A Case of Complex Pulmonary Hypertension: the Importance of Diagnostic Investigation

Pulmonary hypertension (PH) encompasses several heterogeneous groups of multiple diseases characterized by abnormal pulmonary arterial blood pressure elevation. Unrepaired atrial septal defect (ASD) may be associated with pulmonary arterial hypertension (PAH), indicating pulmonary vascular remodeling. Furthermore, unrepaired ASD could also be associated with other conditions, such as left heart disease or thromboembolism, contributing to the disease progression. We present a case of a 61-years-old woman with complex PH comprising several etiologies, which are PAH due to unrepaired Secundum ASD, mitral regurgitation caused by mitral valve prolapse as a group 2 PH, pulmonary embolism (PE) which progress to chronic thromboembolism PH (CTEPH) and post-acute sequelae of SARS Cov-2. We highlighted the importance of diagnostic investigation in PH, which is crucial to avoid misdiagnosis and inappropriate treatment that could be detrimental for the patient.

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Metalloproteinase inhibition by Batimastat attenuates pulmonary hypertension in chronically hypoxic rats

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00167.2002 ◽

2003 ◽

Vol 285 (1) ◽

pp. L199-L208 ◽

Cited By ~ 28

Author(s):

Jan Herget ◽

Jana Novotná ◽

Jana Bíbová ◽

Viera Povýšilová ◽

Marie Vaňková ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Vascular Remodeling ◽

Chronic Hypoxia ◽

Causative Factor ◽

Systemic Arterial Pressure ◽

Collagenolytic Activity ◽

Pulmonary Vascular Remodeling ◽

Arterial Blood ◽

Fraction Of Inspired Oxygen ◽

Lung Vessels

Chronic hypoxia induces lung vascular remodeling, which results in pulmonary hypertension. We hypothesized that a previously found increase in collagenolytic activity of matrix metalloproteinases during hypoxia promotes pulmonary vascular remodeling and hypertension. To test this hypothesis, we exposed rats to hypoxia (fraction of inspired oxygen = 0.1, 3 wk) and treated them with a metalloproteinase inhibitor, Batimastat (30 mg/kg body wt, daily ip injection). Hypoxia-induced increases in concentration of collagen breakdown products and in collagenolytic activity in pulmonary vessels were inhibited by Batimastat, attesting to the effectiveness of Batimastat administration. Batimastat markedly reduced hypoxic pulmonary hypertension: pulmonary arterial blood pressure was 32 ± 3 mmHg in hypoxic controls, 24 ± 1 mmHg in Batimastat-treated hypoxic rats, and 16 ± 1 mmHg in normoxic controls. Right ventricular hypertrophy and muscularization of peripheral lung vessels were also diminished. Batimastat had no influence on systemic arterial pressure or cardiac output and was without any effect in rats kept in normoxia. We conclude that stimulation of collagenolytic activity in chronic hypoxia is a substantial causative factor in the pathogenesis of pulmonary vascular remodeling and hypertension.

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Curcumin Improves Pulmonary Hypertension Rats by Regulating Mitochondrial Function

BioMed Research International ◽

10.1155/2021/1078019 ◽

2021 ◽

Vol 2021 ◽

pp. 1-10

Author(s):

Jing Chen ◽

Wen Jiang ◽

Fei Zhu ◽

Qiong Wang ◽

Haiyan Yang ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Mitochondrial Function ◽

Vascular Remodeling ◽

Control Group ◽

Sprague Dawley ◽

Pulmonary Vascular Remodeling ◽

Sprague Dawley Rats ◽

Pulmonary Arterial ◽

Toxicological Mechanism ◽

And Function

Objective. To investigate the role of curcumin in regulating pathogenesis of pulmonary arterial smooth muscle cells (PASMCs) derived from pulmonary arterial hypertension (PAH) model. Methods. Male Sprague Dawley rats were injected with monocrotaline (MCT) to establish the PAH experimental model. The rats were divided into control group, MCT group, and curcumin group. At the end of the study, hemodynamic data were measured to determine pulmonary hypertension. Proliferation ability of PASMCs, a remodeling indicator of pulmonary artery and right ventricle, was detected. In addition, the morphology and function of mitochondria, antiglycolysis and antiproliferation pathways, and genes were also analyzed. Results. Curcumin may function by reversing MCT-mediated pulmonary vascular remodeling in rats. Curcumin effectively improved pulmonary vascular remodeling, promoted PASMC apoptosis, and protected mitochondrial function. In addition, curcumin treatment suppressed the PI3K/AKT pathway in PASMCs and regulated the expression of antiproliferative genes. Conclusion. Curcumin can improve energy metabolism and reverse the process of PAHS. However, there were side effects of curcumin in MCT-induced rats, suggesting that the dosage should be treated with caution and its toxicological mechanism should be further studied and evaluated.

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Deficiency of Akt1, but not Akt2, attenuates the development of pulmonary hypertension

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00242.2014 ◽

2015 ◽

Vol 308 (2) ◽

pp. L208-L220 ◽

Cited By ~ 35

Author(s):

Haiyang Tang ◽

Jiwang Chen ◽

Dustin R. Fraidenburg ◽

Shanshan Song ◽

Justin R. Sysol ◽

...

Keyword(s):

Cell Proliferation ◽

Pulmonary Hypertension ◽

Smooth Muscle ◽

Vascular Remodeling ◽

Pulmonary Vascular Remodeling ◽

Akt Isoforms ◽

Cell Proliferation And Migration ◽

Pulmonary Arterial ◽

And Migration ◽

Proliferation And Migration

Pulmonary vascular remodeling, mainly attributable to enhanced pulmonary arterial smooth muscle cell proliferation and migration, is a major cause for elevated pulmonary vascular resistance and pulmonary arterial pressure in patients with pulmonary hypertension. The signaling cascade through Akt, comprised of three isoforms (Akt1–3) with distinct but overlapping functions, is involved in regulating cell proliferation and migration. This study aims to investigate whether the Akt/mammalian target of rapamycin (mTOR) pathway, and particularly which Akt isoform, contributes to the development and progression of pulmonary vascular remodeling in hypoxia-induced pulmonary hypertension (HPH). Compared with the wild-type littermates, Akt1 −/− mice were protected against the development and progression of chronic HPH, whereas Akt2 −/− mice did not demonstrate any significant protection against the development of HPH. Furthermore, pulmonary vascular remodeling was significantly attenuated in the Akt1 −/− mice, with no significant effect noted in the Akt2 −/− mice after chronic exposure to normobaric hypoxia (10% O2). Overexpression of the upstream repressor of Akt signaling, phosphatase and tensin homolog deleted on chromosome 10 (PTEN), and conditional and inducible knockout of mTOR in smooth muscle cells were also shown to attenuate the rise in right ventricular systolic pressure and the development of right ventricular hypertrophy. In conclusion, Akt isoforms appear to have a unique function within the pulmonary vasculature, with the Akt1 isoform having a dominant role in pulmonary vascular remodeling associated with HPH. The PTEN/Akt1/mTOR signaling pathway will continue to be a critical area of study in the pathogenesis of pulmonary hypertension, and specific Akt isoforms may help specify therapeutic targets for the treatment of pulmonary hypertension.

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Targeting JP2: A New Treatment for Pulmonary Hypertension

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/2003446 ◽

2021 ◽

Vol 2021 ◽

pp. 1-9

Author(s):

Rubin Tan ◽

Cui Li ◽

Chuan Xu ◽

Qi Wu ◽

Liping Gao ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Vascular Remodeling ◽

Heart Diseases ◽

Experimental Studies ◽

Structural Basis ◽

Pulmonary Vascular Remodeling ◽

Arterial Blood ◽

Drug Treatments ◽

New Treatment ◽

Contraction And Relaxation

Pulmonary hypertension (PH) is a disease with a complex etiology and high mortality rate. Abnormal pulmonary vasoconstriction and pulmonary vascular remodeling lead to an increase in mean pulmonary arterial blood pressure for which, and there is currently no cure. Junctophilin-2 (JP2) is beneficial for the assembly of junctional membrane complexes, the structural basis for excitation-contraction coupling that tethers the plasma membrane to the sarcoplasmic reticulum/endoplasmic reticulum and is involved in maintaining intracellular calcium concentration homeostasis and normal muscle contraction function. Recent studies have shown that JP2 maintains normal contraction and relaxation of vascular smooth muscle. In some experimental studies of drug treatments for PH, JP2 expression was increased, which improved pulmonary vascular remodeling and right ventricular function. Based on JP2 research to date, this paper summarizes the current understanding of JP2 protein structure, function, and related heart diseases and mechanisms and analyzes the feasibility and possible therapeutic strategies for targeting JP2 in PH.

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Therapeutic hypercapnia prevents chronic hypoxia-induced pulmonary hypertension in the newborn rat

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00480.2005 ◽

2006 ◽

Vol 291 (5) ◽

pp. L912-L922 ◽

Cited By ~ 65

Author(s):

Crystal Kantores ◽

Patrick J. McNamara ◽

Lilian Teixeira ◽

Doreen Engelberts ◽

Prashanth Murthy ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Right Ventricular ◽

Vascular Remodeling ◽

Chronic Hypoxia ◽

Antioxidant Properties ◽

Ventricular Performance ◽

Pulmonary Vascular Remodeling ◽

Beneficial Effects ◽

Arterial Resistance ◽

Pulmonary Arterial

Induction of hypercapnia by breathing high concentrations of carbon dioxide (CO2) may have beneficial effects on the pulmonary circulation. We tested the hypothesis that exposure to CO2 would protect against chronic pulmonary hypertension in newborn rats. Atmospheric CO2 was maintained at <0.5% (normocapnia), 5.5%, or 10% during exposure from birth for 14 days to normoxia (21% O2) or moderate hypoxia (13% O2). Pulmonary vascular and hemodynamic abnormalities in animals exposed to chronic hypoxia included increased pulmonary arterial resistance, right ventricular hypertrophy and dysfunction, medial thickening of pulmonary resistance arteries, and distal arterial muscularization. Exposure to 10% CO2 (but not to 5.5% CO2) significantly attenuated pulmonary vascular remodeling and increased pulmonary arterial resistance in hypoxia-exposed animals ( P < 0.05), whereas both concentrations of CO2 normalized right ventricular performance. Exposure to 10% CO2 attenuated increased oxidant stress induced by hypoxia, as quantified by 8-isoprostane content in the lung, and prevented upregulation of endothelin-1, a critical mediator of pulmonary vascular remodeling. We conclude that hypercapnic acidosis has beneficial effects on pulmonary hypertension and vascular remodeling induced by chronic hypoxia, which we speculate derives from antioxidant properties of CO2 on the lung and consequent modulating effects on the endothelin pathway.

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Fluorofenidone attenuates vascular remodeling in hypoxia-induced pulmonary hypertension of rats

Canadian Journal of Physiology and Pharmacology ◽

10.1139/cjpp-2013-0056 ◽

2014 ◽

Vol 92 (1) ◽

pp. 58-69 ◽

Cited By ~ 4

Author(s):

Xian-Wei Li ◽

Jie Du ◽

Gao-Yun Hu ◽

Chang-Ping Hu ◽

Dai Li ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Vascular Remodeling ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β ◽

Brdu Incorporation ◽

Pulmonary Vascular Remodeling ◽

Collagen Iii ◽

Pulmonary Arterial

Fluorofenidone (AKF-PD) is a novel pyridone derivate that targets transforming growth factor-β1 (TGF-β1) signaling. Previous studies have proven that AKF-PD functions as an antifibrotic agent in pulmonary fibrosis and renal fibrosis models. Activated TGF-β1 signaling is thought to be a major feature of pulmonary hypertension (PH). TGF-β1 exerts powerful pro-proliferation effects on pulmonary arterial smooth muscle cells (PASMCs), and hence, prompts vascular remodeling. This study is designed to investigate the effect of AKF-PD on vascular remodeling in a rat model of hypoxia-induced PH. PH was induced in rats by 4 weeks of hypoxia. The expression of TGF-β1, collagen I, and collagen III was analyzed by ELISA, immunohistochemistry, real-time PCR, or Western blot. Proliferation of cultured PASMCs was determined by the BrdU incorporation method and flow cytometry. The results showed that AKF-PD treatment (0.5 or 1.0 g·(kg body mass)·d−1) for 4 weeks attenuated pulmonary vascular remodeling and improved homodynamic parameters. TGF-β1 level was significantly down-regulated by AKF-PD both in vivo and in vitro. Furthermore, hypoxia- and TGF-β1-induced PASMC proliferation and collagen expression were both significantly suppressed by AKF-PD. These results suggest that AKF-PD ameliorates the progression of PH induced by hypoxia in rats through its regulation of TGF-β1 expression, PASMC proliferation, and the extracellular matrix.

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Exaggerated pulmonary hypertension with monocrotaline in rats susceptible to chronic mountain sickness

Journal of Applied Physiology ◽

10.1152/jappl.1997.83.1.25 ◽

1997 ◽

Vol 83 (1) ◽

pp. 25-31 ◽

Cited By ~ 12

Author(s):

Gene L. Colice ◽

Nicholas Hill ◽

Yan-Jie Lee ◽

Hongkai Du ◽

James Klinger ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Single Dose ◽

Vascular Remodeling ◽

Chronic Hypoxia ◽

Minute Ventilation ◽

Chronic Mountain Sickness ◽

Pulmonary Vascular Remodeling ◽

Increased Sensitivity ◽

Pulmonary Arterial ◽

Mountain Sickness

Colice, Gene L., Nicholas Hill, Yan-Jie Lee, Hongkai Du, James Klinger, James C. Leiter, and Lo-Chang Ou. Exaggerated pulmonary hypertension with monocrotaline in rats susceptible to chronic mountain sickness. J. Appl. Physiol. 83(1): 25–31, 1997.—Hilltop (H) strain Sprague-Dawley rats are more susceptible to chronic mountain sickness than are the Madison (M) strain rats. It is unclear what role pulmonary vascular remodeling, polycythemia, and hypoxia-induced vasoconstriction play in mediating the more severe pulmonary hypertension that develops in the H rats during chronic hypoxia. It is also unclear whether the increased sensitivity of the H rats to chronic mountain sickness is specific for a hypoxia effect or, instead, reflects a general propensity toward the development of pulmonary hypertension. Monocrotaline (MCT) causes pulmonary vascular remodeling and pulmonary hypertension. We hypothesized that the difference in the pulmonary vascular response to chronic hypoxia between H and M rats reflects an increased sensitivity of the H rats to any pulmonary hypertensive stimuli. Consequently, we expected the two strains to also differ in their susceptibility to MCT-induced pulmonary hypertension. Pulmonary arterial pressures in conscious H and M rats were measured 3 wk after a single dose of MCT, exposure to a simulated high altitude of 18,000 ft (barometric pressure = 380 mmHg), and administration of a single dose of saline as a placebo. The H rats had significantly higher pulmonary arterial pressures and right ventricular weights after MCT and chronic hypoxia than did the M rats. The H rats also had more pulmonary vascular remodeling, i.e., greater wall thickness as a percentage of vessel diameter, after MCT and chronic hypoxia than did the M rats. The H rats had significantly lower arterial[Formula: see text] than did the M rats after MCT, but the degree of hypoxemia was mild [arterial[Formula: see text] of 72.5 ± 0.8 (SE) Torr for H rats vs. 77.4 ± 0.8 Torr for M rats after MCT]. The H rats had lower arterial [Formula: see text] and larger minute ventilation values than did the M rats after MCT. These ventilatory differences suggest that MCT caused more severe pulmonary vascular damage in the H rats than in the M rats. These data support the hypothesis that the H rats have a general propensity to develop pulmonary hypertension and suggest that differences in pulmonary vascular remodeling account for the increased susceptibility of H rats, compared with M rats, to both MCT and chronic hypoxia-induced pulmonary hypertension.

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The Isoquinoline-Sulfonamide Compound H-1337 Attenuates SU5416/Hypoxia-Induced Pulmonary Arterial Hypertension in Rats

Cells ◽

10.3390/cells11010066 ◽

2021 ◽

Vol 11 (1) ◽

pp. 66

Author(s):

Hiroki Shoji ◽

Yoko Yoshida ◽

Takayuki Jujo Sanada ◽

Akira Naito ◽

Junko Maruyama ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Pulmonary Arterial Hypertension ◽

Right Ventricle ◽

Arterial Hypertension ◽

Vascular Remodeling ◽

Myosin Light Chain ◽

Pulmonary Vasculature ◽

Pulmonary Vascular Remodeling ◽

Pulmonary Arterial ◽

Sulfonamide Compound

Pulmonary arterial hypertension (PAH) is characterized by elevated pulmonary arterial pressure and right heart failure. Selective pulmonary vasodilators have improved the prognosis of PAH; however, they are not able to reverse pulmonary vascular remodeling. Therefore, a search for new treatment agents is required. H-1337 is an isoquinoline-sulfonamide compound that inhibits multiple serine/threonine kinases, including Rho-associated protein kinase (ROCK) and mammalian target of rapamycin (mTOR). Here, we investigated the effects of H-1337 on pulmonary hypertension and remodeling in the pulmonary vasculature and right ventricle in experimental PAH induced by SU5416 and hypoxia exposure. H-1337 and H-1337M1 exerted inhibitory effects on ROCK and Akt. H-1337 inhibited the phosphorylation of myosin light chain and mTOR and suppressed the proliferation of smooth muscle cells in vitro. H-1337 treatment also suppressed the phosphorylation of myosin light chain and mTOR in the pulmonary vasculature and decreased right ventricular systolic pressure and the extent of occlusive pulmonary vascular lesions. Furthermore, H-1337 suppressed aggravation of right ventricle hypertrophy. In conclusion, our data demonstrated that inhibition of ROCK and mTOR pathways with H-1337 suppressed the progression of pulmonary vascular remodeling, pulmonary hypertension, and right ventricular remodeling.

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Resistin-like Molecule β Acts as a Mitogenic Factor in Hypoxic Pulmonary Hypertension via Ca2+ dependent PI3K/Akt/mTOR and PKC/MAPKs Signaling Pathway

10.21203/rs.3.rs-50645/v1 ◽

2020 ◽

Author(s):

Heshen Tian ◽

Lei Liu ◽

Wu Yin ◽

Ruiwen Wang ◽

Yongliang Jiang ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Signaling Pathway ◽

Expression Pattern ◽

Vascular Remodeling ◽

De Novo ◽

Underlying Mechanism ◽

Pulmonary Vascular Remodeling ◽

Mean Pulmonary Arterial Pressure ◽

Pulmonary Arterial ◽

Ventricle Hypertrophy

Abstract BACKGROUND: Pulmonary arterial smooth muscle cells(PASMCs) proliferation plays a crucial role in Hypoxia-induced pulmonary hypertension(HPH). Previous studies have found that Resistin-like molecule β(RELM-β) up-regulated de novo in response to hypoxia in cultured primary human PASMCs(HASMCs). RELM-β has been proved to promote PASMCs proliferation and involved in pulmonary vascular remodeling of patients with PAH. However, the expression pattern, the effects, and the mechanisms of RELM-β in HPH keep unknown. METHODS: We assessed the expression pattern, mitogenetic effect, and underlying mechanism of RELM-β in the rat HPH model and HASMCs. RESULTS: Overexpression of RELM-β alone caused the hemodynamic change in the rat model of HPH, similar to that caused by chronic hypoxia, with increased mean pulmonary arterial pressure(mPAP), right ventricle hypertrophy(RVSP), and thickening of small pulmonary arterioles. Knocking down of RELM-β partially blocked the increased mPAP, RVSP, and vascular remodeling induced by hypoxia. Phosphorylated PI3K/Akt/mTOR and PKC/MAPKs proteins were significantly up- or down-regulated by RELM-β gene overexpression or silencing. Recombinant RELM-β protein increase primary cultured human PASMCs intracellular Ca 2+ concentration and promote HASMCs proliferation. The mitogenic effect of RELM-β on HASMCs and phosphorylated PI3K/Akt/mTOR and PKC/MAPKs was suppressed by Ca 2+ inhibitor. CONCLUSIONS: Our findings suggested that RELM-β acts as a cytokine-like growth factor in the development of HPH and that this process is likely mediated by the Ca 2+ dependent PI3K/Akt/mTOR and PKC/MAPKs pathway. Keywords : hypoxic pulmonary arterial hypertension; resistin-like molecule β; Ca 2+ ; pulmonary vascular remodeling; signaling pathway

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Surgical Strategy in Patients with Atrial Septal Defect and Severe Pulmonary Hypertension

The Heart Surgery Forum ◽

10.1532/hsf98.20111085 ◽

2012 ◽

Vol 15 (2) ◽

pp. 111 ◽

Cited By ~ 9

Author(s):

Yang Hyun Cho ◽

Tae-Gook Jun ◽

Ji-Hyuk Yang ◽

Pyo Won Park ◽

June Huh ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Atrial Septal Defect ◽

Tricuspid Regurgitation ◽

Septal Defect ◽

Maze Procedure ◽

Severe Pulmonary Hypertension ◽

Tricuspid Annuloplasty ◽

Pulmonary Arterial ◽

Asd Closure

The aim of the study was to review our experience with atrial septal defect (ASD) closure with a fenestrated patch in patients with severe pulmonary hypertension. Between July 2004 and February 2009, 16 patients with isolated ASD underwent closure with a fenestrated patch. All patients had a secundum type ASD and severe pulmonary hypertension. Patients ranged in age from 6 to 57 years (mean � SD, 34.9 � 13.5 years). The follow-up period was 9 to 59 months (mean, 34.5 � 13.1 months). The ranges of preoperative systolic and pulmonary arterial pressures were 63 to 119 mm Hg (mean, 83.8 � 13.9 mm Hg) and 37 to 77 mm Hg (mean, 51.1 � 10.1 mm Hg). The ranges of preoperative values for the ratio of the pulmonary flow to the systemic flow and for pulmonary arterial resistance were 1.1 to 2.7 (mean, 1.95 � 0.5) and 3.9 to 16.7 Wood units (mean, 9.8 � 2.9 Wood units), respectively. There was no early or late mortality. Tricuspid annuloplasty was performed in 14 patients (87.5%). The peak tricuspid regurgitation gradient and the ratio of the systolic pulmonary artery pressure to the systemic arterial pressure were decreased in all patients. The New York Heart Association class and the grade of tricuspid regurgitation were improved in 13 patients (81.2%) and 15 patients (93.7%), respectively. ASD closure in patients with severe pulmonary hypertension can be performed safely if we create fenestration. Tricuspid annuloplasty and a Cox maze procedure may improve the clinical result. Close observation and follow-up will be needed to validate the long-term benefits.

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