Masayoshi Ajioka

Leukotoxin, 9, 10-epoxy-12-octadecenoate, causes cardiac failure in dogs

An epoxy derivative of linoleate, 9, 10-epoxy-12-octadecenoate, was demonstrated to be biosynthesized by leukocytes, thus nominated as leukotoxin. Its chemical structure was determined by gas-chromatography/mass spectrometry and nuclear magnetic resonance measurements. When it was injected intravenously, 15 mg/kg, canine heart showed signs of a typical cardiac failure; viz. Aortic flow started to drop immediately after the injection, and fell to 22% of the original at 40 min after the injection. At that point, systolic aortic pressure dropped to 35%, diastolic aortic pressure to 23%, and electronically differentiated maximal rate of left ventricular pressure rise (LV dp/dt) to 29%. All of experimental dogs died 40 to 50 min after the injection. On the contrary, administration of linoleic acid (15 mg/kg) did not affect these hemodynamical parameters. Therefore, leukotoxin seems to be an important factor to the genesis of heart failure.

Mechanism of cardiac arrhythmias induced by epinephrine in dogs with hypokalemia

To investigate the mechanism of ventricular arrhythmias induced by epinephrine in dogs with hypokalemia, 30 adult mongrel dogs were separated into a control group (n = 13) and a hypokalemia group (n = 17). In the hypokalemia group, sodium polystyrene sulfonate (5 g/kg body weight) was infused into the colon. In both groups, the serum concentrations of sodium, potassium and calcium were measured every 15 minutes for 60 minutes. The mean (+/- standard deviation) serum potassium level of the hypokalemia group decreased significantly from 3.81 +/- 0.21 to 2.92 +/- 0.36 mEq/liter; there were no significant changes in other electrolytes. After 60 minutes, epinephrine (10 micrograms/kg) was injected intravenously in the hypokalemia and control groups, and the arrhythmia ratio (the number of ventricular ectopic beats divided by the total heart rate) was calculated for 5 minutes. Each group was further classified into subgroups of dogs with an arrhythmia ratio higher or lower than 10%. An arrhythmia ratio over 10% was observed in 7.7% of the control group and 53% of the hypokalemia group. Immediately after 5 minutes of epinephrine injection, myocardial mitochondria and plasma membrane fraction were prepared from each group. Mitochondrial calcium content and phospholipase activity of plasma membrane fraction were determined. Significant increases in both mitochondrial calcium content and phospholipase activity were observed in the dogs with hypokalemia and an arrhythmia ratio greater than 10%.(ABSTRACT TRUNCATED AT 250 WORDS)

The role of phospholipase in the genesis of reperfusion arrhythmia

To clarify the mechanism of reperfusion arrhythmia, the following experiments were performed. In vivo study: Using anesthetized mongrel dogs, the left anterior descending coronary artery was occluded for 15 min and the ligation was released. The dogs were divided into two groups depending on whether the pretreatment was with saline or coenzyme Q10 (CoQ10), 15 mg/kg, before the ligation, i.e., the control and the CoQ10 groups. Each group was further divided into two subgroups depending on the presence or the absence of reperfusion arrhythmia. Reperfusion arrhythmia was observed in 12 out of 38 dogs in the control, whereas in the CoQ10 group none developed arrhythmia. Nine species of free fatty acids (FFA) were detected in the plasma membrane in each group. In the dogs in the control group with arrhythmia, all species of detected FFA increased, and phospholipid content in plasma membrane decreased. These changes were not observed in the dogs without arrhythmia in both the control and the CoQ10 groups. In vitro study: Incubation of myocardial plasma membrane with phospholipase (PLase) A2 increased only unsaturated FFA, while PLase C increased all detected FFA. Premedication with CoQ10 prevented the increase in FFA caused by PLases. Perfusion with PLase A2 or C altered membrane action potential. Premedication with CoQ10 also prevented changes in membrane action potential. PLase liberates fatty acids from phospholipids, and CoQ10 is known to protect the membrane phospholipids from the attack of PLase. These facts and results suggest that activation of PLase associated with coronary reperfusion is closely related to the development of reperfusion arrhythmia.

A Randomized Controlled Study of Finerenone vs. Eplerenone in Japanese Patients With Worsening Chronic Heart Failure and Diabetes and/or Chronic Kidney Disease

BACKGROUND Finerenone, a nonsteroidal mineralocorticoid receptor antagonist, was evaluated in Japanese patients with heart failure (HF) with reduced ejection fraction and chronic kidney disease and/or diabetes mellitus. METHODSANDRESULTS ARTS-HF Japan was a randomized, double-blind, phase 2b study. Patients (n=72) received oral, once-daily (o.d.) finerenone (2.5, 5, 7.5, 10 or 15 mg, up-titrated to 5, 10, 15, 20, or 20 mg, respectively, on day 30) or eplerenone (25 mg every other day, increased to 25 mg o.d. on day 30, and 50 mg on day 60) for 90 days. The primary endpoint was the proportion of individuals with a decrease of >30% in plasma NT-proBNP at day 90. Safety endpoints included the incidence of hyperkalemia. Decreases in NT-proBNP occurred in 23.1% of patients in the eplerenone group and 15.4%, 23.1%, 45.5%, 27.3% and 45.5% in the 2.5→5 mg, 5→10 mg, 7.5→15 mg, 10→20 mg and 15→20 mg finerenone groups, respectively (all P=NS). Mean changes in serum potassium levels were similar between groups. CONCLUSIONS Because of the small sample size, limited conclusions can be drawn. Considering the results of ARTS-HF and that finerenone was well tolerated in Japanese patients in ARTS-HF Japan, the safety and efficacy of finerenone should be further explored in a large outcomes trial including Japanese patients. (Circ J 2016; 80: 1113-1122).

Measurement of Anti-Factor Xa Activity in Patients on Apixaban for Non-Valvular Atrial Fibrillation

BACKGROUND Chromogenic anti-factor Xa activity (AXA) assay is reported to be the most appropriate method to measure the pharmacodynamics of apixaban, but the distribution of AXA in non-valvular atrial fibrillation (NVAF) patients on apixaban therapy has not been fully elucidated. METHODSANDRESULTS Steady-state trough and peak AXA were measured in 124 NVAF patients taking apixaban. In 25 patients, baseline, first peak, and trough AXA were also examined, and were 0.01±0.02 IU/ml, 0.83±0.43 IU/ml, and 0.34±0.17 IU/ml, respectively. First trough AXA was significantly lower than steady-state trough AXA, although it was significantly higher than baseline (P<0.0001). Similarly, first peak AXA was significantly lower than steady-state peak AXA (P<0.0001). In 124 patients, steady-state peak AXA was significantly higher in the 5-mg b.i.d. group than in the 2.5-mg b.i.d. group (2.05±0.73 IU/ml vs. 1.51±0.65 IU/ml, respectively; P<0.001), although there was no significant difference in trough AXA. Other than dose, age and serum creatinine were significantly related to both trough and peak AXA. CONCLUSIONS The distribution of AXA in Japanese NVAF patients on apixaban therapy in daily clinical practice both in the acute and steady-state phase was measured. In patients taking apixaban, measurement of AXA clearly showed the pharmacodynamic profile of this drug.

Acceleration of recovery of mitochondrial function after coronary reperfusion by various coronary dilating drugs in canine hearts.

This study was designed to evaluate whether or not increase in coronary blood flow after reperfusion accelerates the recovery of ischemia-induced mitochondrial damage. Using anesthetized dogs, the left anterior descending coronary artery was occluded for 30 min, followed by 20 min of reperfusion. Five minutes after reperfusion, either physiological saline (n = 9), 0.5 mg/kg of dilazep (n = 7), 0.2 mg/kg of diltiazem (n = 7), or 0.5 mg/kg of nicorandil (n = 8) were administered intravenously. Arterial blood pressure, heart rate, and coronary blood flow were measured throughout the experiment. Twenty minutes after reperfusion, heart mitochondria from normal and reperfused areas were prepared, and mitochondria) function was measured. Significant in-crease in coronary flow was observed during reperfusion in all drug-treated groups; however, no significant in-crease was observed in the control group 10 min after reperfusion. Significant hemodynamic changes were not observed in all groups. Mitochondrial function from reperfused areas was recovered significantly in all drug-treated groups, though in the control group mitochondrial dysfunction persisted. Coronary dilative mechanisms of drugs used here differ; however, a similar effect was demonstrated, i.e., administration of a coronary dilator accelerates the recovery of mitochondria after reperfusion. Therefore, it is concluded that coronary flow after reperfusion might be a primary factor in the recovery of ischemia-induced mitochondrial damage.

Influence of proton pump inhibitors on blood dabigatran concentrations in Japanese patients with non-valvular atrial fibrillation

Dabigatran is a direct thrombin inhibitor used to decrease the risk of ischemic stroke in patients with non‐valvular atrial fibrillation (NVAF). Its prodrug, dabigatran etexilate (DE) is often co‐administrated with a proton pump inhibitor (PPI) because of its adverse effects on the gastrointestinal tract. Drug‐drug interactions between DE and PPIs in daily clinical practice have not been fully elucidated.

Distribution of Anti-Factor Xa Activity in Patients on Edoxaban Therapy for Non-Valvular Atrial Fibrillation.

BACKGROUND The distribution of anti-factor Xa activity (AXA) values in non-valvular atrial fibrillation (NVAF) patients on edoxaban therapy has not been fully elucidated. METHODSANDRESULTS The steady-state trough and peak AXA values were measured in 66 NVAF patients. The trough AXA value did not differ significantly between the 60-mg and the 30-mg OD groups (0.17±0.13 IU/ml vs. 0.12±0.11 IU/ml, respectively; P=0.17). Similarly, the peak AXA value did not differ significantly between the 2 groups (1.45±0.81 IU/ml vs. 1.25±0.48 IU/ml, respectively; P=0.26). CONCLUSIONS Recommended dosing should be followed for sufficient efficacy of edoxaban. (Circ J 2016; 80: 745-747).

Enhancement of Warfarin Anticoagulant Reaction in Patients with Repeated Oral Tolvaptan Administration

The pharmacokinetics and pharmacodynamics of warfarin remained unaffected by tolvaptan during clinical trials. However, tolvaptan prolonged the prothrombin time-international normalized ratio (PT-INR) level of patients with cardiovascular disease taking warfarin. Tolvaptan was prescribed to 576 patients from December 2010 to December 2015. Of these patients, 37 underwent anticoagulant therapy. We investigated PT-INR fluctuation immediately before tolvaptan therapy was initiated. PT-INR remained unchanged in the control group and in groups administered with less than 7.5 mg/d tolvaptan, whereas it was significantly increased (p=0.03) in the group administered with more than 7.5 mg/d tolvaptan. This result indicates the possibility that tolvaptan affects the pharmacodynamics of warfarin in vivo. However, further research is necessary to clarify the mechanism of this phenomenon.

Treatment of Sirolimus-Eluting Stent Restenosis: Additional Stent, Balloon Angioplasty, and Coronary Artery Bypass Graft

Sirolimus‐eluting stent (SES) has shown a significant efficacy in reducing restenosis after percutaneous coronary interventions. However, an increase in total number of SES use along with targeting more complex lesions generated a large number of SES restenosis. This study aimed to investigate the clinical and angiographic outcomes of different revascularization strategies for SES restenosis.