This SAMHD1-dNTP-mtDNA-NLRP3 axis is supported by emerging evidence as a potential upstream checkpoint that may set macrophage inflammatory tone and may contribute to three major manifestations of obesity-associated cardiovascular pathology: accelerated atherosclerosis, diastolic dysfunction in obesity cardiomyopathy, and exaggerated ischemia-reperfusion injury. Here, SAMHD1 is linked to cardiomyopathy.