Heme oxygenase-1 (HO1) catalyzes oxidation of the heme molecule in concert with NADPH-cytochrome P450 reductase following the specific cleavage of heme into carbon monoxide, iron, and biliverdin, which is rapidly metabolized to bilirubin. HO1 is a stress-inducible protein that protects cells against oxidative injury, but its protective mechanism is not fully understood. The Eizai hyperbilirubinemic rat (EHBR), a mutant strain derived from the Sprague-Dawley rat (SDR), has a mutation in the gene for the canalicular multispecific organic anion transporter, which results in a phenotype of hyperbilirubinemia, and thus is a model of Dubin-Johnson syndrome in humans. In this study, we compared EHBR and SDR with regard to neuronal death induced by 2 hr of occlusion of the middle cerebral artery and reperfusion. In EHBR, the area that was immunoreactive for microtubule-associated protein-2 was significantly reduced, and the HO1-immunoreactive area was smaller than that in SDR. These results suggest that bilirubin has essentially a neuroprotective effect against focal ischemia and may participate in HO1-induced neuroprotection.

Background: Atrial fibrillation and atrial flutter occur commonly in patients with heart failure. Ultrashortacting b-blockers, including landiolol, can rapidly control heart rate. As part of postmarketing surveillance for landiolol in Japan, a real-world drug-use survey (AF-CHF landiolol survey) was established for the treatment of atrial fibrillation and atrial flutter in patients with heart failure. We report the safety and effectiveness of landiolol from this survey, focusing on adverse events/adverse drug reactions. Methods: Consecutive patients with cardiac dysfunction who received landiolol (continuous intravenous infusion, starting at 1 mg/kg/min) for atrial fibrillation or atrial flutter in routine clinical practice in Japan were enrolled between June 2014 and May 2016. Safety variables included adverse events and adverse drug reactions (number of patients and events, incidence rate, types, seriousness). Effectiveness variables included the proportion of patients with a !20% decrease in heart rate. Results: Data were available for 1121 patients (safety analysis set); 888 patients were evaluable for effectiveness parameters. Mean (AE standard deviation) patient age was 72.5 AE 13.5 years, 57.2% were male. Most patients (84.2%) received landiolol for atrial fibrillation. Overall, 174 adverse events occurred in 140 patients (12.5%), including 105 serious adverse events. The most common type of adverse events was cardiac (60 events). Seventy-five events in 63 patients were categorized as adverse drug reactions (5.6% of patients). Mean heart rate decreased substantially after treatment with landiolol, by !20% in 77.5% of patients. Conclusions: In a real-world setting in Japan, landiolol for the treatment of atrial fibrillation or atrial flutter with heart failure was acceptable without new safety concerns, and most patients achieved effective heart rate control during their arrhythmias.

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Background: The aim of the prospective post-marketing AF-CHF Landiolol Survey was to evaluate the safety and effectiveness of landiolol for the treatment of atrial fibrillation or atrial flutter in patients with cardiac dysfunction in clinical practice in Japan. This analysis reports mid-term prognoses with a focus on switching from landiolol to oral β-blockers. Methods and Results: The AF-CHF Landiolol Survey took place between June 2014 and May 2016 and involved 1,121 patients with cardiac dysfunction and atrial fibrillation/atrial flutter. Data collected about switching from landiolol to oral β-blockers were analyzed in relation to all-cause mortality within 180 days after landiolol initiation. Among 1,002 patients with available follow-up data, the 6-month all-cause mortality rate was 14. 6% (n=146 patients), of whom 39.7% had died from heart failure (HF). Kaplan-Meier survival curves showed significantly longer survival in patients who had switched to oral β-blockers vs. those who had not, with hazard ratios of 0.39 (95% confidence interval [CI] 0.28–0.55) for all-cause mortality and 0.40 (95% CI: 0.23–0.70) for death from HF. Only male sex and advanced age were independently associated with all-cause mortality and death from HF. Conclusions: This large-scale routine practice survey of landiolol in HF patients with atrial fibrillation/flutter showed high mid-term all-cause mortality. Switching from landiolol to oral β-blockers was apparently, although not independently, associated with lower all-cause mortality and death from HF.

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