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Various Causes of Pulmonary Hypertension: A Multidisciplinary Approach

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A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Pulmonology".

Deadline for manuscript submissions: closed (1 March 2020) | Viewed by 52180

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Special Issue Editors

Dr. Mirjam Kool

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Guest Editor

ILD&PH research group, Department of Pulmonary Medicine, Erasmus MC, Rotterdam, The Netherlands
Interests: pulmonary hypertension; interstitial lung diseases; mucosal immunology; dendritic cells; T-cells; chronic immune activation

Dr. Daphne Merkus

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Division of Experimental Cardiology, Department of Cardiology, Erasmus MC, Rotterdam, The Netherlands
Interests: CTEPH; type II pulmonary hypertension; exercise; metabolic derangement; coronary microcirculation; right ventricle

Dr. Karin Boomars

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Department of Pulmonary Medicine, Erasmus MC, Rotterdam, The Netherlands
Interests: pulmonary hypertension; CTEPH; collagen vascular disease; interstitial lung disease; cardio pulmonary rehabilitation

Special Issue Information

Dear Colleagues,

Pulmonary hypertension (PH) is a hemodynamic state defined as a mean pulmonary artery pressure of ≥25 mm Hg assessed by right heart catheterization at rest. PH can be the consequence of different clinical conditions, which translate into the five groups used in the WHO classification: (1) Pulmonary artery hypertension (PAH), (2) left-heart disease, (3) lung disease/hypoxemia, (4) chronic thromboembolic PH (CTEPH), and (5) PH with unclear and/or multifactorial mechanisms. PH patients are often treated by a team of PH specialists, pulmonary physicians, cardiologists, immunologists/rheumatologists, and specialist PH nurses. There are multiple pathological drivers of PH, including abnormal proliferation, inflammation, metabolism, neurohumoral, oxidative stress, and dysregulation of vascular tone.

For an upcoming Special Issue in the Journal of Clinical Medicine (PubMed indexed), we invite investigators to contribute original research articles (including human and animal studies; experimental and/or translational research will be given priority), as well as review articles that will stimulate the continuing efforts to get an early diagnosis, to gain new insights into pathobiological mechanisms, as well as to improve treatment of PH and quality of life.

Potential topics may include but are not limited to:

Early diagnostic markers of different classes of PH;
Genetics in PH;
Cellular, molecular, and/or hemodynamic mechanisms that drive PH;
Effect of thrombus formation/composition on the development of PH;
Potential new treatments for PH;
Improving quality of life of patients with PH.

Dr. Mirjam Kool
Dr. Daphne Merkus
Dr. Karin Boomars
Guest Editors

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Keywords

pulmonary hypertension
diagnosis
treatment
PH pathobiology
genetics
quality of life

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Published Papers (11 papers)

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13 pages, 1829 KiB

Open AccessArticle

Lower Plasma Melatonin Levels Predict Worse Long-Term Survival in Pulmonary Arterial Hypertension

by Zongye Cai, Theo Klein, Laurie W. Geenen, Ly Tu, Siyu Tian, Annemien E. van den Bosch, Yolanda B. de Rijke, Irwin K. M. Reiss, Eric Boersma, Dirk J. Duncker, Karin A. Boomars, Christophe Guignabert and Daphne Merkus

J. Clin. Med. 2020, 9(5), 1248; https://doi.org/10.3390/jcm9051248 - 25 Apr 2020

Cited by 9 | Viewed by 3209

Abstract

Exogenous melatonin has been reported to be beneficial in the treatment of pulmonary hypertension (PH) in animal models. Multiple mechanisms are involved, with melatonin exerting anti-oxidant and anti-inflammatory effects, as well as inducing vasodilation and cardio-protection. However, endogenous levels of melatonin in treatment-naïve patients with PH and their clinical significance are still unknown. Plasma levels of endogenous melatonin were measured by liquid chromatography-tandem mass spectrometry in PH patients (n = 64, 43 pulmonary arterial hypertension (PAH) and 21 chronic thromboembolic PH (CTEPH)) and healthy controls (n = 111). Melatonin levels were higher in PH, PAH, and CTEPH patients when compared with controls (Median 118.7 (IQR 108.2–139.9), 118.9 (109.3–147.7), 118.3 (106.8–130.1) versus 108.0 (102.3–115.2) pM, respectively, p all <0.001). The mortality was 26% (11/43) in the PAH subgroup during a long-term follow-up of 42 (IQR: 32–58) months. Kaplan–Meier analysis showed that, in the PAH subgroup, patients with melatonin levels in the 1st quartile (<109.3 pM) had a worse survival than those in quartile 2–4 (Mean survival times were 46 (95% CI: 30–65) versus 68 (58–77) months, Log-rank, p = 0.026) with an increased hazard ratio of 3.5 (95% CI: 1.1–11.6, p = 0.038). Endogenous melatonin was increased in treatment-naïve patients with PH, and lower levels of melatonin were associated with worse long-term survival in patient with PAH. Full article

(This article belongs to the Special Issue Various Causes of Pulmonary Hypertension: A Multidisciplinary Approach)

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13 pages, 562 KiB

Open AccessArticle

The Clinical Impact of Flow Titration on Epoprostenol Delivery via High Flow Nasal Cannula for ICU Patients with Pulmonary Hypertension or Right Ventricular Dysfunction: A Retrospective Cohort Comparison Study

by Jie Li, Payal K. Gurnani, Keith M. Roberts, James B. Fink and David Vines

J. Clin. Med. 2020, 9(2), 464; https://doi.org/10.3390/jcm9020464 - 7 Feb 2020

Cited by 19 | Viewed by 3447

Abstract

(1) Background: inhaled epoprostenol (iEPO) delivered via high-flow nasal cannula (HFNC) has been reported to be effective for pulmonary hypertension and right ventricular dysfunction. In vitro studies have identified HFNC gas flow as a key factor in trans-nasal aerosol delivery efficiency; however, little evidence is available on the clinical impact of flow titration on trans-nasal aerosol delivery. At our institution, iEPO via HFNC was initiated in 2015 and the concept of flow titration during iEPO via HFNC has been gradually accepted and carried out by clinicians in the recent years. (2) Methods: a retrospective review of the electronic medical records for all adult patients who received iEPO via HFNC in a tertiary teaching hospital. Pre- and post- iEPO responses were reported for patients whose HFNC flow was titrated or maintained constant during iEPO delivery. Positive response to iEPO was defined as the reduction of mean pulmonary arterial pressure (mPAP) > 10% for pulmonary hypertension patients or the improvement of oxygenation [pulse oximetry (SpO₂)/fraction of inhaled oxygen (F_IO₂)] > 20%. The number of responders to iEPO was compared between groups with titrated vs constant flow. (3) Results: 51 patients who used iEPO to treat pulmonary hypertension and/or right ventricular dysfunction were reviewed. Following iEPO administration via HFNC, mPAP decreased (43.6 ± 11.7 vs. 36.3 ± 9.7 mmHg, p < 0.001). Among the 51 patients, 24 had concomitant refractory hypoxemia, their oxygenation (SpO₂/F_IO₂) improved after iEPO delivery (127.8 ± 45.7 vs. 157.6 ± 62.2, p < 0.001). During iEPO initiation, gas flow was titrated in 25 patients and the remaining 26 patients used constant flow. The percentage of patients in the flow titration group who met the criteria for a positive response was higher compared to the group with constant flow (85.7% vs. 50%, p = 0.035). Pre- vs post-iEPO responses were significant in the flow titration group included improvement in cardiac output (p = 0.050), cardiac index (p = 0.021) and F_IO₂ reduction (p = 0.016). These improvements in hemodynamics and F_IO₂ were not observed in the constant flow group. (4) Conclusion: in patients with pulmonary hypertension and/or right ventricular dysfunction, trans-nasal iEPO decreased pulmonary arterial pressure. It also improved oxygenation in patients with combined refractory hypoxemia. These improvements were more evident in patients whose gas flow was titrated during iEPO initiation than those patients using constant flow. Full article

(This article belongs to the Special Issue Various Causes of Pulmonary Hypertension: A Multidisciplinary Approach)

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18 pages, 2295 KiB

Open AccessArticle

Total, Bioavailable, and Free Vitamin D Levels and Their Prognostic Value in Pulmonary Arterial Hypertension

by Maria Callejo, Gema Mondejar-Parreño, Sergio Esquivel-Ruiz, Miguel A. Olivencia, Laura Moreno, Isabel Blanco, Pilar Escribano-Subias, Angel Cogolludo, Joan Albert Barbera and Francisco Perez-Vizcaino

J. Clin. Med. 2020, 9(2), 448; https://doi.org/10.3390/jcm9020448 - 6 Feb 2020

Cited by 22 | Viewed by 3114

Abstract

Introduction: Epidemiological studies suggest a relationship between vitamin D deficiency and cardiovascular and respiratory diseases. However, whether total, bioavailable, and/or free vitamin D levels have a prognostic role in pulmonary arterial hypertension (PAH) is unknown. We aimed to determine total, bioavailable, and free 25-hydroxy-vitamin D (25(OH)vitD) plasma levels and their prognostic value in PAH patients. Methods: In total, 67 samples of plasma from Spanish patients with idiopathic, heritable, or drug-induced PAH were obtained from the Spanish PH Biobank and compared to a cohort of 100 healthy subjects. Clinical parameters were obtained from the Spanish Registry of PAH (REHAP). Results: Seventy percent of PAH patients had severe vitamin D deficiency (total 25(OH)vitD < 10 ng/mL) and secondary hyperparathyroidism. PAH patients with total 25(OH)vitD plasma above the median of this cohort (7.17 ng/mL) had better functional class and higher 6-min walking distance and TAPSE (tricuspid annular plane systolic excursion). The main outcome measure of survival was significantly increased in these patients (age-adjusted hazard ratio: 5.40 (95% confidence interval: 2.88 to 10.12)). Vitamin D-binding protein (DBP) and albumin plasma levels were downregulated in PAH. Bioavailable 25(OH)vitD was decreased in PAH patients compared to the control cohort. Lower levels of bioavailable 25(OH)vitD (<0.91 ng/mL) were associated with more advanced functional class, lower exercise capacity, and higher risk of mortality. Free 25(OH)vitD did not change in PAH; however, lower free 25(OH)vitD (<1.53 pg/mL) values were also associated with high risk of mortality. Conclusions: Vitamin D deficiency is highly prevalent in PAH, and low levels of total 25(OH)vitD were associated with poor prognosis. Full article

(This article belongs to the Special Issue Various Causes of Pulmonary Hypertension: A Multidisciplinary Approach)

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15 pages, 3109 KiB

Open AccessArticle

Inhibition of Anaplerosis Attenuated Vascular Proliferation in Pulmonary Arterial Hypertension

by Mathews Valuparampil Varghese, Joel James, Cody A Eccles, Maki Niihori, Olga Rafikova and Ruslan Rafikov

J. Clin. Med. 2020, 9(2), 443; https://doi.org/10.3390/jcm9020443 - 6 Feb 2020

Cited by 11 | Viewed by 3447

Abstract

Vascular remodeling is considered a key event in the pathogenesis of pulmonary arterial hypertension (PAH). However, mechanisms of gaining the proliferative phenotype by pulmonary vascular cells are still unresolved. Due to well-established pyruvate dehydrogenase (PDH) deficiency in PAH pathogenesis, we hypothesized that the activation of another branch of pyruvate metabolism, anaplerosis, via pyruvate carboxylase (PC) could be a key contributor to the metabolic reprogramming of the vasculature. In sugen/hypoxic PAH rats, vascular proliferation was found to be accompanied by increased activation of Akt signaling, which upregulated membrane Glut4 translocation and caused upregulation of hexokinase and pyruvate kinase-2, and an overall increase in the glycolytic flux. Decreased PDH activity and upregulation of PC shuttled more pyruvate to oxaloacetate. This results in the anaplerotic reprogramming of lung vascular cells and their subsequent proliferation. Treatment of sugen/hypoxia rats with the PC inhibitor, phenylacetic acid 20 mg/kg, starting after one week from disease induction, significantly attenuated right ventricular systolic pressure, Fulton index, and pulmonary vascular cell proliferation. PC inhibition reduced the glycolytic shift by attenuating Akt-signaling, glycolysis, and restored mitochondrial pyruvate oxidation. Our findings suggest that targeting PC mediated anaplerosis is a potential therapeutic intervention for the resolution of vascular remodeling in PAH. Full article

(This article belongs to the Special Issue Various Causes of Pulmonary Hypertension: A Multidisciplinary Approach)

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6 pages, 1193 KiB

Open AccessCommunication

Pulmonary Arterial Hypertension Induces a Distinct Signature of Circulating Metabolites

by Ruslan Rafikov, Dawn K Coletta, Lawrence J. Mandarino and Olga Rafikova

J. Clin. Med. 2020, 9(1), 217; https://doi.org/10.3390/jcm9010217 - 14 Jan 2020

Cited by 4 | Viewed by 2920

Abstract

Pulmonary arterial hypertension (PAH) is an incurable, progressive disorder, and the early diagnosis and treatment of PAH are associated with increased survival [...] Full article

(This article belongs to the Special Issue Various Causes of Pulmonary Hypertension: A Multidisciplinary Approach)

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17 pages, 1522 KiB

Open AccessArticle

Characterization of Patients with Pulmonary Arterial Hypertension: Data from the Polish Registry of Pulmonary Hypertension (BNP-PL)

by Grzegorz Kopeć, Marcin Kurzyna, Ewa Mroczek, Łukasz Chrzanowski, Tatiana Mularek-Kubzdela, Ilona Skoczylas, Beata Kuśmierczyk, Piotr Pruszczyk, Piotr Błaszczak, Ewa Lewicka, Danuta Karasek, Katarzyna Mizia-Stec, Michał Tomaszewski, Wojciech Jacheć, Katarzyna Ptaszyńska-Kopczyńska, Małgorzata Peregud-Pogorzelska, Anna Doboszyńska, Agnieszka Pawlak, Zbigniew Gąsior, Wiesława Zabłocka, Robert Ryczek, Katarzyna Widejko-Pietkiewicz, Marcin Waligóra, Szymon Darocha, Michał Furdal, Michał Ciurzyński, Jarosław D. Kasprzak, Marek Grabka, Karol Kamiński, Piotr Hoffman, Piotr Podolec and Adam Torbicki Show full author list Hide full author list

J. Clin. Med. 2020, 9(1), 173; https://doi.org/10.3390/jcm9010173 - 8 Jan 2020

Cited by 58 | Viewed by 6969

Abstract

Current knowledge of pulmonary arterial hypertension (PAH) epidemiology is based mainly on data from Western populations, and therefore we aimed to characterize a large group of Caucasian PAH adults of Central-Eastern European origin. We analyzed data of incident and prevalent PAH adults enrolled in a prospective national registry involving all Polish PAH centers. The estimated prevalence and annual incidence of PAH were 30.8/mln adults and 5.2/mln adults, respectively and they were the highest in females ≥65 years old. The most frequent type of PAH was idiopathic (n = 444; 46%) followed by PAH associated with congenital heart diseases (CHD-PAH, n = 356; 36.7%), and PAH associated with connective tissue disease (CTD-PAH, n = 132; 13.6%). At enrollment, most incident cases (71.9%) were at intermediate mortality risk and the prevalent cases had most of their risk factors in the intermediate or high risk range. The use of triple combination therapy was rare (4.7%). A high prevalence of PAH among older population confirms the changing demographics of PAH found in the Western countries. In contrast, we found: a female predominance across all age groups, a high proportion of patients with CHD-PAH as compared to patients with CTD-PAH and a low use of triple combination therapy. Full article

(This article belongs to the Special Issue Various Causes of Pulmonary Hypertension: A Multidisciplinary Approach)

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16 pages, 2474 KiB

Open AccessArticle

Echocardiographic Pulmonary to Left Atrial Ratio (ePLAR): A Comparison Study between Ironman Athletes, Age Matched Controls and A General Community Cohort

by Mai Tran, Agatha Kwon, David Holt, Rebecca Kierle, Benjamin Fitzgerald, Isabel Scalia, William Scalia, Geoffrey Holt and Gregory Scalia

J. Clin. Med. 2019, 8(10), 1756; https://doi.org/10.3390/jcm8101756 - 22 Oct 2019

Cited by 4 | Viewed by 3561

Abstract

Background: During exercise there is a proportionally lower rise in systemic and pulmonary pressures compared to cardiac output due to reduced vascular resistance. Invasive exercise data suggest that systemic vascular resistance reduces more than pulmonary vascular resistance. The aim of this study was the non-invasive assessment of exercise hemodynamics in ironman athletes, compared with an age matched control group and a larger general community cohort. Methods: 20 ironman athletes (40 ± 11 years, 17 male) were compared with 20 age matched non-athlete controls (43 ± 7 years, 10 male) and a general community cohort of 230 non-athletes individuals (66 ± 11 years, 155 male), at rest and after maximal-symptom limited treadmill exercise stress echocardiography. Left heart parameters (mitral E-wave, e’-wave and E/e’) and right heart parameters (tricuspid regurgitation maximum velocity and right ventricular systolic pressure), were used to calculate the echocardiographic Pulmonary to Left Atrial Ratio (ePLAR) value of the three groups. Results: Athletes exercised for 12.2 ± 0.53 min, age matched controls for 10.1 ± 2.8 min and general community cohort for 8.3 ± 2.6 min. Mitral E/e’ rose slightly for athletes (0.9 ± 1.8), age matched controls (0.6 ± 3.0) and non-athletes (0.4 ± 3.2). Right ventricular systolic pressure increased significantly more in athletes than in both non-athlete cohorts (35.6 ± 17 mmHg vs. 20.4 ± 10.8 mmHg and 18 ± 9.6 mmHg). The marker of trans-pulmonary gradient, ePLAR, rose significantly more in athletes than in both non-athlete groups (0.15 ± 0.1 m/s vs. 0.07 ± 0.1 m/s). Conclusions: Pulmonary pressures increased proportionally four-fold compared with systemic pressures in ironman athletes. This increase in pulmonary vascular resistance corresponded with a two-fold increase in ePLAR. These changes were exaggerated compared with both non-ironman cohorts. Such changes have been previously suggested to lead to right ventricle dysfunction, arrhythmias and sudden cardiac death. Full article

(This article belongs to the Special Issue Various Causes of Pulmonary Hypertension: A Multidisciplinary Approach)

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12 pages, 1218 KiB

Open AccessArticle

The Prognostic Value of Soluble ST2 in Adults with Pulmonary Hypertension

by Laurie W. Geenen, Vivan J. M. Baggen, Robert M. Kauling, Thomas Koudstaal, Karin A. Boomars, Eric Boersma, Jolien W. Roos-Hesselink and Annemien E. van den Bosch

J. Clin. Med. 2019, 8(10), 1517; https://doi.org/10.3390/jcm8101517 - 20 Sep 2019

Cited by 19 | Viewed by 3044

Abstract

Soluble ST2 (sST2) is upregulated in response to myocardial stress and may serve as biomarker in adults with pulmonary hypertension (PH). This prospective cohort study investigated sST2 levels and its association with echocardiographic and hemodynamic measures, and adverse clinical outcomes in adults with PH of different etiologies. sST2 was measured during the diagnostic right heart catheterization for PH, in adult patients enrolled between May 2012 and October 2016. PH due to left heart failure was excluded. The association between sST2 and a primary endpoint composed of death or lung transplantation and a secondary composite endpoint including death, lung transplantation or heart failure, was investigated using Cox regression with adjustment for NT-proBNP. In total 104 patients were included (median age was 59 years, 66% woman, 51% pulmonary arterial hypertension). Median sST2 was 28 [IQR 20–46] ng/mL. Higher sST2 was associated with worse right ventricular dysfunction and higher mean pulmonary and right atrial pressures. Median follow-up was 3.3 [IQR 2.3–4.6] years. The primary and secondary endpoint occurred in 33 (31.7%) and 43 (41.3%) patients, respectively. sST2 was significantly associated with both endpoints (HR per 2-fold higher value 1.53, 95%CI 1.12–2.07, p = 0.007 and 1.45, 95%CI 1.10–1.90, p = 0.008, respectively). However, after adjustment for NT-proBNP, both associations did not reach statistical significance. In conclusions, higher sST2 levels are associated with more severe PH and right ventricular dysfunction and yields prognostic value in adults with PH, although not independently of NT-proBNP. Full article

(This article belongs to the Special Issue Various Causes of Pulmonary Hypertension: A Multidisciplinary Approach)

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16 pages, 2000 KiB

Open AccessArticle

Intervening with the Nitric Oxide Pathway to Alleviate Pulmonary Hypertension in Pulmonary Vein Stenosis

by Richard W. B. van Duin, Kelly Stam, André Uitterdijk, Beatrijs Bartelds, A. H. Jan Danser, Irwin K. M. Reiss, Dirk J. Duncker and Daphne Merkus

J. Clin. Med. 2019, 8(8), 1204; https://doi.org/10.3390/jcm8081204 - 12 Aug 2019

Cited by 8 | Viewed by 3153

Abstract

Pulmonary hypertension (PH) as a result of pulmonary vein stenosis (PVS) is extremely difficult to treat. The ideal therapy should not target the high-pressure/low-flow (HP/LF) vasculature that drains into stenotic veins, but only the high-pressure/high-flow (HP/HF) vasculature draining into unaffected pulmonary veins, reducing vascular resistance and pressure without risk of pulmonary oedema. We aimed to assess the activity of the nitric oxide (NO) pathway in PVS during the development of PH, and investigate whether interventions in the NO pathway differentially affect vasodilation in the HP/HF vs. HP/LF territories. Swine underwent pulmonary vein banding (PVB; n = 7) or sham surgery (n = 6) and were chronically instrumented to assess progression of PH. Pulmonary sensitivity to exogenous NO (sodium nitroprusside, SNP) and the contribution of endogenous NO were assessed bi-weekly. The pulmonary vasodilator response to phosphodiesterase-5 (PDE5) inhibition was assessed 12 weeks after PVB or sham surgery. After sacrifice, 12 weeks post-surgery, interventions in the NO pathway on pulmonary small arteries isolated from HP/LF and HP/HF territories were further investigated. There were no differences in the in vivo pulmonary vasodilator response to SNP and the pulmonary vasoconstrictor response to endothelial nitric oxide synthase (eNOS) inhibition up to 8 weeks after PVB as compared to the sham group. However, at 10 and 12 weeks post-PVB, the in vivo pulmonary vasodilation in response to SNP was larger in the PVB group. Similarly, the vasoconstriction to eNOS inhibition was larger in the PVB group, particularly during exercise, while pulmonary vasodilation in response to PDE5 inhibition was larger in the PVB group both at rest and during exercise. In isolated pulmonary small arteries, sensitivity to NO donor SNP was similar in PVB vs. sham groups irrespective of HP/LF and HP/HF, while sensitivity to the PDE5 inhibitor sildenafil was lower in PVB HP/HF and sensitivity to bradykinin was lower in PVB HP/LF. In conclusion, both NO availability and sensitivity were increased in the PVB group. The increased nitric oxide sensitivity was not the result of a decreased PDE5 activity, as PDE5 activity was even increased. Some vasodilators differentially effect HP/HF vs. HP/LF vasculature. Full article

(This article belongs to the Special Issue Various Causes of Pulmonary Hypertension: A Multidisciplinary Approach)

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23 pages, 1083 KiB

Open AccessReview

Pulmonary Arterial Hypertension and Chronic Thromboembolic Pulmonary Hypertension: An Immunological Perspective

by Thomas Koudstaal, Karin A. Boomars and Mirjam Kool

J. Clin. Med. 2020, 9(2), 561; https://doi.org/10.3390/jcm9020561 - 19 Feb 2020

Cited by 35 | Viewed by 14487

Abstract

Pulmonary hypertension (PH) is a debilitating progressive disease characterized by increased pulmonary arterial pressures, leading to right ventricular (RV) failure, heart failure and, eventually, death. Based on the underlying conditions, PH patients can be subdivided into the following five groups: (1) pulmonary arterial hypertension (PAH), (2) PH due to left heart disease, (3) PH due to lung disease, (4) chronic thromboembolic PH (CTEPH), and (5) PH with unclear and/or multifactorial mechanisms. Currently, even with PAH-specific drug treatment, prognosis for PAH and CTEPH patients remains poor, with mean five-year survival rates of 57%–59% and 53%–69% for PAH and inoperable CTEPH, respectively. Therefore, more insight into the pathogenesis of PAH and CTEPH is highly needed, so that new therapeutic strategies can be developed. Recent studies have shown increased presence and activation of innate and adaptive immune cells in both PAH and CTEPH patients. Moreover, extensive biomarker research revealed that many inflammatory and immune markers correlate with the hemodynamics and/or prognosis of PAH and CTEPH patients. Increased evidence of the pathological role of immune cells in innate and adaptive immunity has led to many promising pre-clinical interventional studies which, in turn, are leading to innovative clinical trials which are currently being performed. A combination of immunomodulatory therapies might be required besides current treatment based on vasodilatation alone, to establish an effective treatment and prevention of progression for this disease. In this review, we describe the recent progress on our understanding of the involvement of the individual cell types of the immune system in PH. We summarize the accumulating body of evidence for inflammation and immunity in the pathogenesis of PH, as well as the use of inflammatory biomarkers and immunomodulatory therapy in PAH and CTEPH. Full article

(This article belongs to the Special Issue Various Causes of Pulmonary Hypertension: A Multidisciplinary Approach)

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16 pages, 1209 KiB

Open AccessReview

Skeletal and Respiratory Muscle Dysfunctions in Pulmonary Arterial Hypertension

by Marianne Riou, Mégane Pizzimenti, Irina Enache, Anne Charloux, Mathieu Canuet, Emmanuel Andres, Samy Talha, Alain Meyer and Bernard Geny

J. Clin. Med. 2020, 9(2), 410; https://doi.org/10.3390/jcm9020410 - 3 Feb 2020

Cited by 30 | Viewed by 3946

Abstract

Pulmonary arterial hypertension (PAH) is a rare disease, which leads to the progressive loss and remodeling of the pulmonary vessels, right heart failure, and death. Different clinical presentations can be responsible for such a bad prognosis disease and the underlying mechanisms still need to be further examined. Importantly, skeletal and respiratory muscle abnormalities largely contribute to the decreased quality of life and exercise intolerance observed in patients with PAH. At the systemic level, impaired oxygen supply through reduced cardiac output and respiratory muscle dysfunctions, which potentially result in hypoxemia, is associated with altered muscles vascularization, inflammation, enhanced catabolic pathways, and impaired oxygen use through mitochondrial dysfunctions that are likely participate in PAH-related myopathy. Sharing new insights into the pathological mechanisms of PAH might help stimulate specific research areas, improving the treatment and quality of life of PAH patients. Indeed, many of these muscular impairments are reversible, strongly supporting the development of effective preventive and/or therapeutic approaches, including mitochondrial protection and exercise training. Full article

(This article belongs to the Special Issue Various Causes of Pulmonary Hypertension: A Multidisciplinary Approach)

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