Cigarette smoking impairs arterial function and promotes atherosclerosis. However, whether smoking status is associated with cardiac overload has not yet been fully examined, particularly from an epidemiologic viewpoint. The present study examined the relation of smoking status to serum levels of N-terminal pro–brain natriuretic peptide (NT–pro-BNP), a marker of cardiac overload, in middle-aged men without overt cardiovascular disease. Serum NT–pro-BNP levels were measured in a work-site based population of 969 men (mean age 44 ± 6 years) who did not have any history or presence of cardiovascular disease. Smoking status was evaluated by self-reported questionnaire. Four hundred fifty-nine, 222, and 288 subjects were never, former, and current smokers, respectively. NT–pro-BNP levels were significantly higher in current smokers (21.7 ± 2.3 pg/ml) than in never smokers (17.9 ± 2.1 pg/ml, p <0.001). This significant difference was maintained even after adjusting for age, obesity, heart rate, hypertension, dyslipidemia, impaired fasting glucose/diabetes mellitus, left ventricular hypertrophy, estimated glomerular filtration rate, high-sensitivity C-reactive protein, alcohol consumption, and regular exercise. Current smokers had an increased odds ratio (3.04, 95% confidence interval 1.64 to 5.61, p <0.001) for elevated NT–pro-BNP (>54.5 pg/ml) compared to never smokers, even after adjusting for the studied variables. In contrast, former smokers did not show a significantly increased odds ratio for elevated NT–pro-BNP. NT–pro-BNP levels showed a weak, but significant negative correlation with duration of smoking cessation (partial r = −0.15, p = 0.034) in former smokers. In conclusion, these results suggest that cigarette smoking increases cardiac overload, whereas smoking cessation ameliorates these conditions.
Brain natriuretic peptide (BNP) is secreted predominantly from the ventricular myocardium in response to increased ventricular wall stretch. In the process of secreting BNP, pro-BNP in cardiomyocytes is cleaved into the active hormone BNP and inactive N-terminal pro-BNP (NT–pro-BNP). In daily clinical practice, circulating BNP and NT–pro-BNP levels are measured to diagnose heart failure and to identify subjects with cardiac overload. Cigarette smoking, which is a completely modifiable risk factor for cardiovascular disease (CVD), impairs arterial function and promotes atherosclerosis. However, whether smoking status is associated with cardiac overload has not yet been fully examined, particularly from an epidemiologic viewpoint. The present study examined the relation of smoking status to serum NT–pro-BNP levels in a work-site based population of middle-aged men without overt CVD.
Methods
This study was conducted during an annual health examination at a company in Kanagawa, Japan in 2005. The business of this company was the development of precision equipment. In total 1,082 men 35 to 63 years of age underwent a complete health examination. All workers were engaged in daytime desk work. Of these subjects, any on medication for hypertension, dyslipidemia, or diabetes mellitus (n = 63) and those with a history or presence of CVD, malignancy, or acute or chronic inflammatory disorders (n = 14) were excluded from the study ( Figure 1 ). We also excluded any subjects with serum high-sensitivity C-reactive protein (hs-CRP) levels >10.0 mg/L (n = 16) to rule out any occult inflammatory or infectious disorders, in accordance with the scientific statement of the American Heart Association/Centers for Disease Control and Prevention. Because clearance of NT–pro-BNP is substantially impaired in subjects with renal dysfunction, we further excluded any subjects with an estimated glomerular filtration rate <60 ml/min/1.73 m 2 (n = 20). Thus, 969 subjects were selected to participate in the present study. This study was approved by the ethics committee of Nippon Medical School (Tokyo, Japan), and all participants gave written informed consent.
A self-administered questionnaire was used to collect subjects’ data regarding their family history, smoking status, alcohol consumption, exercise habits, and medical information including use of prescribed drugs. Right brachial blood pressure (BP) was measured by well-trained staff members using a mercury sphygmomanometer with a subject in the sitting position after 5 minutes of rest. Standard 12-lead electrocardiogram was recorded in the supine position. Each electrocardiogram was coded, according to the Minnesota Code, by expert cardiologists who were unaware of any participant information.
Smoking status was categorized as current, former, and never. Current smoking was defined as cigarette consumption on a regular basis (≥1 cigarette/day) at the time of study participation. Former smoking was defined as a history of cigarette consumption on a regular basis but no current smoking. Current and former smokers were asked about number of cigarettes smoked (per day) and duration they had smoked (years). Former smokers were further asked about duration that had passed since quitting smoking (years). Cigarette pack-years were calculated as duration of smoking (years) multiplied by number of smoked cigarettes (per day), divided by 20.
Blood samples were obtained from the antecubital vein after overnight fasting. Current smokers refrained from smoking for ≥1 hour before blood sampling. Standard enzymatic methods were used to measure serum total cholesterol, triglycerides, creatinine, and plasma glucose. Serum high-density lipoprotein cholesterol level was measured using the direct method. Serum hs-CRP level was measured using a highly sensitive, latex turbidimetric immunoassay. Residual sera after these measurements were stored at −30°C for 3 years and then used to measure NT–pro-BNP levels for the present study using an electrochemiluminescence immunoassay (Elecsys NT–pro-BNP II, Roche Diagnostics, Ltd., Rotkreuz, Switzerland). The manufacturer’s stated lower detection limit for NT–pro-BNP is 5.0 pg/ml and intra- and interassay coefficients of variation are ≤1.8% and ≤2.1%, respectively.
Hypertension was defined as systolic BP ≥140 mm Hg or diastolic BP ≥90 mm Hg. Dyslipidemia was defined as total cholesterol ≥220 mg/dl, high-density lipoprotein cholesterol <40 mg/dl, or triglycerides ≥150 mg/dl. Impaired fasting glucose/diabetes mellitus was defined as fasting plasma glucose ≥110 mg/dl. Obesity was defined as body mass index ≥25 kg/m 2 . Estimated glomerular filtration rate was calculated using serum creatinine and age according to the equation presented by the Japanese Society of Nephrology. Elevated hs-CRP was defined as >3.0 mg/L. Regular exercise was defined as continuous exercise for ≥15 minutes for ≥2 days per week for ≥1 year. As a surrogate marker of left ventricular hypertrophy, high R-wave voltage on electrocardiogram was defined as Minnesota Code 3-1 or 3-3. Elevated NT–pro-BNP was defined as >54.5 pg/ml according to a report by Seino et al. This cut-off level was determined based on higher than mean + 2 SD of NT–pro-BNP level in healthy volunteers.
All statistical tests were performed using SPSS 11.0.1 (SPSS, Inc., Chicago, Illinois). Continuous variables were expressed as mean ± SD. Those with an extremely skewed distribution were expressed as geometric mean ± SD and transformed to a common logarithm for subsequent analyses, if needed. Categorical data were expressed as percent of total. Clinical characteristics among smoking statuses were compared by analysis of variance or chi-square test, as appropriate. Difference in NT–pro-BNP levels among smoking statuses was tested by analysis of variance and analysis of covariance with multiple potential confounders as covariates, followed by multiple comparisons with Bonferroni correction. Multiple logistic regression analysis was performed to obtain the odds ratio for elevated NT–pro-BNP according to smoking status. In these multivariate analyses, the following variables were used as potential confounders: age, obesity, heart rate, hypertension, dyslipidemia, impaired fasting glucose/diabetes mellitus, left ventricular hypertrophy, estimated glomerular filtration rate, hs-CRP, amount of alcohol consumption, and regular exercise. In current smokers, a partial correlation coefficient between NT–pro-BNP levels and cigarette pack-years or number of cigarettes per day was analyzed with adjustment for the studied confounders. In former smokers, a partial correlation coefficient between NT–pro-BNP levels and duration of smoking cessation was analyzed with adjustment for the studied confounders plus cigarette pack-years. All statistical tests were 2-sided, and a p value <0.05 was considered statistically significant.
Results
In the entire study population, mean age was 44 ± 6 years, mean NT–pro-BNP level was 19.3 ± 2.3 pg/ml, and prevalence of elevated NT–pro-BNP was 8.2%. Four hundred fifty-nine, 222, and 288 subjects were never, former, and current smokers, respectively. Numbers of cigarette pack-years were 20.0 ± 11.4 and 8.6 ± 8.5 in current and former smokers, respectively. Number of cigarettes per day was 18 ± 7 in current smokers. Duration of smoking cessation in former smokers was 14.6 ± 8.4 years. Clinical characteristics of study participants according to smoking status are listed in Table 1 .
| Variables | Smoking Status | p Value | ||
|---|---|---|---|---|
| Never (n = 459) | Former (n = 222) | Current (n = 288) | ||
| Age (years) | 43 ± 6 | 45 ± 7 | 44 ± 7 | <0.001 |
| Body mass index (kg/m 2 ) | 22.9 ± 2.9 | 23.6 ± 2.7 | 23.5 ± 3.2 | 0.004 |
| Obesity ⁎ | 10.9% | 23.0% | 27.8% | 0.023 |
| Heart rate (beats/min) | 69 ± 10 | 68 ± 10 | 70 ± 11 | 0.033 |
| Systolic blood pressure (mm Hg) | 119 ± 13 | 121 ± 14 | 119 ± 13 | 0.034 |
| Diastolic blood pressure (mm Hg) | 76 ± 10 | 77 ± 10 | 76 ± 9 | 0.123 |
| Hypertension † | 10.9% | 13.1% | 11.5% | 0.707 |
| Total cholesterol (mg/dl) | 199 ± 31 | 203 ± 31 | 200 ± 35 | 0.277 |
| High-density lipoprotein cholesterol (mg/dl) | 58 ± 13 | 59 ± 16 | 52 ± 13 | <0.001 |
| Triglycerides (mg/dl) | 103 ± 83 | 110 ± 77 | 140 ± 147 | <0.001 |
| Dyslipidemia ‡ | 36.2% | 38.3% | 45.1% | 0.047 |
| Fasting plasma glucose (mg/dl) | 91 ± 12 | 92 ± 9 | 92 ± 12 | 0.435 |
| Impaired fasting glucose/diabetes mellitus § | 3.1% | 4.5% | 6.3% | 0.111 |
| Estimated glomerular filtration rate (ml/min/1.73 m 2 ) | 83.9 ± 13.5 | 84.0 ± 13.6 | 86.5 ± 14.2 | 0.036 |
| High-sensitivity C-reactive protein (mg/L) ∥ | 0.29 ± 2.55 | 0.32 ± 2.71 | 0.40 ± 2.84 | <0.001 |
| Elevated high-sensitivity C-reactive protein ¶ | 2.8% | 4.1% | 5.6% | 0.174 |
| Left ventricular hypertrophy # | 19.6% | 18.9% | 13.9% | 0.120 |
| Regular exercise ⁎⁎ | 22.7% | 27.9% | 12.8% | <0.001 |
| Alcohol consumption (g/week) ∥ | 30.8 ± 6.4 | 63.8 ± 6.0 | 55.6 ± 6.6 | <0.001 |
| N-terminal pro–brain natriuretic peptide (pg/ml) ∥ | 17.9 ± 2.1 | 19.5 ± 2.7 | 21.7 ± 2.3 | 0.008 |
| Elevated N-terminal pro–brain natriuretic peptide †† | 4.6% | 9.0% | 13.2% | <0.001 ‡‡ |
⁎ Body mass index ≥25 kg/m 2 .
† Systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg.
‡ Total cholesterol ≥220 mg/dl, high-density lipoprotein cholesterol <40 mg/dl, or triglycerides ≥150 mg/dl.
§ Fasting plasma glucose ≥110 mg/dl.
⁎⁎ Continuous exercise for ≥15 minutes for ≥2 days per week for ≥1 year.
Serum NT–pro-BNP levels were significantly different in never, former, and current smokers ( Table 1 ). Post hoc multiple comparisons revealed NT–pro-BNP levels to be significantly higher in current smokers than in never smokers (p = 0.006), whereas no significant difference was seen between never and former smokers. These results were maintained even after adjusting for multiple potential confounders ( Figure 2 ). Prevalence of elevated NT–pro-BNP was significantly different in never, former, and current smokers and it gradually increased in the same order ( Table 1 ). In logistic regression analysis, former and current smokers had increased crude odds ratios for elevated NT–pro-BNP compared to never smokers ( Table 2 ). A significantly increased odds ratio for elevated NT–pro-BNP was also found in current smokers after adjusting for age (age-adjusted model) and further adjusting for multiple potential confounders (multi-adjusted model). In contrast, former smokers did not maintain a significantly increased odds ratio under the age- or multi-adjusted model.
