Primary Pulmonary Hypertension (PPH) - The Basics

What Is Primary Pulmonary Hypertension?

Primary Pulmonary Hypertension (PPH) is increased pressure in the pulmonary arteries. These pulmonary arteries carry blood from your heart to your lungs to pick up oxygen.

Primary Pulmonary Hypertension (PPH) causes symptoms such as shortness of breath during routine activity (for example, climbing two flights of stairs), tiredness, chest pain, and a racing heartbeat. As the disease worsens, its symptoms may limit all physical activity.


The lower right chamber of your heart, the right ventricle, pumps blood to your pulmonary arteries. The blood then travels to your lungs, where it picks up oxygen. This oxygen-rich blood is pumped to the rest of your body.

Three types of changes can affect the pulmonary arteries and cause Primary Pulmonary Hypertension (PPH):

  • The walls of the pulmonary arteries tighten.
  • The walls of the pulmonary arteries are stiff at birth or become stiff from an overgrowth of cells.
  • Blood clots form in the pulmonary arteries.

These changes make it hard for the heart to push blood through the pulmonary arteries and into the lungs. Thus, the pressure in the pulmonary arteries rises. Also, as a result of the heart working harder, the right ventricle becomes strained and weak.

The heart may become so weak that it can't pump enough blood to the lungs. This causes heart failure. Heart failure is the most common cause of death in people who have Primary Pulmonary Hypertension (PPH).

Primary Pulmonary Hypertension (PPH) is divided into five groups based on its causes. In all groups, the average pressure in the pulmonary artery is higher than 25 mmHg at rest or 30 mmHg during physical activity. The pressure in a normal pulmonary artery is about 15 mmHg at rest. (The mmHg is millimeters of mercury—the units used to measure blood pressure.)

Usually, other diseases or conditions, such as heart and lung diseases or blood clots, cause Primary Pulmonary Hypertension (PPH). Some people inherit the condition. In some cases, the cause isn't known.


Primary Pulmonary Hypertension (PPH) has no cure. However, research for new treatments is ongoing. The earlier Primary Pulmonary Hypertension (PPH) is treated, the easier it is to control.

Treatments include medicines, procedures, and other therapies. These treatments can relieve Primary Pulmonary Hypertension (PPH) symptoms and slow the progress of the disease. Lifestyle changes also can help control symptoms.

Classification of Primary Pulmonary Hypertension (PPH)

Primary Pulmonary Hypertension (PPH) represents Group 1 within the Pulmonary Hypertension (PH) WHO clinical classification system (Venice 2003 revision) and is one of five such groups. The groups are divided based on aetiology.

Group I.Primary Pulmonary Hypertension (PPH)
  • Idiopathic
  • Familial
  • Associated with:
    • Connective tissue disease
    • Congenital systemic-to-pulmonary shunts
    • Portal Hypertension
    • HIV infection
    • Drugs and toxins
    • Other (thyroid disorders, glycogen storage disease, Gaucher's disease, hereditary haemorragic telangiectasia, haemoglobinopathies, myeloproliferative disorders, splenectomy)
  • Associated with significant venous or capillary involvement
    • Pulmonary veno-occlusive disease (PVOD)
    • Pulmonary capillary haemangiomatosis (PCH)
  • Persistent pulmonary hypertension of the newborn (PPHN)
Group II.Primary Pulmonary Hypertension (PPH) associated with left heart diseases
Group III.Primary Pulmonary Hypertension (PPH) associated with respiratory diseases and / or hypoxemia (including chronic obstructive pulmonary disease)
Group IV.Primary Pulmonary Hypertension (PPH) due to chronic thrombotic and/or embolic disease
Group V.Miscellaneous group
  • eg. sarcoidosis, histiocytosis X and lymphangiomatosis

Ideopathic Primary Pulmonary Hypertension (PPH), which by definition has no identifiable underlying cause, is one of the more common types of Primary Pulmonary Hypertension (PPH). Familial PAH (FPAH) accounts for at least 6% of cases of IPAH and mutations in the bone morphogenetic protein receptor 2 (BMPR2) have been identified in the majority of cases of FPAH.

Primary Pulmonary Hypertension (PPH) can also be associated with a number of conditions (Associated Pulmonary Arterial Hypertension - APAH), which together account for most other cases of Primary Pulmonary Hypertension (PPH). These conditions include;

1.Connective Tissue Diseases
  • including systemic sclerosis (scleroderma) and systemic lupus erythematosus (SLE)
2.Congenital heart disease
  • including Eisenmenger's syndrome
3.Human immunodeficiency viruinfection
4.Sickle Cell Disease

Primary Pulmonary Hypertension (PPH) is also a rare side effect of certain anorexigenic agents, such as fenfluramine and dexfenfluramine. However, the incidence of drug-induced Primary Pulmonary Hypertension (PPH) is decreasing as these agents are no longer available.

1. Primary Pulmonary Hypertension (PPH) associated with connective tissue disease
Primary Pulmonary Hypertension (PPH) is a well-recognised complication of connective tissue diseases such as systemic sclerosis and SLE and in affected patients may also occur in association with Interstitial lung disease. The prevalence of Primary Pulmonary Hypertension (PPH) in patients with systemic sclerosis has been reported to be up to 16% and in systemic sclerosis patients, pulmonary complications, such as interstitial lung disease and Primary Pulmonary Hypertension (PPH), are now the leading causes of death. Patients with Primary Pulmonary Hypertension (PPH) associated with systemic sclerosis have a particularly poor prognosis compared to those with systemic sclerosis without Primary Pulmonary Hypertension (PPH).

2. Primary PulmonaryHypertension (PPH) associated with congenital heart disease
Congenital heart disease is relatively common, affecting around 1% of the population. Within this population 15% will go on to develop Primary Pulmonary Hypertension (PPH). As determined by the level of pulmonary vascular resistance, the most severe form of Primary Pulmonary Hypertension (PPH) is Eisenmenger's Physiology, which is associated with the reversal of an initial left to right shunt causing Cyanosis and limited exercise capacity.

3. Primary Pulmonary Hypertension (PPH) associated with HIV infection
Primary Pulmonary Hypertension (PPH) is a rare (estimated prevalence in patients with HIV: 0.5%) but relatively well-documented complication of HIV infection. With the advent of highly active anti-retroviral therapy (HAART) and markedly improved survival, Primary Pulmonary Hypertension (PPH) and other non-infectious manifestations of HIV infection are increasingly responsible for HIV-associated morbidity and poor prognosis. In patients with HIV, the HIV-1 envelope glycoprotein GP120 may stimulate the production of endothelin by macrophages. HIV-associated Primary Pulmonary Hypertension (PPH) shows a similar clinical picture to IPAH and seems to be independent of the degree of immunosuppression.

4. Primary Pulmonary Hypertension (PPH) associated sickle cell disease
The prevalence of Primary Pulmonary Hypertension (PPH) in patients with sickle cell disease is 20%-40%

What are Primary and Secondary Pulmonary Hypertension?

In the conventional classification, Pulmonary Hypertension, which is also called Pulmonary Arterial Hypertension, is divided into two main categories; 1) Primary Pulmonary Hypertension (PPH) (not caused by any other disease or condition); and 2) Secondary Pulmonary Hypertension (caused by another underlying condition). Secondary Pulmonary Hypertension is much more common than primary pulmonary hypertension.

A newer classification of this condition is based on the main underlying cause of pulmonary hypertension. This system classifies the condition based on whether it is due to:

  • left sided heart disease

  • lung disease

  • blood clots

  • constriction of arteries due to any reasons (including Primary Pulmonary Hypertension (PPH)), and

  • obstruction from outside of blood vessel (for example from diseases of the chest wall compressing the blood vessels).

What causes Primary Pulmonary Hypertension (PPH)?

Primary Pulmonary Hypertension (PPH) has no identifiable underlying cause. Primary Pulmonary Hypertension (PPH) is also referred to as Idiopathic Pulmonary Hypertension.

Primary Pulmonary Hypertension (PPH) is an unusually aggressive and often fatal form of Pulmonary Hypertension that commonly affects young people. Whereas it is known that the arterial obstruction is caused by a building up of the smooth muscle cells that line the arteries, the underlying cause of the disease has long been a mystery.

A genetic cause of the familial form of Primary Pulmonary Hypertension (PPH) has been discovered. It is caused by mutations in a gene called BMPR2. BMPR2 encodes a receptor (a transforming growth factor beta type II receptor) that sits on the surface of cells and binds molecules of the TGF-beta superfamily. Binding triggers conformational changes that are shunted down into the cell's interior where a series of biochemical reactions occur, ultimately affecting the cell's behavior. The mutations block this process. This discovery may provide a means of genetic diagnosis and a potential target for the therapy of people with familial (and possibly also sporadic) Primary Pulmonary Hypertension (PPH).

Signs and Symptoms of Primary Pulmonary Hypertension (PPH)

Because symptoms of Primary Pulmonary Hypertension (PPH) may develop very gradually, patients may delay seeing a physician for years. Common symptoms of Primary Pulmonary Hypertension (PPH) are shortness of breath fatigue, non-productive cough, angina pectoris fainting or syncope, peripheral edema (swelling around the ankles and feet), and rarely hemptysis (coughing up blood).

Primary Pulmonary Hypertension (PPH) venous typically presents with shortness of breath while lying flat or sleeping (orthopnea) or paroxysmal nocturnal dyspnea), while Primary Pulmonary Hypertension (PPH) arterial typically does not.

A detailed family history is established to determine whether the Primary Pulmonary Hypertension (PPH) might be familial. A history of exposure to drugs such as cocaine, methamphetamines, alcohol leading to cirrhosis, and tobacco leading to emphysema are considered significant. A physical examination is performed to look for typical signs of Primary Pulmonary Hypertension (PPH), including a loud P2 (pulmonic valve closure sound), (para)sternal heave, jugular venous distension, pedal edema, ascites, hepatojugular reflux, clubbing etc. Evidence of tricuspid insufficiency is also sought and, if present, is consistent with the presence of Primary Pulmonary Hypertension (PPH).

What is Pulmonary Arterial Hypertension (PAH)?

Pulmonary arterial hypertension (PAH) is a syndrome characterised by a progressive increase in pulmonary vascular resistance leading to right ventricular overload and eventually to right ventricular failure and premature death.

The increase in pulmonary vascular resistance is related to a number of progressive changes in the pulmonary arterioles, including:

  • Vasoconstriction

  • obstructive remodelling of the pulmonary vessel wall through proliferation in the various layers of the blood vessel wall (smooth muscle cell and endothelial cell proliferation)

  • inflammation

  • in-situ thrombosis.

The main histological features include medial Hypertrophy, intimal thickening, adventitial thickening, plexiform lesions and in-situ thrombosis (Figure 1). The plexifom lesion represents a focal proliferation of endothelial and smooth muscle cells and is pathognomonic of Pulmonary Arterial Hypertension (PAH).

Histopathological findings of PAH - Click this image to enlarge. Figure 1

Pulmonary Arterial Hypertension (PAH) is defined as a sustained elevation of mean pulmonary arterial pressure to more than 25 mmHg at rest or to more than 30 mmHg while exercising, with a normal pulmonary wedge pressure.

In most cases the earliest symptom is Dyspnoea on physical exertion. Other symptoms include syncope or near syncope, fatigue and peripheral oedema. Chest tightness and pain similar to angina may occur, particularly on physical exertion.

How is Pulmonary Arterial Hypertension (PAH) diagnosed?

The early symptoms of Pulmonary Arterial Hypertension (PAH) - such as Dyspnoea, dizziness and fatigue - are often mild and are common to many other conditions. At rest there are often no symptoms of Pulmonary Arterial Hypertension (PAH) and no apparent signs of illness. As a result, diagnosis can be delayed for months or even years meaning that Pulmonary Arterial Hypertension (PAH) is frequently not recognised until the disease is relatively advanced. Pulmonary Arterial Hypertension (PAH) is often diagnosed only once other conditions have been investigated and ruled out.

The non-specific nature of symptoms associated with Pulmonary Arterial Hypertension (PAH) means that the diagnosis cannot be made on symptoms alone. A series of investigations is required to make an initial diagnosis of Pulmonary Arterial Hypertension (PAH), to refine that diagnosis in terms of clinical class of pulmonary hypertension (please click here for a classification of Pulmonary Hypertension) and to evaluate the degree of functional and haemodynamic impairment. Consequently, it can be useful to adopt a four stage approach to diagnosis of Pulmonary Arterial Hypertension (PAH):

1.Clinical suspicion of Pulmonary Hypertension
  • Breathlessness (dyspnoea) without overt signs of specific heart or lung disease
  • Screening of patients with associated conditions (Connective Tissue Disease, Congenital heart disease, HIV, Sickle Cell Disease)
  • Incidental findings on examination for other clinical reasons
2.Detection of Pulmonary Hypertension
  • ECG
  • Chest radiograph, may show evidence of cardiomegaly and enlarged pulmonary arteries (Figure 3)
  • Doppler echocardiogram (Figure 2)
3.Identify other causes of Pulmonary Hypertension
  • pulmonary function tests (PFTs) and arterial blood gas samples
  • ventilation and perfusion lung scan
  • high resolution computed tomography (HRCT)
  • pulmonary angiography
4.Pulmonary Arterial Hypertension (PAH) evaluation and classification (type, functional capacity, haemodynamics)
  • blood tests and immunology, HIV test, abdominal ultrasound scan
  • 6 minute walk test (6-MWT) and peak VO2
  • Right heart catheterisation and vasoreactivity testing.

Introduction to Pregnancy in Primary Pulmonary Hypertension (PPH)

Primary Pulmonary Hypertension (PPH) associated with pregnancy carries a high maternal mortality rate. Short-term epoprostenol infusion has been demonstrated to improve the hemodynamic profile in patients with Primary Pulmonary Hypertension (PPH). We report a successful maternal-fetal outcome with epoprostenol therapy during pregnancy, cesarean section, and postpartum in a patient with Primary Pulmonary Hypertension (PPH). Epoprostenol therapy did not produce any physical or developmental abnormalities in the fetus. A favorable maternal-fetal outcome may occur with a multidisciplinary approach.

Primary Pulmonary Hypertension (PPH) is a rare, progressive condition aggravated by the physiologic changes occurring during pregnancy and surgery. The maternal mortality rate associated with pregnancy and pulmonary hypertension ranges from 30 to 50%. The administration of IV epoprostenol has been well-demonstrated to improve hemodynamics in nonpregnant patients with PPHPrimary Pulmonary Hypertension (PPH) We report a successful maternal-fetal outcome in a pregnant woman in whom Primary Pulmonary Hypertension (PPH) was diagnosed who was treated with IV epoprostenol before, during, and after undergoing cesarean section.

Case Study of Pregnancy in Primary Pulmonary Hypertension (PPH)

A 35-year-old, gravida (G2,P0) patient with a history of hypothyroidism presented at 26 weeks’ gestation with progressive exertional dyspnea and fatigue of several weeks duration. She also reported several recent syncopal episodes. Her first pregnancy was uncomplicated, and she denied prior cardiopulmonary disease, illicit drug use, or ingestion of anorexigens. On physical examination, her vital signs were as follows: BP, 90/60 mm Hg; heart rate, 105 beats/min; respiratory rate, 20 breaths/min; and oxygen saturation as measured by pulse oximetry, 92%. Jugular venous distension was present. Cardiac auscultation revealed a loud S2 and a grade 3/6 systolic murmur over the left lower sternal border that was accentuated on inspiration. Lung fields were clear to auscultation bilaterally. Extremities were without clubbing, and 1+ edema was present. An ECG was interpreted as representing normal sinus rhythm. A chest radiograph was unremarkable for parenchymal infiltrates, and a ventilation-perfusion scan was interpreted as revealing a low probability for a pulmonary embolism. Arterial blood gas measurements revealed the following: pH, 7.45; PCO2, 29 mm Hg; PO2, 79 mm Hg; and bicarbonate level, 20 mEq/L. An echocardiogram displayed a dilated right ventricle, paradoxical septal wall motion, and normal left ventricular wall motion.

The patient was admitted to labor and delivery and was prescribed bed rest, oxygen, diuretics, and heparin. Fetal heart tones were noted at 150 beats/min, and IM corticosteroids were administered to accelerate fetal lung development. Despite this therapy, the patient continued to report progressive dyspnea, and at 32 weeks’ gestation the placement of a pulmonary artery catheter (PAC) demonstrated moderate pulmonary hypertension. IV epoprostenol therapy was initiated at 4 ng/kg/min, producing an improvement in the hemodynamic profile. At 36 weeks’ gestation, while receiving IV epoprostenol, the premature rupture of membranes occurred followed by active labor. However, the progression of labor was inadequate, and a cesarean section was scheduled. Preoperatively, a PAC was placed and epidural anesthesia was administered. Subsequently, the cardiac output declined from 7.4 to 4.1 L/min and the epoprostenol infusion was increased to 10 ng/kg/min. The patient remained hemodynamically stable throughout the cesarean section and delivered a healthy male infant weighing 7 lbs with Apgar scores of 5 and 9, respectively, at 1 and 5 min. A bilateral tubal ligation was performed with patient consent. Following extubation, the PAC was maintained for 48 h to assist with IV fluid administration, and the hemodynamic profile remained stable with the patient receiving 10 ng/kg/min epoprostenol. On postoperative day 2, heparin therapy was resumed.

Three weeks later, the patient underwent a vasodilator trial with calcium-channel blockers but did not have a favorable response, hence, she was continued on epoprostenol therapy. Presently, she has resumed an active lifestyle as a housewife and mother. Furthermore, her 2-year-old son is in good health without any developmental delays.

Discussion of Pregnancy in Primary Pulmonary Hypertension (PPH)

An early case series reported a 50% mortality rate associated with pregnancy and Primary Pulmonary Hypertension (PPH).A more recent account noted a 30% mortality rate and partly attributed the decline in the mortality rate to earlier recognition, better understanding of the pathophysiology of Primary Pulmonary Hypertension (PPH), along with improvements in medical therapy and critical-care obstetrics. Recognition of the elevated maternal-fetal mortality rate has led physicians to recommend effective contraception and, in the event of a pregnancy, early fetal termination. The maternal mortality rate is related principally to the increased demands on the cardiopulmonary system during pregnancy. Under normal circumstances, increases in cardiac output in the range of 30 to 50%, blood volume in the range of 40 to 50%, and oxygen consumption of 20% are observed during pregnancy. Other physiologic changes include an increase in cardiac output during labor in patients receiving local anesthesia (pudendal block) and postpartum intravascular volume shifts resulting from blood loss or diuresis. These physiologic events place a great demand on the cardiovascular system, with the greatest incidence of mortality occurring during the first several postoperative days. This is likely related to changes in pulmonary vascular tone due to intravascular volume shifts, hypoxemia, elevated catecholamine levels, or thromboembolism. Identification of the hemodynamic changes has led to the use of anticoagulants, oxygen, and vasodilators in the management of these patients.

Several reports have demonstrated an improvement in hemodynamics and outcome in nonpregnant patients receiving vasodilator and anticoagulation therapy for the treatment of Primary Pulmonary Hypertension (PPH). Subsequently, several reports have described the use of vasodilator therapy during parturition and postpartum with good outcomes. The majority of patients in these series had improvements in hemodynamics similar to our patient, leading one to speculate that a favorable short-term response to vasodilator therapy may be predictive of a favorable maternal outcome. Accordingly, we elected to use epoprostenol and heparin for several weeks prior to the expected date of delivery in order to maximize the benefits of this therapy. Furthermore, this therapy was continued in the postpartum period given the increased incidence of complications following labor and delivery. Another important point concerns the safety of the fetus following exposure to IV epoprostenol. Although there is little information on this subject, this report indicates that during the last trimester of pregnancy epoprostenol therapy does not result in any fetal deformities or growth retardation.

Several factors have been implicated as potential risk factors for maternal death, including mode of delivery, type and technique of anesthesia, and manner of maternal monitoring. A recent case series described successful outcomes in seven women with Primary Pulmonary Hypertension (PPH) following vaginal delivery. In contrast, greater morbidity and mortality has been associated with the performance of a cesarean section. To our knowledge, this is one of a small number of reports noting a successful maternal-fetal outcome following cesarean section in a patient with Primary Pulmonary Hypertension (PPH). An explanation for this observation has been offered and may be related to the selection of the anesthetic technique (epidural or general anesthesia), although it is not clear whether one technique is superior in the setting of Primary Pulmonary Hypertension (PPH) on and parturition. Another explanation may lie in the fact that cesarean section is more likely to be performed in patients unable to deliver by the vaginal route who subsequently develop hemodynamic instability. While some authors have disputed the need for a PAC, we advocate its use intraoperatively and during the postpartum period. In this report, the epoprostenol infusion was titrated using pulmonary artery pressure and cardiac output measurements obtained with a PAC. An important component in the successful management of these patients involves a multidisciplinary team approach with an obstetrician, pulmonary or cardiology specialist, anesthesiologist, and experienced nursing staff.

In summary, Primary Pulmonary Hypertension (PPH) is likely to worsen during labor and delivery, resulting in a high maternal mortality rate. Early recognition and treatment with vasodilator and anticoagulation therapy may reduce the likelihood of complications. Elective cesarean section may be performed with intraoperative vasodilator administration. The IV epoprostenol dose not give rise to physical deformities or fetal growth retardation. A multidisciplinary approach to the management of patients with Primary Pulmonary Hypertension (PPH) during pregnancy is of great importance for a successful maternal-fetal outcome.