Abstract 1658: Low-dose of β Blocker Improves Cardiac Function in Patients With Acute Heart Failure Partly by Inhibiting Ca2+ Leak Through the Ryanodine Receptor
Background: Although β blocker is inappropriate for patients with acute heart failure (AHF), low-dose of β blocker, which has modest negative chronotropic (but less inotropic) effect, may improve cardiac function in AHF patients. Here, we investigated whether low-dose of β blocker improves cardiac function in human AHF(Protocol 1), and if so, we clarified the cardioprotective mechanism using isolated canine failing cardiomyocytes(Protocol 2).
Methods and Results: In 16 AHF patients (Killip’s classifications;III(n=11) and IV(n=5); heart rate; 115±15 bpm; LVEF; 23 ±5%; Cardiac index(CI), 2.2±0.5 l/min/m2; PCWP, 26±8mmHg), who first underwent conventional therapy by milrinone, vasodilators, and diuretics, we added landiolol (1.5– 6.0 μg/kg/min; i.v.), which is an ultra-short acting β1-selective blocker, to study its effect on hemodynamics. Low-dose of landiolol (1.5–3.0 μg/kg/min) significantly reduced heart rate by 11–15% and rate pressure product, without changing blood pressure (BP), CI and PCWP, whereas its higher dose (>3.0μg/kg/min) decreased BP and CI. After the treatment with landiolol (3.0 μg/kg/min), hemodynamic parameters such as transmitral flow pattern, filling time/RR, E/Ea, and Tei index were all improved (p<0.01), and interestingly, pulsus alternans observed in 7 patients completely disappeared. For protocol 2, cardiomyocytes were isolated from the LV of canine HF model by 4-week’s rapid RV pacing (250 bpm) (EF 27±5%, n=6). Then, we investigated the effect of landiolol on the intracellular Ca2+ transient (CaT), cell shortening(CS), diastolic Ca2+ sparks and sarcoplasmic reticulum (SR) Ca2+ content. In the failing cardiomyocytes, diastolic Ca2+ spark frequency was increased, and both CaT and CS at pacing rate of 0.5 Hz were markedly impaired as compared with normal cardiomyocytes (p<0.01). Upon adding low-dose landiolol (10 nM), however, these abnormalities were significantly improved (p<0.01) accompanied with increased SR Ca2+ content, and moreover CaT alternans observed in untreated failing cardiomyocytes all disappeared.
Conclusion: Low-dose of β blocker improves cardiac function even in patients with AHF, not only by suppressing tachycardia, but also by inhibiting diastolic Ca2+ leak through ryanodine receptor.