Letter by Greyson Regarding Article, “High-Dose Folic Acid Pretreatment Blunts Cardiac Dysfunction During Ischemia Coupled to Maintenance of High-Energy Phosphates and Reduces Postreperfusion Injury”
To the Editor:
Moens et al1 reported that high-dose folic acid (FA) prevents myocardial infarction after occlusion of the left anterior descending coronary artery and reperfusion in open-chest rats; more surprisingly, FA preserved contractile function in the ischemic territory during 30 minutes of ischemia that was otherwise severe enough to induce large infarcts in untreated control rats. The authors hypothesized, and an accompanying editorial discussed, the possibility that FA promotes increased ATP synthesis during ischemia, thereby preserving contractile function and preventing infarction.1,2
A search for previously unknown effects of FA on ATP synthesis is necessary if one accepts the conclusion that ischemic territory blood flow was similar in FA treated and control rats; however, that conclusion appears premature.
Microsphere-based blood flow measurement is commonly used to determine absolute regional myocardial blood flow (MBF) by comparing the ratio of microspheres in a defined quantity of tissue to microspheres in a reference blood sample obtained at the time of microsphere injection.3 In this study, no such reference blood sample was obtained; instead, MBF in ischemic myocardium was expressed relative to MBF in remote nonischemic myocardium. Implicit is the assumption that remote nonischemic MBF was the same in both groups, but this was almost certainly not the case.
FA-treated rats had higher cardiac output and left ventricular pressure, which would likely result in higher nonischemic-territory work and therefore higher nonischemic-territory oxygen demand and MBF. The maximum coronary perfusion pressure of FA-treated rats (approximately equal to left ventricular systolic minus left ventricular diastolic pressure) was 80 mm Hg versus 60 mm Hg for control rats, likely further increasing nonischemic-territory MBF in FA-treated versus control rats because of the dependence of MBF on coronary perfusion pressure. FA also increases MBF at constant coronary perfusion pressure, further increasing nonischemic-territory MBF in FA-treated rats.4 Therefore, it is probable that absolute nonischemic-territory MBF was much higher in FA-treated rats than in control rats, in which case, absolute ischemic-territory MBF was also higher in FA-treated rats than in control rats.
Clearly, FA had pronounced effects on hemodynamics in vivo and on myocardial infarct size in unloaded isolated perfused hearts. Although it is possible that preservation of the nucleotide pool by FA treatment protected against the development of infarction in vivo and in vitro, none of the mechanisms discussed in the article or editorial explain the dramatic increase in myocardial efficiency that would be required to generate substantial external work during ischemia otherwise severe enough to induce large infarcts. On the other hand, higher ischemic-territory MBF in FA-treated rats could explain most or all of the differences in contractile function, infarct size, and ATP in vivo.
Before concluding that the apparent in vivo effects of FA were mediated through effects on purine metabolism rather than through the known effects of FA on vascular function and conventional hemodynamic mechanisms (ie, higher coronary perfusion and increased collateral flow), further studies, perhaps in large animals in which regional MBF can be more carefully measured and controlled, are needed.
Sources of Funding
Dr Greyson receives funding from the Department of Veterans Affairs and the National Institutes of Health/National Heart, Lung, and Blood Institute.
Moens AL, Champion HC, Claeys MJ, Tavazzi B, Kaminski PM, Wolin MS, Borgonjon DJ, Nassauw LV, Haile A, Zviman M, Bedja D, Wuyts FL, Elsaesser RS, Cos P, Gabrielson KL, Lazzarino G, Paolocci N, Timmermans JP, Vrints CJ, Kass DA. High-dose folic acid pretreatment blunts cardiac dysfunction during ischemia coupled to maintenance of high-energy phosphates and reduces postreperfusion injury. Circulation. 2008; 117: 1810–1819.
Tian R, Ingwall JS. How does folic acid cure heart attacks? Circulation. 2008; 117: 1772–1774.