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HDL subclass distribution: match the treatment to the disorder
THE PAST AND THE PRESENT: PROLOGUES TO THE FUTURE
based on differences in density or size. In general, large lipoprotein particles are buoyant, and small lipoprotein particles are dense when assessed by analytical ultracentrifugation (ANUC) (Figure 1). Subclasses of LDL and HDL particles that differ in density or size have quite different attributes that contribute to atherosclerosis risk or protection from atherosclerosis. At the University of California, Berkeley, work by Krauss and Blanche (2) has resulted in a nomenclature that classifies individuals as LDL pattern A, B or I. Pattern A represents people with predominantly (but not exclusively) large (buoyant) LDL particles, LDL pattern B represents people with predominantly (but not exclusively) small (dense) LDL particles and LDL pattern I (intermediate) represents individuals with LDL particles midway between large and small, or individuals with multiple LDL peaks (2). This nomenclature relies on a gradient gel electrophoresis (GGE) system developed at the Donner Laboratory, University of California. Approximately 30 – 40% of individuals have two or more major LDL particle types. Reliance on classification as only pattern A, B or I ignores the heterogeneity within these three classifications. For that
K. Lance Gould, MD, Guest Editor BRIEF REVIEW
Lipid Altering Drugs LDL/HDL Subclass Distribution: Match the Treatment to the Disorder H. Robert Superko, MD, Berkeley Heartlab, Lawrence Orlando Berkeley National Laboratory, University of California, Cholesterol, Genetics, and Heart Disease Institute, San Mateo, California ow-density lipoprotein (LDL) and high-density lipoprotein (HDL) subclass distribution has become accepted as an important component of diagnosis and therapeutic decision making with regard to disorders of lipoprotein metabolism and coronary atherosclerosis (1). LDL and HDL particles are present in all individuals as a heterogeneous population of particles that can be defined
L
Figure 1. Large, buoyant very–low-density lipoprotein (VLDL) particles are produced in the liver, and large or small VLDLs are metabolized to either four small LDL types (types 4,5,6,7) whereas small VLDL particles are metabolized to three large LDL types (types 1,2,3). Lipoprotein lipase (LPL) and hepatic lipase (HL) are enzymes that play key roles in this pathway. Increased HL activity favors the formation of small, dense LDL particles whereas LPL activity favors the production of large, buoyant LDL particles. HDL-particles are initially produced as a flat discoid form (HDL3) that becomes engorged with cholesterol, and in this form, it is described as HDL2b. ACC CURRENT JOURNAL REVIEW May/June 2000 © 2000 by the American College of Cardiology Published by Elsevier Science Inc.
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1062-1458/00/$20.00 PII S1062-1458(00)00043-X
THE PAST AND THE PRESENT: PROLOGUES TO THE FUTURE
have measured LDL and HDL subclass distribution by both LDL GGE and the gold standard of lipoprotein subclass distribution determination, ANUC. ANUC is too expensive and time consuming for clinical use. Because large clinical trials have measured both GGE and ANUC, clinical lessons learned from ANUC can be applied to patient care by using the less expensive GGE methodology. Appreciation of the variability in lipoprotein electrophoresis patterns illustrates the importance of incorporating the concept of multiple LDL peaks and percent distribution in clinical decision making. Figure 2 represents a typical LDL pattern A subject with a peak particle diameter of 268.3 Å and only 17% of LDLs in regions 4 and 5. Figure 3 represents a typical LDL pattern B subject with a peak particle diameter of 249 Å and 43% in regions 4 and 5. Figure 4 illustrates how reliance on only a single peak particle diameter may be misleading. The peak on the left is in the large region and is slightly taller than the peak on the right. Using peak particle diameter as the only criteria would result in the subject being classified with LDL pattern A. However, the peak on the right clearly represents a substantial amount of small LDL with 30.8% in regions 4 and 5. Reliance on peak particle diameter alone will miss approximately 40% of subjects who have two or more peaks. The importance of lipoprotein heterogeneity is not new and dates back to the work of Gofman et al. (3) at the University of California, Berkeley in the 1950s and 1960s when they developed the atherogenic index based on Framingham and Livermore study data that was analyzed for lipoprotein subclass distribution by ANUC. Since then, four prospective studies (Boston Heart Study, Stanford Five Cit-
Figure 2. LDL subclass pattern A on GGE. Note the single primary peak at 268.3 Å and 17% of the LDLs in regions 4 and 5.
reason, assessment of the percent distribution of LDL or HDL particles in particular regions is an alternative approach to classifying individuals with regard to LDL and HDL heterogeneity and provides useful clinical information. In general, more than 20% of particles in the small LDL regions 4 and 5 indicates a predominance of small, dense particles (consistent with LDL pattern B), and less than 15% in regions 4 and 5 indicates a predominance of large, buoyant LDL particles (consistent with LDL pattern A). However, in some cases, the bulk of LDL particles can be in the very small regions 6 and 7 with relatively low levels in regions 4 and 5, illustrating how reliance on only peak particle diameter, or percent distribution, in regions 4 and 5 can be misleading. The entire distribution curve needs to be assessed to appreciate the clinical implications of LDL heterogeneity. In a similar manner, HDL subclass distribution can be determined by a modified GGE method. However, because of the concave nature of HDL peaks, HDL peak particle diameter is not a useful measurement. Percent distribution in five HDL regions is used to determine if disorders of HDL subclass distribution are present. HDL2b is the region that correlates with HDL2 on ANUC. Low levels or HDL2b have been associated with coronary artery disease (CAD) risk, arteriographic severity and arteriographic CAD progression. GGE is a laboratory method that can allow precise differentiation of multiple LDL peak particle diameters and percent distribution in seven LDL regions and five HDL regions. At the Lawrence Berkeley National Laboratory, many studies
Figure 3. LDL subclass pattern B on LDL GGE. Note the peak particle diameter of 249.3 Å and 43% of the LDL in the small regions 4 and 5. A less prominent LDL peak is noted at 263.7 Å.
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THE PAST AND THE PRESENT: PROLOGUES TO THE FUTURE
Figure 4. LDL GGE with two LDL peaks of almost equal height. One peak is clearly in the large region (272.5 Å), and the second is clearly in the small region (250.7 Å). 30.8% is in regions 4 and 5. the small LDL pattern B trait. ALP is inherited in a dominant fashion and has been linked to a position on chromosome 19, although at least four other genes impact expression. In addition to the importance of lipoprotein heterogeneity in CAD risk prediction, it is also important with regard to differences in response to many common lipid therapies. Multiple studies at the University of California, Berkeley, Berkeley HeartLab and Stanford University have indicated that many treatments have a significantly different result in individuals classified as LDL pattern A or B by GGE or ANUC (Table 1).
ies Project, Harvard Physicians Health Survey, Quebec Cardiovascular Study) have demonstrated that LDL peak particle diameter is an independent risk factor for future cardiovascular events. Six arteriographic studies have contributed information that indicates individuals with a predominance of small, dense LDL have a two-fold greater rate of arteriographic progression, but they have a significantly greater arteriographic benefit to treatment. In several studies, change in dense LDL was the best predictor of arteriographic outcome (4). The small LDL pattern B disorder is a heritable trait associated with an atherogenic milieu that includes an abundance of small LDL, increased intermediate density lipoproteins, reduced HDL2b, insulin resistance and predisposition to type 2 diabetes, enhanced lipoprotein susceptibility to oxidative damage, rapid entry of small LDL into arterial walls and greatly increased blood fats following a meal (postprandial lipemia). For this reason, the more inclusive term, atherogenic lipoprotein profile (ALP), has been used to describe the atherogenic milieu associated with
Treatments Lifestyle Low-fat diets are often high in simple carbohydrates as a source of calories. Work by Dreon et al. (5) has convincingly demonstrated that switching to a low-fat diet results in greater LDL cholesterol and apo B reduction in LDL pattern B individuals compared with A individuals; however, ap-
Table 1. GENERAL EFFECT OF TREATMENTS ON LDL AND HDL SUBCLASS DISTRIBUTION Small LDL HDL2b Differential A/B effect
Low-Fat Diet
Garlic
Fat Weight Loss
Niacin
Fibrates
Statins
Resins
Beta-Blockers
1 2
A A
2 1
2 1
2 1
A A
A A
1 2
Yes
No
Yes
Yes
Yes
No
No
Yes
1 indicates an increase in small LDL distribution following treatment, 2 indicates a decrease in small LDL or HDL2b distribution following treatment and A indicates no significant change in small LDL distribution or HDL2b distribution following treatment. A/B effect indicates whether a differential response to treatment effect is seen between LDL pattern A and B subjects.
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THE PAST AND THE PRESENT: PROLOGUES TO THE FUTURE
and a significant reduction in HDL2b. Thus, low-fat, highcarbohydrate diets may exacerbate ALP in some individuals. Loss of excess body fat can significantly improve both LDL and HDL subclass distribution, which can occur regardless of whether the weight was lost by caloric restriction or by exercise with no change in diet (6).
Table 2. EFFECT OF TREATMENT ON PERCENT CHANGE IN LDL CHOLESTEROL AND SMALL LDL IN SUBJECTS CLASSIFIED AS LDL PATTERN A OR B LDL Cholesterol ⌬
Small LDL ⌬
Treatment
A
B
A
B
Low-fat diet Garlic Fiber Resin Niacin Gemfibrozil Statin Hormone replacement therapy
⫺10 ⫹0.5 ⫺10 ⫺26 ⫺25 ⫺4 ⫺24
⫺20* ⫺2 ⫺13 ⫺40 ⫺18 0 ⫺24
⫹1 ⫹10 ⫺1 ⫺28 ⫹5 ⫹2 no change
⫺9* (apo B) ⫺2 ⫹2 ⫺47* ⫺19* ⫺19*
⫺5
⫺14*
⫺6
Nicotinic Acid Niacin can have a substantial effect on reducing triglycerides and LDL cholesterol while increasing HDL cholesterol. At the same time, it has a powerful effect on reducing small LDL and increasing HDL2b. A differential effect is seen in that pattern B subjects have a significantly greater lipoprotein change response to niacin than do pattern A subjects (7). Figure 5 illustrates the differential effect of 1,500 mg daily of niacin on LDL subclass distribution in an LDL pattern B subject with a second LDL peak in the large LDL region. Note that although the LDL cholesterol was little changed (121 to 109 mg/dL, ⫺9.9%), the distribution in the small LDL regions (4 and 5) was reduced from 36% to 15% (relative percent decrease of 58.3%). The reduction in the small LDL region was much greater than reflected in the LDL cholesterol reduction alone. The change in LDL subclass
⫺16*
* p ⬍ 0.05.
proximately 40% of LDL pattern A subjects convert to pattern B on the low-fat/high-carbohydrate diet (5). Consuming a diet in which only 10% of calories are derived from fat results in little change in lipoprotein measurements in individuals who are LDL pattern A and remain pattern A on the 10%-fat diet. However, pattern A subjects who convert to pattern B reveal a significant increase in small, dense LDL
Figure 5. The differential effect of niacin can be seen in this patient who initially was LDL pattern B with two peaks (266 and 254 Å). Following 1,500 mg of niacin daily, there was a reduction in LDL 4 and 5 from 36% to 15% (⫺ 58.3%). Regions 4 and 5 have been darkened for illustration purposes. Note that the LDL cholesterol was reduced from 121 to 109 mg/dL (⫺ 9.9%). ACC CURRENT JOURNAL REVIEW May/June 2000
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THE PAST AND THE PRESENT: PROLOGUES TO THE FUTURE
Figure 6. Example of an individual’s HDL subclass distribution prior to and following 1,000 mg daily of niacin. HDL2b is the region most associated with cardiovascular protection and reflects reverse cholesterol transport. HDL2b has been artificially darkened for illustration purposes.
Beta-Blockers Selective and nonselective beta-blockers increase triglycerides and reduce HDL cholesterol. The increase in triglycerides is associated with a shift in LDL density toward denser LDL subclasses (10). The reduction in HDLC is accompanied by an even greater reduction in HDL2. In this regard, the results of the Milan Regression Study are of interest because patients randomized to a nonselective beta-blocker had significantly greater arteriographic progression compared with the group randomized to nitroglycerin therapy.
distribution was also not reflected by the small changes in triglycerides and HDL cholesterol. Figure 6 shows the effect of nicotinic acid on HDL subclass distribution in a case example. Note that the effect on HDL subclass distribution was far in excess of what one would have anticipated by the changes in routine measurements of HDL cholesterol. Fibrates Not all fibrates have the same effect on LDL and HDL subclass distribution. In general, fibrates reduce small LDL particularly when elevated triglycerides are reduced, and they may increase HDL2b. However, different fibrates can have different effects on HDL subclass distribution. Gemfibrozil has been shown to reduce small, dense LDL significantly in LDL pattern B subjects but have little to no effect on small LDL in pattern A subjects (8). Figure 7 illustrates the differential effect of fenofibrate on LDL subclass distribution in a LDL pattern B subject. LDL cholesterol was reduced from 127 to 95 mg/dL (⫺ 25%), but the percent in regions 4 and 5 decreased from 37.8% to 10.2% (⫺ 73%).
Hormone Replacement Therapy Treatment with 0.625 mg daily of conjugated equine estrogen and 2.5 mg daily of medroxyprogesterone in postmenopausal women results in significant reductions in both small (dense) LDL and large (buoyant) LDL. HDL2 is significantly increased and appears to be mediated through increased lipoprotein lipase activity and reduced hepatic lipase activity (11). In women classified as LDL subclass pattern B by ANUC and GGE, reduction in LDL cholesterol and apo B was significantly greater than in LDL pattern A women. This result indicated that the reputedly beneficial effect of hormone replacement therapy on LDL cholesterol and apo B is concentrated in LDL subclass pattern B postmenopausal women.
Statins Statins do not appear to have a differential effect on LDL or HDL subclass distribution in LDL pattern A vs. B subjects (9). Although statin drugs significantly reduce the total mass of lipoprotein particles, there does not appear to be the differential effect as seen with nicotinic acid and gemfibrozil.
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THE PAST AND THE PRESENT: PROLOGUES TO THE FUTURE
Figure 7. This case illustrates the effect of fenofibrate (67 mg three times daily) on LDL subclass distribution. Note the abundance of LDL particles in regions 4 and 5 (37.8%) prior to treatment. Treatment resulted in a shift of LDL peak particle diameter from 251 Å to 270 Å, and the distribution in regions 4 and 5 decreased from 37.8% to 10.2%. ACC CURRENT JOURNAL REVIEW May/June 2000
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THE PAST AND THE PRESENT: PROLOGUES TO THE FUTURE
Conclusions A differential response to treatment can be observed in patients characterized metabolically. With respect to ALP (or the small, dense LDL trait), LDL pattern B patients have a significantly greater reduction in small LDL following niacin and gemfibrozil treatment. Hormone replacement therapy has a beneficial effect on the ALP profile. Agents that tend to have an adverse effect on LDL or HDL subclass distribution include beta-blockers, high simple-carbohydrate diets and factors associated with body-fat weight gain. This conclusion is of clinical significance because CAD patients with predominantly dense LDL particles have a two-fold greater rate of arteriographic progression, and treatment that results in a shift away from small, dense LDL toward large, buoyant LDL has been associated with a beneficial arteriographic outcome.
5. Dreon DM, Fernstrom H, Miller B, Krauss RM. Low density lipoprotein subclass patterns and lipoprotein response to a reduced-fat diet in men. FASEB J 1994;8:121– 6. 6. Williams PT, Krauss RM, Vranizan KM, Wood PD. Changes in lipoprotein subfractions during diet-induced and exercise-induced weight loss in moderately overweight men. Circulation 1990;81:1293–304. 7. Superko HR, Krauss RM. Differential effects of nicotinic acid in subjects with different LDL subclass patterns. Atherosclerosis 1992;95:69 –76. 8. Franceschini G, Lovati MR, Manzoni C, et al. Effect of gemfibrozil treatment in hypercholesterolemia on low density lipoprotein (LDL) subclass distribution and LDL-cell interaction. Atherosclerosis 1995;114:61–71. 9. Superko HR, Krauss RM, DiRicco C. Effect of HMGCoA reductase inhibitor (fluvastatin) on LDL peak particle diameter. Am J Cardiol 1997; 80:78 – 81. 10. Superko HR, Wood PD, Krauss RM. Effect of alpha- and selective beta-blockade for hypertension control on plasma lipoproteins, apoproteins, lipoprotein subclasses, and postprandial lipemia. Am J Med 1989;86 (Suppl 1B):26 –31. 11. Superko HR, Blanche P, Holl L, Orr J, Shoenfeld MJ, Krauss RM. Reduction of plasma LDL and apo B levels with combined estrogen ⫹ progestin therapy in post-menopausal women is greater in women with dense rather than buoyant LDL. Circulation 1998;98:I–7.
REFERENCES 1. Superko HR. The atherogenic lipoprotein profile. Science and Medicine 1997;4:36 – 45. 2. Krauss RM, Blanche PJ. Detection and quantitation of LDL subfractions. Curr Opin Lipidol 1992;3:377– 83. 3. Gofman JW, Young W, Tandy R. Ischemic heart disease, atherosclerosis and longevity. Circulation 1966;34:679 –97. 4. Superko HR. What can we learn about dense LDL and lipoprotein particles from clinical trials? Curr Opin Lipidol 1996;7:363– 8.
The author has provided an important list of additional references. These references are available by contacting the Editorial Office by FAX 317-2744469.
Address correspondence and reprint requests to Robert Superko, MD, Berkeley HeartLab, Inc., 1875 South Grant Street, Suite 700, San Mateo, CA 94402.
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based on differences in density or size. In general, large lipoprotein particles are buoyant, and small lipoprotein particles are dense when assessed by analytical ultracentrifugation (ANUC) (Figure 1). Subclasses of LDL and HDL particles that differ in density or size have quite different attributes that contribute to atherosclerosis risk or protection from atherosclerosis. At the University of California, Berkeley, work by Krauss and Blanche (2) has resulted in a nomenclature that classifies individuals as LDL pattern A, B or I. Pattern A represents people with predominantly (but not exclusively) large (buoyant) LDL particles, LDL pattern B represents people with predominantly (but not exclusively) small (dense) LDL particles and LDL pattern I (intermediate) represents individuals with LDL particles midway between large and small, or individuals with multiple LDL peaks (2). This nomenclature relies on a gradient gel electrophoresis (GGE) system developed at the Donner Laboratory, University of California. Approximately 30 – 40% of individuals have two or more major LDL particle types. Reliance on classification as only pattern A, B or I ignores the heterogeneity within these three classifications. For that
K. Lance Gould, MD, Guest Editor BRIEF REVIEW
Lipid Altering Drugs LDL/HDL Subclass Distribution: Match the Treatment to the Disorder H. Robert Superko, MD, Berkeley Heartlab, Lawrence Orlando Berkeley National Laboratory, University of California, Cholesterol, Genetics, and Heart Disease Institute, San Mateo, California ow-density lipoprotein (LDL) and high-density lipoprotein (HDL) subclass distribution has become accepted as an important component of diagnosis and therapeutic decision making with regard to disorders of lipoprotein metabolism and coronary atherosclerosis (1). LDL and HDL particles are present in all individuals as a heterogeneous population of particles that can be defined
L
Figure 1. Large, buoyant very–low-density lipoprotein (VLDL) particles are produced in the liver, and large or small VLDLs are metabolized to either four small LDL types (types 4,5,6,7) whereas small VLDL particles are metabolized to three large LDL types (types 1,2,3). Lipoprotein lipase (LPL) and hepatic lipase (HL) are enzymes that play key roles in this pathway. Increased HL activity favors the formation of small, dense LDL particles whereas LPL activity favors the production of large, buoyant LDL particles. HDL-particles are initially produced as a flat discoid form (HDL3) that becomes engorged with cholesterol, and in this form, it is described as HDL2b. ACC CURRENT JOURNAL REVIEW May/June 2000 © 2000 by the American College of Cardiology Published by Elsevier Science Inc.
18
1062-1458/00/$20.00 PII S1062-1458(00)00043-X
THE PAST AND THE PRESENT: PROLOGUES TO THE FUTURE
have measured LDL and HDL subclass distribution by both LDL GGE and the gold standard of lipoprotein subclass distribution determination, ANUC. ANUC is too expensive and time consuming for clinical use. Because large clinical trials have measured both GGE and ANUC, clinical lessons learned from ANUC can be applied to patient care by using the less expensive GGE methodology. Appreciation of the variability in lipoprotein electrophoresis patterns illustrates the importance of incorporating the concept of multiple LDL peaks and percent distribution in clinical decision making. Figure 2 represents a typical LDL pattern A subject with a peak particle diameter of 268.3 Å and only 17% of LDLs in regions 4 and 5. Figure 3 represents a typical LDL pattern B subject with a peak particle diameter of 249 Å and 43% in regions 4 and 5. Figure 4 illustrates how reliance on only a single peak particle diameter may be misleading. The peak on the left is in the large region and is slightly taller than the peak on the right. Using peak particle diameter as the only criteria would result in the subject being classified with LDL pattern A. However, the peak on the right clearly represents a substantial amount of small LDL with 30.8% in regions 4 and 5. Reliance on peak particle diameter alone will miss approximately 40% of subjects who have two or more peaks. The importance of lipoprotein heterogeneity is not new and dates back to the work of Gofman et al. (3) at the University of California, Berkeley in the 1950s and 1960s when they developed the atherogenic index based on Framingham and Livermore study data that was analyzed for lipoprotein subclass distribution by ANUC. Since then, four prospective studies (Boston Heart Study, Stanford Five Cit-
Figure 2. LDL subclass pattern A on GGE. Note the single primary peak at 268.3 Å and 17% of the LDLs in regions 4 and 5.
reason, assessment of the percent distribution of LDL or HDL particles in particular regions is an alternative approach to classifying individuals with regard to LDL and HDL heterogeneity and provides useful clinical information. In general, more than 20% of particles in the small LDL regions 4 and 5 indicates a predominance of small, dense particles (consistent with LDL pattern B), and less than 15% in regions 4 and 5 indicates a predominance of large, buoyant LDL particles (consistent with LDL pattern A). However, in some cases, the bulk of LDL particles can be in the very small regions 6 and 7 with relatively low levels in regions 4 and 5, illustrating how reliance on only peak particle diameter, or percent distribution, in regions 4 and 5 can be misleading. The entire distribution curve needs to be assessed to appreciate the clinical implications of LDL heterogeneity. In a similar manner, HDL subclass distribution can be determined by a modified GGE method. However, because of the concave nature of HDL peaks, HDL peak particle diameter is not a useful measurement. Percent distribution in five HDL regions is used to determine if disorders of HDL subclass distribution are present. HDL2b is the region that correlates with HDL2 on ANUC. Low levels or HDL2b have been associated with coronary artery disease (CAD) risk, arteriographic severity and arteriographic CAD progression. GGE is a laboratory method that can allow precise differentiation of multiple LDL peak particle diameters and percent distribution in seven LDL regions and five HDL regions. At the Lawrence Berkeley National Laboratory, many studies
Figure 3. LDL subclass pattern B on LDL GGE. Note the peak particle diameter of 249.3 Å and 43% of the LDL in the small regions 4 and 5. A less prominent LDL peak is noted at 263.7 Å.
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THE PAST AND THE PRESENT: PROLOGUES TO THE FUTURE
Figure 4. LDL GGE with two LDL peaks of almost equal height. One peak is clearly in the large region (272.5 Å), and the second is clearly in the small region (250.7 Å). 30.8% is in regions 4 and 5. the small LDL pattern B trait. ALP is inherited in a dominant fashion and has been linked to a position on chromosome 19, although at least four other genes impact expression. In addition to the importance of lipoprotein heterogeneity in CAD risk prediction, it is also important with regard to differences in response to many common lipid therapies. Multiple studies at the University of California, Berkeley, Berkeley HeartLab and Stanford University have indicated that many treatments have a significantly different result in individuals classified as LDL pattern A or B by GGE or ANUC (Table 1).
ies Project, Harvard Physicians Health Survey, Quebec Cardiovascular Study) have demonstrated that LDL peak particle diameter is an independent risk factor for future cardiovascular events. Six arteriographic studies have contributed information that indicates individuals with a predominance of small, dense LDL have a two-fold greater rate of arteriographic progression, but they have a significantly greater arteriographic benefit to treatment. In several studies, change in dense LDL was the best predictor of arteriographic outcome (4). The small LDL pattern B disorder is a heritable trait associated with an atherogenic milieu that includes an abundance of small LDL, increased intermediate density lipoproteins, reduced HDL2b, insulin resistance and predisposition to type 2 diabetes, enhanced lipoprotein susceptibility to oxidative damage, rapid entry of small LDL into arterial walls and greatly increased blood fats following a meal (postprandial lipemia). For this reason, the more inclusive term, atherogenic lipoprotein profile (ALP), has been used to describe the atherogenic milieu associated with
Treatments Lifestyle Low-fat diets are often high in simple carbohydrates as a source of calories. Work by Dreon et al. (5) has convincingly demonstrated that switching to a low-fat diet results in greater LDL cholesterol and apo B reduction in LDL pattern B individuals compared with A individuals; however, ap-
Table 1. GENERAL EFFECT OF TREATMENTS ON LDL AND HDL SUBCLASS DISTRIBUTION Small LDL HDL2b Differential A/B effect
Low-Fat Diet
Garlic
Fat Weight Loss
Niacin
Fibrates
Statins
Resins
Beta-Blockers
1 2
A A
2 1
2 1
2 1
A A
A A
1 2
Yes
No
Yes
Yes
Yes
No
No
Yes
1 indicates an increase in small LDL distribution following treatment, 2 indicates a decrease in small LDL or HDL2b distribution following treatment and A indicates no significant change in small LDL distribution or HDL2b distribution following treatment. A/B effect indicates whether a differential response to treatment effect is seen between LDL pattern A and B subjects.
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THE PAST AND THE PRESENT: PROLOGUES TO THE FUTURE
and a significant reduction in HDL2b. Thus, low-fat, highcarbohydrate diets may exacerbate ALP in some individuals. Loss of excess body fat can significantly improve both LDL and HDL subclass distribution, which can occur regardless of whether the weight was lost by caloric restriction or by exercise with no change in diet (6).
Table 2. EFFECT OF TREATMENT ON PERCENT CHANGE IN LDL CHOLESTEROL AND SMALL LDL IN SUBJECTS CLASSIFIED AS LDL PATTERN A OR B LDL Cholesterol ⌬
Small LDL ⌬
Treatment
A
B
A
B
Low-fat diet Garlic Fiber Resin Niacin Gemfibrozil Statin Hormone replacement therapy
⫺10 ⫹0.5 ⫺10 ⫺26 ⫺25 ⫺4 ⫺24
⫺20* ⫺2 ⫺13 ⫺40 ⫺18 0 ⫺24
⫹1 ⫹10 ⫺1 ⫺28 ⫹5 ⫹2 no change
⫺9* (apo B) ⫺2 ⫹2 ⫺47* ⫺19* ⫺19*
⫺5
⫺14*
⫺6
Nicotinic Acid Niacin can have a substantial effect on reducing triglycerides and LDL cholesterol while increasing HDL cholesterol. At the same time, it has a powerful effect on reducing small LDL and increasing HDL2b. A differential effect is seen in that pattern B subjects have a significantly greater lipoprotein change response to niacin than do pattern A subjects (7). Figure 5 illustrates the differential effect of 1,500 mg daily of niacin on LDL subclass distribution in an LDL pattern B subject with a second LDL peak in the large LDL region. Note that although the LDL cholesterol was little changed (121 to 109 mg/dL, ⫺9.9%), the distribution in the small LDL regions (4 and 5) was reduced from 36% to 15% (relative percent decrease of 58.3%). The reduction in the small LDL region was much greater than reflected in the LDL cholesterol reduction alone. The change in LDL subclass
⫺16*
* p ⬍ 0.05.
proximately 40% of LDL pattern A subjects convert to pattern B on the low-fat/high-carbohydrate diet (5). Consuming a diet in which only 10% of calories are derived from fat results in little change in lipoprotein measurements in individuals who are LDL pattern A and remain pattern A on the 10%-fat diet. However, pattern A subjects who convert to pattern B reveal a significant increase in small, dense LDL
Figure 5. The differential effect of niacin can be seen in this patient who initially was LDL pattern B with two peaks (266 and 254 Å). Following 1,500 mg of niacin daily, there was a reduction in LDL 4 and 5 from 36% to 15% (⫺ 58.3%). Regions 4 and 5 have been darkened for illustration purposes. Note that the LDL cholesterol was reduced from 121 to 109 mg/dL (⫺ 9.9%). ACC CURRENT JOURNAL REVIEW May/June 2000
21
THE PAST AND THE PRESENT: PROLOGUES TO THE FUTURE
Figure 6. Example of an individual’s HDL subclass distribution prior to and following 1,000 mg daily of niacin. HDL2b is the region most associated with cardiovascular protection and reflects reverse cholesterol transport. HDL2b has been artificially darkened for illustration purposes.
Beta-Blockers Selective and nonselective beta-blockers increase triglycerides and reduce HDL cholesterol. The increase in triglycerides is associated with a shift in LDL density toward denser LDL subclasses (10). The reduction in HDLC is accompanied by an even greater reduction in HDL2. In this regard, the results of the Milan Regression Study are of interest because patients randomized to a nonselective beta-blocker had significantly greater arteriographic progression compared with the group randomized to nitroglycerin therapy.
distribution was also not reflected by the small changes in triglycerides and HDL cholesterol. Figure 6 shows the effect of nicotinic acid on HDL subclass distribution in a case example. Note that the effect on HDL subclass distribution was far in excess of what one would have anticipated by the changes in routine measurements of HDL cholesterol. Fibrates Not all fibrates have the same effect on LDL and HDL subclass distribution. In general, fibrates reduce small LDL particularly when elevated triglycerides are reduced, and they may increase HDL2b. However, different fibrates can have different effects on HDL subclass distribution. Gemfibrozil has been shown to reduce small, dense LDL significantly in LDL pattern B subjects but have little to no effect on small LDL in pattern A subjects (8). Figure 7 illustrates the differential effect of fenofibrate on LDL subclass distribution in a LDL pattern B subject. LDL cholesterol was reduced from 127 to 95 mg/dL (⫺ 25%), but the percent in regions 4 and 5 decreased from 37.8% to 10.2% (⫺ 73%).
Hormone Replacement Therapy Treatment with 0.625 mg daily of conjugated equine estrogen and 2.5 mg daily of medroxyprogesterone in postmenopausal women results in significant reductions in both small (dense) LDL and large (buoyant) LDL. HDL2 is significantly increased and appears to be mediated through increased lipoprotein lipase activity and reduced hepatic lipase activity (11). In women classified as LDL subclass pattern B by ANUC and GGE, reduction in LDL cholesterol and apo B was significantly greater than in LDL pattern A women. This result indicated that the reputedly beneficial effect of hormone replacement therapy on LDL cholesterol and apo B is concentrated in LDL subclass pattern B postmenopausal women.
Statins Statins do not appear to have a differential effect on LDL or HDL subclass distribution in LDL pattern A vs. B subjects (9). Although statin drugs significantly reduce the total mass of lipoprotein particles, there does not appear to be the differential effect as seen with nicotinic acid and gemfibrozil.
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THE PAST AND THE PRESENT: PROLOGUES TO THE FUTURE
Figure 7. This case illustrates the effect of fenofibrate (67 mg three times daily) on LDL subclass distribution. Note the abundance of LDL particles in regions 4 and 5 (37.8%) prior to treatment. Treatment resulted in a shift of LDL peak particle diameter from 251 Å to 270 Å, and the distribution in regions 4 and 5 decreased from 37.8% to 10.2%. ACC CURRENT JOURNAL REVIEW May/June 2000
23
THE PAST AND THE PRESENT: PROLOGUES TO THE FUTURE
Conclusions A differential response to treatment can be observed in patients characterized metabolically. With respect to ALP (or the small, dense LDL trait), LDL pattern B patients have a significantly greater reduction in small LDL following niacin and gemfibrozil treatment. Hormone replacement therapy has a beneficial effect on the ALP profile. Agents that tend to have an adverse effect on LDL or HDL subclass distribution include beta-blockers, high simple-carbohydrate diets and factors associated with body-fat weight gain. This conclusion is of clinical significance because CAD patients with predominantly dense LDL particles have a two-fold greater rate of arteriographic progression, and treatment that results in a shift away from small, dense LDL toward large, buoyant LDL has been associated with a beneficial arteriographic outcome.
5. Dreon DM, Fernstrom H, Miller B, Krauss RM. Low density lipoprotein subclass patterns and lipoprotein response to a reduced-fat diet in men. FASEB J 1994;8:121– 6. 6. Williams PT, Krauss RM, Vranizan KM, Wood PD. Changes in lipoprotein subfractions during diet-induced and exercise-induced weight loss in moderately overweight men. Circulation 1990;81:1293–304. 7. Superko HR, Krauss RM. Differential effects of nicotinic acid in subjects with different LDL subclass patterns. Atherosclerosis 1992;95:69 –76. 8. Franceschini G, Lovati MR, Manzoni C, et al. Effect of gemfibrozil treatment in hypercholesterolemia on low density lipoprotein (LDL) subclass distribution and LDL-cell interaction. Atherosclerosis 1995;114:61–71. 9. Superko HR, Krauss RM, DiRicco C. Effect of HMGCoA reductase inhibitor (fluvastatin) on LDL peak particle diameter. Am J Cardiol 1997; 80:78 – 81. 10. Superko HR, Wood PD, Krauss RM. Effect of alpha- and selective beta-blockade for hypertension control on plasma lipoproteins, apoproteins, lipoprotein subclasses, and postprandial lipemia. Am J Med 1989;86 (Suppl 1B):26 –31. 11. Superko HR, Blanche P, Holl L, Orr J, Shoenfeld MJ, Krauss RM. Reduction of plasma LDL and apo B levels with combined estrogen ⫹ progestin therapy in post-menopausal women is greater in women with dense rather than buoyant LDL. Circulation 1998;98:I–7.
REFERENCES 1. Superko HR. The atherogenic lipoprotein profile. Science and Medicine 1997;4:36 – 45. 2. Krauss RM, Blanche PJ. Detection and quantitation of LDL subfractions. Curr Opin Lipidol 1992;3:377– 83. 3. Gofman JW, Young W, Tandy R. Ischemic heart disease, atherosclerosis and longevity. Circulation 1966;34:679 –97. 4. Superko HR. What can we learn about dense LDL and lipoprotein particles from clinical trials? Curr Opin Lipidol 1996;7:363– 8.
The author has provided an important list of additional references. These references are available by contacting the Editorial Office by FAX 317-2744469.
Address correspondence and reprint requests to Robert Superko, MD, Berkeley HeartLab, Inc., 1875 South Grant Street, Suite 700, San Mateo, CA 94402.
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