scholarly journals Evolution of pathogenetic therapy of pulmonary arterial hypertension

2019 ◽  
Vol 91 (12) ◽  
pp. 4-9
Author(s):  
I E Chazova ◽  
S Yu Yarovoy ◽  
N M Danilov
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Kinase Inhibitors ◽  
Heart Defects ◽  
New Drugs ◽  
Receptor Antagonists ◽  
Phosphodiesterase Type 5 Inhibitors ◽  
Pulmonary Arterial ◽  
The Right

Pulmonary arterial hypertension (PAH) is a severe, disabling disease characterized by an increase pressure in the pulmonary artery (PA), an increase pressure in the right atrium, and a decrease of the cardiac output. It combines several diseases: idiopathic pulmonary hypertension, inherited pulmonary hypertension, PAH induced by medication and toxins, PAH associated with systemic diseases of connective tissue, HIV infection, portal hypertension, congenital heart defects, schistosomiasis. In the absence of treatment, PAH quickly leads to insufficiency of the right heart and premature death. An effective PAH therapy did not exist for a long time. However, in 1987 there was established a positive effect of taking large doses of calcium channel blockers in patients, who “responded” to their prescription in the short term, and in recently several groups of specific drugs have been developed and approved for the treatment of this pathology: prostacyclin analogues and prostacyclin receptors agonists, endothelin receptor antagonists, phosphodiesterase type 5 inhibitors and soluble guanylate cyclase stimulators. Modern studies of treatment of PAH are based on the latest data of the molecular transmission mechanisms of intracellular and intercellular signals, the action of hormones and tissue enzymes. The available results of these studies allow to suggest the inclusion to clinical guidelines several new drugs for the pathogenetic treatment of PAH in the near future: receptor tyrosine kinase inhibitors, Rho - kinase inhibitors, immunosuppressants and type 2 activin receptor agonists, protein kinase C inhibitors, aromatase inhibitors and estrogen receptor antagonists, poly-(ADP-ribose)-polymerase inhibitors and bromodomain protein 4, elastase inhibitors. Some of the drugs have already passed the III phase of clinical trials (imatinib), others are at the preclinical stage or at the I-II phase tests (olaparib, enzastaurin, elafin).

scholarly journals Algorithms for the diagnosis and treatment of idiopathic pulmonary arterial hypertension

HYPERTENSION ◽  
2021 ◽  
Vol 14 (5) ◽  
pp. 5-28
Author(s):  
Yu.M. Sirenko ◽  
G.D. Radchenko ◽  
I.O. Zhivilo ◽  
Yu.A. Botsyuk
Keyword(s):  
Surgical Treatment ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Heart Defects ◽  
Idiopathic Pulmonary Arterial Hypertension ◽  
Receptor Antagonists ◽  
Hemodynamic Assessment ◽  
Expert Center ◽  
Pulmonary Arterial ◽  
The Right

Background. Pulmonary hypertension (PH) is a hemodynamic and pathophysiological condition characteri-zed by an increase in the average pressure in the pulmonary artery > 20 mm Hg and is evaluated according to the data of the right heart catheterization (RHC). In most cases, PH is not an independent disease but is a manifestation of other diseases. Idiopathic pulmonary arterial hypertension (IPAH) is a diagnosis that it is established by excluding all other causes of PH (damage to the left heart, connective tissue diseases, HIV infection, lung diseases, portal hypertension, congenital heart defects, a history of pulmonary thromboembolism, etc.). In IPAH, the etiology of the disease is unknown. Pathogenesis and symptoms of PH. Vasoconstriction, microthrombosis, and vascular remodeling are the three main pathophysiological elements in PH. Symptoms of PH are non-specific: shortness of breath, rapid fatigue, chest pain during physical exertion, and sometimes syncopal states are observed. Decompensated patients have signs of right-sided heart failure (edemas, ascites, bloating, pulsation of the jugular veins). Diagnosis. The diagnostic algorithm for РH consists of two stages. The first one is located outside the expert сenter, and the second one is located directly in the PH expert center. When this disease is suspected and there are typical symptoms and signs, all patients undergo an echocardiographic examination. Then, under certain conditions (for example, the absence of the underlying cause of PH), the patient is referred to the PH expert center, where it is possible to conduct RHC. Evaluating the prognosis. Evaluation of patients with IPAH is necessary to improve disease control and transition from a higher risk to a lower one. Prognosis assessment is comprehensive and is determined based on clinical status, symptom progression, syncope, results of a 6-minute walk test and NT-proBNP, results of examination methods (cardiopulmonary exercise test, echocardiography or MRI of the heart, hemodynamic assessment). Treatment. The main objectives of IPAH treatment are reducing the severity of symptoms, slowing the progression of the disease, improving the quality and increasing the life expectancy of patients. First of all, these are general measures (physical activity, prevention and management of pregnancy), prevention of infectious diseases, social and psychological assistance, monitoring compliance with the regime, recommendations for travel/journey, maintenance therapy (oral anticoagulants, diuretics, digoxin, oxygen therapy). Patients with a positive vasoreactive test are prescribed with calcium channel blockers. In all other patients, specific PH therapy may include prostaglandins (inhaled, intravenous, and subcutaneous forms), prostacyclin receptor antagonists, endothelin receptor antagonists, phosphodiesterase-5 inhibitors, and soluble guanylate cyclase stimulants. Surgical treatment. One of the options for surgical treatment of IPAH is atrial septostomy — the creation of a perforation in the atrial septum. This leads to decompression of the right chambers of the heart and increases the preload on the left ventricle, which leads to an increase in cardiac output. In case of ineffectiveness of all the above methods of treatment and significant progression of the disease, patients are indicated for lung transplantation or heart — lung complex.

scholarly journals Pulmonary hypertension: reasonable selection of specific therapy

2018 ◽  
Vol 15 (1) ◽  
pp. 45-50
Author(s):  
N A Karoli ◽  
S I Sazhnova ◽  
A P Rebrov
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Structural Changes ◽  
Pulmonary Arteries ◽  
Endothelin Receptor Antagonists ◽  
Endothelin Receptor ◽  
Receptor Antagonists ◽  
Pulmonary Vasodilator ◽  
Pulmonary Arterial

Pulmonary hypertension is characterized with persistent increase in pulmonary vascular resistance leading to progressive worsening of right ventricular failure and death. The basis for pulmonary arterial hypertension is structural changes in pulmonary arteries and arterioles caused by endothelial dysfunction. Endothelin-1 is the main pathogenic trigger of pulmonary hypertension and potential target for therapeutic exposure. The efficacy of endothelin receptor antagonists is proved in various preclinical and clinical studies. In patients with pulmonary arterial hypertension, the efficacy of dual and selective endothelin receptor antagonists is comparable despite the varied activity against various receptors. Bosentan is the most widely used pulmonary vasodilator which improves exercise tolerance and decelerates disease progression.

scholarly journals Medication adherence, hospitalization, and healthcare resource utilization and costs in patients with pulmonary arterial hypertension treated with endothelin receptor antagonists or phosphodiesterase type-5 inhibitors

2020 ◽  
Vol 10 (1) ◽  
pp. 204589401988008 ◽  
Author(s):  
Robert P. Frantz ◽  
Jerrold W. Hill ◽  
Cassandra A. Lickert ◽  
Rolin L. Wade ◽  
Michele R. Cole ◽  
...  
Keyword(s):  
Medication Adherence ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Endothelin Receptor Antagonists ◽  
Endothelin Receptor ◽  
Receptor Antagonists ◽  
Phosphodiesterase Type 5 Inhibitors ◽  
Proportion Of Days Covered ◽  
Pulmonary Arterial ◽  
Phosphodiesterase Type

Adherence to therapy for pulmonary arterial hypertension is essential to optimize patient outcomes, but data on real-world adherence to different pulmonary arterial hypertension drug classes are limited. This retrospective database analysis evaluated relationships between adherence, hospitalization, and healthcare costs in pulmonary arterial hypertension patients treated with endothelin receptor antagonists or phosphodiesterase type-5 inhibitors. From the IQVIA Adjudicated Health Plan Database, patients with pulmonary arterial hypertension were identified based on diagnostic codes and prescriptions for endothelin receptor antagonists (ambrisentan, bosentan, macitentan) or phosphodiesterase type-5 inhibitors (sildenafil, tadalafil) approved for pulmonary arterial hypertension. Patients were assigned to the class of their most recently initiated (index) pulmonary arterial hypertension therapy between 1 January 2009 and 30 June 2015. Medication adherence was measured by proportion of days covered; patients with proportion of days covered ≥80% were considered adherent. The proportion of adherent patients was higher for endothelin receptor antagonists (571/755; 75.6%) than for phosphodiesterase type-5 inhibitors (970/1578; 61.5%; P < 0.0001). In both groups, hospitalizations declined as proportion of days covered increased. Among adherent patients, those on endothelin receptor antagonists had a significantly lower hospitalization rate than those on phosphodiesterase type-5 inhibitors (23.1% versus 28.5%, P = 0. 0218), fewer hospitalizations (mean (standard deviation) 0.4 (0.8) versus 0.5 (0.9); P = 0.02), and mean hospitalization costs during the six-month post-index ($9510 versus $15,726, P = 0.0318). Increasing adherence reduced hospitalization risk more for endothelin receptor antagonists than for phosphodiesterase type-5 inhibitors (hazard ratio 0.176 versus 0.549, P = 0.001). Rates and numbers of rehospitalizations within 30 days post-discharge were similar between groups. Mean total costs were higher with endothelin receptor antagonists than phosphodiesterase type-5 inhibitors in all patients ($91,328 versus $72,401, P = 0.0003) and in adherent patients ($88,867 versus $56,300, P < 0.0001), driven by higher drug costs.

scholarly journals Endothelin Receptor Antagonism: A New Era in the Treatment of Pulmonary Arterial Hypertension

2002 ◽  
Vol 1 (1) ◽  
pp. 13-17 ◽  
Author(s):  
Richard N. Channick ◽  
Lewis J. Rubin
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Endothelin Receptor Antagonists ◽  
Endothelin Receptor ◽  
Receptor Antagonists ◽  
Double Blind ◽  
Beneficial Effects ◽  
Endothelin System ◽  
Pulmonary Arterial

Abstract The endothelin system has been extensively studied over the last several years. It is clear that endothelin-1 (ET-1) is a key mediator in pulmonary vascular biology and physiology. Abnormal increases in ET-1 production and decreased pulmonary clearance appear to play a major pathogenetic and perpetuating role in the pulmonary hypertensive process, through their vasconstrictive, smooth muscle cell proliferative and profibrotic effects. The degree of overexpression of ET-1 may correlate with the severity of pulmonary hypertension (PH). Advances in understanding the role of ET-1 in pulmonary hypertension have driven the development of endothelin receptor antagonists. One such agent, bosentan (Tracleer), is FDA approved for pulmonary arterial hypertension. Bosentan was approved following two randomized, placebo-controlled, double-blind studies that both showed marked improvement in exercise capacity after treatment with bosentan. The beneficial effects of bosentan appear to be sustained in most patients followed for as long as 22 months. Other uses for endothelin receptor antagonists are being examined, such as in combination with epoprostenol (Flolan) or in pediatric PH patients.

scholarly journals PULMONARY HYPERTENSION IN RATS LIVING UNDER COMPRESSED AIR CONDITIONS

1934 ◽  
Vol 59 (2) ◽  
pp. 181-193 ◽  
Author(s):  
Granville A. Bennett ◽  
F. J. C. Smith
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Arterial Hypertension ◽  
Right Ventricle ◽  
Arterial Hypertension ◽  
Pulmonary Circulation ◽  
Barometric Pressure ◽  
Compressed Air ◽  
Perivascular Edema ◽  
Pulmonary Arterial ◽  
The Right

1. Pulmonary arterial hypertension was demonstrated in a series of rats that had been kept for 24–31 days in an environment of compressed air, having a barometric pressure of 3040 mm. Hg. The partial pressure of oxygen was 635 mm. Hg, which is equivalent to an 83.6 per cent oxygen mixture at normal barometric pressure. 2. Sclerosing changes in the pulmonary arterioles have been observed which precede the development of demonstrable hypertension in the pulmonary circulation. These vessels showed histological changes that were indicative of injury after 3 days of exposure. There was a thickening of the walls which stained more intensely with eosin, as well as marked perivascular edema and often a narrowing of the lumina. Progressive thickening, narrowing, and hyalinization of the pulmonary arterioles occurred later, after the disappearance of perivascular edema. These changes appeared very similar to the renal arterial lesions seen at autopsy in patients dying from malignant hypertension. 3. Pathological examination did not reveal significant or constant changes from normal in any organs except the lungs and heart. The blood vessels of the systemic circulation showed no pathological change. 4. The walls of the large pulmonary arteries increased in thickness rapidly after the 3rd day of exposure. This change was due to the progressive formation and condensation of fibrous tissue outside of the media and to a lesser extent to thickening of the alternate layers of elastic tissue and smooth muscle in the arterial wall. 5. Marked dilatation of the right ventricle and conus arteriosus as well as small areas of scar tissue formation in the right ventricle were present on prolonged exposure. A few hearts showed larger areas of fibrosis that were visible on macroscopic examination. 6. The systemic arterial blood pressure of a small series of rats exposed to compressed air for 38 days and examined 7 to 10 days after decompression was in each instance less than one-half the average normal pressure. 7. The findings in this study are consistent with the clinical and pathological signs of pulmonary hypertension in man. 8. The anatomical alterations observed in the alveolar units of the lungs were essentially the same as those previously described (1). 9. A method has been devised whereby pulmonary arterial hypertension, accompanied by important sclerotic changes in the arteries of the pulmonary circulation can be induced for investigation.

ID: 119: PATHOGENIC ROLES OF CALCIUM-SENSING RECEPTORS AND TRANSIENT RECEPTOR POTENTIAL CANONICAL CHANNELS 6 IN THE DEVELOPMENT AND PROGRESSION OF PULMONARY HYPERTENSION

2016 ◽  
Vol 64 (4) ◽  
pp. 967.3-968
Author(s):  
H TANG ◽  
Y Gu ◽  
SM Black ◽  
JG Garcia ◽  
A Makino ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Transient Receptor Potential ◽  
Acute Hypoxia ◽  
New Drugs ◽  
Calcium Sensing ◽  
Pulmonary Vasoconstriction ◽  
Pulmonary Arterial

RationalAn increase [Ca2+]cyt in pulmonary arterial smooth muscle cells (PASMC) is a major trigger for pulmonary vasoconstriction and a critical stimulation for PASMC proliferation and migration. We previously demonstrated that expression and function of calcium sensing receptors (CaSR) in PASMC from patients with idiopathic pulmonary arterial hypertension (IPAH) and animals with experimental pulmonary hypertension (PH) were greater than in PASMC from normal subjects and control animals. However, the mechanisms by which CaSR triggers Ca2+ influx in PASMC and the implication of CaSR in the development of PH remain elusive.ObjectiveTo test the hypothesis that CaSR functionally interacts with TRPC6 to regulate [Ca2+]cyt in PASMC in the development of pulmonary hypertension.Methods and ResultsDownregulation of CaSR or TRPC6 with siRNA inhibited Ca2+-induced [Ca2+]cyt increase in IPAH-PASMC (in which CaSR is upregulated), while overexpression of CaSR or TRPC6 enhanced Ca2+-induced [Ca2+]cyt increase in normal PASMC (in which CaSR expression level is low). The upregulated CaSR in IPAH-PASMC was also associated with enhanced Akt phosphorylation, while blockade of CaSR in IPAH-PASMC attenuated cell proliferation. In in vivo experiments, deletion of the CaSR gene in mice (casr−/−) significantly inhibited the development and progression of experimental PH and markedly attenuated acute hypoxia-induced pulmonary vasoconstriction.ConclusionsThese data indicate that functional interaction of upregulated CaSR and upregulated TRPC6 in PASMC from IPAH patients and animals with experimental PH may play an important role in the development and progression of sustained pulmonary vasoconstriction and pulmonary vascular remodeling. Blockade or downregulation of CaSR and/or TRPC6 with siRNA or miRNA may be a novel therapeutic strategy to develop new drugs for patients with pulmonary arterial hypertension.KeywordsG protein-coupled receptor; ionic ligand; hypoxia-induced pulmonary hypertension.

scholarly journals Riociguatas the first innovative guanylatecyclase stimulators class drugs for pulmonary arterial hypertension patients treatment

2013 ◽  
Vol 10 (4) ◽  
pp. 70-75
Author(s):  
I E Chazova ◽  
T V Martynyuk
Keyword(s):  
Single Dose ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
New Drugs ◽  
Phase Iii ◽  
Dose Titration ◽  
Endothelin Receptor Antagonists ◽  
Endothelin Receptor ◽  
Receptor Antagonists ◽  
Pulmonary Arterial

Pulmonary arterial hypertension (PAH) drug therapy including prostanoids, endothelin receptor antagonists, type 5 phosphodiesterase inhibitors, can improve the possibilities for treatment and control of this progressive and irreversible disease. The modern research vector aims at exploring the potential therapeutic targets, as at developing new drugs that can affect the previously set target. NO synthase production disturbance plays an important role in PAH pathogenesis; this is determined by the powerful vasodylative action, as well as by anti-inflammatory, anti-proliferative, and antiaggregatory effects. Riociguat is the first in a new class of soluble guanylatecyclase stimulators to have proved effective in phase II of clinical trials. In a randomized, double-blind, placebo-controlled phase III of PATENT-1 (Pulmonary Arterial Hypertension soluble Guanilatcyclase-Stimulator Trial) study, 443 patients with PAH symptoms were randomized to receive placebo of riociguat in a single dose of 2,5 mg (with a dose titration based on tolerability to 2,5 mg three times a day) or a dose of 1,5 mg (with a dose titration according to portability to 1,5 mg three times a day). The study included patients not previously treated with PAH-specific therapy or those who have already taken endothelin receptor antagonists or prostanoids (except for parenteral ones). The primary endpoint of the PATENT-1 study was the distance dynamics in the 6-minute walk test (D6MH) to 12th treatment week. Secondary endpoints were: the dynamics of pulmonary vascular resistance (PVR), the level of NT-proBNP, functional class (FC) (WHO), the change in the time to developing of clinical deterioration, dyspnea (Borg index), indicators of quality of life and safety. By the 12th riociguat treatment week D6MH hasincreased by an average of 30 m in the group treated with the maximum single dose of 2,5 mg, or has decreased by an average of 6m in the placebo group (difference between groups, 36 m, 95% confidence interval 20–52 m, p

scholarly journals Comparison of vectorcardiographic parameters with structural-functional state of the right ventricle in patients with pulmonary hypertension

2015 ◽  
Vol 12 (4) ◽  
pp. 57-60
Author(s):  
E V Blinova ◽  
T A Sakhnova ◽  
M A Saidova ◽  
A S Loskutova ◽  
G V Ryabykina ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Arterial Hypertension ◽  
Right Ventricle ◽  
Arterial Hypertension ◽  
Functional State ◽  
Longitudinal Strain ◽  
Echocardiographic Parameters ◽  
Pulmonary Arterial ◽  
Moderate Negative Correlation ◽  
The Right

Changes of the vectrocardiographic ventricular gradient (VG) in patients with pulmonary arterial hypertension (PAH) are indicative of right ventricular (RV) overload and may be used to assess its severity. The study aim was to evaluate interrelations between vectrocardiographic VG, spatial QRS-T angle and echocardiographic parameters of structural-functional state of the RV.The following parameters were assessed in 30 PAH patients: RV dimensions; tricuspid annular plane systolic excursion (TAPSE); RV fractional area change (FAC); RV peak systolic annular velocity (TDI-S’), and longitudinal strain (LS). VG and spatial QRS-T angle were calculated using the orthogonal leads derived from standard echocardiography.Spatial component VG-Y had moderate negative correlation with LS (r=-0.62; p

scholarly journals Potts Shunt in Children With Familial Primary Pulmonary Hypertension: A Case Report and Brief Literature Review

2021 ◽  
Vol 9 (3) ◽  
pp. 247-254
Author(s):  
Mahya Mobinikhaledi ◽  
◽  
Ali Arjmand Shabestari ◽  
Yazdan Ghandi ◽  
◽  
...  
Keyword(s):  
Heart Failure ◽  
Pulmonary Hypertension ◽  
Pulmonary Arterial Hypertension ◽  
Right Ventricle ◽  
Arterial Hypertension ◽  
Medical Treatment ◽  
Right Heart Failure ◽  
Right Heart ◽  
Pulmonary Arterial ◽  
The Right

Introduction: The primary concern about Familial Pulmonary Arterial Hypertension (FPAH) is the development of right heart failure, which ultimately leads to sudden death. Despite recent advances in pharmacological therapy, the mortality rate in children is still high, emphasizing the importance of novel treatments. Moreover, there is still no definitive treatment for children with severe pulmonary hypertension. The consequences of right heart failure led to the proposal of a surgical approach, the Potts shunt, to decompress the right ventricle, providing shunting of deoxygenated blood to lower extremities and improving overall cardiac output. This surgical technique creates an anastomosis between the left pulmonary artery and the descending aorta, providing a palliative treatment to off-load the right ventricle. Case Presentation: We report an 11-year-old girl with familial pulmonary arterial hypertension and right ventricular failure who benefited from a Potts shunt with good mid-term results. The patient was diagnosed at the age of 5 when she had a history of fainting and persistent syncope. The patient was under medical treatment therapy with bosentan, sildenafil, acetylsalicylic acid, and warfarin for six years. The results of molecular genetic testing, which was confirmed with direct sequencing of the Bone Morphogenetic Protein Receptor Type 2 (BMPR2) gene, revealed a heterozygous pathogenic mutation. Since she was diagnosed with Pulmonary Arterial Hypertension (PAH), she lost her grandmother, an aunt, and father because of PAH. Her 14-year-old sister also had mutated the BMPR2 gene without developing FPAH. Conclusions: The Potts shunt provides an interventional step for palliation of patients with familial pulmonary hypertension and severe right heart failure refractory to medical treatment. It opens the door to the possibility of lung transplantation in the future. We did not see any complications within 6 years after placing the Potts shunt.

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