Psychologist Kurt Koffka termed the phrase ‘the whole is other than the sum of its parts’. Often incorrectly translated as ‘the whole is greater than the sum of the parts’, such a phrase can also describe the debate on the properties of metabolic syndrome (MetS). There continues to be discussion as to whether this syndrome is a distinct pathophysiologic gestalt, or something that reflects the association of its various clinical, physiological, and biochemical cardiovascular risk factors 1–3.
The National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III panel 1 defined MetS as the presence of three or more of the following risk determinants: (a) increased waist circumference [>102 cm (>40 inches) for men, >88 cm (>35 inches) for women]; (b) elevated triglycerides (≥150 mg/dl); (c) low HDL cholesterol (<40 mg/dl in men, <50 mg/dl in women); (d) hypertension (≥130/≥85 mmHg); and (e) impaired fasting glucose (≥110 mg/dl) 1. Is it really the combination of these risk factors that directly increases the risk of atherosclerotic cardiovascular disease, type 2 diabetes mellitus, and all-cause mortality, or does each individual risk factor play a significant but separate role?
In this issue of Cardiovascular Endocrinology, Khaliq et al. 4 investigated as to whether MetS is associated with a greater risk for ischemic heart disease-related adverse events compared with the individual components of MetS. The authors evaluated the relative contribution of MetS versus the individual components of MetS using intravascular ultrasound (IVUS) measures (as defined by number of lesions, percentage of lesions, atheroma volume, and percentage atheroma volume). IVUS as an intravascular imaging modality provides a more comprehensive in-vivo assessment of atherosclerotic plaque. They examined studies of coronary atherosclerosis in a cohort of women with signs of ischemia, but without obstructive coronary artery disease (CAD).
In the study by Khaliq et al. 4, 100 women who had undergone coronary angiography for suspected ischemia, but had no angiographically significant CAD, underwent IVUS imaging of a segment of the left coronary artery. Later assessment of the IVUS with MetS (and its components) was entered into multiple regression models to assess associations with IVUS measurements. The authors revealed that IVUS measurements were available in 87 women, and of these 36% had MetS, including 29% with type II diabetes mellitus, and 78% had atheroma. When comparing women with and without MetS, there were significant differences observed for seven IVUS atherosclerosis measures, although these were not significant after adjusting for the MetS components. They suggested that systolic blood pressure and waist circumference components remained independently positively associated with the IVUS measures after adjusting for age, diabetes, CAD family history, dyslipidemia, smoking, and hormone replacement. The authors concluded that 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 group cluster. This suggests that MetS is a convenient grouping of risk factors rather than an independent risk predictor. However, the small sample size, as the authors acknowledged, limited the power for the analysis. Nevertheless, it showed that, among the MetS components, the strongest components that drove the association between MetS and presence and association of coronary atherosclerosis were waist circumference and systolic blood pressure. As a result, this supports the concept that MetS is a convenient clustering of risk factors rather than an independent risk predictor, and emphasizes that the critical factors for coronary atherosclerosis are potentially modifiable.
We commend the authors on their study assessing predictors of nonobstructive disease in women. Although there were limitations (small patient population, limited IVUS examination, not excluding those with type II diabetes mellitus, lack of information on severity of glucose intolerance with measures such as hemoglobin A1c), their study does suggest that in women with MetS the presence of atherosclerosis appears to be driven predominantly by individual components and not by the presence of the syndrome itself. Abdominal obesity disproportionately affects women; data from National Health and Nutrition Examination Survey (NHANES) show that abdominal obesity is prevalent in 61.8% of women compared with 43.7% of men in the USA 5. It would thus be seen that women have a greater burden of adverse sequelae related to obesity. Abdominal obesity results in adverse cardiometabolic profile due to activation of several biological pathways that increase risk for MetS, type II diabetes mellitus, and subsequent cardiovascular risk by both traditional risk factors and novel biomarkers involving platelet activation, inflammation, and endothelial dysfunction. Finding abdominal obesity as a critical component of MetS in this study associated with IVUS measures of atherosclerosis bolters the importance of visceral obesity. Atheroma formation is a complex process, and obesity is related to many novel risk factors, whose role future studies could elucidate. Given that obesity can be prevented, this study highlights the need for aggressive efforts to more effectively address the obesity, particularly in women.
The initial concept of MetS began in 1920 when Kylin, a Swedish physician, demonstrated the association between hypertension, hyperglycemia, and gout 6. Since then several groups have attempted to develop diagnostic criteria for MetS, including the WHO, the National Cholesterol Education Program Adult Treatment Panel (NCEP/ATP), the American Association of Clinical Endocrinologists, and the International Diabetes Federation 6. Although these criteria have tried to describe MetS as a constellation of interconnected disease entities, studies have not always supported the predictive value of MetS beyond individual risk factors. This current investigation should encourage future studies to further our understanding of MetS and type II diabetes mellitus, especially in women, given the disproportionately higher relative risk for cardiovascular disease associated with these risk factors in women compared with men 7. Further research collaborations should also be encouraged between different medical specialties to look at improving our knowledge, prevention, and clinical outcome strategies for MetS and the different entities that make up this syndrome. In addition, novel risk factors such as inflammation and endothelial dysfunction, which are also associated with obesity, need to be considered when assessing MetS. Defined by a cluster of interconnected factors that directly increase the risk for atherosclerotics cardiovascular disease and type 2 diabetes, the concept that MetS is a separate entity that may be derived from the sum of its parts may now be more consistent with Koffka’s true meaning of the original phrase, ‘the whole is other than the sum of its parts’.
Conflicts of interest
There are no conflicts of interest.
1. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA 2001; 285:2486–2497.
2. Sattar N, McConnachie A, Shaper AG, Blauw GJ, Buckley BM, de Craen AJ, et al.. Can metabolic syndrome usefully predict cardiovascular disease and diabetes? Outcome data from two prospective studies. Lancet 2008; 371:1927–1935.
3. Wang J, Ruotsalainen S, Moilanen L, Lepisto P, Laakso M, Kuusisto J. The metabolic syndrome predicts cardiovascular mortality: a 13-year follow-up study in elderly non-diabetic finns. Eur Heart J 2007; 28:857–864.
4. Khaliq A, Johnson BD, Anderson RD, Bavry AB, Cooper-Dehoff RM, Handberg EM, et al.. Relationships between components of metabolic syndrome and coronary intravascular ultrasound atherosclerosis measures in women without obstructive coronary artery disease: the NHLBI-Sponsored Women’s Ischemia Syndrome Evaluation (WISE) Study. Cardiovasc Endocrinol 2012; 59:E1742.
5. Ford ES, Li C, Zhao G, Tsai J. Trends in obesity and abdominal obesity among adults in the United States from 1999–2008. Int J Obes (Lond) 2011; 35:736–743.
6. Kaur J. A comprehensive review on metabolic syndrome. Cardiol Res Pract 2014; 2014:1–22.
7. Peters SA, Huxley RR, Woodward M. Diabetes as risk factor for incident coronary heart disease in women compared with men: a systematic review and meta-analysis of 64 cohorts including 858 507 individuals and 28 203 coronary events. Diabetologia 2014; 57:1542–1551.