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Homocysteine impairs coronary microvascular dilator function in humans
Ahmed Tawakol1, Marc A Forgione, Markus Stuehlinger
1Departments of Medicine (Cardiac Unit), Massachusetts General Hospital, Boston, Massachusetts 02114, USA. atawakol@partners.org
Insights
Acute hyperhomocysteinemia impairs coronary microvascular dilation by reducing nitric oxide (NO) bioavailability. This study used positron emission tomography (PET) to demonstrate this effect in healthy humans.
Area of Science:
- Cardiovascular Physiology
- Metabolic Disorders
- Diagnostic Imaging
Background:
- Hyperhomocysteinemia is linked to impaired vasodilation in peripheral arteries.
- Its impact on the coronary circulation remains largely unknown.
- Understanding this relationship is crucial for cardiovascular health.
Purpose of the Study:
- To investigate the effect of hyperhomocysteinemia on coronary microvascular dilator function.
- To test the hypothesis that elevated homocysteine levels adversely affect coronary blood flow regulation.
- To elucidate the role of nitric oxide (NO) in this process.
Main Methods:
- Positron emission tomography (PET) was used to measure myocardial blood flow (MBF) in 18 healthy subjects.
- A double-blind, crossover design involved inducing hyperhomocysteinemia with methionine and measuring MBF response to adenosine.
- Brachial artery ultrasonography assessed flow-mediated dilation, and NG-monomethyl-l-arginine (l-NMMA) was used to inhibit nitric oxide synthase.
Main Results:
- Hyperhomocysteinemia significantly reduced the dose-response of MBF to adenosine, particularly at low doses (p < 0.05).
- Flow-mediated brachial artery vasodilation was also impaired during hyperhomocysteinemia (p < 0.05).
- Inhibition of NO synthesis with l-NMMA blunted the MBF response to adenosine, confirming NO's role.
Conclusions:
- Acute hyperhomocysteinemia impairs microvascular dilation in the human coronary circulation.
- This impairment is attributed to a reduction in nitric oxide (NO) bioavailability.
- The findings highlight a potential mechanism linking elevated homocysteine to cardiovascular risk.
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).
Conclusion:
The data, therefore, support the hypothesis that acute hyperhomocysteinemia impairs microvascular dilation in the human coronary circulation as a result of reduced NO bioavailability.