Association of N-terminal pro-brain natriuretic peptide with cardiac disease, but not with vascular disease, in systemic lupus erythematosus.

Accelerated atherosclerosis is an important health threat facing systemic lupus erythematosus (SLE) patients. Traditional cardiac risk factors do not appear to adequately identify the SLE patients who are at increased risk for the development of atherosclerosis (1). Additionally, SLE patients are more likely to develop other cardiac and vascular abnormalities such as left ventricular (LV) hypertrophy and other abnormalities of LV structure and function as well as inflammation-related arterial stiffening (1). As a result, cardiovascular risk is likely underestimated in these patients, and there is a need for reliable biomarkers to identify patients at increased risk. NT-proBNP is beginning to show promise as a potentially clinically helpful biomarker of cardiovascular risk in the general population including those without existing heart disease (2). ProBNP is released from cardiac myocytes in response to volume and pressure overload. Once released, it is cleaved into two peptides, NT-proBNP and BNP. NT-proBNP has no known activity in vivo, whereas BNP has two major effects on the systemic circulation: vasodilation and sodium and water balance through diuresis and natriuresis. While NT-proBNP has no known biological effects in vivo, both BNP and NT-proBNP have been useful in aiding the diagnosis of congestive heart failure and stratifying risk for cardiovascular disease in the general population (2). NT-proBNP levels are elevated in the settings of congestive heart failure, arterial stiffness, acute coronary syndromes, first cardiovascular events, stroke, renal failure and death (2, 3). Little is known about NT-proBNP in SLE patients. It has been suggested that serum NT-proBNP levels are higher in SLE patients than in control subjects, but its relationship with markers of vascular and myocardial function is sparely investigated (4, 5). NT-proBNP levels appear to correlate with SLE disease damage and duration, but not with markers of vascular disease such as coronary calcification and augmentation index (4). An association between BNP levels and echocardiographic left atrial diameter was found in 59 SLE patients (5). We hypothesized that serum NT-proBNP levels would correlate with markers of both vascular and myocardial function in SLE patients. To test this hypothesis, we studied 124 patients meeting American College of Rheumatology diagnostic criteria for SLE who were participating in a longitudinal study of cardiovascular disease at Hospital for Special Surgery. Patients underwent clinical and laboratory assessment. Patients were defined as having atherosclerosis based on the presence of plaque (focal protrusion >50% of the thickness of the surrounding wall) on carotid ultrasonography (6). Arterial stiffness was estimated by the pressure-independent arterial stiffness index as previously defined (6). Echocardiography was performed using standard techniques as previously described (7). SLEDAI was used to calculate SLE disease activity. Serum NT-proBNP levels were measured using a validated electrochemiluminescence method (Roche Elecsys 2010) with CVs < 6%. Independent correlates of log NT-proBNP, carotid plaque, arterial stiffness, LV mass, LV ejection fraction, and left atrial diameter were determined by unstandardized multivariate regression analysis (B-coefficient), adjusting for important covariates based on bivariate analyses. The mean age of the 124 SLE patients was 43.4 ± 13.7 years; 95.2% were female. The mean SLEDAI score was 3.7± 4.8; range 0–22, and mean SLE duration was 11.8±8.9 years. The mean body mass index was 25.4 and mean serum creatinine was 1.0 mg/dL; range 0.5–4.5 mg/dL. Only 2.6% of the patients had diabetes, 12.7% were current smokers, and 21.7% had a history of hypertension. Atherosclerotic plaque was present in 38.2 %. Median serum NT-proBNP was 82.5 pg/ml (mean 346.1±1251 pg/ml, range 5–12905 pg/ml). As a broad reference, the median NT-proBNP was approximately 20 pg/ml in a cohort of women ages 40–49 who did not have a history of cardiovascular disease(8). NT-proBNP was related to all vascular (atherosclerosis and stiffness index) and cardiac (LV mass, LV ejection fraction, and left atrial size) parameters in bivariate analyses. After including all variables in the models, log NT-proBNP was inversely associated with body mass index and ejection fraction and positively associated with serum creatinine and SLICC damage scores (Table 1). Because renal failure is associated with elevated NT-proBNP levels (3), we excluded subjects with a creatinine >1.0 mg/dl. Log NT-proBNP was still inversely associated with body mass index and ejection fraction and positively associated with SLICC damage scores, while NT-proBNP was no longer independently associated with creatinine. The independent association of BNP with lower ejection fraction, in conjunction with our earlier observation of higher left ventricular mass in SLE patients (7), suggests elevated NT-proBNP may predict myocardial dysfunction. Table 1 Multivariate Analysis of the Correlates of log NT-proBNP in SLE Patients Our data support earlier reports of an increase in NT-proBNP in patients with SLE. Similar to the general population, serum NT-proBNP levels in our large, well-phenotyped cohort of SLE patients were inversely correlated with BMI and ejection fraction. However, NT-proBNP levels were not associated with plaque or arterial stiffness, suggesting that NT-proBNP may be a marker of ventricular dysfunction and not atherosclerosis in SLE patients. Our findings also support the earlier report of an association between cumulative damage in SLE and extend this observation to include renal involvement (higher serum creatinine levels) which may modulate cardiac output pressure via blood volume homeostasis. Taken together, our data implicate both traditional physiologic mechanisms as well as SLE-specific factors in the increase in NT-proBNP levels in SLE. Whether NT-proBNP is a marker for risk of congestive heart failure remains a question that warrants longitudinal studies.