(Study type: Blood collected in a gold-, red-, red/gray-, or green-top [Na or Li heparin] tube for cholesterol and fractions; blood collected in a lavender-top (EDTA) for ceramides; related body system: Circulatory system.) Plasma values (Na or Li heparin) may be 10% lower than serum values.

Cholesterol is a lipid needed to form cell membranes, bile salts, adrenal corticosteroid hormones, and other hormones such as estrogen and the androgens. Cholesterol is obtained from the diet and also synthesized in the body, mainly by the liver and intestinal mucosa. Very low cholesterol values, as are sometimes seen in critically ill patients, can be as life-threatening as very high levels. Maintaining cholesterol levels less than 200 mg/dL (SI: Less than 5.2 mmol/L) significantly reduces the risk of coronary heart disease. Beyond the total cholesterol and HDLC values, other important risk factors must be considered. Many myocardial infarctions (MIs) occur even in patients whose cholesterol levels are considered to be within acceptable limits or who are in a moderate-risk category. Evidence-based risk factors include age, gender, ethnicity, total cholesterol, HDLC, LDLC, blood pressure, blood-pressure treatment status, statin treatment outcomes, diabetes, and current use of tobacco products. The combination of risk factors and lipid values helps identify individuals at risk so that appropriate interventions can be taken. If the cholesterol level is greater than 200 mg/dL (SI: greater than 5.2 mmol/L), repeat testing after a 12- to 24-hr fast is recommended.

HDLC and LDLC are the major transport proteins for cholesterol in the body. It is believed that HDLC may have protective properties in that its role includes transporting cholesterol from the arteries to the liver. LDLC is the major transport protein for cholesterol to the arteries from the liver. LDLC can be calculated using total cholesterol, total triglycerides, and HDLC levels.

Studies have shown that CAD is inversely related to LDLC particle number and size. The nuclear magnetic resonance (NMR) lipid profile uses NMR imaging spectroscopy to determine HDL particle number and size (desirable is an HDL particle number greater than 30.5 micromol/L and greater than 8.9 nm in size), LDLC particle number and size (desirable is an LDL particle number less than 1,000 nmol/L and greater than 20.5 nm in size; an elevated LDL particle number plus small LDL particle size increases the risk of developing CAD), and measurement of the traditional lipid markers to provide information about a patient’s relative risk of developing CAD. The panel also includes information about lipoprotein markers also associated with insulin resistance and increased risk of developing diabetes (interpreted as an elevated small LDL particle number and small LDL particle size).

HDLC levels less than 40 mg/dL or less than 1 mmol/L in most people represent a coronary risk factor. There is an inverse relationship between HDLC and risk of CAD (i.e., lower HDLC levels represent a higher risk of CAD). Levels of LDLC in terms of risk for CAD are directly proportional to risk and vary by age group. Many laboratories now use a direct LDLC method to obtain results. The LDLC can also be estimated using the Friedewald formula: LDLC = (Total Cholesterol) - (HDLC) - (VLDLC)or LDLC = (Total Cholesterol) - (HDLC) - (Trig/5)

Very-low-density lipoprotein cholesterol (VLDLC) is estimated by dividing the triglycerides (conventional units) by 5. Triglycerides in SI units would be divided by 2.18 to estimate VLDLC. It is important to note that the formula is valid only if the triglycerides are less than 400 mg/dL or 4.52 mmol/L.

Lipoprotein electrophoresis measures lipoprotein fractions to determine abnormal distribution and concentration of lipoproteins in the serum, an important risk factor in the development of CAD. The lipoprotein fractions, in order of increasing density, are (1) chylomicrons, (2) VLDL, (3) low-density lipoprotein (LDL), and (4) high-density lipoprotein (HDL). Chylomicrons and VLDL contain the highest levels of triglycerides and lower amounts of cholesterol and protein. LDL and HDL contain the lowest amounts of triglycerides and relatively higher amounts of cholesterol and protein. Studies have shown that CAD is directly related to elevated LDLC and inversely related to LDL particle size. Elevated levels of sdLDL particles (non-A) carry a threefold risk for developing CAD over the presence of larger, more buoyant LDL particles (pattern A). The sdLDL particles are believed to penetrate the arterial wall more readily than the other LDL particle subtypes, boosting the development of atherosclerotic plaque.

Ceramides are a class of naturally occurring lipids. They are synthesized in tissue cells from saturated fats and sphingosine, are involved in cell cycle regulation, and share some of the same cellular functions as other lipids, such as maintenance of cell membrane integrity. Ceramides have long been associated with skin care products. The application of ceramide levels as a predictor of CAD remains under study; specifically ceramides Cer 16:0, Cer 18:0, and Cer 24:1. Ceramides are believed to be a strong, independent predictor of MI, stroke, and death. Ceramides are involved in the various processes that result in atherosclerosis, and ceramide levels increase as the degree of atherosclerotic development advances. Dyslipidemias and excessive caloric intake stimulate the transport of ceramides by LDLs into blood vessel tissue cells, which are not normally used for fat storage. The infiltration of LDL and accumulation of ceramides in the blood vessel wall causes an inflammatory response that signals monocytes to come into the endothelium and phagocytize the lipoproteins. The chain reaction intensifies with the release of cytokines and results in increased endothelial cell adhesion and platelet activation (in response to endothelial cell damage). Release of cytokines stimulates further ceramide synthesis. Ceramide levels can be decreased by the same treatments used to reduce other lipid levels to include diet, exercise, and statin therapy.

There are other nonlipid markers used to provide evidence of ASCVD. For example, elevated levels of C-reactive protein are associated with increased risk for ASCVD related to the effects of inflammation on the cardiovascular system. Complex macro-interrelationships of the various body systems are only beginning to be better understood. Environmental and lifestyle factors also significantly influence and interact at the genetic level to regulate bodily functions. The rapid expansion of molecular technologies has led to the development of DNA sequencing techniques now used to identify some of the genetic determinants of kidney and heart disease. Blood pressure is controlled by the renin-angiotensin-aldosterone system, which affects the kidneys, heart, lungs, blood vessels, and central nervous system. Sequence variations of the angiotensin-converting enzyme gene (AGT) and angiotensin II type 1 receptor (AGTR1) gene in the renin-angiotensin-aldosterone system are strongly associated with an increased risk for hypertension and cerebrovascular disease, chronic kidney disease, and stroke secondary to hypertension. Identification of these associations is the initial step. Hypertension affects millions of people in the United States and is called a “silent killer” because it does not present with noticeable symptoms, so people are often unaware of their condition. Treatment regimens based on test results are still in development due to the number of genetic variants that have been identified, the variety of genetic expressions within the same sequence variation, and inconsistent associations between different ethnic populations that have been studied.

Guidelines for the prevention and management of cardiovascular disease have been jointly developed, refined, and updated since the 1980s by the American College of Cardiology (ACC) and American Heart Association (AHA). The American Diabetes Association (ADA) Standards of Care include targets for blood pressure. The guidelines are based in large part on scientific data. Studies over time have also demonstrated the significant impact of socioeconomic inequities on risk of developing cardiovascular disease. The Centers for Medicare and Medicaid Services (CMS) developed a screening tool in 2017 to assess areas unrelated to health that affect health outcomes, which include access to housing, food, transportation, utilities, and interpersonal safety. The ACC/AHA guidelines for the prevention of cardiovascular disease and the American Diabetes Association (ADA) recommendations regarding diabetes self-management education and support suggest these topics be included in the patient-HCP conversation along with assessment of evidence-based risk factors in order to better and more realistically improve diabetes and cardiovascular disease health outcomes. Especially important are patient concerns that result in cost-related medication nonadherence to treatment.

The ACC/AHA has developed guidelines for reducing risk of ASCVD through management of cholesterol levels with statin therapy. Previous ACC/AHA evidence-based guidelines redefined the condition of concern as ASCVD, which involves atherosclerotic disease in any of the blood vessels in the body and expanded ASCVD to include CAD, which specifically involves vessels that supply the heart, cerebrovascular disease, which involves vessels that supply the brain (e.g., stroke), and peripheral arterial/venous disease (PAD/PVD), which involves vessels that supply the arms and legs. Some of the important highlights from previous and current guidelines include the following:

• Movement away from the use of LDL cholesterol targets as the main focus in determining treatment with statins. Recommendations that focus on selecting (1) the patients who fall into specific risk group categories by age and comorbidity who are most likely to benefit from statin therapy and (2) the level of statin intensity most likely to affect or reduce development of ASCVD.
• Development of a new 10-yr risk assessment tool based on findings from a large, diverse population to include socioeconomic as well as clinical risk factors. Evidence-based risk factors include age, gender, ethnicity, diet, weight, exercise and physical activity level, total cholesterol, HDLC, blood pressure, blood-pressure treatment status, diagnosis of diabetes, and current use of tobacco products.
• Recommendations for aspects of lifestyle that would encourage prevention of ASCVD include discussions about diet and regular participation in aerobic exercise to promote the benefits of maintaining a healthy weight.
• Recognition that additional biological markers, such as family history, high-sensitivity C-reactive protein, ankle-brachial index (ABI), and coronary artery calcium score, may be selectively used with the assessment tool to assist in predicting and evaluating risk.
• Recognition that other biomarkers, such as apolipoprotein B, estimated glomerular filtration rate (eGFR), creatinine, lipoprotein (a) or Lp(a), and urine albumin (formerly microalbumin), warrant further study and may be considered for inclusion in future guidelines.