Published online before print May 28, 2007, doi: 10.1161/CIRCULATIONAHA.106.652842
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(Circulation. 2007;115:3079-3085.)
© 2007 American Heart Association, Inc.
Epidemiology |
Associations of Plasma Natriuretic Peptide, Adrenomedullin, and Homocysteine Levels With Alterations in Arterial Stiffness
The Framingham Heart Study
From the NHLBI Framingham Heart Study, Framingham, Mass (D.L., S.-J.H., E.J.B., R.S.V., T.J.W., M.G.L., M.J.K.); the National Heart, Lung, and Blood Institute, Bethesda, Md (D.L., S.-J.H.); Department of Medicine, MetroWest Medical Center, Framingham, Mass (A.K.); Division of Cardiology, Massachusetts General Hospital, Boston, Mass (T.J.W.), Jean Mayer USDA Human Nutrition Research Center on Aging and Friedman School of Nutrition Science and Policy, Tufts University, Boston, Mass (J.S., P.F.J.); Departments of Mathematics and Statistics, Boston University, Boston, Mass (H.P., M.G.L.); Cardiology Section (D.L., E.J.B., R.S.V., J.A.V.) and Preventive Medicine and Epidemiology (E.J.B., R.S.V., M.G.L., D.L.), Boston University School of Medicine, Boston, Mass; and Cardiovascular Engineering, Inc, Waltham, Mass (G.F.M.).
Correspondence to Daniel Levy, MD, 73 Mt Wayte Ave, Ste 2, Framingham, MA 01702.
Received July 18, 2006; accepted April 3, 2007.
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Abstract |
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Background— Increased arterial stiffness and higher plasma natriuretic peptide and homocysteine levels are associated with elevated risk for cardiovascular disease. Little is known about the relations of natriuretic peptides and homocysteine to arterial wall stiffness in the community.
Methods and Results— We assessed the relations of plasma N-terminal atrial natriuretic peptide, B-type natriuretic peptide, adrenomedullin, and homocysteine concentrations to arterial stiffness in participants in the Framingham Heart Study. Central pulse pressure, forward pressure wave, reflected pressure wave, carotid-femoral pulse wave velocity, and carotid-radial pulse wave velocity were assessed by tonometry in 1962 participants (mean age, 61 years; 56% women) in the Framingham Heart Study. Central systolic and diastolic blood pressures were 123/75 mm Hg in men and 119/66 mm Hg in women. After adjustment for age and clinical covariates, N-terminal atrial natriuretic peptide and B-type natriuretic peptide were associated with carotid-femoral pulse wave velocity (men: partial correlation, 0.069, P=0.043 and r=0.115, P
0.001, respectively; women: r=–0.063, P=0.037 and r=–0.062, P=0.040), and carotid-radial pulse wave velocity (men: r=–0.090, P=0.009 and r=–0.083, P0.015; women: r=–0.140, P0.001 and r=-0.104, P=0.001, respectively). In men, N-terminal atrial natriuretic peptide and B-type natriuretic peptide also were associated with forward and reflected wave and carotid pulse pressure. In men, adrenomedullin was associated with mean arterial pressure (r=0.089, P=0.009), and homocysteine was associated with carotid-femoral pulse wave velocity (r=0.072, P=0.036), forward pressure (r=0.079, P=0.02), and central pulse pressure (r=0.072, P=0.035). Interaction tests indicated sex differences in the relations of several biomarkers to measures of arterial stiffness.
Conclusions— Plasma natriuretic peptide, adrenomedullin, and homocysteine levels are associated with alterations in conduit vessel properties that differ in men and women.
Key Words: arteries • elasticity • epidemiology • hemodynamics • homocysteine • natriuretic peptides
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Introduction |
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Increased arterial stiffness is associated with increased risk for cardiovascular disease (CVD). A simple but indirect indicator of central aortic stiffness is arterial pulse pressure. There is a considerable body of research indicating that pulse pressure is an important predictor of CVD risk.1–9 Arterial tonometry provides a more direct indication of arterial stiffness, and there is increasing evidence of a link between tonometric measures of vascular stiffness and CVD morbidity and mortality.2,10–13 Stiffening of the aorta increases the amplitude of the forward-traveling pressure wave produced by ventricular ejection and increases arterial pulse wave velocity (PWV). The larger forward wave therefore travels to the periphery faster and returns to the heart during systole as a proportionally larger reflected wave, which augments systolic pressure, pulse pressure, and cardiac load.14,15 Increased pressure pulsatility and premature wave reflection contribute to regional abnormalities in tensile and shear stresses, which may contribute to plaque rupture and the progression of subclinical atherosclerosis to clinical CVD events. A vicious cycle may ensue with the augmented systolic and pulse pressure accelerating the stiffening of the aorta, which in turn increases the PWV and the early return of the reflected wave during systole.16 Excessive pressure pulsatility and premature wave reflection have a deleterious effect on left ventricular systolic and diastolic function, leading to atrial and ventricular remodeling and hypertrophy.17,18
Clinical Perspective p 3085
Natriuretic peptide and adrenomedullin levels have important and complex associations with measures of arterial stiffness. Atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) are released by the heart in response to atrial and ventricular loading conditions, respectively,19 and act to reduce overload by virtue of their natriuretic properties. In addition, they favorably affect cardiac remodeling through antiproliferative effects on left ventricular hypertrophy and cardiac fibrosis.20 It is believed that ANP and BNP also have beneficial effects on arterial wall structure and remodeling.21 Adrenomedullin also has potent vascular, natriuretic, and vasodilatory actions.22 Despite the postulated beneficial effects of ANP, BNP, and adrenomedullin on the heart and vasculature, the direction of the association may be counterintuitive. We and others have recently shown that elevated natriuretic peptide levels are associated with increased risk for CVD.23 The probable reason is that natriuretic peptide levels are increased primarily in the setting of myocardial hypertrophy and strain and thus serve as markers of risk despite their counterregulatory and protective actions. For this reason, we hypothesized a priori that natriuretic peptide and adrenomedullin levels are positively associated with measures of arterial stiffness.
Homocysteine has emerged as a CVD risk factor. Elevated plasma homocysteine levels are associated with increased risk of myocardial infarction, stroke, heart failure, occlusive peripheral arterial disease, and CVD and all-cause mortality.24–28 Studies of patients with homocystinuria, a rare familial form of hyperhomocysteinemia, noted the early and severe development of pathological vascular alterations.29 The association of homocysteine with CVD risk may be mediated by its effects on vascular endothelium and smooth muscle with resultant alterations in arterial structure and function. The putative mechanisms for such effects have been reviewed by Welch and Loscalzo30 and include oxidative damage, vascular smooth muscle proliferation, and fibrosis and matrix deposition of sulfated glycosaminoglycans. Associations of homocysteine with CVD risk and with alterations in vascular properties have prompted studies of its association with arterial wall stiffness. Investigators have reported a significant association of plasma homocysteine with pulse pressure31 and arterial PWV.32,33
The Framingham Heart Study has assessed arterial stiffness using arterial tonometry and measured homocysteine and natriuretic peptides in 
2000 study participants attending routine examinations. The present study setting provides an opportunity to explore the relations of plasma natriuretic peptides, adrenomedullin, and homocysteine to indexes of arterial stiffness in a community-based cohort.
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Methods |
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Study Sample
The design and recruitment of the Framingham Heart Study offspring cohort are described elsewhere.34 Arterial tonometry was performed in offspring cohort participants undergoing their seventh clinic examination cycle (1998 to 2001). Of 3334 individuals who attended the seventh clinic visit, tonometry was attempted in 2640 and was optimal in 2253 (85%); of these, 291 were excluded from analysis for the following criteria: prior myocardial infarction or heart failure (n=114), unavailable natriuretic peptide levels (n=153), no creatinine measurement or creatinine
2 mg/dL (n=15), no homocysteine measurement (n=7), and missing covariate information (n=2), leaving 1962 participants available for analysis. The Boston Medical Center Institutional Review Board approved the protocol, and each participant gave written informed consent.
Biomarker Measurements
Measurements of N-terminal pro-ANP (NT-ANP), BNP, and adrenomedullin were obtained on study participants attending the sixth Framingham Heart Study offspring cohort examination (1995–1998). Levels of natriuretic peptides were measured with high-sensitivity, noncompetitive immunoradiometric assays, which are based on a 2-site sandwich antibody system (Shionogi Co, Osaka, Japan). The lower limits of the working range were 4 pg/mL for BNP and 94 pmol/L for NT-ANP. Adrenomedullin level was determined by immunoradiometric assay (Shionogi Co)35 on the same specimens used for natriuretic peptide assay; the detection limit of this assay was 0.5 pmol/L. Fasting plasma samples for homocysteine determination were obtained at the seventh examination cycle, refrigerated immediately after phlebotomy, and stored at or below –70°C. Plasma total homocysteine levels were measured using liquid chromatography with fluorometric detection.36
Arterial Tonometry
Arterial tonometry was performed on participants in the supine position after 5 minutes of rest. Supine brachial systolic and diastolic blood pressures were obtained with an oscillometric device (Dinamap, Critikon, Inc, Tampa, Fla). Arterial tonometry with simultaneous ECG was obtained from brachial, radial, femoral, and carotid arteries with a commercially available tonometer (SPT-301, Millar Instruments, Houston, Tex). Transit distances were assessed by body surface measurements from the suprasternal notch to each pulse recording site. Tonometry and ECG data were digitized during the primary acquisition (1000 Hz) and analyzed by researchers blinded to clinical data at the core laboratory (Cardiovascular Engineering, Inc, Waltham, Mass). Tonometry waveforms were signal averaged with the ECG R wave as a fiducial point.37 Average systolic and diastolic cuff pressures were used to calibrate the peak and trough of the signal-averaged brachial pressure waveform. Diastolic and integrated mean brachial pressures were then used to calibrate carotid, radial, and femoral pressure tracings.38 Calibrated carotid pressure was used as a surrogate for central pressure.39 Carotid-brachial, carotid-radial, and carotid-femoral PWVs were calculated from tonometry waveforms and body surface measurements as previously described.38 Reflected wave transit time was measured from the foot of the carotid pressure waveform to the first inflection point, which corresponds to the foot of the global reflected pressure wave.40 Forward pressure wave amplitude was defined as the difference between pressure at the waveform foot and pressure at the first systolic inflection point or peak of the carotid pressure waveform. Reflected pressure wave amplitude was defined as the difference between the central systolic pressure and the pressure at the forward wave peak.
Statistical Analysis
The tonometry-derived measures included in analyses were central (carotid) pulse pressure, central mean arterial pressure, forward pressure wave (amplitude), reflected pressure wave (amplitude), carotid-radial PWV, and carotid-femoral PWV.
Baseline characteristics and tonometry variables were tabulated separately for men and women. Sex-specific regression models were performed to test for significance between tonometry variables and plasma NT-ANP, BNP, adrenomedullin, and homocysteine with the biomarkers log transformed to normalize their distribution. Partial Pearson product-moment correlation coefficients (and probability values) for biomarker-tonometry associations were calculated after adjustment for age, age squared, body mass index, the ratio of total to high-density lipoprotein (HDL) cholesterol, hypertension treatment, current cigarette smoking, diabetes (defined as a fasting serum glucose level >125 mg/dL or diabetes treatment), prior diagnosis of CVD (other than myocardial infarction or heart failure, which were criteria for exclusion), and current use of postmenopausal hormone replacement in women. For descriptive purposes, fully adjusted least-square means and SEs for tonometry variables were calculated for sex-specific biomarker level tertiles. In addition, to determine whether the relations of biomarkers to arterial stiffness differed between men and women, sex interaction terms for each biomarker were considered in secondary analyses. Analyses were performed with SAS version 8.1 (SAS, Cary, NC). A 2-sided value of P<0.05 was considered significant.
All authors had full access to and take full responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.
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Results |
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A total of 1962 participants (mean age, 61 years; 856 men, 1106 women) were eligible for analyses. The mean systolic and diastolic blood pressures were 128/76 mm Hg in men and 126/72 mm Hg in women. Clinical characteristics of the study sample and mean tonometry values are presented in Table 1. The sex-specific tertile ranges for each biomarker are presented in Table 2. NT-ANP and BNP were highly correlated (r=0.64, P<0.0001 in men; r=0.68, P<0.0001 in women); the correlations for other biomarker pairs were all <0.2.
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The results of multivariable-adjusted analyses are presented in Tables 3 and 4
. Increasing levels of NT-ANP and BNP were associated with carotid-femoral PWV (men: P=0.043 and P=<0.001, respectively; women: P=0.037 and P=0.040) and carotid-radial PWV (men: P=0.009 and P=<0.015; women: P=<0.001 and P=0.001). In men, NT-ANP and BNP also were associated with reflected wave pressure, forward wave pressure, and carotid pulse pressure. Adrenomedullin was associated with mean arterial pressure in men (P=0.009). Plasma homocysteine was associated with carotid-femoral PWV (P=0.036), forward pressure P=0.02), and central pulse pressure (P=0.035) in men. In men, there was a 3-mm Hg higher mean carotid pulse pressure in the highest versus lowest tertiles of NT-ANP, BNP, and homocysteine. Interaction tests indicated sex differences in the relations of several biomarkers to measures of arterial stiffness, including NT-ANP and BNP with carotid-femoral PWV (P=0.002 and P<0.001, respectively) and homocysteine with forward pressure wave and central pulse pressure (P=0.005 and P=0.006, respectively).
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Discussion |
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In this large sample of nearly 2000 men and women from the Framingham Heart Study, we observed associations of plasma natriuretic peptides with several indexes of arterial stiffness in men and women. In addition, adrenomedullin and homocysteine levels were associated with
1 tonometric measures in men. Several intriguing sex interactions emerged. In men, higher levels of the natriuretic peptides were associated with higher carotid-femoral PWV, whereas an inverse relation was seen in women. In both sexes, however, natriuretic peptide levels were inversely related to carotid-radial PWV. These results are consistent with the hypothesis that plasma natriuretic peptide levels, adrenomedullin, and homocysteine are associated with alterations in arterial properties that differ in men and women. Despite their protective effects on vascular remodeling, we hypothesized a priori that natriuretic peptides would be positively related to indexes of arterial stiffness because of their counterregulatory action and their positive relations to CVD risk in our study sample.23 To our surprise, BNP and NT-ANP were both inversely related to carotid-radial PWV in men and women. In contrast, we identified directionally opposite results for the relations of natriuretic peptides to carotid-femoral PWV in men (positive) and women (inverse). We also observed a positive relation of natriuretic peptides to central pulse pressure, with a 3-mm Hg difference across tertiles of the natriuretic peptides in men but not women. These findings are consistent with those of a prior Framingham publication41 that reported an association of higher BNP levels with blood pressure progression in men but not in women. Several other studies also have reported positive associations of natriuretic peptides with blood pressure.42–44 Recently, Yambe and colleagues,45 using a plethysmographic method, reported a positive association of BNP with brachial-ankle PWV (derived from differences in pulse wave transit time) in a sample of 725 healthy Japanese men (mean age, 54 years). It is not clear, given differences in methodology, if our results are directly comparable to those of Yambe et al.
We observed an association of adrenomedullin with mean arterial pressure in men. Little is known about the relations of adrenomedullin to blood pressure or arterial properties. Of interest, Kita and coworkers46 previously reported a positive association of adrenomedullin with PWV in a sample of 126 patients; sex differences were not reported.
We found evidence of association of plasma homocysteine with central pulse pressure and forward wave pressure in men. An association of homocysteine with higher blood pressure has been reported in some but not all prior studies. Nygard and colleagues47 found a modest association between higher homocysteine levels and higher diastolic blood pressure in a sample of >12 000 men and women from western Norway. That study did not report on differences in systolic blood pressure across homocysteine categories, and the association with blood pressure was confined to individuals 40 to 42 years of age. Data from 5978 participants in the Third National Health and Nutrition Examination Survey also suggested a modest association of homocysteine with higher diastolic and systolic blood pressures of 0.5 to 1.2 mm Hg per 1-SD increment in homocysteine.48 A recent Framingham report did not find an association of homocysteine with hypertension incidence or with longitudinal blood pressure progression.49 To the best of our knowledge, there are no large, community-based studies examining the association of homocysteine with alterations in arterial stiffness. In a small study (n=14) of methionine loading to raise circulating homocysteine, Davis et al31 reported an acute increase in pulse pressure that was suggestive of increased arterial stiffness. Bortolotto and colleagues33 assessed arterial stiffness in 236 patients with hypertension and found an association of higher homocysteine levels with higher carotid-femoral PWV. In a study of 130 subjects with elevated plasma homocysteine levels, van Dijk et al50 reported that homocysteine lowering therapy had no effect on common carotid artery stiffness.
This is a large, community-based cohort of adults who were not selected on the basis of biomarker levels or vascular disease status; thus, it represents a sample in which selection bias is inherently low. The present investigation, however, has several limitations. The sample is almost exclusively white and middle-aged to elderly; the results may not be applicable to other ethnic samples or to younger individuals in whom biomarker levels or prevalence of altered vascular stiffness may differ from those in our cohort. Plasma homocysteine levels were measured after the implementation of a national program to fortify grain products with folic acid, which has resulted in a leftward shift in the population distribution of homocysteine levels and a marked decline in the prevalence of high values.51 Compared with plasma homocysteine values measured 849 and 452 years earlier in our study sample, the top quartile partition values have declined steadily (12.4, 11.8, and 10.3 µmol/L, respectively, in men; 11.2, 10.3, and 8.7 µmol/L in women). As such, the postfortification timing of the present study may underestimate the true association of homocysteine with alterations in vascular properties. Whereas plasma homocysteine was determined from blood specimens obtained at the index examination at which tonometry was performed, the natriuretic peptides were measured on blood specimens obtained on average 4 years earlier; we would expect this to bias results toward the null. Nevertheless, several significant results were observed for natriuretic peptides. It cannot be determined from the present study whether threshold biomarker levels exist above which vascular abnormalities are even more prevalent. This cross-sectional study is suitable for identifying associations between biomarker levels and vascular measures; it is not designed to establish causal relations. Additionally, whereas the results are adjusted for multiple covariates that may be associated with circulating biomarkers levels or with altered vascular properties, the possibility of residual confounding remains. Finally, 4 biomarkers were studied in relation to 6 tonometry measures, and the results were not adjusted for multiple testing. Additional studies are needed to verify the findings of the present investigation.
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Acknowledgments |
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Sources of Funding
The Framingham Heart Study is funded by NIH/NHLBI contract N01-HC25195. The project was supported in part by the Donald W. Reynolds Foundation and by NIH grants 1R01-HL60040 and 1R01-HL70100.
Disclosures
Dr Mitchell is president of Cardiovascular Engineering, Inc (Waltham, Mass), which contributed equipment and performed the tonometry measurements used in the present study. Dr Mitchell has reported receiving consulting and speaking fees from OMRON Healthcare, Inc. The other authors report no conflicts.
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  W. Lieb, M. G. Larson, E. J. Benjamin, X. Yin, G. H. Tofler, J. Selhub, P. F. Jacques, T. J. Wang, J. A. Vita, D. Levy, et al. Multimarker Approach to Evaluate Correlates of Vascular Stiffness: The Framingham Heart Study Circulation, January 6, 2009; 119(1): 37 - 43. [Abstract] [Full Text] [PDF]
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