In
Medicine , (PH) is an increase in blood pressure in the
Pulmonary Artery or
Lung vasculature. Depending on the cause, it can be a severe disease with a markedly decreased exercise tolerance and right-sided
Heart Failure . It was first identified by Dr Ernst von Romberg in 1891. It can be one of five different types, ''arterial, venous, hypoxic, thromboembolic,'' or ''miscellaneous''.
A history usually reveals gradual onset of
Shortness Of Breath ,
Fatigue , non-productive
Cough ,
Angina Pectoris ,
Syncope (fainting), peripheral
Edema , and rarely
Hemoptysis . Pulmonary ''arterial'' hypertension () typically does not present with
Orthopnea or
Paroxysmal Nocturnal Dyspnea , while pulmonary ''venous'' hypertension typically does.
In order to establish the cause, the physician will generally conduct a thorough medical history. A detailed family history is taken to determine whether the disease might be familial.
Physical Examination is performed to look for typical signs of pulmonary hyertension including a loud P2 (pulmonic valve closure sound), (para)sternal heave, jugular venous distension, pedal
Edema ,
Ascites , hepatojugular reflux, etc.
The most common cause of pulmonary hypertension is left
Heart Failure leading to pulmonary ''venous'' hypertension. This may be due to
Systolic or
Diastolic malfunction of the left
Ventricle or due to valvular dysfunction such as
Mitral Regurgitation or
Mitral Stenosis . It usually manifests as
Pulmonary Edema .
Common causes of pulmonary ''arterial'' hypertension (PAH) include
HIV ,
Scleroderma and other
Autoimmune disorders,
Cirrhosis and
Portal Hypertension ,
Sickle Cell Disease ,
Congenital Heart Disease ,
Thyroid diseases, and others. Use of weight loss pills such as
Fen-Phen ,
Aminorex ,
Fenfluramine (Pondimin), and
Phentermine led to the development of PAH in the past. When none of these causes can be found, the disease is termed idiopathic pulmonary arterial hypertension (IPAH).
Lung diseases that lower oxygen in the blood (
Hypoxia ) are well known causes of pulmonary hypertension, including
COPD ,
Interstitial Lung Disease ,
Pickwickian Syndrome or obesity-hypoventilation syndrome, and possibly
Sleep Apnea .
Pulmonary Embolism also leads to pulmonary hypertension, acutely as well as chronically.
Other causes include
Sarcoidosis ,
Histiocytosis X , and fibrosing mediastinitis.
Normal pulmonary arterial pressure in a person living at sea level has a mean value of 12-16 mmHg. Definite pulmonary hypertension is present when mean pressures at rest exceed 25 mmHg. If mean pulmonary artery pressure rises above 30 mmHg with exercise, that is also considered pulmonary hypertension.
Diagnosis of PAH requires the presence of pulmonary hypertension with two other conditions. Pulmonary artery occlusion pressure (PAOP or PCWP) must be less than 15 mmHg and pulmonary vascular resistance (PVR) must be greater than 3 Wood units (or 240 dyn•sec•cm
-5).
Although pulmonary arterial pressure can be estimated on the basis of
Echocardiography , pressure sampling with a
Swan-Ganz Catheter provides the most definite measurement. PAOP and PVR can not be measured directly with
Echocardiography . Therefore diagnosis of PAH requires a cardiac catheterization.
Swan-Ganz Catheter can also measure the
Cardiac Output , which is far more important in measuring disease severity than the pulmonary arterial pressure.
Other diagnostic tests generally include
Pulmonary Function Test s,
Blood Test s,
Electrocardiography (ECG),
Arterial Blood Gas measurements,
X-ray s of the chest (followed by high-resolution
CT Scan ning if
Interstitial Lung Disease is suspected), and ventilation-perfusion or
V/Q Scan ning to exclude chronic thromboembolic pulmonary hypertension. Biopsy of the lung is usually not indicated unless the pulmonary hypertension is thought to be secondary to an underlying interstitial lung disease but is fraught with risks of bleeding because of high pressure. Clinical improvement is often measured by a "six-minute walk test", i.e. the distance a patient can walk in six minutes. Stability and improvement in this measurement correlate with reduced mortality.
The terms primary and secondary pulmonary hypertension (PPH and SPH) were formerly used to classify the disease. This led to the assumption that only the primary disease should be treated, and the secondary variety should be ignored. In fact all forms of pulmonary arterial hypertension are treatable. Unfortunately, this classification system still persists in the minds of many physicians, and probably leads to many patients with being denied treatment. This nihilistic approach to pulmonary arterial hypertension may also contribute to underdiagnosis. It is estimated that there are about 100,000 patients with PAH in the US, but only 15-20,000 have been diagnosed. Many others have been misdiagnosed as
COPD ,
Asthma , or
CHF .
The term primary pulmonary hypertension (PPH) has now been replaced with idiopathic pulmonary arterial hypertension (IPAH). When a family history exists, the disease is termed familial pulmonary arterial hypertension (FPAH). IPAH and FPAH are now considered to be
Genetic Disorder s linked to mutations in the ''BMPR2'' gene, which encodes a
Receptor for bone morphogenic proteins, as well as the ''5-HT(2B)'' gene, which codes for a
Serotonin receptor.
In 2003, the 3rd World Symposium on Pulmonary Hypertension was convened in Venice to modify the classification based on the new understanding of disease mechanisms. The revised system developed by this group provides the current framework for understanding pulmonary hypertension.
The system includes several improvements over the former 1998 Evian Classification system. Risk factor descriptions were updated, and the classification of congenital systemic-to pulmonary shunts was revised. A new classification of genetic factors in PH was recommended, but not implemented because available data were judged to be inadequate.
The Venice 2003 Revised Classification system can be summarized as follows:
- WHO Group I - Pulmonary arterial hypertension (PAH)
- WHO Group II - Pulmonary hypertension associated with left heart disease
- WHO Group III - Pulmonary hypertension associated with lung diseases and/or hypoxemia
- WHO Group IV - Pulmonary hypertension due to chronic thrombotic and/or embolic disease
- WHO Group V - Miscellaneous
IPAH is a rare disease with an annual incidence is about 1-10 in 1,000,000. Women are almost three times as likely to present with IPAH than men.
Other forms of PAH are far more common. In
Scleroderma the incidence has been estimated to be 6 to 60% of all patients, in
Rheumatoid Arthritis up to 21%, in
Systemic Lupus Erythematosus 4 to 14%, in
Portal Hypertension between 2 to 5%, in HIV about 0.5%, and in sickle cell disease ranging from 20 to 40%.
Diet pills such as
Fen-Phen produced an annual incidence of 25-50 per million.
Treatment is determined by whether the PH is arterial, venous, hypoxic, thromboembolic, or miscellaneous. Since pulmonary hypertension is synonymous with
CHF , the treatment is to optimize left ventricular function by the use of
Diuretic s,
Beta Blocker s,
ACE Inhibitor s, etc., or to repair/replace the
Mitral Valve .
In PAH, lifestyle changes,
Digoxin ,
Diuretic s, oral
Anticoagulant s, and oxygen therapy are considered therapy, but have never been proven to be beneficial in a randomized, prospective manner.
High dose calcium channel blockers are useful in only 5% of IPAH patients who are ''vasoreactive'' by
Swan-Ganz Catheter . Unfortunately, calcium channel blockers have been largely misused, being prescribed to many patients with non-vasoreactive PAH, leading to excess morbidity and mortality.
Prostacyclin (
Prostaglandin I
2) is commonly considered the most effective treatment for PAH.
Epoprostenol (synthetic
Prostacyclin marketed as
Flolan ®) is given via continuous infusion that requires a semi-permanent
Central Venous Catheter . This delivery system can cause
Sepsis and
Thrombosis .
Flolan ® is unstable, and therefore has to be kept on ice during administration. Since it has a half-life of 3 to 5 minutes, the infusion has to be continuous (24/7), and interruption can be fatal. Other
Prostanoid s have therefore been developed. Treprostinil (Remodulin®) can be given subcutaneously, but can be very painful. It can also be given intravenously, like Flolan®.
Iloprost (Ventavis®) is the only inhaled form of this class of drug approved for use in the US and Europe.
Iloprost (Ilomedin®) is also used in Europe intravenously.
and
Ambrisentan .
Sildenafil , better known for its effects on
Erectile Dysfunction as
Viagra ®, was approved in
2005 . It is marketed for PAH as Revatio®.
Tadalafil , marketed as Cialis® for
Erectile Dysfunction is currently in clinical trials for PAH. The advantage of
Tadalafil over
Sildenafil is its longer half-life leading to once daily dosing versus thrice daily.
Other promising agents for PAH include
Vasoactive Intestinal Peptide ,
Serotonin antagonists, and
Imatinib (Gleevec® or Glivec®).
Atrial septostomy is a surgical procedure that creates a communication between the right and left
Atria . It relieves pressure on the right side of the heart, but at the cost of lower oxygen levels in blood (
Hypoxia ). It is best performed in experienced centers.
Lung Transplant ation cures pulmonary arterial hypertension, but leaves the patient with the complications of transplantation, and a survival of about 5 years.
Pulmonary thromboendarterectomy (PTE) is a surgical procedure that is used for chronic thromboembolic pulmonary hypertension. It is the surgical removal of an organized
Thrombus (clot) along with the lining of the pulmonary artery; it is a large and very difficult procedure that is currently performed in
San Diego, California and a few other centers. Case series show remarkable success in most patients.
Treatment for hypoxic and miscellaneous varities of pulmonary hypertension have not been established. However, studies of several agents are currently enrolling patients. Many physicians will treat these diseases with the same medications as for PAH, until better options become available.
The NIH IPAH registry from the 1980's showed an ''untreated'' median survival of 2-3 years from time of diagnosis, with the cause of death usually being right ventricular failure (
Cor Pulmonale ). Although this figure is widely quoted, it is probably irrelevant today. Outcomes have changed dramatically over the last two decades. This maybe because of newer drug therapy, better overall care, and earlier diagnosis (lead time bias). A recent outcome study of those patients who had started treatment with bosentan (Tracleer®) showed that 86% patients were alive at 3 years. With multiple agents now available, combination therapy is increasingly used. Impact of these agents on survival is not known, since many of them have been developed only recently. It would not be unreasonable to expect median survival to extend past 10 years in the near future.
