Matrix Metalloproteinases and Tissue Inhibitors of Metalloproteinases in Extracellular Matrix Remodeling during Left Ventricular Diastolic Dysfunction and Heart Failure with Preserved Ejection Fraction: A Systematic Review and Meta-Analysis

Abstract

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.

Matrix Metalloproteinases and Their Role in Mechanisms Underlying Effects of Quercetin on Heart Function in Aged Zucker Diabetic Fatty Rats

“…Changes in MMPs activation could be related to structural disorganizations of the cardiac extracellular space associated with disruption of cardiac function. Increased MMPs were found to be related to development of cardiac fibrosis and left ventricular diastolic dysfunction [ 35 ]. Moreover, application of MMP inhibitor was found to protect the heart against ischemia/reperfusion and this was associated with improved recovery of cardiac work, cardiac output, and aortic flow during reperfusion [ 36 ].…”

Neutrophil degranulation biomarkers characterize restrictive echocardiographic pattern with diastolic dysfunction in patients with diabetes

“…Well established is instead the association between MMPs and LVDD in animal models. 31 Equally interesting is the evidence about the potential involvement of resistin in diabetic cardiomyopathy. Traditionally known as is cysteine-rich adipokine with downregulating effect of insulin signalling, 32 resistin is highly expressed in mononuclear cells and stored in the primary granules of neutrophils.…”

“…With regard to myocardial function, neutrophil degranulation has been associated with increased intraventricular diastolic pressure in patients with hypertensive heart disease 29 and severe chronic kidney disease, 30 but not yet in diabetic patients. Well established is instead the association between MMPs and LVDD in animal models 31 …”

Role of Diabetes Mellitus in Heart Failure With Preserved Ejection Fraction: A Review Article

“…Several pathways involved in the downregulation of matrix degradation are also activated, further causing a worsened imbalance between matrix deposition and degradation. LV diastolic dysfunction and HFpEF are partly due to this imbalance [ 20 ].…”