Symptomatic periesophageal vagal nerve injury by different energy sources during atrial fibrillation ablation.

Background: Symptomatic gastric hypomotility (SGH) is a rare but major complication of atrial fibrillation (AF) ablation, but data on this are scarce. Objective: We compared the clinical course of SGH occurring with different energy sources. Methods: This multicenter study retrospectively collected the characteristics and clinical outcomes of patients with SGH after AF ablation. Results: The data of 93 patients (67.0 ± 11.2 years, 68 men, 52 paroxysmal AF) with SGH after AF ablation were collected from 23 cardiovascular centers. Left atrial (LA) ablation sets included pulmonary vein isolation (PVI) alone, a PVI plus a roof-line, and an LA posterior wall isolation in 42 (45.2%), 11 (11.8%), and 40 (43.0%) patients, respectively. LA ablation was performed by radiofrequency ablation, cryoballoon ablation, or both in 38 (40.8%), 38 (40.8%), and 17 (18.3%) patients, respectively. SGH diagnoses were confirmed at 2 (1-4) days post-procedure, and 28 (30.1%) patients required re-hospitalizations. Fasting was required in 81 (92.0%) patients for 4 (2.5-5) days; the total hospitalization duration was 11 [7-19.8] days. After conservative treatment, symptoms disappeared in 22.3% of patients at 1 month, 48.9% at 2 months, 57.6% at 3 months, 84.6% at 6 months, and 89.7% at 12 months, however, one patient required surgery after radiofrequency ablation. Symptoms persisted for >1-year post-procedure in 7 patients. The outcomes were similar regardless of the energy source and LA lesion set. Conclusions: The clinical course of SGH was similar regardless of the energy source. The diagnosis was often delayed, and most recovered within 6 months, yet could persist for over 1 year in 10%.

Long-term pharmacological therapy of Brugada syndrome: is J-wave attenuation a marker of drug efficacy?

We herein describe two patients with Brugada syndrome in whom J-waves were successfully modified by drugs. Case 1 was a 54-year-old man who presented with repeated ventricular fibrillations (VF) and J-point elevation in the right precordial and lateral leads. After administration of cilostazol (200 mg/d), J-waves disappeared and coved-type ST-segment elevation changed to a saddleback-type for 25 months. Case 2 was a 31-year-old man who presented with a VF storm and J-point elevation in the lateral leads. After administration of quinidine (300 mg/d), J-waves and coved-type ST-segment elevation disappeared for 20 months. J-wave disappearance and coved-type ST-segment elevation were followed by VF suppression, probably due to transient outward potassium current (Ito) suppression.

Controlled release of matrix metalloproteinase-1 plasmid DNA prevents left ventricular remodeling in chronic myocardial infarction of rats.

BACKGROUND: The present study investigated whether administration of controlled release matrix metalloproteinase-1 (MMP-1) plasmid DNA prevents left ventricular (LV) remodeling in a rat chronic myocardial infarction (MI) model. METHODS AND RESULTS: Rats with a moderate-sized MI were randomized to 2 groups: injection of phosphate buffered saline (PBS) containing microspheres into the peri-infarct area (MI group, n=14) and injection of cationized gelatin microspheres incorporating MMP-1 plasmid DNA (MI+MMP-1 group, 50 microg MMP-1/20 microl; n=14). As a control group (n=14), rats received neither the coronary artery ligation nor the injection of PBS. Echocardiography, cardiac catheterization and histological studies were performed. At 2 and 4 weeks after the treatment, the MI+MMP-1 group had smaller LV end-diastolic and end-systolic dimensions, better fractional area change and smaller akinetic areas than the MI group. The LV end-systolic elastance and time constant of isovolumic relaxation were also better in the MI+MMP-1 group compared with the MI group 4 weeks after the treatment. Fibrosis evaluated with Masson's trichrome staining was less in the MI+MMP-1 group than the MI group. CONCLUSIONS: Gelatin microspheres for the controlled release of MMP-1 plasmid DNA are promising for improving cardiac remodeling and function when they are administered during the chronic phase of MI.

Latent genetic backgrounds and molecular pathogenesis in drug-induced long-QT syndrome.

BACKGROUND: Drugs with I(Kr)-blocking action cause secondary long-QT syndrome. Several cases have been associated with mutations of genes coding cardiac ion channels, but their frequency among patients affected by drug-induced long-QT syndrome (dLQTS) and the resultant molecular effects remain unknown. METHODS AND RESULTS: Genetic testing was carried out for long-QT syndrome-related genes in 20 subjects with dLQTS and 176 subjects with congenital long-QT syndrome (cLQTS); electrophysiological characteristics of dLQTS-associated mutations were analyzed using a heterologous expression system with Chinese hamster ovary cells together with a computer simulation model. The positive mutation rate in dLQTS was similar to cLQTS (dLQTS versus cLQTS, 8 of 20 [40%] versus 91 of 176 [52%] subjects, P=0.32). The incidence of mutations was higher in patients with torsades de pointes induced by nonantiarrhythmic drugs than by antiarrhythmic drugs (antiarrhythmic versus others, 3 of 14 [21%] versus 5 of 6 [83%] subjects, P<0.05). When reconstituted in Chinese hamster ovary cells, KCNQ1 and KCNH2 mutant channels showed complex gating defects without dominant negative effects or a relatively mild decreased current density. Drug sensitivity for mutant channels was similar to that of the wild-type channel. With the Luo-Rudy simulation model of action potentials, action potential durations of most mutant channels were between those of wild-type and cLQTS. CONCLUSIONS: dLQTS had a similar positive mutation rate compared with cLQTS, whereas the functional changes of these mutations identified in dLQTS were mild. When I(Kr)-blocking agents produce excessive QT prolongation (dLQTS), the underlying genetic background of the dLQTS subject should also be taken into consideration, as would be the case with cLQTS; dLQTS can be regarded as a latent form of long-QT syndrome.

A novel KCNH2 mutation as a modifier for short QT interval.

In a 34-year-old man showing short QT interval (QTc 329 ms), we identified a novel C-terminal KCNH2 mutation, R1135H. Using a heterologous expression system with CHO cells, the mutant channels were found to display a significantly slow deactivation, which resulted in a gain-of-function for reconstituted 'I(Kr)' channels. This mutation could modify clinical phenotypes for this patient.

A paradoxical effect of lidocaine for the N406S mutation of SCN5A associated with Brugada syndrome.

BACKGROUND: Accelerated intermediate inactivation, which is caused by mutations in the cardiac voltage-gated sodium channel alpha-subunit gene (SCN5A), is one of the molecular mechanisms underlying Brugada syndrome. The N406S mutation associated with Brugada syndrome results in the accelerated intermediate inactivation, in addition to unique pharmacological characteristics. METHODS: Functional sodium channels were expressed transiently in HEK293 cells by transfecting equally the alpha- and beta-subunit plasmids (1 microg/ml) and the sodium current were measured in whole-cell mode of patch-clamp recording. RESULTS: Since the N406S mutant channel has a greatly reduced use-dependent block of lidocaine, we took the advantage of the mutant channel to examine the effect of lidocaine on intermediate inactivation using wild-type (WT) and N406S mutant channels recombinantly expressed in HEK293 cells. Lidocaine (100 microM) slowed the recovery from the fast inactivation similarly for WT and N406S. On the other hand, whereas lidocaine slowed the recovery from the intermediate inactivation for WT, lidocaine accelerated the recovery for N406S. Activity-dependent loss of channel availability by repetitive 500-ms pulses was more strongly enhanced and accelerated by lidocaine for WT, but lidocaine exerted little effect on the N406S channel. CONCLUSION: We demonstrate that lidocaine may suppress Brugada syndrome associated with the N406S mutation by preventing the sodium channel from accumulating in the intermediate inactivation state.

Calcium-mediated coupling between mitochondrial substrate dehydrogenation and cardiac workload in single guinea-pig ventricular myocytes.

We measured mitochondrial NADH autofluorescence or Ca(2+) using Rhod-2, simultaneously with cell shortening in isolated guinea-pig ventricular myocytes. When both frequency and amplitude of twitch shortening (work intensity) were increased by raising stimulus frequency in incremental steps from 0.1 to 3.3 Hz, the steady level of NADH signal increased in a frequency-dependent manner. Mitochondrial Ca(2+) also increased with increasing work intensity. Applying Ru360, an inhibitor of mitochondrial Ca(2+) uniporter, largely attenuated the response of both NADH fluorescence and mitochondrial Ca(2+). The increase in mitochondrial Ca(2+) was slow with t(1/2)=~12 s and no obvious cyclic changes were observed in the NADH signal. When a step change from 0.1 to 3.3 Hz stimulation was applied, the NADH signal first decreased to 83% and then increased to 155% of the control level. Upon returning to 0.1 Hz, the NADH signal showed an overshoot before declining to the control level. The biphasic onset time course was well explained by the delayed Ca(2+) activation of the substrate dehydrogenation superimposed on the feedback control of the ATP synthesis, while the offset time course with a delayed deactivation of dehydrogenation. A computer simulation using an oxidative phosphorylation linked to the cardiac excitation contraction model well reconstructed the response of NADH. This model simulation predicts that the activation of substrate dehydrogenation provides ~23% of driving force of the ATP synthesis to meet the increased workload induced by the jump of stimulus from 0.1 to 3.3 Hz, and remaining ~77% is supplied by the feedback control.

Beta-adrenergic stimulation does not activate Na+/Ca2+ exchange current in guinea pig, mouse, and rat ventricular myocytes.

The effect of beta-adrenergic stimulation on cardiac Na(+)/Ca(2+) exchange has been controversial. To clarify the effect, we measured Na(+)/Ca(2+) exchange current (I(NCX)) in voltage-clamped guinea pig, mouse, and rat ventricular cells. When I(NCX) was defined as a 5 mM Ni(2+)-sensitive current in guinea pig ventricular myocytes, 1 microM isoproterenol apparently augmented I(NCX) by approximately 32%. However, this increase was probably due to contamination of the cAMP-dependent Cl(-) current (CFTR-Cl(-) current, I(CFTR-Cl)), because Ni(2+) inhibited the activation of I(CFTR-Cl) by 1 microM isoproterenol with a half-maximum concentration of 0.5 mM under conditions where I(NCX) was suppressed. Five or ten millimolar Ni(2+) did not inhibit I(CFTR-Cl) activated by 10 microM forskolin, an activator of adenylate cyclase, suggesting that Ni(2+) acted upstream of adenylate cyclase in the beta-adrenergic signaling pathway. Furthermore, in a low-extracellular Cl(-) bath solution, 1 microM isoproterenol did not significantly alter the amplitude of Ni(2+)-sensitive I(NCX) at +50 mV, which is close to the reversal potential of I(CFTR-Cl). No change in I(NCX) amplitude was induced by 10 microM forskolin. When I(NCX) was activated by extracellular Ca(2+), it was not significantly affected by 1 microM isoproterenol in guinea pig, mouse, or rat ventricular cells. We concluded that beta-adrenergic stimulation does not have significant effects on I(NCX) in guinea pig, mouse, or rat ventricular myocytes.

Simulation of ATP metabolism in cardiac excitation-contraction coupling.

To obtain insights into the mechanisms underlying the membrane excitation and contraction of cardiac myocytes, we developed a computer model of excitation-contraction coupling (Kyoto model: Jpn. J. Physiol. 53 (2003) 105). This model was further expanded by incorporating pivotal reactions of ATP metabolism; the model of mitochondrial oxidative phosphorylation by Korzeniewski and Zoladz (Biophys. Chem. 92 (2001) 17). The ATP-dependence of contraction, and creatine kinase and adenylate kinase were also incorporated. After minor modifications, the steady-state condition was well established for all the variables, including the membrane potential, contraction, and the ion and metabolite concentrations in sarcoplasmic reticulum, mitochondria and cytoplasm. Concentrations of major metabolites were close to the experimental data. Responses of the new model to anoxia were similar to experimental results of the P-31 NMR study in whole heart. This model serves as a prototype for developing a more comprehensive model of excitation-contraction-metabolism coupling.

An in silico study of energy metabolism in cardiac excitation-contraction coupling.

The heart produces and uses ATP at a high rate. Each step involved in ATP metabolism has been extensively studied. However, functional coupling between ATP production and membrane excitation-contraction coupling, which is the main ATP consumption process, is not yet fully understood because of complicated interactions and the lack of quantitative data obtained in vivo. Computer simulation is a powerful tool for integrating experimental data and for solving their complicated interactions. To investigate the mechanisms underlying cardiac excitation-contraction-energy metabolism coupling, we have developed a computer model of cardiac excitation-contraction coupling (Kyoto model) that includes the major processes of ATP production, such as oxidative phosphorylation that was originally developed for skeletal muscle by Korzeniewski and Zoladz [Biophys Chem 92: 17-34, 2001], creatine kinase, and adenylate kinase. In this review, we briefly summarize cardiac energy metabolism and discuss the regulation of mitochondrial ATP synthesis, using the Kyoto model.