Cardiovascular risk beyond LDL-C levels

Other lipids are performers in cholesterol story

David T. Nash, MD

VOL 116 / NO 3 / SEPTEMBER 2004 / POSTGRADUATE MEDICINE

CME learning objectives

• To review the role of triglyceride-rich lipoproteins in coronary artery disease
• To understand the significance of apolipoprotein A-1 Milano
• To have a practical therapeutic approach to raising high-density lipoprotein cholesterol levels

The author discloses no financial interests in this article and no unlabeled uses of any product mentioned.

Preview: High levels of low-density lipoprotein cholesterol (LDL-C) are an obvious culprit in coronary artery disease (CAD). However, the search for lipid factors that influence cardiovascular health does not end there. In this article, Dr Nash presents the various lipid factors involved, for better or worse, in CAD. He emphasizes that although studies have expanded the understanding of this disease, the knowledge needs to be put to use more consistently in clinical practice in order to provide optimal patient care.
Nash DT. Cardiovascular risk beyond LDL-C levels: other lipids are performers in cholesterol story. Postgrad Med 2004;116(3):11-5

The American Heart Association and the National Cholesterol Education Program have succeeded in informing the public at large and the medical community in particular about the need to increase their efforts to predict and prevent CAD, the most common cause of disability and death in Western societies. The good news is that there is clear evidence of a reduction in mortality rate from CAD in many nations, including the United States.

There is also bad news, however. In the United States and in countries with rapidly rising standards of living, income, and access to a large variety of foods and an abundance of calories, the population is growing older and fatter in a rapidly increasing fashion. There is another type of bad news: so much of the therapeutic approach to primary and secondary prevention of CAD is directed at reducing the level of LDL-C that other approaches may be underemphasized or even neglected.

In addition, physicians all too often think of a pill as the means to reduce LDL-C values. Few physicians or patients spend adequate time or energy on the hygienic approaches known to have beneficial impact on vascular diseases--especially an appropriate diet, exercise, and complete discontinuation of cigarette smoking.

Investigators in major clinical double-blind, placebo-controlled, randomized trials have examined the effects of LDL-C reduction on a variety of clinical end points, including death, acute myocardial infarction, acute cardiovascular events, and stroke. However, the effects of therapy directed at high levels of triglycerides or low levels of high-density lipoprotein cholesterol (HDL-C) have been explored primarily in ancillary studies or retrospectively. This is the natural result of a lack of specific drugs that only reduce triglyceride concentrations or only raise HDL-C levels to the exclusion of all else. Additionally, even in the successful trials, there was a 15% to 30% reduction of hard cardiac events, which means that the majority of patients still experienced these events, despite use of the therapy being investigated.

Therefore, it is appropriate to examine and consider these two less commonly discussed lipid risk factors--low levels of HDL-C and elevated levels of triglycerides. Before turning to the new roles played by these often neglected lipid factors, this article briefly reviews what is known about them.

HDL-C and triglycerides

Patients with CAD often present with dyslipidemia characterized by a combination of abnormalities in plasma levels of triglycerides and HDL-C with or without elevated levels of LDL-C. Important elements in the risk of premature CAD are qualitative and quantitative abnormalities in circulating triglyceride-rich lipoproteins. Even after adjustments for other factors, it has been shown that triglyceride-rich lipoproteins are independent risk factors for ischemic heart disease and are capable of penetrating the arterial wall and initiating or aggravating atherogenesis.

Lipoproteins are macromolecular complexes composed of thousands of core lipid molecules (triglycerides and cholesterol esters) that have a surface covering of phospholipids and one or more apolipoproteins (apo). Plasma levels of triglyceride-rich lipoproteins are determined by secretion rates in the intestines and liver and by catabolism. Apo C-III is the most abundant apolipoprotein in these lipoproteins (1), which have been isolated from within human atherosclerotic plaques (2).

Patients with hypertriglycer-idemia may have an increased rate of secretion of very low-density lipoprotein cholesterol (VLDL-C). The most common physiologic basis for this is insulin resistance, which is associated with increased free fatty acid flux from the periphery and insulin-stimulated lipogenesis, which drives VLDL-C production (3).

The atherogenic potential of triglyceride-rich lipoproteins derives some effect from association with increased levels of VLDL-C, low levels of HDL-C, and increased numbers of small, dense LDL-C particles (4). The Cholesterol Lowering Atherosclerosis Study showed that increased concentrations of apo C-III in HDL-C, a surrogate for the efficient catabolism of triglyceride-rich lipoproteins, were linked to stabilization of atherosclerosis in subjects randomly assigned to niacin and colestipol combination therapy versus placebo (5). The Cholesterol and Recurrent Events (CARE) trial (6) reported on the importance of apo C-III-enriched apo B particles in VLDL-C and LDL-C in predicting cardiovascular events. Clearly, elevated triglyceride levels do count, and high concentrations of triglyceride-rich lipoproteins contribute to CAD through, at least in part, their relationship with insulin resistance.

Dangerous demographic trends

It requires little more objective research than an observant eye and a long walk (or jog) down a busy metropolitan street to identify some of the underlying public health threats to the US population. Simply put, we are getting older and fatter, which contributes to our growing abdominal girth, increasing blood pressure, rising triglyceride levels, and likelihood of insulin resistance.

After all, high triglyceride levels (>150 mg/dL [1.69 mmol/L]) and low HDL-C concentrations (<50 mg/dL [1.29 mmol/L] in women; <40 mg/dL [1.03 mmol/L] in men) are two of the five factors involved in the so-called metabolic syndrome. The other three factors are a blood pressure reading of 130/85 mm Hg or greater, a blood glucose level of 110 mg/dL (6.1 mmol/L) or greater, and a waist measurement that exceeds 88 cm (35 in) in women or 102 cm (40 in) in men. The diagnosis of metabolic syndrome requires a combination of any three of these five factors.

Various demographic investigations, including studies prompted by concerns about the long-term fiscal viability of Social Security and Medicare, provide evidence of the growing dangers related to these cardiovascular risk factors. Since it is known that increasing obesity adversely affects lipids, blood pressure, and the risk of insulin resistance, physicians are now able to approach this looming public health crisis with greater resolve to direct their efforts at increasing exercise and improving dietary approaches. The goal is progress toward achieving an ideal weight for the majority of the US population.

Adjustments for healthful living

Lifestyle change is the primary approach to improving the lipid abnormalities associated with obesity and metabolic syndrome. While there are great individual variations in the effect of exercise, between 30 and 60 minutes of moderate exercise (eg, walking) generally suffices to prevent further weight gain and to start the process of weight reduction. Appropriate exercise can be anything the patient wishes to do, including swimming, using a treadmill, and jogging. Repetitive, moderate exercise tends to raise HDL-C levels and reduce elevated triglyceride levels.

Other less technically sophisticated methods are available to patients and physicians attempting to raise HDL-C levels. For example, discontinuation of cigarette smoking has been known to increase the levels of this favorable lipid.

Dietary approaches to reduce elevated triglyceride concentrations include reduction in intake of simple sugars and avoidance of excess calories and excess alcohol consumption. Generally, the efficacy of this approach depends on a patient's compliance with such lifestyle changes.

Studies have showed that grapeseed oil supplements can raise serum HDL-C levels. Grape-seed oil can be taken as a dietary supplement or consumed as a salad dressing or cooking oil. For hundreds of years, it has been produced in Europe as an edible oil by-product of the region's extensive wine industry. Grape-seed oil is 75% linoleic acid, 15% oleic acid, and 1% linolenic acid. In one study (7), 56 subjects ingested up to 45 mL of grape-seed oil as part of their daily diet. In 3 weeks, their HDL-C values rose from 31.6 mg/dL (0.82 mmol/L) to 35.6 mg/dL (0.92 mmol/L), and their ratio of total cholesterol to HDL-C was reduced by 15.3%.

Although physicians are loath to encourage inappropriate intake of alcohol just before driving, it is true that small amounts (one alcoholic drink a day) can increase HDL-C levels in many patients who do not have alcoholism or hypertriglyceridemia.

HDL-C treatment trials and CAD

Hygienic measures alone may not suffice, however. What data are available from studies examining both the role of therapy that raises HDL-C levels and the effect of this treatment on CAD events? The beneficial effects of HDL-C were recognized more than 50 years ago and are thought to be related to reverse cholesterol transport from the tissues, through the bloodstream, and back to the liver.

The first large-scale prospective trial of the effect of raising HDL-C levels on CAD incidence was the Helsinki Heart Study (8), a primary prevention trial among men with elevated levels of non-HDL-C cholesterol. The study showed that an 11% increase in HDL-C concentration was independently associated with a 34% reduction in CAD events. It compared gemfibrozil treatment to placebo.

In the Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial (9), 2,531 men with documented CAD, a mean baseline LDL-C level of 140 mg/dL (3.62 mmol/L) or less, and an HDL-C level of 40 mg/dL (1.03 mmol/L) or less were randomly assigned to receive either gemfibrozil or placebo. LDL-C concentrations were unchanged, but in the treatment group, HDL-C values rose 6% and the relative risk of CAD end points was reduced 22%.

Use of the fibric acid derivatives and niacin has been a method available to patients and physicians attempting to raise HDL-C levels.

Discovery of new apolipoprotein

While results of these trials were encouraging, they were not enough to alter medical therapy at the time. However, this changed at the American Heart Association annual meeting in November 2003. The story really starts two decades earlier in a small Italian village, when an astute physician noted a curious development (10). On the basis of the physician's observation, about 40 adults were identified who had a naturally occurring variant of apo A-I, which came to be known as apo A-I Milano. These persons had very low levels of HDL-C. However, they had more longevity and much less atherosclerosis than their HDL-C levels would imply. After much research, it was learned that apo A-I Milano differs from apo A-I in that cysteine is substituted for arginine at position 173.

Animal studies of recombinant apo A-I Milano-phospholipid complex, formulated to mimic the properties of nascent HDL-C, demonstrated antiatherosclerotic effects with rapid mobilization of cholesterol and reduction in the lipid and macrophage content of plaque (11). Accordingly, a double-blind, placebo-controlled trial (12) was performed using two different doses of the test complex, named ETC-216. In total, 47 patients both met the study inclusion requirement of acute coronary syndrome in a middle-aged patient and completed the study.

The patients underwent an initial intravascular ultrasound examination, which was repeated within 2 weeks after the last of five weekly injections of ETC-216. Use of a motorized pullback device permitted evaluation of a series of slices, 0.5 mm apart, in the length of the affected coronary artery chosen to provide a 20% to 50% luminal narrowing throughout a 30-mm segment. With careful analysis, it was possible to compare the total atheroma volume between the intravascular ultrasound examinations performed before and after treatment.

The results were dramatic: a small but statistically significant reduction in plaque atheroma volume occurred in the treatment groups but was not seen in the placebo group. The observed reduction in total atheroma volume varied from 1% to 4% and was detected in both drug-treatment groups. No significant change was seen in the prespecified secondary efficacy end point as determined by coronary angiography. The mechanism of action of apo A-I Milano that results in lesion regression is not known, but it probably relates to reverse cholesterol transport from atherosclerotic plaque to the bloodstream and then to the liver for removal (12).

A number of caveats seem appropriate in discussion of this trial. In the treated groups, there occasionally were significant events, which may or may not have been drug-related, including gastrointestinal side effects, an episode of cholelithiasis, and one hypersensitivity reaction. One patient had a stroke, which was not otherwise described. The small sample size of this intriguing study limits the ability to judge the long-term safety and efficacy of this approach and, of course, means that no data on cardiovascular end points can be expected. No doubt a larger trial will be conducted and will test the additional efficacy of a preplanned, aggressive statin treatment component.

Impetus for action

We physicians now have a great deal of additional information about the role of elevated triglyceride levels and low HDL-C levels in initiation and progression of CAD. We also have a cornucopia of information on the effectiveness of lowering LDL-C levels to reduce the event rate in patients with known CAD. However, the truth is that we have yet to achieve good control of the risk factors discussed previously. In fact, in the apo A-I Milano trial, a highly sophisticated study performed by expert cardiologists at select medical centers, fewer than half of the participants--all of whom had known heart disease--received lipid-lowering therapy. Also, no information about how many patients were at their goal LDL-C level was included in the preliminary report (12).

In an earlier study (13), patients with dramatic hyperlipidemia who were admitted to a medical school teaching hospital received neither a diagnosis of their condition nor treatment of it. Another study (14) examined therapy patterns and the distribution of LDL-C levels in treatment-eligible adults in the United States. The study included more than 7,400 subjects and found that 82% of adults with known CAD were not at their LDL-C target goal of 100 mg/dL (2.59 mmol/L).

This failure to apply knowledge based on published studies should not come as a surprise. Treatment to reverse dietary-induced hyperlipidemia has been available for decades, but therapeutic nihilism persists. The reasons are multiple: physicians, patients, and the healthcare system have erected barriers to treatment. Many physicians lack basic knowledge about the powerful effects of primary and secondary preventive therapies. Patients are often reluctant to change their behavior or lifestyle while they remain asymptomatic yet at high risk for cardiovascular events. These patients often look on preventively oriented physicians as being excessively meddlesome or therapeutic zealots. Many HMO administrators have forgotten that this abbreviation stands for health maintenance organization and are loath to fund preventive efforts for a mobile population that often has their cardiac events on someone else's watch in another, distant HMO.

Nevertheless, with a wealth of accurate information and a host of effective tools at our disposal, we physicians can do better at addressing lipid management in clinical practice and can escalate our efforts to predict, prevent, and treat CAD.

References

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2. Rapp JH, Lespine A, Hamilton RL, et al. Triglyceride-rich lipoproteins isolated by selected-affinity anti-apolipoprotein B immunosorption from human atherosclerotic plaque. Arterioscler Thromb 1994;14(11):1767-74
3. Ginsberg HN. Insulin resistance and cardiovascular disease. J Clin Invest 2000;106(4):453-8
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7. Nash DT, Nash SD, Grant WD. Grapeseed oil, a natural agent which raises serum HDL-C levels. Presented at the American College of Cardiology 42nd Annual Scientific Session, Mar 15, 1993, Anaheim, Calif
8. Manninen V, Tenkanen L, Koskinen P, et al. Joint effects of serum triglyceride and LDL cholesterol and HDL cholesterol concentrations on coronary heart disease risk in the Helsinki Heart Study: implications for treatment. Circulation 1992;85(1):37-45
9. Rubins HB, Robins SJ, Collins D, et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. N Engl J Med 1999;341(6):410-8
10. Gualandri V, Franceschini G, Sitori SR, et al. AIMilano apoprotein identification of the complete kindred and evidence of a dominant genetic transmission. Am J Hum Genet 1985;37(6):1083-97
11. Shah PK, Yano J, Reyes O, et al. High-dose recombinant apolipoprotein A-I(Milano) mobilizes tissue cholesterol and rapidly reduces plaque lipid and macrophage content in apolipoprotein E-deficient mice: potential implications for acute plaque stabilization. Circulation 2001;103(25):3047-50
12. Nissen SE, Tsunoda T, Tuzcu EM, et al. Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial. JAMA 2003;290(17):2292-300
13. Nash DT. Hypercholesterolemia during hospitalization: the case for closer surveillance. Postgrad Med 1986;79(2):303-10
14. Hoerger TJ, Bala MV, Bray JW, et al. Treatment patterns and distribution of low-density lipoprotein cholesterol levels in treatment-eligible United States adults. Am J Cardiol 1998;82(1):61-5

Dr Nash is a fellow of the Council on Epidemiology, American Heart Association; clinical professor of medicine, State University of New York Upstate Medical University College of Medicine, Syracuse; and president, Syracuse Preventive Cardiology. Correspondence: David T. Nash, MD, Syracuse Preventive Cardiology, Presidential Plaza, Suite 204, 600 E Genesee St, Syracuse, NY 13202-3108.

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