By Louise Lazear
Markers for cardiac disease play a role in both risk assessment and diagnosis, assisting at every stage of intervention from primary to acute care. Advances in understanding mechanisms of atherosclerotic lesion formation and rupture, as well as identification of lipid subclasses and markers of inflammation, have led to a burgeoning arsenal of new markers with the potential to identify risk in patients at even earlier stages of disease development.
Risk factors for coronary heart disease (CHD) have been well established, and most of them can be controlled through life-habit decisions and drug therapies that reduce cholesterol, lower blood pressure, and deter prothrombotic processes. In an effort to impact the high rates of illness and death from CHD, in 1985 the National Heart, Lung, and Blood Institute of the NIH launched the National Cholesterol Education Program (NCEP) designed to increase public awareness of the risks of high cholesterol. Through a partnership of major medical professional organizations, NCEP formed the Adult Treatment Panel (ATP), a team of experts that determine and recommend guidelines for the detection, evaluation, and treatment of high cholesterol. According to NCEP, their efforts have made a significant impact: tests for cholesterol have risen, and blood cholesterol levels and CHD mortality continue to decline.
ATP III, the most recent guideline issued in spring 2001, recommends fasting lipid profiles (total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride (TG)) every five years for adults 20 years and older, as well as a ten-year (short-term) risk assessment to define therapeutic categories. Based upon this information, patients are treated with lifestyle changes, and/or drug therapy, including statins, bile acid sequestrants, and nicotinic acid. In addition, treatment for high triglycerides and identification and treatment of metabolic syndromes is recommended as well. ATP III continues to target LDL reduction as the primary therapeutic goal, reducing the LDL treatment threshold from 160 mg/dL to 130 mg/dL for some higher risk primary prevention patients, and to less than 100 mg/dl in those with known coronary artery disease.
Despite the significant impact of NCEP, reliance upon the use of traditional lipid panels as serum indicators for CHD risk has a downside: about 50 percent of people who come to an emergency department for a cardiac event have normal cholesterol levels. While lipid reduction therapy based upon current risk assessment techniques has the potential to significantly decrease risk for CHD, ATP III clearly recognized that other factors, including measurement of lipoprotein (a) (Lp(a)), very low density lipoprotein cholesterol (VLDL-C), and certain apolipoproteins have been identified as potential risk markers. “The panel thought of it in two general ways: when would someone want to order these tests, and what advice would one give to a clinician when faced with the results,” said Richard Pasternak, M.D., director of preventive cardiology at Massachusetts General Hospital in Boston, and member of ATP III. Generally, ATP III recommends that these novel markers be used to fine-tune risk assessment for those patients that fall into a “gray zone,” for example, those with a global ten year risk score at the low end of the 10-20 percent range, but with a very positive family history of disease. According to Pasternak, who also acts as a spokesperson for the AHA, these factors may then be used to help guide therapeutic decisions.
Several lipid subclasses and components have been identified as prognostic indicators of disease. Lp(a) was one of the first subclasses to be identified and approved as a predictor of CHD in patients with a familial history of disease. Lp(a) differs from LDL in that it contains an additional block of a carbohydrate-rich protein, apolipoprotein (a), which has distinct physiochemical properties allowing for differentiation from LDL-C and other lipoprotein particles. Elevated Lp(a) has also been linked with diabetes and renal disease. Persons with elevated Lp(a) may be targeted for both drug and diet therapy, even though LDL may be within normal limits.
Other lipids called apolipoproteins, which are molecules that transport both cholesterol and triglycerides in the bloodstream, have also been found to correlate with high risk, and recent studies suggest that apolipoprotein B (apoB) may actually be better than LDL as a predictor of disease risk in women. “One could imagine that apoB measurement, as it is starting to in Canada, could actually replace the lipid profile we are now measuring… ApoB is emerging (as a risk marker) and may well be in the next five years or so, a measure that many more people turn to,” said Pasternak. Recent research from Sweden demonstrated that in a prospective study of 175,000 people over five years, the ratio of apoB to apolipoprotein A-I, which is the principle lipoprotein on HDL, was directly related to the risk of a fatal heart attack. Apolipoproteins A-II, C-II, C-III, and E are also under evaluation as potentially independent markers of risk for CHD. ApoE is part of the panel of DNA-based cardiovascular risk factors manufactured by Third Wave Technologies. Certain genetic markers may hold an advantage in cardiovascular risk assessment, offering a “yes” or “no” analysis of gene mutation, rather than a measured snapshot in time during the course of disease progression.
Remnant-like lipoproteins (RLPs), which are lypolytic byproducts of triglyceride-rich lipoproteins, are also under evaluation as independent cardiovascular disease risk factors, as they are thought to be particularly atherogenic. Recent studies have shown that RPL-cholesterol (RLP-C) can provide significantly more information than triglycerides in evaluation for CHD. “It is thought that with RLP measurement alone, we may be able to identify at least 25 percent of the people we’ve been missing with traditional lipid panels,” according to Michael Sanfilippo, technical product manager at Polymedco, Inc., which distributes the test.
Recent research also suggests that LDL-C subtyping may be useful, where VLDL-C is separated from other non-HDL-C. “LDL-C subtyping is thought by some to be of value in identifying people who are at higher risk, and also to help target therapies, since nicotinic acid possibly in combination with statin, may be a more effective agent in people with small dense LDL,” said Pasternak. On another front, researchers debate the use of total non-HLDL-C measurement as a replacement for LDL-C. Since non-HDL-C theoretically encompasses all atherogenic lipoproteins (LDL cholesterol, triglyceride-rich RPLs, and VLDL cholesterol), some think it may be a better predictor of risk. However, since the atherogenicity of triglycerides is controversial, and because all recommendations are currently based on LDL-C, non-HDL-C as a predictive marker remains under investigation. Ultimately, it is likely that development of assay techniques to better isolate lipid components will fuel additional interest in their roles as potential markers for disease.
Homocysteine, high-sensative C-reactive protein (CRP), autoimmune response, and infection have also been investigated as risk factors for CHD. According to the AHA, two European studies have confirmed a relationship of high homocysteine levels to increased risk of CHD. Homocysteine may also affect the development of atherosclerosis by causing damage to arteries and promoting clot formation. While not identified as a major risk factor, the AHA considers homocysteine screening as a tool, albeit expensive, for use in patients with familial history and no other identifiable risks.
CRP at high levels is an indicator of inflammation as well as myocardial infarction. Prospective studies of a physician population show that apparently healthy men with hs-CRP levels in the highest quartile are at three times greater risk of myocardial infarction than those with the lowest hs-CRP levels, while women with LDL-C below 130mg/dL but high hs-CRP are at three times the risk of future coronary events. In another recent study among post-menopausal women, those with the highest CRP levels were up to five times more likely to be at risk for CHD, independent of cholesterol levels.
While hs-CRP is used clinically as marker of risk, other proteins associated with cardiac processes may hold even greater promise for the future. “CRP is just the tip of the iceberg,” said Richard A. Grimm, DO, cardiologist and director of the cardiovascular imaging fellowship at the Cleveland Clinic Foundation. “There are various other proteins on the horizon that are being investigated as more specific markers of atherosclerotic processes. For example, myeloperoxidase and metalloproteinase enzymes, which are believed to be involved in plaque rupture, would be a much more sensitive measurement of an impending heart attack or stroke than CRP.”
Immune processes are also gaining attention as potential risk factors for CHD. Atherosclerosis is thought to begin with damage to the endothelial component of blood vessels by lipid deposits, inciting an immune response. Some hypothesize that these immune responses may also be triggered by previous exposure to infectious agents.
The ability to diagnose and predict cardiac disease changes daily with technological advances across the healthcare technology spectrum. Researchers using electron-beam (ultra-fast) CT have developed a method to assess for and score the level of calcification in coronary arteries. Magnetic resonance angiography and spectroscopy may eventually be able to visualize as well as analyze plaque for chemical composition, a possible predictor for plaque rupture. And further advances are also being made in echocardiography and ultrasound imaging.
These advances are fast and furious as the medical community searches to find the various “holy grail” predictors of cardiac disease. As our aging population increases, screening tools will become more important than ever in identifying those at risk and initiating therapies to moderate, if not circumvent, disease development. Cost issues and reimbursement, of course, will be key factors in what eventually will find its way into the clinical mainstream. Yet, one must wonder if more markers, at least for risk, will ultimately be of value. “In reality, many feel that we don’t need additional markers for risk,” said Pasternak. “Several large epidemiological studies demonstrate you can predict, or basically eliminate, coronary disease in as high as 93 percent of the population by targeting the risk factors that we already know about. Yet 21 percent of Americans still smoke, and only a quarter of those with identified hypertension and high cholesterol are treated to goal. So that leads many of us to think we need to put our efforts into doing a better job with the things we already know about.” Have a heart-healthy day.
Louise Lazear is a freelance writer in Charlotte, N.C.