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Pulmonary Arterial Hypertension

PAH

Pulmonary arterial hypertension is characterized by an increased resistance of the pulmonary artery, a condition that stresses the right ventricle and atrium and may lead to heart failure. Primary pulmonary arterial hypertension is an idiopathic disorder; secondary pulmonary arterial hypertension most commonly results from other lung diseases.

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Presentation

  • 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
  • Other symptoms that may be present include: Dizziness Fatigue Swelling around the ankles and feet Fainting Tightening feeling in the chest[aoporphan.com]
  • CASE PRESENTATION: 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]
  • Abstract 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]
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]
  • Severe shortness of breath is the most frequent initial symptom and can lead to fatigue, weakness, chest pains, dizziness, and fainting.[pulmonaryhypertensionnews.com]
  • Symptoms may include shortness of breath, excessive fatigue, dizziness, weakness, ankle swelling, syncope and chest pain.[cathlabdigest.com]
Raynaud Phenomenon
  • The pSS patients with Raynaud's phenomenon, high-titer rheumatoid factor, hepatic injury or pericardial effusion should be screened for PAH. 2018 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.[ncbi.nlm.nih.gov]
  • More rarely, abdominal distension, clubbing of digits and Raynaud phenomenon (predominantly in females) are observed. Hemoptysis has also been reported.[orpha.net]
  • 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]
  • Other symptoms may include: Chest pain (angina pectoris) Dizziness Fainting (syncope) Loss of energy Swelling of the arms, legs, ankles, or abdomen (edema) Dry cough Raynaud’s phenomenon (chalky white or dusky blue fingers that may be painful and can[pfizer.com]
  • Almost everyone with scleroderma experiences Raynaud’s phenomenon as well. (For more information on this disorder, choose “scleroderma” as your search term in the Rare Disease Database.)[rarediseases.org]
Chest Discomfort
  • Abstract 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).[merckmanuals.com]
Weight Loss
  • Within 1 month of the procedure, before significant weight loss, right ventricular function improved by echocardiography ( Fig. 1 ).[care.diabetesjournals.org]
  • 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]
Dyspnea
  • A 57-year-old woman complained of dyspnea and was subsequently diagnosed with HPS and PoPH caused by congenital portosystemic shunts.[ncbi.nlm.nih.gov]
  • Treatment with an alternate tyrosine kinase inhibitor was initiated and had been continued without development of dyspnea or elevation of RVSP.[ncbi.nlm.nih.gov]
  • 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]
  • A 43-year-old woman with stage IV breast cancer presented with dyspnea on exertion. After excluding other secondary causes of pulmonary hypertension, a diagnosis of moderately severe PAH was made based on right heart catheterization.[ncbi.nlm.nih.gov]
  • PATIENT CONCERNS: A 27-year-old pregnant woman was admitted to the hospital at 32weeks with progressive dyspnea. DIAGNOSES: The pregnant was diagnosed with ventricular septal defect 12 years prior to presentation.[ncbi.nlm.nih.gov]
Cough
  • 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]
  • Other important side effects of VENTAVIS include: bleeding red face (flushing) increased cough low blood pressure headaches nausea spasm of your jaw muscles that makes it hard to open your mouth Talk to your doctor if you have any side effect that bothers[4ventavis.com]
  • PAH may also cause a cough, sometimes with blood.[pulmonaryhypertensionnews.com]
Dry Cough
  • 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]
  • cough Who is likely to develop it PAH can affect any one of any age, sex or race.[nhcs.com.sg]
  • Other symptoms may include: Chest pain (angina pectoris) Dizziness Fainting (syncope) Loss of energy Swelling of the arms, legs, ankles, or abdomen (edema) Dry cough Raynaud’s phenomenon (chalky white or dusky blue fingers that may be painful and can[pfizer.com]
  • Symptoms may include: Bluish lips and skin Chest pain (angina) Dizziness Dry cough Extreme tiredness (fatigue) Fainting Feeling like your heart is fluttering or beating fast or hard (palpitations) Racing pulse Swelling in the ankles or legs Trouble breathing[cedars-sinai.org]
Hemoptysis
  • Hemoptysis has also been reported.[orpha.net]
  • 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]
  • Pulmonary hypertension can lead to bleeding into the lungs and coughing up blood (hemoptysis). This is another potentially fatal complication. Dec. 28, 2017[mayoclinic.org]
  • Hemoptysis is rare but may be fatal. Hoarseness due to recurrent laryngeal nerve compression by an enlarged pulmonary artery (ie, Ortner syndrome) also occurs rarely.[merckmanuals.com]
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]
  • Exertional dyspnea, fatigue, and dizziness are commonly seen in the clinician's office, but they are so nonspecific that the differential diagnoses can sometimes be elusive.[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]
  • 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).[merckmanuals.com]
Nausea
  • 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]
  • Observed adverse events were nausea and hepatic function abnormal in 1 patient each, and both events were mild.[ncbi.nlm.nih.gov]
Vomiting
  • 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]
Heart Failure
  • KEYWORDS: Heart failure with preserved ejection fraction; Sjögren syndrome; pulmonary arterial hypertension; pulmonary venous hypertension[ncbi.nlm.nih.gov]
  • INTRODUCTION: 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]
  • Patients note symptoms of right heart failure at rest. Generalized cyanosis and peripheral edema are commonly observed.[symptoma.com]
  • BACKGROUND: Pulmonary arterial hypertension (PAH) is a progressive disease and ultimately leads to right heart failure. Endothelin receptor antagonists (ERAs) have been demonstrated to significantly improve prognosis in PAH.[ncbi.nlm.nih.gov]
  • The progression of this devastating disease is characterized by increase in pulmonary vascular resistance resulting in elevated pulmonary pressure, eventually leading to right heart failure and death.[ncbi.nlm.nih.gov]
Chest Pain
  • 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]
  • 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]
  • 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]
  • Increased blood pressure in the heart and arteries may cause chest pain or pressure. An overworked heart may also cause unusual chest pain or chest pressure. Each person with PAH will experience a different assortment of symptoms.[healthline.com]
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]
  • Initial symptoms include dyspnea, syncope, chest pain, palpitations and pedal edema.[orpha.net]
  • You have chest pain or heart palpitations (strong, fast heartbeats). Care Agreement You have the right to help plan your care. Learn about your health condition and how it may be treated.[drugs.com]
  • Ultimately, this may cause an erratic heartbeat , a racing pulse , or heart palpitations . Increased blood pressure in the heart and arteries may cause chest pain or pressure. An overworked heart may also cause unusual chest pain or chest pressure.[healthline.com]
Cyanosis
  • 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]
  • 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]
  • Generalized cyanosis and peripheral edema are commonly observed. Workup of a clinical presentation consistent with PAH is generally initiated by the following examinations: Thorough anamnesis and general examination.[symptoma.com]
Tachycardia
  • Here, we present the case of an 11-year-old boy with pulmonary arterial hypertension (PAH) and junctional ectopic tachycardia associated with CAEBV.[ncbi.nlm.nih.gov]
  • He had undergone biological mitral valve replacement 3 years previously for mitral valve stenosis and ablation of atrioventricular nodal reentry tachycardia 18 months previously.[ncbi.nlm.nih.gov]
  • Bowden and Nikolai Petrovsky Related Book First chapter Accurate Detection of Paediatric Ventricular Tachycardia in AED By U. Irusta, E. Aramendi, J. Ruiz and S. Ruiz de Gauna We are IntechOpen, the world's leading publisher of Open Access books.[intechopen.com]
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]
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]
Blurred Vision
  • METHODS: A 40-year-old man with heritable pulmonary arterial hypertension presented with blurred vision in his left eye and was followed up for 1 year with clinical examination, enhanced depth optical coherence tomography, fluorescein and indocyanine[ncbi.nlm.nih.gov]
Retinal Pigmentation
  • RESULTS: At presentation, atypical central serous chorioretinopathy with multiple retinal pigment epithelial detachments, a thick subfoveal choroid, and dilated choroidal vessels were seen in the patient's symptomatic left eye.[ncbi.nlm.nih.gov]
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]
  • Other symptoms that may be present include: Dizziness Fatigue Swelling around the ankles and feet Fainting Tightening feeling in the chest[aoporphan.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]
  • 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]
Lethargy
  • 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]
  • Pulmonary hypertension symptoms may include: Shortness of breath that worsens with activity Other common complaints are cough, fatigue, dizziness, and lethargy.[medicinenet.com]
Neglect
  • Abstract Pulmonary arterial hypertension, a disease largely neglected until a few decades ago, is presently the object of intense studies by several research teams.[ncbi.nlm.nih.gov]

Workup

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.

Right Ventricular Hypertrophy
  • Obstructive pulmonary vascular remodeling in PAH increases right ventricular afterload causing right ventricular hypertrophy.[ncbi.nlm.nih.gov]
  • Mean pulmonary arterial pressure (mPAP) and the right ventricular hypertrophy index (RVHI) in the ADSCs-APN-treated mice were significantly decreased as compared with the ADSCs and ADSCs-V treatments. Pulmonary vascular remodeling was assessed.[ncbi.nlm.nih.gov]
  • Several studies showed that calcium channel blockers (CCBs) reduce right ventricular hypertrophy and improve long-term haemodynamics in PAH. Objectives: To evaluate the clinical efficacy and harms of CCBs for people with PAH.[cochrane.org]
  • Electrocardiography may reveal right axis deviation indicating right ventricular hypertrophy.[symptoma.com]
  • Specifically, the study found that rivaroxaban, in a dose-dependent fashion, attenuated the increase in right ventricular systolic pressure and right ventricular hypertrophy caused by monocrotaline.[acc.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]

Treatment

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.

Prognosis

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.

Etiology

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:

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

Epidemiology

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.

Sex distribution
Age distribution

Pathophysiology

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.

Prevention

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.

Summary

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.

Patient Information

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.

References

Article

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  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.
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Last updated: 2018-06-21 18:45