In individuals with diabetic hypertension, silent coronary artery disease (CAD) is common due to underlying chronic inflammation but there is no biomarker to monitor this high-risk group of individuals before noticeable symptoms emerge clinically. cfDNA from dying endothelial cells triggers chronic inflammation, leading us to hypothesize that enzymes that degrade cfDNA, DNase I and/or II, could serve as more sensitive biomarkers for silent CAD. To test this, we conducted a study with 30 hypertensive diabetic patients with clinical symptoms of CAD (CAD-HTN-DM) and 30 controls without CAD (HTN-DM). Negligible serum DNase II activity was detected in both groups. Student's t test was used to compare between cfDNA, DNase I activity, and groups. We observed elevated serum DNase I activity in CAD-HTN-DM group (1.71 ± 0.1 units/ml) compared to HTN-DM group (1.12 ± 0.1 units/ml) (p <
0.0001). Among CAD-HTN-DM group, DNase I activity was significantly higher in patients with all three coronary arteries blocked even though the cfDNA levels were similar in both groups. Elevated DNase I activity was associated with a 1.5-fold increased risk of major adverse cardiac events, despite ongoing treatment with statins, antihypertensive medications, and antidiabetic therapies. Surprisingly, serum DNase I activity was lower in patients who suffered a myocardial infraction. By leveraging our observations, we hope that regular monitoring of serum DNase I activity will identify individuals at high risk for the clinical onset of CAD, enabling early intervention to mitigate its adverse effects and slow its progression.