Prof. Sevda Özdoğan 2013

 Pulmonary hypertension (PH) is characterized by elevated pulmonary arterial pressure and secondary right ventricular failure (ie, cor pulmonale). It is a progressive, fatal disease if untreated, although the rate of progression is highly variable.  PAH is defined according to right heart catheterization. Mean pulmonary artery pressure (mPAP) >25 mmHg at rest A mean pulmonary artery pressure of 8 to 20 mmHg at rest is considered normal, while a mean pulmonary artery pressure of 21 to 24 mmHg at rest has uncertain clinical implications.

 This group consists of sporadic IPAH, heritable IPAH, and PAH due to diseases that localize to small pulmonary muscular arterioles (eg: connective tissue diseases, HIV infection, portal hypertension, congenital heart disease, schistosomiasis, chronic hemolytic anemia, persistent pulmonary hypertension of the newborn, pulmonary veno-occlusive disease, and pulmonary capillary hemangiomatosis)

 Abnormal bone morphogenetic protein receptor type II (BMPR2) appears to play an important role in the pathogenesis of IPAH.  In hereditary IPAH, the gene that encodes BMPR2 (IPAH1) appears to be transmitted as an autosomal dominant trait. It has been estimated that up to 80 percent of hereditary IPAH is due to mutations in BMPR2

 Connective tissue diseases  Rheumatoid arthritis and systemic lupus erythematosus (SLE) can also lead to fibrous obliteration of the pulmonary vascular bed, with a marked female predominance

 Drug- and toxin-induced PAH is also considered group 1 PAH. (eg: aminorex, fenfluramine, dexfenfluramine, (appetite supressants) and toxic rapeseed oil) Also amphetamines, cocaine (chronic use), L-tryptophan, phenylpropanolamine, chemotherapeutic agents (thyrosine kinase inhibitors, interferon), and selective serotonin reuptake inhibitors are considered likely to cause PAH

 The cause of HIV-related PAH is uncertain, but viral and host factors both likely play an important role.  PAH associated with portal hypertension is referred to as portopulmonary hypertension (PPHTN), The most widely accepted hypothesis is that a humoral substance (which would normally be metabolized by the liver) is able to reach the pulmonary circulation through portosystemic collaterals, resulting in PPHTN.  PAH due to congenital heart disease is due to pulmonary blood volume overload due to intracardiac shunting. Left to right shunts are most common, especially due to large (nonrestrictive) ventricular septal defects (VSD). PAH also occurs in patients with atrial septal defects (ASD).

 Pulmonary hypertension owing to left heart disease. (systolic dysfunction, diastolic dysfunction, or mitral and aortic valve disease, restrictive cardiomyopathy, constrictive pericarditis, and left atrial myxoma)

 Pulmonary hypertension owing to lung diseases or hypoxemia. This group includes PH due to severe chronic obstructive pulmonary disease, interstitial lung disease, pulmonary diseases with a mixed restrictive and obstructive pattern, sleep- disordered breathing, alveolar hypoventilation disorders

 Chronic thromboembolic pulmonary hypertension  Pulmonary hypertension with unclear multifactorial mechanisms. In: hematologic disorders (eg, myeloproliferative disorders), systemic disorders (eg, sarcoidosis), metabolic disorders (eg, glycogen storage disease), or miscellaneous causes (eg, sickle cell disease)

 the prevalence of pulmonary hypertension in patients with SCD is 20 to 40 percent  Red cell hemolysis resulting in increased plasma levels of cell-free hemoglobin, which rapidly depletes the potent pulmonary vasodilator nitric oxide (NO) is the proposed mechanism of PH in SCD

 Sypmptoms:  exertional dyspnea,  lethargy, and fatigue  Symptoms and signs of PH may be difficult to recognize because they are nonspecific. These symptoms are frequently attributed incorrectly to age, deconditioning, or a coexisting medical condition.  The initial symptoms of PH are the result of an inability to adequately increase cardiac output during exercise

 Exertional chest pain  Subendocardial hypoperfusion  Compression of the enlarged pulmonary artery to left main coronary artery  Exertional syncope is due to the inability to increase cardiac output during activity.  Peripheral edema is due to increased right sided cardiac pressures  Anorexia and/or abdominal pain in the right upper quadrant due to passive hepatic congestion.

 Less common symptoms:  cough,  Hemoptysis,  Hoarseness (caused by compression of the left recurrent laryngeal nerve by a dilated main pulmonary artery)

 increased intensity of the pulmonic component of the second heart sound  Right-sided systolic ejection murmur  A high-pitched systolic murmur of tricuspid regurgitation.  Signs of right ventricular failure:  Signs of elevated jugular venous pressure  Hepatomegaly,  An enlarged and pulsatile liver,  peripheral edema,  ascites and pleural effusion may also exist

 Diagnostic testing is indicated whenever PH is suspected.  The purpose of the diagnostic testing is to confirm that PH exists, determine its severity, and identify its cause  It has been estimated that more than 20 percent of patients have symptoms of PH for longer than two years before the PH is recognized

 Chest X ray  enlargement of the central pulmonary arteries with attenuation of the peripheral vessels, resulting in oligemic lung fields  Right ventricular enlargement (diminished retrosternal space) and right atrial dilatation (prominent right heart border)  Signs of the underlying cause of the PH (eg, interstitial lung disease).

 ECG  Echocardiography  Pulmonary Function Tests (to identify and characterize underlying lung disease that may be contributing to PH)  Polysomnography  V/Q scan/ CT Angiography/ Pulmoner angiography  Laboratory tests:  HIV serology  Liver function tests  Antinuclear antibody (ANA), rheumatoid factor (RF), and antineutrophil cytoplasmic antibody (ANCA) titers

 Exercise tests  Screens for alternative causes of the patient's symptoms  Determines the patient's functional capacity which guides therapy  Provides prognostic information, since a longer distance walked during the 6MWT is associated with longer survival  Right Hearth Catheterization  Necessary to confirm the diagnosis of PH  Helpful in distinguishing patients who have PH due to left heart disease

 The diagnosis of PAH also requires right heart catheterization: Several criteria must be met:  Mean pulmonary artery pressure is ≥25 mmHg at rest  Mean pulmonary capillary wedge pressure <15 mmHg (to exclude PH owing to left heart disease  Chronic lung diseases and other causes of hypoxemia are mild or absent  Venous thromboembolic disease is absent  Certain miscellaneous disorders are absent, including systemic disorders (eg, sarcoidosis), hematologic disorders (eg, myeloproliferative diseases), and metabolic disorders (eg, glycogen storage disease).

 Asthma  Chronic obstructive pulmonary disease (COPD)  Interstitial lung disease  Myocardial dysfunction  Obesity/deconditioning  Liver disease  Budd-Chiari syndrome (Thrombosis of hepatic veins)

 PH is a progressive, fatal condition if untreated. However, the rate of progression is highly variable and depends upon the type and severity of the PH.  Symptomatic patients with IPAH who do not receive treatment have a median survival of approximately three years. Symptomatic patients with PAH associated with another disease (eg, liver disease, systemic sclerosis [also called scleroderma]) generally have a worse prognosis  Patients with severe PAH or right heart failure die sooner without treatment (usually within one year) than patients with mild PAH or no right heart failure

 The main cause of death in patients with PAH is thought to be right heart failure with circulatory collapse and superimposed respiratory failure.  Primary therapy is directed at the underlying cause of the PH.  Some patients progress to advanced therapy, which is therapy directed at the PH itself. It includes treatment with prostanoids, endothelin receptor antagonists, phosphodiesterase 5 inhibitors, or, rarely, certain calcium channel blockers.

 Diuretics — Diuretics are used to treat fluid retention due to PH because diuresis will diminish hepatic congestion and peripheral edema  Continuous oxygen administration remains the cornerstone of therapy in patients with group 3 PH  It is generally accepted that anticoagulation is indicated in patients with IPAH, hereditary pulmonary artery hypertension, drug-induced PAH, or group 4 PH (CTEPH).   Exercise training appears to be beneficial for patients with PH