Background, New Concepts & Perspectives
Dyslipidemia is considered one of the top five risk factors for cardiovascular disease (CVD), along with hypertension, diabetes mellitus (DM), smoking and obesity.[1] There are an infinite number of vascular insults to the vascular system and blood vessel, but the vascular endothelium, vascular and cardiac smooth muscle can only respond in only three finite ways to these insults. These three responses include inflammation, oxidative stress and vascular immune dysfunction.[2–4] These pathophysiologic processes lead to endothelial dysfunction (ED) and vascular smooth muscle and cardiac dysfunction. The vascular consequences include CVD, coronary heart disease (CHD), myocardial infarction (MI) and cerebrovascular accidents (CVA).[4]
Genetics, epigenetics, chronic inflammatory micro- and macro-nutrient intake, obesity (visceral obesity), chronic infections, toxins and some specific pharmacological agents including some of the older β-blockers and the thiazide or thiazide-like diuretics, tobacco products, DM and lack of exercise contribute to dyslipidemia.[5,6]
Several genetic phenotypes, such as APOE, result in variable serum lipid responses to diet, as well as contributing to CHD and MI risk.[7,8] In addition, HDL proteomics that affect PON-1 and SR–BI increase CVD.[9] The sortilin I allele variants on chromosome 1p13 increase LDL and CHD risk by 29%.[10]
Recent studies suggest that increasing dietary cholesterol intake will not significantly alter serum total or LDL cholesterol levels or CHD risk. Some saturated fats, depending on their carbon chain length, may have minimal influences on serum lipids and CHD risk, whereas monounsaturated and polyunsaturated fats have a favorable influence on serum lipids and CHD risk. Increased refined carbohydrate intake may be more important in changing serum lipids and lipid subfractions than saturated fats and cholesterol. Refined carbohydrates have more adverse effects on insulin resistance, atherogenic LDL, small dense LDL, LDL particle number (LDL-P), VLDL, triglycerides, total HDL, HDL subfractions and HDL particle number, thus contributing to CHD risk more than saturated fats.[5,11–17]
Postprandial hyperglycemia, hypertriglyceridemia and endotoxemia coupled with inflammation, oxidative stress and immune vascular dysfunction are highly associated with atherosclerosis.[18–21] Activation of chylomicron and cholecystokinin, GLP-1, low nitric oxide (NO), elevated asymmetric dimethylarginine, increased lipid peroxidation, inflammatory cytokines, TNF-α, stimulation of NF-κB, pattern recognition receptors, Toll-like receptors (TLR-2 and -4), NOD-like receptors, caveolae and lipid rafts increase the inflammatory pathways after meals inducing endothelial dysfunction.[18–21] Increased dietary intake of sodium chloride, not balanced with potassium further increases ED and asymmetric dimethylarginine and reduces NO. Many phytoalexins, phytonutrients and polyphenols may block the TLR and NOD-like receptor inflammatory response.[22,23] In addition, a 'metabolic memory' of cells and the blood vessel exists due to an innate immune response, which will increase inflammation. These responses are perpetuated long after the original insult and are heightened with smaller insults.[18]
The validity of the "Diet Heart Hypothesis" that implies that dietary saturated fats, dietary cholesterol and eggs increase the risk of CHD has been questioned.[12–14] Trans-fatty acids have definite adverse effects on serum lipids and increase CVD and CHD risk but omega 3 fatty acids and monounsaturated fats improve serum lipids and reduce CVD risk.[5,11–17]Trans-fats suppress TGF-β responsiveness, which increases the deposition of cholesterol into cellular plasma membranes in vascular tissue.[16]
Expanded lipid profiles that measure lipids, lipid subfractions, particle size and number, and Apo lipoprotein B and A are preferred to standard lipid profiles that measure only the total cholesterol, LDL, TG or HDL. These expanded lipid profiles such as the lipoprotein particles (SpectraCell Laboratories, TX, USA), nuclear magnetic resonance (Liposcience), Berkley Heart Labs, Boston Heart Labs, Health Diagnostics Lab and vertical auto profile (Atherotec), improve serum lipid analysis and CHD risk profiling.[24,25] It is now proven that LDL-P is the primary lipid parameter that drives the risk for CHD and MI, as well as coronary artery calcification as measured by CT angiogram..[26,27] Dense LDL type B or LDL type 3 and type 4 have secondary roles in CHD only if the LDL-P is elevated.
Dysfunctional HDL[28–31] may be inflammatory, atherogenic and lose its atheroprotective effects especially in patients with DM, metabolic syndrome and obesity due to vascular inflammatory effects.[31] Oxidation and inflammation of apolipoprotein A-1 often results in higher levels of HDL that are dysfunctional and not protective.[31] The ability to evaluate HDL functionality, either directly or indirectly, measuring reverse cholesterol transport, cholesterol efflux capacity[29] or myeloperoxidase[30,31] will improve the assessment of dyslipidemic-induced vascular disease, CHD risk and treatment. An understanding of the pathophysiological steps in dyslipidemic-induced vascular damage is mandatory for optimal and logical treatment (Figure 1). The ability to interrupt all of the various steps in this pathway will allow more specific pathophysiological treatments to reduce vascular injury, improve vascular repair systems, maintain and restore vascular health. Native LDL, especially large type A LDL is not usually atherogenic until modified. However, there exists an alternate pinocytosis mechanism that allows macrophage ingestion of native LDL, which accounts for up to 30% of foam cell formation in the subendothelium that occur during chronic inflammation or infections.[32,33] For example, decreasing LDL modification, the atherogenic form of LDL cholesterol, by decreasing oxidized (ox-LDL), glycated (glyLDL), glyco-oxidized LDL (gly-ox-LDL) and acetylated LDL (acLDL), decreasing the uptake of modified LDL into macrophages by the scavenger receptors (CD 36 SR), decreasing the inflammatory, oxidative stress and autoimmune responses will reduce vascular damage beyond treating the LDL cholesterol level.[34–40] There are at least 38 mechanistic pathways that can be treated to interrupt the dyslipidemic-induced vascular damage and disease (Box 1). Reduction in HS-CRP, an inflammatory marker, reduces vascular events independent of reductions in LDL cholesterol through numerous mechanisms.[39] Many patients cannot or will not use pharmacologic treatments such as statins, fibrates, bile acid resin binders or ezetimibe to treat dyslipidemia.[5] Statin-induced or fibrate-induced muscle disease with myalgias or muscle weakness, abnormal, liver function tests, neuropathy, memory loss, mental status changes, gastrointestinal disturbances, glucose intolerance or diabetes mellitus are some of the reasons that patients may need to use nutritional supplements.[41–45] Many patients have other clinical symptoms or laboratory abnormalities such as chronic fatigue, exercise-induced fatigue, decrease in lean muscle mass, reduced exercise tolerance, reductions in coenzyme Q 10, carnitine, vitamin E, vitamin D, omega 3 fatty acids, selenium and free T3 levels (hypothyroidism) with prolonged usage or the administration of high-dose statins.[5,41–53]
Figure 1.
Lipoproteins and atherosclerosis: it matters what you have. The various steps in the uptake of LDL cholesterol, modification, macrophage ingestion with scavenger receptors, foam cell formation, oxidative stress, inflammation and autoimmune cytokines and chemokine production.
?: Probable but not completely confirmed.
New treatment approaches that combine weight loss, reduction in visceral and total body fat, increase in lean muscle mass, optimal aerobic and resistance exercise, scientifically proven nutrition and use of nutraceutical supplements that may be integrated with drug therapies offer not only improvement in serum lipids but also reductions in inflammation, oxidative stress, immune dysfunction, endothelial and vascular smooth muscle dysfunction. In addition, surrogate markers for vascular disease or clinical vascular target organ damage such as CHD and carotid IMT are reduced in many clinical trials using a nonpharmacologic approach.[5]
Clin Lipidology. 2014;9(3):333-354. © 2014 Future Medicine Ltd.
