Juan F Ascaso M.D., Ph.D., Hospital Clínico, University of Valencia, Valencia, Spain, E-mail: ascaso@uv.es

Familial combined hyperlipidemia (FCH) is a frequent form (1-2% of the general population) of primary hyperlipidemia characterized by varying phenotypic expression (IIa, IIb, or IV), increased apolipoprotein B, and high incidence of premature cardiovascular disease [1-3]. The genetic and molecular bases of the disease have not been fully defined yet and specific biological markers are lacking. The lipoprotein phenotype expression of the disease is modified by genetic, metabolic and environmental factors.

Several studies have described the presence of insulin-resistance in FCH subjects. We have previously studied [4] 20 FCH and 20 control healthy men, matched for age, BMI, waist-to-hip ratio (WHR), and systolic and diastolic blood pressure. The intravenous glucose tolerance test (modified version of Bergman’s Minimal Model [MM]), showed a decrease of the peripheral sensitivity to insulin (Si index) in the FCH group, indicating the existence of insulin resistance (IR). In the multivariate analysis, using the Si value as the independent variable and controlling for WHR, triglycerides (TG), and free fatty acids (FFA), the correlation for WHR and FFA remained significant. We concluded that insulin resistance is an important component of the metabolic disturbances present in FCH[5].

It is clear that abdominal obesity, hyperinsulinemia, and insulin resistance antedate disorders like type 2 diabetes, CHD, and hypertension [6,7]. Obesity aggravates insulin resistance and, as has been repeatedly shown, intra-abdominal fat plays a key role in the expression of the insulin resistance syndrome in both lean and obese individuals [8].

In another series of studies, we investigated the impact of obesity and central obesity on insulin resistance in FCH. For this purpose, 36 FCH subjects were classified according to the presence or not of central obesity (WHR ³ 1). Significantly lower Si values (indicating greater insulin resistance) were found in obese and non-obese FCH subjects with respect to controls, showing a negative correlation with WHR. Our data demonstrates that, compared with controls, FCH subjects have peripheral insulin resistance even when their BMI value is less than 27. In addition, we investigated the correlation between BMI and insulin resistance in a group of 67 FCH (45 male and 22 female) and in 67 clinically healthy controls of similar age, gender, and BMI [9]. We found fasting hyperinsulinemia in 38.8% of FCH subjects, rising to 77.6% 2 hours after the oral glucose tolerance test (OGTT) with 75 g glucose. When individuals were classified by BMI, FCH subjects showed a higher prevalence of hyperinsulinemia, even in the absence of obesity. In the non-obese FCH subgroup, 25% had fasting hyperinsulinemia versus 0% in controls, and 67.8% had hyperinsulinemia 2 hours after OGTT compared to 3.5% in controls. Our findings have been supported by those of Bredie et al. [10].

To analyze potential different factors contributing to CHD prevalence in FCH subjects, we performed a case-control study [1]. A total of 33 FCH men were divided into two groups, those with and without CHD. In response to the MM, the Si index was lower in FCH subjects with CHD. The logistic regression analysis showed a significant relationship between the presence of CHD in FCH subjects and sensitivity to insulin (Si < 2x10-4 mU/L/min), diastolic pressure above 90 mmHg, and Lp(a) ³ 20 mg/dl.

Clinical and experimental studies have demonstrated a relationship between basal insulinemia and CHD [12]. Whether this relation occurs per se or because of its association to other risk factors in insulin resistance syndromes is unclear. In our model, basal and post-OGTT insulinemia and the area under the curve of insulin (AUCi) are elevated in FCH subjects with CHD. Similar results were obtained by Tzagournis et al. in young patients with coronary heart disease [13].

Most coronary risk factors, like insulin resistance, dyslipidemia, diabetes, hypertension, and central obesity are present in FCH and in the so-called metabolic syndrome (MS), as we have previously mentioned. Therefore, the two entities, FCH and MS represent an important risk for premature CHD [14].

In another study [15], we have classified the subjects according to IDF or ATPIII criteria to define the MS. The MS define a subgroup of subjects with important plasma lipids alterations and cardiovascular risk factors: increase of non-HDL cholesterol, high TC:HDL-C ratio and elevated apo B. The TC:HDL-C ratio was ≥ 6 in 28.6 % of the subjects with MS and only in 9.4 % of the subjects without MS (p 0.0001) defined by IDF criteria. Using ATPIII criteria 34.6% of the subjects with MS has TC:HDL-C ratio ≥ 6 versus 8,6% without MS (p 0.0001). Apo B ≥ 1.2 g/l was observed in 44% of the subjects with MS and only in 26% without MS IDF criteria (p < 0.0001), and only in 47.6% and 28.6%, respectively by ATPIII criteria (p < 0.0001). Our conclusion is that the MS defined by the IDF or ATPIII criteria identifies subjects with atherogenic dyslipidemia (increase of non HDL-C, of the TC: HDL-C ration and of plasma the apo B values). And therefore subjects with high cardiovascular risk. In addition, Liu at al. [16] reported that non–HDL-C and very-low-density lipoprotein cholesterol, components of MS, were independent risk predictors of coronary heart disease.

In a recent study [17], our aim was to investigate the prevalence of the MS and its association with cardiovascular disease (survivors of myocardial infarction) in subjects with familial combined hyperlipemia. We studied 40 FCH males (20 survivors of myocardial infarction and 20 without myocardial infarction) and 20 controls. The 3 groups had similar age, gender distribution, and BMI. Plasma lipids, glucose, and insulin were determined and the MS was defined according to WHO and NCEP-ATPIII criteria.

Different studies have indicated that the presence of MS (WHO or ATPIII criteria) is the best predictor of cardiovascular risk in the general population, in diabetic subjects, and in non-diabetic subjects with or without obesity [18,19]. MS defined by WHO criteria was found in 19 subjects with familial combined hyperlipemia and myocardial infarction, in 11 subjects with familial combined hyperlipemia without myocardial infarction, and in 6 controls (p < 0.001). There were significant differences (p < 0.01) in the prevalence of MS comparing FCH subjects with and without myocardial infarction. The MS, defined by ATP-III criteria was found in 18, 14, and 10 subjects, respectively. No differences were found within the subgroups of FCH subjects.

Comparing FCH subjects with and without MI, we found significant differences (p < 0.01) in the prevalence of IR (HOMA-IR) and MS (defined using WHO) between groups. In contrast, we did not found significant differences in the prevalence of MS defined by ATPIII criteria between FCH subgroups.

These results indicate that in the FCH subjects, the MS defined by WHO criteria, which include the presence of IR, is a more sensitive predictor of MI prevalence, than using ATPIII criteria for MS. MS defined according to ATPIII criteria is not a good predictor of MI in FCH subjects, since ATPIII give major importance to the lipid abnormalities, that are presence in the definition of FCH.
In conclusion, FCH is a primary dyslipidemia frequently associated with IR and high cardiovascular risk. The presence of MS, defined according to WHO criteria, is the best independent predictor of MI prevalence in FCH subjects.

References

1. Albers JJ, Chait A, Grundy SM, Groszek E, McDonald GB. Plasma lipoproteins in familial combined hyperlipidemia and monogenic familial hypertriglyceridemia. J Lipid Res 1983;24:147-55.
2. Ascaso JF, Serrano S, Martínez-Valls J, Hernández A, DeLera, Carmena R. Plasma lipoproteins in familial combined hyperlipidemia: a study of hyperlipemic and normolipidemic kindreds. Nutr Metab Cardiovasc Dis 1992;2:165-69.
3. Goldstein JL, Hazzard WR, Schrott G, Bierman EL, Motulsky AG. Hyperlipidemia in coronary heart disease. I. Lipid levels in 500 survivors of myocardial infarction. J Clin Invest 1973;52:1533-43.
4. Ascaso JF, Merchante A, Lorente R, Real JT, Marttínez-Valls J, Carmena R. A study of insulin resistance using minimal model in nondiabetic familial combined hyperlipidemic patients. Metabolism 1998;47:508-13.
5. Real JT, Ascaso JF, Carmena R. Insulin resistance and familial combined hyperlipidemia. Cardiovas Risk Factors 1999;9:101-6.
6. Bergstrom RW, Newel-Morris LL, Leonetti DL, Shuman WP, Wahl PW, Fujimoto WJ. Association of elevated fasting c-peptide level and increased intra-abdominal fat distribution with development of NIDDM in Japanese American men. Diabetes 1990;39:104-11.
7. Blair D, Habricht JP, Sims EAH, Sylvester D, Abraham S. Evidence for an increase risk for hypertension with centrally located body fat and the effect of race and sex on this risk. Am J Epidemiol 1984;119:526-40.
8. Hollenbeck CB, Reaven G. Variations in insulin-stimulated glucose uptake in healthy individual with normal glucose tolerance. J Clin Endocrinol Metab 1987;64:1169-73.
9. Ascaso JF, Sales J, Merchante A, et al. Influence of obesity on plasma lipoproteins, glycaemia and insulinaemia in patients with familial combined hyperlipidaemia. Int J Obes 1997;21:360-66.
10. Bredie SJH, Tack CJJ, Smits P, Stalenhoef AFH. Non-obese patients with familial combined are insulin resistant as compared with their non-affected relatives. Arterioscler Thromb Vasc Biol 1997;17:1465-71.
11. Ascaso JF, Lorente R, Merchante A, Real JT, Priego A, Carmena R. Insulin resistance in patients with familial combined hyperlipidemia and coronary heart disease. Am J Cardiol 1997;80:1484-87.
12. Deprés JP, Lamarche B, Mauriege P, et al. Hyperinsulinemia as an independent risk factor for ischemic heart disease. N Engl J Med 1996;334:952-57.
13. Tzagournis M, Chiles R, Ryan JM, Skillman TG. Interrelation ship of hyperinsulinism and hypertrygliceridemia in young patients with coronary heart disease. Circulation 1968;38:1156-63.
14. Brunzell JD, Schrott HG, Motulsky AG, Bierman E. Myocardial infarction in the familial forms of hypertriglyceridemia. Metabolism 1976;25:313-20.
15. Real JT, Romero P, Martinez Hervas S, Pedro T, Carmena R, Ascaso JF. Role of atherogenic dyslipidemia in the development of metabolic syndrome. Med Clin (Barc) 2006;127(9):321-24.
16. Liu J, Sempos CT, Donahue RP, Dorn J, Trevisan M, Grundy SM. Non-high-density lipoprotein and very-low-density lipoprotein cholesterol and their risk predictive values in coronary heart disease. Am J Cardiol 2006;98:1363-68.
17. Martinez-Hervas S, Real JT, Priego A, et al. Familial combined hyperlipidemia, metabolic syndrome and cardiovascular disease. Rev Esp Cardiol 2006;59(11):1195-98.
18. Bonora E, Targher G, Formentini G, et al. The metabolic syndrome is an independent predictor of cardiovascular disease in Type 2 diabetic subjects. Prospective data from the Verona Diabetes Complications Study. Diabetes Care 2001;24:1629-33.
19. Isomaa B, Almgren P, Tuomi T, et al. Cardiovascular morbidity and mortality associated with the metabolic syndrome. Diabetes Care 2001;24:683-89.