Allan D. Sniderman

2009 Canadian Cardiovascular Society/Canadian guidelines for the diagnosis and treatment of dyslipidemia and prevention of cardiovascular disease in the adult – 2009 recommendations

The present article represents the 2009 update of the Canadian Cardiovascular Society guidelines for the diagnosis and treatment of dyslipidemia and prevention of cardiovascular disease in the adult.

Lipids, lipoproteins, and apolipoproteins as risk markers of myocardial infarction in 52 countries (the INTERHEART study): a case-control study

BACKGROUND Whether lipoproteins are better markers than lipids and lipoproteins for coronary heart disease is widely debated. Our aim was to compare the apolipoproteins and cholesterol as indices for risk of acute myocardial infarction. METHODS We did a large, standardised case-control study of acute myocardial infarction in 12,461 cases and 14,637 age-matched (plus or minus 5 years) and sex-matched controls in 52 countries. Non-fasting blood samples were available from 9345 cases and 12,120 controls. Concentrations of plasma lipids, lipoproteins, and apolipoproteins were measured, and cholesterol and apolipoprotein ratios were calculated. Odds ratios (OR) and 95% CI, and population-attributable risks (PARs) were calculated for each measure overall and for each ethnic group by comparison of the top four quintiles with the lowest quintile. FINDINGS The apolipoprotein B100 (ApoB)/apolipoprotein A1 (ApoA1) ratio had the highest PAR (54%) and the highest OR with each 1 SD difference (1.59, 95% CI 1.53-1.64). The PAR for ratio of LDL cholesterol/HDL cholesterol was 37%. PAR for total cholesterol/HDL cholesterol was 32%, which was substantially lower than that of the ApoB/ApoA1 ratio (p<0.0001). These results were consistent in all ethnic groups, men and women, and for all ages. INTERPRETATION The non-fasting ApoB/ApoA1 ratio was superior to any of the cholesterol ratios for estimation of the risk of acute myocardial infarction in all ethnic groups, in both sexes, and at all ages, and it should be introduced into worldwide clinical practice.

The relation of risk factors to the development of atherosclerosis in saphenous-vein bypass grafts and the progression of disease in the native circulation: a study 10 years after aortocoronary bypass surgery

We examined 82 patients 10 years after saphenous-vein aortocoronary bypass surgery to determine their angiographic status and to relate those findings to the risk factors for coronary-artery disease. Of 132 grafts shown to be patent 1 year after surgery, only 50 were unaffected at 10 years. The remainder were narrowed (43) or occluded (39). Disease progression in coronary arteries without grafts was also frequent, both in vessels that were normal (15 of 32) and in those with minor stenosis (25 of 53). New lesions did not develop in 15 patients, whereas they did in 67--in the grafts, the native vessels, or both. There was no significant difference between the two groups in the incidence of hypertension, diabetes, or smoking, whereas plasma levels of very-low-density lipoproteins (VLDLs) and low-density lipoproteins (LDLs) were higher, and high-density lipoprotein (HDL) levels were lower in those with new disease than in those without. Univariate analysis showed that plasma cholesterol and triglyceride levels were significantly higher at the time of surgery and at the 10-year examination in those with new lesions. Multivariate analysis indicated that among the lipoprotein indexes, levels of HDL cholesterol and plasma LDL apoprotein B best distinguished the two groups. The findings indicate that atherosclerosis in these patients was a progressive disease, frequently affecting both the grafts and the native vessels, and that the course of such disease may be related to the plasma lipoprotein levels.

Apolipoproteins versus lipids as indices of coronary risk and as targets for statin treatment

More Nobel prizes have been awarded for the study of cholesterol than for any other molecule. Presently, concentration of LDL cholesterol is the fundamental index of risk of vascular disease. It is an estimate of the mass of cholesterol in the LDL fraction in plasma. By contrast, the value for apolipoprotein B is a measurement of the total number of atherogenic particles. Results of many studies show that apolipoprotein B is a better marker of risk of vascular disease and a better guide to the adequacy of statin treatment than any cholesterol index. Moreover, the ratio of apolipoprotein B/apolipoprotein A-1 seems superior to the ratio of total cholesterol/HDL cholesterol as an overall index of the risk of vascular disease. We review this evidence and include observations that were not previously published. The pathophysiological bases for the superiority of apolipoprotein B to cholesterol as a predictor of risk are reported elsewhere. 1

Apo B versus cholesterol in estimating cardiovascular risk and in guiding therapy: report of the thirty-person/ten-country panel.

There is abundant evidence that the risk of atherosclerotic vascular disease is directly related to plasma cholesterol levels. Accordingly, all of the national and transnational screening and therapeutic guidelines are based on total or LDL cholesterol. This presumes that cholesterol is the most important lipoprotein‐related proatherogenic risk variable. On the contrary, risk appears to be more directly related to the number of circulating atherogenic particles that contact and enter the arterial wall than to the measured concentration of cholesterol in these lipoprotein fractions. Each of the atherogenic lipoprotein particles contains a single molecule of apolipoprotein (apo) B and therefore the concentration of apo B provides a direct measure of the number of circulating atherogenic lipoproteins. Evidence from fundamental, epidemiological and clinical trial studies indicates that apo B is superior to any of the cholesterol indices to recognize those at increased risk of vascular disease and to judge the adequacy of lipid‐lowering therapy. On the basis of this evidence, we believe that apo B should be included in all guidelines as an indicator of cardiovascular risk. In addition, the present target adopted by the Canadian guideline groups of an apo B <90 mg dL−1 in high‐risk patients should be reassessed in the light of the new clinical trial results and a new ultra‐low target of <80 mg dL−1 be considered. The evidence also indicates that the apo B/apo A‐I ratio is superior to any of the conventional cholesterol ratios in patients without symptomatic vascular disease or diabetes to evaluate the lipoprotein‐related risk of vascular disease.

Hypertriglyceridemic hyperapoB: The unappreciated atherogenic dyslipoproteinemia in type 2 diabetes mellitus

Worldwide, more than 100 million people have type 2 diabetes mellitus, and that number will more than double in the next 10 years (1). Of these persons, more than three of fourthat is, more than 150 million peopleare expected to die of cardiovascular disease over the next decade (2). A history of diabetes is equivalent in risk for death to a history of myocardial infarction, and the combination compounds the risk (3). For some time, the hope has been that better control of glucose would substantially reduce the risk for vascular disease. To date, however, that has not been the case. The United Kingdom Prospective Diabetes Study found that better control reduced the frequency of microvascular disease, but the trend toward a reduced frequency of macrovascular disease was not statistically significant (4). In addition, the frequency of macrovascular disease in patients with type 2 diabetes varies geographically (5), suggesting that factors other than diabetes play an important role in the pathogenesis of the vascular disease. One such factor may be the dyslipoproteinemias that are common in diabetic patients. This review focuses on hypertriglyceridemic hyperapoB: the combination of hypertriglyceridemia; increased numbers of small, dense low-density lipoprotein (LDL) particles; and, often, low levels of high-density lipoprotein (HDL) cholesterol. This atherogenic lipoprotein profile is not restricted to persons with type 2 diabetes mellitus (6, 7); it is also common in persons with insulin resistance (8-11), those who will develop diabetes (12-15), and those with coronary disease (16-18). Accordingly, we believe that physicians should understand its pathophysiology in order to better select and monitor therapy. Lipoprotein Particles and Lipoprotein Lipids Clinical practice has been based on plasma concentrations of the major lipoprotein lipids triglycerides and cholesterol. Both substances are insoluble in water and therefore must circulate in plasma within lipoprotein particles. Because very-low-density lipoproteins (VLDLs) are much larger than LDL particles, the distinction between the concentration of lipids in plasma and the concentration of lipoprotein particles in plasma is critical. Figure 1 illustrates this principle in a patient with a plasma triglyceride level of 3 mmol/L (264 mg/dL) and an LDL cholesterol level of 3 mmol/L (116 mg/dL). The cholesterol is mainly present within LDL particles, and triglyceride is mainly found within VLDL particles. In this example, the plasma concentrations of triglyceride and LDL cholesterol are the same as measured in mmol/L, but the triglyceride concentration is twice as great when measured in mg/dL. Nevertheless, because LDL particles are much smaller than VLDL particles, there are always many more LDL particles than VLDL particles per volume of plasma. Figure 1. Differences between lipoprotein lipids and lipoprotein particles in a patient with a plasma triglyceride level of 3 mmol/L (264 mg/dL) and a low-density lipoprotein ( LDL ) cholesterol level of 3 mmol/L (116 mg/dL). The hepatic apoB lipoproteins are shown in Figure 2. They include VLDL particles; intermediate-density lipoprotein particles, which are produced by the partial hydrolysis of triglycerides within VLDL and are therefore smaller because they contain fewer triglycerides; and LDL particles, which are the end product of VLDL metabolism. Very-low-density lipoprotein, intermediate-density lipoprotein, and LDL are spherical particles covered by a phospholipid monolayer, within which are intercalated molecules of free cholesterol and a single molecule of a very large protein, apoB100 (19) (Figure 2). The molecule of apoB100 provides structural integrity for the particle and remains part of it for the particles entire lifetime. ApoB100 binds to the LDL receptor and is a crucial link in the normal pathway by which LDL is removed from plasma (20). Numerous other proteins are also present in the monolayer of a VLDL particle but are gradually shed as VLDL is converted to LDL. The one molecule of the apoB100 is the only protein in the LDL external monolayer. Triglycerides and cholesterol ester are the two lipids within the core of the particle, but their absolute and relative amounts differ in the various apoB lipoproteins. In VLDL, most of the core lipids are triglycerides; intermediate-density lipoproteins are almost half triglycerides and half cholesterol esters; and LDL is mainly composed of cholesterol ester. Figure 2. The relative number of very-low-density lipoprotein (VLDL) ( left ), intermediate-density lipoprotein ( middle ), and low-density lipoprotein (LDL) ( right ) particles. Because each hepatic apoB lipoprotein secreted by the liver contains one molecule of apoB100, the concentration of apoB in plasma measures the total number of VLDL, intermediate-density lipoprotein, and LDL lipoprotein particles in plasma (19). Lipoprotein(a) also contains one molecule of apoB but characteristically does not contribute substantially to total apoB in hyperapoB (21). Most LDL particles are metabolic products of VLDL particles, but their half-lives differ greatly because LDL particles persist in the circulation for about nine times longer than do VLDL particles. This explains why there are nine times more LDL particles than VLDL particles, even in hypertriglyceridemic patients (22) (Figure 2). For clinical purposes, therefore, the number of LDL particles can be inferred from the plasma apoB concentration. Measurement of apoB is now standardized and automated (23-25), and apoB can be accurately measured in clinical laboratories. Reference values have been determined (26-28) and fasting samples are not required (29), features that are especially important in diabetic patients. Small, Dense LDL Particles Not only does the composition of the various apoB lipoproteins differ, but the composition of particles within a particular class can differ importantly. In the case of LDL particles, some are larger and more buoyant (LDL A), whereas others are smaller and denser (LDL B) (30) (Figure 2). The LDL A particles contain more cholesterol ester per particle than do the LDL B particles. Most LDL B particles are formed from LDL A particles (31); Figure 3 shows the mechanisms responsible for this transformation. Figure 3. Formation of small, dense low-density lipoprotein ( LDL ) particles. CETP LPL HL Originally, it was thought that the core lipids cholesterol ester and triglyceride were fixed components of the particles and could not be exchanged among them. However, Morton and Zilversmits (32) description of cholesterol ester transfer protein changed this viewpoint. If a triglyceride molecule is exchanged for another triglyceride molecule and a cholesterol ester is exchanged for another cholesterol ester, the core lipid composition will remain the same. In contrast, if a triglyceride from VLDL is exchanged for a cholesterol ester in LDL, the core lipid composition of both lipoproteins will change: The VLDL becomes enriched in cholesterol ester, and LDL becomes enriched in triglyceride (Figure 3). This first step does not change their size or density. However, if the triglyceride in LDL is hydrolyzed by lipoprotein lipase or hepatic lipase, a smaller, denser LDL particle will be produced. The rate at which this remodeling occurs depends on the triglyceride content of the donor particle (33) and the number of donor and recipient particles. Therefore, increased VLDL secretion results in increased generation of small, dense LDL particles (34)that is, it causes hypertriglyceridemic hyperapoB (Figure 4). Increased plasma fatty acid levels also increase LDL remodeling (35). On the other hand, abnormalities in glucose metabolism alone do not seem to influence the process, although the evidence is mixed (36, 37). The size of LDL particles cannot be measured directly in routine clinical laboratories, but the relationship between plasma triglyceride and small, dense LDL is predictable. Thus, when triglyceride concentrations are less than 1.5 mmol/L (132 mg/dL), small, dense LDL particles are unlikely to be present, but at triglyceride concentrations of 1.5 mmol/L or greater, and particularly greater than 2.0 mmol/L (176 mg/dL), the opposite is the case (17, 38, 39). Figure 4. ApoB lipoprotein particles in healthy persons ( left ) and those with hypertriglyceridemic hyperapoB ( right ). A low HDL cholesterol level is very common in patients with coronary disease (40). It is often caused by the core lipid exchanges described above, but in this instance, they also lead to accelerated clearance of HDL particles. These interactions explain why hypertriglyceridemia and low HDL cholesterol levels so frequently coexist. Atherogenic Risks of Hypertriglyceridemic HyperapoB Hypertriglyceridemia and low HDL cholesterol levels are much more common in patients with coronary disease than are elevations in total and LDL cholesterol levels (41); thus, from an epidemiologic perspective, both are important risk factors for premature vascular disease. The HDL cholesterol level appears to be the more important factor; both univariate and multivariate analyses usually show it to be a significant risk factor, whereas hypertriglyceridemia is often not significant on multivariate analyses. However, the importance of this should not be overstated, particularly given the role of triglyceride in lipoprotein remodeling and, therefore, in producing low HDL cholesterol levels (42, 43). A low HDL cholesterol level was originally thought to result from impaired reverse transport of cholesterol from the periphery to the liver (44). This is not invariably the case, however; for example, genetic mutations that result in a low HDL cholesterol level are not always associated with an increased risk for vascular disease (45). High-density lipoprotein cholesterol may have other roles, including inhibition of LDL oxidation and expression of endothelial adhesion molecules (46

A Meta-Analysis of Low-Density Lipoprotein Cholesterol, Non-High-Density Lipoprotein Cholesterol, and Apolipoprotein B as Markers of Cardiovascular Risk

Background— Whether apolipoprotein B (apoB) or non-high-density lipoprotein cholesterol (HDL-C) adds to the predictive power of low-density lipoprotein cholesterol (LDL-C) for cardiovascular risk remains controversial. Methods and Results— This meta-analysis is based on all the published epidemiological studies that contained estimates of the relative risks of non-HDL-C and apoB of fatal or nonfatal ischemic cardiovascular events. Twelve independent reports, including 233 455 subjects and 22 950 events, were analyzed. All published risk estimates were converted to standardized relative risk ratios (RRRs) and analyzed by quantitative meta-analysis using a random-effects model. Whether analyzed individually or in head-to-head comparisons, apoB was the most potent marker of cardiovascular risk (RRR, 1.43; 95% CI, 1.35 to 1.51), LDL-C was the least (RRR, 1.25; 95% CI, 1.18 to 1.33), and non-HDL-C was intermediate (RRR, 1.34; 95% CI, 1.24 to 1.44). The overall comparisons of the within-study differences showed that apoB RRR was 5.7%>non-HDL-C (P<0.001) and 12.0%>LDL-C (P<0.0001) and that non-HDL-C RRR was 5.0%>LDL-C (P=0.017). Only HDL-C accounted for any substantial portion of the variance of the results among the studies. We calculated the number of clinical events prevented by a high-risk treatment regimen of all those >70th percentile of the US adult population using each of the 3 markers. Over a 10-year period, a non-HDL-C strategy would prevent 300 000 more events than an LDL-C strategy, whereas an apoB strategy would prevent 500 000 more events than a non-HDL-C strategy. Conclusions— These results further validate the value of apoB in clinical care.

Association of hyperapobetalipoproteinemia with endogenous hypertriglyceridemia and atherosclerosis

Researchers disagree on whether plasma triglyceride levels are an independent risk factor for atherosclerotic coronary artery disease. We hypothesized that patients with endogenous hypertriglyceridemia would differ: Some would have normal values of plasma low-density lipoprotein (LDL) B protein; others, despite their normal level of LDL cholesterol, would have increased levels of LDL B protein. We believe the latter patients--those with hyperapobetalipoproteinemia--would be the ones at risk for atherosclerosis. We studied two populations. Group 1, consisting of 162 patients with type IV lipoprotein patterns, was divided into two groups. One subgroup (A), which included 38 patients with elevated plasma LDL B atherosclerotic disease than the other subgroup (B) of 36 patients with normal levels of plasma LDL B protein (10 patients versus two, p less than 0.02). Group 2 consisted of 100 patients who had had myocardial infarction. Eighty-one percent of the 47 hypertriglyceridemic and 70% of the 53 normotriglyceridemic patients had elevated plasma LDL B protein levels (129 mg/dL or greater)--a proportion significantly higher than that in Group 1 (p less than 0.001). Thus, an elevated plasma level of LDL B protein not only identifies subgroups of patients with type IV lipoprotein patterns, but also may be an important marker for atherosclerotic disease.

Metabolic basis of hyperapobetalipoproteinemia. Turnover of apolipoprotein B in low density lipoprotein and its precursors and subfractions compared with normal and familial hypercholesterolemia.

The turnover of apolipoprotein B (apo B) in very low density, intermediate density, and low density lipoproteins (VLDL, IDL, and LDL) and in the light and heavy fractions of LDL was determined in seven patients with hyperapobetalipoproteinemia (hyperapo B), six normolipidemic subjects, and five patients with heterozygous familial hypercholesterolemia (FH). After receiving an injection of 125I-VLDL, hyperapo B patients were found to have a higher rate of synthesis of VLDL-apo B than controls (40.1 vs. 21.5 mg/kg per d, P less than 0.05) but a reduced fractional catabolic rate (FCR) (0.230 vs. 0.366/h, P less than 0.01). After receiving an injection of 131I-LDL, hyperapo B patients had higher rates of LDL-apo B synthesis than controls (23.1 vs. 13.0 mg/kg per d, P less than 0.001), as did FH patients (22.7 mg/kg per d). The FCR of LDL was similar in hyperapo B patients and controls (0.386 vs. 0.366/d) but was markedly decreased in FH patients (0.192/d). Most subjects exhibited precursor-product relationships between VLDL and IDL, and all did between IDL and light LDL; an analogous relationship between light and heavy LDL was evident in most hyperapo B patients and controls but not in FH patients. Simultaneous injection of differentially labeled LDL fractions and deconvolution analysis showed increased light LDL synthesis with normal conversion into heavy LDL in hyperapo B, whereas in FH conversion of light LDL was reduced and there was independent synthesis of heavy LDL. These data show that the increased concentration of LDL-apo B in hyperapo B is solely due to increased LDL synthesis, which is secondary to increased VLDL synthesis; in contrast, in FH there is both an increase in synthesis of LDL (which is partly VLDL-independent) and reduced catabolism.

The apoB/apoA-I ratio is better than the cholesterol ratios to estimate the balance between plasma proatherogenic and antiatherogenic lipoproteins and to predict coronary risk

Abstract Background: The apolipoprotein B (apoB)/apoA-I ratio represents the balance of proatherogenic and antiatherogenic lipoproteins. The purpose of this study was to determine whether the apoB/apoA-I ratio was superior to any of the cholesterol ratios – total cholesterol/high-density lipoprotein cholesterol (TC/HDL-C), low-density lipoprotein cholesterol (LDL-C)/HDL-C and non-HDL-C/HDL-C – in predicting the risk of coronary disease. Moreover, we examined whether any lipids, lipoproteins or cholesterol ratios add significant predictive information beyond that provided by the apoB/apoA-I ratio. Methods: Plasma lipids, lipoproteins, apoB, and apoA-I were measured in 69,030 men and 57,168 women above 40years of age. After a mean follow-up of 98months, 1183 men and 560 women had died from a myocardial infarction in this prospective apolipoprotein-related mortality risk (AMORIS) study. Results: High apoB and a high apoB/apoA-I ratio were strongly related to increased coronary risk, while high apoA-I was inversely related to risk. The apoB/apoA-I ratio was superior to any of the cholesterol ratios in predicting risk. This advantage was most pronounced in subjects with LDL-C levels <3.6mmol/l. Addition of lipids, lipoproteins or any cholesterol ratio to apoB/apoA-I in risk models did not further improve the strong predictive value of apoB/apoA-I. Conclusions: These results indicate that the apoB/apoA-I ratio is at present the best single lipoprotein-related variable to quantitate coronary risk. Given the additional advantages apolipoproteins possess – fasting samples are not required, apoB/apoA-I is a better index of the adequacy of statin therapy than LDL-C, and the measurement of apoB and apoA-I are standardized, whereas LDL-C and HDL-C are not – there would appear to be considerable advantage to integrating apolipoproteins into clinical practice.