Health  Vol.10 No.3 , March 2018
Classification of New Biomarkers of Dilated Cardiomyopathy Based on Pathogenesis—An Update
Abstract: Dilated Cardiomyopathy (DCM) is a complex heart disease affecting the heart musculature and vasculature, involving one or several underlying pathophysiological mechanisms. Identifying potential biomarkers for dilated cardiomyopathy is a challenge owing to various aetiologies involved. Studying the biomarkers involved in DCM will ultimately give a better insight about which pathophysiological pathways are involved in the onset of the disease. Owing to its multifactorial aetiologies, response to treatment is usually poor. If we can find the exact underlying causes, a better treatment approach could be implemented. One way to obtain better insight of DCM is to study the biomarkers released. Through biomarkers, we can know which underlying mechanisms are involved. Biomarkers can provide us with clinical information such as diagnostic, prognostic, risk stratification as well as response to treatment. Underlying mechanisms such as inflammation, stress/strain, myocyte injury, matrix remodelling, oxidative stress, neurohormones involvement, among others, can contribute to the onset of DCM. Different mechanisms will yield different biomarkers. So it would be wise to classify those biomarkers involving in DCM based on their respective pathogenesis. Moreover, most importantly is to be able to make use of the information that biomarker pertains. However, specificity of those biomarkers poses a problem. One way of making these biomarkers clinically useful is to make use of a biomarker modelling score system.
Cite this paper: Dookhun, M. , Sun, Y. , Zou, H. , Cao, X. and Lu, X. (2018) Classification of New Biomarkers of Dilated Cardiomyopathy Based on Pathogenesis—An Update. Health, 10, 300-312. doi: 10.4236/health.2018.103024.

[1]   Merlo, M., Pivetta, A., Pinamonti, B., Stolfo, D., Zecchin, M., Barbati, G., Di Lenarda, A. and Sinagra, G. (2014) Long-Term Prognostic Impact of Therapeutic Strategies in Patients with Idiopathic Dilated Cardiomyopathy: Changing Mortality over the Last 30 Years. European Journal of Heart Failure, 16, 317-324.

[2]   Xiong, Q., et al. (2015) Elevated Serum Bisphenol Alevelin Patients with Dilated Cardiomyopathy. International Journal of Environmental Research and Public Health, 12, 5329-5337.

[3]   Lang, R.M., et al. (2005) Recommendations for Chamber Quantification: A Report from the American Society of Echocardiography’s Guidelines and Standards Committee and the Chamber Quantification Writing Group, Developed in Conjunction with the European Association of Echocardiography, a Branch of the European Society of Cardiology. Journal of the American Society of Echocardiography, 18, 1440-1463.

[4]   Davies, M.J. and Mckenna, W.J. (1994) Dilated Cardiomyopathy: An Introduction to Pathology and Pathogenesis. Heart, 72, No. 6.

[5]   McNally, E.M., Golbus, J.R. and Puckelwartz, M.J. (2013) Genetic Mutations and Mechanisms in Dilated Cardiomyopathy. Journal of Clinical Investigation, 123, 19-26.

[6]   Yuan, F., et al. (2015) A Novel NKX2-5 Loss-of-Function Mutation Predisposes to Familial Dilated Cardiomyopathy and Arrhythmias. International Journal of Molecular Medicine, 35, 478-486.

[7]   Garciapavia, P., et al. (2013) Genetics in Dilated Cardiomyopathy. Biomarkers in Medicine, 7, 517-533.

[8]   Keeling, P.J., et al. (1995) Familial Dilated Cardiomyopathy in the United Kingdom. Heart, 73, 417-421.

[9]   Mestroni, L., et al. (1999) Familial Dilated Cardiomyopathy: Evidence for Genetic and Phenotypic Heterogeneity. Journal of the American College of Cardiology, 34, 181-190.

[10]   Puggia, I., Merlo, M., Barbati, G., Rowland, T.J., Stolfo, D., Gigli, M., et al. (2016) Natural History of Dilated Cardiomyopathy in Children. Journal of the American Heart Association, 5, 1-10.

[11]   Grogan, M., et al. (1995) Long-Term Outcome of Patients with Biopsy-Proved Myocarditis : Comparison with Idiopathic Dilated Cardiomyopathy. Journal of the American College of Cardiology, 26, 80-84.

[12]   Michels, V.V., et al. (1992) The Frequency of Familial Dilated Cardiomyopathy in a Series of Patients with Idiopathic Dilated Cardiomyopathy. The New England Journal of Medicine, 326, 77-82.

[13]   Maeda, K., Tsutamoto, T., Wada, A., Hisanaga, T. and Kinoshita, M. (1998) Plasma Brain Natriuretic Peptide as a Biochemical Marker of High Left Ventricular End-Diastolic Pressure in Patients with Symptomatic Left Ventricular Dysfunction. American Heart Journal, 135, 825-832.

[14]   Tsutamoto, T., Wada, A., Maeda, K., Hisanaga, T., Maeda, Y., Fukai, D., et al. (1997) Attenuation of Compensation of Endogenous Cardiac Natriuretic Peptide System in Chronic Heart Failure: Prognostic Role of Plasma Brain Natriuretic Peptide Concentration in Patients with Chronic Symptomatic Left Ventricular Dysfunction. Circulation, 96, 509-516.

[15]   Clapp, B.R., et al. (2005) Inflammation and Endothelial Function. Circulation, 111, 1530-1536.

[16]   Verma, S., et al. (2002) Endothelin Antagonism and Interleukin-6 Inhibition Attenuate the Proatherogenic Effects of C-Reactive Protein. Circulation, 105, 1890-1896.

[17]   Kaneko, K., Kanda, T., Yamauchi, Y., Hasegawa, A., Iwasaki, T., Arai, M., et al. (1999) C-Reactive Protein in Dilated Cardiomyopathy. Cardiology, 91, 215-219.

[18]   Sato, Y., Takatsu, Y., Kataoka, K., Yamada, T., Taniguchi, R., Sasayama, S., et al. (1999) Serial Circulating Concentrations of C-Reactive Protein, Inter-Leukin (IL)-4, and IL-6 in Patients with Acute Left Heart Decompensation. Clinical Cardiology, 22, 811-813.

[19]   Steele, I.C., Nugent, A.M., Maguire, S., Hoper, M., Campbell, G., Halliday, M.I., et al. (1996) Cytokine Profile in Chronic Cardiac Failure. European Journal of Clinical Investigation, 26, 1018-1022.

[20]   Alonso-Martinez, J.L., Llorente-Diez, B., Echegaray-Agara, M., Olaz-Preciado, F., Urbieta-Echezarreta, M. and Gonzalez-Arencibia, C. (2002) C-Reactive Protein as a Predictor of Improvement and Readmission in Heart Failure. European Journal of Heart Failure, 4, 331-336.

[21]   Yin, W.H., Chen, J.W., Jen, H.L., Chiang, M.C., Huang, W.P., Feng, A.N., et al. (2004) Independent Prognostic Value of Elevated High-Sensitivity C-Reactive Protein in Chronic Heart Failure. American Heart Journal, 147, 931-938.

[22]   Chitose, I., et al. (2004) Plasma C-Reactive Protein Is an Independent Prognostic Predictor in Patients with Dilated Cardiomyopathy. Journal of Cardiac Failure, 10, S161.

[23]   Katz, S.D., et al. (2005) Vascular Endothelial Dysfunction and Mortality Risk in Patients with Chronic Heart Failure. Circulation, 111, 310-314.

[24]   Ishikawa, C., et al. (2006) Prediction of Mortality by High-Sensitivity C-Reactive Protein and Brain Natriuretic Peptide in Patients with Dilated Cardiomyopathy. Circulation Journal, 70, 857-863.

[25]   Li, X., et al. (2014) Plasma NT pro-BNP , hs-CRP and Big-ET Levels at Admission as Prognostic Markers of Survival in Hospitalized Patients with Dilated Cardiomyopathy: A Single-Center Cohort Study. BMC Cardiovascular Disorders, 14, 67.

[26]   Fu, M. (2009) Inflammation in Chronic Heart Failure: What Is Familiar, What Is Unfamiliar? European Journal of Heart Failure, 11, 111-112.

[27]   Anker, S.D. and von Haehling, S. (2004) Inflammatory Mediators in Chronic Heart Failure: An Overview. Heart, 90, 464-470.

[28]   Arruda-Olson, A.M., Reeder, G.S., Bell, M.R., Weston, S.A. and Roger, W.L. (2009) Neutrophilia Predicts Death and Heart Failure after Myocardial Infarction: A Community-Based Study. Circulation: Cardiovascular Quality and Outcomes, 2, 656-662.

[29]   Ommen, S.R., Hodge, D.O., Rodeheffer, R.J., McGregor, C.G., Thomson, S.P. and Gibbons, R.J. (1998) Predictive Power of the Relative Lymphocyte Concentration in Patients with Advanced Heart Failure. Circulation, 97, 19-22.

[30]   Han, Y.C., Yang, T.H., Kim, D.I., Jin, H.Y., Chung, S.R., Seo, J.S., et al. (2013) Neutrophil to Lymphocyte Ratio Predicts Long-Term Clinical Outcomes in Patients with ST-Segment Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention. Korean Circulation Journal, 43, 93-99.

[31]   Avci, A., et al. (2014) Neutrophil/Lymphocyte Ratio Is Related to the Severity of Idiopathic Dilated Cardiomyopathy. Scandinavian Cardiovascular Journal, 48, 202-208.

[32]   Solomon, S.D., Anavekar, N., Skali, H., McMurry, J.J., Swedberg, K., Yusuf, S., et al. (2005) Influence of Ejection Fraction on Cardiovascular Outcomes in a Broad Spectrum of Heart Failure Patients. Circulation, 112, 3738-3744.

[33]   Kralisch, S., et al. (2009) Interleukin-1B Induces the Novel Adipokine Chemerin in Adipocytes in Vitro. Regulatory Peptides, 154, 102-106.

[34]   Parlee, S.D., et al. (2011) Serum Chemerin Levels Vary with Time of Day and Are Modified by Obesity and Tumor Necrosis Factor-α. Endocrinology, 151, 2590-2602.

[35]   Zhang, O., et al. (2015) Circulating Chemerin Levels Elevated in Dilated Cardiomyopathy Patients with Overt Heart Failure. Clinica Chimica Acta, 448, 27-32.

[36]   Ji, Q., et al. (2014) Chemerin Is a Novel Biomarker of Acute Coronary Syndrome But Not of Stable Angina Pectoris. Cardiovascular Diabetology, 13, 145-145.

[37]   Sharma, U., Rhaleb, N.-E., Pokharel, S., et al. (2008) Novel Anti-Inammatory Mechanisms of N-Acetyl-Ser-Asp-Lys-Pro in Hypertension-Induced Target Organ Damage. E-American Journal of Physiology—Heart and Circulatory Physiology, 294, H1226-H1232.

[38]   Sharma, U.C., Pokharel, S., van Brakel, T.J., et al. (2004) Galectin-3 Marks Activated Macro-Phages in Failure-Prone Hypertrophied Hearts and Contributes to Cardiac Dysfunction. Circulation, 110, 3121-3128.

[39]   Masci, P.G., Barison, A., Aquaro, G.D., et al. (2012) Myocardial Delayed Enhancement in Paucisymptomatic Nonischemic Dilated Cardiomyopathy. International Journal of Cardiology, 157, 43-47.

[40]   Gulati, A., Jabbour, A., Ismail, T.F., et al. (2013) Association of Fibrosis with Mortality and Sudden Cardiac Death in Patients with Nonischemic Dilated Cardiomyopathy. JAMA, 309, 896-908.

[41]   Masci, P.G., Doulaptsis, C., Bertella, E., et al. (2014) The Incremental Prognostic Value of Myocardial Fibrosis in Patients with Non-Ischemic Cardiomyopathy without Congestive Heart Failure. Circulation: Heart Failure, 7, 448-456.

[42]   Vergaro, G., et al. (2015) Galectin-3 and Myocardial Fibrosis in Nonischemic Dilated Cardiomyopathy. International Journal of Cardiology, 184, 96-100.

[43]   Maisel, A.S., et al. (2002) Rapid Measurement of B-Type Natriuretic Peptide in the Emergency Diagnosis of Heart Failure. The New England Journal of Medicine, 347, 161-167.

[44]   Nagagawa, O., Ogawa, Y., Itoh, H., Suga, S., Komatsu, Y. and Kishimoto, I. (1995) Rapid Transcriptional Activation and Early mRNA Turnover of BNP in Cardiocyte Hypertrophy: Evidence for BNP as an “Emergency” Cardiac Hormone against Ventricular Overload. The Journal of Clinical Investigation, 96, 1280-1287.

[45]   Braunwald, E. (2008) Biomarkers in Heart Failure. The New England Journal of Medicine, 358, 2148-2159.

[46]   Tigen, K., Karaahmet, T., Cevik, C., Gurel, E., Pala, S., Mutlu, B. and Basaran, Y. (2009) Prognostic Utility of Right Ventricular Systolic Functions Assessed by Tissue Doppler Imaging in Dilated Cardiomyopathy and Its Correlation with Plasma NT-Pro-BNP Levels. Congest Heart Fail, 15, 234-239.

[47]   Omland, T., et al. (2007) Prognostic Value of B-Type Natriuretic Peptides in Patients with Stable Coronary Artery Disease: The PEACE Trial. Journal of the American College of Cardiology, 50, 205-214.

[48]   Shah, R.V. and Januzzi Jr., J.L. (2010) ST2: A Novel Remodeling Biomarker in Acute and Chronic Heart Failure. Current Heart Failure Reports, 7, 9-14.

[49]   Rehman, S.U., Mueller, T. and Januzzi Jr., J.L. (2008) Characteristics of the Novel Interleukin Family Biomarker ST2 in Patients with Acute Heart Failure. Journal of the American College of Cardiology, 52, 1458-1465.

[50]   Weinberg, E.O., Shimpo, M., De Keulenaer, G.W., MacGillivray, C., Tominaga, S., Solomon, S.D., Rouleau, J.L. and Lee, R.T. (2002) Expression and Regulation of ST2, an Interleukin-1 Receptor Family Member, in Cardiomyocytes and Myocardial Infarction. Circulation, 106, 2961-2966.

[51]   Kawahara, C., Tsutamoto, T., Nishiyama, K., et al. (2011) Prognostic Role of High-Sensitivity Cardiac Troponin T in Patients with Nonischemic Dilated Cardiomyopathy. Circulation Journal, 75, 656-661.

[52]   Sato, Y., Yamada, T., Taniguchi, R., et al. (2001) Persistently Increased Serum Concentrations of Cardiac Troponin t in Patients with Idiopathic Dilated Cardiomyopathy Are Predictive of Adverse Outcomes. Circulation, 103, 369-374.

[53]   Baba, Y. et al. (2015) Clinical Significance of High-Sensitivity Cardiac Troponin T in Patients with Dilated Cardiomyopathy. International Heart Journal, 56, 309-313.

[54]   Schaap, F.G., van der Vusse, G.J. and Glatz, J.F. (1998) Fatty Acid-Binding Proteins in the Heart. Molecular and Cellular Biochemistry, 180, 43-51.

[55]   Goto, T., et al. (2003) Circulating Concentrations of Cardiac Proteins Indicate the Severity of Congestive Heart Failure. Heart, 89, 1303-1307.

[56]   Copeland, O., Sadayappan, S., Messer, A.E., Steinen, G.J., van der Velden, J. and Marston, S.B. (2010) Analysis of Cardiac Myosin Binding Protein-C Phosphorylation in Human Heart Muscle. Journal of Molecular and Cellular Cardiology, 49, 1003-1011.

[57]   Doesch, A.O., et al. (2010) Impact of Troponin I-Autoantibodies in Chronic Dilated and Ischemic Cardiomyopathy. Basic Research in Cardiology, 106, 25-35.

[58]   Kasahara, H., et al. (1994) Autoimmune Myocarditis Induced in Mice by Cardiac C-Protein. Cloning of Complementary DNA Encoding Murine Cardiac C-Protein and Partial Characterization of the Antigenic Peptides. Journal of Clinical Investigation, 94, 1026-1036.

[59]   Kaya, Z., Leib, C. and Katus, H.A. (2012) Autoantibodies in Heart Failure and Cardiac Dysfunction. Circulation Research, 110, 145-158.

[60]   Garcia, R.A., Brown, K.L., Pavelec, R.S., Go, K.V., Covell, J.W. and Villarreal, F. (2004) Abnormal Cardiac Wall Motion and Early Matrix Metalloproteinase Activity. American Journal of Physiology-Heart and Circulatory Physiology, 288, H1080-H1087.

[61]   Vasilyev, N., Williams, T., Brennan, M.L., Unzek, S., Zhou, X., Heinecke, J.W., Spitz, D.R., Topol, E.J., Hazen, S.L. and Penn, M.S. (2005) Myeloperoxidase-Generated Oxidants Modulate Left Ventricular Remodeling But Not Infarct Size after Myocardial Infarction. Circulation, 112, 2812-2820.

[62]   Nicholls, S.J. and Hazen, S.L. (2005) Myeloperoxidase and Cardiovascular Disease. Arteriosclerosis, Thrombosis, and Vascular Biology, 25, 1102-1111.

[63]   Tang, W.H., Tong, W., Troughton, R.W., Martin, M.G., Shrestha, K., Borowski, A., Jasper, S., Hazen, S.L. and Klein, A.L. (2007) Prognostic Value and Echocardiographic Determinants of Plasma Myeloperoxidase Levels in Chronic Heart Failure. Journal of the American College of Cardiology, 49, 2364-2370.

[64]   Love, M.P. and McMurray, J.J.V. (1996) Endothelin in Chronic Heart Failure: Current Position and Future Prospects. Cardiovascular Research, 31, 665-674.

[65]   Hiroe, M., et al. (1991) Plasma Endothelin-1 Levels in Idiopathic Dilated Cardiomyopathy. American Journal of Cardiology, 68, 1114-1115.

[66]   Plumpton, C., Ashby, M.J., Kuc, R.E., O’Reilly, G. and Davenport, A.P. (1996) Expression of Endothelin Peptides and mRNA in the Human Heart. Clinical Science, 90, 37-46.

[67]   Herrmann, S., et al. (2001) A Polymorphism in the Endothelin—A Receptor Gene Predicts Survival in Patients with Idiopathic Dilated Cardiomyopathy. European Heart Journal, 22, 1948-1953.

[68]   Telgmann, R., et al. (2007) The G-231A Polymorphism in the Endothelin—A Receptor Gene Is Associated with Lower Aortic Pressure in Patients with Dilated Cardiomyopathy. American Journal of Hypertension, 20, 32-37.

[69]   Pousset, F., Isnard, R., Lechat, P., et al. (1997) Prognostic Value of Plasma Endothelin-1 in Patients with Chronic Heart Failure. European Heart Journal, 18, 254-258.

[70]   Pacher, R., Stanek, B., Hülsmann, M., et al. (1996) Prognostic Impact of Big-Endothelin Plasma Concentrations Compared with Invasive Hemodynamic Evaluation in Severe Heart Failure. Journal of the American College of Cardiology, 27, 633-641.

[71]   Roura, S., et al. (2016) Circulating Endothelial Progenitor Cells: Potential Biomarkers for Idiopathic Dilated Cardiomyopathy. Journal of Cardiovascular Translational Research, 9, 80-84.

[72]   Roura, S. and Bayesgenis, A. (2009) Vascular Dysfunction in Idiopathic Dilated Cardiomyopathy. Nature Reviews Cardiology, 6, 590-598.

[73]   Roura, S., Gálvez-Montón, C. and Bayes-Genis, A. (2013) The Challenges for Cardiac Vascular Precursor Cell Therapy: Lessons from a Very Elusive Precursor. Journal of Vascular Research, 50, 304-323.

[74]   Theiss, H.D., David, R., Engelmann, M.G., Barth, A., Schotten, K., Naebauer, M., Reichart, B., et al. (2007) Circulation of CD34+ Progenitor Cell Populations in Patients with Idiopathic Dilated and Ischaemic Cardiomyopathy (DCM and ICM). European Heart Journal, 28, 1258-1264.

[75]   Smith, C.J., et al. (1996) Reduced Gene Expression of Vascular Endothelial NO Synthase and Cyclooxygenase-1 in Heart Failure. Circulation Research, 78, 58-64.

[76]   Michalowicz, J. (2014) Bisphenol A—Sources, Toxicity and Biotransformation. Environmental Toxicology and Pharmacology, 37, 738-758.

[77]   Genuis, S.J., Beesoon, S., Birkholz, D. and Lobo, R.A. (2012) Human Excretion of Bisphenol A: Blood, Urine, and Sweat (BUS) Study. Journal of Environmental and Public Health, 2012, Article ID: 185731.

[78]   Meeker, J.D., Calafat, A.M. and Hauser, R. (2010) Urinary Bisphenol A Concentrations in Relation to Serum Thyroid and Reproductive Hormone Levels in Men from an Infertility Clinic. Environmental Science & Technology, 44, 1458-1463.

[79]   Zhou, Q., et al. (2013) Serum Bisphenol—A Concentration and Sex Hormone Levels in Men. Fertility and Sterility, 100, 478-482.

[80]   Pascualfigal, D.A., et al. (2009) Sex Hormone-Binding Globulin: A New Marker of Disease Severity and Prognosis in Men with Chronic Heart Failure. Revista Espanola de Cardiologia, 62, 1381-1387.