Abstract and Introduction
Abstract
Aims We investigated the temporal changes in circulating levels of markers of extracellular cardiac matrix (ECCM) turnover and their relationship with infarct size (IS), ejection fraction (EF), and left ventricular (LV) volumes, determined by serial cardiac magnetic resonance (CMR) imaging in patients with first-time ST-elevation myocardial infarction (STEMI).
Methods and results Forty-two patients with a first-time STEMI, successfully revascularized by primary percutaneous coronary intervention (pPCI) had serum samples taken prior to pPCI, 2, 7 days, 2 months, and 1 year following STEMI for the analysis of the markers of collagen synthesis, and collagen degradation. Late enhancement and cine CMR was performed on Days 2, 7, 2 months, and 1-year post-STEMI. There was a significant increase in type I collagen degradation following STEMI that was not accompanied by an increase in collagen type I synthesis until 2 months and 1 year. In contrast to the delay in type I collagen synthesis, there was an immediate increase in type III collagen synthesis that was sustained for 1 year. N-terminal procollagen type I levels assessed prior to pPCI were predictive of adverse LV remodelling at all CMR time-points.
Conclusions Our findings indicate a net type I collagen breakdown in the first week following STEMI compensated by an early increase in collagen type III synthesis. There is an increase in both type I and III collagen synthesis markers at 2 months and 1 year, indicating a persistent increase in collagen turnover even in these apparently successfully treated patients.
Introduction
Myocardial infarction (MI) initiates a complex process of repair within the infarct zone, with an adaptation to the loss of the functional myocardium within the non-infarcted myocardium. While this process may be compensatory, it may also aggravate left ventricular (LV) dysfunction via adverse remodelling, a structural, functional, and genetic process, leading to LV dilatation, abnormal geometry, and chronic volume overload. There is an emerging understanding that dysregulation of the extracellular cardiac matrix (ECCM) is an active contributor to progressive LV remodelling causing either excessive collagen deposition with subsequent fibrosis or insufficient collagen deposition and/or collagen degradation with subsequent LV dilatation.
Extracellular cardiac matrix turnover following MI may be assessed by circulating fragments of collagen synthesis and degradation, and by circulating levels of regulators of extracellular cardiac matrix degradation such as matrix metalloproteinase (MMPs) and their inhibitors, tissue inhibitors of metalloproteinases (TIMPs). Type I and III collagens are the major structural proteins of the ECCM in the human heart. N-terminal type I procollagen (PINP) is considered to be a marker of type I collagen synthesis, whereas C-terminal telopeptide of type I collagen (ICTP) is a marker of collagen type I degradation. Circulating levels of N-terminal type III procollagen (PIIINP) reflect type III collagen synthesis.
Several studies have demonstrated an association between increased MMP and TIMP levels and adverse outcome following MI. Circulating levels of both type I and type III collagen fragments have been shown to have prognostic value in patients who developed heart failure following MI.
These findings suggest a relationship between markers of ECCM turnover and adverse LV remodelling. However, the dynamic relationship between these markers, infarct healing, and LV remodelling has not been elucidated adequately. The present study therefore analysed the temporal relationship between PINP, ICTP, PIIINP, MMP-2, -3, and -9, as well as TIMP-1, -2, and -4, infarct size (IS), and LV remodelling following a first acute ST-elevation MI (STEMI) in patients successfully treated by primary percutaneous coronary intervention (pPCI).