Cardiac Risk Factors and Hyperlipidemia

Michael R. Kohn

Marc S. Jacobson

An important goal of adolescent and young adult (AYA) health care is early intervention to prevent diseases that occur during adulthood. Atherosclerosis, as conceptualized in the “injury hypothesis,” results from chronic inflammation and healing responses of the arterial wall to endothelial damage beginning in childhood, accelerating during adolescence and causing clinical disease in early- to mid-adulthood. Lesions progress to cause cardiovascular disease (CVD) through the interaction of lipoproteins, cholesterol, and a range of white blood cells, with cellular constituents of the arterial wall. Delaying or preventing this progression is critical to successful management. CVD can be prevented through primordial prevention strategies.¹ Screening and lifestyle modification (i.e., adhering to a heart-healthy diet, regular exercise habits, avoidance of tobacco products, and maintenance of a healthy weight) remain critical components of health promotion and CVD risk reduction.² These modifications alone are not sufficient for those AYAs who have genetic abnormalities of lipid metabolism, which significantly elevate risk and shorten their healthy lifespan. For this group of patients, early recognition and aggressive management are paramount.³ The cost effectiveness of CVD reduction by preventive strategies has been established for the statins, a group of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor medications.

Understanding the pivotal role of lipids in evaluating cardiovascular risk is essential. These concepts are reviewed in this chapter, which describes lipid physiology and classification of lipid disorders. Resources tabling epidemiological data for indices of screening and risk are referenced throughout the text. The latter sections of the chapter discuss screening and management of CVD risk and draw upon pediatric, adolescent, and adult guidelines for assessment and treatment. In 2011, the National Heart, Lung, and Blood Institute (NHLBI) released the Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents.⁴ Guidelines on the detection, evaluation, and treatment of high cholesterol in adults were released by the NHLBI as the Adult Treatment Panel (ATP) III guidelines in 2001.⁵,⁶ The ATP IV was convened to update the guidelines and was renamed the American College of Cardiology (ACC)/American Heart Association (AHA) Expert Panel. In late 2013, this panel released the 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults.⁷,⁸ Compared to the ATP III, the 2013 ACC/AHA Blood Cholesterol Guideline is more limited in scope, focusing upon evidence in randomized control trials (RCTs) and disease outcomes wherever possible. Because the transition from ATP III to the new guideline is ongoing (and because the newer guidelines reference some recommendations from the ATP III), the ATP III-recommended targets are also included in this chapter. The links for the guidelines relevant to AYAs are:

Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents—http://www.nhlbi.nih.gov/health-pro/guidelines/current/cardiovascular-health-pediatric-guidelines

Third Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel [ATP] III)—http://www.nhlbi.nih.gov

2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults

Practice Guideline—http://content.onlinejacc.org/article.aspx?articleID=1879710

Full Panel Report Supplement—http://circ.ahajournals.org/content/suppl/2013/11/07/01.cir.0000437738.63853.7a.DC1

LIPID PHYSIOLOGY

Cholesterol and triglycerides are the major blood lipids. Cholesterol is a key constituent of cell membranes and a precursor of bile acids and steroid hormones. Cholesterol circulates in the bloodstream in spherical particles called lipoproteins containing both lipids and proteins called apolipoproteins. These particles consist of a core of triglycerides, cholesterol, and cholesterol esters, in varying amounts, surrounded by an outer shell of cholesterol and phospholipids. The apolipoproteins are embedded in the outer lipid layers (Fig. 14.1).

Classification of lipoproteins: Five major classes of lipoproteins act as transport systems for cholesterol and triglycerides. They differ in physical and chemical characteristics and function, as well as in amounts of cholesterol, triglyceride, phospholipid, and protein. The lipoproteins can be separated by ultracentrifugation or electrophoresis, on the basis of differences in densities and surface properties. Ultracentrifugation yields chylomicrons, very-low-density lipoprotein (VLDL), low-density lipoproteins (LDLs), and high-density lipoproteins (HDLs).

Estimation of lipoproteins: Non-HDL Cholesterol (non-HDL-C) represents the cholesterol content of all plasma lipoproteins and may soon replace LDL-C in risk assessment, particularly when non fasting lipids are used. NonHDL-C
is calculated as follows: Total cholesterol minus HDL-C = nonHDL-C.

FIGURE 14.1 Characteristics of lipoproteins. Apoproteins and volume are detailed below each lipoprotein. Ang, angstroms; VLDL, very-low-density lipoprotein; LDL, low-density lipoprotein; HDL, high-density lipoprotein. (Adapted from Hardoff D, Jacobson MS. Hyperlipidemia. Adolesc Med State Arts Rev 1992;3:475.)

The calculation of the proportion of LDL is made with the following formula:

Total cholesterol = LDL + HDL + VLDL

HDL is measured directly, and VLDL is estimated by dividing the fasting triglyceride concentration by 5 (true, so long as the triglyceride concentration is <400 mg/dL). Therefore,

LDL = Total cholesterol – HDL – (triglycerides/5)

Each lipoprotein has a characteristic apolipoprotein profile. These apolipoproteins serve as cofactors for enzymes involved in lipoprotein metabolism, they help in the binding of lipoproteins to cellular receptors, and they facilitate lipid transfer between lipoproteins. Apolipoprotein B-100 (apoB-100) is an important component of VLDL and is the only apolipoprotein in LDL cholesterol (LDL-C). Uptake of LDL by cells is dependent on its binding to the LDL receptor, which is regulated by apoB-100. Abnormalities in both quality and quantity of these proteins, even in the absence of an elevated cholesterol concentration, may contribute to atherosclerosis.

Lipoprotein circulation and sources: (Fig. 14.2)
- Exogenous: Chylomicrons are formed after absorption of dietary fat. They are secreted into the lymph. Fatty acids are stored in adipose tissue, or are used in skeletal muscle and myocardium, where they release diet-derived triglycerides. This reaction is catalyzed by lipoprotein lipase. The chylomicron remnants are rapidly absorbed in the liver by specific receptors for these particles. In liver cells, the remnants are degraded to free cholesterol, which is excreted into bile.
- Endogenous: The endogenous transport system includes VLDL, intermediate-density lipoprotein (IDL), LDL, and HDL. Excess calories from carbohydrates and fatty acids are metabolized in the liver into triglycerides. The lipoproteins carrying these triglycerides are primarily VLDL, which moves to adipose tissue; the result is the formation of IDL and LDL. The IDL particles are rapidly removed from circulation by LDL receptors in the liver.
  - LDL transports cholesterol to peripheral tissues. In addition to the lipid component, LDL particles contain a single apoB-100 molecule, the protein that binds to LDL receptors. After binding to LDL cell-surface receptors, the LDL particles deliver cholesterol for synthesis of cell membranes in all cells; for steroid hormones in the adrenal glands, ovary, and testes, and for bile acids in the liver. The LDL-C found in macrophages and smooth muscle cells of atherosclerotic lesions enters by additional mechanisms. This LDL-C is modified by intravascular oxidation and is taken up in lesions by oxy-LDL receptors and scavenger receptors. This process may provide alternative pathways for therapeutic intervention.
  - HDL is secreted from the liver or intestine in a lipid-poor form or is made de novo in the plasma. As it matures, HDL accumulates cholesterol from tissues, including blood vessel walls, and therefore has a major role in removing excess cholesterol and delivering it to the liver by means of the triglyceride-rich lipoproteins and cholesterol ester transfer protein.

LIPID PATHOPHYSIOLOGY AND CVD

Epidemiological evidence:
- In populations throughout the world, there is a direct correlation between serum cholesterol levels and CVD rates. The prevalence of hyperlipidemia has been well documented.⁹ Traditional risk factor assessment has focused on parameters derived from the Bogalusa¹⁰,¹¹ and Framingham Heart Study¹² (age, hypertension, cholesterol, family history, and cigarette smoking). New emerging risk factors, both biological and genetic, are reshaping the understanding of heart disease and the approach to risk stratification. The Pathobiological Determinants of Atherosclerosis in Youth Study described the relationship between atherosclerosis and serum lipoprotein cholesterol concentrations and smoking in AYA males.¹³

Genetic evidence (characteristics of inherited hyperlipoproteinemias are listed in Table 14.1):

Familial hypercholesterolemia (FH): In its most common form, FH is an autosomal dominant condition resulting in defects in the LDL receptor and elevated levels of LDL-C. About 1 in 300 to 500 AYAs in the US is heterozygous for the abnormality; these individuals account for 15% of cases of premature CVD. Homozygous individuals (˜1 in 1,000,000) lack LDL cell-surface receptor activity, have very high cholesterol levels, and may develop severe atherosclerosis in the first two decades of life. Clinical manifestations such as xanthomas and other signs of cutaneous lipid deposition are generally seen in the fourth decade of life in heterozygotes and during adolescence in homozygotes (Fig. 14.3).¹⁴

Familial combined hyperlipidemia (FCHL): It is the autosomal dominant syndrome that affects approximately 1% to 2% of the population. Most, if not all, patients with this condition have elevated levels of LDL apoB. Abnormal metabolism of VLDL and partial lipoprotein lipase deficiency have also been described in association with this syndrome. Individuals with FCHL account for a significant proportion of cases of early-onset CVD.

FIGURE 14.2 Pathways of lipoprotein metabolism. LCAT, lecithin-cholesterol acyltransferase; LPL, lipoprotein lipase; HDL, high-density lipoprotein; LDL, low-density lipoprotein; IDL, intermediate-density lipoprotein; VLDL, very-low-density lipoprotein. (From Weis S, Lacko AG. Role of lipoproteins in hypercholesterolemia. Pract Cardiol 1988:12-18.)

Apolipoprotein E (apoE)¹⁵: Three common alleles of apoE, at a single-gene locus on chromosome 19, code for three isoforms of apoE: designated as apoE-II, apoE-III, and apoE-IV. Increased cardiovascular risk is associated with apoE-IV, in comparison with the more common apoE-III.

Novel biomarkers:
- High-sensitivity C-reactive protein (hs-CRP) assays: Inflammation is an important risk factor for atherogenesis. C-reactive protein (CRP), the most studied biomarker of inflammation in CVD, is secreted by foam cells in the arterial wall. CRP is implicated in the development of CVD through its actions: induction of a prothrombotic state, increasing leukocyte adhesion, and promotion of intimal damage. CRP has been shown to be a lipid-independent risk factor for CVD. CRP assays have traditionally been used to detect inflammation and/or infection. Hs-CRP assays detect low levels of CRP and may have utility in predicting a healthy person’s risk of CVD. While guidelines have been proposed for the use of hs-CRP in asymptomatic adults at intermediate risk of CVD, there are currently no clear guidelines for the use of hs-CRP assays to predict CVD risk among AYAs.
- Apolipoprotein-associated phospholipase A2 (Lp-PLA2)¹⁶: The enzyme Lp-PLA2 is a member of the phospholipase A family. It is actively expressed in unstable atherosclerotic plaques, suggesting its role in increasing plaque vulnerability. Lp-PLA2 is both less variable than CRP and a more specific marker of vascular inflammation.
- Myeloperoxidase (MPO) and oxidized LDL¹⁷: Products of the MPO pathway may be good markers of CVD, and possibly therapeutic targets as well.
Interventional trials: Interventional trials support the conclusion that lowering total and LDL-C concentrations reduces the incidence of CVD events. The degree of benefit is greatest in individuals who have other associated risk factors, such as cigarette smoking, diabetes, and hypertension.

Relationship of particular lipoproteins to cardiovascular risk:

LDL-C: Studies show a positive relationship between the level of cholesterol, and the frequency of CVD.

HDL-C: Population studies suggest an inverse relation between HDL-C and CVD. An HDL-C level of <30 mg/dL carries a significantly increased risk of CVD. A level >50 mg/dL is associated with low risk, and >75 mg/dL is associated with very low risk. The Framingham Heart Study demonstrated a 10% increase in CVD for each 4 mg/dL decrease
in HDL. In addition, low HDL-C levels have been correlated with an increased number of diseased coronary arteries. There also appears to be a higher rate of restenosis after angioplasty in individuals with low HDL-C levels. HDL has two components, HDL₂ and HDL₃. The former is considered a better indicator of negative CVD risk than total HDL. Exercise raises the level of cardioprotective HDL₂, whereas ethanol raises the level of HDL₃. Unfortunately, raising HDL-C is not currently a therapeutic option. Pharmaceutical trials have so far failed to show reduction in CVD and some have been discontinued because of higher CVD in drug-treated than placebo groups.

TABLE 14.1 Characteristics of Inherited Hyperlipoproteinemias

Hyperlipoproteinemia	Phenotype	Cholesterol	Triglyceride	Xanthomas	Frequency (%)	Risk of CVD
Familial lipoprotein lipase deficiency	I	Normal	↑	Eruptive	Very rare	0
Familial hypercholesterolemia	IIa	↑	↑	Tendon	0.1-0.5	4+
	IIb			Tuberous xanthelasma
Polygenic hypercholesterolemia	II	↑	Normal	Tuberous	5	2+
Familial dysbetalipoproteinemia	III	↑	↑	Palmar	Rare	4+
				Planar tuberous tendon
Familial combined hyperlipoproteinemia	IIa	↑	↑	Any type	1-2	3+
	IIb
	IV
	Rarely V
Familial hypertriglyceridemia	IV	Normal	↑	Eruptive	1	1+
	Rarely V
CVD, coronary artery disease; NL, normal. From Arky RA, Perlman AJ. Hyperlipoproteinemia. In: Rubenstein E, Federman DD, eds. Scientific American medicine. New York, NY: Scientific American, 1988, with permission.

FIGURE 14.3 Xanthoma. (Courtesy of Dr. Steven Gammer.)

Apolipoproteins: Apolipoproteins A-I (apoA-I), A-II (apoA-II), and apoB are used in predicting the risk of CVD. Elevated concentrations of apoA-I and apoA-II are associated with a lower risk, and an elevated apoB concentration is associated with a higher risk of CVD. Isoforms of apoE have also been implicated in cardiovascular risk, as noted previously. In addition, the measurement of the apoB-100 to apoA-I ratio may provide another assessment of cardiovascular risk.
Ratios: CVD risk rises sharply when the LDL:HDL ratio exceeds 3.0. Another ratio predictive of CVD risk is that of total cholesterol to HDL-C. A ratio of <4.5 denotes below-average risk, whereas the optimum ratio is 3.5:1. The AHA recommends that the absolute numbers for total blood cholesterol, LDL-C, HDL-C, and non-HDL-C be used. The AHA suggests that these numbers are more useful than ratios to the physician determining appropriate treatment for patients.

Other experimental work: Proprotein convertase subtilisin/kinexin type 9 (PCSK9)¹⁶: PCSK9 is a serine protease. It binds the low-density lipoprotein receptor (LDL-R) in circulation and promotes LDL-R degradation. A missense mutation in PCSK9 leads to higher circulating LDL. Several, new therapeutic options targeting PCSK9, including monoclonal antibody-based therapies, have entered trials with promising results in subjects with both familial and nonfamilial forms of hypercholesterolemia.

CLASSIFICATION OF HYPERLIPIDEMIAS

Patients with hyperlipidemia are classified based on lipid pathways, phenotype, pathophysiology, and genetics.¹⁴ The three pathways are the exogenous (intestinal), the endogenous (hepatic), and the reverse cholesterol pathway. Metabolic characteristics of the clinically important derangements in lipid metabolism are summarized in Table 14.2.

TABLE 14.2 Metabolic Classification of Dyslipoproteinemia in Children and Adolescents

1. Disorders of LDL metabolism/disorders with increased LDL

Decreased LDL removal

—Familial hypercholesterolemia

—Defective apoB-100
Increased LDL production

—Familial combined hypercholesterolemia

—Hyperapobetalipoproteinemia
Other

—Polygenic hypercholesterolemia

2. Disorders of triglyceride-rich lipoproteins

Decreased removal (type I dyslipoproteinemia)

—Lipoprotein lipase deficiency

—ApoC-II deficiency (cofactor for lipoprotein lipase)
Production of abnormal VLDL

—Familial hypertriglyceridemia (AD)
Decreased removal/increased production

—Type V dyslipoproteinemia (AD)

—Dysbetalipoproteinemia

3. Deficiency in HDL

Increased HDL removal
Decreased HDL production

LDL, low-density lipoprotein; VLDL, very-low-density lipoprotein; AD, autosomal dominant; HDL, high-density lipoprotein.

From Kwiterovich PO Jr. Diagnosis and management of familial dyslipoproteinemia in children and adolescents. Pediatr Clin North Am 1990;37:1489, with permission.

CARDIOVASCULAR RISK ASSESSMENT

Risk factors for CVD have genetic, physiologic, behavioral, and environmental components and may be determined by history, physical examination, laboratory, and other assessments (detailed in Table 14.3). The relationship between cardiovascular risk factors and CVD has been demonstrated in longitudinal studies.¹³,¹⁸ Risk factors can be identified prior to adulthood and track into adult life.¹⁹ Nonmodifiable risk factors include genetics, parent with elevated total cholesterol (>240 mg/dL), and gender. Modifiable major risk factors include hypertension, smoking, diet, weight, diabetes/insulin resistance (with metabolic syndrome), and dyslipidemia. Interventions exist for the management of this latter group of risk factors, once they are identified. Several medical conditions also confer increased risk for CVD.

Table 14.4 lists elements of the family history and risk factors.
Table 14.5 lists special risk conditions that confer high- and moderate risk for CVD in the Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents.
Table 14.6 lists major risk factors that modify LDL-C goals in the ATP III guidelines.

Screening recommendations for modifiable risk factors are detailed below. Historical factors and patient report alone will lead to identification of only a minority of those with hyperlipidemia; therefore, identification of AYAs with hyperlipidemia requires universal lipid assessment. Non-HDL cholesterol (non-HDL-C) is the best predictor of atherosclerosis, and is elevated in both FH and FCHL—see section Classification of Hyperlipidemia. It is calculated as:

Non-HDL-C = Total cholesterol – HDL-C

A practical advantage of non-HDL-C is that it can be measured in nonfasting patients.

TABLE 14.3 Screening Elements for Cardiovascular Risk Assessment

1. Clinical evaluation: history, including medical conditions leading to dyslipidemia and accelerated atherosclerosis; e.g., insulin resistance (obesity, metabolic syndrome, polycystic ovary syndrome (PCOS), diabetes), chronic inflammatory diseases, endocrine diseases (hypothyroidism, renal disease, organ transplantation) 2. Family history: cardiovascular events prior to 55 y of age, history of risk factors in parents 3. Physical examination: including anthropometric measurement, blood pressure, presence of stigmata of hyperilipidemia; e.g., xanthoma, xanthelasma, corneal arcus 4. Global Risk Scoring (FRS, SCORE, Reynolds; http://www.reynoldsriskscore.org/) 5. Bloods: Established markers LDL-C, non-HDL cholesterol (=Total cholesterol minus HDL-C can be assessed fasting or nonfasting)
	Emerging markers—apolipoprotein B, HDL-C, lipoprotein “little a” (Lp(a)), lipoprotein fractionation and particle (VAP, NMR)*, hsC-reactive protein (CRP) >2 mg/dL, lipoprotein-associated phospholipase A2 (Lp-PLA2) Homocysteine (clinical significance if >10 nmol/L)
6. Noninvasive assessment of subclinical atherosclerosis
	Carotid intima-media thickness using ultrasound CT for coronary calcium Flow-mediated dilatation
FRS, Framingham Risk Score; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; CT, computerized tomography; MRI, magnetic resonance imaging.