Changes in the extracellular environment are of significant importance in heart disease.[18][19] Particularly, regulation of genes that alter fibrosis contribute to the development and progression of HFrEF. This regulation is dynamic and involves changes in fibrillar collagens through increased deposition as well as inhibition of enzymes that break down extracellular matrix components (matrix metalloproteinases, collagenases). While early stage HFrEF is associated with a significant disruption of extracellular matrix proteins initially, as it progresses fibrotic replacement of myocardium may occur, leading to scarring and increased interstitial collagen.[20] Fibrotic changes in HFpEF are more variable.