• Latent pulmonary hypertension corresponds to grade I PAH, according to the classification proposed by the World Health Organization [13]. Those patients may merely show symptoms associated with the respective primary disease, and the latter is often underestimated. Unfortunately, diagnostic delays may allow for PAH progression to irreversible states even if the underlying disorder is curable. It should thus be seriously considered that patients presenting with any of the above mentioned causative diseases may develop PAH.
• As the disease progresses, symptoms of right heart insufficiency manifest. Patients suffering from grade II PAH claim reduced performance due to onset of dyspnea and possibly syncopes under heavy exertion. Chest pain and palpitations may be noted.
• Moderate, grade III PAH is characterized by similar symptoms, which are experienced even under light exercise. Patients may frequently feel dizzy and suffer from repeated syncopes.
• Grade IV PAH is the most advanced stage of the disease. Patients note symptoms of right heart failure at rest. Generalized cyanosis and peripheral edema are commonly observed.

• Fatigue

  Less than ordinary activity causes undue dyspnea or fatigue, chest pain, or near syncope. WHO Class IV - Patients with pulmonary hypertension with inability to carry out any physical activity without symptoms. [bluelipsfoundation.org]

  We report a case of a 60-year-old white Brazilian man, with controlled hypertension and stage 2 obesity who complained of progressive fatigue with moderate to light exertion of approximately 1 year's duration. [ncbi.nlm.nih.gov]

  Other symptoms that may be present include: Dizziness Fatigue Swelling around the ankles and feet Fainting Tightening feeling in the chest [aoporphan.com]

• Inflammation

  Extensive granulomatous inflammation was seen in the resected lungs. The granulomatous inflammation found in the histology supports a sarcoid-like reaction due to pulmonary hypertension in the context of the BMPR2 mutation. [ncbi.nlm.nih.gov]

  Changes in 6MWD were associated with improvements in metabolic parameters, including mean weight loss of 3 kg relative to placebo and reductions in creatine kinase, a marker of muscle inflammation. [reatapharma.com]

  Furthermore, CO has been demonstrated to exert key physiological and protective functions in various models of tissue inflammation and injury. This study will evaluate the safety and potential efficacy of inhaled CO in subjects with severe PAH. [clinicaltrials.gov]

• Weakness

  Some symptoms include chest pain, weakness, shortness of breath, and fatigue. The goal of treatment is control of the symptoms, although the disease usually develops into congestive heart failure. [mountsinai.org]

  Over time, the heart muscle gets weak. It can become enlarged and stop working properly. When your blood doesn’t flow well, your body doesn’t get enough oxygen. Symptoms Many people have PAH for a long time before they realize something is wrong. [webmd.com]

  The strain on the heart causes the heart to become enlarged and weak. Eventually the heart fails to keep up with the body’s demands. This is known as heart failure. [nationwidechildrens.org]

  Severe shortness of breath is the most frequent initial symptom and can lead to fatigue, weakness, chest pains, dizziness, and fainting. [pulmonaryhypertensionnews.com]

  Heart failure occurs when the heart becomes too weak to pump enough blood to the lungs. [heart.org]

• Weight Loss

  Within 1 month of the procedure, before significant weight loss, right ventricular function improved by echocardiography ( Fig. 1 ). [care.diabetesjournals.org]

  Examples include: Aminorex Certain weight loss drugs Toxic rapeseed oil Testing There are many tests the doctor may want to use. For an accurate diagnosis, certain tests may rule out other conditions or confirm PAH. [nationwidechildrens.org]

  The medication most famous for causing PAH is fen-phen (fenfluramine and phentermine), a weight loss drug that was popular in the 1960s and 1970s but is no longer on the market. [jnj.com]

  Changes in 6MWD were associated with improvements in metabolic parameters, including mean weight loss of 3 kg relative to placebo and reductions in creatine kinase, a marker of muscle inflammation. [reatapharma.com]

• Chest Discomfort

  A 51-year-old female patient with a recent hospital admission reported to the emergency room (ER) with progressive worsening of fatigue, dyspnoea and chest discomfort. [ncbi.nlm.nih.gov]

  Eventually dizziness leads to syncope, an ominous sign of low cardiac output, and minimal exertion causes chest discomfort secondary to RV ischemia. [clinicaladvisor.com]

  Some of the most common symptoms include: shortness of breath during physical or normal activities feeling tired at all times or chronic fatigue dizziness especially when climbing stairs or prolonged standing up chest discomfort palpitations syncope swollen [nhcs.com.sg]

  General considerations Symptoms with no overt explanation: If a patient presents with symptoms, signs or history suggestive of pulmonary hypertension such as exertional dyspnea and easy fatigability, atypical chest discomfort and exertional light-headedness [escardio.org]

  Symptoms are fatigue, exertional dyspnea, and, occasionally, chest discomfort and syncope. Diagnosis is made by finding elevated pulmonary artery pressure (estimated by echocardiography and confirmed by right heart catheterization). [msdmanuals.com]

• Dyspnea

  History revealed that the dyspnea began with the initiation of 4-AP. [ncbi.nlm.nih.gov]

  Less than ordinary activity causes undue dyspnea or fatigue, chest pain, or near syncope. WHO Class IV - Patients with pulmonary hypertension with inability to carry out any physical activity without symptoms. [bluelipsfoundation.org]

• Cough

  COVID-19 is primarily spread via respiratory droplets when people cough or sneeze. Normally, symptoms of COVID-19 begin 2 to 14 days after exposure. [aoporphan.com]

  Other symptoms may include dizziness, fatigue, inability to exercise, chronic cough, fast heart rate, shortness of breath or swollen legs. [sleepdrs.com]

  Symptoms of PH may include: Breathlessness Chest pain (also called angina pectoris) Dizziness Fainting (also called syncope) Loss of energy Swelling of the arms, legs, ankles or abdomen (also called edema) Dry cough Raynaud’s phenomenon (chalky white [phassociation.org]

  The early symptoms are: Shortness of breath during normal physical activity Fatigue Chest pains A racing heartbeat As the disease gets worse, you may also have: Lightheadedness Fainting Swelling in your legs, hands, or belly Dry cough, sometimes with [webmd.com]

• Hemoptysis

  This is a case report of diffuse PAVF in a patient with PAH.This case report describes a patient with recurrent hemoptysis and chest pain. Systemic examination was unremarkable except for P2 attenuation on auscultation. [ncbi.nlm.nih.gov]

  Hemoptysis has also been reported. [orpha.net]

• Exertional Dyspnea

  Abstract A 17-year-old Japanese girl visited our hospital for an evaluation of exertional dyspnea. A diagnosis of pulmonary arterial hypertension (PAH) was confirmed based on the findings of right heart catheterization. [ncbi.nlm.nih.gov]

  Right ventricular failure limits cardiac output during exertion. Symptoms and Signs Progressive exertional dyspnea and easy fatigability occur in almost all patients. [msdmanuals.com]

  S, age 36, complains of progressive dyspnea on exertion that has been present for six months. Initially her dyspnea was mild, occurring only when walking up a flight of stairs. [clinicaladvisor.com]

  General considerations Symptoms with no overt explanation: If a patient presents with symptoms, signs or history suggestive of pulmonary hypertension such as exertional dyspnea and easy fatigability, atypical chest discomfort and exertional light-headedness [escardio.org]

• Hoarseness

  Cough, hemoptysis, and hoarseness are less common symptoms. Women are more likely to be symptomatic than men. Physical Examination Physical findings in persons with PAH can be quite variable. [emedicine.medscape.com]

  Affected individuals may also have a cough, sometimes with blood (hemoptysis), an enlarged heart and liver, low blood pressure (hypotension), and hoarseness due to compression of a nerve in the chest by an enlarged pulmonary artery. [rarediseases.org]

• Nausea

  Adverse events during the transitions were headache, nausea, vomiting, diarrhea, and jaw pain. [ncbi.nlm.nih.gov]

  If you take too much VENTAVIS, you may have a headache, red face, dizziness, nausea, vomiting and diarrhea. If this happens stop taking VENTAVIS. If your symptoms do not go away, call your doctor or get emergency help right away. [4ventavis.com]

  Other side effects may include headache, diarrhea, nausea, rash, jaw pain, vasodilatation, dizziness, edema (swelling), pruritus (itching), and hypotension. [en.wikipedia.org]

  Adverse events include headache, nausea, diarrhea, and jaw pain. Oral treprostinil, like all prostacyclin analogs, inhibits platelet aggregation and may increase bleeding risk, particularly in patients receiving oral anticoagulants. [uscjournal.com]

• Vomiting

  Adverse events during the transitions were headache, nausea, vomiting, diarrhea, and jaw pain. [ncbi.nlm.nih.gov]

  If you take too much VENTAVIS, you may have a headache, red face, dizziness, nausea, vomiting and diarrhea. If this happens stop taking VENTAVIS. If your symptoms do not go away, call your doctor or get emergency help right away. [4ventavis.com]

  You are vomiting and cannot eat or drink. You are confused or feel like you are going to faint. You have chest pain or heart palpitations (strong, fast heartbeats). Care Agreement You have the right to help plan your care. [drugs.com]

  Reactions The most common adverse reactions occurring more frequently (>/=3%) on Adempas than placebo were headache (27% vs 18%), dyspepsia/gastritis (21% vs. 8%), dizziness (20% vs 13%), nausea (14% vs 11%), diarrhea (12% vs 8%), hypotension (10% vs 4%), vomiting [prnewswire.com]

• Heart Failure

  Idiopathic pulmonary arterial hypertension is defined as a group of diseases characterized by a progressive increase in pulmonary vascular resistance that results in right heart failure and premature death. [ncbi.nlm.nih.gov]

• Chest Pain

  Less than ordinary activity causes undue dyspnea or fatigue, chest pain, or near syncope. WHO Class IV - Patients with pulmonary hypertension with inability to carry out any physical activity without symptoms. [bluelipsfoundation.org]

  This is a case report of diffuse PAVF in a patient with PAH.This case report describes a patient with recurrent hemoptysis and chest pain. Systemic examination was unremarkable except for P2 attenuation on auscultation. [ncbi.nlm.nih.gov]

  Symptoms include shortness of breath, extreme fatigue, dizziness, fainting, swollen ankles and legs and chest pain (especially during physical activity). [news-medical.net]

  Symptoms The symptoms of Pulmonary arterial hypertension are: Syncope with exertion Shortness of breath with exertion Fatigue Ankle edema Chest pain Auscultatory Signs of PAH The signs of Pulmonary Arterial Hypertension are heard at the following auscultatory [practicalclinicalskills.com]

  Other symptoms include: Ankle and leg swelling Bluish color of the lips or skin ( cyanosis ) Chest pain or pressure, usually in the front of the chest Dizziness or fainting spells Fatigue Increased abdomen size Weakness People with pulmonary hypertension [mountsinai.org]

• Palpitations

  We herein report the first case of AS associated PAH in a 27-year-old Taiwanese man with a chief complaint of intermittent palpitations lasting for two years. [ncbi.nlm.nih.gov]

  This in turn can cause symptoms such as shortness of breath, fatigue, dizziness, fainting, heart palpitations, and chest pain. Among those diagnosed with PAH, heart failure is the leading cause of death. [uabmedicine.org]

  […] of more common conditions, including: Chest Pain Dizziness Shortness of Breath Fatigue Edema or swelling Cyanosis or skin discoloration As the disease progresses, these symptoms may become more severe and be accompanied by an increased pulse, heart palpitations [bluelipsfoundation.org]

  Initial symptoms include dyspnea, syncope, chest pain, palpitations and pedal edema. [orpha.net]

  PAH is a chronic and progressive disease in which the arteries that supply blood to the lungs are constricted, resulting in symptoms such as shortness of breath, heart palpitations, fatigue and others. [sciencedaily.com]

• Cyanosis

  The symptoms most often associated with PAH mirror those of more common conditions, including: Chest Pain Dizziness Shortness of Breath Fatigue Edema or swelling Cyanosis or skin discoloration As the disease progresses, these symptoms may become more [bluelipsfoundation.org]

  This condition is called cyanosis. Increased pressure in the heart makes the heart’s muscles work harder than they should. Over time, these muscles grow weaker. A weakened heart can’t beat as well or as regularly as it once did. [healthline.com]

  In its advanced stages, severe PAH can lead to right heart failure, due to the increased workload that the heart is under, and cyanosis, or a bluish tinge to the skin due to abnormally low levels of oxygen. [pulmonaryhypertensionnews.com]

  Other symptoms include: Ankle and leg swelling Bluish color of the lips or skin ( cyanosis ) Chest pain or pressure, usually in the front of the chest Dizziness or fainting spells Fatigue Increased abdomen size Weakness People with pulmonary hypertension [mountsinai.org]

• Hypotension

  Hypotension. Adempas reduces blood pressure. [prnewswire.com]

  Importantly, use of riociguat with phosphodiesterase-5 inhibitors and nitrates is contraindicated due to the additive risk of hypotension. [uscjournal.com]

  The most common adverse events included syncope, headache, dyspepsia, peripheral edema, and hypotension. Cases of hemoptysis have also been reported. Concomitant use of riociguat and PDE-5 inhibitors is contraindicated due to hypotension. [content.onlinejacc.org]

  Common side effects: In clinical studies, common adverse reactions due to inhaled iloprost included: vasodilation (flushing, 27%), cough (39%), headache (30%), flu syndrome (14%), nausea (13%), neck spasms (12%), hypotension (11%), insomnia (8%), and [en.wikipedia.org]

• Hepatomegaly

  Jugular venous distension and hepatomegaly occur with heart failure, sometimes causing a pulsatile liver later in the disease state. Edema and ascites are commonly seen in this patient population, prompting the use of diuretics. [clinicaladvisor.com]

  […] large V waves are often present because of the commonly present severe tricuspid regurgitation, and large a waves thought to be secondary to poor right ventricular compliance may also be present. [16] Right-sided S3 gallop Other findings may include hepatomegaly [emedicine.medscape.com]

  Edema may present as jugular vein distension, hepatomegaly, peripheral edema, or ascites. 6 DIAGNOSTIC TESTING Diagnostic testing options for PAH are listed in Table 3. 6 Electrocardiography (ECG) may show right ventricular hypertrophy and right axis [aafp.org]

• Pulsatile Liver

  Jugular venous distension and hepatomegaly occur with heart failure, sometimes causing a pulsatile liver later in the disease state. Edema and ascites are commonly seen in this patient population, prompting the use of diuretics. [clinicaladvisor.com]

• Dizziness

  Shortness of breath, dizziness, and chest pressure are common symptoms of PAH. Other symptoms may include dizziness, fatigue, inability to exercise, chronic cough, fast heart rate, shortness of breath or swollen legs. [sleepdrs.com]

  Do not drive a car or operate any tools or machines if dizziness or fainting from low blood pressure is a problem for you. [4ventavis.com]

  Symptoms include shortness of breath, extreme fatigue, dizziness, fainting, swollen ankles and legs and chest pain (especially during physical activity). [news-medical.net]

  Other symptoms that may be present include: Dizziness Fatigue Swelling around the ankles and feet Fainting Tightening feeling in the chest [aoporphan.com]

  This symptom is seen in patients with pulmonary arterial hypertension, a rare disease that causes fatigue, dizziness, and shortness of breath because the blood vessels that supply the lungs narrow, forcing the heart to work harder to push blood through [clinicaltrials.gov]

• Lethargy

  Signs and Symptoms Infants and Young Children Poor growth Poor appetite Raid breathing Respiratory distress Lethargy (drowsiness) Blue colored lips or skin Older Children, Adolescents and Adults Difficulty laying flat Swelling of ankles or legs Difficulty [nationwidechildrens.org]

  The most common symptoms and their frequency, reported in a national prospective study, are as follows: Dyspnea (60% of patients) Weakness (19%) Recurrent syncope (13%) Additional symptoms include fatigue, lethargy, anorexia, chest pain, and right upper [emedicine.medscape.com]

  Pulmonary hypertension symptoms may include: Shortness of breath that worsens with activity Other common complaints are cough, fatigue, dizziness, and lethargy. [medicinenet.com]

Workup of a clinical presentation consistent with PAH is generally initiated by the following examinations [14]:

• Thorough anamnesis and general examination. A family history of IPAH, a medical history of diseases potentially leading to SPAH, and clinical findings implying right heart failure strongly support a tentative diagnosis of PAH. With regards to auscultation, systolic murmurs indicating tricuspid regurgitation may be heard in mild to moderate PAH, whereas diastolic murmurs due to pulmonary valve insufficiency reveals compromise of the right atrium in more severe cases.
• Radiographic images of the thorax may be obtained to assess the condition of lungs and heart. Frequent findings are pulmonary arterial dilatation as well as enlargement of the right atrium and ventricle. Even though images may be normal, radiography generally allows to rule out left heart disease.
• Electrocardiography may reveal right axis deviation indicating right ventricular hypertrophy.

Neither of the aforementioned results is specific for PAH, though, and a definite diagnosis cannot be made without determination of the pulmonary arterial pressure. Transthoracic Doppler echocardiography and right heart catheterization may be conducted to this end, with the former yielding less precise results but being less invasive. Right atrial and ventricular enlargement as well as an increased tricuspid regurgitation are additional, common echocardiographic findings.

If PAH is confirmed, clinical tests should be conducted to evaluate the severity of the disease. Pulmonary function tests and the ascertainment of the maximum walking distance within six minutes are often carried out and yield comparable parameters.

Of note, additional measures are usually required to distinguish IPAH from SPAH. These may comprise laboratory analyses of blood samples, lung biopsy and abdominal sonography, among others, and aim at diagnosing or ruling out those primary diseases mentioned above.

• Pulmonary Arterial Pressure Increased

  Practice Essentials Idiopathic pulmonary arterial hypertension (IPAH) is a rare disease characterized by elevated pulmonary artery pressure with no apparent cause. [emedicine.medscape.com]

• Prominent A-Wave

  The jugular venous pulse tracing demonstrates a prominent a wave without a c or v wave being observed. The phonocardiograms (fourth left interspace and cardiac apex) show a murmur of tricuspid insufficiency and ventricular and atrial gallops. [en.wikipedia.org]

  Physical examination findings sometimes observed in PH and right ventricular (RV) dysfunction include: an elevated jugular venous pressure with prominent A waves (due to increased RV stiffness) and V waves (due to tricuspid regurgitation [TR]); Kussmaul [content.onlinejacc.org]

• Pleural Effusion

  After treatment with dasatinib he had multiple pleural effusions which were suspected to be caused by congestive heart failure. [ncbi.nlm.nih.gov]

  Complications Complications of IPAH include the following: Advanced right-sided heart failure with hepatic congestion Pedal edema Pleural effusions Ascites Worsening dyspnea upon exertion [Guideline] Badesch DB, Abman SH, Ahearn GS, Barst RJ, McCrory [emedicine.medscape.com]

  The characteristic CT features of pulmonary venous hypertension are interlobular septal thickening, pleural effusion, and, occasionally, airspace opacities. [pubs.rsna.org]

  This causes pulmonary edema and pleural effusions.[30] In the absence of pulmonary blood vessel narrowing, the increased back pressure is described as ‘isolated post-capillary pulmonary hypertension’ (older terms include ‘passive’ or ‘proportionate’ pulmonary [en.wikipedia.org]

Thanks to a better understanding of the role of cytokines and other mediators in PAH pathogenesis, several compounds have been tested and could be approved for treatment of PAH during recent years. Drugs applied in PAH therapy mainly aim at remedying the lack of PGI2 and the excess of ET1 and mediating vasodilation. To this end, phosphodiesterase-5 inhibitors, prostacyclin analogues and ET1 receptor antagonists may be administered.

• Phosphodiesterase-5 inhibitor tadalafil has largely replaced the related drug sildenafil because it allows for more convenient dosing intervals [15].
• Epoprostenol, treprostinil, beraprost and iloprost are prostacyclin analogues approved for PAH therapy. These drugs differ with regards to their route of administration and the required frequency of application; the most appropriate compound for an individual patient should be selected based on their response to treatment, side effects and adverse events [16].
• Three different ET1 receptor antagonists are available for PAH therapy: bosentan, ambrisentan, and macitentan.

Compounds pertaining to distinct drug classes are frequently combined in order to relieve symptoms by means of a tolerable therapeutic regimen. As a first-line treatment, tadalafil is usually combined with ET1 receptor antagonists. Only if this therapy fails, prostacyclin analogues are applicated.

Patients who test positive for vasoreactivity may not require any of the aforementioned drugs but may respond to oral administration of calcium channel blockers [17]. However, this is to be expected only for a minor share of individuals suffering from PAH.

In case drug therapy is insufficient to treat PAH, surgical interventions may be required. Atrial septostomy may provide a short-term solution and may be considered to bridge the time gap until lung transplantation can be carried out.

PAH is a progressive, often fatal disease. There is no causative treatment for IPAH, and median survival rates one, two and three years after diagnosis have been estimated to be 85%, 70% and 55%, respectively [11]. Female gender, lower right atrial pressure, higher cardiac output, and a greater walk distance over a limited period of time have been identified as favorable prognostic factors in the aforecited study. On the other hand, male gender, age, highly increased pulmonary vascular resistance and the presence of symptoms of heart failure at rest have been shown to negatively correlate with survival [12].

In case of SPAH, the patient's prognosis depends on the underlying disease, which may be curable, and the progression of PAH. If pulmonary hypertension develops due to connective tissue disorders or portal hypertension, survival times are particularly short.

IPAH and SPAH have to be distinguished from an etiological point of view as well as with regards to treatment.

IPAH is considered an idiopathic disease, but its alternative designations familial or hereditary PAH indicate its genetic background. According to a recent publication, about 75% of IPAH patients, namely those with a family history of PAH, present with any one of more than 300 known mutations of the gen encoding for bone morphogenetic protein receptor type 2 (BMPR2) [2]. The remaining 25% of individuals, i.e., those presenting without a family history of PAH, are likely to carry de novo mutations of the BMPR2 gene. BMPR2 binds bone morphogenetic protein and transforming growth factor-β (TGF-β), and dysfunction of this receptor causes altered cellular responses to those mediators and affects feedback mechanisms. The importance of TGF-β signaling in PAH pathogenesis is further illustrated by the fact that mutations of those genes encoding for activin A receptor type II-like kinase-1 (ACVRL1) or endoglin - type I and III receptors for TGF-β and related ligands, respectively - have also been related to IPAH. Since BMPR2 gene variants predisposing for PAH are inherited with an autosomal dominant trait but low penetrance, the interaction of several genetic and possibly environmental factors is likely to account for the onset of PAH symptoms [3].

SPAH may develop as a complication of the following diseases:

• Chronic obstructive pulmonary disease
• Pulmonary fibrosis
• Congenital heart disease
• Portal hypertension
• Connective tissue disorders
• Hemoglobinopathy
• Sarcoidosis
• Infection with the human immunodeficiency virus (HIV)/AIDS
• Schistosomiasis

It may also be induced by determined drugs, as has been shown for appetite suppressants modulating serotonergic signaling [4].

The overall prevalence of PAH has been estimated to be up to 50 per 1,000,000 inhabitants, with IPAH being more frequently diagnosed than SPAH [5]. Other estimates go far beyond those values and it has even been suggested that up to 1% of the world population suffers from PAH [6]. Women are affected more often than men, and the female-to-male ratio has been reported to be greater than 2:1. To date, the causes of this apparent gender predilection remain elusive.

With regards to those diseases triggering SPAH, their prevalence differs depending on geographic region and developmental state. In general, pulmonary and heart diseases most often cause SPAH, but in developing countries, infectious diseases like HIV and schistosomiasis are of epidemiological importance, too [6]. PAH is a pathological condition typically encountered in the elderly, but infectious diseases and related SPAH are more prevalent in young adults.

The condition underlying PAH is an increased resistance of the pulmonary artery, and this condition is provoked by chronic vasoconstriction, smooth muscle cell and fibroblast proliferation as well as thrombus formation. These processes are mutually dependent, but the precise trigger to induce this vicious cycle cannot be identified in any case.

• According to current knowledge, chronic vasoconstriction is the result of a reduced release of vasodilators like nitric oxide (NO) and prostacyclin (PGI2), and elevated concentrations of vasoconstrictors like endothelin-1 (ET1) and thromboxane A2 (TXA2) [7].
• Moreover, NO and PGI2 inhibit smooth muscle cell and fibroblast proliferation, while ET1 and TXA2 mediate the opposite effect. Thus, the predominance of vasoconstrictive mediators contributes to excess cell proliferation. Cell proliferation may additionally be stimulated by serotonin and elevated serum levels of this mediator have been found in patients suffering from IPAH and drug-induced SPAH [8].
• Lack of NO, PGI2 and anticoagulants like thrombomodulin, creates a prothrombotic, antifibrinolytic environment in pulmonary vessels. At the same time TXA2 and serotonin favor platelet aggregation [9].

Considerable shares of vasodilators/growth inhibitors/anticoagulants and vasoconstrictors/mitogens/platelet aggregants are produced by endothelial cells, and the aforedescribed imbalances may thus originate from an endothelial dysfunction.

IPAH has also been related to clonal expansion of endothelial cells [10], and if this hypothesis is confirmed, IPAH may need to be reclassified as a cancer-like disorder. Despite considerable differences between PAH pathogenesis and carcinogenesis, inhibition of clonal cell proliferation may constitute a new therapeutic target.

No specific measures can be recommended to prevent PAH, but lifestyle decisions consistent with cardiovascular health may also have beneficial effects on the condition of pulmonary circulation.

Pulmonary arterial hypertension (PAH) refers to an elevated resistance of the large vessel extending from the right ventricle to the lungs. This vessel is designated pulmonary artery and forms part of the functional pulmonary circulation, i.e., it does not supply the lungs with oxygen and nutrients but rather carries "venous" blood for it to be enriched with oxygen. Physiologically and under resting conditions, mean pulmonary artery pressure (mPAP) is 8 to 20 mmHg [1]. Slight elevations to 21 to 24 mmHg are generally considered borderline values and affected individuals are diagnosed with latent PAH. Manifest PAH corresponds to mPAP > 25 mmHg. Increases in mPAP affect the right heart, which has to work harder in order to pump blood against the enhanced resistance of the respective vascular system. Thus, chronic PAH results in right heart insufficiency and possibly in right heart failure. Symptoms associated with PAH are characteristic of circulatory failure and may comprise dyspnea, cough and syncopes. Complaints worsen progressively.

There are two main forms of PAH, namely primary pulmonary hypertension (IPAH) and secondary pulmonary hypertension (SPAH). The former is deemed idiopathic, although it has recently been related to determined gene variants and altered concentrations of cytokines and other mediators [2]. SPAH, in contrast, is the result of an underlying primary disorder like chronic obstructive pulmonary disease, pulmonary fibrosis or heart disease.

Pulmonary arterial hypertension (PAH) refers to the condition of an increased blood pressure in the large vessel extending from the right cardiac ventricle to the lungs. This vessel is the pulmonary artery and it carries deoxygenated blood to the lungs for it to be enriched with oxygen. Subsequently, this blood is transported to the left ventricle and pumped through the whole body.

If the resistance of the pulmonary artery is elevated, the right ventricle has to work harder in order to pump blood into the lungs. As pulmonary arterial blood pressure increases, the patient may thus develop right heart insufficiency and heart failure. Unfortunately, symptoms may not be noted until the heart starts to succumb to pathological loads. Only then, patients note reduced performance, breathing difficulties, dizziness and syncopes. PAH is a progressive disease and while the aforementioned symptoms initially appear under exercise, they may eventually become an issue even at rest.

Treatment options comprise drug therapy, surgery and lung transplantation, but most cases of PAH are not curable. The median survival time after diagnosis of PAH is approximately three years.

1. Heresi GA, Minai OA, Tonelli AR, et al. Clinical characterization and survival of patients with borderline elevation in pulmonary artery pressure. Pulm Circ. 2013; 3(4):916-925.
2. Soubrier F, Chung WK, Machado R, et al. Genetics and genomics of pulmonary arterial hypertension. J Am Coll Cardiol. 2013; 62(25 Suppl):D13-21.
3. Hamid R, Cogan JD, Hedges LK, et al. Penetrance of pulmonary arterial hypertension is modulated by the expression of normal BMPR2 allele. Hum Mutat. 2009; 30(4):649-654.
4. Bazan IS, Fares WH. Review of the Ongoing Story of Appetite Suppressants, Serotonin Pathway, and Pulmonary Vascular Disease. Am J Cardiol. 2016; 117(10):1691-1696.
5. Hoeper MM, Simon RGJ. The changing landscape of pulmonary arterial hypertension and implications for patient care. Eur Respir Rev. 2014; 23(134):450-457.
6. Hoeper MM, Humbert M, Souza R, et al. A global view of pulmonary hypertension. Lancet Respir Med. 2016; 4(4):306-322.
7. Morrell NW, Adnot S, Archer SL, et al. Cellular and molecular basis of pulmonary arterial hypertension. J Am Coll Cardiol. 2009; 54(1 Suppl):S20-31.
8. West JD, Carrier EJ, Bloodworth NC, et al. Serotonin 2B Receptor Antagonism Prevents Heritable Pulmonary Arterial Hypertension. PLoS One. 2016; 11(2):e0148657.
9. Lopes AA. Pathophysiological basis for anticoagulant and antithrombotic therapy in pulmonary hypertension. Cardiovasc Hematol Agents Med Chem. 2006; 4(1):53-59.
10. Lee SD, Shroyer KR, Markham NE, Cool CD, Voelkel NF, Tuder RM. Monoclonal endothelial cell proliferation is present in primary but not secondary pulmonary hypertension. J Clin Invest. 1998; 101(5):927-934.
11. Humbert M, Sitbon O, Chaouat A, et al. Survival in patients with idiopathic, familial, and anorexigen-associated pulmonary arterial hypertension in the modern management era. Circulation. 2010; 122(2):156-163.
12. Benza RL, Miller DP, Gomberg-Maitland M, et al. Predicting survival in pulmonary arterial hypertension: insights from the Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL). Circulation. 2010; 122(2):164-172.
13. Rich S, ed. Executive summary from the World Symposium on Primary Pulmonary Hypertension. Evian, France, 1998.
14. Galiè N, Torbicki A, Barst R, et al. Guidelines on diagnosis and treatment of pulmonary arterial hypertension. The Task Force on Diagnosis and Treatment of Pulmonary Arterial Hypertension of the European Society of Cardiology. Eur Heart J. 2004; 25(24):2243-2278.
15. Frantz RP, Durst L, Burger CD, et al. Conversion from sildenafil to tadalafil: results from the sildenafil to tadalafil in pulmonary arterial hypertension (SITAR) study. J Cardiovasc Pharmacol Ther. 2014; 19(6):550-557.
16. Galiè N, Manes A, Branzi A. Prostanoids for pulmonary arterial hypertension. Am J Respir Med. 2003; 2(2):123-137.
17. Stringham R, Shah NR. Pulmonary arterial hypertension: an update on diagnosis and treatment. Am Fam Physician. 2010; 82(4):370-377.