No abstract

Objective: Recently, we reported that low-dose landiolol (1.5 µg·kg^-1·min^-1), an ultra-short-acting β-blocker, safely decreased the heart rate (HR) in patients with acute decompensated heart failure (ADHF) and sinus tachycardia, thereby improving cardiac function. We investigated whether low-dose landiolol effectively decreased the HR in ADHF patients with rapid atrial fibrillation (AF). Methods: We enrolled 23 ADHF patients with rapid AF (HR ≥120 beats·min^-1 and New York Heart Association class III-IV) and systolic heart failure (SHF: n = 12) or diastolic heart failure (DHF: n = 11) who received conventional therapy with diuretics, vasodilators, and/or low-dose inotropes. They were administered continuous intravenous infusion of low-dose landiolol (1.0-2.0 µg·kg^-1·min^-1), and their electrocardiograms and blood pressures were monitored for 24 h thereafter. Results: Two hours after starting landiolol, the HR was reduced significantly (22%), without a reduction in blood pressure, and remained constant thereafter. The HR reduction 2 h after landiolol administration was significantly greater in the DHF group than in the SHF group. No incidence of hypotension was recorded. Conclusions: Digitalis or amiodarone is currently recommended for HR control in ADHF patients with rapid AF. Our results showed that continuous infusion of low-dose landiolol may also be useful as first-line therapy in these patients.

U-8-OHdG levels are associated with VT in patients with active CS diagnosed by F-flurodeoxyglucose positron-emission tomography, providing additive and relevant information about the arrhythmia substrate.

ObjectivesThe purpose of this study was to investigate whether adding a low-dose β1-blocker to milrinone improves cardiac function in failing cardiomyocytes and the underlying cardioprotective mechanism.BackgroundThe molecular mechanism underlying how the combination of low-dose β1-blocker and milrinone affects intracellular Ca2+ handling in heart failure remains unclear.MethodsWe investigated the effect of milrinone plus landiolol on intracellular Ca2+ transient (CaT), cell shortening (CS), the frequency of diastolic Ca2+ sparks (CaSF), and sarcoplasmic reticulum Ca2+ concentration ({Ca2+}SR) in normal and failing canine cardiomyocytes and used immunoblotting to determine the phosphorylation level of ryanodine receptor (RyR2) and phospholamban (PLB).ResultsIn failing cardiomyocytes, CaSF significantly increased, and peak CaT and CS markedly decreased compared with normal myocytes. Administration of milrinone alone slightly increased peak CaT and CS, while CaSF greatly increased with a slight increase in {Ca2+}SR. Co-administration of β1-blocker landiolol to failing cardiomyocytes at a dose that does not inhibit cardiomyocyte function significantly decreased CaSF with a further increase in {Ca2+}SR, and peak CaT and CS improved compared with milrinone alone. Landiolol suppressed the hyperphosphorylation of RyR2 (Ser2808) in failing cardiomyocytes but had no effect on levels of phosphorylated PLB (Ser16 and Thr17). Low-dose landiolol significantly inhibited the alternans of CaT and CS under a fixed pacing rate (0.5 Hz) in failing cardiomyocytes.ConclusionA low-dose β1-blocker in combination with milrinone improved cardiac function in failing cardiomyocytes, apparently by inhibiting the phosphorylation of RyR2, not PLB, and subsequent diastolic Ca2+ leak.

Reduced CaM binding to RyR2 seems to play a critical role in the pathogenesis of aberrant Ca(2+) release in failing hearts. Correction of the reduced CaM binding to RyR2 stabilizes the RyR2 channel function and thereby restores normal Ca(2+) handling and contractile function to failing hearts.