Natriuretic peptides are positively associated with incident cardiovascular disease (CVD), but data in women, particularly with regard to improvements in risk prediction, are sparse. We measured the N -terminal prohormone form of B-type natriuretic peptide (NT-proBNP) in 480 cases of incident CVD (myocardial infarction, stroke, and cardiovascular death) and a reference subcohort of 564 women from the Women’s Health Study who were followed for a median of 12.0 (interquartile range 7.6 to 13.4) years. Median (interquartile range) NT-proBNP concentrations were greater in women who developed CVD (81 ng/l [50 to 147]) than those who did not (64 ng/l [38 to 117]; p <0.0001). For women in the highest compared to the lowest quartile, NT-proBNP was 65% greater after adjusting for established cardiovascular risk factors and kidney function (adjusted hazard ratio [aHR] 1.65, 95% confidence interval [CI] 1.03 to 2.64, p trend = 0.03). When analyzed as a continuous variable, the aHR per 1 − SD difference in Ln(NT-proBNP) was 1.22 (1.03 to 1.44; p = 0.02). The per 1 − SD change in Ln(NT-proBNP) appeared stronger for cardiovascular death (aHR 1.43, 95% CI 1.05 to 1.94, p = 0.02) and stroke (aHR 1.24, 95% CI 1.03 to 1.50, p = 0.03) than myocardial infarction (aHR 1.09, 95% CI 0.87 to 1.37, p = 0.44). When added to traditional risk co-variables, NT-proBNP did not significantly improve the C-statistic (0.751 to 0.757; p = 0.09) or net reclassification into <5%, 5 to <7.5%, and ≥7.5% 10-year CVD risk categories (0.014; p = 0.18). In conclusion, in this prospective study of initially healthy women, NT-proBNP concentrations showed statistically significant association with incident CVD that was independent of traditional cardiovascular risk factors but did not substantially improve measures of CVD risk prediction.
B-type natriuretic peptides are widely used for the diagnosis of heart failure in patients presenting with shortness of breath. Natriuretic peptides also consistently associate with adverse cardiovascular events in stable patients with and without preexisting cardiovascular disease (CVD). However, the published data in primary prevention populations are largely derived from studies that include a small number of events in women, or excluded women altogether. Recently, we reported a strong relation between the N -terminal prohormone fragment of B-type natriuretic peptide (NT-proBNP) and incident CVD in a cohort of women, but whether those findings extend to other populations of women is not known. In addition, a few studies have assessed whether natriuretic peptides might improve measures of CVD risk prediction in healthy populations, but only one study has addressed that question specifically in women. We sought to address these issues by measuring NT-proBNP concentrations in a prospective case–cohort study of 480 cases of incident cardiovascular disease (myocardial infarction [MI], stroke, or cardiovascular death) and a reference subcohort of 564 women from the Women’s Health Study.
Methods
Women included in this study were enrolled in the Women’s Health Study (WHS), a completed, randomized, double-blind, placebo-controlled 2 × 2 factorial trial of aspirin and vitamin E in the prevention of CVD and cancer. The WHS enrolled 39,876 female health professionals, 28,345 of whom provided a blood sample before randomization. Of these, 19,871 women (70.1%) were fasting at the time of sample collection and were eligible for inclusion in this ancillary study. WHS participants have been followed continuously for the occurrence of CVD, a composite of nonfatal MI, nonfatal stroke (ischemic and hemorrhagic), and cardiovascular death.
We used a case–cohort study design to efficiently address the study hypothesis. From 19,871 nondiabetic women with fasting blood samples, we first selected a random sample of CVD cases (n = 465) and then chose 564 women for inclusion in the reference subcohort, which was frequency matched on age (5-year increments) and race with the selected CVD cases. Women who developed CVD during follow-up were eligible for inclusion in the reference subcohort, and by chance, 15 of the 564 women chose developed incident CVD during follow-up. Thus, the final sample size of women with incident CVD was 480.
Plasma NT-proBNP was measured using an electrochemiluminescent assay provided by Roche Diagnostics (Indianapolis, Indiana). Plasma samples were also previously measured for total, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol, high-sensitivity C-reactive protein (hsCRP), high-sensitivity cardiac troponin T (hsTnT; Roche Diagnostics), and creatinine.
Medians and proportions in the cases and reference subcohort were compared using the Wilcoxon rank sum and chi-square tests, respectively. NT-proBNP concentrations were divided into increasing quartiles on the basis of the distribution in the reference subcohort. Using methods appropriate for a case–cohort sample, Cox proportional hazards models were used to test for association between baseline NT-proBNP and incident CVD. The risk per 1 − SD unit of natural logarithm–transformed [Ln(NT-proBNP)] was also calculated. Models were adjusted for age, race, and aspirin assignment, those co-variables plus traditional CVD risk factors (body mass index, current smoking, family history of MI, systolic blood pressure, total and HDL cholesterol, and hsCRP). The last 2 models included age, race, aspirin, CVD risk factors, and estimated glomerular filtration rate with and without hsTnT.
To directly compare the performance of risk prediction algorithms with and without NT-proBNP, we compared a model including the co-variables used in the American College of Cardiology (ACC)/American Heart Association (AHA) 2013 pooled cohort atherosclerotic CVD risk model (age, race, systolic blood pressure, treatment for hypertension, smoking, and total and HDL cholesterol) and hemoglobin A1c and randomized aspirin assignment to the same model plus Ln(NT-proBNP). Diabetes was omitted from the model because none of the women included in this case–cohort had diabetes at baseline. We also compared a model using the Reynolds Risk Score co-variables (age, race, systolic blood pressure, smoking, total and HDL cholesterol, family history of MI, hemoglobin A1C, and hsCRP) and randomized aspirin assignment to the same model plus Ln(NT-proBNP). We calculated C-statistics and the integrated discrimination improvement (IDI) and then used the categorical net reclassification index (NRI) to determine whether NT-proBNP improved our ability to classify women into 10-year CVD risk categories of <5%, 5 to <7.5%, and ≥7.5%. Sensitivity analyses were conducted with the previous 10-year risk thresholds of <5%, 5 to <10%, 10 to <20%, and >20%. Statistical tests of discrimination measures were performed using 1,000 bootstrap samples.
The study was approved by the Brigham and Women’s Hospital Institutional Review Board. Financial support for the measurement of NT-proBNP and hsTnT was provided by Roche Diagnostics. The sponsor had no role in the study design, collection, analysis, or interpretation of the data, in the writing of this report, or the decision to submit this report for publication.
Results
A total of 480 cases of incident CVD and 564 in the reference subcohort were included for analyses. The median (Q1 to Q3) follow-up for the population was 12.0 (7.6 to 13.4) years. The women who developed incident CVD had a higher prevalence of cardiovascular risk factors including hypertension, high cholesterol, and smoking ( Table 1 ). Median (Q1 to Q3) NT-proBNP concentrations at baseline were greater in women who had incident CVD than in those in the reference subcohort ( Table 1 ).
| Characteristic | CVD Cases ∗ (n=480) | Reference Subcohort ∗ (n=564) | P-value |
|---|---|---|---|
| Age (years) | 61 (54-67) | 57 (51-58) | 0.06 |
| White | 457 (95%) | 519 (92%) | – |
| BMI (kg/m 2 ) | 25.0 (22.7-28.3) | 25.6 (23.0-28.3) | 0.42 |
| Systolic blood pressure (mmHg) | 135 (125-145) | 125 (115-135) | <0.0001 |
| Current smoker | 109 (23%) | 56 (10%) | <0.0001 |
| Family history of MI | 61 (13%) | 68 (12%) | 0.39 |
| Alcohol use ≥1 drink per day | 176 (37%) | 225 (40%) | 0.20 |
| Exercise ≥1 times per week | 177 (37%) | 260 (46%) | 0.002 |
| Hypertension | 228 (48%) | 180 (32%) | <0.0001 |
| Elevated cholesterol history | 207 (43%) | 191 (34%) | 0.02 |
| Hormone therapy use | 167 (35%) | 191 (34%) | 0.62 |
| Randomized aspirin use | 223 (46%) | 277 (49%) | 0.37 |
| High cholesterol treatment | 30 (6%) | 24 (4%) | 0.38 |
| Total cholesterol (mg/dL) | 221 (197-249) | 214 (188-240) | 0.001 |
| LDL cholesterol (mg/dL) | 133 (112-156) | 125 (107-149) | 0.02 |
| HDL cholesterol (mg/dL) | 50.2 (41.4-60.1) | 51.6 (43.0-62.1) | 0.11 |
| eGFR, (ml/min/1.73m 2 ) | 45 (37-55) | 47 (39-57) | 0.07 |
| hsCRP (mg/L) | 2.7 (1.2-5.5) | 2.2 (0.9-4.6) | 0.004 |
| NT-proBNP (ng/L) | 81 (50-147) | 64 (38-117) | <0.0001 |
| ln(NT-proBNP) | 4.4 (3.9-5.0) | 4.2 (3.7-4.8) | <0.0001 |
∗ Numbers are N (%) for categorical variables and median (Q1-Q3) for continuous variables. Women selected for the reference subcohort who developed cardiovascular disease during follow up are included in both groups for calculation of the N (%) and medians (Q1-Q3), but were excluded from the analysis for statistical testing.
Women with NT-proBNP concentrations in the highest quartile (≥117.4 ng/l) were at increased risk of incident CVD ( Table 2 ). In risk factor–adjusted models, the risk of incident CVD for women in the highest compared to the lowest quartile of NT-proBNP was nearly 70% greater. These estimates remained largely unchanged after adjusting for renal function and hsTnT ( Table 2 ).
| Model | Hazard Ratio (95% CI) | P-trend | Hazard Ratio (95% CI) per 1-SD of Ln(NT-proBNP) | P-value | |||
|---|---|---|---|---|---|---|---|
| Quartile 1 | Quartile 2 | Quartile 3 | Quartile 4 | ||||
| NT-proBNP range (ng/L) | <37.8 | 37.8 to <64.3 | 64.3 to <117.4 | ≥117.4 | |||
| Age, race, aspirin-adjusted | 1.0 | 1.17 (0.80-1.71) | 1.33 (0.91-1.94) | 1.40 (0.95-2.09) | 0.08 | 1.21 (1.05-1.41) | 0.01 |
| CV risk factor adjusted ∗ | 1.0 | 1.28 (0.84-1.95) | 1.66 (1.07-2.59) | 1.69 (1.05-2.66) | 0.02 | 1.23 (1.04-1.45) | 0.02 |
| CV risk factor + eGFR | 1.0 | 1.28 (0.84-1.96) | 1.69 (1.09-2.64) | 1.65 (1.03-2.64) | 0.03 | 1.22 (1.03-1.44) | 0.02 |
| CV risk factor + eGFR + hsTnT adjusted | 1.0 | 1.26 (0.82-1.93) | 1.69 (1.08-2.64) | 1.65 (1.02-2.65) | 0.03 | 1.21 (1.02-1.44) | 0.03 |
∗ Cardiovascular disease (CVD) risk factor adjusted model is adjusted for age, race, body mass index, current smoking, family history of myocardial infarction, randomized aspirin assignment, and natural logarithm transformed systolic blood pressure, total cholesterol, high-density lipoprotein cholesterol and high sensitivity C-reactive protein.
The association between NT-proBNP and incident CVD was consistent across a broad array of high- and low-risk subgroups, including age greater or less than 60 years, body mass index greater or less than 30, presence or absence of hypertension, and lipid and hsCRP concentrations ( Figure 1 ). The association between NT-proBNP and the composite outcome appeared to be driven by its association with cardiovascular death and stroke ( Table 3 ). The association with incident MI did not appear to be as strong.
| Endpoint | Hazard Ratio (95% CI) | P-trend | Hazard Ratio (95% CI) per 1-SD of Ln(NT-proBNP) | P-value | |||
|---|---|---|---|---|---|---|---|
| Quartile 1 | Quartile 2 | Quartile 3 | Quartile 4 | ||||
| Composite CV outcome (n=480) | 1.0 | 1.28 (0.84-1.96) | 1.69 (1.09-2.64) | 1.65 (1.03-2.64) | 0.03 | 1.22 (1.03-1.44) | 0.02 |
| CV Death (n=108) | 1.0 | 0.95 (0.43-2.08) | 1.26 (0.57-2.80) | 1.62 (0.72-3.63) | 0.17 | 1.43 (1.05-1.94) | 0.02 |
| Myocardial infarction (n=168) | 1.0 | 1.37 (0.75-2.51) | 1.78 (0.96-3.31) | 1.31 (0.65-2.61) | 0.34 | 1.09 (0.87-1.37) | 0.44 |
| Stroke (n=254) | 1.0 | 1.45 (0.86-2.45) | 1.97 (1.15-3.36) | 1.97 (1.13-3.44) | 0.01 | 1.24 (1.03-1.50) | 0.03 |
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
