Recent Advances in Molecular Diagnostics and Treatment of Heart Muscle Diseases

Abstract

Cardiomyopathies are acute or chronic disorders of myocardium. Diagnostic characterization of disease entities demands endomyocardial biopsy analyses with histological, immunohistochemical and molecular biological tissue evaluations to establish a final diagnosis. Only such biopsy-based information allows so far a specific treatment of distinct cardiomyopathy subgroups. In order to reduce sampling error, tissue specimens have to be obtained and analyzed to get clinically relevant data for specific treatment options. Specific gene expression and microRNA (miRNAs) profiles as well as genetic markers add additional valuable information which not only reduce the sampling error but also improve patient management. Advantages of such biomarkers result from their general expression within the entire altered myocardium. Thus, obtained information does not depend on small tissue areas reached by biopsy. This very fact allows prediction of a myocardial infection even in virus-negative areas adjoining positive biopsy specimen. The combination of multiple deregulated miRNAs or genes into one disease specific diagnostic profile demands the integration of new profiling technologies in the routine workflows of cardiological laboratories. In future, multiplex approaches allowing rapid and absolutely reliable identification of inflammatory or virally-induced myocardial diseases will replace singleplex methods such as direct detection of viral genomes in one single biopsy. miRNAs are stable biomarkers which are not only detectable in tissue samples but also in body fluids. Consequently, the determination of distinct miRNA patterns in e.g. peripheral blood samples will provide a systemic diagnostic approach for the characterization of distinct cardiomyopathies by means of non-invasive methods. This will reduce the number of undiagnosed patients who have to undergo endomyocardial biopsy for final confirmation of their myocardial complaints. The resulting molecular diagnostics will pave the way from biopsy focused interpretation to systemic analysis of cardiomyopathies. To reach this goal, the set-up of modern diagnostics harks back to the broad portfolio of high-end analytical techniques and tools.

Share and Cite:

D. Lassner, C. Siegismund, J. Stehr, M. Rohde, F. Escher, C. Tschöpe, U. Gross, U. Kühl and H. Schultheiss, "Recent Advances in Molecular Diagnostics and Treatment of Heart Muscle Diseases," Journal of Analytical Sciences, Methods and Instrumentation, Vol. 3 No. 2, 2013, pp. 98-109. doi: 10.4236/jasmi.2013.32012.

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1] P. P. Liu and H.-P. Schultheiss, “Myocarditis,” In: Baunwalded, Ed., Heart Disease, 8th Edition, W. B. Saunders Co., Philadelphia, 2008, pp. 1775-1792.
[2] H.-P. Schultheiss, U. Kühl and L. T. Cooper, “The Management of Myocarditis,” European Heart Journal, Vol. 33, No. 21, 2011, pp. 2616-2625.
[3] L. T. Cooper, K. L. Baughman, A. M. Feldman, et al., “The Role of Endomyocardial Biopsy in the Management of Cardiovascular Disease,” European Heart Journal, Vol. 28, 2007, pp. 3076-3093.
[4] H. T. Aretz, “Myocarditis: The Dallas Criteria,” Human Pathology, Vol. 18, No. 6, 1987, pp. 619-624. doi:10.1016/S0046-8177(87)80363-5
[5] M. Noutsias, M. Pauschinger, K. Ostermann, F. Escher, J. H. Blohm, H.-P. Schultheiss and U. Kühl, “Digital Image Analysis System for the Quantification of Infiltrates and Cell Adhesion Molecules in Inflammatory Cardiomyopathy,” Medical Science Monitor, Vol. 8, No. 5, 2002, pp. 59-71.
[6] J. C. Silverio, L. M. de-Oliveira-Pinto, A. A. da Silva, G. M. de Oliveira and J. Lannes-Vieira, “Perforin-Expressing Cytotoxic Cells Contribute to Chronic Cardiomyopathy in Trypanosomacruzi Infection,” International Journal of Experimental Pathology, Vol. 91, No. 1, 2010, pp. 72-86. doi:10.1111/j.1365-2613.2009.00670.x
[7] I. Kindermann, M. Kindermann, R. Kandolf, K. Klingel, B. Bültmann, T. Müller, A. Lindinger and M. Bohm, “Predictors of Outcome in Patients with Suspected Myocarditis,” Circulation, Vol. 118, No. 6, 2008,pp. 639-648. doi:10.1161/CIRCULATIONAHA.108.769489
[8] A. Gulati, A. Jabbour, T. F. Ismail, K. Guha, J. Khwaja, S. Raza, K. Morarji, T. D. Brown, N. A. Ismail, M. R. Dweck, E. Di Pietro, M. Roughton, R. Wage, Y. Daryani, R. O’Hanlon, M. N. Sheppard, F. Alpendurada, A. R. Lyon, S. A. Cook, M. R. Cowie, R. G. Assomull, D. J. Pennell and S. K. Prasad, “Association of Fibrosis with Mortality and Sudden Cardiac Death in Patients with Nonischemic Dilated Cardiomyopathy,” JAMA, Vol. 309, No. 9, 2013, pp. 896-908. doi:10.1001/jama.2013.1363
[9] U. Kühl, D. Lassner, M. Pauschinger, U. M. Gross, B. Seeberg, M. Noutsias, W. Poller and H.-P. Schultheiss, “Prevalence of Erythrovirus Genotypes in the Myocardium of Patients with Dilated Cardiomyopathy,” Journal of Medical Virology, Vol. 80, No. 8, 2008, pp. 1243-1251. doi:10.1002/jmv.21187
[10] U. Kühl, M. Rohde, D. Lassner, U. M. Gross, F. Escher and H. P. Schultheiss, “miRNA as Activity Markers in Parvo B19 Associated Heart Disease,” Herz, Vol. 37, No. 6, 2012, pp. 637-643. doi:10.1007/s00059-012-3656-3
[11] U. Kuhl, M. Pauschinger, M. Noutsias, et al., “High Prevalence of Viral Genomes and Multiple Viral Infections in the Myocardium of Adults with ‘Idiopathic’ Left Ventricular Dysfunction,” Circulation, Vol. 111, 2005, pp. 887-893. doi:10.1161/01.CIR.0000155616.07901.35
[12] P. E. Pellett, D. V. Ablashi, P. F. Ambros, et al., “Chromosomally Integrated Human Herpesvirus 6: Questions and Answers,” Reviews in Medical Virology, Vol. 22, No. 3, 2012, pp. 144-155. doi:10.1002/rmv.715
[13] C. T. Bock, K. Klingel and R. Kandolf, “Human Parvovirus B19-Associated Myocarditis,” The New England Journal of Medicine, Vol. 362, No. 13, 2010, pp. 1248-1249.
[14] A. L. Caforio, F. Calabrese, A. Angelini, et al., “A Prospective Study of Biopsy-Proven Myocarditis: Prognostic Relevance of Clinical and Aetiopathogenetic Features at Diagnosis,” European Heart Journal, Vol. 28, No. 11, 2007, pp. 1326-1333. doi:10.1093/eurheartj/ehm076
[15] U. Kühl, D. Lassner, J. von Schlippenbach, W. Poller and H. P. Schultheiss “Interferon-Beta Improves Survival in Enterovirus-Associated Cardiomyopathy,” Journal of the American College of Cardiology, Vol. 60, No. 14, 2012, pp. 1295-1296. doi:10.1016/j.jacc.2012.06.026
[16] A. Willitzki, R. Hiemann, V. Peters, U. Sack, P. Schierack, S. Rodiger, U. Anderer, K. Conrad, D. P. Bogdanos, D. Reinhold and D. Roggenbuck, “New Platform Technology for Comprehensive Serological Diagnostics of Autoimmune Diseases,” Clinical and Developmental Immunology, Vol. 2012, 2012, Article ID: 284740.
[17] N. Deubner, D. Berliner, A. Schlipp, G. Gelbrich, A. L. Caforio, S. B. Felix, M. Fu, H. Katus, C. E. Angermann, M. J. Lohse, G. Ertl, S. Stork, R. Jahns, Etiology, Titre-Course and Survival-Study Group, “Cardiac Beta1-Adrenoceptor Autoantibodies in Human Heart Disease: Rationale and Design of the Etiology, Titre-Course, and Survival (ETiCS) Study,” European Journal of Heart Failure, Vol. 12, No. 7, 2010, pp. 753-762. doi:10.1093/eurjhf/hfq072
[18] C. Skurk, F. Wittchen, L. Suckau, H. Witt, M. Noutsias, H. Fechner, H.-P. Schultheiss and W. Poller, “Description of a Local Cardiac Adiponectin System and Its Deregulation in Dilated Cardiomyopathy,” European Heart Journal, Vol. 29, No. 9, 2008, pp. 1168-1180. doi:10.1093/eurheartj/ehn136
[19] K. L. Kellar, R. R. Kalwar, K. A. Dubois, D. Crouse, W. D. Chafin and B. E. Kane, “Multiplexed Fluorescent Bead-Based Immunoassays for Quantitation of Human Cytokines in Serum and Culture Supernatants,” Cytometry, Vol. 45, No. 1, 2001, pp. 27-36. doi:10.1002/1097-0320(20010901)45:1<27::AID-CYTO1141>3.0.CO;2-I
[20] F. Wittchen, L. Suckau, H. Witt,C. Skurk, D. Lassner, H. Fechner, I. Sipo, U. Ungethüm, P. Ruiz, M. Pauschinger, C. Tschope, U. Rauch U, Kühl, H.-P. Schultheiss and W. Poller, “Genomic Expression Profiling of Human Inflammatory Cardiomyopathy (DCMi) Suggests Novel Therapeutic Targets,” European Heart Journal, Vol. 85, No. 3, 2007, pp. 257-271. doi:10.1007/s00109-006-0122-9
[21] S. V. Naga Prasad, Z. H. Duan, M. K. Gupta, et al., “Unique microRNA Profile in End-Stage Heart Failure Indicates Alterations in Specific Cardiovascular Signaling Networks,” The Journal of Biological Chemistry, Vol. 284, 2009, pp. 27487-27499. doi:10.1074/jbc.M109.036541
[22] D. Baek, J. Villen, C. Shin, F. D. Camargo, S. P. Gygi and D. P. Bartel, “The Impact of microRNAs on Protein Output,” Nature, Vol. 4355, No. 7209, 2008, pp. 64-71. doi:10.1038/nature07242
[23] P. S. Mitchell, R. K. Parkin, et al., “Circulating microRNAs as Stable Blood-Based Markers for Cancer Detection,” PNAS, Vol. 105, 2008, pp. 10513-10518.
[24] G. Wang, E. S. Chan, B. C. Kwan, P. K. Li, S. K. Yip, C. C. Szeto and C. F. Ng, “Expression of miRNAs in the Urine of Patients with Bladder Cancer,” Clinical Genitourinary Cancer, Vol. 10, No. 2, 2012, pp. 106-113. doi:10.1016/j.clgc.2012.01.001
[25] P. Puerta-Gil, R. Garcia-Baquero, A. Y. Jia, S. Ocana, M. Alvarez-Mugica, J. L. Alvarez-Ossorio, C. Cordon-Cardo, F. Cava and M. Sanchez-Carbayo, “miR-143, miR-222, and miR-452 Are Useful as Tumor Stratification and Noninvasive Diagnostic Biomarkers for Bladder Cancer,” American Journal of Pathology, Vol. 180, No. 5, 2012, pp. 1808-1815. doi:10.1016/j.ajpath.2012.01.034
[26] E. V. Grigorenko, E. Ortenberg, J. Hurley, A. Bond and K. Munnelly, “miRNA Profiling on High-Throughput OpenArrayTM System,” Methods in Molecular Biology, Vol. 676, 2011, pp. 101-110. doi:10.1007/978-1-60761-863-8_8
[27] R. E. Hershberger, J. Lindenfeld, L. Mestroni, C. E. Seidman, M. R. Taylor and J. A. Towbin, “Genetic Evaluation of Cardiomyopathy: A Heart Failure Society of America Practice Guideline,” Journal of Cardiac Failure, Vol. 15, No. 2, 2009, pp. 83-97. doi:10.1016/j.cardfail.2009.01.006
[28] C. Andreasen, J. B. Nielsen, L. Refsgaard, A. G. Holst, A. H. Christensen, L. Andreasen, A. Sajadieh, S. Haunso, J. H. Svendsen and M. S. Olesen, “New Population-Based Exome Data Are Questioning the Pathogenicity of Previously Cardiomyopathy-Associated Genetic Variants,” European Journal of Human Genetics, 2013. doi:10.1038/ejhg.2012.283
[29] D. Lassner, M. Rohde, U. M. Gross, F. Escher, H. P. Schultheiss, R. P. Linke and U. Kühl, “Classification of Four Chemically Different Amyloid Types in Routine Endomyocardial Biopsies by Advanced Immunohistochemistry,” Amyloid, Vol. 18, Suppl. 1, 2011, pp. 76-78. doi:10.3109/13506129.2011.574354027
[30] D. A. Wheeler, M. Srinivasan, M. Egholm, et al., “The Complete Genome of an Individual by Massively Parallel DNA Sequencing,” Nature, Vol. 452, No. 7189. 2008, pp. 872-876. doi:10.1038/nature06884
[31] K. Hopp, K. Weber, D. Bellissimo, S. T. Johnson and B. Pietz, “High-Throughput Red Blood Cell Antigen Genotyping Using a Nanofluidic Real-Time Polymerase Chain Reaction Platform,” Transfusion, Vol. 50, No. 1, 2010, pp. 40-46. doi:10.1111/j.1537-2995.2009.02377.x
[32] L. J. Cooper, J. M. Hare, H. D. Tazelaar, et al., “Usefulness of Immunosupp. Ression for Giant Cell Myocarditis,” American Journal of Cardiology, Vol. 102, 2008, pp. 1535-1539. doi:10.1016/j.amjcard.2008.07.041
[33] A. Frustaci, C. Chimenti, F. Calabrese, et al., “Immunosupp. Ressive Therapy for Active Lymphocytic Myocarditis: Virological and Immunologic Profile of Responders versus Nonresponders,” Circulation, Vol. 107, 2003, pp. 857-863. doi:10.1161/01.CIR.0000048147.15962.31
[34] A. Frustaci, M. A. Russo and C. Chimenti, “Randomized Study on the Efficacy of Immunosupp. Ressive Therapy in Patients with Virus-Negative Inflammatory Cardiomyopathy: The TIMIC Study,” European Heart Journal, Vol. 30, No. 16, 2009, pp. 1995-2002. doi:10.1093/eurheartj/ehp249
[35] U. Kuhl, M. Pauschinger, P. L. Schwimmbeck, B. Seeberg, C. Lober and M. Noutsias, “Interferon-Beta Treatment Eliminates Cardiotropic Viruses and Improves Left Ventricular Function in Patients with Myocardial Persistence of Viral Genomes and Left Ventricular Dysfunction,” Circulation, Vol. 107, No. 22, 2003, pp. 2793-2798. doi:10.1161/01.CIR.0000072766.67150.51
[36] C. Schmidt-Lucke, F. Spillmann, T. Bock, U. Kühl, S. Van Linthout, H.-P. Schultheiss and C. Tschope “Interferon Beta Modulates Endothelial Damage in Patients with Cardiac Persistence of Human Parvovirus b19 Infection,” The Journal of Infectious Diseases, Vol. 201 No. 6, 2010, pp. 936-945. doi:10.1086/650700
[37] T. M. Wheeler, A. J. Leger, S. K. Pandey, A. R. MacLeod, M. Nakamori, S. H. Cheng, B. M. Wentworth, C. F. Bennett and C. A. Thornton, “Targeting Nuclear RNA for in Vivo Correction of Myotonic Dystrophy,” Nature, Vol. 488, No. 7409, 2012, pp. 111-115. doi:10.1038/nature11362
[38] T. G. Hullinger, R. L. Montgomery, A. G. Seto, B. A. Dickinson, et al., “Inhibition of miR-15 Protects against Cardiac Ischemic Injury,” Circulation Research, Vol. 110, No. 1, 2012, pp. 71-81. doi:10.1161/CIRCRESAHA.111.244442
[39] L. T. Cooper, K. L. Baughman, A. M. Feldman, A. Frustaci, M. Jessup, U. Kuhl, G. N. Levine, J. Narula, R. C. Starling, J. Towbin and R. Virmani, American Heart Association, American College of Cardiology, European Society of Cardiology, Heart Failure Society of America and Heart Failure Association of the European Society of Cardiology, “The Role of Endomyocardial Biopsy in the Management of Cardiovascular Disease: A Scientific Statement from the American Heart Association, the American College of Cardiology, and the European Society of Cardiology. Endorsed by the Heart Failure Society of America and the Heart Failure Association of the European Society of Cardiology,” Journal of the American College of Cardiology, Vol. 50, No. 19, 2007, pp. 1914-1931. doi:10.1016/j.jacc.2007.09.008

Copyright © 2024 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.