PULMONARY CIRCULATION The pulmonary circulation is the vascular system that conducts blood from the right to left side of the heart through the lungs Pulmonary arteries are very thin walled and distensible. Pulmonary vascular resistance (PVR) is a measure of the impedance to flow in the pulmonary vasculature PVR Depends on pulmonary artery pressure ,left atrial pressure and the cardiac output Normal pulmonary artery pressure=25/8 mmHg Normal mean pulmonary artery pressure=15+/-3mmHg
INTRODUCTION Pulmonary hypertension (PH) is an abnormal elevation in pulmonary artery pressure It is a feature of advanced disease. The pulmonary artery pressure and pulmonary vascular resistance progressively rises, leading to right heart failure and death. Over the years, improvement in understanding the pathogenesis has resulted in the development of targeted approaches to the treatment of PH. Survival advantage has also been shown with some of the pharmacologic agents.
DEFINATIONS Pulmonary hypertension (PH) is haemodynamic and pathophysiological condition defined as mean pulmonary artery pressure > 25 mmHg at rest by Right heart Catheterization(RHC). Pulmonary arterial hypertension (PAH) is a clinical condition characterized by the presence of pre- capillary PH in absence of other causes of pre- capillary PH such as PH due to lung diseases, chronic thromboembolic PH, or other rare diseases
HISTORY E. Romberg, German doctor published description of autopsy, showed thickening of the pulmonary artery but no heart or lung disease. In 1951, 39 cases were reported by Dr. D.T. Dresdale in the United States. Between 1967 and 1973, a 10-fold increase in unexplained PH was reported in central Europe. The rise was subsequently traced to Aminorex fumarate, an amphetamine-like drug introduced in Europe in 1965 to control appetite.
CLASSIFICATION OF PULMONARY HYPERTENSION First version was proposed in 1973 at the first international conference on PPH by WHO. Second and third world meetings on PAH in 1998 and 2003, respectively. Fourth World meet on PH held in 2008 in Dana Point, California,adopted new clinical classification.
GROUP 1. PULMONAY ARTERIAL HYPERTENSION Key feature: Elevation in PAP with normal PCWP Idiopathic (IPAH) Heritable ( BMPR2, ALK1, endoglin , Unknown) Exposure to drugs or toxins Persistent pulmonary hypertension of the newborn Associated with (APAH) Collagen vascular disease Congenital heart diseases Portal hypertension HIV infection Schistosomiasis Chronic haemolytic anaemia GROUP 1’ Pulmonary veno-occlusive disease(PVOD) and pulmonary capillary haemangiomatosis
GROUP 2. Pulmonary venoushypertension Key feature: Elevation in PAP with elevation in PCWP Includes: Systolic dysfunction Diastolic dysfunction Valvular disease
GROUP 3. PH ASSOCIATED WITHHYPOXEMIC LUNG DISEASE.Key feature: chronic hypoxia with mild elevation of PAP, Includes: Chronic obstructive lung disease Interstitial lung disease Sleep-disordered breathing Alveolar hypoventilation disorders Chronic exposure to high altitude Developmental abnormalities
GROUP 4. PH DUE TO CHRONICTHROMBOEMBOLIC DISEASEKey feature: elevation of PA pressure with documentation of pulmonary arterial obstruction for >3 months Includes: Chronic pulmonary thromboembolism
GROUP 5. WITH UNCLEAR AND/OR MULTIFACTORIAL MECHANISMSKey feature: elevation in PAP in association with a systemic disease where a causal relationship is not clearly understood. Includes: Haematological disorders: myeloproliferativedisorder,splenectomy. Systemic disorders : sarcoidosis, pulmonary Langerhans cell histiocytosis, neurofibromatosis, vasculitis Metabolic disorders: Glycogen storage disease, Gaucher disease Thyroid disorders Others: Tumoural obstruction, fibrosing mediastinitis chronic renal failure on dialysis
PATHOLOGY OF PH Different pathological features characterize the diverse clinical PH groups.Group 1 - PAH Affect the distal pulmonary arteries (<500 um of diameter) in particular, are characterized by Medial hypertrophy, Eccentric and concentric intimal fibrosis, Recanalized thrombi appearing as fibrous webs, Plexiform lesions Pulmonary veins are classically unaffected.
PATHOLOGY OF PHGroup 1’ : Includes mainly PVOD Which involves septal veins and pre-septal venules with occlusive fibrotic lesions, venous muscularization, capillary proliferation , pulmonary oedema, occult alveolar haemorrhage, lymphatic dilatation and lymph node enlargement. Distal pulmonary arteries are affected .
PATHOLOGY OF PHGroup 2 - PH due to left heart disease: Characterized by enlarged and thickened pulmonary veins, pulmonary capillary dilatation, interstitial oedema,alveolar haemorrhage, and lymphatic vessel and lymph node enlargement. Distal pulmonary arteries may be affected Group 3 - PH due to lung diseases and/or hypoxia: Include medial hypertrophy and intimal obstructive proliferation of the distal pulmonary arteries. A variable degree of destruction of the vascular bed in emphysematous or fibrotic areas may also be present.
PATHOLOGY OF PHGroup 4 -CTEPH: Characterized by organized thrombi tightly attached to medial layer in pulmonary arteries, replacing the normal intima. These may completely occlude the lumen or form different grades of stenosis, webs, and bands. Collaterals from the systemic circulation can grow. Group 5-PH - unclear and/or multifactorial mechanisms: Includes conditions with different pathological pictures Aetiology is unclear or multifactorial.
PATHPHYSIOLOGY OF PHGroup 1-The exact processes that initiate the pathological changes seen in PAH are still unknown The increase in PVR is related to vasoconstriction,proliferative and obstructive remodelling of the pulmonary vessel wall, inflammation, and thrombosis. Excessive vasoconstriction related to abnormal function or expression of potassium channels in the smooth muscle cells and endothelial dysfunction.Group 2- the mechanisms are multiple and include Passive backward transmission of the pressure elevation . The elevation of PVR is due to an increase in vasomotor tone of pulmonary arteries and fixed structural obstructive remodelling Vasoconstrictive reflexes arising from stretch receptors in the left atrium and pulmonary veins, and endothelial dysfunction
PATHPHYSIOLOGY OF PHGroup 3- mechanisms include Hypoxic vasoconstriction, mechanical stress of hyperinflated lungs, inflammation and toxic effects of cigarette smoke.Group 4 - Non-resolution of acute embolic masses which later undergo fibrosis leading to mechanical obstruction of pulmonary arteries Pulmonary thromboembolism or in situ thrombosis may be initiated or aggravated by abnormalities in either the clotting cascade, endothelial cells, or platelets,Group 5- PH with unclear and/or multifactorial mechanisms
PULMONARY ARTERIAL HYPERTENSION PAH refers to a variety of diseases that include idiopathic PAH. PAH Characterized by presence of pre-capillary PH in the absence of other causes of pre-capillary PH. Mean PAP >25 mmHg PCWP< 15 mmHg . CO normal or reduced
MOLECULAR ABNORMALITIES IN PAHProstacyclin Prostacyclin is a potent vasodilator, inhibits platelet activation, and has antiproliferative properties Prostacyclin synthase is decreased in the pulmonary arteries in PAHEndothelin-1 Endothelin-1 (ET-1) is a potent vasoconstrictor and stimulates PASMC proliferation. Plasma levels of ET-1 are increased in PAH and clearance is reducedNitric Oxide Nitric oxide (NO) is a vasodilator and inhibitor of platelet activation and vascular smooth-muscle cell proliferation. Once formed, the effects of NO are largely mediated by cGMP which is rapidly inactivated by PDE, especially the PDE-5 isoenzymes.
MOLECULAR ABNORMALITIES IN PAHSerotonin (5-HT) is a vasoconstrictor and promotes PASMC hypertrophy and hyperplasia. Allelic variation in serotonin transporter present in PAHVasoactive intestinal peptide (VIP) has a pharmacologic profile similar to prostacyclins. Serum and lung tissue VIP levels are decreased in PAH patients
GENETICS OF PAHBONE MORPHOGENETIC PROTEIN RECEPTOR 2 GENE(BMPR2) BMPR2 gene encodes a type 2 receptor for bone morphogenetic proteins, which belong to the TGF-b superfamily involved in the control of vascular cell proliferation mutations are detected in at least 70% of cases PAH occurs in a familial context. Mutations of this gene can also be detected in 11–40% of apparently sporadic cases.ACTIVIN RECEPTOR-LIKE KINASE 1 AND ENDOGLIN, have been identified in PAH
IDIOPATHIC PAH IPAH corresponds to sporadic disease,without any familial history of PAH or known triggering factor. Formerly referred to as primary pulmonary hypertension 1-2 cases per million Females>males (1.7:1)
SYMPTOMSEasy fatigability, lethargyExertional chest discomfortSyncope with exertionCoughHemoptysisHoarseness of voice
SIGNS Increased intensity of the pulmonic component of the second heart sound (P2) Systolic ejection murmur from TR S/O Advanced Disease. Diastolic murmur of PI in severe PH. left parasternal lift or heave Prominent ‘a’ wave in jugular venous system. Signs of RV failure: Jugular venous distension Hepatomegaly Ascites, and/or peripheral edema
WHO CLASSIFICATION OF FUNCTIONAL STATUS OFPATIENTS WITH PH Class Description I Patients with PH in whom there is no limitation of usual physical activity; ordinary physical activity does not cause increased dyspnea, fatigue, chest pain, or presyncope. II Patients with PH who have mild limitation of physical activity. There is no discomfort at rest, but normal physical activity causes increased dyspnea, fatigue, chest pain, or presyncope. III Patients with PH who have a marked limitation of physical activity. There is no discomfort at rest, but less than ordinary activity causes increased dyspnea, fatigue, chest pain, or presyncope. IV Patients with PH who are unable to perform any physical activity at rest and who may have signs of right ventricular failure. Dyspnea and/or fatigues may be present at rest, and symptoms are increased by almost any physical activity. Chest 2004:126 (Suppl), JACC 2004:43 (Suppl)
NATURAL HISTORY AND SURVIVAL Median survival 2.8 years, with 1-, 3-, and 5-year survival rates of 68%, 48%, and 34%, respectively. Functional class remains a strong predictor of survival The prognosis in patients with PAH associated with the scleroderma is worse than for IPAH. CHD have a better prognosis than those with IPAH Cause of death is usually RV failure, manifest by progressive hypoxemia, tachycardia, hypotension, and edema
PARAMETERS OF WORSE PROGNOSISIN PAH Presence of RV failure Rapid progression of symptoms Syncope WHO –FC IV 6 MWT < 300 m Pericardial effusion
ELECTROCARDIOGRAPHY ECG has sensitivity(55%) and specificity (70%) detecting significant PH ,may demonstrate Right ventricular hypertrophy or strain Right axis deviation P pulmonale due to right atrial enlargement. Ventricular arrhythmias are rare. SVT may be present in advanced stages
ElectrocardiogramElectrocardiogramdemonstrating the Right ventricular hypertrophy with strain Right axis deviation , Increased P-wave amplitude in lead II
CHEST RADIOGRAPH In 90% of patients with IPAH the chest radiograph is abnormal. Findings include central pulmonary arterial dilatation, which contrasts with ‘pruning’ (loss) of the peripheral blood vessels. Right atrium and RV enlargement may be seen
CHEST RADIOGRAPH Enlargement of the central pulmonary arteries with attenuation of the peripheral vessels Right ventricular enlargement and seen.
ECHOCARDIOGRAPHY Is performed to estimate the pulmonary artery systolic pressure and to assess RV size, thickness, and function. In addition, left ventricular systolic and diastolic function, and valve function, while detecting pericardial effusions and intracardiac shunts. PH may have echocardiographic signs of right ventricular pressure overload, including paradoxical bulging of the septum into the left ventricle during systole and hypertrophy of the right ventricular free wall. As the right ventricle fails, there is dilation and hypokinesis, septal flattening, right atrial dilation, and tricuspid regurgitation
ECHOCARDIOGRAPHY Echocardiography uses Doppler ultrasound to estimate the pulmonary artery systolic pressure . This technique takes advantage of the tricuspid regurgitation that usually exists. The maximum tricuspid regurgitant jet velocity is recorded and the pulmonary artery systolic pressure (PASP) is then calculated by Bernoulli’s equation PAP systolic = 4 x ( tricuspid jet velocity squared)m/s + RAP Theoretically, calculation of mean PAP from PA systolic pressure is possible mean PAP =0.61 X PAP systolic + 2 mmHg. A systolic PAP greater than 40 mmHg is suggestive of PH.
ECHOCARDIOGRAPHYA four-chamberechocardiographicview of a patient whohas severe PAH.Note the massivelydilated right ventricle(RV) and right atrium(RA) that haveshifted the septa andnarrowed the leftventricle (LV) andleft atrium (LA).
Representation of echocardiographic findings inpulmonary hypertension
VENTILATION-PERFUSION SCANNING Is used to evaluate patients for thromboembolic disease. A normal V/Q scan accurately excludes chronic thromboembolic disease with a sensitivity of 90 to 100 percent and a specificity of 94 to 100 percent . Pulmonary angiography is necessary to confirm the positive V/Q scan and to define the extent of disease.
PULMONARY ANGIOGRAMUsed to measurecirculation in the lungs andto visualize clots in thelung on x-rays.
PULMONARY FUNCTION TESTS Pulmonary function tests (PFTs) are performed to identify and characterize underlying lung disease contributing to PH. An obstructive pattern is suggestive of COPD, Restrictive disease suggests ILD, neuromuscular weakness, or chest wall disease. In most circumstances, PH should not be attributed to lung disease if the PFTs are only mildly abnormal.
LABORATORY TESTS HIV serology to screen for HIV-associated PH Liver function tests to screen for porto-pulmonary hypertension Antinuclear antibody (ANA) Thyroid function test NT-proBNP is the precursor of BNP in right heart failure . Anti-centromere antibodies in scleroderma Thrombophilia screening including anti-phospholipid antibodies, lupus anticoagulant, and anti-cardiolipin antibodies should be performed in CTEPH
OVERNIGHT OXIMETRY Nocturnal oxyhemoglobin desaturation can be identified by overnight oximetry in patients with PH —obstructive sleep apnea-hypopnea (OSAH) coexists . Polysomnography is the gold standard diagnostic test for OSAH.ULTRASONOGRAPHY Useful in portal hypertension
EXERCISE TESTING Exercise testing is most commonly performed using the six minute walk test (6MWT) Provide benchmarks for disease severity, response to therapy, and progression. In addition to distance walked, dyspnoea on exertion and finger O2 saturation are recorded. Walking distances , <250 m and O2 desaturation 10% indicate impaired prognosis in PAH.
RIGHT HEART CATHETERIZATION Right heart catheterization is necessary to confirm the diagnosis of PH . Accurately determine the severity of the hemodynamic derangements. PH is confirmed if the mean pulmonary artery pressure is greater than 25 mmHg at rest . RHC is required to guide therapy An additional benefit of RHC is that the presence and/or severity of a congenital or acquired left-to-right shunt.
VASOREACTIVITY TESTAim: To detect the residual properties of vasodilatation of small pulmonary arteries and arterioles . It is recommended in patients with group 1 PAH . This involves the administration of a short-acting vasodilator and then measurement of the hemodynamic response . Agents commonly used for vasoreactivity testing include epoprostenol, adenosine, and inhaled nitric oxide . Epoprostenol is infused at a starting rate of 1 to 2 ng/kg per min and increased by 2 ng/kg per min every 5 to 10 minutes until a clinically significant fall in blood pressure, an increase in heart rate, or adverse symptoms develop .
VASOREACTIVITY TEST Test is positive if mPAP decreases at least 10 mmHg and to a value less than 40 mmHg, with an increased or unchanged cardiac output, and a minimally reduced or unchanged systemic blood pressure. Patients with a positive vasoreactivity test are candidates for a trial of CCB therapy. Negative vasoreactivity test should be treated with an alternative agent .
COMPUTERIZED TOMOGRAPHY High-resolution CT provides detailed views of the lung parenchyma and facilitates the diagnosis of interstitial lung disease and emphysema. High-resolution CT may be very helpful where there is a clinical suspicion of PVOD Contrast CT angiography of the PA is helpful in determining whether there is evidence of surgically accessible CTEPH.
MAGNETIC RESONANCE IMAGING Cardiac MRI may soon supersede this as the gold standard. RV mass which is difficult to quantify by other methods can be accurately done by MRI. By MRI, it can be shown that right ventricle has a crescent shape and left ventricle has a more circular shape. When the right ventricle pressure is elevated quite the opposite happens. This can be well demonstrated by MRI.
LUNG BIOPSY Is reserved only in an unusual patient in whom PH is not thought to be the primary disease. In such patients, one always finds abnormalities such as lung infiltrates or other findings such as pulmonary hemangiomatosis or pulmonary venoocclusive disease.
TREATMENT OF PH Early identification and treatment PH is generally suggested because advanced disease may be less responsive to therapy . Treatment begins with a baseline assessment of disease severity, followed by primary therapy. 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, rather than the underlying cause of the PH. It includes treatment with prostanoids, endothelin receptor antagonists, phosphodiesterase 5 inhibitors, or, rarely, certain calcium channel blockers.
BASELINE ASSESSMENT The baseline severity assessment is essential because the response to therapy will be measured as the change from baseline. The functional significance of the PH is determined by measuring exercise capacity. From the exercise capacity, the patients WHO functional class can be determined . Pulmonary artery systolic pressure and right ventricular function can be estimated by echocardiography, and then used to make a presumptive diagnosis of PH. Right heart catheterization must be performed to accurately measure the hemodynamic parameters and confirm that PH exists.
PRIMARY THERAPY Primary therapy refers to treatment that is directed at the underlying cause of the PH.Group 1 PAH There are no effective primary therapies for most types , advanced therapy is often needed.Group 2 PH — Patients with group 2 PH have PH secondary to left heart diseases. Primary t/t of the underlying heart disease.Group 3 PH — Patients with group 3 PH have PH secondary to various causes of hypoxemia. treatment of the underlying cause of hypoxemia and correction of the hypoxemia with supplement of oxygen
PRIMARY THERAPYGroup 4 PH — Patients with group 4 PH have PH due to thromboembolic occlusion . Anticoagulation is primary medical therapy for patients . Surgical thromboendarterectomy is primary surgical therapy for selected patients with thromboembolic obstruction of the proximal pulmonary arteries . Perioperative mortality for this procedure is less than 10 percentGroup 5 PH — Group 5 PH is uncommon and includes PH with unclear multifactorial mechanisms. Primary therapy is directed at the underlying cause.
GENERAL MEASURES All groups — Several therapies should be considered in all patients with PH. . Diuretics — Diuretics are used to treat fluid retention due to PH . Should be administered with caution to avoid decreased cardiac output , arrhythmias induced by hypokalemia, and metabolic alkalosis.Oxygen therapy — Oxygen the cornerstone of therapy in patients with group 3 PH. Oxygen is generally administered at 1 to 4 L/min and adjusted to maintain the oxygen saturation above 90 percent . Supplemental oxygen will not significantly improve the oxygen saturation of patients who have Eisenmenger physiology.
GENERAL MEASURESDigoxin — Improves the right ventricular ejection fraction of patients with group 3 PH due to COPD and biventricular failure helps control the heart rate of patients who have SVT associated with RV dysfunction .Anticoagulation — increased risk for intrapulmonary thrombosis and thromboembolism, due to sluggish pulmonary blood flow, dilated right heart chambers, venous stasis, and a sedentary lifestyle. indicated in patients with IPAH , hereditary PAH , drug- induced PAH , or group 4 PH. The anticoagulant of choice is warfarin. Goal of an INR of approximately 2.
GENERAL MEASURES It is recommended to avoid pregnancy Immunization against influenza and pneumococcal infection is recommended. Psychosocial support should be considered in patients with PAH. Epidural anaesthesia instead of general anaesthesia should be utilised, if possible, for elective surgery. Excessive physical activity that leads to distressing symptoms is not recommended in patients.
ADVANCED THERAPY Advanced therapy is directed at the PH itself, rather than the underlying cause of the PH. It includes treatment with prostanoids, endothelin receptor antagonists, phosphodiesterase 5 inhibitors, or, rarely, certain calcium channel blockers. Patient selection — Advanced therapy is considered for patients who have evidence of persistent PH and a World Health Organization WHO functional class II, III.
CALCIUM CHANNEL BLOCKERS(CCB) Patient who may benefit from CCB therapy can be identified acute vasodilator response test in PAH. The dosages used are quite high; 90–180 mg/day for nifedipine (up to 240 mg/day) and 240–720 mg/day for diltiazem (up to 900 mg/day). or amlodipine, 20 mg/d <20% of patients respond to calcium channel blockers in the long term. Not effective in patients who are not vasoreactive. Patients with BMPR2 receptor mutation do not respond . Side effects – constipation, nausea, headache, rash, edema, drowsiness, dizzi ness, low blood pressure
PROSTACYCLIN The main product of arachidonic acid in the vascular endothelium causes relaxation of smooth muscle Also results in inhibition of growth of smooth muscle cells. Intravenous prostacyclin was first introduced in the early 1980s. Successfully used in the treatment of PH resulting from left to right shunt, portal hypertension and HIV infection.
EPOPROSTENOL Potent vasodilator ,Unstable at acidic pH, not taken orally. Very short half life,<6 min requires constant Iv administration Initial dose: 1 – 2 ng/kg/min Titrating in increments of 1- 2 ng/kg/min, based upon side effects and tolerance to reach a “plateau” between 20 – 40 ng/kg/min Side effects: Flushing, headache, jaw pain with first bite of food, diarrhea, nausea, erythematous rash and musculoskeletal pain. Chronic IV therapy: Line related infections, catheter associated venous thrombosis, thrombocytopenia Not available in India.
TREPROSTINIL Stable prostacyclin analogue. Can be given intravenously or subcutaneously and Inhalation. Half life of 3 hours. Stable at room temperature Initially 1.25 ng/kg/min up to maximum of 22.5 ng/kg/min. Side effects: Headache, diarrhea, nausea, rash, jaw pain, infusion site pain, erythema or induration.
ILOPROST Prostacyclin analogue. Serum half-life of 20 – 25 mins For functional class 3 – 4. Administered via nebulized aerosol. Administered 6 – 9 times a day, each inhalation requires 10 – 15 mins. Dose: 2.5 – 5 ug, median inhaled dose of 30 ug/day. Side effects: Cough, headache and flushing.
BERAPROST First chemically stable and orally active prostacyclin analogue. Peak concentration is reached after 30 minutes and elimination half-life is 35 – 40 minutes after oral administration. Median dose of 80 ug PO daily.
ENDOTHELIN RECEPTOR ANTAGONISTS Endothelin-1 is a potent vasoconstrictor and smooth muscle mitogen. High concentrations of endothelin-1 have been recorded in the lungs of patients with group 1 PAH, including scleroderma and congenital cardiac shunt lesions . Emerged as an initial therapy for group 1 PAH in the late 1990s.
BOSENTAN Nonselective endothelin receptor antagonist, improves hemodynamics and exercise capacity in patients with group 1 PAH. Orally active nonpeptide antagonist of both endothelin receptor subtypes. Prevents and even reverses the development of PH, pulmonary vascular remodelling and right ventricular hypertrophy. Initial dose of 62.5 mg bid for first 4 weeks and followed by target dose of 125 mg bid. Side effects: Hepatotoxicity and teratogenicity. Available in India.
SITAXSENTAN Selective ETA antagonist Has oral bioavailability and a long duration of action (t 1/2, 5-7h) . Side effects: ↑ INR and PT .AMBRISENTAN ETA selective antagonist Under research
PHOSPHODIESTERASE INHIBITORSSILDENAFIL Orally administered cyclic GMP phosphodiesterase 5 (PDE5) inhibitors that prolong the vasodilatory effect of NO in group 1 PAH. Approved dose is 20 mg t.i.d., but the durability of effect up to a up-titration beyond 20 mg t.i.d. (mainly 40–80 mg t.i.d.) is needed quite frequently. Contraindicated with Nitrates and nicorandil. Prevent rebound pulmonary vasoconstrictionTadalafil and vardenafil also appear to improve outcomes in patients with group 1 PAH.
NITRIC OXIDE Inhaled form. Acts as direct smooth muscle relaxant via activation of the guanylate cyclase system. Short therapeutic half life. Ameliorates hypoxemia and lowers PVR by direct pulmonary vasodilatation.
SURGICAL INTERVENTIONSBalloon Atrial Septostomy Allow R - L shunting to increase systemic output that In spite of fall in the systemic arterial oxygen saturation, will produce an increase in systemic oxygen transport. Shunt at the atrial level would allow decompression of the RA and RV, alleviating s/s of right heart failure. Considered after short term failure of maximal medical therapy. Severe IPAH has been the main indication other include PAH associated with surgically corrected CHD, CTD, distal CTEPH, PVOD, and pulmonary capillary haemangiomatosis.
HEART / LUNG TRANSPLANTATION 1 year survival of 70%. 5 year survival of 50%. Effective therapy for patients with end stage pulmonary vascular disease.Other areas of research for treatment of PH includes Gene therapy serotonin transporter vasoactive intestinal peptide and tyrosine kinase inhibitors. Angiogenic factors and stem cells . Imatinib
:Treatment algorithm for pulmonaryarterial hypertension
REFERENCES European Heart Journal (2009) 30, 2493– 2537doi:10.1093/eur heart/ehp297 Journal of the American College of Cardiology/Volume 53, Issue 17, April Â 28,2009. Harrisons Principles of Internal Medicine18 th edition . http://www.uptodate.com/contents/treatment-of- pulmonary-hypertension-in-adults Indian Heart Journal 6401 (2012) 60–73
COLLAGEN TISSUE DISEASES Occurs commonly with the CREST syndrome . Often have coexistent interstitial pulmonary fibrosis. Fall in diffusing capacity precede the development of PH. Treatment is identical to that of patients with IPAH but is less effective. The treatment of the PH, not affect the natural history of the underlying collagen vascular disease. Immunosuppressive may result in clinical improvement in patients with PAH associated with SLE or mixed CTD
CONGENITAL SYSTEMIC TO PULMONAY SHUNTS It is common for large post-tricuspid cardiac shunts (e.g.VSD, PDA) less common, in pre tricuspid shunts (e.g. ASD). 3-year survival rate of 77% compared with 35% for untreated IPAH. Prevalence of PAH in adult CHD, 5–10%. Secondary erythrocytosis is beneficial for adequate O2 transport and delivery. Bosentan is currently approved in Europe for WHO-FC III Eisenmenger’s syndrome patients. Heart–lung or lung transplantation with heart surgery is an option in special cases
PORTAL HYPERTENSION 1–2%of patients with liver disease and portal hypertension develop PAH. The pathogenesis may be related to toxic substances derived from the gastrointestinal tract, due to portosystemic shunts, causing damage to the lung endothelium. Another possibility is high CO state is inducing PAH. Epoprostenol,bosentan, and sildenafil may exert beneficial haemodynamic and clinical effects in patients. Anticoagulation is not recommended Significant PAH is a contraindication to liver transplantation if mean PAP is 35 mmHg
LV DIASTOLIC DYSFUCTION PH as a result of LV diastolic failure is common but often unrecognized . It can occur with or without LV systolic failure. The most common risk factors are hypertensive heart disease; coronary artery disease; and impaired LV compliance related to age, diabetes, obesity, and hypoxemia. Symptoms of orthopnea and paroxysmal nocturnal dyspnea are prominent. Many patients improve considerably if LV end-diastolic pressure is lowered.
MITRAL VALVE DISEASE Mitral stenosis and mitral regurgitation represent important causes of PH from reactive pulmonary vasoconstriction resulting in marked elevations in PAP. In patients with MS, corrective surgery predictably results in a reduction in PAP and PVR. Patients with MR, however, may not have as dramatic a response to surgery because of persistent elevations in LV end- diastolic pressure.
CHRONIC OBSTRUCTIVE LUNG DISEASE(COPD) COPD associated with mild PH in the advanced stages . Incidence of PH in COPD with at least one previous hospitalization for exacerbation is 20%. In advanced COPD, PH is highly prevalent 50% . Echocardiography is recommended as a screening . Continuous oxygen therapy relieves the pulmonary vasoconstriction, reverses chronic ischemia and improves survival. Long-term oxygen therapy is indicated if the resting arterial Po2 remains <55 mmHg. vasodilators can worsen gas exchange and not used.
INTERSTITIAL LUNG DISEASE PH in interstitial lung disease that results from parenchymal and vascular remodelling . The prevalence of PH is between 32 and 39%. Coexisting hypoxemia occurs frequently and contributes to morbidity. ILD often associated with the collagen vascular diseases. Many patients have pulmonary fibrosis of unknown etiology. The pulmonary vasodilators approved for PAH have not been shown to be helpful.
THROMBOEMBOLIC DISEASES Most patients treated for acute PTE with IV heparin and oral warfarin do not develop chronic PH. Pulmonary thromboendarterectomy is an established surgical treatment in patients whose thrombi are accessible . Lifelong anticoagulation using warfarin is mandatory Target INR 2.0 .
SICKLE CELL DISEASE The etiology is multifactorial, including hemolysis, hypoxemia, thromboembolism, chronic high cardiac output, and chronic liver disease. Intravascular hemolysis leading to NO deficiency is hypothesized as a major pathogenetic mechanism for PAH in SCD. Prevalance 32 and mortality is 40% in 45 month gldwin etal Intensification of SCD–specific therapy appears to reduce the morbidity.
HIV INFECTION Pathogenesis of HIV-related PAH remains unclear Incidence is estimated at 1 per 200 cases. Treatment is less well established in comparison with other forms of PAH. Epoprostenol, inhaled iloprost may improve exercise tolerance, haemodynamics and symptoms 3-year survival rate as low as 21% in the most advanced cases (WHO-FC III/IV)