CLINICAL STUDY: ATHEROSCLEROSIS
Homocysteine impairs coronary microvascular dilator function in humans
Ahmed Tawakol, MD*,*,
Marc A. Forgione, MD ,
Markus Stuehlinger, MD||,
Nathaniel M. Alpert, MD ,
John P. Cooke, MD, PhD, FACC||,
Joseph Loscalzo, MD, PhD, FACC,
Alan J. Fischman, MD, PhD,
Mark A. Creager, MD, FACC and
Henry Gewirtz, MD*
* Departments of Medicine (Cardiac Unit), Massachusetts General Hospital, Boston, Massachusetts, USA
Department of Radiology and Nuclear Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
Department of Medicine (Cardiovascular Division), Brigham and Women’s Hospital, Boston, Massachusetts, USA
Department of Medicine, Boston University Medical Center, Boston, Massachusetts, USA
|| Department of Medicine, Stanford University Medical Center, Stanford, California, USA
Manuscript received November 28, 2001;
revised manuscript received May 7, 2002,
accepted June 12, 2002.
* Reprint requests and correspondence: Dr. Ahmed Tawakol, Cardiac Unit/Vincent Burnham 3, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
atawakol{at}partners.org
OBJECTIVES: We sought to use positron emission tomography (PET) to test the hypothesis that hyperhomocysteinemia adversely effects coronary microvascular dilator function.
BACKGROUND: Hyperhomocysteinemia is associated with abnormal endothelium-dependent vasodilation in peripheral human arteries. However, its effect on the coronary circulation is not known.
METHODS: Eighteen healthy humans, age 24 to 56 years, were enrolled in a double-blind, crossover trial. Basal and adenosine-stimulated myocardial blood flow (MBF) was determined by PET: after ingestion of placebo and after methionine-induced hyperhomocysteinemia. Further, brachial ultrasonography was used to assess flow-mediated vasodilation. Additionally, to assess the role of nitric oxide (NO) in adenosine-mediated vasodilation, the MBF response to adenosine was measured in the presence and absence of the NO synthase antagonist NG-monomethyl-l-arginine (l-NMMA) (0.3 mg/kg/min intravenously).
RESULTS: Hyperhomocysteinemia resulted in a reduction in the MBF dose-response curve to adenosine (p < 0.05). This was most apparent with low dose adenosine, where MBF augmentation was significantly blunted during hyperhomocysteinemia (1.06 ± 1.00 ml/min/g vs. 0.58 ± 0.78 ml/min/g, placebo vs. methionine, p < 0.05). Similarly, flow-mediated brachial artery vasodilation was impaired during hyperhomocysteinemia (4.4 ± 2.6% vs. 2.6 ± 2.3%, placebo vs. methionine, p < 0.05). In a separate series of experiments, MBF during adenosine was reduced in the presence of l-NMMA (p < 0.05 analysis of variance). This was most apparent at the low dose of adenosine, where MBF response to adenosine was blunted in the presence of l-NMMA (2.08 ± 1.34 ml/min/g vs. 1.48 ± 1.32 ml/min/g, placebo vs. l-NMMA, p < 0.05).
CONCLUSIONS: The data, therefore, support the hypothesis that acute hyperhomocysteinemia impairs microvascular dilation in the human coronary circulation as a result of reduced NO bioavailability.
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Abbreviations and Acronyms
| | ADMA | | asymmetric dimethylarginine | | G | | myocardial conductance | | HR | | heart rate | | l-NMMA | | NG-monomethyl-l-arginine | | MAP | | mean arterial pressure | | MBF | | myocardial blood flow | | METH | | methionine-induced hyperhomocysteinemia | | NO | | nitric oxide | | NOS | | nitric oxide synthase | | PET | | positron emission tomography | | RPP | | rate-pressure product | | SBP | | systolic blood pressure |
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