Folic acid improves global coronary vasoreactivity in coronary artery disease patients with normal or elevated homocysteine levels13N-Ammoniak-PETFolsäure verbessert die globale koronare Flussreserve bei koronar herzkranken Patienten mit normaler oder erhöhter Homocysteinkonzentration
S. Graf
1
Department of Cardiology (Head: Gerald Maurer MD)
,
M. Nikfardjam
1
Department of Cardiology (Head: Gerald Maurer MD)
,
A. Khorsand
1
Department of Cardiology (Head: Gerald Maurer MD)
,
S. Ofluoglu
2
Department of Nuclear Medicine (Head Robert Dudczak MD), Medical University of Vienna
,
S. Nekolla
3
Department of Technical University Munich (Head: Markus Schwaiger MD), Munich, Germany
,
R. Dudczak
2
Department of Nuclear Medicine (Head Robert Dudczak MD), Medical University of Vienna
,
G. Maurer
1
Department of Cardiology (Head: Gerald Maurer MD)
,
K. Kletter
1
Department of Cardiology (Head: Gerald Maurer MD)
,
K. Huber
4
Department of Cardiology (Head: Kurt Huber MD), Wilhelminen Spital, Vienna
,
C. Pirich
5
Department of Nuclear Medicine (Head: Christian Pirich MD), Private Medical University of Salzburg, Austria
Aim: Hyperhomocysteinaemia (Hhcy) is known to be an independent risk factor for vascular disease. Coronary flow reserve (CFR) measured by positron emission tomography (PET) is a sensitive method to monitor the effects of pharmacologic interventions in Hhcy. We assessed coronary vascular reactivity by PET in patients with coronary artery disease (CAD) dependent on their homocysteine (Hcy) levels before and under high dose folic acid supplementation therapy (FAST). Patients, methods: Twelve patients with CAD underwent rest/adenosine 13N-ammonia PET for quantification of myocardial blood flow (MBF) and CFR before and after nine weeks FAST (10 mg/day). Results: Folate levels increased from 21 ± 6 to 210 ± 34 μg/l (+900%, p <0.0001) while Hcy levels decreased from 12.1 ± 3.6 to 9.1 ± 3.1 μmol/l (–25%; p <0.01). Global resting MBF remained nearly unchanged after FAST, while stress MBF (from 2.61 ± 0.93 to 3.25 ± 1.15 ml/ g/min; p = 0.05) and CFR (from 3.00 ± 0.76 to 3.72 ± 0.93 ml/g/min; p <0.05; +24%) significantly increased in patients with normal and elevated Hcy levels (cut off 12 μmol/l). An inverse relation was found between Hcy and CFR (R = –0.53; p = 0.08) and between Hcy and MBF at rest (R = –0.62; p < 0.05) at baseline conditions, not persisting after FAST. Conclusion: Coronary vascular reactivity can be improved by FAST in patients with CAD and normal or elevated Hcy levels. FAST might lower an increased cardiovascular risk in CAD patients possibly by mechanisms that are not related to Hcy.
Zusammenfassung
Ziel: Hyperhomocysteinämie (Hhcy) ist ein bekannter Risikofaktor für vaskuläre Erkrankungen. Die Bestimmung der koronaren Flussreserve (KFR) mittels Positronenemissionstomographie (PET) ist eine sensitive Methode um die Effektivität pharmakologischer Interventionen bei Hhcy zu überwachen. Wir untersuchten die koronare Gefäßreaktivität mittels PET in Abhängikeit der Homocystein(Hcy)-Konzentration bei Patienten mit koronarer Herzkrankheit (KHK) vor und unter hoch dosierter Folsäure-Substitutionstherapie (FAST). Patienten, Methoden: Bei zwölf Patienten mit KHK erfolgten eine Ruhe/Adenosin-13N-Ammoniak-PETUntersuchung zur Quantifizierung des myokardialen Blutflusses (MBF) und der KFR vor und neun Wochen nach FAST (10 mg/Tag). Ergebnisse: Die Folsäurekonzentrationen stiegen von 21 ± 6 auf 210 ± 34 μg/l (+900%, p <0.0001) während die Hcy-Spiegel von 12.1 ± 3.6 auf 9.1 ± 3.1 μmol/l (–25%; p <0.01) fielen. Der globale Ruhe-MBF blieb unter FAST unverändert, während der Stress-MBF (von 2.61 ± 0.93 auf 3.25 ± 1.15 ml/ g/min; p = 0.05) und die KFR (von 3.00 ± 0.76 auf 3.72 ± 0.93 ml/g/min; p <0.05; +24%) sowohl bei Patienten mit normalen als auch bei jenen mit erhöhter Hcy-Konzentration (Grenzwert: 12 μmol/l) signifikant stiegen. Initial fand sich eine inverse Relation zwischen Hcy und KFR (R = –0.53; p = 0.08) sowie zwischen Hcy und Ruhe MBF (R = –0.62; p <0.05), welche nach FAST nicht mehr vorhanden war. Schlussfolgerung: Die koronare Gefäßreaktivität kann durch FAST bei KHK-Patienten mit normaler oder erhöhter Homocysteinkonzentration verbessert werden. Es ist denkbar, dass bei KHK-Patienten durch FAST ein erhöhtes kardiovaskuläres Risiko gesenkt werden kann, dies möglicherweise durch Mechanismen, die nicht in direktem Zusammenhang mit Homocystein stehen.
Homocystein -
koronare Flussreseve -
koronare Herzkrankheit -
PET
References
1
Anderson JL,
Muhlestein JB,
Horne BD.
et al.
Plasma homocysteine predicts mortality independently of traditional risk factors and C-reactive protein in patients with angiographically defined coronary artery disease. Circulation 2000; 102: 1227-32.
4
Bottcher M,
Madsen MM,
Refsgaard J.
et al.
Peripheral flow response to transient arterial forearm occlusion does not reflect myocardial perfusion reserve. Circulation 2001; 103: 1109-14.
5
Boushey CJ,
Beresford SA,
Omenn GS.
et al.
A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. Probable benefits of increasing folic acid intakes. JAMA 1995; 274: 1049-57.
7
Chambers JC,
Ueland PM,
Obeid OA.
et al.
Improved vascular endothelial function after oral B vitamins: An effect mediated through reduced concentrations of free plasma homocysteine. Circulation 2000; 102: 2479-83.
8
Chao CL,
Kuo TL,
Lee YT.
Effects of methionineinduced hyperhomocysteinemia on endotheliumdependent vasodilation and oxidative status in healthy adults. Circulation 2000; 101: 485-90.
14
Graham IM,
Daly LE,
Refsum HM.
et al.
Plasma homocysteine as a risk factor for vascular disease. The European Concerted Action Project. JAMA 1997; 277: 1775-81.
15
Guethlin M,
Kasel AM,
Coppenrath K.
et al.
Delayed response of myocardial flow reserve to lipidlowering therapy with fluvastatin. Circulation 1999; 99: 475-81.
17
Huggins GS,
Pasternak RC,
Alpert NM.
et al.
Effects of short-term treatment of hyperlipidemia on coronary vasodilator function and myocardial perfusion in regions having substantial impairment of baseline dilator reverse. Circulation 1998; 98: 1291-6.
18
Hutchins GD,
Caraher JM,
Raylman RR.
A region of interest strategy for minimizing resolution distortions in quantitative myocardial PET studies. J Nucl Med 1992; 33: 1243-50.
19
Hutchins GD,
Schwaiger M,
Rosenspire KC.
et al.
Noninvasive quantification of regional blood flow in the human heart using N-13 ammonia and dynamic positron emission tomographic imaging. J Am Coll Cardiol 1990; 15: 1032-42.
20
Kjaer A,
Meyer C,
Nielsen FS.
et al.
Dipyridamole, cold pressor test, and demonstration of endothelial dysfunction: a PET study of myocardial perfusion in diabetes. J Nucl Med 2003; 44: 19-23.
21
Krivokapich J,
Smith GT,
Huang SC.
et al.
13N ammonia myocardial imaging at rest and with exercise in normal volunteers. Quantification of absolute myocardial perfusion with dynamic positron emission tomography. Circulation 1989; 80: 1328-37.
25
Nagamachi S,
Czernin J,
Kim AS.
et al.
Reproducibility of measurements of regional resting and hyperemic myocardial blood flow assessed with PET. J Nucl Med 1996; 37: 1626-31.
26
Nekolla SG,
Miethaner C,
Nguyen N.
et al.
Reproducibility of polar map generation and assessment of defect severity and extent assessment in myocardial perfusion imaging using positron emission tomography. Eur J Nucl Med 1998; 25: 1313-21.
27
Schnyder G,
Roffi M,
Flammer Y.
et al.
Effect of homocysteine-lowering therapy with folic acid, vitamin B12, and vitamin B6 on clinical outcome after percutaneous coronary intervention: the Swiss Heart study: a randomized controlled trial. JAMA 2002; 288: 973-9.
28
Schnyder G,
Roffi M,
Pin R.
et al.
Decreased rate of coronary restenosis after lowering of plasma homocysteine levels. N Engl J Med 2001; 345: 1593-600.
29
Stanger O,
Semmelrock HJ,
Wonisch W.
et al.
Effects of folate treatment and homocysteine lowering on resistance vessel reactivity in atherosclerotic subjects. J Pharmacol Exp Ther 2002; 303: 158-62.
30
Stanger O,
Weger M.
Interactions of homocysteine, nitric oxide, folate and radicals in the progressively damaged endothelium. Clin Chem Lab Med 2003; 41: 1444-54.
31
Tawakol A,
Forgione MA,
Stuehlinger M.
et al.
Homocysteine impairs coronary microvascular dilator function in humans. J Am Coll Cardiol 2002; 40: 1051-58.
32
Tawakol A,
Migrino RQ,
Aziz KS.
et al.
High-dose folic acid acutely improves coronary vasodilator function in patients with coronary artery disease. J Am Coll Cardiol 2005; 45: 1580-4.
33
Tawakol A,
Omland T,
Gerhard M.
et al.
Hyperhomocyst( e)inemia is associated with impaired endothelium-dependent vasodilation in humans. Circulation 1997; 95: 1119-21.
34
Thambyrajah J,
Landray MJ,
Jones HJ.
et al.
A randomized double-blind placebo-controlled trial of the effect of homocysteine-lowering therapy with folic acid on endothelial function in patients with coronary artery disease. J Am Coll Cardiol 2001; 37: 1858-63.
35
Title LM,
Cummings PM,
Giddens K.
et al.
Effect of folic acid and antioxidant vitamins on endothelial dysfunction in patients with coronary artery disease. J Am Coll Cardiol 2000; 36: 758-65.
36
Toole JF,
Malinow MR,
Chambless LE.
et al.
Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke, myocardial infarction, and death: the Vitamin Intervention for Stroke Prevention (VISP) randomized controlled trial. JAMA 2004; 291: 565-75.
37
Uren NG,
Marraccini P,
Gistri R.
et al.
Altered coronary vasodilator reserve and metabolism in myocardium subtended by normal arteries in patients with coronary artery disease. JAm Coll Cardiol 1993; 22: 650-8.
38
Usui M,
Matsuoka H,
Miyazaki H.
et al.
Endothelial dysfunction by acute hyperhomocyst(e)inaemia: restoration by folic acid. Clin Sci (Lond) 1999; 96: 235-9.
40
Willems FF,
Aengevaeren WR,
Boers GH.
et al.
Coronary endothelial function in hyperhomocysteinemia: improvement after treatment with folic acid and cobalamin in patients with coronary artery disease. JAm Coll Cardiol 2002; 40: 766-72.
