Hypertension
4. CLINICAL PRESENTATION AND DIAGNOSIS 1. Symptoms and Signs
The clinical presentation and diagnosis of connective tissue disease-related pulmonary hypertension are similar to those of idiopathic PAH.
Dyspnea is the most common presenting symptom and is generally insidious in onset. An early manifestation on physical examination is an increased intensity of P2, the sound of pulmonic valve closure, which intensifies as pulmonary artery pressure rises. Depending on the extent of right heart involvement, a right ventricular (RV) heave, murmur of tricuspid regurgitation, and evidence of right heart failure (jugular venous distension, peripheral edema, and/or ascites) may follow.
4.2. General Approach
When pulmonary hypertension is suspected based on symptoms, signs, and risk factors, further evaluation is initiated. The findings of right-axis deviation and right ventricular hypertrophy on an electro-cardiogram and right ventricular enlargement and/or prominence of pulmonary arteries on a chest radiograph are specific but not sensitive indicators of pulmonary hypertension. As with idiopathic PAH, echocardiography is the most useful screening tool, and repeated echocardiography in high-risk CTD patients, such as those with limited disease, has been suggested on an annual basis, as discussed below, to detect early manifestations of pulmonary hypertension. Right heart catheterization (RHC) remains necessary to confirm the diagnosis, though, and to exclude other causes of pulmonary hypertension such as
Table 1
World Health Organization (WHO) Classification of Functional Status of Patients with Pulmonary Hypertension (PH) (from Reference 76)
Functional 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 fatigue may be present at rest, and symptoms are increased by almost any physical activity.
left-sided heart disease or congenital shunts. A functional status should also be assessed, based on the modified NYHA/WHO functional classi-fication and a six-minute walk test (Table 1), to serve as a baseline.
The latter may have limited value, however, when CTD patients have significant musculoskeletal pain or arthropathy.
4.3. Pulmonary Function Testing
Although restriction is a common finding on pulmonary function testing in patients with SSc, perhaps related to stiffening of the chest wall and/or interstitial disease, it is usually mild unless there is advanced fibrosis. An isolated reduction in DLCO occurs in 20% of patients with limited SSc and is the most common abnormality found on pulmonary function testing in SSc (77,78). Although a reduction in DLCO is a nonspecific finding in SSc and only a minority (an estimated 11%) of such patients go on to develop pulmonary hypertension (78), most patients with pulmonary hypertension have a severely reduced DLCO, which is lower than similar SSc patients without pulmonary hypertension (17). In one study, 88% of SSc patients with pulmonary hypertension had a DLCO < 43% predicted, as opposed to only 12%
of those without pulmonary hypertension (8). Thus, a DLCO < 43%
has been suggested as an indicator of pulmonary hypertension in CTD patients, and a progressive decline of DLCO over time correlates with the development of pulmonary hypertension. In fact, a decreasing DLCO has been identified as the strongest predictor of pulmonary hypertension (16) and inversely correlates (r = 0.60) with invasively measured PA systolic pressure (79).
However, some findings on the utility of DLCO in predicting the presence of pulmonary hypertension in CTD patients have been conflicting; in one study, 23 of 54 (43%) patients with SSc-PH had a DLCO > 55%, demonstrating that a relatively preserved DLCO is not sufficient to exclude the diagnosis of pulmonary hypertension in patients with SSc. The correlation between DLCO and mean PA pressure (mPAP) determined by right heart catheterization was also quite weak in this study (r2 = 0.0908) (80). Differences in the patient populations (limited SSc vs. diffuse SSc and the proportion of patients with concomitant interstitial lung disease) as well as differences in the definitions and severity for pulmonary hypertension probably explain the inconsistencies between the studies. One approach to improving the predictability of DLCO for pulmonary hypertension has been to use an FVC (% predicted)/DLCO(% predicted) ratio > 1.6 to detect those who have a disproportionate reduction in DLCO, although the sensitivity and specificity of this approach are still under investigation (Steen VD, personal communication). Despite the inconsistencies, the American College of Chest Physicians’ 2004 evidence-based clinical practice guidelines for pulmonary arterial hypertension recommended pulmonary function testing with diffusing capacity (DLCO) every 6 to 12 months in patients with SSc to improve the detection of pulmonary vascular disease (81).
4.4. Doppler Echocardiography
Doppler echocardiographic estimates of PA systolic pressure correlate well with catheter-measured pressures in general, but they are often inaccurate in individual patients (81). Several studies have specifically examined the performance of Doppler echocardiography in detecting pulmonary hypertension in patients with SSc. In one study of 33 SSc patients suspected of having pulmonary hypertension, Doppler echocardiography had a sensitivity of 90% and a speci-ficity of 75%, correctly identifying 19 of 21 patients with right heart catheterization-proven pulmonary hypertension. Doppler echocardio-graphy was also fairly accurate in this study, with a mean absolute
difference for PA systolic pressure between it and right heart catheter-ization of 11.4 mm Hg (79). In a similar study of 54 patients with isolated SSc-PH, Doppler echocardiography had a sensitivity of 85%
when a triscuspid gradient >30 was used as the threshold for defining pulmonary hypertension, but the specificity was only 42% (80). In summary, Doppler echocardiography has good sensitivity (85–90%) but limited specificity in identifying SSc-PH. For this reason, it is an acceptable screening test, and the World Health Organization has recommended annual echocardiography to screen SSc patients for pulmonary hypertension. Presently, there are no studies assessing the utility of Doppler echocardiography as a screening test for pulmonary hypertension in other connective tissue diseases.
4.5. Brain Natriuretic Peptide
Brain natriuretic peptide (BNP) performs similar roles in patients with SSc-PH and idiopathic PAH, increasing in proportion to the degree of right ventricular hypertrophy and dysfunction, and serving as a prognostic indicator (82). In a prospective study of 40 patients with SSc, a precursor of BNP, N-terminal proBNP (NT-proBNP), was measured at baseline, acutely following three doses of a calcium channel blocker, then six to nine months later. The 10 patients in this study with SSc-PH (based on estimated PA systolic pressure >
40 by Doppler echocardiography) had a higher mean NT-proBNP than patients without evidence of pulmonary hypertension. Short-term calcium channel blockade significantly decreased the NT-proBNP concentration (from 146 to 82) and decreased the number of patients with an elevated NT-proBNP from 13 to 3. At the later assessment six to nine months later, the significant differences were no longer apparent, although the number of patients available for long-term follow-up was small (83). Thus, although this small study suggests that BNP may have a role in detecting patients with SSc who have underlying pulmonary hypertension, serving as a prognostic indicator and guiding therapy, this role remains to be established.
5. THERAPY OF SSC-PH