Pulmonary Hypertension
Praneet Kumar
Wilson W.H. Tang
I. INTRODUCTION.
Pulmonary hypertension (PH) is a routinely made diagnosis in contemporary cardiology and pulmonary clinics. It is essential for the specialist as well as the internist to have a high index of clinical suspicion for this devastating disease, as early diagnosis and referral may affect the survival. Substantial advances are being made in the management of pulmonary arterial hypertension (PAH), which is more rapidly available at centers specializing in PH.
A. Terminology/definitions. PH is defined as mean pulmonary artery pressure (mPAP) > 25 mm Hg.
PH encompasses a heterogeneous group of diseases with a common clinical manifestation. The terms PH, which is a hemodynamic and pathophysiologic condition, and PAH, a clinical condition, are different terminologies that should not be used interchangeably. The clinical classification of PH is based on hemodynamic data derived from right heart catheterization (RHC). Some terminologies that are commonly employed in PH include the following:
1. Trans-pulmonary gradient (TPG) is defined as the pressure difference between mean left atrial pressure (LAP) (more commonly pulmonary capillary wedge pressure [PCWP] is used as a surrogate) and mPAP.
2. Pulmonary vascular resistance (PVR) is defined as TPG divided by the cardiac output (PVR = TPG/CO in Wood units).
3. PAH is hemodynamically defined as PH (i.e., mPAP ≥ 25 mm Hg) with increased PVR (more than 3 Wood units) and normal wedge pressure (< 15 mm Hg). It is a clinical condition characterized by precapillary PH and pathologic changes in the lung microcirculation.
4. Pulmonary venous hypertension is characterized by mPAP ≥ 25 mm Hg, PVR > 3 Wood unit, and elevated wedge pressure (PCWP ≥ 15 mm Hg).
B. Classification.
The World Health Organization has endorsed the clinical classification of PH based upon pathologic, pathophysiologic, and therapeutic characteristics. The most recent classification derived from the world symposium on PH held in Dana Point, California, in 2008 is listed in Table 14.1.
C. Epidemiology.
The total PH burden of the disease is substantial as it represents an end stage of multiple disease processes such as left-sided heart disease, chronic lung diseases, as well as PAH which is very rare. Most of the patients who are diagnosed with PH on routine testing (echocardiogram with pulmonary arterial systolic pressure [PASP] > 40 mm Hg) will end up having left heart disease (nearly 80%), some with lung disease and hypoxia (10%), and only a small minority (4%) will have PAH.
Data from registries estimate the prevalence at around 15 to 50 cases/million adults and its incidence at around 2.4 cases/million adults/year. Idiopathic PAH (IPAH) and familial PAH (previously known as “primary PH”) are rare diseases with a prevalence of around 6 cases/million. Familial cases account for 5% to 10% of all PAH cases. Mutations in the bone morphogenetic protein receptor-II (BMPR2)
gene have been identified in about 70% of patients with familial PAH and 10% to 40% of patients with sporadic IPAH. Hence, relatives of patients with familial IPAH should be advised about the availability of genetic testing and counseling in addition to echocardiographic screening.
gene have been identified in about 70% of patients with familial PAH and 10% to 40% of patients with sporadic IPAH. Hence, relatives of patients with familial IPAH should be advised about the availability of genetic testing and counseling in addition to echocardiographic screening.
TABLE 14.1 Dana Point Classification of Pulmonary Hypertension (Simplified) | ||||||||||||||||||||||
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PAH has been associated with environmental factors such as the use of drugs and toxins. Anorexigens (appetite suppressant drugs that increase serotonin release and block serotonin reuptake) have been associated with PAH, with agents such as aminorex fumarate and (dex) fenfluramine. Select patient populations at an increased risk of developing PAH are discussed below.
1. Patients with connective tissue diseases (CTDs), especially the limited cutaneous form of systemic sclerosis (formerly referred to as the CREST syndrome). The prevalence of hemodynamically proven PAH in systemic sclerosis is around 10%. In other CTDs, such as systemic lupus erythematosus, mixed CTD, rheumatoid arthritis, dermatomyositis, and Sjögren’s syndrome, PAH is observed less frequently.
2. Human immunodeficiency virus (HIV) infection is associated with approximately 0.5% incidence of PAH. However, because of this low incidence, routine screening is not recommended.
3. Patients with cirrhosis and portal hypertension are at an increased incidence of PH (5% of patients were referred for liver transplantation).
4. Congenital heart disease may lead to PAH when the underlying systemicto-pulmonary shunt is not corrected. Most commonly, it occurs with conditions where blood flow is high and the pulmonary vasculature is exposed to systemic level pressures (e.g., ventricular septal defect and patent ductus arteriosus). However, high blood flow alone, as in atrial septal defect, may be sufficient. Once PVR approaches or exceeds the systemic vascular resistance, the shunt is reversed, leading to desaturation and cyanosis (Eisenmenger syndrome).
II. SIGNS AND SYMPTOMS
A. Symptoms.
The symptoms of PH are nonspecific and are gradual in onset; therefore, there is a lag time of about 2 years (from symptom onset to diagnosis) in 90% of patients with PAH. These symptoms may include dyspnea on exertion, fatigue, weakness, chest pain, palpitations, syncope, abdominal distention, and pedal edema. Symptoms at rest occur only at late stages of the disease and portend poor prognosis.
Some patient populations are at an increased risk for developing PH and should be carefully screened by clinicians by careful history taking, examination, and laboratory tests. These populations include patients with known, or relatives of those with, BMPR2 mutations, CTD, HIV infection, portal hypertension, prior appetite suppressant use, congenital heart disease with shunt, recent acute pulmonary embolism, left heart disease, chronic obstructive pulmonary disease, interstitial lung disease, or sleep apnea.
It is advisable to perform annual screening with echocardiography in select highrisk groups, such as
(1) those with known BMPR2 mutation;
(2) first-degree relative of the patient with BMPR2 mutation or within pedigree of two or more patients with PAH;
(3) those with systemic sclerosis; and
(4) those with sickle cell disease.
B. Physical examination.
Physical examination may provide clues as to the cause of PH. Findings of telangiectasia, digital ulceration, and sclerodactyly suggest scleroderma, while inspiratory crackles may point toward interstitial lung disease. Patients should be carefully screened for the presence of stigmata of liver disease, such as spider naevi, testicular atrophy, and palmar erythema. The presence of clubbing suggests congenital heart disease or pulmonary veno-occlusive disease. Cardiovascular examination of patients with PH may reveal a left parasternal lift, a loud P2 at the apex, a pansystolic murmur of tricuspid regurgitation that increases with inspiration, a diastolic murmur of pulmonary insufficiency, and a right ventricular (RV) S3. Lung sounds are usually normal (except for those with class 3 PH). Jugular vein distension, hepatomegaly with a pulsatile liver, peripheral edema, and ascites are ominous signs suggestive of advanced stages with right-sided heart failure.
III. LABORATORY EVALUATION
A. Blood work
1. Routine biochemistry, hematology, and thyroid function tests.
2. Serologic testing is important to detect the underlying CTDs, HIV (mandatory screening), thrombophilia (in chronic thromboembolic pulmonary hypertension [CTEPH]), and hepatitis (in patients with suspected liver disease). More than a third of patients with IPAH have low-titer elevation in antinuclear antibodies. Systemic sclerosis is the most important CTD to exclude because of high prevalence of PAH in this syndrome. Anti-centromere antibodies are usually positive in limited scleroderma as are other antinuclear antibodies, including dsDNA, anti-Ro, U3-RNP, B23, Th/To, and U1-RNP. In the diffuse variety of scleroderma, U3-RNP is positive. In patients with systemic lupus erythematosus, anticardiolipin antibodies may be found.
3. Biomarkers. Several circulating biomarkers have prognostic implications in patients with PAH, but their value in everyday clinical practice is still not established. Uric acid levels are shown to be increased in patients with IPAH, and elevated plasma troponin T levels (> 150 pg/mg) have been associated with worse outcomes in patients with CTEPH and PAH. BNP levels have also been used to monitor response to therapy or clinical course, as those with persistently elevated levels have worse outcomes. Similarly, NT-proBNP below cutoff levels < 1,400 pg/mL has been associated with better outcomes. BNP/NT-proBNP plasma levels should be checked for the initial risk stratification and may be considered for monitoring the effects of treatment, in view of their prognostic implications. Low and stable or decreasing BNP/NT-proBNP may be a marker of successful disease control in PAH.
B. The electrocardiogram (ECG).
In typical cases of PH, the ECG shows right atrial (RA) dilatation, RV hypertrophy with strain, and a right axis deviation. In advanced stages of the disease, atrial flutter or atrial fibrillation often occurs, leading to further clinical deterioration.
C. Chest radiograph.
Initial chest x-rays are abnormal in majority (90%) of patients with IPAH at the time of diagnosis. There is often central pulmonary arterial (PA) dilatation with “pruning” (loss) of the peripheral blood vessels, clear lung fields, and a prominent RV border. The chest x-ray may also point to lung abnormalities and show features suggestive of left heart disease.
D. Echocardiography.
If PH is suspected based on history, risk factor assessment, and physical examination, an echocardiogram is the next appropriate study. By using the Doppler technique, peak velocity of the tricuspid regurgitation jet can be measured. From this measured velocity, the pressure difference between right ventricle and right atrium can be estimated by employing the simplified Bernoulli equation (ΔP = 4v2). On condition that there is no pulmonic valve stenosis, PASP = 4 × (tricuspid regurgitant jet velocity)2 + right atrial pressure (RAP). RAP can be estimated on the basis of inferior vena cava (IVC) characteristics. If the IVC is plethoric and there is clinical evidence of Jugular venous distension (JVD), RAP is presumed to be 10 to15 mm Hg, whereas if findings are normal, it is usually calculated as 5 mm Hg.
Other echocardiographic characteristics may raise the suspicion of PH, such as RA or RV dilatation, flattening of the interventricular septum with D-shaped left ventricle, increased RV wall thickness, dilatation of the pulmonary artery, and the presence of pericardial effusion. These features tend to occur later in the course of the disease.
Although echocardiography is a useful screening tool, Doppler-derived pressure estimation can both underestimate PASP in patients with severe tricuspid regurgitation and overestimate PASP in non-PH patients. Ultimate confirmation requires RHC.
E. Right heart catheterization.
RHC is required to confirm the diagnosis of PH, to assess the etiology and severity, and to test for vasoreactivity of the pulmonary circulation. At experienced centers, morbidity (1.1%) and mortality (0.055%) rates are low. Consecutively, RAP, right ventricular pressure (RVP), PAP, and PCWP are recorded using a balloon-tipped fluid-filled catheter (Table 14.2). Cardiac output can be determined using the thermodilution method and/or the Fick method (measurement of mixed venous saturation SvO2 needed). The PCWP is taken as a surrogate measure of LAP and, in the absence of mitral stenosis, left ventricular end-diastolic pressure (LVEDP). This measurement is very important because it helps differentiate PH associated with left heart disease from other conditions. However, it is subject to error in measurement and interpretation. Occasionally, it may be necessary to perform a left heart catheterization for direct measurement of LVEDP.
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