Circulation Journal Official Journal of the Japanese Circulation Society http://www. j-circ.or.jp he N-terminal (1-619 amino acid) and central (2,000-2,500 amino acid) domains of the ryanodine receptors (skeletal: RyR1, cardiac: RyR2) harbor many mutations associated with malignant hyperthermia (MH), catecholaminergic polymorphic ventricular tachycardia (CPVT), and arrhythmogenic right ventricular cardiomyopathy type 2. 1 There is strong evidence to suggest that the interdomain interaction between these regions plays an important role in the mechanism of channel regulation. 2- 16 We reported that dantrolene, a specific agent for the treatment of MH, prevented abnormal Ca 2+ leak by correction of the defective inter-domain interaction between the N-terminal and central domains within MH RyR1 (i.e., aberrant formation of a channel-activating unzipped configuration of the N-terminal/central domain pair in an otherwise resting state). 9 We further showed that, in failing hearts, dantrolene corrected the defective inter-domain interaction within the RyR2, thereby inhibiting Ca 2+ leak through RyR2. 11 More recently, by using the knock-in (KI) mouse model with a human CPVT-associated RyR2 mutation (R2474S), we clarified that a single amino acid mutation within the RyR2 sensitizes the RyR2 channel to activation by luminal [Ca 2+ ] (i.e., a decreased threshold of luminal [Ca 2+ ] for channel activation), and in turn induces spontaneous Ca 2+ sparks and DAD, leading to CPVT, and that danrrolene stabilized the leaky RyR2 by correcting the defective inter-domain interaction. 13 Here, we investigated the in vivo anti-arrhythmic effect of dantrolene in the KI mice model. Background: Dantrolene, a specific agent for the treatment of malignant hyperthermia, was found to inhibit Ca 2+ leak through not only the skeletal ryanodine receptor (RyR1), but also the cardiac ryanodine receptor (RyR2) by correcting the defective inter-domain interaction between N-terminal (1-619 amino acid) and central (2,000-2,500 amino acid) domains of RyRs. Here, the in vivo anti-arrhythmic effect of dantrolene in a human catecholaminergic polymorphic ventricular tachycardia (CPVT)-associated RyR2 R2474S/+ knock-in (KI) mouse model was investigated.

The defective inter-domain interaction between N-terminal and central domains within RyR2 reduces the binding affinity of CaM to RyR2, thereby causing the spontaneous Ca(2+) release events in failing hearts. Correction of the defective CaM binding may be a new strategy to protect against the aberrant Ca(2+) release in heart failure.

No abstract

In HF, urinary 8-OHdG seems to reflect the level of oxidative stress and various parameters related to symptomatic status and functional severity of CHF.

Circulation Journal Official Journal of the Japanese Circulation Society http://www. j-circ.or.jp nalysis of the transmitral inflow (TMF) and of the tissue Doppler imaging (TDI)-derived mitral annular velocities is commonly used for evaluating left ventricular (LV) filling pressure, 1,2 and these measures provide valuable information for the management of patients with heart failure (HF) and sinus rhythm. In particular, the ratio of the early transmitral peak velocity to the early mitral annular velocity (E/e'), which is used for evaluating LV filling pressure, is widely used in the clinical setting. The E/e' range from 8 to 15 is recognized as a gray or indeterminate zone for the estimation of LV filling pressure. 2,3 Furthermore, the measurement of the time interval between the onset of E and the onset of e' (TE-e') has been proposed as another calculation using E and e' that can predict LV filling pressure. 4-9 In addition, the clinical utility of TE-e' in patients with normal systolic function and an indeterminate E/e' has been reported. 10 In contrast, the utilization of TMF and TDI pattern analysis in patients with atrial fibrillation (AF) has not been established because of the lack of atrial contraction and variability of the heart rate. Recently, the usefulness of the simultaneous recording of the ratio of early transmitral peak velocity to flow propagation velocity (E/Vp) and E/e', using a dual Doppler system, for the assessment of LV filling pressure in patients with AF was reported. 11-13 The usefulness of TE-e' obtained by simultaneous recording of the onset of E and e' for the assessment of LV filling pressure in patients with AF, however, was not evaluated.The purpose of the present study was therefore to investigate the following: (1) the usefulness of TE-e' in patients with AF for the assessment of LV filling pressure using the simultaneous recording of TMF and TDI with a dual Doppler system; and (2) the added benefit of using TE-e' to predict LV filling pressure, in addition to the measurement of E/e'. The time interval between the onset of early transmitral flow velocity (E) and that of early diastolic mitral annular velocity (e') (TE-e') is a good predictor of elevated left ventricular (LV) filling pressure in patients with sinus rhythm. Although the evaluation of LV filling pressure using E/e' has been challenging in atrial fibrillation (AF), the usefulness of TE-e' is unknown.

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.

Two-dimensional Doppler scanning revealed a significant increase in the mean and peak velocities in the soleal and popliteal veins with SFC-IPC but not with IF-IPC in patients with CHF. These results indicate that SFC-IPC could have favorable effects in preventing DVT in patients with CHF.