Lipoprotein Measures and Cardiovascular Disease

Lipoprotein particles that transport cholesterol and triglycerides in plasma are the direct mediators of the atherosclerotic process.  LDL particles (and to a lesser extent very-low-density lipoprotein [VLDL] and remnant particles) promote atherosclerosis, while HDL particles entering the artery wall antagonize this process. The overall risk of cardiovascular disease depends on the balance between these atherogenic and anti-atherogenic particles.

Due to the difficulty of measuring lipoprotein particles directly, plasma triglycerides (TG) have come to serve as a surrogate measure of VLDL levels, while LDL cholesterol (LDL-C) and HDL cholesterol (HDL-C) values serve as indicators of the concentrations of LDL and HDL particles.  Few people have regarded the surrogate relationship of lipids to lipoproteins as a clinical limitation.  Data from genetic, epidemiologic and clinical intervention trials have demonstrated that, at a population level, abnormal lipid levels are strongly related to atherosclerosis and CHD events. 

As a result, lipid values are used for both risk assessment and to monitor the progress of therapeutic interventions.  For risk assessment, Adult Treatment Panel III (ATPIII) guidelines recommend that elevated LDL-C along with age, gender, blood pressure, HDL-C, diabetes, smoking, family history, and metabolic syndrome all be taken into account to determine the patient’s global CHD risk.  The assigned risk category defines the corresponding LDL-C treatment goal needed to mitigate that risk.  When used for risk management, lipid measurements are not employed in conjunction with other information, but as a stand-alone measure of progress towards a treatment goal.  The LDL-C level indicate which patients have lowered their risk to acceptable levels (as inferred from their treatment goal having been reached) and which have not (indicating a need for more aggressive treatment).  Recognizing the potential contribution to risk of other atherogenic lipoproteins besides LDL, such as VLDL remnants, ATP III designated LDL + VLDL cholesterol (non-HDL cholesterol or non-HDL-C) as “atherogenic cholesterol” and recommended its use as a secondary target of therapy in patients with elevated triglyceride levels (200-500 mg/dL). 

Nevertheless, practical limitations to this approach are encountered in clinical practice.  Numerous trials have demonstrated a curvilinear relationship of LDL-C with CHD events in which risk is linked strongly to increasing LDL-C when LDL-C is high, but more weakly when LDL-C levels are moderate to low.   LDL-C levels are thus relatively insensitive discriminators of risk when they approach the levels designated as treatment goals for high-risk (<100 mg/dL) or moderately high-risk (<130 mg/dL) patients.  In prospective epidemiologic trials substantial variability in CHD risk is present across a wide range of cholesterol values, as well as among patients followed in placebo and active therapy groups of clinical intervention trials.  Additionally, on-trial lipid values often are weak predictors of CHD risk in intervention studies. 

Our work focuses on the degree to which these limitations may emanate from a deficiency of lipids to accurately quantify the lipoprotein particles in which they are carried.  Listed below are a number of recent publications that address various analytic and clinical issues related to this topic.

Original Work:

  

Cromwell WC, Otvos JD, Keyes MJ, Pencina MJ, Sullivan L, Vasan RS, Wilson PWF, D’Agostino RB.  LDL particle number and risk of future cardiovascular disease in the Framingham Offspring Study – Implications for LDL management. J Clin Lipidology. 2007;1(6):582-593.

This paper focuses on several clinically relevant issues related to alternate measures of LDL quantity.  First, it compares the ability of alternative measures of LDL to provide cardiovascular disease (CVD) risk discrimination at relatively low potential target levels. Second, it provides new insights into why non-HDL-C is a better CVD risk predictor than LDL-C.  Finally, it includes new data showing that low LDL concentration by itself causes cholesterol depletion of LDL particles and a corresponding discordance between LDL-C and LDL-P levels.

 

Cromwell WC, Otvos JD. Heterogeneity of LDL particle number among patients with type 2 diabetes mellitus and LDL cholesterol <100 mg/dL. Amer J Cardiol. 2006;98(12): 1599-1602.

 

The purpose of this study was to determine how many type 2 diabetic patients with low LDL cholesterol (LDL-C) have correspondingly low numbers of LDL particles (LDL-P), and the extent to which those achieving target levels of LDL-C and non-HDL cholesterol (non-HDL-C) might still harbor residual risk arising from elevated LDL-P.  By performing split sample Friedewald LDL-C and nuclear magnetic resonance (NMR) spectroscopy measured LDL-P among 2,355 ambulatory care patients with  type 2 diabetes mellitus and LDL-C <100 mg/dL, we found substantial LDL-P heterogeneity to be present even at LDL-C values <70 mg/dL.    

 

Book Chapters:

  Cromwell WC. Clinical utilization of advanced lipid testing. IN: Clinical Challenges in Dyslipidemia Management. Edited by PP Toth and DA Sica. Oxford

Atlas Medical: 2007. (In Press).

 Cromwell WC, Otvos JD. Clinical utilization of lipoprotein subfractions. IN: Therapeutic Lipidology. Edited by MH Davidson, PP Toth, K Maki K. Totawa, NJ:

Humana Press: 2007 (In Press). 

 Cromwell, WC, Bays HE, Toth PP. Lipoprotein subfraction analysis using nuclear magnetic resonance spectroscopy. IN: Clinical Applications of Markers in

Cardiology: A Case-Oriented Approach. Edited by J Adams, F Apple, A Jaffe. London: Blackstone 2007: 217-250.

  

Review Articles:

  Cromwell WC. HDL associations with coronary heart disease: Does measurement of cholesterol content give the best result? J Clin Lipidology. 2007;1:57-64. Jeyarajah EJ, Cromwell WC, Otvos JD. Lipoprotein particle analysis by nuclear magnetic resonance spectroscopy. Clin Lab Med. 2006:26(4);847-870 Cromwell WC, Otvos JD. Low-density lipoprotein particle number and risk for cardiovascular disease. Curr Athero Reports. 2004;6:381-387.