Your body uses a specific enzyme called ALDH-2 to turn nitroglycerin (a heart medicine) into something that helps relax blood vessels. But if your body is under stress and produces too many harmful molecules, this enzyme gets blocked — which is why the medicine stops working as well over time.

In humans with angina, comparing nitroglycerin efficacy in those with genetically confirmed ALDH-2 deficiency vs. wild-type, while measuring nitrate tolerance development over 7 days of daily dosing, with plasma nitrite/nitrate and vascular reactivity as primary outcomes.

Direct demonstration that ALDH-2 inhibition by oxidative stress (e.g., via H2O2 or peroxynitrite) reduces nitroglycerin bioactivation in human vascular smooth muscle cells and that restoring ALDH-2 activity reverses tolerance.

That ALDH-2 knockout mice develop nitrate tolerance faster than wild-type mice when administered low-dose nitroglycerin, and that oxidative stress markers correlate with loss of vasodilatory response.

That patients developing nitrate tolerance show lower ALDH-2 activity and higher oxidative stress markers compared to non-tolerant patients on identical nitroglycerin regimens.

That individuals with the ALDH-2*2 loss-of-function polymorphism (rs671) are more likely to develop nitrate tolerance within 7 days of low-dose nitroglycerin therapy.