There seems to be substantial biological support for our finding that a low TG–high HDL-C concentration is associated with a very low risk of IHD, whereas a high TG–low HDL-C concentration is a central risk factor of IHD. We think that our results should be considered with special reference to the absence or presence of the metabolic syndrome.19- 21 The metabolic syndrome describes the frequent aggregation in a single person of multiple interrelated abnormalities in glucose and lipid metabolism, including insulin resistance, glucose intolerance, an atherogenic dyslipidemia, and hypertension,19- 21 and the metabolic syndrome is believed to play a major role in the pathogenesis and clinical course of what are often referred to as diseases of Western civilization.21 The characteristic lipid abnormality seen in people with the metabolic syndrome is a lipid profile with high TG–low HDL-C levels,19- 21 whereas a lipid profile with low TG–high HDL-C levels is the characteristic finding in people without this syndrome.19 The metabolic syndrome with high TG–low HDL-C concentrations has an effect on LDL particle size, density distribution, and composition, leading to a smaller and denser LDL particle22,23 that is more easily oxidized24 and thus much more atherogenic.25,26 The metabolic syndrome with high TG–low HDL-C concentrations includes an increased amount of TG-rich lipoproteins, some of which are very atherogenic, leading to progression of coronary artery lesions.27,28 The metabolic syndrome with high TG–low HDL-C concentrations is closely associated with deficient fibrinolysis through higher levels of plasminogen activator inhibitor-121,29 and is closely associated with hyperinsulinemia and hyperglycemia, 2 other changes known to be important risk factors of IHD.30,31 Thus, it is clear that when a high TG–low HDL-C concentration is present, several other important, well-established risk factors of IHD will also frequently be present to enhance the risk of IHD.20,21 In contrast, when a low TG–high HDL-C concentration is present, people will be without this cluster of risk factors and thus tend to have a much lower risk. A high level of LDL-C is not associated with the metabolic syndrome per se,32 and when a high LDL-C level is present with a low TG–high HDL-C level, the LDL particle is larger, more buoyant,22,33 and less easily oxidized24 and thus much less atherogenic.25 This, together with the absence of the other risk factors in the metabolic syndrome, might explain why isolated hypercholesterolemia is not necessarily associated with a high risk of IHD. Thus, in accordance with our findings, in the West of Scotland Coronary Prevention Study,34 middle-aged men with isolated hypercholesterolemia had a 5-year risk of IHD of only 5.3%, whereas middle-aged men with evidence of the metabolic syndrome had a 5-year event rate of 14.1%. Finally, the results from 3 other recently published prospective cardiovascular studies35- 37 also suggest that the metabolic syndrome plays an important role in IHD.