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.
Highlights
Left ventricular diastolic dysfunction (LVDD) is an early common alteration in many cardiovascular diseases (CVDs) and highly prevalent in the general population, with reported incidence ranging from 3% to 39% [1,2]
In our systematic review concerning animal models of LVDD/heart failure (HF) with preserved ejection fraction (HFpEF) and cardiac fibrosis in relation to Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs), we aimed to identify patterns associating extracellular matrix (ECM) dynamics with LVDD and HFpEF pathology
Our study shows that when MMPs and TIMPs are studied in relation to LVDD/HFpEF, cardiac mRNA expression is still most frequently measured while this does not seem to resemble cardiac ECM dynamics in these experimental models
Summary
Left ventricular diastolic dysfunction (LVDD) is an early common alteration in many cardiovascular diseases (CVDs) and highly prevalent in the general population, with reported incidence ranging from 3% to 39% [1,2]. LVDD leads to elevated LV filling pressures which result from increased chamber stiffness, reduced restoring forces and impaired left atrial (LA) function and LV relaxation [3,4,5]. Evidence from clinical studies supports the concept that HFrEF and HFpEF have a different pathophysiology [14]. LVDD appears to be a chronic systemic syndrome resulting from CVD co-morbidities [15] which include hypertension and chronic kidney disease (CKD) [16,17], diabetes [18], obesity and metabolic syndrome [19,20] and ageing [21]
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