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

doi:10.1371/journal.pone.0173371

Abstract

BackgroundMatrix 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 resultsIn 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.ConclusionsEven 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.

Highlights

Takotsubo cardiomyopathy (TTC), a form of acute heart failure, mimics myocardial infarction with similar electrocardiogram and cardiac enzyme findings [1]
We aimed to discover whether their serum tissue inhibitors of matrix metalloproteinases (TIMPs)-1 and Matrix metalloproteinases (MMPs)-8 levels correlate with severity or variant of the contraction abnormality in takotsubo cardiomyopathy (TTC), and may play a role in the underlying pathophysiology
Among the cardiovascular risk factors, the controls had a lower body mass index (BMI) than did those with acute coronary syndrome (ACS) or TTC

Summary

Introduction

Takotsubo cardiomyopathy (TTC), a form of acute heart failure, mimics myocardial infarction with similar electrocardiogram and cardiac enzyme findings [1]. Disturbance in MMP and TIMP balance may raise or lower the ECM fibrotic material and accompany inflammation Such changes, especially in MMP-8 and TIMP-1 levels, accompany the pathogenesis of atherosclerosis and acute coronary syndrome [6,7,8,9]. In myocardial ECM, an altered MMP and TIMP balance may lead to structural and functional changes, and subsequent impairment of cardiac function as seen in heart failure and various cardiomyopathy patients [10,11]. 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.

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Results

Discussion

Conclusion