Abstract
In this observational cohort study, we examined the prognostic value of growth and differentiation factor 15 (GDF15) in indicating and monitoring general mitochondrial disease severity and progression in adult carriers of the m.3243A>G mutation.
Ninety-seven adult carriers of the m.3243A>G mutation were included in this study. The Newcastle mitochondrial disease adult scale was used for rating mitochondrial disease severity. In parallel, blood was drawn for GDF15 analysis by ELISA. Forty-nine carriers were included in a follow-up study. In a small subset of subjects of whom an echocardiogram was available from general patient care, myocardial deformation was assessed using two-dimensional speckle-tracking strain analysis.
A moderate positive correlation was found between the concentration of GDF15 and disease severity (r = 0.59; p < 0.001). The concentration of serum GDF15 was higher in m.3243A>G carriers with diabetes mellitus, cardiomyopathy, and renal abnormalities. After a 2-year follow-up, no significant correlation was found between the change in disease severity and the change in the concentration of GDF15 or between the GDF15 level at the first assessment and the change in disease severity. In the subcohort of patients of whom an echocardiogram was available, the concentration of GDF15 correlated moderately to longitudinal global strain (r = 0.55; p = 0.006; n = 23) but not to circumferential or radial strain.
Our results indicate that serum GDF15 is not a strong surrogate marker for general mitochondrial disease severity. Its value in indicating myocardial deformation should be confirmed in a prospective longitudinal study.
Competing interests: None declared
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References
Association WM (2013) Declaration of Helsinki – ethical principles for medical research involving human subjects. 64th WMA General Assembly, Fortaleza, Brazil
Bates MG, Hollingsworth KG, Newman JH et al (2013) Concentric hypertrophic remodelling and subendocardial dysfunction in mitochondrial DNA point mutation carriers. Eur Heart J Cardiovasc Imaging 14:650–658
Breit SN, Carrero JJ, Tsai VW et al (2012) Macrophage inhibitory cytokine-1 (MIC-1/GDF15) and mortality in end-stage renal disease. Nephrol Dial Transplant 27:70–75
Bulten BF, Mavinkurve-Groothuis AM, de Geus-Oei LF et al (2014) Early myocardial deformation abnormalities in breast cancer survivors. Breast Cancer Res Treat 146:127–135
de Laat P, Koene S, van den Heuvel LP, Rodenburg RJ, Janssen MC, Smeitink JA (2012) Clinical features and heteroplasmy in blood, urine and saliva in 34 Dutch families carrying the m.3243A>G mutation. J Inherit Metab Dis 11:1059–1969
Dominguez-Rodriguez A, Abreu-Gonzalez P, Avanzas P (2014) Usefulness of growth differentiation factor-15 levels to predict diabetic cardiomyopathy in asymptomatic patients with type 2 diabetes mellitus. Am J Cardiol 2:01367–01368
Emma F, Bertini E, Salviati L, Montini G (2012) Renal involvement in mitochondrial cytopathies. Pediatr Nephrol 27:539–550
Hirano M, Konishi K, Arata N et al (2002) Renal complications in a patient with A-to-G mutation of mitochondrial DNA at the 3243 position of leucine tRNA. Intern Med 41:113–118
Ho JE, Mahajan A, Chen MH et al (2012) Clinical and genetic correlates of growth differentiation factor 15 in the community. Clin Chem 58:1582–1591
Ho JE, Hwang SJ, Wollert KC et al (2013) Biomarkers of cardiovascular stress and incident chronic kidney disease. Clin Chem 59:1613–1620
Hollingsworth KG, Gorman GS, Trenell MI et al (2012) Cardiomyopathy is common in patients with the mitochondrial DNA m.3243A>G mutation and correlates with mutation load. Neuromuscul Disord 22:592–596
Izumiya Y, Hanatani S, Kimura Y et al (2014) Growth differentiation factor-15 is a useful prognostic marker in patients with heart failure with preserved ejection fraction. Can J Cardiol 30:338–344
Kalko SG, Paco S, Jou C et al (2014) Transcriptomic profiling of TK2 deficient human skeletal muscle suggests a role for the p53 signalling pathway and identifies growth and differentiation factor-15 as a potential novel biomarker for mitochondrial myopathies. BMC Genomics 15:91
Kempf T, Wollert KC (2013) Risk stratification in critically ill patients: GDF-15 scores in adult respiratory distress syndrome. Crit Care 17:173
Koene S, de Laat P, van Tienoven DH et al (2014) Serum FGF21 levels in adult m.3243A>G carriers: clinical implications. Neurology 6:125–133
Lee SK, Kim J, Kim HD, Lee JS, Lee YM (2010) Initial experiences with proton MR spectroscopy in treatment monitoring of mitochondrial encephalopathy. Yonsei Med J 51:672–675
Lok SI, Winkens B, Goldschmeding R et al (2012) Circulating growth differentiation factor-15 correlates with myocardial fibrosis in patients with non-ischaemic dilated cardiomyopathy and decreases rapidly after left ventricular assist device support. Eur J Heart Fail 14:1249–1256
Mayeux R (2004) Biomarkers: potential uses and limitations. NeuroRx 1:182–188
Montoro-Garcia S, Hernandez-Romero D, Jover E et al (2012) Growth differentiation factor-15, a novel biomarker related with disease severity in patients with hypertrophic cardiomyopathy. Eur J Intern Med 23:169–174
Moore AG, Brown DA, Fairlie WD et al (2000) The transforming growth factor-ss superfamily cytokine macrophage inhibitory cytokine-1 is present in high concentrations in the serum of pregnant women. J Clin Endocrinol Metab 85:4781–4788
Pfeffer G, Horvath R, Klopstock T et al (2013) New treatments for mitochondrial disease-no time to drop our standards. Nat Rev Neurol 9:474–481
Plana JC, Galderisi M, Barac A et al (2014) Expert consensus for multimodality imaging evaluation of adult patients during and after cancer therapy: a report from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. Eur Heart J Cardiovasc Imaging 15:1063–1093
Schaefer AM, Phoenix C, Elson JL, McFarland R, Chinnery PF, Turnbull DM (2006) Mitochondrial disease in adults: a scale to monitor progression and treatment. Neurology 66:1932–1934
St John Sutton M, Ky B, Regner SR et al (2014) Longitudinal strain in Friedreich Ataxia: a potential marker for early left ventricular dysfunction. Echocardiography 31:50–57
Suomalainen A (2011) Biomarkers for mitochondrial respiratory chain disorders. J Inherit Metab Dis 34:277–282
Trovik J, Salvesen HB, Cuppens T, Amant F, Staff AC (2014) Growth differentiation factor-15 as biomarker in uterine sarcomas. Int J Gynecol Cancer 24:252–259
Xu X, Li Z, Gao W (2011) Growth differentiation factor 15 in cardiovascular diseases: from bench to bedside. Biomarkers 16:466–475
Yang CZ, Ma J, Zhu DW et al (2014) GDF15 is a potential predictive biomarker for TPF induction chemotherapy and promotes tumorigenesis and progression in oral squamous cell carcinoma. Ann Oncol 24:24
Yatsuga S, Koga Y (2014) Growth differentiation factor 15 and fibroblast growth factor 21: novel biomarkers for mitochondrial diseases United Mitochondrial Disease Foundation Conference 2014
Acknowledgments
This work was partly supported by the Netherlands Organisation for Scientific Research (the NWO Centres for Systems Biology Research initiative), ZonMW (AGIKO grants Saskia Koene and Dennis Vriens), and Stichting Energy4All. We thank Inge Konijnenberg-Kramer for sample handling. Jan Smeitink is the CEO of Khondrion BV.
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Communicated by: Shamima Rahman, FRCP, FRCPCH, PhD
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Take-Home Message
In adult m.3243A>G carriers, serum GDF15 levels correlate to mitochondrial disease severity and myocardial strain, but not to disease progression
Conflict of Interest
Saskia Koene received research support from the Netherlands Organisation for Scientific Research (NWO).
Paul de Laat received research support from the Stichting Energy4all.
Doorlène H. van Tienoven reports no disclosures.
Gert Weijers reports no disclosures.
Dennis Vriens received research support from the Netherlands Organisation for Scientific Research (NWO) and the Dutch Cancer Society, not related to the current study.
Prof. Fred C.G.J. Sweep reports no disclosures.
Janneke Timmermans reports no disclosures.
Livia Kapusta reports no disclosures.
Dr. Mirian C.H. Janssen reports no disclosures.
Prof. Smeitink is the founder and CEO of Khondrion and is funded by the Netherlands Organisation for Scientific Research and by ongoing Marie Curie and Eurostars grants and grants of Stichting Energy4All, none related to the current study.
This study was not industry sponsored.
Informed Consent
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2013. Informed consent was obtained from all patients for being included in the study.
Details of the Contributions of Authors
Saskia Koene: manuscript preparation, study coordination, and statistical analyses
Paul de Laat: sample collection and patient inventory
Doorlène H. van Tienoven: ELISA and sample handling
Gert Weijers: strain analysis and manuscript revision
Dennis Vriens: statistical analysis, figures, and manuscript revision
Fred C.G.J. Sweep: ELISA, preparations of the analyses, and manuscript revision
Janneke Timmermans: echocardiography
Livia Kapusta: strain analyses and manuscript revision
Mirian C.H. Janssen: patient collection and manuscript revision
Jan A.M. Smeitink: manuscript preparation, study design, and manuscript revision
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Koene, S. et al. (2015). Serum GDF15 Levels Correlate to Mitochondrial Disease Severity and Myocardial Strain, but Not to Disease Progression in Adult m.3243A>G Carriers. In: Zschocke, J., Baumgartner, M., Morava, E., Patterson, M., Rahman, S., Peters, V. (eds) JIMD Reports, Volume 24. JIMD Reports, vol 24. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2015_436
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DOI: https://doi.org/10.1007/8904_2015_436
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