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Pulmonary hypertension (PH) is a spectrum of disease involving pulmonary vasculatue , and is defined as an elevation in pulmonary arterial pressure (mean pulmonary artery pressure > 22 mmhg). pulmonary arterial hypertension (PAH) is a relatively rare form of PH and is characterized by symptoms of dyspnea , chest pain , and syncope. If left untreated , the disease carries a high mortality rate , with the most common cause of death being decompensated right heart failure. There have been significant advances in this field in regard to understanding the pathogenesis , diagnosis , and classification of PAH. Despid these significant advances , there is still a substantial delay in diagnosis of up 2 years. In many cases , patients whose primary complaint is dyspnea on exertion are freqently misdiagnosed with more common disease such as asthma or chronic obstructive pulmonary disease. The availability of newer drugs has resulted in a radical change in the management of this disease with significant improvement in both quality of life and mortality. A delay in diagnosis results in an obviouse delay in the intiation of appropriate treatment. Clinicians should be able to recognize the signs and symptoms of PH and to complate a systematic workup in patients suspected of having it. In this way , early diagnosis , prompt treatment , and improved outcomes for ratients become achievable.
PATHOBOLOGY Vasoconstriction , vascular proliferation , thrombosis , and inflammation appear to underlie the development of PAH. In long-standing PH , intimal proliferation and fibrosis , medial hypertrophy , and in situ thrombosis characterize the pathologic findings in the pulmomary vasculature. Vascular remodeling at earlier stages maybe confined to the small pulmomary arteries , as the disease advances , intimal proliferation and pathologic remodeling progress , resulting in decreased compliance and increased elestanse of the pulmomary vasculature. The outzome is a progresive increase in the right ventricular afterload or total pulmonary vascular resistance (PVR) and ,thus ,right ventricular work .in subjects with moderate to sever pulmonary vascular disease with significantly increased PVR ,as the vesting PVR increase ,there will be a corresponding increase in mean pulmonary artery pressure(PAP)untill the cardiac output (CO)is compromised and starts to fall .with a decline CO ,the PAP with fall ,as CO declines as a result of increase afterload and decreasd contractility ,tachycardia is a compensatory response .tachycardia decrease filling time and ,thus ,preload ,and results in a reduced fraction of strock volume available to distend the pulmonary vascular tree .
Abnormalitis in multiple molecular pathway and genes that regulate the pulmonary vascular endothelial and smooth muscle cells have been indentified .these abnormalities include decreased expression of the voltage_regulated potassium channel ,mutation in the bone morphogenetic protein receptore_2 ,increased tissue factor expression ,overactivation of the serotonin transport ,hypoxia_induced activation of hypoxia_inducible factor_1α and activation of nuclear factor of activated T cells .as a result ,there is a decrease in apoptosis of the smoth muscle cells and the emergance of apoptosis_resistant andothelial cells that promote their yaccumulation and can obliterate the vascular lumen ,in addition ,thrombosis deposition in the pulmonary vasculature from the prothrombotic state that develops as an independent abnormality or as a result of endothelial dysfunction may amplify vascular cell proliferation and the obliterative arteriopathy .
DIAGNOSIS AND CLASSIFICATION The diagnosis of PH can be missed without a reasonable index of suspicion .Dyspnea is the most common presenting symptome ,but this complaint is for from specific for the diagnosis of PH .PH symptoms are including asthma and other lung disease and cardiac disease .the symptoms of PH are often nonspecific and variable .most patients will present with dyspnea and/or fatigrrue ,wherease adema ,chest pain ,presyncope ,and frank syncope are less common and associated with more advanced disease ,on examination ,there may beevidance of right ventricular failure with elevated jugular venous presssure ,lower extremity edema ,and ascits additionally ,the cardiovascular examination may reveal on accentuted p2 component of the second heart sound ,a right sided s3 or s4 and a holosystolic tricuspid regurgitant murmur.
It is also important to seek signs of the disease that are often concurrent with PH:clubbing may be seen is some chronic lung disease ,sclerodactyly and telangictasia may signify scleroderma ,and crackles and sysytemic hypertension may be clues to left sided sysytolic or diastolic heart failure . Once clinical suspicion is raised ,a systemic approach to diagnosis and assessment is essential .an echocardiogram with (if indicated)a bubble study is the most important screening test .echocardiography is important for the diagnosis of PH and often essential for detemining the cause .all forms of PH may demonstrate a hypertrophied and dilated right ventricle .with elevated estimated pulmonary artery systolic pressure .important additional information can be gleaned about specific etiologies of PH such as valvular disease left ventricular systolic and diastolic function ,intracardiac shunts and othere cardiac disease .although the accuracy of doppler echocardiography is often debated .
A high_quality echocardiogram that is absolutely normal may obviate the need for further evaluation for PH .an echocardiogram is a screening test ,whereas invasive hemodynamic monitoring is the gold standard for diagnosis and assessment of disease severity .with a normal echocardiogram ,there may still be some concern for PH :this is particularly true if there is unexplained dyspnea or hypoxemia .in this setting ,it is reasonable to proceed to right heart catheterization for definitive diagnosis .alteronatively , if the patient has a reasonable functional capacity ,a cardiopulmonary exersise test may help to identify a true physiologic limitation as well as differentiate between cardiac and pulmonary causes of dyspnea .if this test is normal ,there is no indication for a right heart catheterization .if a cardiovascular limitation to exercise is found,a right heart catheterization.should be presued .
If the echocardiogram or cardiopulmonary exercise test(CPET)suggests PH and the diagnosis is confirmed by catheterization ,a reasonable effort must be made to establish the etiology because this will largely determine the theraputic approach .A stepwise approach to evaluation is out lined below . Chest imaging and lung function tests are essential because lung disease is an important cause of PH .A sign of PH that may be evident on chest x_ray include enlargment of the central pulmonary arteries associated with “vascular pruning” ,a relative paucity of prepheral vessele . Cardiomegaly ,with specific evidance of right atrial and ventricular enlargment ,can often be observed .the chest x_ray may also demonstrate significant interstitial lund disease ,wich may be the underlying cause or contributor to the development of PH .high_resolation computed tomography(CT)may provide additional useful information .
Classic finding of PH on CT include those found on chest x_ray :enlarge pulmonary arteries peripheral pruning of the smaal vessels ,and enlarged right ventricle and atrium .however ,high_resolation CT may also reveal signs of venous congestion including centrilobular ground_glass infiltrate and thickened septal lines .in the absense of left heart disease ,these finding suggest pulmonary veno_occlusive disease .a rare cause of PAH that can be quite challenging to disease .CT angiogram are commonly used to evaluate acute thromboembolic disease and have demonstrated .excellent sensitivity and specificity for that purpose .ventilation_perfusion(V/Q)scanning has traditionally been used for screening because of its high sensitivity and its role in qualifying patients for surgical intervention .the role of CT angiogram in the diagnosis of chronic thromboembolic pulmonary hypertension (CTEPH)remains controversial ,even with the advent of spiral CT .although anegative V/Q virtually rules out CTEPH ,some cases maybe missed through the use of CTangiogram
Pulmonary function tests are on important component of the evaluation .although an isolated reduction in DLco is the classic finding tests may also suggest restrictive or obstructive lung disease as the cause of dyspnea or PH .the 6_minute walk test is also important to evaluate the degree of exertional hypoxemia and limitation and to monitor progression and response to therapy .sleep study is generally necessary only when indicated by the patients history .nocturnal desaturation is a common finding in PH ,even in the absence of sleep_disordered breathing .thus ,all patient should undergo nocturnal oximetry screening , regardless of whether classic symptoms of obstructive sleep apnea or obesity_hypoventilation syndrome are observed .laboratory tests that are important for screening include on HIV test when clinically indicated .in addition ,all patients should have antinuclear antibodies ,rhumatoid factor ,and scl_70 antibodies ,assessed to screen for the most common rheumatologic disease associated with PH if clinically indicated .
Liver function and hepatitis serology tests are important to screen for underlying liver disease .finally ,there is an increasing role for brain natriuretic peptide(BNP)testing in the diagnosis and management af PH .BNP and the N_terminus of its propeptide(NT_proBNP)correlate with right ventricular function ,hemodynamic severity ,and functional starus in PAH . Right heart cateterization with pulmonary vasodilator testing remains the gold standard both to stablish the diagnosis of PH and to enable selection of appropriate medical therapy .the definition of precapillary PH or PAH requires(1)an incresaed mean pulmonary artery pressure(mPAP >25mmhg)(2) a pulmonary capillary wedge pressure(PCWP) ,left arterial pressure ,or left ventricular and diastolic pressure <15mmhg:and (3)PVR>3 woood units .
Post capillary PH is differentiated from precapillary PH by a PCWP of >15mmhg: this is further differentiated into passive ,based on a transpulmonary gradient <12mmhg ,or reactive ,based on atranspulmonary gradient >12mmhg and a increased PVR .in either case ,the CO may be normal or reduced .vasodilators with a short duration of action ,such as inhaled nitric oxide ,inhaled epoprostenol ,or intravenous adenosine ,are preferred for vasodilator testing .A decrease in mPAP by >10mmhg to an obsulate level of <40mmhg without a decrease in CO is defined as a positive pulmonary vasodilator response ,and responders are considered for long_term treatment with cacium channel blockers(CCBs) .less than 12% of patients are deemend vasoreactive during testing ,and even fewer exhibite long_term responsiveness to CCBs .acute vasodilator_induced reductions in PVR and mPAP predict better long_term survival even among patients not treated with CCBs .
The need for invasive hemodynamic measuurements to diagnose PH accurately poses an additional problem when evaluating older patients .physicians are often reluctant to refer older patients for invasive procedures .however ,the diagnosis of PH is increasing in the older population ,at least in part because of increased awareness of this disease in the elderly and increased use of screening echocardiogras . Futhermore ,the increased availaility of oral and less complicated therapeutic options has oncouraged the referral of older patients for evalution and treatment .
PULMONARY HYPERTENSION AS A COMORBID DISEASE PAH is just of a number of disease classifications that affect the pulmonary vascular bed .PH was previously classified as primary or secondry ,but as understanding of the various contributing disease has increased ,classification systems have attempted to group these disease by clinical feature to aid in diagnosis .the word health organization(WHO) formulated a clinical classification of the various manifestations of PH ,of which PAH is a subgroup ,according to similaritiesin pathophysiologic mechanisms and clinical presentation .PH is a diverse mix of pathologies in which the only unifying theme is elevated PAP relative to left arterial pressure .
The categorization of PH was designed by convenience for the purpose .of facilitating novel treatments to be tested across different presentations and is not based on a molecular understanding of the pathology and is not a guide formanagment decisions . The current classification system ,last revised in 2013during the fifth world symposium on pulmonary hypertension ,recognizes five categories of PH ,including PAH ,PH due to left heart disease ,PH due to chronic thromboemboli , and a group of miscellaneous disease that only rarely cause PH .
