This Article Full Text Full Text (PDF) All Versions of this Article: 117/14/1810    most recent CIRCULATIONAHA.107.725481v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Moens, A. L. Articles by Kass, D. A. Search for Related Content PubMed PubMed Citation Articles by Moens, A. L. Articles by Kass, D. A. Related Collections Biochemistry and metabolism Primary prevention Animal models of human disease Ischemic biology - basic studies Acute coronary syndromes Oxidant stress Related Article

(Circulation. 2008;117:1810-1819.)
© 2008 American Heart Association, Inc.

Heart Failure

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

An L. Moens, MD; Hunter C. Champion, MD, PhD; Marc J. Claeys, MD, PhD; Barbara Tavazzi, MD, PhD; Pawel M. Kaminski, MD, PhD; Michael S. Wolin, MD, PhD; Dirk J. Borgonjon, MS; Luc Van Nassauw, PhD; Azeb Haile, MS; Muz Zviman, PhD; Djahida Bedja, MS; Floris L. Wuyts, PhD; Rebecca S. Elsaesser, PhD; Paul Cos, PhD; Kathy L. Gabrielson, DVM, PhD; Giuseppe Lazzarino, MD, PhD; Nazareno Paolocci, MD, PhD; Jean-Pierre Timmermans, PhD; Christiaan J. Vrints, MD, PhD; David A. Kass, MD

From the Johns Hopkins Medical Institutions, Divisions of Cardiology (A.L.M., H.C.C., A.H., M.Z., D.B., K.L.G., N.P., D.A.K.) and Pathology (R.S.E.), Baltimore, Md; University of Antwerp, Departments of Cardiology (A.L.M., M.J.C., D.J.B., P.C., C.J.V.), Cell Biology and Histology (L.V.N., J.-P.T.), and Biomedical Statistics (F.L.W.), Antwerp, Belgium; University of Rome, Department of Chemical Science, Rome, Italy (B.T., G.L.); and New York Medical College, Department of Physiology, Valhalla (P.M.K., M.W.S.).

Correspondence to David A. Kass, MD, Johns Hopkins Medical Institutions, Division of Cardiology, Ross Research Bldg, Room 835, 720 Rutland Ave, Baltimore, MD 21205. E-mail dkass{at}jhmi.edu

Received July 5, 2007; accepted January 11, 2008.

Background— The B vitamin folic acid (FA) is important to mitochondrial protein and nucleic acid synthesis, is an antioxidant, and enhances nitric oxide synthase activity. Here, we tested whether FA reduces myocardial ischemic dysfunction and postreperfusion injury.

Methods and Results— Wistar rats were pretreated with either FA (10 mg/d) or placebo for 1 week and then underwent in vivo transient left coronary artery occlusion for 30 minutes with or without 90 minutes of reperfusion (total n=131; subgroups used for various analyses). FA (4.5x10^–6 mol/L IC) pretreatment and global ischemia/reperfusion (30 minutes/30 minutes) also were performed in vitro (n=28). After 30 minutes of ischemia, global function declined more in controls than in FA-pretreated rats (dP/dtmax, –878±586 versus –1956±351 mm Hg/s placebo; P=0.03), and regional thickening was better preserved (37.3±5.3% versus 5.1±0.6% placebo; P=0.004). Anterior wall perfusion fell similarly (–78.4±9.3% versus –71.2±13.8% placebo at 30 minutes), yet myocardial high-energy phosphates ATP and ADP reduced by ischemia in controls were better preserved by FA pretreatment (ATP: control, 2740±58 nmol/g; ischemia, 947±55 nmol/g; ischemia plus FA, 1332±101 nmol/g; P=0.02). Basal oxypurines (xanthine, hypoxanthine, and urate) rose with FA pretreatment but increased less during ischemia than in controls. Ischemic superoxide generation declined (3124±280 cpm/mg FA versus 5898±474 cpm/mg placebo; P=0.001). After reperfusion, FA-treated hearts had smaller infarcts (3.8±1.2% versus 60.3±4.1% placebo area at risk; P<0.002) and less contraction band necrosis, terminal deoxynucleotidyl transferase–mediated dUTP nick-end labeling positivity, superoxide, and nitric oxide synthase uncoupling. Infarct size declined similarly with 1 mg/d FA.

Conclusions— FA pretreatment blunts myocardial dysfunction during ischemia and ameliorates postreperfusion injury. This is coupled to preservation of high-energy phosphates, reducing subsequent reactive oxygen species generation, eNOS-uncoupling, and postreperfusion cell death.

---

 

CLINICAL PERSPECTIVE

Related Article:

Clinical Summaries
Circulation 2008 117: 1769. [Extract] [Full Text]

This article has been cited by other articles:

				C. S. Thompson-Torgerson, H. C. Champion, L. Santhanam, Z. L. Harris, and A. A. Shoukas Cyclohexanone contamination from extracorporeal circuits impairs cardiovascular function Am J Physiol Heart Circ Physiol, June 1, 2009; 296(6): H1926 - H1932. [Abstract] [Full Text] [PDF]

				C. Antoniades, A. S. Antonopoulos, D. Tousoulis, K. Marinou, and C. Stefanadis Homocysteine and coronary atherosclerosis: from folate fortification to the recent clinical trials Eur. Heart J., January 1, 2009; 30(1): 6 - 15. [Abstract] [Full Text] [PDF]

				C. R. Greyson 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" Circulation, November 18, 2008; 118(21): e703 - e703. [Full Text] [PDF]

				A. L. Moens, H. C. Champion, A. Haile, M. Zviman, D. Bedja, K. L. Gabrielson, N. Paolocci, D. A. Kass, R. S. Elsaesser, M. J. Claeys, et al. 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" Circulation, November 18, 2008; 118(21): e704 - e704. [Full Text] [PDF]

				R. Tian and J. S. Ingwall How Does Folic Acid Cure Heart Attacks? Circulation, April 8, 2008; 117(14): 1772 - 1774. [Full Text] [PDF]