Response to Letter Regarding Article High-Dose Folic Acid Pretreatment Blunts Cardiac Dysfunction During Ischemia Coupled to Maintenance of High-Energy Phosphates and Reduces Postreperfusion Injury

In his letter, Greyson questions whether enhanced myocardial blood flow rather than altered high-energy phosphate (HEP) metabolism reduced infarct size and better preserved ATP and ADP levels in hearts pretreated with folic acid (FA). He argues that by measuring relative rather than absolute flow reduction between remote and ischemic territories, we missed higher total flows to the heart in FA-pretreated animals despite similar relative flow reduction. However, this question presents a chicken-egg problem: Does FA primarily enhance flow to improve function and ischemic outcome, or is it the other way around? Although our flow analysis has limitations, and further studies with more comprehensive flow analysis would be useful, we believe our findings1 favor the latter hypothesis. First, in isolated hearts in which coronary perfusion was constant, postischemic myocardial preservation was similar to that for the in vivo studies. Although HEP analysis was not performed in these hearts, the data indicate that relevant alternative mechanisms beyond coronary flow must exist. Second, systolic pressure during ischemia was 80 versus 100 mm Hg for FA-treated versus control rats, respectively. Both values fall in an autoregulating range for rats,2 so this difference would not necessarily result in a meaningful disparity of absolute flow and improved function. Although left ventricular end-diastolic pressure rose somewhat more in controls, potentially further reducing the transcoronary pressure gradient, this occurred in the first 10 minutes after occlusion, when function (dP/dtmax, stroke work, relaxation, etc) was similarly maintained in both groups.