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Pulmonary Hypertension: From Bench to Bedside

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A special issue of Life (ISSN 2075-1729). This special issue belongs to the section "Medical Research".

Deadline for manuscript submissions: closed (15 October 2022) | Viewed by 28900

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Dr. Satoshi Akagi

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Department of Cardiovascular Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8530, Japan
Interests: pulmonary hypertension; right ventricular dysfunction
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Pulmonary arterial hypertension is life-threatening diseases caused by constriction and remodeling of pulmonary arteries. Prostacyclin, endothelin receptor antagonist, phosphodiesterase 5 inhibitor and soluble guanylate cyclase stimulator is an available for treatment of pulmonary arterial hypertension, which improve hemodynamics and exercise capacity. However, sufficient improvement of long-term prognosis is not achieved in all patients with pulmonary arterial hypertension. New findings from basic research contribute to therapeutic advances of pulmonary arterial hypertension. In this special issue, we focus on basic research in pulmonary arterial hypertension.

Prof. Dr. Satoshi Akagi
Guest Editor

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Keywords

proliferative signaling
inflammation
metabolic dysfunction
growth factor
autophagy
shear stress
epigenetic change
immunology

Published Papers (10 papers)

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Research

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12 pages, 1510 KiB

Open AccessArticle

Microvasculopathy Evaluated by Dual-Energy Computed Tomography in Patients with Chronic Thromboembolic Pulmonary Hypertension and Pulmonary Arterial Hypertension

by Keisuke Miwa, Yu Taniguchi, Hiroyuki Fujii, Yoichiro Matsuoka, Hiroyuki Onishi, Kenichi Yanaka, Yu Izawa, Yasunori Tsuboi, Atsushi Kono, Noriaki Emoto and Kenichi Hirata

Life 2022, 12(8), 1232; https://doi.org/10.3390/life12081232 - 15 Aug 2022

Viewed by 1406

Abstract

Background: Poor subpleural perfusion (PSP) on dual-energy computed tomography (DE-CT) suggests microvasculopathy in chronic thromboembolic pulmonary hypertension (CTEPH). However, whether the microvasculopathy findings are equivalent to those in pulmonary arterial hypertension (PAH) remains unclear. The aim of this study was to elucidate the characteristics of microvasculopathy in CTEPH compared to those of that in PAH. Methods: We retrospectively reviewed subpleural perfusion on DE-CT and the hemodynamics of 23 patients with PAH and 113 with inoperable CTEPH. Subpleural perfusion on DE-CT was classified as poor (subpleural spaces in all segments with little or no perfusion) or normal. Results: PSP was observed in 51% of patients with CTEPH and in 4% of those with PAH (p < 0.01). CTEPH patients with PSP had poorer baseline hemodynamics and lower diffusing capacity for carbon monoxide divided by the alveolar volume (DLCO/VA) than those with CTEPH with normal perfusion (pulmonary vascular resistance [PVR]: 768 ± 445 dynes-sec/cm⁵ vs. 463 ± 284 dynes-sec/cm⁵, p < 0.01; DLCO/VA, 60.4 ± 16.8% vs. 75.9 ± 15.7%, p < 0.001). Despite the existence of PSP, hemodynamics improved to nearly normal in both groups after balloon pulmonary angioplasty. Conclusions: PSP on DE-CT, which is one of the specific imaging findings in CTEPH, might suggest a different mechanism of microvasculopathy from that in PAH. Full article

(This article belongs to the Special Issue Pulmonary Hypertension: From Bench to Bedside)

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9 pages, 1127 KiB

Open AccessArticle

Beneficial Effects of Pulmonary Vasodilators on Pre-Capillary Pulmonary Hypertension in Patients with Chronic Kidney Disease on Hemodialysis

by Keiji Kimuro, Kazuya Hosokawa, Kohtaro Abe, Kohei Masaki, Satomi Imakiire, Takafumi Sakamoto and Hiroyuki Tsutsui

Life 2022, 12(6), 780; https://doi.org/10.3390/life12060780 - 24 May 2022

Cited by 1 | Viewed by 1967

Abstract

Background: In patients with chronic kidney disease (CKD) on hemodialysis, comorbid pulmonary hypertension (PH) aggravates exercise tolerance and eventually worsens the prognosis. The treatment strategy for pre-capillary PH, including combined pre- and post-capillary PH (Cpc-PH), has not been established. Objectives: This study aimed to evaluate the impact of pulmonary vasodilators on exercise tolerance and pulmonary hemodynamics in patients with CKD on hemodialysis. Methods and Results: The medical records of 393 patients with suspected PH who underwent right heart catheterization were reviewed. Of these, seven patients had isolated pre-capillary PH and end-stage CKD on hemodialysis. Pulmonary vasodilators decreased pulmonary vascular resistance from 5.9 Wood units (interquartile range (IQR), 5.5–7.6) at baseline to 3.1 Wood units (IQR, 2.6–3.3) post-treatment (p = 0.02) as well as increased pulmonary capillary wedge pressure from 10 mmHg (IQR, 7–11) to 11 mmHg (IQR, 8–16) (p = 0.04). Pulmonary vasodilators increased the World Health Organization functional class I or II from 0% to 100% (p = 0.0002) and the 6 min walk distance from 273 m (IQR, 185–365) to 490 m (IQR, 470–550) (p = 0.03). Conclusions: Pulmonary vasodilators for PH in patients with CKD on hemodialysis decrease pulmonary vascular resistance and eventually improve exercise tolerance. Pulmonary vasodilators may help hemodialysis patients with pre-capillary PH, although careful management considering the risk of pulmonary edema is required. Full article

(This article belongs to the Special Issue Pulmonary Hypertension: From Bench to Bedside)

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12 pages, 1709 KiB

Open AccessArticle

Pulmonary Artery Pressure-Guided Telemonitoring Reduced Pulmonary Artery Pressure but Did Not Result in Higher Doses of Guideline-Directed Medical Therapy–Observations from an Advanced Elderly German Heart Failure Cohort

by Ester J. Herrmann, Badrinarayanan Raghavan, Nina Eissing, Stephan Fichtlscherer, Christian W. Hamm and Birgit Assmus

Life 2022, 12(5), 766; https://doi.org/10.3390/life12050766 - 21 May 2022

Viewed by 1763

Abstract

Introduction: Remote pulmonary artery pressure (PAP)-guided heart failure (HF) therapy for NYHA class III patients has been shown to reduce hospitalizations and increase survival. We aimed to assess whether PAP monitoring allows for the increase in HF directed medication in an elderly German cohort of advanced HF patients already receiving clinically optimized HF medication. Methods: We analyzed PAP and HF medication dosage, including diuretics, in 24 patients (mean age, 76 years) using implanted PAP-sensors during the first 12 months of PAP-guided HF care in an interdisciplinary HF unit. Results: During 12 months of PAP-guided HF therapy, PAP decreased significantly (△PAP systolic–6 ± 10, △PAP diastolic–4 ± 7, △PAP mean–4 ± 8 mm Hg, p < 0.01 for all). 16% of patients had an unplanned HF hospitalization. There was no significant change over time with respect to the dosage of RAAS inhibitors (ACE-I/ARB/ARNI), Beta blockers, or MRA treatments. In contrast, the dosage of loop diuretics increased significantly (2.1 ± 0.5-fold) over time. In the comparison of a “responder” (patients with PAP and diuretic dose decline) and “non-responder” (patients with PAP and diuretic dose increase) group, there were no significant differences between any of the baseline, medication, or HF hospitalization characteristics between the two groups. Conclusions: In elderly patients treated with clinically optimized HF medication, no further evidence-based medication increase could be achieved using PAP-guided HF care. However, by individual adjustment of diuretic dosage, a significant decline in PAP over time occurred, which could not be predicted by any of the baseline characteristics. Full article

(This article belongs to the Special Issue Pulmonary Hypertension: From Bench to Bedside)

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12 pages, 1873 KiB

Open AccessArticle

Quantification of Lung Perfusion Blood Volume in Dual-Energy Computed Tomography in Patients with Pulmonary Hypertension

by Satoko Ugawa, Satoshi Akagi, Kentaro Ejiri, Kazufumi Nakamura and Hiroshi Ito

Life 2022, 12(5), 684; https://doi.org/10.3390/life12050684 - 5 May 2022

Viewed by 1695

Abstract

Dual-energy computed tomography (DECT) is a promising technique for the assessment of the lung perfused blood volume (LPBV) in the lung parenchyma. This study was performed to compare the LPBV by DECT of patients with pulmonary hypertension (PH) and controls and to evaluate the association between the LPBV and the perfusion ratio derived by lung perfusion scintigraphy. This study involved 45 patients who underwent DECT (25 patients with PH and 20 controls). We measured the total LPBV and distribution of the LPBV in each lung. The total LPBV was significantly lower in the PH group than the control group (38 ± 9 vs. 45 ± 8 HU, p = 0.024). Significant differences were observed between the LPBV of the upper lung of the PH and control groups (34 ± 10 vs. 47 ± 10, p = 0.021 and 37 ± 10 vs. 47 ± 8, p < 0.001). A significant correlation was observed between the LPBV and the lung perfusion scintigraphy. A lower total LPBV and lower LPBV of the upper lung as detected by DECT might be specific findings of PH. Full article

(This article belongs to the Special Issue Pulmonary Hypertension: From Bench to Bedside)

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12 pages, 492 KiB

Open AccessArticle

Correlation of Hemodynamic and Respiratory Parameters in Invasive Cardiopulmonary Exercise Testing (iCPET)

by Dirk Habedank, Anne Obst, Alexander Heine, Beate Stubbe and Ralf Ewert

Life 2022, 12(5), 655; https://doi.org/10.3390/life12050655 - 28 Apr 2022

Cited by 3 | Viewed by 2448

Abstract

Background: Invasive cardiopulmonary exercise testing (iCPET) is an integral part in the advanced diagnostic workup of pulmonary hypertension (PH). Our study evaluated the relation between hemodynamic and respiratory parameters at two different resting conditions and two defined low exercise levels with a close synchronization of measurements in a broad variety of dyspnea patients. Subjects and methods: We included 146 patients (median age 69 years, range 22 to 85 years, n = 72 female) with dyspnea of uncertain origin. Invasive hemodynamic and gas exchange parameters were measured at rest, 45° upright position, unloaded cycling, 25 and 50 W exercise. All measurements were performed in a single RHC procedure. Results: Oxygen uptake (VO

_{2}

/body mass) correlated significantly with cardiac index (all p ≤ 0.002) at every resting and exercise level and with every method of cardiac output measurement (thermodilution, method of Fick). Mean pulmonary arterial pressure (PAPmean) correlated with all respiratory parameters (respiratory rate, partial end-tidal pressures of oxygen and carbon dioxide [petCO

_{2}

and petO

_{2}

], ventilation/carbon dioxide resp. oxygen ratio [VE/VCO

_{2}

, VE/VO

_{2}

], and minute ventilation [VE], all p < 0.05). These correlations improved with increasing exercise levels from rest via unloaded cycling to 25 W. There was no correlation with right atrial or pulmonary arterial wedge pressure. Summary: In dyspnea patients of different etiologies, the cardiac index is closely linked to VO

_{2}

at every level of rest and submaximal exercise. PAPmean is the only pressure that correlates with different respiratory parameters, but this correlation is highly significant and stable at rest, unloaded cycling and at 25 W. Full article

(This article belongs to the Special Issue Pulmonary Hypertension: From Bench to Bedside)

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11 pages, 1436 KiB

Open AccessArticle

End-Systolic Eccentricity Index Obtained by Enhanced Computed Tomography Is a Predictor of Pulmonary Vascular Resistance in Patients with Chronic Thromboembolic Pulmonary Hypertension

by Yoshinori Tsutsumi, Shiro Adachi, Yoshihisa Nakano, Shingo Iwano, Shinji Abe, Katsuhiko Kato and Shinji Naganawa

Life 2022, 12(4), 593; https://doi.org/10.3390/life12040593 - 17 Apr 2022

Cited by 1 | Viewed by 1669

Abstract

The usefulness of the parameters of biventricular function simultaneously measured using enhanced multi-detector computed tomography (MDCT) pulmonary angiography in patients with chronic thromboembolic pulmonary hypertension (CTEPH) has not been clarified. This study aimed to verify the correlation between left and right ventricular (RV) parameters and pulmonary vascular resistance (PVR). Patients who underwent enhanced MDCT before diagnostic right heart catheterization at Nagoya University Hospital between October 2014 and April 2021 were enrolled. The correlation of biventricular function and volume parameters with PVR was assessed. Eighty patients were retrospectively analyzed. Patients’ mean age was 65 ± 13 years, mean PVR was 9.1 (range, 6.1–11.3) Wood units, and mean end-systolic eccentricity index (esEI) was 1.76 ± 0.50. RV end-systolic volume (ESV) (p = 0.007), RV cardiac output (CO) (p < 0.001), RV ejection fraction (p < 0.001), LV end-diastolic volume (EDV) (p < 0.001), left ventricular (LV) ESV (p = 0.006), LVCO (p < 0.001), end-diastolic EI (p < 0.001), and esEI (p < 0.001) were significantly correlated with PVR. The LVEDV (p = 0.001) and esEI (p < 0.009) were independent predictors of PVR. Systolic pulmonary arterial pressure (PAP) (p < 0.001), diastolic PAP (p < 0.001), mean PAP (p < 0.001), right atrial pressure (p < 0.023), and PVR (p < 0.001) were significantly higher in the high esEI group than in the low esEI group. The esEI was a simple predictor of CTEPH severity. Full article

(This article belongs to the Special Issue Pulmonary Hypertension: From Bench to Bedside)

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Review

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14 pages, 716 KiB

Open AccessReview

Exercise-Induced Pulmonary Hypertension: A Valid Entity or Another Factor of Confusion?

by Elina Khattab, Nikolaos Velidakis, Evaggelia Gkougkoudi and Nikolaos P.E. Kadoglou

Life 2023, 13(1), 128; https://doi.org/10.3390/life13010128 - 3 Jan 2023

Cited by 3 | Viewed by 6461

Abstract

Exercise-induced pulmonary hypertension EIPH has been defined as an increase in mean pulmonary arterial pressure (mPAP) during exercise in otherwise normal values at rest. EIPH reflects heart and/or lung dysfunction and may precede the development of manifest pulmonary hypertension (PH) in a proportion of patients. It is also associated with decreased life expectancy in patients with heart failure with reduced ejection fraction (HFrEF) or left ventricle (LV) valvular diseases. Diastolic dysfunction exacerbated during exercise relates to increased LV filling pressure and left atrial pressure (LAP). In this context backward, transmitted pressure alone or accompanied with backward blood flow promotes EIPH. The gold standard of EIPH assessment remains the right heart catheterization during exercise, which is an accurate but invasive method. Alternatively, non-invasive diagnostic modalities include exercise stress echocardiography (ESE) and cardiopulmonary exercise testing (CPET). Both diagnostic tests are performed under gradually increasing physical stress using treadmill and ergo-cycling protocols. Escalating workload during the exercise is analogous to the physiological response to real exercise. The results of the latter techniques show good correlation with invasive measurements, but they suffer from lack of validation and cut-off value determination. Although it is not officially recommended, there are accumulated data supporting the importance of EIPH diagnosis in the assessment of other mild/subclinical or probably fatal diseases in patients with latent PH or heart failure or LV valvular disease, respectively. Nevertheless, larger, prospective studies are required to ensure its role in clinical practice. Full article

(This article belongs to the Special Issue Pulmonary Hypertension: From Bench to Bedside)

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8 pages, 234 KiB

Open AccessReview

Balloon Pulmonary Angioplasty for Takayasu Arteritis and Peripheral Pulmonary Artery Stenosis Mimicking Chronic Thromboembolic Pulmonary Hypertension

by Shigefumi Fukui, Yuko Shirota, Takao Nakano, Tsukasa Sato, Kaoru Hasegawa, Hisashi Kikuta, Takeyoshi Kameyama, Koji Kumagai and Tatsuya Komaru

Life 2022, 12(11), 1797; https://doi.org/10.3390/life12111797 - 6 Nov 2022

Cited by 1 | Viewed by 1489

Abstract

Balloon pulmonary angioplasty (BPA) has been reported to be effective and safe to an acceptable level in patients with distal-type, inoperable chronic thromboembolic pulmonary hypertension (CTEPH), resulting in improved long-term survival. However, evidenced treatment options and strategy including medical therapy of antithrombotic therapy, glucocorticoids, immunosuppressants, and pulmonary hypertension (PH)-specific therapies are scarce in patients with significant PH and right heart failure associated with Takayasu arteritis and peripheral pulmonary artery stenosis, both of which mimic CTEPH. Moreover, there has been still concern on safety and lack of established methodology in performing BPA for these conditions. In this report, we would like to review recent publications including several case reports and discuss the efficacy, safety, and suitable methods of BPA in this population. Full article

(This article belongs to the Special Issue Pulmonary Hypertension: From Bench to Bedside)

19 pages, 2272 KiB

Open AccessReview

The Platelet-Derived Growth Factor Pathway in Pulmonary Arterial Hypertension: Still an Interesting Target?

by Julien Solinc, Jonathan Ribot, Florent Soubrier, Catherine Pavoine, France Dierick and Sophie Nadaud

Life 2022, 12(5), 658; https://doi.org/10.3390/life12050658 - 29 Apr 2022

Cited by 4 | Viewed by 4600

Abstract

The lack of curative options for pulmonary arterial hypertension drives important research to understand the mechanisms underlying this devastating disease. Among the main identified pathways, the platelet-derived growth factor (PDGF) pathway was established to control vascular remodeling and anti-PDGF receptor (PDGFR) drugs were shown to reverse the disease in experimental models. Four different isoforms of PDGF are produced by various cell types in the lung. PDGFs control vascular cells migration, proliferation and survival through binding to their receptors PDGFRα and β. They elicit multiple intracellular signaling pathways which have been particularly studied in pulmonary smooth muscle cells. Activation of the PDGF pathway has been demonstrated both in patients and in pulmonary hypertension (PH) experimental models. Tyrosine kinase inhibitors (TKI) are numerous but without real specificity and Imatinib, one of the most specific, resulted in beneficial effects. However, adverse events and treatment discontinuation discouraged to pursue this therapy. Novel therapeutic strategies are currently under experimental evaluation. For TKI, they include intratracheal drug administration, low dosage or nanoparticles delivery. Specific anti-PDGF and anti-PDGFR molecules can also be designed such as new TKI, soluble receptors, aptamers or oligonucleotides. Full article

(This article belongs to the Special Issue Pulmonary Hypertension: From Bench to Bedside)

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Other

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7 pages, 617 KiB

Open AccessCommentary

RNF213-Associated Vascular Disease: A Concept Unifying Various Vasculopathies

by Takahiro Hiraide, Hisato Suzuki, Mizuki Momoi, Yoshiki Shinya, Keiichi Fukuda, Kenjiro Kosaki and Masaharu Kataoka

Life 2022, 12(4), 555; https://doi.org/10.3390/life12040555 - 8 Apr 2022

Cited by 6 | Viewed by 3670

Abstract

The ring finger protein 213 gene (RNF213) encodes a 590 kDa protein that is thought to be involved in angiogenesis. This gene was first recognized as a vasculopathy-susceptibility locus through genome-wide association studies undertaken in a Japanese population, demonstrating that heterozygotes for RNF213 p.Arg4810Lys (c.14429G>A, rs112735431) had a greatly increased risk of moyamoya disease. The association of RNF213 p.Arg4810Lys as a susceptibility variant of moyamoya disease was reproduced in Korean and Chinese individuals and, later, in Caucasians. Variants of the RNF213 gene have been linked to a number of vascular diseases such as moyamoya disease, intracranial major artery stenosis, pulmonary arterial hypertension, and peripheral pulmonary artery stenosis, and have also been associated with co-occurrent diseases and vascular disease in different organs. Based on the findings that we have reported to date, our paper proposes a new concept of “RNF213-associated vascular disease” to unify these conditions with the aim of capturing patients with multiple diseases but with a common genetic background. This concept will be highly desirable for clarifying all of the diseases in the RNF213-associated vascular disease category by means of global epidemiological investigations because of the possibility of such diseases appearing asymptomatically in some patients. Full article

(This article belongs to the Special Issue Pulmonary Hypertension: From Bench to Bedside)

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