Getting a handle on syndrome X

Summarized by Robert W. Griffith, MD
September 18, 2000 (Reviewed: January 15, 2003)

Introduction

Syndrome X is a metabolic disorder, in the first instance; that's why it's also known as the 'metabolic syndrome'. There are multiple interrelated abnormalities in glucose and lipid metabolism, which are manifested by insulin-resistant hyperglycemia accompanied by hyperinsulinemia, a high triglyceride (TG) level, a low high-density lipoprotein cholesterol (HDL-C) level, and abdominal/visceral obesity. It also known as the insulin-resistance syndrome. In addition to the metabolic changes, hypertension, premature atherosclerotic changes, and an increased risk of myocardial infarction are also seen in syndrome X. It has been known for some time that just treating hypertension in syndrome X subjects does not produce the expected reduction in ischemic heart disease (IHD). The study summarized here examines the predictive value of blood pressure levels for IHD in syndrome X patients.

Method

The Copenhagen Male Study examines cardiovascular parameters in over 5,200 men recruited in 1970. Over 3,300 survivors were examined between 1985 and 1986, when their mean age was 63 years. Those with cardiovascular disease were excluded, as well as those with missing data. A total of 2,906 men were left in the study. The examinations at this baseline included full fasting lipid levels, lifestyle factors questionnaire, body mass index (BMI), blood pressure and enquiry about a diagnosis of type 2 diabetes.

In 1995 morbidity and mortality were assessed for the cohort, based on hospital admission data and death certificates. The Danish national registers have demonstrated high validity in the past.

Subgroups were formed according to baseline systolic blood pressure, baseline diastolic pressure, presence of high TG/low HDL-C levels, and antihypertensive use. Differences between groups were tested statistically, and multiple logistic regression models were used to test associations between variables.

Results

Over the 8-year period, 229 men (7.9%) developed IHD, which proved fatal in about one quarter of them. Analyses showed that in subjects with high TG/low HDL-C levels, the relative risk of IHD was independent of the level of the systolic blood pressure. In the rest of the study population, there was a steady increase in the risk of IHD with increasing systolic blood pressure, after adjustment for other major IHD risk factors. This is shown in the following table giving the adjusted relative risk (95% confidence interval):

Systolic Blood Pressure	High TG /Low HDL-C	Others
< 120 mm Hg	1.0 (reference)	1.0 (reference)
120 - 140 mm Hg	1.1 (0.6-1.9)	1.6 (1.1-2.4)
>140 mm Hg	0.9 (0.4-2.2)	2.2 (1.4-3.6)
	trend test: not significant	trend test: p=0.002

Similar findings were obtained for groupings according to the diastolic blood pressure.

Men taking antihypertensive medication had a significantly higher absolute risk of IHD compared to others in the study. However, in drug-treated men with high TG/low HDL-C levels the absolute risk of IHD was again independent of the level of the systolic and diastolic blood pressures.

This study shows that middle-aged and elderly white men, free of overt cardiovascular disease but with a high TG/low HDL-C at baseline, had an increased risk of IHD after 8 years that was not directly related to their blood pressure readings. The overall incidence of IHD in subjects with high TG/low HDL-C was almost double that of rest of the population - 12.3% (71/576) and 6.8% (158/2,330), respectively.

Comment

The high TG/low HDL-C subjects in this study had lipid profiles concordant with that seen in syndrome X. Jeppesen argues that syndrome X subjects also have increased amounts of atherogenic lipoproteins (e.g. small dense LDL particles), high levels of plasminogen activator inhibitor-I (which leads to deficient fibrinolysis), hyperinsulinemia and hyperglycemia - all important risk factors for IHD.

What are the clinical implications of these findings? Clearly, it's important to recognize syndrome X subjects, as they have a high risk of IHD, and then address their lipid profile rather than their blood pressure. The benefits of this strategy have already received support from results of large randomized placebo-controlled clinical trials of 'statin' drugs¹, ². Patients must be made aware that LDL-cholesterol is not the only lipid parameter of importance. And all risk factors for coronary artery disease, not just hypertension and raised cholesterol levels, should be actively managed if we are to curb IHD effectively.

Syndrome X is relatively common in Scandinavia, and much of the research into its nature and clinical relevance come from there. Similarities exist between the syndrome and untreated growth hormone deficiency in adults³. A polymorphism early in the central glucocorticoid receptor gene locus has been shown in 14% of Swedish males, associated with abdominal obesity and insulin resistance. Treatment of men of this type with growth hormone for 9 months reduced their total body fat, their abdominal subcutaneous and visceral adipose tissue, improved their insulin sensitivity, reduced total cholesterol and triglyceride levels, and lowered diastolic blood pressure⁴. It seems, therefore, that there may be several ways to attack the problem, once the need for this is recognized.

Source

• High triglycerides and low HDL cholesterol and blood pressure and risk of ischemic heart disease. J Jeppesen, HO. Hein, P. Suadicani, F. Gyntelberg, Hypertension, 2000, vol. 36, pp. 226--232

Footnotes
1. Air Force/Texas Coronary Atherosclerosis Prevention Study: extending the benefit of primary prevention to healthy elderly men and women. EJ. Whitney, JR. Downs, M. Clearfield,  et al., Circulation (supplement), 1998, vol. 98, pp. 1--46
2. A tale of two trials: The West of Scotland Coronary Prevention Study and the Texas Coronary Atherosclerosis Prevention Study. J. Shepherd, Atherosclerosis., 1998, vol. 139, pp. 223--229
3. Hypothalamic origin of the metabolic syndrome X. P. Bjorntorp, R. Rosmond, Ann N Y Acad Sci, 1999, vol. 892, pp. 297--307
4. Growth hormone and the metabolic syndrome. J. Johannsson, BA. Bengtsson, J Endocrinol Invest, 1999, vol. 22, pp. 41--46

Related Links
The risk of elevated plasma lipids for coronary artery disease in old persons
Tackling coronary heart disease risk factors

Please take a moment to give us your comments. For questions about Health matters you may check our "Questions & Answers" Portal and Service.