© 2001 American Heart Association, Inc.
Letters to the Editor |
Familial Combined Hyperlipidemia and Insulin Resistance
University of British Columbia, Vancouver, Canada
McGill University, Quebec, Canada
To the Editor:
In the last paragraph of this editorial (Arterioscler Thromb Vasc Biol. 2001;21:469–470), Dr Eckel mentions that assays for apo B remain less than optimal and quotes our article that deals with standardization of the DAIS Study.1 In fact, after the decision was made on a common International Federation of Clinical Chemistry/World Health Organization standard for the 2 laboratories involved in DAIS, there was very little bias in the apo B values (see Figure 5A of our article). Apo B assays have been standardized2,3 and reference values established in both the United States and Canada (for a review, see Bhatnagar et al4).
Plasma apo B concentration, a measure of LDL particle number, has been shown in both epidemiological studies and prospective, double-blind, placebo controlled clinical trials to be related to clinical outcomes.5–7 In the Quebec Cardiovascular Study,5 apo B was the single most important lipid parameter that predicted cardiovascular events. Similarly, data from AFCAPS/TEXCAPS6 have demonstrated that although LDL cholesterol, HDL cholesterol, and apo B predict cardiac outcomes before therapy is initiated, the lipid levels and their ratios did not predict outcome on treatment, whereas apo B and the ratio of apo B to apo A1 did. Similarly, on treatment, apo B and apo A1 were the significant predictors in a secondary prevention study of van Lennep et al.7 This also fits well with observational data by Moss and colleagues8 in 1045 postinfarction patients. Target values have been established and accepted by the Canadian Cardiovascular Society.9
Although apo B should not be the only parameter measured in the initial assessment of the risk of disease, it is, in addition to serum lipids, an excellent parameter for the follow-up of patients. In the most common type of dyslipidemia, namely, mild to moderate hypertriglyceridemia, low HDL cholesterol and higher numbers of small, dense LDL particles, measurement of apo B can distinguish between those at risk, ie, those with familial combined hyperlipidemia and those with familial hypertriglyceridemia (ie, those with "good" and "bad" hypertriglyceridemia).
In conclusion, apo B is a standardized, well-characterized, and validated measurement that could greatly simplify diagnosis and treatment of patients with dyslipidemia.
References
1. McGuinness C, Seccombe DW, Frohlich JJ, Ehnholm C, Sundvall J, Steiner G. Laboratory standardization of a large international clinical trial: the DAIS experience. Clin Biochem. 2000; 33: 15–24.[Medline] [Order article via Infotrieve]
2.
Albers JJ, Marcovina SM, Kennedy H. International Federation of Clinical Chemistry standardization project for measurements of apolipoproteins A-I and B, II: evaluation and selection of candidate reference materials. Clin Chem. 1992; 38: 658–662.
3.
Marcovina SM, Albers JJ, Kennedy H, Mei JV, Henderson LO, Hannon WH. International Federation of Clinical Chemistry standardization project for measurements of apolipoproteins A-I and B, IV: comparability of apolipoprotein B values by use of International Reference Material. Clin Chem. 1994; 40: 586–592.
4. Bhatnagar D, Durrington PN. Measurement and clinical significance of apolipoproteins AI and B.In: Rafai N, Warnick GR, Dominiczak MH, eds. Handbook of Lipoprotein Testing, 2nd ed. Washington, DC: AACC Press; 2000: 287–310.
5.
Lamarche B, Tchernof A, Moorjani S, Cantin B, Dagenais GR, Lupien PJ, Despres JP. Small, dense low-density lipoprotein particles as a predictor of the risk of ischemic heart disease in men: prospective results from the Quebec Cardiovascular Study. Circulation. 1997; 95: 69–75.
6.
Gotto AM, Whitney E, Stein EA, Shapiro DR, Clearfield M, Weis S, Jou JY, Langendorfer A, Beere PA, Watson DJ, Downs JR, de Cani JS. Relationship between baseline and on-treatment lipid parameters and first acute major coronary events in the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS). Circulation. 2000; 101: 477–484.
7.
Van Lennep JE, Westerveld HT, van Lennep HWO, Zwinderman AH, Erkelens DW, van der Wall EE. Apolipoprotein concentrations during treatment and recurrent coronary artery disease events. Arterioscler Thromb Vasc Biol. 2000; 20: 2408–2413.
8.
Moss AJ, Goldstein RE, Marder VJ, Sparks CE, Oakes D, Greenberg H, Weiss HJ, Zareba W, Brown MW, Liang CS, Lichstein E, Little WC, Gillespie JA, Van Voorhees L, Krone RJ, Bodenheimer MM, Hochman J, Dwyer EMJr, Arora R, Marcus FL, Watelet LF, Case RB. Thrombogenic factors and recurrent coronary events. Circulation. 1999; 99: 2517–2522.
9. Collins-Nakai RL, Dagenais GR. The role of the cardiovascular specialist in the prevention of cardiovascular diseases: executive summary. Can J Cardiol. 1999; 15: 7G–10G.[Medline] [Order article via Infotrieve]
Department of Medicine, Physiology, and Biophysics, University of Colorado Health Sciences Center, Denver, Colorado
In Response:
I would like to begin by thanking Drs Frohlich and Sniderman for their thoughtful letter in response to my recent editorial "Familial combined hyperlipidemia and insulin resistance: distant relatives linked by intra-abdominal fat."1 Their predominant concerns relate to my recommendations as to when apo B determinations should be obtained and the technical quality of the assay for apo B.
When fasting plasma triglycerides are >200 mg/dL and the National Cholesterol Education Program (NCEP) treatment goal for LDL cholesterol has been achieved, ie, <160, <130, or <100 mg/dL, the secondary treatment goal outlined by the recent report of the NCEP is a non-HDL cholesterol level of <190, <160, or <130 mg/dL, respectively, not apo B.2 In fact, apo B was not recommended by the NCEP panel as a tool to assess coronary heart disease (CHD) risk under any circumstances. As stated by Drs Frohlich and Sniderman, non-HDL cholesterol may not be a perfect surrogate for apo B. However, the fact that the correlation coefficient is stronger between non-HDL cholesterol and total cholesterol than between non-HDL cholesterol and apo B is not surprising, considering the presence of total cholesterol in both of the correlation covariates (cholesterol and non-HDL cholesterol, the latter of which is total cholesterol minus HDL cholesterol).
Presumably, but not stated, is that the NCEP panel viewed (1) the clinical evidence in support of apo B as a better predictor of CHD than non-HDL cholesterol and/or (2) the assays available to measure apo B insufficient to encourage the routine use of apo B. Although, as noted in the letter by Drs Frohlich and Sniderman, some studies have shown the superiority of apo B in predicting CHD events, many studies either have not reported apo B data (WOSCOPS, 4S) or have not indicated the relative merit of 1 determinant versus the other (CARE)3 in predicting outcome. If the data were substantial to support the superiority of apo B and one could assume that all commercial assays for apo B had the accuracy and quality control of reference labs,4,5 I would strongly agree and extend my recommendations to patients with hypertriglyceridemia and LDL cholesterol levels >130 but <160 mg/dL. However, this certainty is not apparent. When LDL cholesterol levels are >160 mg/dL, I remain convinced that apo B is elevated and its measurement is redundant. Despite the progress in Canada to add apo B to their CHD risk assessment,6 it is interesting to note that lipid and lipoprotein measurements have not been eliminated.
Overall, my opinion that apo B has tremendous value in the assessment of cardiovascular risk in patients with hypertriglyceridemia is in agreement with the position of Drs Frohlich and Sniderman. Such an approach to risk assessment is used by few physicians in the United States, and I am confident that increasing and appropriate use of apo B in the assessment of patients with hypertriglyceridemia may improve therapeutic strategies and outcomes in at least some of these patients. However, the NCEP expert panel has stopped short of such recommendations. It will be interesting to see the rationale for this lack of enthusiasm when the complete report is released.
References
1. Eckel RH. Familial combined hyperlipidemia and insulin resistance: distant relative linked by intra-abdominal fat? Arterioscler Thromb Vasc Biol. 2001; 4: 469–470.
2.
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: 2486–2509.
3.
Sacks FM, Alaupovic P, Moye LA, Cole TG, Sussex B, Stampfer MJ, Pfeffer MA, Brunwald E. VLDL, apolipoprotein B, CIII, and E, and risk of recurrent coronary events in the Cholesterol and Recurrent Events (CARE) Trial. Circulation. 2000; 102: 1886–1892.
4.
Marcovina SM, Albers JJ, Kennedy H, Mei JV, Henderson LO, Hannon WH. International Federation of Clinical Chemistry Standardization Project for Measurements of Apolipoproteins A-1 and B, IV: comparability of apolipoprotein B values by use of International Reference Material. Clin Chem. 1994; 40: 586–592.
5. McGuiness C, Seccombe DW, Frohlich JJ, Ehnholm C, Sandovall J, Steiner G, for the DAIS Project Group. Laboratory standardization of a large international clinical trial: the DIAS experience. Clin Biochem. 2000; 33: 15–24.[Medline] [Order article via Infotrieve]
6. Collins-Nakai RL, Dagenais GR. The role of the cardiovascular specialist in the prevention of cardiovascular diseases: executive summary. Can J Cardiol. 1999; 15: 7G–10G.[Medline] [Order article via Infotrieve]
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