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CLINICAL RESEARCH: INTERVENTIONAL CARDIOLOGY

Heme oxygenase-1 genotype and restenosis after balloon angioplasty: a novel vascular protective factor

Martin Schillinger, MD^*, Markus Exner, MD, Erich Minar, MD^*, Wolfgang Mlekusch, MD^*, Marcus Müllner, MD, MSc(Epi), Christine Mannhalter, PhD, Fritz H. Bach, MD and Oswald Wagner, MD^,*

^* Angiology, University of Vienna, Medical Faculty, Vienna, Austria
Laboratory Medicine, University of Vienna, Medical Faculty, Vienna, Austria
Emergency Medicine, University of Vienna, Medical Faculty, Vienna, Austria
Harvard Medical School, Boston, Massachusetts, USA

Manuscript received July 3, 2003; revised manuscript received September 11, 2003, accepted September 29, 2003.

^* Reprint requests and correspondence: Dr. Oswald Wagner, Department of Laboratory Medicine, University of Vienna, Medical Faculty, Waehringer Guertel 18-20, A-1090 Vienna, Austria.
oswald.wagner{at}univie.ac.at

OBJECTIVES: We investigated the association of the heme oxygenase-1 (HO-1) promoter genotype with the inflammatory response and restenosis after balloon angioplasty.

BACKGROUND: Heme oxygenase-1, which is induced by balloon angioplasty, can inhibit neointima formation and vascular remodeling. A dinucleotide repeat in the HO-1 gene promoter shows a length polymorphism that modulates HO-1 gene transcription. Short (<25 guanosine thymidine [GT]) repeats are associated with a 10-fold greater up-regulation of HO-1 than are longer repeats.

METHODS: We studied 381 consecutive patients who underwent femoropopliteal balloon angioplasty (n = 210) and comparison groups with femoropopliteal stenting (n = 68) and lower limb angiography (n = 103). C-reactive protein (CRP) was measured at baseline, 24, and 48 h. We evaluated patency at six months by duplex sonography and assessed the association of the length of GT repeats in the HO-1 gene promoter with postintervention CRP and restenosis.

RESULTS: Restenosis within six months was found in 74 patients (35%) after balloon angioplasty and in 21 patients (31%) after stenting. After balloon angioplasty, carriers of the short length (<25 GT) dinucleotide repeats had a lower postintervention CRP at 24 h (p = 0.009) and 48 h (p < 0.001) and a reduced risk for restenosis (adjusted relative risk 0.43, 95% confidence interval: 0.24 to 0.71, p < 0.001) compared with patients with longer alleles. After stenting or angiography, we found no association between the HO-1 genotype with CRP or restenosis.

CONCLUSIONS: The HO-1 promoter genotype that controls the degree of HO-1 up-regulation in response to stress stimuli is associated with the postintervention inflammatory response and the restenosis risk after balloon angioplasty.

Abbreviations and Acronyms   CI = confidence interval   CO = carbon monoxide   CRP = C-reactive protein   GT = guanosine thymidine   HO-1 = heme oxygenase-1   IQR = interquartile range (range from the 25th to the 75th percentile)   PAD = peripheral artery disease   PSV = peak systolic velocity   PTA = percutaneous transluminal angioplasty   RR = risk ratio   SMC = smooth muscle cell

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