In addition, given the significant cross talk between diabetes and MetS, a sensitivity analysis excluding the women with diabetes (29% of the total cohort) was also conducted. Consistent with the prior analyses that included diabetes, women with MetS continued to have worse risk factors compared with those without MetS even though most of these differences (except BMI) did not reach statistical significance. Not surprisingly, the exceptions were those risk factors used to classify MetS. When excluding the women with diabetes, the women with MetS still had consistently higher IVUS measures, although the P-values were attenuated because of smaller numbers and high standard deviation resulting in diminished statistical power (Table 4).
To the best of our knowledge, the current study is the first to analyze the relationship between MetS, its components and IVUS-derived measure of atherosclerotic burden in women with suspected ischemia, but without obstructive CAD. The major findings of our study follow: (a) the relationship between the MetS cluster and IVUS measures of coronary atherosclerosis is not significant in a multiple regression model, suggesting that the relationship is largely driven by individual MetS components rather than the cluster. These findings support our hypothesis that the MetS is a convenient clustering of risk factors, rather than a novel or an independent risk predictor. (b) Systemic hypertension was an independent predictor of IVUS-measured disease burden (as defined by number of lesions, percentage of lesions, atheroma volume, and percentage atheroma volume). (c) Larger waist circumference (i.e. abdominal obesity) was associated with EEM, internal elastic membrane, and luminal expansion, suggesting positive or adaptive remodeling. (d) In contrast, several risk factors, including diabetes/hyperglycemia and dyslipidemia (high-LDL cholesterol and low-HDL cholesterol), appeared less important than expected.
In recent years, investigators have used IVUS to study the correlation between the MetS and the morphological characteristics of atherosclerotic plaques with variable results 22–25. These studies largely focused on patients who had, or were undergoing, coronary intervention for severe obstructive CAD. The results from our study have important implications for understanding the relationship between MetS and major adverse cardiac events in this specific at-risk patient population. The concept of MetS evolved from the observation of a clustering of risk factors for CAD and diabetes in patients with abdominal obesity 26. However, it has not been conclusively shown that the impact of the syndrome cluster exceeds that of the sum of its parts. Several studies have shown that adverse outcomes appear to be driven by the presence of the individual risk factors 7,8,27. Our current results, in a sample of WISE women using invasive imaging to characterize the association between MetS and atherosclerotic coronary disease burden, are in line with those findings. Although in a univariate model several IVUS parameters were found to be significantly associated with presence of MetS, this association was lost in the subsequent multivariate model. Hypertension and waist circumference were observed to be the main variables associated with IVUS measures of CAD burden.
Abdominal obesity is a key component of the MetS and a marker of dysfunctional adipose tissue that has been shown to independently predict CAD mortality in women 30. Adipose tissue is known to be a major endocrine organ that secretes a variety of bioactive substances, termed adipocytokines 30. Adipocytokine secretion profiles are altered as obesity develops, which may increase the risk of obesity-related cardiovascular disorders. Leptin, an adipocytokine up-regulation in obese individuals, has also been shown to play an important role in the pathophysiology of obesity-related atherogenesis through multiple mechanisms, such as its proinflammatory, prothrombotic, prooxidant, and proliferative effects. Similarly another adipocytokine, adiponectin down-regulation, leads to vascular remodeling and plaque destabilization among other atherogenic effects. Patients with excess of visceral adiposity have elevated plasma C-reactive protein concentrations accompanied by elevated interleukin-6 and tumor necrosis factor-α levels 31,32. It has been shown that visceral adiposity is associated with positive remodeling, low-attenuation noncalcified plaques, and spotty calcification. All of these are characteristic of early proliferative lesions, allowing considerable plaque accumulation despite normal luminal size. These early plaques may be particularly vulnerable to rupture, leading to acute coronary syndrome in the setting of modest luminal stenosis 33,34. Approximately 20% or more of women presenting with acute coronary syndrome have normal or nonobstructive CAD by angiography, yet these women have an increased risk of death or myocardial infarction at 30-day follow-up 18.
In addition, a pooled analysis of 97 cohort studies (with 1.8 million patients) showed that being overweight and obese is incrementally associated with higher risk of CAD and strokes. The hazard ratio for each 5 kg/m2 higher BMI was 1.27 (95% confidence interval 1.23–1.31) for coronary heart disease and 1.18 (1.14–1.22) for stroke after adjustment for confounders. The analysis showed that this risk is driven by the metabolic mediators BP, cholesterol, and glucose. Interestingly, of these, BP was the most important mediator, accounting for 31% (28–35) of the excess risk for coronary heart disease and 65% (56–75) for stroke 35.
The absence of a strong association between HDL levels and IVUS measures of disease burden requires additional comment. Although HDL levels were predictive in univariate analysis, in a multiple regression model this association did not persist. Although some prior studies have shown HDL cholesterol concentration to be a strong predictor of coronary heart disease risk in women 36–38, current evidence shows otherwise. As indicated by recently published cholesterol guidelines, adding one or more nonstatin drugs to high-intensity statin therapy will not provide incremental cardiovascular disease risk reduction benefit with an acceptable margin of safety, suggesting that most likely HDL cholesterol is not a significant risk factor that merits intervention to reduce cardiovascular events 39. Similarly, AIM-HIGH showed a lack of benefit of adding niacin in individuals with low-HDL cholesterol and high triglycerides, and ACCORD demonstrated the futility of adding fenofibrate in persons with diabetes 40–43. Therefore, an association between HDL/triglyceride values and IVUS-defined CAD burden in the current analysis suggests an interaction of multiple complex mechanisms that drive atheroma accumulation.
As expected, there were significantly more diabetics in the MetS group versus the non-MetS group. Diabetes is known to confer higher risk of CAD in women than men (4–6- vs. 3–4-fold), a poorer prognosis after myocardial infarction, and a higher risk of death from cardiovascular disease 44. However, we did not observe a significant correlation with fasting glucose, either when used as a categorical or continuous variable. Whereas older studies have suggested a diabetes-associated cardiovascular disease risk similar to that observed among nondiabetic patients with a prior myocardial infarction (e.g. CAD risk equivalent), more recent trials suggest a substantially lower risk, likely due to improved effectiveness of contemporary antidiabetic and lipid therapies 45,46.
Our study has some limitations. First, the findings are based on a small cohort of women. Therefore, we cannot exclude the possibility that our study may lack power to demonstrate the interaction of dyslipidemia and fasting glucose with IVUS atherosclerosis measures. Second, IVUS examination was limited to only a small proximal portion of the left coronary distribution, and this sampling limitation is likely to underestimate the true prevalence of atherosclerosis in this cohort. Third, we did not include information about hemogobin A1C, as most were well controlled diabetic patients, contributing to the lack of association of diabetes status with atherosclerosis burden. Furthermore, all participants were likely to be somewhat glucose intolerant.
Others have documented that intensive risk modification was as effective in causing plaque regression in women as in men: in women, substantial regression (defined as 5% reduction in atheroma volume vs. baseline) was observed with lowering of LDL cholesterol to less than 80 mg/dl, systolic BP less than 120 mmHg, and C-reactive protein less than 2 mg/l 47. These data suggest important targets for potential therapeutic intervention to more effectively reduce risk in women. Our findings also emphasize the importance of focusing on BP control and weight management, as opposed to HDL/triglyceride management.
This work was supported by contracts from the National Heart, Lung and Blood Institutes nos. N01-HV-68161, N01-HV-68162, N01-HV-68163, N01-HV-68164, grants U0164829, U01 HL649141, U01 HL649241, K23HL105787, T32HL69751, R01 HL090957, 1R03AG032631 from the National Institute on Aging, GCRC grant MO1-RR00425 from the National Center for Research Resources, the National Center for Advancing Translational Sciences Grant UL1TR000124 and UL1TR000064, and grants from the Gustavus and Louis Pfeiffer Research Foundation, Danville, NJ, The Women’s Guild of Cedars-Sinai Medical Center, Los Angeles, CA, The Ladies Hospital Aid Society of Western Pennsylvania, Pittsburgh, PA, and QMED Inc., Laurence Harbor, NJ, the Edythe L. Broad and the Constance Austin Women’s Heart Research Fellowships, Cedars-Sinai Medical Center, Los Angeles, California, the Barbra Streisand Women’s Cardiovascular Research and Education Program, Cedars-Sinai Medical Center, Los Angeles, The Society for Women’s Health Research (SWHR), Washington, DC, The Linda Joy Pollin Women’s Heart Health Program, and the Erika Glazer Women’s Heart Health Project, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Dr Noel Bairey Merz would like to declare that she worked with QMED Inc., Laurence Harbour, NJ, a commercial funder, in the context of receiving digital Holter monitors free of charge for several other Women’s Ischemic Syndrome Evaluation (WISE) substudies. This has no conflict of interest with the content of this paper as no Holters were used in the methods. For the remaining authors there are no conflicts of interest.
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