in clinical practice. In order to ensure the correct evaluation of haemodynamic parameters directly measured or calculated from RHC, attention should be drawn to standardising procedures such as the position of the pressure transducer and catheter balloon inflation volume. Measurement of pulmonary arterial wedge pressure, in particular, is vulnerable to over- or under-wedging, which can give rise to false readings. In turn, errors in RHC measurement and data interpretation can complicate the differentiation of PAH from other PH disorders and lead to misdiagnosis. In addition to diagnosis, the role of RHC in conjunction with noninvasive tests is widening rapidly to encompass monitoring of treatment response and establishing prognosis of patients diagnosed with PAH. However, further standardisation of RHC is warranted to ensure optimal use in routine clinical practice.

Download Full-text

Increased TMEM16A-encoded calcium-activated chloride channel activity is associated with pulmonary hypertension

AJP Cell Physiology ◽

10.1152/ajpcell.00044.2012 ◽

2012 ◽

Vol 303 (12) ◽

pp. C1229-C1243 ◽

Cited By ~ 74

Author(s):

Abigail S. Forrest ◽

Talia C. Joyce ◽

Marissa L. Huebner ◽

Ramon J. Ayon ◽

Michael Wiwchar ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Electromechanical Coupling ◽

Pulmonary Arteries ◽

Doppler Imaging ◽

Heart Weight ◽

Channel Activity ◽

Cl Channels ◽

Pulmonary Arterial ◽

Pulmonary Artery Smooth Muscle

Pulmonary artery smooth muscle cells (PASMCs) are more depolarized and display higher Ca2+ levels in pulmonary hypertension (PH). Whether the functional properties and expression of Ca2+-activated Cl− channels (ClCa), an important excitatory mechanism in PASMCs, are altered in PH is unknown. The potential role of ClCa channels in PH was investigated using the monocrotaline (MCT)-induced PH model in the rat. Three weeks postinjection with a single dose of MCT (50 mg/kg ip), the animals developed right ventricular hypertrophy (heart weight measurements) and changes in pulmonary arterial flow (pulse-waved Doppler imaging) that were consistent with increased pulmonary arterial pressure and PH. Whole cell patch experiments revealed an increase in niflumic acid (NFA)-sensitive Ca2+-activated Cl− current [ ICl(Ca)] density in PASMCs from large conduit and small intralobar pulmonary arteries of MCT-treated rats vs. aged-matched saline-injected controls. Quantitative RT-PCR and Western blot analysis revealed that the alterations in ICl(Ca) were accompanied by parallel changes in the expression of TMEM16A, a gene recently shown to encode for ClCa channels. The contraction to serotonin of conduit and intralobar pulmonary arteries from MCT-treated rats exhibited greater sensitivity to nifedipine (1 μM), an l-type Ca2+ channel blocker, and NFA (30 or 100 μM, with or without 10 μM indomethacin to inhibit cyclooxygenases) or T16AInh-A01 (10 μM), TMEM16A/ClCa channel inhibitors, than that of control animals. In conclusion, augmented ClCa/TMEM16A channel activity is a major contributor to the changes in electromechanical coupling of PA in this model of PH. TMEM16A-encoded channels may therefore represent a novel therapeutic target in this disease.

Download Full-text

Current organization of specialist pulmonary hypertension clinics: results of an international survey

Pulmonary Circulation ◽

10.1177/2045894019855611 ◽

2019 ◽

Vol 9 (2) ◽

pp. 204589401985561 ◽

Cited By ~ 1

Author(s):

Carolyn Doyle-Cox ◽

Gail Nicholson ◽

Traci Stewart ◽

Wendy Gin-Sing

Keyword(s):

Pulmonary Hypertension ◽

Central Component ◽

Multidisciplinary Teams ◽

Full Time ◽

Center Staff ◽

Program Administrator ◽

Nurse Coordinator ◽

Pulmonary Arterial ◽

Ph Management

Optimal pulmonary hypertension (PH) management relies on a timely, accurate diagnosis and follow-up in specialized clinics by multidisciplinary teams that have clearly defined responsibilities and protocols. Internationally agreed criteria for expert center staff are lacking, particularly with respect to nurses, who often act as a central component of the team. This survey aimed to evaluate the current organization of PH clinics and the role of nurses. The survey (35 questions) was online February–December 2015 and was advertised at international PH nurse meetings and through international PH organizations to their corresponding clinics. In total, 126 healthcare professionals from 32 countries responded. According to respondents, 54% of clinics managed >200 patients, of whom 49% had a pulmonary arterial hypertension (PAH) diagnosis, on average. In terms of staff, 66% had a dedicated program administrator, 35% had one full-time nurse coordinator/practitioner/specialist, and 57% had a nurse attend outpatient clinic alongside a physician. Crucially, not all centers had a nurse in their team. The role of a nurse coordinator/practitioner/specialist varied with 51% taking patient histories/examinations and 66% managing outpatients. In 34% of clinics, nurses were involved in their own research. Protocols were available for PH therapies (81%), management of heart failure (37%) and pain (26%), and referring patients who did not have PAH/chronic thromboembolic PH back to their specialist (62%). Not all clinics are meeting all of the standards outlined in the latest guidelines with key areas of improvement being level of support from/for nurses, clear protocols, and referral pathways.

Download Full-text

Pulmonary Hypertension Associated with Connective Tissue Disease

Seminars in Respiratory and Critical Care Medicine ◽

10.1055/s-0039-1685214 ◽

2019 ◽

Vol 40 (02) ◽

pp. 173-183 ◽

Cited By ~ 6

Author(s):

Hossam Fayed ◽

J. Gerry Coghlan

Keyword(s):

Rheumatoid Arthritis ◽

Pulmonary Hypertension ◽

Connective Tissue ◽

Connective Tissue Disease ◽

Best Practice ◽

Reference Source ◽

History Of ◽

Pulmonary Arterial ◽

Primary Physicians

Pulmonary hypertension (PH) is common in most forms of connective tissue disease (CTD); the prevalent type of PH depends on the particular CTD. Thus, pulmonary arterial hypertension (PAH) is dominantly associated with scleroderma, while postcapillary PH is most common in rheumatoid arthritis and lung disease-associated PH is typically found in myositis and sarcoidosis.Considerable expertise is required to identify, diagnose, and manage CTD-PH, as the primary physicians providing the majority of care for this population, rheumatologists, need a good working knowledge of CTD-PH, its rather subtle presentation, and how to access the necessary investigations to screen for and identify patients with PH. The role of the rheumatologist does not stop at diagnosis; in some conditions such as lupus, optimizing immunosuppression is key to the management of PH, and unlike simple idiopathic PAH, the natural history of CTD-PH is often punctuated by complications of the CTD rather than just events due to progression of PH or therapy-related adverse events.The aim of this article is to provide an overview of all forms of CTD-PH, and to provide an easy reference source on current best practice.

Download Full-text