Finally, B-vitamin/folate strategies address homocysteine, a vascular toxin that upregulates MMP-9 and disrupts endothelial integrity; mechanistic human data link hyperhomocysteinemia to excess MMP-9, providing a biologic rationale for homocysteine-lowering regimens as indirect MMP-9 modulators in atherosclerotic risk states [145]. This evidence concerns the gene MMP9 and hyperhomocysteinemia.