Heart Disease Biomarkers in Diabetes Research

Introduction

Cardiovascular disease (CVD) encompasses a constellation of diseases related to the heart and circulatory system. Despite efforts to understand and combat CVD complications from diabetes, 65% of diabetics will pass away from cardiovascular issues¹. Part 2 of The Common Denominator eBook series examines the relationship between diabetes and cardiovascular disease, and how investigators are using established heart disease biomarkers in diabetes research to understand the molecular mechanisms behind cardiovascular complications from diabetes.

Overview of the Cardiovascular System

The purpose of the cardiovascular system is to circulate blood throughout the body². Blood flow not only allows for the transportation of oxygen and nutrients to organs, but also allows for the disposal of waste products². Without this system, cells and organs would not be able to function.

Specialized organs work together to make blood circulation possible including the blood, heart, blood vessels, and lungs.

The Relationship Between Diabetes and Cardiovascular Disease

Transporting blood, oxygen, glucose, and insulin throughout the body is a necessity. Cardiovascular disease (CVD) is the overall term used for many diseases that can affect the cardiovascular system and its ability to effectively orchestrate the flow of compounds in the body.

The cardiovascular system uses blood to transport glucose from digested food to cells for fuel. Additionally the blood is used to transport insulin from the pancreas to cells in response to blood glucose levels³. The transportation of glucose and insulin make blood an important factor in the process of energy homeostasis³.

Diabetics are at an increased risk to develop CVD complications such as atherosclerosis⁴, hypertension⁵, and myocardial infarction⁶.

Heart Disease Biomarkers in Diabetes Research

Teams around the globe are researching the molecular mechanisms behind cardiovascular complications from diabetes. The use of oxidative health and heart disease biomarkers in diabetes research is continually growing in the effort to fully understand the relationship between diabetes and cardiovascular disease.

Atrial Natriuretic Peptide (ANP)

ANP is a powerful hormone secreted by atrial myocytes that helps to reduce blood pressure⁷. NT-proANP (1-98) has been shown to be a better method of measuring ANP secretion over the biologically active α-ANP hormone due to its longer half-life, slower clearance rate, and higher circulation levels^8,9.

Brain-Derived Natriuretic Peptide (BNP)

BNP is a hormone secreted by the ventricles, resulting in decreased blood volume and pressure¹⁰. It is involved in the regulation of cardiovascular and renal homeostasis, fatty acid metabolism, and body weight^10,11. NT-proBNP fragments are better measurements of BNP in a system because they have longer half-lives over the BNP hormone¹².

Asymmetric Dimethylarginine (ADMA)

ADMA is an analogue of L-arginine naturally found circulating in the blood. ADMA is formed when methylated proteins are broken down in endothelial and tubular cells^13,14,15. Elevated ADMA levels can lead to oxidative stress and endothelia dysfunction^13,14,15.

Myeloperoxidase (MPO)

MPO is a leukocyte inflammatory protein that is part of a very strong anti-microbial system that generates Reactive Oxygen Species (ROS) to digest foreign invaders^16,17. Failure to balance ROS production can lead to excess free radicals and oxidative stress¹⁶.

Oxidized Low Density Lipoprotein (Oxidized-LDL)

Ox-LDL is a product of lipid peroxidation, a natural process occurring when cholesterol reacts with free radicals in the body¹⁸. Excessive Ox-LDL can cause cholesterol accumulation in macrophages leading to the formation of foam cells and plaque¹⁹.

Summary

Researchers have been working diligently to better understand the molecular mechanisms behind the cardiovascular complications of diabetes. Using heart disease biomarkers in diabetes research can continue to help bridge the knowledge gap between diabetes and cardiovascular disease.

The Common Denominator is a three part eBook series reviewing diabetes, cardiovascular and kidney complications associated with diabetes, as well as important biomarkers that have become useful in researching these areas.

Part 2: Connecting Diabetes and Cardiovascular Disease reviews the CVD complications of diabetes and discusses the use of traditional heart disease biomarkers in diabetes research.

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References

1. The US Department of Health and Human Services. (2007). The Link Between Diabetes and Cardiovascular Diseases Fact Sheet. National Diabetes Education Program. nih.gov
2. Texas Heart Insitute. (2015). Anatomy – The Cardiovascular System. TexasHeart.org.
3. Weiss et al. (2014). Insulin Biosynthesis, Secretion, Structure, and Structure-Activity Relationships. Regulation of Plasma Glucose by insulin. Endotext. PMID: 25905258.
4. National Heart, Lung, and Blood Institute. (2011). What Is Diabetic Heart Disease? NHLBI.
5. American Diabetes Association. (2014). Living with Diabetes: Complications-High Blood Pressure (Hypertension). Diabetes.org.
6. American Heart Association. (2015). Cardiovascular Disease and Diabetes.  Heart.org.
7. Louros et al. (2013). An N-terminal pro-atrial natriuretic peptide (NT-proANP) ‘aggregation-prone’ segment involved in isolated atrial amyloidosis. FEBS Letters 588, 52–57. PMID: 24220659
8. Yandle et al. (1986) Metabolic clearance rate and plasma half life of alpha-human atrial natriuretic peptide in man. Life Sci., 38, 1827–1833. PMID: 2939312.
9. Arjamaa et al. (1996). Atrial plasma ANP and NH2-terminal proANP during right atrial pressure increase in humans. Acta Physiol Scand, 157(4), 481-485. PMID: 8869731.
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11. Moro & Smith. (2009). Natriuretic Peptides: New Players in Energy Homeostasis. Diabetes, 58, 27-26. PMCID: PMC2780882.
12. Clerico et al. (2011). Thirty years of the heart as an endocrine organ: physiological role and clinical utility of cardiac natriuretic hormones. Am J Physiol Heart Circ Physiol, 301, H12-H20. PMID: 21551272.
13. Kielstein et al. (1999). Asymmetric dimethylarginine plasma concentrations differ in patients with end-stage renal disease: Relationship to treatment method and atherosclerotic disease. J Am Soc Nephrol,10, 594 – 600. PMID: 10073610.
14. Böger et al. (1998). Asymmetric dimethylarginine: a novel risk factor for endothelial dysfunction. Its role in hypercholesterolemia. Circulation, 98, 1842 – 1847. PMID: 9799202.
15. Zakrzewicz & Eickelberg. (2009). From arginine methylation to ADMA: A novel mechanism with therapeutic potential in chronic lung diseases. BMC Pulmonary Medicine, 9(5).  doi: 10.1186/1471-2466-9-5.
16. Zhang et al. (2001). Association between myeloperoxidase levels and risk of coronary artery disease. JAMA, 286, 2136-2142. PMID: 11694155.
17. Searle et al. (2013). The role of myeloperoxidase (MPO) for prognostic evaluation in sensitive cardiac troponin I negative chest pain patients in the emergency department. Eur Heart J Acute Cardiovasc Care, 2(3), 203–210. PMCID: PMC3821817.
18. Parthasarathy et al. (2010). Oxidized Low-Density Lipoprotein. Methods Mol Biol, 610, 403–417. PMCID: PMC3315351.
19. Forst et al. (2009). Cardiovascular Effects of Disturbed Insulin Activity in Metabolic Syndrome and in Type 2 Diabetic Patients. Horm Metab Res, 41(2), 123-31. PMID: 19214922.