Pulmonary Arterial Hypertension

Pulmonary hypertension is a syndrome characterized by marked remodeling of the pulmonary vasculature and a progressive increase in pulmonary vascular load, leading to hypertrophy and remodeling of the right ventricle. Death occurs from right ventricular failure if pulmonary hypertension is not treated.

Currently, pulmonary hypertension is defined hemodynamically by a mean pulmonary arterial pressure greater than 20 mm Hg at rest, measured by right heart catheterization.1

Precapillary pulmonary hypertension due to pulmonary vascular disease is further defined by an elevation in pulmonary vascular resistance of at least 3 Wood units (WU), in contrast to isolated postcapillary pulmonary hypertension , in which pulmonary vascular resistance is less than 3 WU and elevation of mean pulmonary arterial pressure is due to elevation of filling pressures on the left side of the heart.

The various forms of pulmonary hypertension are classified into five groups. This review focuses on the relatively rare form of pulmonary arterial hypertension ( group 1 ).

Tremendous progress has been made in gaining an understanding of the mechanisms, natural history, and genetic characteristics of pulmonary arterial hypertension and in establishing targeted therapy. A full appreciation of the pathophysiology of the syndrome is important, as diagnosis requires a thorough clinical investigation to rule out other, more common forms of pulmonary hypertension, for which treatment of the underlying disease should be the primary goal.

The first anatomical description of pulmonary hypertension is attributed to von Romberg.2 However, it was the advent of human right heart catheterization, first performed by Forssmann on himself in 1929,3 that led to a flurry of physiological observations on the heart. and pulmonary circulation by Cournand and Richards in the 1940s. The three researchers received the Nobel Prize in Physiology or Medicine in 1956 for their work. In his illuminating Nobel lecture, Richards noted that, as a result of his collective work, “many forms and degrees of failure were defined and their responses to treatment measured.”4

In 1951, Dresdale, a disciple of Cournand and Richards, and his colleagues presented the first case series of patients with pulmonary hypertension of unknown origin, defined as “primary pulmonary hypertension.”5 Increased awareness of the disease developed in the 1950s. 1960, after an epidemic of primary pulmonary hypertension that was associated with the use of the appetite suppressant aminorex.6 This led the World Health Organization to convene a first meeting of experts on hypertension in 1973, to standardize clinical nomenclature and pathological of primary pulmonary hypertension, the first attempt at an organized classification.7  

The first and second meetings on pulmonary hypertension were separated by 25 years, but thereafter the World Symposium on Pulmonary Hypertension (WSPH) was convened every 5 years. The meetings further refined the classification of pulmonary hypertension, with five distinct groups based on similar clinical and pathological findings and responses to treatment. Idiopathic pulmonary arterial hypertension has replaced the term primary pulmonary hypertension, in recognition of the hemodynamic and clinical similarities with other conditions that directly affect the pulmonary arterial vasculature and for which therapy is available.

The recognition that some people have a genetic predisposition to the disorder (familial pulmonary arterial hypertension) led to the discovery of mutations in the gene encoding the bone morphogenetic protein (BMP) receptor type 2 (BMPR2).8,9 Since the 80% of pulmonary arterial hypertension cases and up to 20% of sporadic cases have germline BMPR2 mutations, and since additional mutations were identified in several genes, the term familial pulmonary arterial hypertension was later changed to pulmonary arterial hypertension hereditary.

In the first two decades of this century, a flurry of new oral, injectable, and inhaled medications emerged, driven by growing interest in and understanding of pulmonary arterial hypertension. The development of these drugs continued and was based on several well-conducted, placebo-controlled studies.

The prevalence of pulmonary hypertension varies according to the WSPH group classification. Pulmonary arterial hypertension (group 1) affects 25 people (mostly women) per 1 million inhabitants per year in Western countries, with an annual incidence of 2 to 5 cases per million.10

The disease is more severe in older men,11 although it is less common in this population, who are more likely to have group 2 disease. For other groups in the pulmonary hypertension classification, prevalence varies depending on the cause and the status of the disease, but it is likely to be greatly underestimated worldwide.12

Many widespread diseases of the cardiopulmonary systems are complicated by pulmonary hypertension, which significantly increases morbidity and mortality. Due to the high prevalence of congenital heart disease worldwide, particularly in developing countries,13 it is estimated that there are 25 cases of pulmonary arterial hypertension associated with congenital heart disease per 1 million population worldwide.14

Valvular and left-sided heart disease are much more common,15,16 and more than 100 million people may have pulmonary hypertension due to left-sided heart disease (group 2) worldwide.

Similarly, pulmonary hypertension complicates chronic lung diseases, such as obstructive lung disease (global burden, >500 million cases) and interstitial lung disease (estimated incidence, 10 to 70%); prevalence increases among patients with advanced disease.14 Additionally, more than 140 million people live at high altitudes (above 2500 m),17 but the prevalence of pulmonary hypertension due to chronic hypoxia among people living at high altitude areas or people moving to such areas is unclear.

Additionally, pulmonary hypertension complicates highly prevalent viral infections (e.g., human immunodeficiency virus [HIV] infection) and parasitic diseases (e.g., schistosomiasis), as well as hemoglobinopathies such as sickle cell and thalassemia; Therefore, a large number of patients are affected in low- and middle-income areas of Africa, Asia, and South and Central America.18,19

Thus, it is estimated that 1% of the world’s population and up to 10% of people over 65 years of age have pulmonary hypertension.14 Furthermore, 80% of these people live in developing countries and, due to the prohibitive cost,20 lack of approved medications, or limited access to necessary medical and surgical support (for example, for the treatment of chronic thromboembolic pulmonary hypertension [group 4]), they are unlikely to receive treatment.12,14

The histological characteristics of pulmonary arterial hypertension are complex and variable due to the multiplicity of underlying diseases.

However, there are common pathological features of the disorder, such as remodeling of the three layers of the distal pulmonary vasculature, which involves uncontrolled growth of endothelial and smooth muscle cells and fibroblasts,22 and infiltration of inflammatory cells,23 which mainly affects to the precapillary vessels with a caliber of 50 to 500 μm. There is also extension of the smooth muscle cell layer to the typically non-muscularized distal capillaries.

Post-capillary vessels with similar venous remodeling may be involved in specific syndromes, such as pulmonary veno-occlusive diseases and pulmonary capillary hemangiomatosis, scleroderma-associated pulmonary arterial hypertension,24 chronic thromboembolic pulmonary hypertension25 and group 2 heart diseases in which vascular remodeling may begin. in the postcapillary compartment.26 In situ thrombosis affecting small muscular arteries has long been recognized22 to be due to platelet activation and loss of endothelial integrity.27

These changes result in luminal narrowing or complete obliteration of small vessels. Plexiform lesions, which may arise from anastomoses involving bronchial arteries or vasa vasorum that penetrate the wall structure of the pulmonary vessels,28 are common features of pulmonary arterial hypertension.

The events that lead to severe remodeling have not been clearly identified, although stress-induced endothelial dysfunction, hypoxia, autoimmune phenomena, viral infections, drugs and toxins, or genetic alterations may initiate the process of excess vasoconstriction, inflammation, and uncontrolled cell growth. .27

The findings of highly organized lymphoid follicles juxtaposed against pulmonary arterial hypertension lesions, infiltration of T and B lymphocytes,29 and circulating inflammatory markers that correlate with disease severity,30 combined with the fact that pulmonary arterial hypertension often complicates autoimmune or inflammatory diseases, have lent substantial credence to a role for inflammation in the pathogenesis of pulmonary arterial hypertension.23,31

Right ventricular function is the major determinant of clinical outcomes and survival among patients with pulmonary hypertension.32 In response to an increase in the resistance of the pulmonary vasculature by a factor of 5 to 10, the right ventricle undergoes hypertrophy, dilation, of the chamber, fat deposition, fibrosis, and metabolic changes as pulmonary hypertension progresses.32

Right ventricular remodeling can be adaptive, with concentric hypertrophy, preservation of myocardial microcirculation, and minimal fibrosis, or it can be maladaptive, with eccentric hypertrophy, microvascular rarefaction leading to an imbalance between oxygen demand and myocardial fibrosis.32 The mechanisms that lead to such changes, or the transition between these two states, remain poorly understood but may involve altered angiogenesis, a shift from glucose oxidation to glycolysis and fatty acid oxidation, and altered mitochondrial bioenergetics.33

Pressure-volume loop technology with a high-fidelity conductance catheter, the standard for assessment of intrinsic right ventricular myocardial function and right ventricular-pulmonary vascular coupling, is invasive and requires special expertise.32 The techniques non-invasive surrogates (echocardiography or cardiac magnetic resonance [MRI])34-36 remain to be validated against this standard, although they predict outcomes.34,37 The mechanisms of right ventricular dysfunction, the lack of treatments targeting the right ventricle, and the Remaining gaps in progress have recently been emphasized.32,38

Better right ventricular ejection fractions in women than in cardiovascular disease-free men39 have been attributed to differences in sex hormones40 and to sex-related responses to certain drugs (e.g., phosphodiesterase inhibitors and endothelin receptor antagonists). 41 However, further investigation is warranted.

The in vitro study of cardiomyocytes has provided great insight into intrinsic myocardial contractility, revealing a hypercontractile phenotype in patients with pulmonary arterial hypertension associated with idiopathic or congenital heart disease, 42 in marked contrast to a hypocontractile phenotype in patients with associated pulmonary arterial hypertension. to scleroderma.43 These results, in correlation with in vivo measurements of right ventricular contractility, may explain the worse clinical outcomes and shorter survival in the latter group. The molecular underpinnings of these phenotypes remain poorly studied.

An important advance occurred in 2000, when two independent groups8,9 described heterozygous mutations in BMPR2, a member of the transforming growth factor β (TGF-β) superfamily. This advance, combined with advances in genetic technology, such as whole-genome and whole-exome sequencing, has substantially advanced the understanding of the role that certain genes play in the pathogenesis of pulmonary arterial hypertension.

BMPR2 mutations are identified in approximately 80% of patients with familial pulmonary arterial hypertension, with variable penetrance between male and female carriers, and in up to 20% of patients with sporadic disease. This was quickly followed by the identification of mutations in ACVRL1 (activin A encoding receptor type II like 1 [also known as activin-like receptor kinase 1]) and ENG (endoglin encoding)44,45 in families with hereditary hemorrhagic telangiectasia, a syndrome that Sometimes it is complicated by pulmonary arterial hypertension. Both ACVRL1 and endoglin participate in BMPR-II signaling through dimerization.

Additional analyzes of large cohorts of patients with pulmonary arterial hypertension have identified additional mutations21 in genes encoding the transcription factors SMAD1, SMAD4 and SMAD9,46 part of the BMPR-II downstream signaling complex and other genes in families that are negative for BMPR2 mutations,47 including the gene encoding caveolin-1 (CAV1)48 (which serves to colocalize with BMP receptors) and the gene encoding K subfamily of potassium channels, member 3 (KCNK3),49 which is involved in the maintenance of membrane potential and pulmonary vascular tone.

Mutations in TBX4 (T-box encoding transcription factor 4), a gene associated with small patella syndrome,50 were detected in a number of children with intellectual disabilities and dystrophic features, in some of their parents, and in a small cohort of adults with pulmonary arterial hypertension.50 BMPR2 mutations predominate in large cohorts.

Other novel mutations involve ATP13A3 (encoding ATPase 13A3); SOX17, which encodes SRY-box 17 and is an important risk factor for pulmonary arterial hypertension associated with congenital heart disease)51; AQP1 (encoding aquaporin 1); and GDF2 (encoding growth differentiation factor 2, also known as BMP9).47

Biallelic mutations in EIF2AK4, which encodes eukaryotic translation initiation factor 2 alpha kinase 4, have been reported in hereditary pulmonary capillary hemangiomatosis 52 and pulmonary veno-occlusive disease 53 and in up to 25% of sporadic cases of these diseases. More recently, germline mutations of TET2, encoding the ten-eleven (tet) translocation of methylcytosine dioxygenase 2, a key enzyme in DNA demethylation, were reported in a large cohort of patients with pulmonary arterial hypertension.54

The role of altered BMPR-II signaling in the pathogenesis of pulmonary arterial hypertension cannot be overestimated. Most of the mutations discovered involve BMPR2 or genes that encode proteins that complex or interact with BMP or BMPR-II signaling. Functional loss of BMPR-II leads to endothelial dysfunction and the altered balance between proliferation and apoptosis that is characteristic of pulmonary arterial hypertension, explaining the growing interest in therapy aimed at increasing BMPR-II expression55 or ligand levels, as attempted in preclinical models of BMP9 delivery.56

Physicians have an ethical obligation to inform patients and their families about any genetic condition, particularly in the case of idiopathic or hereditary pulmonary arterial hypertension, pulmonary veno-occlusive disease or pulmonary capillary hemangiomatosis, and congenital pulmonary arterial hypertension associated with heart disease.

The implications for family members and their offspring who may be carriers of the mutation must be considered, along with screening, genetic and psychological counseling by a multidisciplinary team of experts, and patient education.57 Various technologies and affordable platforms to probe multiple genes simultaneously.

Genetic testing, which promises to further our understanding of the disease and improve therapy through targeted targeting, is a focus of several national collaborations and international studies58 and the National Institutes of Health-sponsored Pulmonary Vascular Disease Phenomics (PVDOMICS) initiative. ).59

> History and physical examination

The symptoms of pulmonary arterial hypertension are nonspecific (dyspnea on exertion, fatigue, chest pain and fluid retention, as well as syncope in advanced cases), which explains a substantially delayed diagnosis in many cases. The presence of an underlying disease, such as HIV infection or liver or connective tissue disease, or a history of exposure to drugs or toxins should raise the suspicion of pulmonary arterial hypertension.

A major diagnostic challenge is to rule out other forms of pulmonary hypertension for which management should focus primarily on the underlying disease, so it is important to consider risk factors or symptoms of left-sided heart disease or chronic lung disease.

Physical findings suggestive of pulmonary hypertension include an increased second lung sound, a murmur of tricuspid regurgitation, and evidence of right ventricular overload (eg, increased jugular venous pressure and foot edema). Other findings could suggest an underlying cause of pulmonary hypertension, including sequelae of chronic liver disease or rheumatologic disorders.

> Diagnostic tests

Transthoracic echocardiography (TTE), the single most important screening test, provides a set of measurements to measure the prevalence, cause, and severity of the disease. These measures include dilation of the right side chambers; presence and severity of tricuspid regurgitation, which allows estimating right ventricular systolic pressure; the presence of pericardial effusion; and abnormal septal deviation due to right ventricular volume and pressure. TTE can also identify left ventricular systolic or diastolic dysfunction and valvular abnormalities, findings that shift the focus toward group 2 pulmonary hypertension.

In addition to a complete blood count and metabolic panel, measurement of antinuclear antibody titers and HIV serologic testing may help uncover a specific underlying disorder, such as connective tissue disease or HIV disease, respectively. The serum N-terminal natriuretic peptide level, measured as a nonspecific biomarker of the heart, can be incorporated into risk stratification (see discussion below), as the value tracks the severity of pulmonary arterial hypertension and can be used to predict survival.61

A chest x-ray may suggest cardiac enlargement and dilated pulmonary arteries, as well as abnormalities of the lung parenchyma or chest wall. Chest computed tomography (CT) is routinely performed to rule out parenchymal disease. A ventilation-perfusion scan remains essential in the clinical algorithm, as normal perfusion makes chronic thromboembolic pulmonary hypertension (CTEPH) an unlikely diagnosis.

Chest CT angiography, although considered less sensitive than a ventilation-perfusion scan, may reveal signs of chronic thromboembolic disease such as filling defects or irregular linear or wedge-shaped opacities of previous thrombi. It also helps determine the surgical accessibility of lesions and can rule out other diagnoses (eg, pulmonary artery stenosis or tumor and fibrosing mediastinitis).

Pulmonary function tests may suggest obstructive or restrictive lung disease. The carbon monoxide diffusing capacity of the lungs in a single breath, which is normally decreased in pulmonary arterial hypertension, can be incorporated along with other clinical findings and TTE findings (right atrial enlargement and tricuspid regurgitation velocity), in an evidence-based algorithm to detect hypertension in asymptomatic patients with scleroderma spectrum diseases.62 An electrocardiogram is important to look for evidence of atrial or ventricular hypertrophy, signs of ischemic heart disease, or arrhythmias.

Cardiac MRI is the standard for right ventricular evaluation because it provides accurate measurements of cardiac chamber anatomy and volume, mass, function, and flow, as well as myocardial perfusion. 38 Not widely available, it is increasingly used in centers with experience in the diagnosis and management of pulmonary hypertension. Other advanced imaging techniques that remain in the field of research include three-dimensional echocardiography, four-dimensional flow magnetic resonance imaging, and positron emission tomography, which can provide unique insights into the metabolic activity of the right ventricle.63

> Hemodynamics

Right heart catheterization is required for the diagnosis of pulmonary arterial hypertension to directly assess pulmonary hemodynamics and cardiac output and estimate pulmonary vascular resistance. This is a necessary step in the diagnostic algorithm before treatment.

It is essential for confirmation of the presence and type of pulmonary hypertension (precapillary, postcapillary or combined) and provides essential measures for risk stratification. A structured clinical evaluation helps assign a patient to a specific pulmonary hypertension group, which is essential for determining appropriate therapy, although it is increasingly clear that any patient may belong to more than one group.

> Risk stratification

The importance of risk assessment was recognized early in the study of idiopathic pulmonary arterial hypertension, at which time the focus was essentially based on baseline hemodynamics.64 The 2015 European Society of Cardiology–European Respiratory Society (ESC) guidelines -ERS) for pulmonary hypertension65 highlighted as a growing priority the stratification of patients, at baseline and follow-up, into low, intermediate and high-risk groups based on a combination of clinical, functional and hemodynamic measures, as a tool for choosing therapy.

The ESC-ERS “risk table” and other risk scores (e.g., the REVEAL66 [Registry for Early Evaluation and Disease Management of Long-Term PAH] risk score calculator) have been successfully used to evaluate survival in retrospective analyzes of data from pulmonary arterial hypertension registries 67-69 and a post hoc analysis of data from a large prospective clinical trial.70

The predictive ability of stratification methods is enhanced by machine learning algorithms, which reveal a dynamic and interdependent influence of multiple risk factors, thus avoiding the assumption that limited clinical measures have independent relationships with a specific outcome.71

Basic supportive measures, a consistent component of treatment long before the availability of targeted therapy, include diuretics to achieve euvolemia and supplemental oxygen when needed at rest, during sleep, or with exercise to maintain adequate oxygen saturation. in hemoglobin. Disturbed breathing during sleep, which can complicate any form of cardiopulmonary disorder, is common among patients with precapillary pulmonary hypertension72 and should be diagnosed and treated when appropriate.

Anticoagulant therapy , once recommended based on retrospective analyzes showing a survival benefit,73,74 is now recommended only for idiopathic pulmonary arterial hypertension (not for other forms of pulmonary arterial hypertension, according to data from a European registry),75 analyzing on a case-by-case and risk-benefit basis and for group 4 pulmonary hypertension (CTEPH), in which increased clotting is a major issue.

 A cardiopulmonary exercise program is recommended based on a meta-analysis of controlled trials,76 depending on patient tolerance. Vaccines must be kept up to date.

Although four decades separated the initial clinical description of pulmonary hypertension and the approval of the first effective therapy for pulmonary arterial hypertension, based on a randomized, non-placebo-controlled trial of prostacyclin in patients with “primary pulmonary hypertension,”77 recent 20 years have seen a series of clinical trials aimed essentially at three signaling pathways identified in pulmonary arterial hypertension78. These trials established the current targeted therapy for pulmonary arterial hypertension (group 1) and CTEPH (group 4).

The findings do not apply to other groups in the WSPH classification, with the exception of inhaled treprostinil, which is now approved by the Food and Drug Administration (FDA) for pulmonary hypertension associated with interstitial lung disease (group 3) based on a recent phase 3 randomized clinical trial.79 An evaluation for CTEPH is best performed in specialized centers, where definitive therapy with pulmonary endarterectomy should be considered first. Medical therapy, balloon pulmonary angioplasty, or both are considered for patients with inoperable disease or residual pulmonary hypertension after endarterectomy.

There have been important changes in the design of randomized controlled trials (RCTs) over approximately the last decade. The 6-minute walk distance was the primary endpoint in most early RCTs, usually with a 12-week study period. However, in response to several calls to establish more relevant endpoints, 80 RCTs switched to composite endpoints, including a combination of hospitalization, worsening pulmonary arterial hypertension, mortality, and escalation of therapy.

Another important change in the design of the RCTs was an evaluation of new therapy added to background treatment for pulmonary arterial hypertension or combined upfront treatment instead of monotherapy. These changes required enrollment of many more patients and more time to reach the primary results. An example is SERAFÍN (Study with an Endothelin Receptor Antagonist in Pulmonary Arterial Hypertension to Improve Clinical Outcome), which revealed the effectiveness of macitentan, a dual endothelin receptor antagonist, in reducing the first appearance of a spot. composite primary endpoint in a study population of more than 700 patients with symptoms of pulmonary arterial hypertension who were receiving placebo or background therapy (inhaled or oral drugs, excluding other endothelin receptor antagonists).81

A subsequent RCT, the AMBITION (Ambrisentan and Tadalafil in Patients with Pulmonary Arterial Hypertension) trial, compared initial combination therapy with two FDA-approved medications (ambrisentan and tadalafil) with each drug alone in treatment-naïve patients for pulmonary arterial hypertension.82 The risk of the primary end point (the first clinical failure event in a time-to-event analysis) was reduced with combination therapy compared with monotherapy with either drug.

In these two large trials, however, the primary end point was predominantly driven by decreased hospitalization rates (essentially due to worsening pulmonary arterial hypertension), a clinically relevant outcome, since admission for right ventricular failure, main cause of hospitalization among patients with pulmonary arterial hypertension, portends a very poor prognosis.83

Despite the lack of an effect of oral combination therapy on survival in most of the most recent large RCTs, 81,82,84 a large meta-analysis of RCTs evaluating therapy for pulmonary arterial hypertension, with a mean of 12 to 16 weeks duration, showed a significant reduction in mortality with the therapy compared to placebo,85 which is consistent with data obtained from large registries.86,87

Treatment algorithms designed to guide therapy, with class and level of evidence recommendations for various approved therapies for pulmonary arterial hypertension, are available in comprehensive guidelines.65 Patients who have pulmonary vasoreactivity (typically to inhaled nitric oxide during initial catheterization right heart), based on strict criteria (a reduction in mean pulmonary arterial pressure of ≥10 mm Hg, to an absolute value of ≤ 40 mm Hg, accompanied by an increase or no change in cardiac output), can be treated with high-dose calcium channel blockers alone, provided that this therapy results in New York Heart Association (NYHA) functional class I or II with sustained hemodynamic improvement on repeat testing after at least 1 year of therapy1 (achieved in less than 10% of patients with idiopathic pulmonary arterial hypertension88).

In case of clinical deterioration or loss of vasoreactivity, specific therapy for pulmonary arterial hypertension should be added according to accepted algorithms.

Monotherapy can be used for patients with a positive response to acute vasoreactivity and those with a good historical response (NYHA functional class I or II with sustained hemodynamic improvement), elderly patients (>75 years of age) with significant risk factors for left heart disease (e.g., systemic hypertension, coronary artery disease, or atrial fibrillation), those suspected of having pulmonary veno-occlusive disease or pulmonary capillary hemangiomatosis, patients with very mild disease (functional class I of the NYHA and pulmonary vascular resistance of 3 to 4 WU, with normal right ventricular function on echocardiography), and patients in whom combination therapy is associated with an unacceptable side effect profile.60

Otherwise, most patients with pulmonary arterial hypertension are currently treated with initial combination therapy consisting of two oral agents, with dose escalation within a drug class when appropriate, or with sequential combination therapy. Referral for evaluation for lung transplantation is recommended when medical therapy fails to reduce the risk to a low or intermediate level. The role of upfront triple combination therapy in patients with pulmonary arterial hypertension remains unclear.

Atrial septostomy is occasionally considered in patients with end-stage pulmonary arterial hypertension or those awaiting a lung transplant. Atrial septostomy has the advantage of unloading the right atrium and right ventricle and delays right ventricular failure while improving left ventricular preload and cardiac output at the cost of reduced right-to-left oxygenation.

Increasingly sophisticated computational power, combined with advanced proteomic platforms89 or imaging,90 has led to machine learning techniques that can be used to develop promising and powerful diagnostic tools for pulmonary arterial hypertension.

The current trend of large-scale biomarker research and various other “-omics” (proteomics and genomics) should facilitate the characterization of mechanistic pathways (common or distinct) between pulmonary hypertension groups) in a completely agnostic fashion; The trend should also lead to precision medicine that takes into account genetic, environmental and lifestyle factors, a process similar to that which led to current cancer therapy.

However, to be successful, this will require strong collaborative efforts between centers, nationally and internationally, to create large registries (for clinical and imaging phenotyping) and biobanks of tissues, biomarkers, genetics and proteomics. This is particularly important in the case of a rare syndrome such as pulmonary arterial hypertension. A current realistic goal is to integrate a molecular classification into the current classification, as indicated by proteomics91 and genomic studies.59

Consistent with the notion that dysregulated immunity may trigger or contribute to the pathogenesis of pulmonary hypertension, clinical trials targeting specific immune pathways have recently been launched. Targeting B cells in scleroderma-associated pulmonary arterial hypertension appeared to benefit a subset of patients identified by machine learning analysis of biomarkers, suggesting a potential role as an adjuvant immunotherapy for this disease. 92

Similarly, targeting altered growth factor signaling continues to generate interest, despite the warning of the tyrosine kinase inhibitor imatinib, which showed encouraging results in a phase 2 trial but serious side effects (i.e., subdural hemorrhage ) in a phase 3 trial, preventing FDA approval of imatinib for the treatment of pulmonary arterial hypertension.93

Finally, a trial of the calcineurin inhibitor FK506,94 which was shown to upregulate BMPRII expression,55 is noteworthy, considering the importance of rescuing BMPR-II signaling to counteract proliferative and proinflammatory TGF pathways. -β.

Similarly, a recent phase 2 clinical trial showed that sotatercept (a first-in-class fusion protein designed to bind the TGF-β ligand activin) reduced pulmonary vascular resistance and serum levels of N-terminal B-type natriuretic peptide. and improved functional capacity in patients with pulmonary arterial hypertension who were receiving background therapy.95 This very promising new treatment is now being tested in phase 3 clinical trials.

The present review highlights the importance of considering pulmonary arterial hypertension in patients with nonspecific symptoms such as dyspnea, fatigue, chest pain and fluid retention, without another associated cause.

In turn, it is necessary to diagnose diseases that can cause pulmonary hypertension secondarily, such as infections and rheumatological diseases, which leads to other diagnostic and treatment approaches.

Early suspicion allows initial diagnostic tests such as transthoracic echocardiography to be performed and the patient to be assigned to a pulmonary hypertension group, which will allow treatment to begin before functional deterioration occurs, thus improving quality of life. On the other hand, it is essential to carry out genetic counseling for the patient and her family environment.