The pathobiological impact of individual components of the metabolic syndrome (MS) on cardiac structural and functional parameters in women with isolated MS is not known. The objectives of this study were (1) to compare biochemical (prothrombotic, lipogenic, and inflammatory) and imaging (carotid intima-media thickening and basic cardiac structural measurements) markers in women with and without MS and (2) to examine if any of these markers associated or predicted cardiac structural differences between the 2 groups. This cross-sectional pilot study included 88 women with MS and 35 women without it. MS was defined according to the National Cholesterol Education Program Adult Treatment Panel III criteria. Patients with diagnosis of diabetes were excluded. Compared with healthy subjects, women with MS had higher levels of intercellular adhesion molecule, myeloperoxidase, C-reactive protein, plasminogen activator inhibitor-1, leptin, apolipoprotein-B, and lower levels of apolipoprotein-A1 (p <0.001 for all). They also had higher mean ventricular septum, posterior wall thickness, left ventricular (LV) mass, carotid intima-media thickness (p <0.001 for all), and left atrial diameter (p = 0.015). In multivariable regression models, waist circumference and systolic blood pressure (BP) were significant predictors of: ventricular septum (p = 0.005 and p = 0.001, respectively), posterior wall thickness (p = 0.008 and p = 0.040, respectively), and LV mass (p <0.001 and p = 0.013, respectively). Significant predictors for carotid intima-media thickness were systolic BP, glucose, and leptin (p <0.0001, p = 0.034, and p = 0.002, respectively). In conclusion, there are significant clinical, biochemical, and cardiovascular structural differences in women with isolated MS compared with those without. Waist circumference and systolic BP had the strongest association with cardiac structural differences in this group of women.
Metabolic syndrome (MS) is associated with increased risk of cardiovascular disease and mortality. It consists of interrelated risk factors, many of which are of metabolic origin. The National Cholesterol Education Program Adult Treatment Panel III, the most commonly used MS criteria, includes atherogenic dyslipidemia (elevated triglycerides, low high-density lipoprotein cholesterol [HDL-C] concentration), elevated plasma glucose, increased waist circumference (WC), and elevated blood pressure (BP). It is also recognized that a prothrombotic and a proinflammatory state underlies this syndrome and that prevalence of MS risk factors is high in women. There are data to suggest that MS imparts a greater risk for cardiovascular disease and diabetes for women than for men. Emerging data suggest an association of MS with increased left ventricular (LV) mass index and LV diastolic dysfunction in women, thus identifying women with early ventricular dysfunction, thereby suggesting a possible pathophysiological mechanism for MS. There is limited knowledge regarding the association between individual components of MS, prothrombotic inflammatory markers and preclinical carotid or cardiac structural and functional abnormalities. Therefore, the present study was conducted to (1) determine differences in thrombogenic, lipogenic, and inflammatory markers and preclinical carotid and cardiac structural measurements between women with and without MS and (2) evaluate the association of individual components of MS and serum markers with cardiac and carotid structural findings.
Methods
From December 2006 to January 2009, 88 consecutive women volunteers between the ages of 18 to 75 years, with MS and no history of coronary artery disease who had enrolled in a randomized trial (not part of this report—study in progress) with our group, were selected from the Women’s Heart Program outpatient clinic at the University of Rochester from both clinical records and flyers describing the study placed around the clinic. Participants with a known history of diabetes were excluded from the study. Only baseline characteristics are reported in this cross-sectional pilot study. MS was defined (ATP III criteria) by having at least 3 of 5 of the following: WC >88 cm (35 inches), hypertriglyceridemia ≥150 mg/dl, HDL-C <40 mg/dl, BP ≥130 or ≥85 mm Hg, and fasting glucose ≥100 mg/dl. After the initial study had begun (34 participants into the study), additional funding became available for collecting more information on subsequent participants. After protocol amendment, the subsequent consecutive 54 volunteers also underwent basic carotid ultrasound intima-media and echocardiographic measurements. Simultaneously, 35 volunteer women without MS or other conditions were recruited in the same way as controls. The number of participants in the control and imaging subgroups were both determined by available resources.
All participants underwent a detailed medical history; physical examination and blood samples were collected after 12-hour fasting. All subjects signed a written informed consent document. The study was approved by the institutional review board at the University of Rochester and the University of Florida College of Medicine at Jacksonville.
The examination included: (1) evaluation of clinical markers of MS, such as measurement of brachial BP and anthropometric evaluation of WC. BP was obtained by averaging values from 2 measurements taken at 5-minute intervals, using a Welch Allyn ADC multicuff sphygmomanometer with the patient in the sitting position. WC measurement was obtained to the nearest centimeter, midway between the lower limit of the rib cage and the iliac crest, with the subject standing using a flexible and nondistensible tape. (2) Collection of blood samples at room temperature with the patients sitting in a comfortable position. Blood sample specimens were collected for (1) fasting glucose; (2) lipogenic markers, such as total cholesterol, triglycerides, very low–density lipoprotein, low-density lipoprotein, HDL-C, apolipoprotein-A1, apolipoprotein-B, and leptin; (3) inflammatory markers: high-sensitive C-reactive protein and serum cell adhesion molecules (intercellular adhesion molecule-1 and serum vascular adhesion molecule-1); (4) thrombogenic and oxidative stress markers, such as plasminogen activator inhibitor-1 and myeloperoxidase, respectively; and (5) platelet activity and platelet aggregation in response to adenosine diphosphate (ADP) and collagen.
Platelet aggregation/inhibition was measured using Plateworks (Helena Laboratories, Beaumont, Texas) with strict adherence to manufacturers assay performance recommendations, using ADP and collagen as agonists. Results were reported as percentage of aggregation/inhibition.
Closure time was performed within 1 hour by a trained technologist using a PFA-100 instrument and Collagen/Epinephrine and Collagen/ADP cartridges (Siemens, Tarrytown, New York). Serum chemistry assays was performed using VITROS 3600 and 5600 instrumentation and reagents (Ortho Clinical Diagnostics Inc., Rochester, New York) and performed on the day of collection.
Human leptin, serum intercellular adhesion molecules-1, serum vascular adhesion molecules-1, myeloperoxidase, and high-sensitive C-reactive protein were assessed using Quantikine Elisa kits (R&D Systems, Minneapolis, Minnesota).
Serum samples for apolipoprotein A1 and apolipoprotein B were sent to a national reference laboratory, ARUP (Salt Lake City, Utah, http://www.aruplab.com/ ) for testing and results reported in milligrams per deciliter. Apolipoprotein A1 (normal range 104 to 225 mg/dl), apolipoprotein B (normal range 60 to 133 mg/dl), and apolipoprotein B/A1 ratio were reported. Other details on laboratory methods are provided as Supplementary Material .
Noninvasive carotid ultrasound assessment of far wall carotid intima-media thickness (CIMT) was measured under conditions at rest bilaterally at the common carotid artery. The mean of the mean right and left common carotid artery measurements were used for statistical analyses.
Two-dimensional and M-mode echocardiography was also performed in these subjects using American Society of Echocardiography guidelines for wall thickness and chamber dimensions. The echocardiographic measurements included ventricular septum thickness, LV mass, posterior wall thickness, left atrial diameter, fractional shortening, LV end-diastolic dimension, and LV end-systolic dimension. The LV mass was calculated from the corrected American Society of Echocardiography method using end-diastolic parameters: LV mass = 0.8{1.04[([VS + PW + LVEDD] 3 − LVEDD 3 )]} + 0.6.
The outcomes of interest were (1) differences in serum (thrombogenic, lipogenic, and inflammatory) and imaging (preclinical carotid and cardiac structural parameters) markers in women with and without MS and (2) the association and potential impact of components of MS on biochemical and imaging structural markers.
Descriptive summaries are presented as mean ± SD for continuous variables and as proportions for categorical variables. The chi-square statistic was used to determine differences in categorical variables between MS and non-MS groups. Differences between groups were assessed by independent-sample Student’s t tests and Wilcoxon’s rank-sum test (because many parameters were highly skewed). Spearman correlations were estimated between predictor variables in part to assess associations between variables. For each echocardiographic parameter, analysis of covariance models was fit to compare MS and non-MS groups adjusting for race (as a factor) and age (as a covariate). Multivariable regression models were then fit using a Lasso variable selection procedure to identify predictors of the echocardiographic parameters. Best models were selected such that each included variable was significant or decreased Akaike’s corrected information criterion by at least 2. Separate models were fit for each parameter for which there was a significant difference between the groups. Predictors included WC, systolic BP, diastolic BP, glucose, triglycerides, HDL-C, apolipoprotein A1, apolipoprotein B, Apolipoprotein ratio, C-reactive protein, leptin, serum intercellular adhesion molecule-1, serum vascular adhesion molecule-1, myeloperoxidase, and plasminogen activator inhibitor-1.
A 2-tailed p value <0.05 was considered statistically significant. Bonferroni correction for multiple testing was done. All statistical analyses were done using SAS for Windows, version 9.3, 2012 (Cary, North Carolina).
Results
The study sample comprised 88 women with MS and 35 healthy women. None of the participants were on lipid-lowering therapy and only one was on aspirin (81 mg). None of the participants had known inflammatory conditions. Three participants were taking antihypertensive medications at the time of study. One of the participants was on hydrochlorothiazide 12.5 mg, another on lisinopril 2.5 mg, and a third one on losartan 25 mg daily. Controls and MS women were of same age range, socioeconomic status, and educational level. Table 1 summarizes differences in clinical characteristic of women with and without MS.
| Parameters | Controls (n=35) | MS (n=88) | p-value ∗ |
|---|---|---|---|
| Age (years) | 53.7 + 9.0 | 51.9 + 9.3 | 0.313 |
| White (%) † | 31 (97%) | 70 (84%) | 0.039 |
| Waist circumference (cm) | 84.6 ± 13.5 | 108.2 ± 14.5 | <0.001 |
| Systolic blood pressure (mmHg) | 114.5 ± 12.6 | 132.3 ± 15.9 | <0.001 |
| Diastolic blood pressure (mmHg) | 74.6 ± 7.1 | 82.9 ± 8.3 | <0.001 |
| High-density lipoprotein cholesterol (mg/dl) | 66.6 ± 9.7 | 46.3 ± 10.1 | <0.001 |
| Low-density lipoprotein cholesterol (mg/dl) | 119.9 ± 24.4 | 133.3 ± 33.9 | 0.018 |
| Triglyceride (mg/dl) | 94.3 ± 53.1 | 197.4 ± 101.6 | <0.001 |
| Fasting blood glucose (mg/dl) | 84.3 ± 11.4 | 95.7 ± 21.4 | 0.002 |
| Platelet ADP (PAU) | 98.3 ± 1.9 | 98.2 ± 2.0 | 0.979 |
| Platelet Collagen (PAU) | 95.4 ± 3.4 | 92.5 ± 8.2 | 0.045 |
| Intercellular adhesion molecule (ng/mL) | 179.2 ± 39.9 | 212.9 ± 70.2 | 0.004 |
| Vascular adhesion molecule (ng/mL) | 614.8 ± 108.9 | 525.0 ± 127.4 | 0.005 |
| Myeloperoxidase (ng/mL) | 43.7 ± 9.8 | 52.3 ± 17.1 | 0.001 |
| Apolipolipoprotein-A1 (mg/dL) | 172.0 ± 17.4 | 134.3 ± 24.0 | <0.001 |
| Apolipoprotein-B (mg/dL) | 86.3 ± 14.9 | 107.2 ± 23.4 | <0.001 |
| Apo-B/Apo-A1 Ratio | 0.5 ± 0.1 | 0.8 ± 0.2 | <0.001 |
| High sensitive C-reactive protein (pg/mL) | 1.76 ± 1.52 | 3.59 ± 1.53 | <0.001 |
| Leptin (fg/mL) | 163.9 ± 133.2 | 455.2 ± 258.0 | <0.001 |
| Plasminogen activator inhibitor-1 (ng/mL) | 4.5 ± 0.7 | 6.2 ± 1.1 | <0.001 |
∗ Bonferroni-adjusted significance level for comparisons: p <0.002.
† Three subjects did not report race in each group and were omitted here.
The mean age of women with MS was 51.9 ± 9.3 years and 53.7 ± 9.0 years for controls (p = 0.313, not significant by Bonferroni correction). Most of the women studied were self-identified Caucasian, 70 (84.3%) with MS, and 31 (96.8%) controls (p = 0.039, not significant by Bonferroni correction). WC >88 cm was the most prevalent component of MS (98% [85 of 88]), followed by HDL-C <50 mg/dl (77% [68 of 88]). MS was associated with higher levels of lipogenic (apolipoprotein B, apolipoprotein B/A ratio, leptin), thrombogenic (plasminogen activator −1), inflammatory (high sensitivity C-reactive protein), and oxidative stress (myeloperoxidase) markers. Although a statistical difference was seen with serum intercellular and vascular adhesion molecules, this dissipated when using Bonferroni correction. No difference was seen in platelet reactivity with ADP or collagen as agonists with or without Bonferroni adjustment.
Least-square means (adjusted for race and age) of echocardiographic and carotid ultrasound parameters of the subgroup of women with MS that underwent imaging (n = 54) and those without MS (n = 35) are presented in Table 2 . The mean ventricular septum, posterior wall, LV mass, and CIMT were significantly higher in women with MS (p <0.001 for all). There was a trend toward a slightly larger LA diameter among participants with MS (p = 0.0146), but this was not significant after Bonferroni adjustment. There was no difference in LV end-diastolic, LV end-systolic dimension, and or fractional shortening between the 2 groups.
| Imaging Marker | Controls (n=35) | MS (n=54) | p-value ∗ |
|---|---|---|---|
| Ventricular septum (cm) | 0.89±0.04 † | 1.05±0.23 | <0.001 |
| Posterior wall (cm) | 0.85±0.03 | 0.97±0.02 | <0.001 |
| Left ventricular mass (g) | 127.00±9.00 | 165.00±7.00 | <0.001 |
| Left atrial diameter (cm) | 18.00±0.90 | 20.00±0.60 | 0.015 |
| Fractional shortening | 0.34±0.02 | 0.35±0.01 | 0.404 |
| End diastolic dimension (cm) | 4.50±0.09 | 4.64±0.71 | 0.108 |
| End systolic dimension (cm) | 2.99±0.10 | 3.02±0.08 | 0.773 |
| Carotid intima-media (mm) | 0.68±0.02 | 0.72±0.02 | <0.001 |
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