Original Article

Change in Bilirubin Level Following Acute Myocardial Infarction Is an Index for Heme Oxygenase Activation

Authors: Koichiro Okuhara, MD, Tomohiko Kisaka, MD, Ryoji Ozono, MD, PhD, Satoshi Kurisu, MD, PhD, Ichiro Inoue, MD, PhD, Junko Soga, MD, Yoko Yano, MD, Tetsuya Oshima, MD, PhD, Yasuki Kihara, MD, PhD, Masao Yoshizumi, MD, PhD

Abstract

Objectives: Heme oxygenase 1 (HO-1) is rapidly induced by stress, degrading pro-oxidant heme into carbon monoxide, bilirubin, and free iron (Fe). Induction of HO-1 is an important defense mechanism against tissue injury. Here, we tested the hypothesis that HO-1 is activated in the myocardium after acute myocardial infarction (AMI) in humans.


Methods: Changes in the HO-1 activity after AMI were analyzed by measuring serum levels of bilirubin and Fe. Blood samples were collected in patients with AMI (n = 41) serially after the interventional therapy and compared with non-AMI subjects (n = 18). HO-1 protein levels were measured in a sample of AMI patients (n = 12).


Results: In AMI patients, but not in non-AMI subjects, serum levels of bilirubin (1.57 fold,P < 0.001) and Fe (1.35 fold, P < 0.01) were transiently elevated, both levels peaking 18–21 hours after the start of sampling. The peak changes in the levels of bilirubin and Fe in AMI patients were significantly correlated with each other. Furthermore, the serum HO-1 protein level was elevated, and its change was significantly correlated with the change in bilirubin level (r = 0.82, P < 0.005). Those with a high bilirubin response (peak levels >0.5 mg/dL) had richer collateral flow into the ischemic myocardium.


Conclusions: These results suggest that heme oxygenase (HO) was activated following AMI, and it was detectable in the serum. Our data provide the first evidence of HO-1 induction following stress in humans. The change in bilirubin level may be a novel index for high collateral flow formation following AMI.


Key Points


* A substantial body of evidence suggests that an upregulation of heme oxygenase 1 (HO-1) confers protection against tissue damage in models of ischemic heart disease, left ventricular hypertrophy, and atherosclerosis.


* Two of the catalytic products of heme oxygenase (HO) reaction transiently increased after acute myocardial infarction (AMI) and pericutaneous coronary intervention (PCI), and the changes in the bilirubin concentration were significantly correlated with changes in the serum HO-1 level.


* The presence of collateral flow into the ischemic myocardium is an important determinant of the clinical course of AMI, and measuring bilirubin level after AMI may be a novel clinical procedure to assess the risk of patients.


* The clinical measurement of HO activity may play an important role in better understanding the pathogenesis of oxidative stress-related diseases, and in developing improved treatment strategies.

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