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Association of polymorphisms of zinc metalloproteinases with clinical response to stem cell therapy

Verbindung zwischen Polymorphismen von Zink-Metalloproteinasen und deren klinischer Antwort auf Stammzelltherapie

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Abstract

Aim

The purpose of this study was to assess the associations of polymorphisms in two metalloproteinase genes—metalloproteinase-2 (MMP-2) and angiotensin converting enzyme (ACE)—with clinical response to autologous transplantation of mononuclear bone marrow cells (MBMC) in patients with acute myocardial infarction.

Methods

The double centre study included 48 patients with a first acute myocardial infarction treated with primary coronary angioplasty, stent implantation and transplantation of MBMC. According to the changes in perfusion defect size, left ventricle ejection fraction, end-systolic volume and peak systolic velocity of the infracted wall (dSaMI) after cell therapy, the patients were retrospectively divided into group A (responders) and group B (non-responders). Genomic DNA was isolated from peripheral leukocytes by a standard technique using proteinase K. Three MMP-2 promoter (-1575G/A, -1306C/T and -790T/G) as well as I/D ACE gene polymorphisms were detected by PCR methods with restriction analyses (when necessary) according to standard protocols.

Results

Of the 48 patients who received MBMC transplantation, 17 responded to the therapy. There were no significant differences in the prevalence of matrix metalloproteinase-2 triple genotype GGCCTT between responder/non-responder groups (71% versus 61%, p=0.375). Similarly, no differences in either genotype distribution or allelic frequencies of I/D ACE polymorphism between responders and non-responders to the cell therapy were observed (p=0.933). Compared to patients with ACE genotype ID or DD, the patients with ACE II genotype significantly improved in regional systolic LV function of the infarcted wall after implantations of MBMC (dSaMI – 0.4 versus 1.4 cm/s, p=0.037).

Conclusion

In our study, the ACE genotype II was associated with improvement of regional systolic LV function of the infarcted wall after implantations of MBMC. The detected polymorphism in matrix metalloproteinase-2 gene was not associated with clinical response to cell therapy.

Zusammenfassung

Fragestellung

Ziel der Studie war, die Verbindung zwischen zwei Zink-Metalloproteinase-Genen − Matrix-Metalloproteinase-2 (MMP-2) und Angiotensin-converting-Enzym (ACE) − und deren klinische Reaktion auf autologe Transplantation von mononukleären Knochenmarkzellen (MBMC) bei Patienten mit einem akuten Myokardinfarkt zu untersuchen.

Patienten und Methodik

In die an zwei Zentren durchgeführte Studie waren 48 Patienten eingeschlossen, die wegen eines erstmaligen Myokardinfarkts mit primärer Koronarangioplastie, Stentimplantation und MBMC-Transplantation behandelt wurden. In Abhängigkeit von der Größenänderung des Perfusionsdefekts, der linksventrikulären Ejektionsfraktion (LVEF), des endsystolischen Volumens und der systolischen Maximalgeschwindigkeit der infarzierten Wand (dSaMI) nach der Stammzelltherapie wurden die Patienten retrospektiv in Gruppe A (Responder) und Gruppe B (Nonresponder) eingeteilt. Die Genom-DNA wurde aus peripheren Leukozyten mittels standardisierter Techniken unter Verwendung von Proteinase K isoliert. Sowohl drei MMP-2-Promotoren (-1575G/A, -1306C/T und -790T/G) als auch I/D-ACE-Polymorphismen wurden mittels Polymerase-Kettenreaktion (PCR) und mit Restriktionsanalysen unter Beachtung von Standardprotokollen nachgewiesen.

Ergebnisse

Von 48 Patienten, die eine MBMC-Transplantation erhielten, waren 17 Therapieresponder. Bezüglich der Prävalenz der MMP-2-Triple-Genotypen GGCCTT konnte zwischen Respondern und Nonrespondern (71% vs. 61%; p=0,375) kein signifikanter Unterschied nachgewiesen werden. In ähnlicher Weise wurden weder Unterschiede in der Genotypverteilung noch bei den Allelfrequenzen der I/D-ACE-Polymorphismen zwischen Respondern und Nonrespondern bezüglich der Zelltherapie beobachtet (p=0,933). Im Vergleich zu Patienten mit ACE-Genotyp ID oder DD zeigten die Patienten mit dem ACE-Genotyp II eine signifikante Verbesserung in Bezug auf die regionale systolische linksventrikuläre Funktion der infarzierten Herzmuskelwand nach Implantation von MBMC (dSaMI – 0,4 vs. 1,4 cm/s; p=0,037).

Schlussfolgerung

Im Rahmen dieser Studie konnte für den ACE-Genotyp II eine Verbesserung der regionalen systolischen linksventrikulären Funktion der infarzierten Muskelwand nach MBMC-Implantation nachgewiesen werden. Der detektierte Polymorphismus der MMP-2-Gene war nicht mit einer klinischen Antwort auf die Zelltherapie assoziiert.

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Acknowledgements

The work was supported by a grant of the Ministry of Education of the Czech Republic No. MSM 0021622402.

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Authors and Affiliations

  1. 1st Department of Internal Medicine/Cardioangiology, International Clinical Research Center Brno – ICRC,St. Anna Hospital, Masaryk University, Pekařská 53, 656 91, Brno, Czech Republic

    R. Panovsky Ph.D., J. Meluzin, V. Kincl & L. Groch

  2. Institute of Pathological Physiology, Faculty of Medicine, Masaryk University, Brno, Czech Republic

    A. Vasku

  3. Department of Nuclear Medicine, University Hospital Olomouc, Olomouc, Czech Republic

    M. Kaminek

  4. Department of Internal Medicine/Hematooncology, Brno University Hospital, Masaryk University, Brno, Czech Republic

    J. Mayer & M. Navratil

  5. Department of Internal Medicine/Cardiology, Brno University Hospital, Masaryk University, Brno, Czech Republic

    S. Janousek

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  1. R. Panovsky Ph.D.
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Correspondence to R. Panovsky Ph.D..

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Panovsky, R., Vasku, A., Meluzin, J. et al. Association of polymorphisms of zinc metalloproteinases with clinical response to stem cell therapy. Herz 35, 309–316 (2010). https://doi.org/10.1007/s00059-010-3353-z

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