Basis Of Pulmonary Arterial Hypertension Research Articles

Molecular Pathways in Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension is a multifactorial, chronic disease process that leads to pulmonary arterial endothelial dysfunction and smooth muscular hypertrophy, resulting in impaired pliability and hemodynamics of the pulmonary vascular system, and consequent right ventricular dysfunction. Existing treatments target limited pathways with only modest improvement in disease morbidity, and little or no improvement in mortality. Ongoing research has focused on the molecular basis of pulmonary arterial hypertension and is going to be important in the discovery of new treatments and genetic pathways involved. This review focuses on the molecular pathogenesis of pulmonary arterial hypertension.

The physiological basis of pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a rare dyspnoea-fatigue syndrome caused by a progressive increase in pulmonary vascular resistance and eventual right ventricular (RV) failure. In spite of extensive pulmonary vascular remodelling, lung function in PAH is generally well preserved, with hyperventilation and increased physiological dead space, but minimal changes in lung mechanics and only mild to moderate hypoxaemia and hypocapnia. Hypoxaemia is mainly caused by a low mixed venous oxygen tension from a decreased cardiac output. Hypocapnia is mainly caused by an increased chemosensitivity. Exercise limitation in PAH is cardiovascular rather than ventilatory or muscular. The extent of pulmonary vascular disease in PAH is defined by multipoint pulmonary vascular pressure–flow relationships with a correction for haematocrit. Pulsatile pulmonary vascular pressure–flow relationships in PAH allow for the assessment of RV hydraulic load. This analysis is possible either in the frequency domain or in the time domain. The RV in PAH adapts to increased afterload by an increased contractility to preserve its coupling to the pulmonary circulation. When this homeometric mechanism is exhausted, the RV dilates to preserve flow output by an additional heterometric mechanism. Right heart failure is then diagnosed by imaging of increased right heart dimensions and clinical systemic congestion signs and symptoms. The coupling of the RV to the pulmonary circulation is assessed by the ratio of end-systolic to arterial elastances, but these measurements are difficult. Simplified estimates of RV–pulmonary artery coupling can be obtained by magnetic resonance or echocardiographic imaging of ejection fraction.

Genetic basis of pulmonary arterial hypertension: a prospective study from a highly inbred population.

Pulmonary arterial hypertension (PAH), whether idiopathic PAH (IPAH), heritable PAH, or associated with other conditions, is a rare and potentially lethal disease characterized by progressive vascular changes. To date, there is limited data on the genetic basis of PAH in the Arab region, and none from Saudi Arabian patients. This study aims to identify genetic variations and to evaluate the frequency of risk genes associated to PAH, in Saudi Arabian patients. Adult PAH patients, diagnosed with IPAH and pulmonary veno-occlusive disease, of Saudi Arabian origin, were enrolled in this study. Forty-eight patients were subjected to whole-exome sequencing, with screening of 26 genes suggested to be associated with the disease. The median age at diagnosis was 29.5 years of age, with females accounting for 89.5% of our cohort population. Overall, we identified variations in nine genes previously associated with PAH, in 16 patients. Fourteen of these variants have not been described before. Plausible deleterious variants in risk genes were identified in 33.3% (n = 16/48) of our entire cohort and 25% of these cases carried variants in BMPR2 (n = 4/16). Our results highlight the genetic etiology of PAH in Saudi Arabia patients and provides new insights for the genetic diagnosis of familial and IPAH as well as for the identification of the biological pathways of the disease. This will enable the development of new target therapeutic strategies, for a disease with a high rate of morbidity and mortality.

Bases Genéticas De La Hipertensión Arterial Pulmonar

Bases Genéticas De La Hipertensión Arterial Pulmonar

This Month in Anesthesiology.

This Month in Anesthesiology.

Emerging Concepts in the Molecular Basis of Pulmonary Arterial Hypertension: Part II: Neurohormonal Signaling Contributes to the Pulmonary Vascular and Right Ventricular Pathophenotype of Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is defined foremost by a distinct pulmonary vascular pathophenotype that occurs as a result of dysregulated vascular cell proliferation, intimal and medial hypertrophy, inflammation, and fibrosis. This plexogenic arteriopathy with subtotal luminal obliteration increases pulmonary vascular resistance and imposes a hemodynamic stress on the right ventricle (RV). The chronically increased afterload leads to RV hypertrophy and failure that contributes to premature death. Owing to the functional interrelatedness of the pulmonary vasculature and the RV, these 2 compartments are increasingly considered as a collective unit and assessed by examining RV-pulmonary arterial coupling in studies that focus on the pathophysiology of PAH.1 Ideal RV-pulmonary arterial coupling is present when contractility of the RV is sufficient to match the afterload imposed by the pulmonary artery, which is determined by its distensibility or compliance, and is recognized by minimal pressure fluctuation during systole.2 Optimal RV-pulmonary arterial coupling may be defined further based on the ratio of ventricular to arterial elastance, which typically achieves a ratio of 1.5:2.0 and reflects a balance between RV work and oxygen consumption.3 RV-pulmonary arterial uncoupling, therefore, occurs when there is a mismatch between RV contractility and pulmonary arterial compliance. Based on this premise, it is now acknowledged that factors that decrease normal pulmonary vascular compliance to increase resistance adversely affect RV-pulmonary arterial coupling kinetics. This results in a decline in ventricular efficiency and an increased probability of developing right-sided heart failure.4 Similarly, a decrease in RV contractility owing to RV cardiomyocyte dysfunction or impaired RV myocardial performance decreases RV tolerance to increased afterload and lowers the threshold at which pulmonary vascular disease may become clinically evident.5 Although PAH is a disease of pulmonary vascular origin with subsequent effects on the RV, the pathobiology and PAH disease severity may be subject …

Emerging Concepts in the Molecular Basis of Pulmonary Arterial Hypertension

Mitochondria are central to cellular metabolism. The mitochondria’s metabolic pathways include fatty acid oxidation, glucose oxidation and glutaminolysis. The initial step in glucose metabolism occurs in the cytosol, where glycolysis converts glucose to pyruvate1 (Figure 1). Figure 1 Mechanism of impaired glucose oxidation and enhanced aerobic glycolysis in PAH. Changes in redox signaling, such as downregulation of SOD2 and the resultant decrease in H2O2 signaling, can activate transcription factors (i.e. HIF-1α) which in ... Normally, glycolysis is coupled to glucose oxidation, meaning that the pyruvate is transported into the mitochondria where it serves as a substrate for pyruvate dehydrogenase (PDH)3. Under pathologic conditions, such as inhibition of PDH, glycolysis may be uncoupled from glucose oxidation and remain a wholly cytosolic reaction that terminates in the generation of lactate. Metabolism is quite plastic and the relative importance of each pathway can change in response to environmental stimuli, such as substrate availability, the organism’s developmental stage, and pathologic stimuli, such as hypoxia, shear stress, pressure overload, ischemia and hypertrophy. In addition, the activity of one metabolic pathway alters the activity of competing pathways. Examples of this metabolic crosstalk include the reciprocal relationship between fatty acid and glucose oxidation. Fatty acid oxidation suppresses glucose oxidation, through a mechanism called the Randle cycle (Figure 2), named after Phillip Randle who first described the phenomenon3. Another example of metabolic plasticity is the uncoupling of glycolysis from glucose oxidation, so called aerobic glycolysis. Aerobic glycolysis is also called the Warburg effect, in honor of Otto Warburg who first described the phenomenon in cancer cells5. Warburg noted that this shift to glycolysis contributed to the growth and survival advantage of cancer cells5. He also observed, but could not explain, accumulation of ammonia in his cancer tissue culture. Ultimately this proved to relate to a concomitant upregulation of glutaminolysis in cancer cells. Aerobic glycolysis results in a reliance on glycolysis to produce ATP despite the presence of sufficient oxygen to have allowed pyruvate generation and mitochondrial glucose oxidation. Aerobic glycolysis usually reflects active inhibition of one or more mitochondrial enzymes, notably inhibition of PDH by pyruvate dehydrogenase kinases (PDK). These acquired changes in metabolism alter the cell’s bioenergetics status, susceptibility to hypertrophy and fibrosis, rates of proliferation and apoptosis, angiogenesis and contractility. Importantly, the cell’s metabolic choices can be pharmacologically manipulated, offering the potential for metabolic therapies. Figure 2 Manipulating fatty acid and glucose oxidation in PAH: The Randle’s cycle. Randle’s cycle is the reciprocal relationship between glucose oxidation and fatty acid oxidation. Note how the acetyl CoA and citrate produced by β-oxidation ... In addition to generating adenosine triphosphate (ATP), mitochondria are constantly dividing and joining together6. These highly conserved and regulated processes are called fission and fusion, respectively7. These non-canonical mitochondrial functions (fission, fusion), as well as migration, are called mitochondrial dynamics.8 Mitochondrial dynamics are important in physiology, participating in oxygen sensing9 and the distribution of mitochondria to daughter cells during mitosis10. Mitochondrial dynamics are also involved in cellular quality control, notably participating in mitophagy and apoptosis. Acquired and inherited disorders of mitochondrial dynamics are involved in diseases, including pulmonary arterial hypertension (PAH), cancer, and cardiac ischemia reperfusion injury7. Both metabolic plasticity and mitochondrial dynamics are relevant to the pathogenesis of PAH and offer new therapeutic targets in the pulmonary vasculature and the right ventricle.

Accurate genetic diagnosis of Finnish pulmonary arterial hypertension patients using oligonucleotide-selective sequencing.

The genetic basis of pulmonary arterial hypertension (PAH) among Finnish PAH patients is poorly understood. We adopted a novel-targeted next-generation sequencing (NGS) approach called Oligonucleotide-Selective Sequencing (OS-Seq) and developed a custom data analysis and interpretation pipeline to identify pathogenic base substitutions, insertions, and deletions in seven genes associated with PAH (BMPR2, BMPR1B, ACVRL1, ENG, SMAD9, CAV1, and KCNK3) from Finnish PAH patients. This study represents the first clinical study with OS-Seq technology on patients suffering from a rare genetic disorder. We analyzed DNA samples from 21 Finnish PAH patients, whose BMPR2 and ACVRL1 mutation status had been previously studied using Sanger sequencing. Our sequencing panel covered 100% of the targeted base pairs with >15× sequencing depth. Pathogenic base substitutions were identified in the BMPR2 gene in 29% of the Finnish PAH cases. Two of the pathogenic variant-positive patients had been previously tested negative using Sanger sequencing. No clinically significant variants were identified in the six other PAH genes. Our study validates the use of targeted OS-Seq for genetic diagnostics of PAH and revealed pathogenic variants that had been previously missed using Sanger sequencing.

The genetic basis of pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a rare disease characterized by distinctive changes in pulmonary arterioles that lead to progressive elevation of pulmonary artery pressure, pulmonary vascular resistance, right ventricular failure, and a high mortality rate. The etiology of PAH is heterogeneous and incompletely understood. Based on clinical classification, WHO Group 1 PAH includes sporadic disease (idiopathic PAH), inherited PAH (heritable PAH), and association with certain medical conditions (associated PAH). Genes play an important role in idiopathic and heritable PAH. Mutations in bone morphogenetic protein receptor 2 (BMPR2), a member of the transforming growth factor β (TGFβ) superfamily of receptors, have been identified in 70% of cases of familial PAH, as well as in 10-40% of cases of idiopathic PAH. Mutations in ALK-1, ENG, SMAD4 and SMAD8, other TGFβ family members, are additional rare causes of PAH. CAV1 regulates SMAD2/3 phosphorylation, and mutations in CAV1 are a rare cause of PAH. KCNK3 is a member of the two-pore domain potassium channels expressed in pulmonary artery smooth muscle cells, and mutations in KCNK3 are a rare cause of both familial and IPAH. The genetics of PAH are complex due to incomplete penetrance and genetic heterogeneity. In addition to rare mutations as a monogenic cause of HPAH, common variants in cerebellin 2 (CBLN2) increase the risk of PAH by approximately twofold. PAH in children is much more heterogeneous than in adults and can be associated with several genetic syndromes, specifically syndromes with congenital heart disease, vascular disease, and hepatic disease. Clinical genetic testing is available for PAH and should be considered in families to allow for more definitive risk stratification and allow for reproductive planning.

Emerging therapies for the treatment of pulmonary hypertension

Current treatment of pulmonary arterial hypertension, which includes the use of prostacyclins, endothelin receptor antagonists, and phosphodiesterase type 5 inhibitors, either alone or in combination, often leads to improvements in functional capacity and modest decreases in pulmonary artery pressure. Disappointingly, however, two recent meta-analysis reviewing the controlled trials in pulmonary arterial hypertension, using these three agents, demonstrated little or no increase in survival. Importantly, however, increasing knowledge of the cellular and molecular basis of pulmonary arterial hypertension has led to the development of new agents aimed at either reversing sustained vasoconstriction or stopping/reversing the abnormal cell and extracellular matrix accumulation that, in combination, obstruct pulmonary blood flow and ultimately cause right heart failure. Rho kinase inhibitors, vasodilator peptides (such as vasoactive intestinal peptide and adrenomedullin), and endothelial nitric oxide synthase coupling agents (cicletanine) have been shown sometimes to exert potent pulmonary vasodilatory effects in animal models and in pilot studies in humans. Tyrosine kinase inhibitors (platelet-derived growth factor and epidermal growth factor receptor inhibitors), multikinase inhibitors (tyrosine kinase and serine/threonine kinase), elastase inhibitors, metabolic modulators (e.g., dichloroacetate), survivin inhibitors, and HMG-COA reductase inhibitors have been shown to reverse pulmonary hypertension in rodent models of pulmonary hypertension through inhibition of cell proliferation and induction of apoptosis. Early success in human pulmonary arterial hypertension with tyrosine kinase inhibitors has appeared in case reports. Furthermore, anti-inflammatory/immunomodulatory agents (thiazolidinedinones, rapamycin, cyclosporine, and STAT3 inhibitors) have been demonstrated to be effective at reducing vascular remodeling in animal models. Collectively, these studies are exciting and open potential new avenues for treatment. Caution should be exercised, however, as many agents, which are successful at preventing or reversing pulmonary arterial hypertension in currently used animal models, do not result in similar long-term success in the treatment of human pulmonary arterial hypertension.

Prevalence and Predictors of Pulmonary Arterial Hypertension in Hemoglobin E/ β-Thalassemia Patients.

Abstract 2015Poster Board I-1037 Introduction:Pulmonary arterial hypertension (PAH) associated with thalassemia (Thal) hemoglobinopathy is now an accepted clinical entity. Most of the reports are in sickle cell disease and splenectomized β-Thal patients. Once manifested, it connotes poor prognosis. We herein present its prevalence and predictors in hemoglobin E/β-Thal (E/β-Thal) patients. Patients and Methods:One hundred and ten clinically stable E/β-Thal outpatients, on no medication aside from folic acid and who received no blood transfusion in the preceding 4 weeks were studied. All gave written informed consent, and study protocol was approved by the institution ethics committee on studies in humans (#0774/2548). Echocardiogram was used to estimate systolic PA pressure (SPAP). PAH was defined as an estimated SPAP ≥36 mmHg. Clinical features and laboratory data were stratified according to the presence or absence of PAH, and statistical analysis was done by STATA version 10 (Stata Corp, Texas), considering a P value <0.05 as statistically significant. Predictors of PAH were considered in univariate analysis. Results:There were 110 patients, 56 of whom were female and 61 were asplenic. PAH was present in 41 patients (37.3%), all of whom had normal left ventricular ejection fraction. There was no gender difference between the 2 groups (p=0.055). Selected statistically significant results are shown in the table.ResultsWith PAH (41 Patients)Without PAH (69 Patients)P valueAge at 1st transfusion (median)6 years11.25 years0.03Total transfusions (median)37 units PRBC15 units PRBC0.04Splenectomy78%42%<0.001Cardiomegaly52.5%32.3%0.042Extramedullary hematopoiesis56.4%30.6%0.01RBC count3.24 +/- 0.93 × 106/μL3.65 +/- 0.9 × 106/μL0.034Corrected reticulocyte count (median)4%1.7%0.02Nucleated RBC (median)530/100 WBCs15.5/100 WBCs<0.001Corrected WBC count9.34 +/- 4 × 103/μL7.8 +/- 3.5 × 103/μL0.036Platelet count627.7 +/- 313.2 × 103/μL436 +/- 267.4 × 103/μL0.001Globulin4.4 +/- 1.2 g/dL3.8 +/-0.8 g/dL0.002LDH323.3 +/- 117.2 u/L243.3 +/- 85.6 u/L<0.001Free hemoglobin (median)4.42 mg/dL2.7 mg/dL0.001C-reactive protein (high sens) (median)2.9 mg/L1.3 mg/L0.008Soluble VCAM-11,896.1 +/- 553.5 ng/mL1,463 +/- 622 ng/mL0.004NT pro BNP11.7 pmol/L6.2 pmol/L0.026 Conclusions:Prevalence of PAH in E/β-Thal patients is 37.3% without gender preponderance. Predictors are asplenia, more severe hemolysis, higher number of circulating (activated) platelets and nucleated RBCs, increased chronic low grade inflammation and increased cellular adhesion between blood and endothelial cells. These changes could facilitate development of thrombotic pulmonary arteriopathy, the underlying basis of PAH. Serum NT pro BNP assay can be utilized as a predictor or a screener of PAH in these patients. Disclosures:No relevant conflicts of interest to declare.

Pulmonary Arterial Hypertension: An Overview

Pulmonary arterial hypertension (PAH) was first described over 100 years ago, but a thorough understanding of its patho-genesis and a successful approach to curing the disease remain elusive. Increased research activity has greatly enhanced our understanding of the disease and led to new therapies that retard disease progression and improve patient function and survival. The disease is rare, but effects people of all ages and is associated with several seemingly unconnected diseases. It is not clear whether all forms of PAH represent the same disease or the same pathologic endpoint of different pulmonary vascular disease processes. Recent attempts to classify different forms of pulmonary hyper-tension by the diseases with which they are associated has helped researchers organize data collected from patient registries and clinical trials. This overview discusses the history, epidemiology, and genetic basis of PAH, new recommendations for disease classification, and prognostic variables shown to adversely affect survival.