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Background: Perfluoro-octyl bromide (PFOB), one of the perfluorochemical oxygen transporters, improved postischemic cardiac dysfunctions. Also norepinephrine (NE) is one of the important inducible factors on reperfusion arrhythmias (ventricular fibrillation [VF]). We used these methods to evaluate the relationship between PFOB emulsion and NE release on reperfusion arrhythmias., Materials and Methods: The perfusion of isolated guinea pig hearts was employed: each of four groups of 6-7 hearts were used with Krebs-Henseleit solution (KHS) as control, and KHS with 5%, 15%, or 30% PFOB emulsion. The hearts were perfused in a constant pressure Langendorff model, stabilized for 30 min, followed by 30 min preischemia, then 30 min ischemia and 45 min reperfusion at normothermia., Results: PFOB emulsion dose-dependently limited VF and inhibited NE release in reperfusion. Only 30% PFOB emulsion showed the significant improvement of VF (p=0.05). In hemodynamic parameters, only 5% PFOB emulsion showed a significant decrease in reperfusion, but there was no difference in coronary flow rate (CFR). No differences among the four groups were demonstrated in cardiac oxygen metabolic parameters., Conclusions: It was most likely that a high concentration of PFOB emulsion attenuated reperfusion arrhythmia by decreasing NE release.

Background: Enhanced expression of G protein-coupled receptor kinase (GRK) has been reported in failing hearts and in the present study the stability of enhanced GRK mRNA expression, and the correlation between the expression level of GRK mRNA in peripheral lymphocytes and in the heart were both evaluated., Methods and Results: Isoproterenol was injected into rats for 2 weeks, and then GRK5 mRNA was assessed by quantitative reverse transcriptase-palymerase chain reaction. An enhanced expression of cardiac GRK5 mRNA was observed even after 4 weeks of recovery. The isoproterenol-induced increased expression of GRK2 and GRK5 mRNA was equally observed in the heart and lymphocytes, and there was a close correlation between the heart and lymphocytes in the level of expression of each GRK mRNA., Conclusions: The GRK mRNA level is maintained at a high level for a long period without continuous beta-adrenergic receptor stimulation. The level in circulating lymphocytes could be used as a surrogate marker to estimate the level of cardiac GRK expression and, presumably, the beta-adrenergic receptor function of cardiomyocytes.

Background: Type 2 diabetes and insulin resistance have been associated with several cardiac features including diastolic heart failure, impaired ventricular function, perimicrovascular fibrosis and increased expression of plasminogen activator inhibitor type-1 (PAI-1) in coronary arterial walls. Insulin receptor substrate-1 (IRS-1) is one mediator of insulin signaling. This study was performed to determine whether induction of cardiac manifestations typical of insulin resistance and increased PAI-1 expression occur developmentally or post-developmentally as a result of loss of IRS-1-mediated signaling., Methods: IRS-1 knockout mice were studied at 20 weeks of age., Results: Compared with control mice, the left ventricular (LV) and cardiac mass to body weight ratios were increased. Diastolic and systolic LV diameters and decreased fractional shortening were indicative of LV dilatation and dysfunction. Coronary perimicrovascular fibrosis, an increased coronary arterial wall to lumen ratio, increased immunoreactivity of PAI-1 in the tunica media and increased PAI-1 mRNA expression were present consistent with constrained mural proteo(fibrino)lysis. These cardiac manifestations were similar to those we and others have observed previously in insulin-resistant mice without impaired IRS-1-mediated signaling., Conclusions: Loss of IRS-1 signaling is sufficient to induce cardiac manifestations typical of insulin resistance including increased coronary arterial mural PAI-1 expression. Furthermore, increased PAI-1 expression is not dependent on IRS-1 signaling.

Cardiovascular complications are the central feature of type 2 diabetes mellitus, and insulin resistance is an early clinical manifestation of type 2 diabetes mellitus. Calcium channel blockers are widely used to treat cardiovascular diseases in diabetic patients; however, it remains unknown how endothelin-1 (ET-1) is altered and associated with cardiac lesions at the insulin-resistant early stage of type 2 diabetes mellitus, and, if so, whether calcium channel blockers can reverse such alterations. We examined plasma and cardiac expression of ET-1 in male Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a spontaneous model of human type 2 diabetes mellitus. At 8 weeks of age, OLETF rats were treated for 12 weeks with a long acting calcium channel blocker, benidipine (3 mg/kg per day p.o.) (BEN, n = 15), or with vehicle (OLETF, n = 15), and age-matched genetic control, male Long-Evans Tokushima Otsuka (LETO) rats were also used (n = 15). Blood pressure was significantly higher in OLETF than LETO rats, and benidipine treatment of OLETF rats for 12 weeks did not reduce their blood pressure significantly. Plasma and cardiac levels of ET-1 were significantly higher in OLETF compared with LETO rats (both P < 0.01), and were reversed after benidipine treatment. Our results suggest that ET-1 plays a pivotal role in the pathogenesis of cardiac complications at the insulin-resistant stage of diabetes mellitus, and that benidipine treatment may have a beneficial effect on these complications.

Unlabelled: The recovery of function in myocardium defined as viable by (18)F-FDG PET may differ from that defined by dobutamine stress echocardiography (DSE). The aim of this study was to investigate the difference in the oxidative metabolic response between myocardial segments with preserved contractile reserve (CR) and those without CR, in segments with and without preserved glucose metabolism (GM), using (11)C-acetate PET., Methods: Twenty patients with previous myocardial infarction (left ventricular ejection fraction, 37.1% +/- 16.5%) underwent dynamic (11)C-acetate PET at rest and during dobutamine (7.5 microg/kg/min) infusion. GM was evaluated using (18)F-FDG PET and CR was evaluated using DSE. Dysfunctional segments were divided into 3 groups: group A (n = 26) with preserved CR and GM, group B (n = 15) without CR but with preserved GM, and group C (n = 41) without CR and without preserved GM., Results: Resting oxidative metabolism (k mono = monoexponential clearance rate) was preserved in group A and group B (0.052 +/- 0.011/min vs. 0.051 +/- 0.012/min, P = not significant) but was reduced in group C (0.040 +/- 0.015/min) (P < 0.03 vs. group A and group B). The change in k mono, as a measure of the metabolic response to low-dose dobutamine, was significantly higher in group A (0.018 +/- 0.012) than that in group B (0.0075 +/- 0.0096, P < 0.03) and group C (0.0080 +/- 0.012, P < 0.005)., Conclusion: Viable segments based on (18)F-FDG PET have preserved resting oxidative metabolism. However, segments without CR but with preserved GM show a reduction in the oxidative metabolic response to low-dose dobutamine infusion. The decrease in CR may be related to the reduction in the metabolic response to inotropic stimulation despite preservation of tissue viability on (18)F-FDG PET.

Gating properties of Na(+) channels are the critical determinants for the state-dependent block by class I antiarrhythmic drugs; however, recent site-directed mutagenesis studies have shown that the Na(+) channel selectivity filter region controls drug access to and dissociation from the binding site. To validate these observations, we have exploited a naturally occurring cardiac Na(+) channel mutation, S1710L, located next to the putative selectivity filter residue of domain 4, and evaluated the pharmacological properties to mexiletine using whole-cell, patch-clamp recordings. Consistent with the large negative shift of steady-state inactivation and the enhanced slow inactivation, the S1710L channel showed greater mexiletine tonic block than wild-type (WT) channel. In contradiction, S1710L showed attenuated use-dependent block by mexiletine and accelerated recovery from block, suggesting that the drug escape though the external access path is facilitated. Extracellularly applied QX-314, a membrane-impermeant derivative of lidocaine, elicited significantly enhanced tonic block in S1710L similar to mexiletine. However, recovery from internally applied QX-314 was accelerated by 4.4-fold in S1710L compared with WT. These results suggest that the drug access to and dissociation from the binding site through the hydrophilic path are substantially altered. Moreover, K(+) permeability was 1.9-fold increased in S1710L, verifying that the mutated residue is located in the ion-conducting pore. We propose that the Na(+) channel selectivity filter region is a structural determinant for the antiarrhythmic drug sensitivity in addition to gating properties of the indigenous Na(+) channels that govern the state-dependent drug block.

Osteopontin (OPN) is upregulated in several experimental models of cardiac fibrosis and remodeling. However, its direct effects remain unclear. We examined the hypothesis that OPN is important for the development of cardiac fibrosis and remodeling. Moreover, we examined whether the inhibitory effect of eplerenone (Ep), a novel aldosterone receptor antagonist, was mediated through the inhibition of OPN expression against cardiac fibrosis and remodeling. Wild-type (WT) and OPN-deficient mice were treated with angiotensin II (Ang II) for 4 weeks. WT mice receiving Ang II were divided into 2 groups: a control group and an Ep treatment group. Ang II treatment significantly elevated blood pressure and caused cardiac hypertrophy and fibrosis in WT mice. Ep treatment and OPN deficiency could reduce the Ang II-induced elevation of blood pressure and ameliorate the development of cardiac fibrosis, whereas Ep-only treatment abolished the development of cardiac hypertrophy. Most compelling, the reduction of cardiac fibrosis led to an impairment of cardiac systolic function and subsequent left ventricular dilatation in Ang II-treated OPN-deficient mice. These results suggest that OPN has a pivotal role in the development of Ang II-induced cardiac fibrosis and remodeling. Moreover, the effect of Ep on the prevention of cardiac fibrosis, but not cardiac hypertrophy, might be partially mediated through the inhibition of OPN expression.

Several clinical studies have shown that iodine-123 labelled 15-(p-iodophenyl)-3-(R, S)-methylpentadecanoic acid (BMIPP) uptake is often lower than the uptake of perfusion tracers in patients with ischaemic heart disease. However, BMIPP accumulation may not decrease during the acute phase of a stunned myocardium in patients with acute coronary syndrome. We evaluated serial changes in BMIPP and perfusion tracer uptake in the myocardium after ischaemia. We performed a 20-min left coronary artery occlusion followed by reperfusion in male Wistar rats. One hour after the reperfusion, echocardiography was performed. Intravenous injection of iodine-125 labelled BMIPP and thallium-201 was performed 1 day (acute group) and 5 days (subacute group) after the operation. To determine the myocardial distribution of 125I-BMIPP and 201Tl, dual-tracer autoradiography was conducted. We identified regions of interest in the anterolateral wall as an area at risk and in the inferoseptum as a remote control area. The anterolateral wall/inferoseptum ratio (A/I ratio) was calculated to compare the distributions of 125I-BMIPP and 201Tl. Coronary occlusion induced hypokinesia in the anterolateral region 1 h after the reperfusion. The A/I ratio of 125I-BMIPP was significantly higher than that of 201Tl in the acute group (1.01 +/- 0.15 vs 0.80 +/- 0.23, P<0.001). On the other hand, there was no significant difference between the A/I ratios of 125I-BMIPP and 201Tl in the subacute group (0.88 +/- 0.18 vs 0.85 +/- 0.18). Two rats showed a significantly lower A/I ratio of 125I-BMIPP than 201Tl in the subacute phase. These data suggest that BMIPP uptake is preserved despite a decrease in perfusion in the acute phase after ischaemia. In the subacute phase, on the other hand, BMIPP uptake is similar to or even lower than thallium uptake. Since BMIPP uptake may change with time after ischaemia, careful interpretation of BMIPP uptake after ischaemia is required in a clinical setting.

Objective: Loss of Na(+) channel function has been implicated in idiopathic ventricular fibrillation (IVF) and Brugada syndrome. We have studied the biophysical properties of an IVF mutation (S1710L) that exhibited an unusual clinical phenotype: rate-dependent bundle branch block without manifestation of Brugada-type ECG pattern., Methods: The mutant S1710L channels were expressed in mammalian cells and their gating properties, studied using whole-cell patch clamp techniques, were compared with wild-type (WT) and a Brugada syndrome mutant channel T1620M., Results: The S1710L channel exhibited significantly faster macroscopic current decay than WT or T1620M. In addition, S1710L showed a negative shift in the voltage-dependence of fast inactivation and slower recovery from fast inactivation than in WT or T1620M. In addition to the alterations in fast inactivation most commonly observed in Brugada syndrome mutations, S1710L exhibited marked enhancement in slow inactivation and a large positive shift of activation that potentially decreases conduction velocity., Conclusions: These functional abnormalities may be responsible for the overlapping clinical phenotypes associated with Brugada syndrome and the cardiac conduction defect, a novel cardiac Na(+) channelopathy.

The detection of viable myocardium is important for the prediction of functional recovery after revascularisation. However, a fixed perfusion defect often includes viable myocardium, and perfusion imaging then underestimates myocardial viability. We previously reported that low-dose dobutamine stress gated single-photon emission tomography (SPET) provides similar findings to dobutamine stress echocardiography in the assessment of myocardial viability. The present study investigated whether low-dose dobutamine stress gated SPET is of additional value as compared with stress-rest technetium-99m tetrofosmin SPET for the detection of myocardial viability. Standard stress-rest perfusion SPET, low-dose dobutamine stress gated SPET and fluorine-18 fluorodeoxyglucose positron emission tomography (FDG PET) were studied in 23 patients (mean age 67±7.6 years) with previous myocardial infarction. Twenty-one of them were successfully studied with each technique. FDG PET viability (FDG uptake ≥50%) was employed as the gold standard. One-day stress-rest [sup 99m]Tc-tetrofosmin myocardial SPET was performed. After the resting study, gated SPET was acquired following infusion of 7.5 µg kg[sup -1] min[sup -1] of dobutamine. Left ventricular wall motion in 16 segments was assessed by cine mode display using a four-point scale. Myocardial viability was considered present when there was improvement by one point. Of a total of 336 segments analysed, 53 had persistent defects on stress-rest perfusion SPET. FDG viability was seen in 16 of 17 dobutamine-responsive segments, but in only 11 of 36 dobutamine non-responsive segments (P<0.01). Thus, in the segments with persistent defects, viability findings on low-dose dobutamine stress gated SPET were concordant with those on FDG PET in 77% of segments (kappa value =0.55). For the detection of FDG-viable myocardium, the combination of stress-rest perfusion SPET and low-dose dobutamine stress gated SPET achieved a better... [ABSTRACT FROM AUTHOR]