In 23 animal studies (36 comparisons), MMP2 and MMP9 activity and TIMP1 protein levels were primarily enhanced in hemodynamic models of LVDD and HFpEF, with no tissue-plasma correlation.
Meta-Analysis (n=23)
In animal models of LVDD and HFpEF, MMP and TIMP profiles vary by underlying pathology and do not correlate between cardiac tissue and plasma, highlighting challenges in using them as circulating biomarkers.
Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) are pivotal regulators of extracellular matrix (ECM) composition and could, due to their dynamic activity, function as prognostic tools for fibrosis and cardiac function in left ventricular diastolic dysfunction (LVDD) and heart failure with preserved ejection fraction (HFpEF). We conducted a systematic review on experimental animal models of LVDD and HFpEF published in MEDLINE or Embase. Twenty-three studies were included with a total of 36 comparisons that reported established LVDD, quantification of cardiac fibrosis and cardiac MMP or TIMP expression or activity. LVDD/HFpEF models were divided based on underlying pathology: hemodynamic overload (17 comparisons), metabolic alteration (16 comparisons) or ageing (3 comparisons). Meta-analysis showed that echocardiographic parameters were not consistently altered in LVDD/HFpEF with invasive hemodynamic measurements better representing LVDD. Increased myocardial fibrotic area indicated comparable characteristics between hemodynamic and metabolic models. Regarding MMPs and TIMPs; MMP2 and MMP9 activity and protein and TIMP1 protein levels were mainly enhanced in hemodynamic models. In most cases only mRNA was assessed and there were no correlations between cardiac tissue and plasma levels. Female gender, a known risk factor for LVDD and HFpEF, was underrepresented. Novel studies should detail relevant model characteristics and focus on MMP and TIMP protein expression and activity to identify predictive circulating markers in cardiac ECM remodeling.
Krebber et al. (2020) conducted a meta-analysis in Left ventricular diastolic dysfunction (LVDD) and heart failure with preserved ejection fraction (HFpEF) in animal models (n=23). In 23 animal studies (36 comparisons), MMP2 and MMP9 activity and TIMP1 protein levels were primarily enhanced in hemodynamic models of LVDD and HFpEF, with no tissue-plasma correlation.