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CVD Metabolism, Inflammation & Oxidative Stress

Myeloperoxidase

Myeloperoxidase (MPO) is an antimicrobial enzyme produced by white blood cells and is important in host defense. It is released from activated neutrophils at sites of inflammation and catalyzes the formation of reactive oxidants (e.g., hypochlorous acid) to kill invading pathogens. However, high MPO levels are atherogenic as they can promote oxidative stress and endothelial dysfunction, adversely modifying LDL and HDL function, and promoting plaque instability by actively participating in degradation of the fibrous cap of the atheroma. Elevated serum MPO strongly suggests the presence of unstable plaque and may aid in risk stratification of patients with chest pain.1 Elevated MPO levels are associated with future risk of CAD and major adverse cardiovascular events, metabolic disease, heart failure, hypertension, peripheral artery disease, arrhythmia, and some autoimmune disorders.2,3 MPO-mediated oxidative damage may also promote neurodegenerative disorders.

  1. Dadu RT, et al. Transl Res 2012;159:265–276.
  2. Wang W, et al. Life Sci 2014;117(1):19–23.
  3. Anatoliotakis N, et al. Curr Top Med Chem 2013;13:115–138.
  4. Lefkowitz, Lefkowitz. Free Radic Biol Med 2008;5(5):726–731.

High Sensitivity C-Reactive Protein

C-reactive protein (CRP) has long been recognized as the blood-based biomarker of choice for evaluating inflammatory conditions or suspected infections.1,2 Synthesized in the liver in response to pro-inflammatory cytokines, CRP is an acute-phase reactant yet nonspecific biomarker whose level in human serum can increase 1000-fold within 48 hours after the onset of inflammation, infection, or tissue injury anywhere in the body.1 It is also a modulator of innate immunity and plays an important role in host defense against invading pathogens.1

Baseline serum CRP levels tend to be stable and characteristic for any one individual, apart from occasional spikes related to minor or subclinical infections, inflammation, or trauma. CRP is a more sensitive indicator of acute inflammation than most other acute-phase reactants; its rapid response and short half-life (19 hours) mean that CRP levels rise and fall rapidly when the inducing stimulus evokes inflammation or subsides.1,3,4

High-sensitivity CRP (hs-CRP) immunoassay systems are the most precise when measuring baseline serum CRP and are sufficiently sensitive to detect low-grade inflammatory processes in chronic conditions such as arthritis and obesity. Consideration should thus be given to other laboratory assessments, if needed, based on the patient’s symptoms and clinical presentation.

  1. Pepys MB, Hirschfield GM. J Clin Invest 2003;111(12):1805–1812.
  2. Wu Y, et al. Biol Chem 2015;396(11):1181–1197.
  3. Dregan A, et al. Circulation 2014;130:837–844.
  4. Ridker P. J Am Coll Cardiol 2016;67:712–723.

Fibrinogen

Fibrinogen is the soluble precursor of fibrin, an insoluble, fibrous protein that is the major component of blood clots. A glycoprotein produced by the liver, fibrinogen is an acute-phase reactant and participates in formation of early-stage atherosclerotic plaque, determining the extent of local or systemic inflammation. Elevated fibrinogen is one of the best-established risk factors for peripheral artery disease and is also associated with increased risk of myocardial infarction and stroke, especially in young individuals.1 Circulating fibrinogen levels tend to rise with age, leading to increased blood viscosity and clotting; this hypercoagulable state may account for higher rates of deep vein thrombosis or pulmonary embolism in older individuals, as well as patients who are genetically predisposed to clotting disorders (e.g., via Factor V Leiden or prothrombin mutations). Fibrinogen levels can be reduced by smoking cessation, exercise, alcohol, estrogens, and fibrates. Markedly decreased fibrinogen may be inherited or acquired and pose increased risk for bleeding.

  1. Davalos D, Akassoglou K. Semin Immunopathol 2012;34:43–62.

Vitamin D

Vitamin D is a fat-soluble precursor of the steroid hormone calcitriol that is essential for healthy bone and mineral metabolism. It produced in the skin upon exposure to sunlight and occurs naturally in a few foods (e.g., oily fish, egg yolks, soy products), is added as fortification to many dairy and grain products, and is a common vitamin supplement. As an important regulator of calcium and phosphorus metabolism, prolonged deficiency may lead to the development of rickets in children or osteomalacia/osteoporosis in adults. Vitamin D is also an important modulator of immune function and has anti-inflammatory, antimicrobial, and antihypertensive properties, enhances insulin sensitivity, and protects mucosal barriers throughout the body.1-3

In observational studies, vitamin D deficiency (present in almost half the US population) has been associated with an adverse cardiovascular risk profile and significantly increased risk of cardiovascular events.1,4,5  Low levels of vitamin D may occur in people with limited exposure to sunlight, insufficient dietary intake (e.g., a strict vegan diet), conditions that cause malabsorption and/or intestinal inflammation (e.g., Crohn’s disease, ulcerative colitis, pancreatic insufficiency, celiac disease, and primary biliary cirrhosis), or use of vitamin D-depleting drugs (e.g., anticonvulsants, bile acid sequestrants, and glucocorticoids). Oral supplementation with 25(OH) (D2 or D3) may attenuate inflammation and autoimmunity, protect the gut mucosal barrier, reduce symptoms and prevent relapse in patients with irritable bowel syndrome and inflammatory bowel diseases, and improve cardiovascular health.

  1. Pilz S, et al. Nat Rev Cardiol 2016;13:404–417.
  2. Chiu KC, et al. Am J Clin Nutr 2004;79:820–825.
  3. Sun J. Curr Opin Gastroenterol 2010;26:591–595.
  4. Wang TJ. Annu Rev Med 2016;67:261–272.
  5. Menezes AR, et al. Curr Opin Cardiol 2014;29(6):571–577.

Homocysteine

Homocysteine is an amino acid intermediate in methionine and cysteine metabolism, and is often a byproduct of protein digestion. As vitamin B12 and folic acid are required for conversion of homocysteine to cysteine in the methylation cycle, elevated homocysteine can reflect deficiencies in these vitamins. Hyperhomocysteinemia is associated with increased inflammation and oxidative stress—a potential mediator of aging—and a variety of aging-related conditions, including CVD, renal disease (in hypertensive individuals), cognitive impairment, osteoporosis, depression, and neurodegenerative diseases. 1,2 Mild-to-moderate hyperhomocysteinemia may also stem from poor diet, hypothyroidism, genetic variants (polymorphisms) of the methylenetetrahydrofolate reductase (MTHFR) gene, or certain drugs, and can lead to vascular injury, endothelial dysfunction, and thrombogenicity, conferring high risk for CHD, stroke, and peripheral vascular disease.3-6

Homocysteine levels increase after menopause and are also associated with polycystic ovarian syndrome—perhaps related to insulin resistance.7 Homocysteine increases significantly with age, approximately doubling between childhood and late adulthood, and can increase risk for pre-eclampsia and miscarriage during pregnancy.8 Chronic elevations of homocysteine may lead to endothelial dysfunction, vascular injury, and thrombogenicity, increasing risk for cardiovascular events and strokes.

Exercise, along with whole nutritious foods, supplemental B vitamins (a good B-vitamin complex containing B6 along with methylated forms of folate and B12 if MTHFR polymorphisms are present) and vitamin D3, may help prevent hyperhomocysteinemia-associated diseases of aging.6 In the setting of folate fortification, the main causes of elevated total homocysteine are renal failure and metabolic B12 deficiency; the latter is very common among stroke patients and frequently missed. While effective in lowering homocysteine levels, supplemental B vitamins have not been shown to reduce cardiovascular mortality, except in the case of stroke.9 More aggressive treatment of other cardiovascular risk factors may be prudent in patients with elevated homocysteine.

  1. Lai WK, Kan MY. Ann Nutr Metab 2015;67(1):1–12.
  2. Bhatia P, Singh N. Fundam Clin Pharmacol 2015;29(6):522–528.
  3. Selhub J. Food Nutr Bull 2008;29(2 Suppl):S116–125.
  4. Marti-Carvajal AJ, et al. Cochrane Database Syst Rev 2013;(1):CD006612.
  5. Santilli F, et al. Vascul Pharmacol 2016;78:1–9.
  6. Moll S, Varag EA. Circulation 2015;132:e6–e9.
  7. Mak W, Dokras A. Semin Thromb Hemost 2009;35(7):613–620.
  8. Murphy MM, Fernandez-Ballart JD. Adv Clin Chem 2011;53:105–137.
  9. Spence JD. Int J Stroke 2016;11(7):744–747.

Vitamin B12

Vitamin B12 is a crucial central and peripheral vitamin: it plays a major role in red blood cell formation, the methylation cycle, amino acid metabolism, and the formation of neurotransmitters. Deficiency can be subtle and related to hyperhomocysteinemia, neurologic disease (including dementia), and megaloblastic anemia. Vitamin B12 is derived mainly from animal-derived food sources (e.g., meat, eggs, and milk) and requires binding of intrinsic factor from the stomach for its absorption. Vitamin B12 deficiency is rare in people who eat animal products, although strict vegans are at risk of megaloblastic anemia. As B12 is stored in the liver, very low levels of B12 may not become apparent for 2–5 years, although it is estimated that up to 12% of the elderly population are B12 deficient, due to reduced intrinsic factor production with age (pernicious anemia).1 Low vitamin B12 levels are also associated with cerebrovascular disease and low bone mineral density.2,3 Both metformin (a widely used insulin resistance and diabetes therapy) and alcohol abuse can cause significant B12 deficiency, which may be related to cognitive impairment.4,5 Combined supplementation of vitamin B12 with B6 and folic acid, which lowers homocysteine levels, may have mild benefits in stroke prevention.6 High levels of vitamin B12 may be of no clinical consequence but can occur in liver disease and some types of leukemia.7

  1. Lindenbaum J, et al.. Am J Clin Nutr 1994;60(1):2–11.
  2. Ryan-Harshman M, et al. Can Fam Physician 2008;54(5):536–541.
  3. Tucker KL, et al. J Bone Miner Res2005;20(1):152–158.
  4. Aroda VR, et al. J Clin Endocrinol Metab 2016;101(4):1754–1761.
  5. Moore EM, et al. Diabetes Care 2013;36(10):2981–2987.
  6. Dong H, et al. PLoS ONE 10(9):e0137533.
  7. Ermens AA, et al. Clin Biochem 2003;36(8):585–590.

RBC Folate

Red blood cell folate (RBC folate) is an accurate measure of folate (vitamin B9) status in the body. Folate is an essential vitamin for normal function of RBCs, cell division, and DNA synthesis and repair, and is especially important for women of childbearing age, to prevent birth defects. Folate is critical for the conversion of homocysteine to methionine; its deficiency can result in excess homocysteine levels, a known risk factor for CVD. The most common cause of folate deficiency is insufficient dietary intake, especially in the elderly. Supplementation with folic acid, especially in combination with B vitamins, lowers blood homocysteine levels and reduces risk of stroke.1 In addition to megaloblastic anemia, folate deficiency has been linked to an array of neurologic and neuropsychiatric disorders, such as depression, poor cognitive function, dementia, and Alzheimer disease.2

  1. Dong H, et al. PLoS ONE 10(9):e0137533.
  2. Reynolds EH. Chapter 61: The neurology of folic acid deficiency. Handbook of Clinical Neurology 120 (3rd series) Neurologic Aspects of Systemic Disease Part II Jose Biller and Jose M. Ferro, Editors © 2014 Elsevier B.V.

MTHFR  C677T & A1298C Genotypes

The methylenetetrahydrofolate reductase (MTHFR) gene codes for the MTHFR enzyme, which catalyzes the conversion of 5,10-MTHF to 5-MTHF (L-methylfolate), the active form of folate and the substrate for the remethylation of homocysteine to methionine in the folate metabolic pathway or “methylation cycle.” Genetic variants called single nucleotide polymorphisms (SNPs) in the MTHFR gene, of which C677T and A1298C are the most common, can lead to reduced activity of the MTHFR enzyme, reduced production of L-methylfolate, and accumulation of homocysteine. Excess homocysteine is harmful to the body and increases risk for cardiovascular disease and strokes. Decreased production of L-methylfolate may also lead to methylation defects and hamper essential bodily processes including DNA synthesis and repair, regulation of gene expression, protein function, antioxidant synthesis, and immune activity. Given the importance of methylation reactions throughout the body, the MTHFR C677T and A1298C genotypes influence susceptibility to a wide array of conditions, such as hyperhomocysteinemia, CVD, stroke, hypertension, neural tube defects, certain cancers, spontaneous abortion, renal failure, and an adverse response to certain drugs.1-3 Decreased production of L-methylfolate resulting from MTHFR variants also affects production of neurotransmitters in the brain, which may increase risk for disorders of mood and cognition (e.g., depression, dementia, and memory/attention deficits).4,5

Heterozygosity of either MTHFR polymorphism (genotype  677 C/T or 1298 A/C) will not usually result in elevated homocysteine, although homozygotes (genotype 677 T/T or 1298 C/C; ~5–10% of the population) or compound heterozygotes (genotype 677 C/T and 1298 A/C; 15–20% of the population) are likely to have elevated homocysteine and increased risk for mental/behavioral and physical symptoms if their folate status is low.2,6 Co-occurrence of MTHFR polymorphisms with Factor V Leiden and/or prothrombin G20210A can markedly increase risk of clotting disorders over that of individual gene variants.7

These MTHFR genotypes may thus guide folate and methylation therapies. Patients with high homocysteine who are heterozygous for either MTHFR polymorphism will respond to folate supplementation with folic acid, but may (like homozygotes) receive greater benefit from L-methylfolate in combination with methylcobalamin (methylated vitamin B12). Other homocysteine-lowering treatments include betaine and riboflavin, which has been shown to reduce high blood pressure in 677 T/T homozygotes.6 Patients often report improvements in symptoms and energy levels upon rectification of folate status, and adjunctive L-methylfolate may provide an effective augmentation strategy for patients with major depression who have an inadequate response to selective serotonin reuptake inhibitors (SSRIs).2,4,8

  1. Toffoli G, DeMattia E. Pharmacogenomics 2008;9(9):1195–1206.
  2. Oberg E, et al. J Nutrigenet Nutrigenom 2015;8:137–150.
  3. Nazki FH, et al. Gene 2014;533:11–20.
  4. Mech AW, Farah A. J Clin Psychiatry 2016;77(5):668–671.
  5. Mitchell ES, et al. Neurosci Biobehav Rev 2014;47:307–320.
  6. Huang T, et al. J Nutr 2011;141:654–659.
  7. Margaglione M, et al. Thromb Haemost 1998;79(5):907–911.
  8. Papakostas GI, et al. Am J Psychiatr 2012;169:1267–1276.

Uric Acid 

Uric acid is a byproduct of purine nucleotide metabolism; excess levels (hyperuricemia) can lead to the formation and accumulation of crystals in the joints and other tissues. Hyperuricemia, which may be caused by increased production or decreased renal elimination of uric acid, is not only a risk factor for gout, but also for CVD—especially stroke. Epidemiologic studies have shown elevated uric acid levels independently predict the development of hypertension, metabolic syndrome, stroke, myocardial infarction, kidney disease, and heart failure.1

  1. Kanbay M, et al. Heart 2013;99:759–766.

Creatine Kinase

A creatine kinase (CK) test may be used to detect inflammation of muscles (myositis) or serious muscle damage and/or to diagnose rhabdomyolysis if a person has signs and symptoms, such as muscle weakness, muscle aches, and dark urine. The urine may be dark because of the presence of myoglobin, another substance released by damaged muscles that can be harmful to the kidneys. A creatine kinase test may help detect muscle damage due to a statin, ethanol or cocaine use, or exposure to a toxin.1 Serum creatine kinase may also be measured to assess the efficacy of hypertension treatment.2 The creatine kinase test may be ordered if a patient has chest pain or other symptoms that could indicate cardiac damage after a myocardial infarction.3

  1. Oudman I, et al. J Hypertension 2013;31:1025–1031.
  2. Stolcpart RS, et al. Am J Cardiovasc Drugs 2010;10 (3):187–192.
  3. Tzivoni D, et al. Am J Cardiol 2008;101:753–757.

 

 

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