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Pulmonary arterial hypertension (PAH) is defined as amean pulmonary artery pressure ≥25 mmHg by right heartcatheterization and a pulmonary artery wedge pressure ≤15mmHg, indicating an absence of left ventricular dysfunction.In many patients, PAH is a progressive disease associated withmorbidity and often fatal.1 The traditional concept of primaryversus secondary pulmonary hypertension has been discardedand per recent classification underlying conditions for pulmonaryhypertension are classified into five groups. These include Group1 PAH and Groups 2, 3 and 4 include categories of pulmonaryhypertension secondary to left heart disease, hypoxemia andlung disease and pulmonary hypertension due to chronicthromboembolism, respectively. Group 5 includes pulmonaryhypertension secondary to diseases where the pathogenesis isunclear and includes sarcoidosis, myeloproliferative disorders andother miscellaneous conditions.1
A number of conditions with common hemodynamic andpathological features are classified as PAH Group 1. Among theseconditions, idiopathic pulmonary arterial hypertension (IPAH -previously known as primary pulmonary hypertension) is a raredisease with poor outcome in the absence of effective therapy.1 Previous data on prognosis of IPAH from the National Instituteof Health registry showed a median survival of 2.8 years.2 At thetime, the only medications available were calcium channel blockersthat are effective only in a small minority of patients.3 Compared toIPAH, which is relatively rare (5.9/million); PAH associated withother group I conditions (APAH), like systemic sclerosis, humanimmune deficiency virus (HIV) infection, congenital heart disease,hemolytic anemia and portal hypertension is not uncommon. Theprevalence of PAH is estimated between 8 to 26.7% in patients withscleroderma 2 to 6% with portal hypertension and 0.5% amongHIV patients. Up to 30% of children with congenital heart diseasewho do not undergo repair develop PAH.1,3 In these conditions,the presence of PAH may be associated with devastating resultsand often, it is the PAH rather than the underlying conditionwhich is responsible for morbidity and mortality. For example,although the incidence of PAH among patients who have HIVinfection is 0.5%; the risk is 6-12 times higher compared to thegeneral population and the impact of PAH is high, considering thenumber of HIV patients globally, and also the fact that PAH maybe the direct cause for mortality in 72% of deaths.1,3,4
In the last decade and a half, several advances have been madein elucidating the pathogenesis, genetic associations, and mostimportantly in the treatment of the disease. At present, in additionto calcium channel blocker; there are several modalities of therapyavailable and include: oral therapies like phosphodiesterase type-5 inhibitors (Sildenafil and Tadalafil) and endothelin-receptorantagonists (Bosentan and Ambrisentan), inhalational therapy(Iloprost and Treprostinil), Infusion therapy (Epoprostenol andTreprostinil) and subcutaneous therapy (Treprostinil).3,5 A recentmeta-analysis suggested that treatment was associated with areduction in mortality of 43%.6 However, a recently publishedanalysis of a large French Registry showed a 3-year median survivalof 58%.7 While there has been improvement in the managementand the outcome of PAH as indicated by the meta-analysis ofrandomized controlled trials cited above, the overall survival isstill far from satisfactory as seen in the French Registry; a 3-yearmedian survival of less than 60% is unacceptable and more couldand should be done.6,7
Some of the factors associated with poor survival include:complex underlying pathophysiology, rapid progression of thedisease and advanced state of the disease at the time of diagnosis.Patients who have functional class symptoms New York HeartAssociation (NYHA) III and IV have poorer prognosis whencompared to patients in class I and II,2,3 thus timely diagnosisand intervention could be very crucial in improving survival. Unfortunately, at the time of diagnosis; about 75% of patientsare usually in NYHA class III and IV.8 Furthermore, the delaybetween onset of symptoms and diagnosis has been reportedas 27 months in a French Registry and 2.8 years in the largestUnited States Registry; suggesting that there is a large window ofopportunity wherein intervention could improve prognosis, hencethe need to capture these patients early.8,9
There appear to be several reasons for the delay in diagnosis. Thesymptoms are nonspecific; in fact in the early stages, patients areasymptomatic and later on, dyspnea on exertion is the predominantsymptom. These nonspecific symptoms frequently lead to awide battery of tests and by the time pulmonary hypertension issuspected as an etiology, crucial time has already been lost. Theetiology of the disease is diverse and patients are usually taken care of by specialists whose awareness of the condition may not be high.Initial clinical signs of pulmonary hypertension are subtle and notalways easy to pick up. By the time a clinician is able to identifysigns like elevated jugular venous pressure, pulsatile hepatomegalyor edema; the patient is in right heart failure and it is already toolate. The therapy of the disease is complex, and response needs tobe closely monitored, which can best be achieved at specializedcenters. Management of patients in non-specialized center settingsfrequently leads to the initiation of inappropriate therapy likecalcium channel blockers in non-responders.10 Practice guidelinespublished by the American College of Chest Physicians call forearly referral to a specialized center.11
The challenge is in diagnosing patients early and getting themto the pulmonary hypertension centers in time. The systematicscreening of whole populations is not practical due to the lowprevalence of this rare disease. Therefore, increased awarenessof treatment options combined with active screening of patientsat high risk is likely to improve survival. Screening programshave proven effective in diagnosing early stage disease in patientswith sickle cell disease, systemic sclerosis and HIV.12 It wouldbe reasonable to consider screening certain high-risk groups,including patients with the scleroderma spectrum of diseases,systemic lupus and other connective tissue diseases, as well as HIV,1st degree relatives with familial and idiopathic PAH, sickle celldisease, cirrhosis and patients with history of drug use. Educationand improving awareness of the condition among specialists takingcare of these patients is crucial. From the perspective of the primarycare physician; any unexplained dyspnea, fatigue, or chest pain(non-specific symptoms of pulmonary hypertension), especiallyamong high-risk patients should warrant a consideration of thepossibility of PAH.
In patients who are at high risk or are suspected to havepulmonary hypertension, particular attention should be directedto early physical signs which include; prominent jugular “a” wave,palpable left parasternal lift, loud second heart sound, earlysystolic ejection click, midsystolic ejection murmur and rightventricular S4 gallop. In advanced stages, there may be signsof valvular regurgitation and right heart failure which includeelevated jugular venous pressure with accentuated V waves(in the presence of tricuspid regurgitation), diastolic murmurof pulmonary regurgitation, holosystolic murmur of tricuspidregurgitation, right ventricular S3 gallop, pulsatile hepatomegaly,peripheral edema and ascites.
On a chest radiograph, features of pulmonary hypertensioninclude enlarged main pulmonary arterial shadows andattenuation of peripheral pulmonary vascular markings; enlargedright ventricle may be recognized as loss of clear retrosternal spaceon lateral chest radiograph. An electrocardiograph may show signsof right ventricular hypertrophy such as: right-axis deviation, a tallR wave and small S wave with lead V1, qR complex in lead V1,rSR’ pattern in lead V1, large S wave and small R wave in leadV5 or V6, S1, S2, S3 pattern and ST-T segment wave depression,and inversion may be present in the right precordial leads. Rightatrial enlargement is indicated by a tall P wave ≥2.5 mm in leadsII, III, and aVF and frontal P-axis of ≥75°. Chest radiograph andEKG findings should not be relied upon in diagnosing or rulingout PAH. In patients suspected to have pulmonary hypertension,an echocardiogram should be obtained as a screening tool andif echo is suggestive of pulmonary hypertension, then diagnosisneeds to be confirmed with right heart catheterization. Earlyreferral to a specialized center is recommended so that diagnosisand treatment can be initiated in a timely manner and patients canbe closely monitored.AcknowledgementsThe authors reported no conflict of interest and no funding wasreceived on this work.
References
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