Low MMP-8/TIMP-1 reflects left ventricle impairment in takotsubo cardiomyopathy and high TIMP-1 may help to differentiate it from acute coronary syndrome

Olavi Parkkonen; Mikko T Nieminen; Paula Vesterinen; Taina Tervahartiala; Markus Perola; Veikko Salomaa; Pekka Jousilahti; Timo Sorsa; Pirkko J Pussinen; Juha Sinisalo

doi:10.1371/journal.pone.0173371

Low MMP-8/TIMP-1 reflects left ventricle impairment in takotsubo cardiomyopathy and high TIMP-1 may help to differentiate it from acute coronary syndrome

PLoS One. 2017 Mar 9;12(3):e0173371. doi: 10.1371/journal.pone.0173371. eCollection 2017.

Authors

Affiliations

¹ Heart and Lung Center, Helsinki University Hospital and Helsinki University, Helsinki, Finland.
² Department of Oral and Maxillofacial Diseases, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
³ National Institute for Health and Welfare, Helsinki, Finland.
⁴ Division of Periodontology, Department of Dental Medicine, Karolinska Institutet, Huddinge, Sweden.

Abstract

Background: Matrix metalloproteinase 8 (MMP-8) is the most potent type-I collagen protease. Such collagen mainly constitutes the transient fibrosis in takotsubo cardiomyopathy (TTC) endomyocardial biopsies. High MMP-8 and tissue-inhibitor of matrix metalloproteinase-1 (TIMP-1) levels are implicated in acute coronary syndrome (ACS). We compared MMP-8 and TIMP-1 levels in consecutive TTC and ACS patients, and their association to TTC severity.

Methods and results: In 45 acute serum samples of TTC, 2072 ACS and 1000 controls, TIMP-1 differed between ACS 146.7ng/mL (115.0-186.3) (median (interquartile range)), TTC 115.7 (94.3-137.7) and controls 80.9 (73.2-90.4), (p<0.0001). MMP-8 levels were similar between ACS and TTC. In receiver-operating characteristics analysis, TIMP-1 differentiated TTC from ACS with an area under the curve (AUC) of 0.679 (p<0.0001) surpassing troponin T (TnT) at 0.522 (p = 0.66). Compared to other differing factors (age, sex, smoking), TIMP-1 improved diagnostic specificity and sensitivity from AUC of 0.821 to 0.844 (p = 0.007). The MMP8/TIMP-1 molar ratio differentiated normal ejection fraction (EF) at 0.27 (0.13-0.51) from decreased EF<50% at 0.08 (0.05-0.20), (p = 0.04) in TTC, but not in ACS.

Conclusions: Even with other differing factors considered, TIMP-1 differentiated TTC from ACS better than TnT. In TTC, the low MMP-8/TIMP-1 molar ratio may reflect decreased proteolysis and increased transient fibrosis, perhaps in part explaining the left-ventricle impairment.

MeSH terms

Acute Coronary Syndrome / blood*
Acute Coronary Syndrome / diagnosis*
Adult
Aged
Diagnosis, Differential
Female
Humans
Male
Matrix Metalloproteinase 8 / blood*
Myocardial Contraction
Takotsubo Cardiomyopathy / blood*
Takotsubo Cardiomyopathy / diagnosis*
Takotsubo Cardiomyopathy / enzymology
Takotsubo Cardiomyopathy / physiopathology
Tissue Inhibitor of Metalloproteinase-1 / blood*
Ventricular Dysfunction, Left*

Substances

Tissue Inhibitor of Metalloproteinase-1
Matrix Metalloproteinase 8

Grants and funding

This study was funded by grants from the Finnish Foundation for Cardiovascular Research (to OP, VS and JS) (http://www.sydantutkimussaatio.fi/en/foundation); the Academy of Finland (#1266053 to PJP) (http://www.aka.fi/en/); the Sigrid Juselius Foundation (to PJP) (http://www.sigridjuselius.fi/foundation); the Yrjö Jahnsson Foundation (to PJP) (http://www.yjs.fi/en/); the Aarno Koskelo Foundation (to JS) (http://www.aarnekoskelonsaatio.fi/); and Helsinki University Central Hospital special government funds (to JS EVO #TYH7215, #TKK2012005, #TYH2012209, #TYH2014312, TS EVO #TYH2014244, #TYH2016251).