Patients initially report with unspecific symptoms such as weakness and fatigue, dyspnea at rest or under exercise, light-headedness, syncopes and possibly palpitations and chest pain. Cough is observed in some cases. Few patients are hoarse. Later, venous congestion, peripheral edema, ascites and pleural effusion may become apparent. Cyanosis may be observed.

These symptoms should prompt an intensive workup to identify possibly underlying causes, but in PPH, no such primary disease can be detected. Diagnosis is further delayed due to little awareness of this disease and years may pass between symptom onset and confirmation of PPH. While alterations of pulmonary vasculature are already advanced when patients experience dyspnea or syncopes, they progress much further during retardation of diagnosis.

PPH is an exclusion diagnosis if patients present without a familial history of pulmonary hypertension. Thus, the workup aims at confirming increased pulmonary arterial pressure and at ruling out different factors that may cause this condition.

Firstly, in an extensive interview, it should be clarified if the respective patients has been using any legal or illegal drug and if they know of close relatives with similar complaints.

Echocardiography with Doppler flow studies allow for a non-invasive assessment of pulmonary artery pressure and additionally permit to evaluate the condition of myocardium and valves. Tricuspid valve regurgitation is characteristic for pulmonary hypertension. Right heart hypertrophy may also be diagnosed based on an electrocardiogram. However, right heart hypertrophy and insufficiency develop rather late in the course of the disease and thus, an electrocardiogram may be little sensitive in less advanced cases of PPH.

Although the aforementioned exams may reveal elevated pulmonary artery pressure and right heart insufficiency, they are not suitable to rule out underlying lung diseases. These may be visualized by diagnostic imaging, possibly with plain radiographs. Of note, pathologically prominent pulmonary arteries on radiographic images hint at augmented blood pressure in these vessels and may even constitute an incidental finding.

Because infectious diseases, infestation with parasites, autoimmune disorders and metabolic diseases may all contribute to pulmonary hypertension, laboratory analysis of blood samples should be carried out. Complete blood count and blood chemistry are required to detect alterations pointing at an HIV infection, schistosomiasis, connective tissue disease, thyroid disorders or any other primary disease. The above mentioned classification system for pulmonary hypertension may provide further differential diagnoses [2].

Hypoxemia and metabolic acidosis may add to pulmonary hypertension and may be identified by blood gas analyses. Of note, blood oxygenation may be altered only under exercise or at night [9]. Even after diagnosis of PPH, regular blood gas analyses are recommended to detect insufficient oxygenation and pH-value alterations.

Pulmonary function tests should be performed to check for obstructive or restrictive pulmonary diseases although they may not have been visible on radiographic images. If doubts remain after carrying out both diagnostic measures, computed tomography scans may pose an alternative to assess the condition of the patient's lungs.

Finally, ventilation/perfusion lung scans may be conducted to rule out pulmonary thrombosis and embolism. If pulmonary vessels are occluded by thrombi, larger segments will remain without perfusion [10].

If the patient remains suspicious for PPH after this workup, they should undergo cardiac catheterization to definitely confirm the diagnosis and precisely quantify its extent.

Patients who develop PPH due to loss-of-function mutations regarding potassium channels may eventually be treated with phospholipase A2 inhibitors that fully restore ion channel function [4]. Such treatment is still under investigation and to date, therapy PPH is solely symptomatic. 

Vasodilators of different drug classes are employed to reduce pulmonary vasoconstriction and may considerable improve survival times [11]. In this line, prostaglandins like prostacyclin or its synthetic analogue epoprostenol are most commonly used to treat PPH patients. However, due to short half-lives the majority of such compounds requires continuous administration. Also, endothelin antagonists, phosphodiesterase inhibitors, soluble guanylate cyclase activators and calcium channel blockers may be utilized to decrease pulmonary arterial pressure [12]. Before patients are recommended for life-long therapies with either of these compounds, their response to treatment should be evaluated, ideally by application of quick acting drugs while a cardiac catheterization is performed. Oxygen supplementation may also contribute to vasodilation. Any hypoxemia should be corrected.

Because endothelial alterations of pulmonary vessels dispose for thrombosis and embolism, patients may benefit from anti-coagulative treatment.

With regards to cardiac function, diuretics may be administered to reduce the afterload of the right ventricle. However, these drugs may also decrease cardiac preload. Thus, an overdose should be avoided by any means since it could further reduce cardiac output and thereby aggravate the patient's condition. Inotropics like digoxin may be administered to increase myocardial contractility.

In any case, patients should be recommended to keep a diet low in salt.

Drug therapy is usually not sufficient to impair disease progress. Lung transplantations may be the only option for patients who do not (any longer) respond to medication.

PPH is a chronic disease and symptoms exacerbate with time. Prognosis is unfavorable. The mean survival time for PPH has been calculated to be less than three years [8]. Five-year survival rates are 35 and 50% for pediatric and adult patients, respectively [3].

Research efforts to understand etiology and pathogenesis of the disease may allow for new therapeutic approaches that could increase survival times for PPH patients.

IPH is a disease of unknown etiology. It cannot be ruled out that many cases of IPH are indeed genetic disorders that could not yet be characterized in detail. Recently, loss-of-function mutations in potassium channels have been related to PPH. These patients had been diagnosed with IPH before [4]. Presumably, environmental factors, infection and inflammation also play an important role in IPH etiology [5]. Furthermore, the latter may trigger the disease in genetically predisposed individuals.

Gene mutations have in fact been identified in several cases of sporadic PPH, i.e., in patients who did not have a familial history of PPH and who would traditionally have been diagnosed with IPH [6]. In this context, the term familial PPH should no longer be used and should be replaced by heritable PPH. Known causes of this form of the disease are mutations in genes encoding for bone morphogenetic protein receptor 2 and activin receptor-like kinase type-1 (both receptors with serine/threonine kinase activity), endoglin (a glycoprotein expressed on the surface of endothelial cells) and SMAD9 (a protein of the SMAD family). All the aforementioned proteins are involved in TGFβ signaling pathways. Additionally, mutations in those genes encoding for caveolin-1 and KCNK3 (potassium channel subfamily K member 3) have been related with PPH. Of note, the aforementioned mutations seem to be compensated in an as of yet unknown manner. In case of bone morphogenetic protein receptor 2, for instance, only one out of five carriers does develop pulmonary hypertension at some point in their life. This fact points out once more the subtle transition between genetic disorder, genetic predisposition and IPH.

The aforementioned proteins may be involved in different signaling pathways, but do all contribute to proliferation of cells forming pulmonary vessels, either by directly stimulating proliferation or by inhibiting apoptosis.

The overall prevalence of IPH and heritable PPH has been estimated to 2-3 per 1,000,000 and 0.2-0.3 per 1,000,000, respectively [3]. Of note, due to the above described knowledge gaps regarding etiology of IPH, distinction of both forms of PPH may not always be possible and PPH patients may not belong unequivocally to either one of these groups.

With regards to heritable PPH, mutations in bone morphogenetic protein receptor 2 are most commonly found. However, these same genetic alterations are also present in up to 40% of IPH patients.

Racial predilections have not been described. For as of yet unknown reasons, females are affected more often than males. The mean age of symptom onset is 36 years, although PPH has also been diagnosed in the elderly [7].

PPH is associated with increased pulmonary arterial pressure and vascular resistance. These result from endothelial and smooth muscle cell proliferation that result in considerable thickening of intima and media as well as functional impairment of these tissues. It is not yet known which factors stimulate cell proliferation, but infectious agents, pro-inflammatory events and mechanical lesions are all conceivable triggers. If cells are genetically predisposed for excess proliferation or if pro-apoptotic mechanisms fail, physiological repair processes may end in pulmonary hypertension.

Moreover, endothelial alterations in pulmonary vessels may lead to thrombotic pulmonary arteriopathy. Additionally, they significantly increase the risk for pulmonary thrombosis and embolism. These conditions further increase pulmonary arterial pressure and are potentially life-threatening.

In the context of the above described hypothesis, PPH is in fact a multifactorial disease. Distinct causes may account for continuously elevated blood pressure, but they all result in an increased afterload for the right ventricle. In an attempt to compensate for the increased resistance, the right ventricle becomes hypertrophic and finally insufficient. These pathophysiological events lead to venous congestion, peripheral edema, ascites and pleural effusion. Oxygen supply to peripheric tissues may be limited due to cardiac functional impairment and cyanosis may indicate ischemia. Several organ systems, e.g., liver, spleen, gastrointestinal tract and kidneys, may be compromised by both congestion and hypoxia.

For an early diagnosis, genetic screening and possibly echocardiographic examinations are indicated in patients pertaining to families with a known history of heritable PPH [13]. However, it has not yet been proven that early initiation of treatment improves the outcome for the patient.

Primary pulmonary hypertension (PPH) is defined as a persistent increase of´the mean pulmonary arterial pressure > 25 mmHg at rest or >30 mmHg under exercise [1]. To date, its etiology remains poorly understood. Contrary to individuals suffering from secondary pulmonary hypertension, PPH patients do not present comorbidities that account for the observed rise of arterial pressure in pulmonary vessels, e.g., left heart disease, obstructive or restrictive lung disorders or neoplasms. However, both forms of pulmonary hypertension share a high risk of right ventricular hypertrophy, right heart failure and death.

Clinical classification of pulmonary hypertension has recently been updated [2] and mentions the following forms of PPH:

• Idiopathic pulmonary hypertension (IPH)
• Pulmonary hypertension due to genetic disorders, namely those affecting genes BMPR2, ALK-1, ENG, SMAD9, CAV1 and KCNK3

Although persistent pulmonary hypertension of the newborn may formally be considered a type of PPH, both diseases differ clinically and thus constitute distinct entities [3].

Symptoms of PPH correspond to heart failure and mainly consist in reduced tolerance to exercise, dyspnea - initially under exercise, in advanced stages of the disease at rest -, visible congestion of the jugular vein and peripheral edema. Symptoms manifest rather late in the course of the disease. Diagnosis requires Doppler echocardiography, pulmonary function tests, blood gas analysis, radiographic imaging of the thorax, scintigraphy to assess pulmonary ventilation and perfusion and possibly cardiac catheterization. Treatment is supportive and mainly consists in long-term administration of prostaglandins. According to current knowledge, PPH is not curable.

Pulmonary hypertension is the medical term for an increased blood pressure in lung vessels. Pulmonary hypertension may develop as a consequence of cardiac insufficiency, obstructive or restrictive lung diseases, tumors and a variety of other pathologies. However, some patients are diagnosed with increased pulmonary arterial pressure without presenting any of these underlying diseases. Here, the condition is designated primary pulmonary hypertension (PPH).

Causes

Gene mutations may account for PPH. Since genetic disorders are heritable, they are usually associated with a familial accumulation of this disease. Other genes may mutate spontaneously and individuals may develop PPH although there are no such cases in their family.

Some PPH patients do not present any gene mutation related to the disease. Here, the causes for PPH are unknown.

Symptoms

An increased pulmonary arterial pressure results in cardiac overload, venous congestion and reduced oxygen supply to peripheric tissues.

In this context, breathing difficulties are the most common symptoms of PPH, some patients experience syncopes. Furthermore, they may feel weak and tired, report palpitations and chest pain. In advanced stages of the disease, peripheral edema and a bluish discoloration of the skin may be noted.

Diagnosis

Diagnosis of PPH is challenging because a variety of other diseases has to be ruled out. The following examinations may be performed:

• Echocardiography
• Chest X-ray
• Analysis of blood samples
• Blood gas analysis
• Pulmonary function test
• Ventilation/perfusion lung scans
• Cardiac catheterization

Treatment

Drug therapy aims at reducing blood pressure in lung vessels. This can be achieved by long-term administration of vasodilators, i.e., of drugs that widen blood vessels. Anti-coagulants may be given to reduce the risk of pulmonary thrombosis and embolism. Diuretics may be employed to reduce cardiac overload and at the same time, inotropics may be prescribed to increase cardiac contractility.

Not all patients respond to medication. If that is not the case, they may be in need of a lung transplant.

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