Natriuretic peptides have multiple beneficial cardiovascular effects. Previous cross-sectional studies have indicated that obese subjects have lower natriuretic peptide concentrations than those of normal weight. It is not known whether this relative natriuretic peptide deficiency is reversible with weight loss. We studied 132 obese subjects undergoing weight loss surgery with serial measurement of plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentrations at preoperative, early (1 to 2 months), and late postoperative (6 months) points. In addition, 20 subjects also underwent echocardiography at baseline and 6 months after surgery. Significant weight loss was observed after surgery (median body mass index 45.1, 41.0, and 32.9 kg/m 2 for the 3 corresponding points, analysis of variance p <0.001). The median NT-proBNP levels increased substantially (31.6, 66.9, and 84.9 pg/ml; p <0.001). The average intrasubject increase in NT-proBNP at the 2 postoperative points was 3.4 and 5.0 times the preoperative level (p <0.001 for both points vs preoperatively). In the multivariate regression models adjusted for clinical characteristics and insulin resistance, the strongest predictor of the change in NT-proBNP level 6 months after weight loss surgery was the change in weight (p = 0.03). Echocardiography showed a mean intrasubject reduction in left ventricular mass index of 18% (p <0.001) and mild improvements in diastolic function, with no change in ejection fraction. In conclusion, we have demonstrated that weight loss is associated with early and sustained increases in NT-proBNP concentrations, despite evidence of preserved systolic and improved diastolic function. These findings suggest a direct, reversible relation between obesity and reduced natriuretic peptide levels.
The natriuretic peptides are secreted by the ventricles in response to increased cardiac wall stress. These molecules have a variety of actions, including natriuresis, vasodilation, and inhibition of cardiac hypertrophy and fibrosis. Persons with obesity have lower levels of natriuretic peptides than lean persons, despite having a high prevalence of conditions normally associated with elevated natriuretic peptides, such as hypertension, left ventricular (LV) hypertrophy, and increased plasma volume. Accordingly, it has been suggested that obese subjects have a “natriuretic handicap,” with a reduced natriuretic peptide response to cardiac wall stress. Because previous studies have been cross-sectional, it is unclear whether reduced plasma natriuretic peptide levels precede or follow the development of obesity and whether weight loss reverses the relative deficiency. Surgery has emerged as a highly effective method of achieving and maintaining significant weight loss in those with severe obesity. Therefore, we conducted a prospective study of patients undergoing weight loss surgery to investigate the effect of weight loss on natriuretic peptide levels.
Methods
Participants for the present study were recruited from consecutive adult patients at the Massachusetts General Hospital Weight Center who were recommended for weight loss surgery (Roux-en- Y gastric bypass or gastric banding). The patients were excluded if they experienced significant perioperative complications such as myocardial infarction, persistent atrial fibrillation, sepsis, or gastrointestinal bleeding requiring blood transfusion >2 U. Of the 161 patients who were screened for the study and had pre- and postoperative blood samples taken, 17 did not undergo gastric bypass surgery and 12 withdrew consent. No significant difference was found in age or gender between those included in the present study and those not included. The institutional human research committee approved the present study, which was conducted in accordance with institutional guidelines. All participants provided written informed consent.
The medical history and medications were verified by chart review. The subjects were considered to have a history of coronary artery disease if they had a history of myocardial infarction, stable angina, or unstable angina documented in the physician notes or had positive stress test or cardiac catheterization findings. The presence of heart failure, arrhythmia, and asthma was determined from the physician notes. Similarly, the subjects were considered to have obstructive sleep apnea (OSA), if this diagnosis was present in the physician notes or if positive findings for a sleep study had been documented. The subjects were evaluated at routinely scheduled clinic visits before surgery and at the early postoperative (1 to 2 months) and late postoperative (6 months) points. These visits included a physical examination, with calculation of the body mass index (BMI) and measurement of blood pressure with the patient in the seated position. Phlebotomy was performed on fasting subjects for the assessment of N-terminal pro-B-type natriuretic peptide (NT-proBNP), blood urea nitrogen, creatinine, glucose, insulin, erythrocyte sedimentation rate, and lipids. Insulin resistance was estimated by the homeostasis model assessment. Creatinine clearance was estimated using the method of Salazar and Corcoran for those with obesity.
The blood samples were drawn in tubes containing ethylenediaminetetraacetic acid and centrifuged within 30 minutes. Plasma was frozen at −80°C until measurement of NT-proBNP using a commercially available automated immunoassay. The lower limit of detection of this assay was 5 pg/ml; samples below the lower limit of detection were assigned a value of 5 pg/ml.
Subjects enrolled in the main study from March 2006 to April 2007 were invited to participate in the echocardiographic substudy if they did not have any of the following: previous myocardial infarction, coronary artery disease, congestive heart failure or abnormal LV ejection fraction, valvular disease, hypertrophic cardiomyopathy, chronic obstructive lung disease, persistent or permanent atrial fibrillation, chronic renal insufficiency, or poorly controlled hypertension (systolic blood pressure ≥170 mm Hg or diastolic blood pressure ≥100 mm Hg). A total of 30 patients agreed to participate in the substudy. Of these, 10 were excluded from analysis—7 because of incomplete data and 3 because of poor image quality. A significantly greater proportion of substudy subjects were men compared to those not in the substudy. The 2 groups were otherwise similar (data not shown).
Participants underwent echocardiography before and 6 months after surgery. The echocardiography was performed by a single investigator (ACT) and interpreted by 2 investigators (ACT, MSC) in a blinded fashion, with the pre- and postoperative echocardiograms randomly ordered. The heart rate and blood pressure were measured. Two-dimensional and pulsewave and tissue Doppler imaging were performed in standard views using a commercial system (Vivid 7, GE Vingmed, Milwaukee, Wisconsin). The images were recorded digitally and off-line analysis was performed using commercial software (EchoPAC, GE Healthcare, Horten, Norway). The measurements were averaged for 3 cardiac cycles. The LV volumes were calculated using the biplane Simpson method to determine the LV ejection fraction. The LV mass was estimated using the area-length method and indexed to the height in meters to the 2.7th power. The early transmitral diastolic velocity (E) and early diastolic tissue Doppler velocity (Ea) at the lateral mitral annulus were measured.
The data were tested for normality using the Kolmogorov-Smirnov test. Normally distributed variables were compared at different points using the paired t test or analysis of variance. The Wilcoxon paired signed ranks test or the Mann-Whitney U test was used, when the assumption of normality was not met. The categorical variables were compared using the chi-square test. Statistical tests of interaction were performed to evaluate possible interactions of NT-proBNP levels with gender or surgery type.
Multivariate linear regression models were fitted to examine the predictors of change in NT-proBNP, including age, gender, change in creatinine clearance, homeostasis model assessment–insulin resistance, antihypertensive and antidiabetic medication use, and weight. Antihypertensive and antidiabetic medication use were treated as dichotomous variables. Statistical analyses were performed using Predictive Analysis Software Statistics, version 17.0 (SPSS, Chicago, Illinois) and Statistical Analysis Systems, version 9.1.3 (SAS Institute, Cary, North Carolina).
Results
Tables 1 and 2 list the characteristics of the study sample at baseline and after surgery. No significant differences were found in the baseline characteristics between patients who had undergone Roux-en- Y gastric bypass surgery and those who had undergone adjustable gastric banding (data not shown). None of the subjects were excluded because of perioperative complications.
| Characteristic | Baseline (n = 132) |
|---|---|
| Age (years) | 46.1 ± 11.3 |
| Women | 94 (71%) |
| Race | |
| Black | 9 (7%) |
| Hispanic | 7 (5%) |
| Asian-American | 1 (0.7%) |
| Bariatric procedure | |
| Open Roux-en- Y gastric bypass | 11 (8%) |
| Laparoscopic Roux-en- Y gastric bypass | 114 (86%) |
| Adjustable gastric banding | 7 (5%) |
| Hypertension | 81 (61%) |
| Diabetes mellitus | 51 (39%) |
| Coronary artery disease ⁎ | 6 (4.6%) |
| Heart failure † | 1 (0.8%) |
| Arrhythmia † | 2 (2%) |
| Asthma † | 23 (17%) |
| Obstructive sleep apnea ‡ | 73 (55%) |
| Smoker | |
| Current | 7 (5%) |
| Former | 48 (36%) |
| Never | 77 (58%) |
⁎ History of myocardial infarction, stable angina, or unstable angina documented in physician notes or positive stress test or cardiac catheterization findings.
† Determined from physician notes.
‡ Diagnosis present in physician notes or documented positive findings from sleep study.
| Variable | Preoperative | Early Postoperative | Late Postoperative | p Value | |
|---|---|---|---|---|---|
| Early Postoperative vs Preoperative | Late Postoperative vs Early Postoperative | ||||
| Weight (kg) | 129 (115–152) | 116 (101–135) | 95 (83–112) | <0.001 | <0.001 |
| Body mass index (kg/m 2 ) | 45 (42–52) | 41 (37–47) | 33 (30–38) | <0.001 | <0.001 |
| β Blocker | 25% | 29% | 22% | 0.25 | 0.02 |
| Angiotensin-converting enzyme inhibitor or angiotensin receptor blocker | 41% | 20% | 20% | <0.001 | 1.00 |
| Diuretic | 30% | 6% | 6% | <0.001 | 1.00 |
| Calcium channel blocker | 9% | 5% | 5% | 0.03 | 0.32 |
| Insulin | 9% | 4% | 0.8% | 0.02 | 0.05 |
| Oral antidiabetic medications | 33% | 8% | 8% | <0.001 | 1.00 |
| Statin or other antilipid medication | 35% | 25% | 21% | <0.001 | 0.10 |
| Heart rate (beats/min) | 80 (72–88) | 72 (66–79) | 72 (66–76) | <0.001 ⁎ | 0.005 ⁎ |
| Systolic blood pressure (mm Hg) | 124 (118–136) | 116 (108–124) | 118 (108–126) | <0.001 † | 0.48 † |
| Diastolic blood pressure (mm Hg) | 80 (73–84) | 76 (70–80) | 75 (70–80) | <0.001 † | 0.16 † |
| Blood urea nitrogen (mg/dl) | 15 (11–18) | 10 (8–13) | 12 (10–15) | <0.001 | <0.001 |
| Creatinine clearance (ml/min) | 129 (104–149) | 126 (104–155) | 114 (95–138) | 0.099 | <0.001 |
| Fasting insulin (μIU/ml) | 16.0 (11.0–25.0) | 9.7 (7–14) | 5.0 (3.0–8.0) | <0.001 ‡ | <0.001 ‡ |
| Fasting glucose (mg/ml) | 101 (89–135) | 93 (87–102) | 88 (83–94) | <0.001 | <0.001 |
| Homeostasis model assessment of insulin resistance | 4.2 (2.5–7.3) | 2.3 (1.6–3.6) | 1.0 (0.7–1.8) | <0.001 ‡ | 0.003 ‡ |
| Erythrocyte sedimentation rate (mm/hr) | 24 (16–40) | 21 (13–30) | 15 (10–24) | 0.002 | <0.001 |
| Total cholesterol (mg/dl) | 190 (162–208) | 154 (130–173) | 156 (141–179) | <0.001 § | 0.001 § |
| Low-density lipoprotein (mg/dl) | 103 (89–123) | 83 (65–103) | 83 (68–97) | <0.001 § | 0.45 § |
| High-density lipoprotein (mg/dl) | 49 (42–56) | 39 (34–48) | 52 (44–61) | <0.001 § | <0.001 § |
| Triglycerides | 133 (100–195) | 123 (94–147) | 92 (76–129) | <0.001 § | 0.004 § |
The mean weight loss at the early and late postoperative points was 14 ± 6 kg and 36 ± 12 kg (10% and 27% of baseline weight), respectively. As expected, after surgery, significant improvements were noted in blood pressure, insulin sensitivity, and lipid profiles, with corresponding decreases in medication use ( Table 2 ).
All subjects had NT-proBNP levels measured at all 3 points. The NT-proBNP levels were significantly greater at both postoperative points compared to baseline ( Figure 1 ). The average intraindividual increase in NT-proBNP compared to baseline was 3.4-fold at 1 to 2 months and 5.0-fold at 6 months (p <0.001 for both). Figure 2 illustrates the relation between the weight lost and the increase in NT-proBNP at the late postoperative point compared to the preoperative values.
