• 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.

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.

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.

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