Low-Temperature Metallization and Laser Trimming Process for Microwave Dielectric Ceramic Filters.

This paper describes a low-temperature metallization and laser trimming process for microwave dielectric ceramic filters. The ceramic was metalized by electroless copper plating at a temperature lower than those of conventional low-temperature co-fired ceramic (LTCC) and direct bond copper (DBC) methods. Compared with filters made via traditional silver paste sintering, the metal in the holes of the microwave dielectric filters is uniform, smooth, and does not cause clogging nor become detached. Further, the batches of fabricated filters do not require individual inspection, reducing energy, labor, cost, and time requirements. A microwave dielectric filter was then manufactured from the prepared ceramic using a laser trimming machine with a line width and position error within ±50 µm; this demonstrates a more accurately controlled line width than that offered by screen printing. After using HFSS software simulations for preliminary experiments, the microwave dielectric filter was tuned to a target Wi-Fi band of 5.15-5.33 GHz; the return loss was <-10 dB, and the insertion loss was >-3 dB. To implement the real-world process, the laser parameters were optimized. Laser trimming has a higher success rate than traditional manual trimming, and the microwave dielectric filter manufactured here verified the feasibility of this process.

Patients with chronic periodontitis are more likely to develop upper urinary tract stone: a nation-wide population-based eight-year follow up study.

BACKGROUND: The purpose of this study was to investigate the relationship between chronic periodontitis (CP) and upper urinary tract stone (UUTS) in Taiwan by using a population-based data set. METHODS: A total of 16,292 CP patients and 48,876 randomly-selected controls without chronic periodontitis were selected from the National research database and studied retrospectively. Subjects selected have not been diagnosed with UUTS previously. These subjects were prospectively followed for at least eight years. Cox regression models were used to explore the connection between risk factors and the development of UUTS. RESULTS: The CP patients have a greater chance of developing UUTS compared to controls (1761/16292, 10.8% vs. 4775/48876, 9.8%, p-values < 0.001). Conditioned logistic regression suggested CP increases the risk of UUTS development (HR 1.14, 95% CI [1.08-1.20], p < 0.001). After respective adjustment for age, gender, hypertension and diabetes, results showed that CP still increases the risk of developing UUTS (HR 1.14, 95% CI [1.08-1.20], p < 0.001). CONCLUSION: By using a population-based database with a minimum eight 8 follow-up of CP in Taiwan, we discovered patients with CP are more likely to develop UUTS.

Dose-related ethanol intake, Cx43 and Nav1.5 remodeling: Exploring insights of altered ventricular conduction and QRS fragmentation in excessive alcohol users.

BACKGROUND: Chronic, excessive ethanol intake has been linked with various electrical instabilities, conduction disturbances, and even sudden cardiac death, but the underlying cause for the latter is insufficiently delineated. METHODS: We studied surface electrocardiography (ECG) in a community-dwelling cohort with moderate-to-heavy daily alcohol intake (grouped as >90g/day, ≤90g/day, and nonintake). RESULTS: Compared with nonintake, heavier alcohol users showed markedly widened QRS duration and higher prevalence of QRS fragmentation (64.3%, 50.9%, and 33.7%, respectively, χ2 12.0, both p<0.05) on surface ECG across the 3 groups. These findings were successfully recapitulated in 14-week-old C57BL/6 mice that were chronically given a 4% or 6% alcohol diet and showed dose-related slower action potential upstroke, reduced resting membrane potential, and disorganized or decreased intraventricular conduction (all p<0.05). Immunodetection further revealed increased ventricular collagen I depots with Cx43 downregulation and remodeling, together with clustered and diminished membrane Nav1.5 distribution. Administration of Cx43 blocker (heptanol) and Nav1.5 inhibitor (tetrodotoxin) in the mice each attenuated the suppression ventricular conduction compared with nonintake mice (p<0.05). CONCLUSIONS: Chronic excessive alcohol ingestion is associated with dose-related phenotypic intraventricular conduction disturbances and QRS fragmentation that can be recapitulated in mice. The mechanisms may involve suppressed gap junction and sodium channel functions, together with enhanced cardiac fibrosis that may contribute to arrhythmogenesis.

Antiarrhythmic effects of dehydroevodiamine in isolated human myocardium and cardiomyocytes.

ETHNOPHARMACOLOGICAL RELEVANCE: Dehydroevodiamine alkaloid (DeHE), a bioactive component of the Chinese herbal medicine Wu-Chu-Yu (Evodiae frutus), exerted antiarrhythmic effect in guinea-pig ventricular myocytes. We further characterize the electromechanical effects of DeHE in the human atrial and ventricular tissues obtained from hearts of patients undergoing corrective cardiac surgery or heart transplantation. MATERIALS AND METHODS: The transmembrane potentials of human myocardia were recorded with a traditional microelectrode technique while sarcolemmal Na(+) and Ca(2+) currents in single human cardiomyocytes were measured by a whole-cell patch-clamp technique. The intracellular pH (pHi) and Na(+)-H(+) exchanger (NHE) activity were determined using BCECF-fluorescence in human atria. RESULTS: In human atria, DeHE (0.1-0.3 µM) depressed upstroke velocity, amplitude of action potential, and contractile force, both in slow and fast response action potential. Moreover, the similar depressant effects of DeHE were found in human ventricular myocardium. Both in isolated human atrial and ventricular myocytes, DeHE (0.1-1 µM) reversibly, concentration-dependently decreased the Na(+) and Ca(2+)currents. Moreover, DeHE (0.1 and 0.3 µM) suppressed delayed afterdepolarizations and aftercontractions, induced by epinephrine and high [Ca(2+)]o in atria. In human ventricular myocardium, the strophanthidin-induced triggered activities were attenuated by pretreating DeHE (0.3 µM). The resting pHi and NHE activity were also significantly increased by DeHE (0.1-0.3 µM). CONCLUSIONS: We concluded for the first time that, in the human hearts, DeHE could antagonize triggered arrhythmias induced by cardiotonic agents through a general reduction of the Na(+) and Ca(2+) inward currents, while increase of resting pHi and NHE activity.

New insights into the roles of Xin repeat-containing proteins in cardiac development, function, and disease.

Since the discovery of Xin repeat-containing proteins in 1996, the importance of Xin proteins in muscle development, function, regeneration, and disease has been continuously implicated. Most Xin proteins are localized to myotendinous junctions of the skeletal muscle and also to intercalated discs (ICDs) of the heart. The Xin gene is only found in vertebrates, which are characterized by a true chambered heart. This suggests that the evolutionary origin of the Xin gene may have played a key role in vertebrate origins. Diverse vertebrates including mammals possess two paralogous genes, Xinα (or Xirp1) and Xinß (or Xirp2), and this review focuses on the role of their encoded proteins in cardiac muscles. Complete loss of mouse Xinß (mXinß) results in the failure of forming ICD, severe growth retardation, and early postnatal lethality. Deletion of mouse Xinα (mXinα) leads to late-onset cardiomyopathy with conduction defects. Molecular studies have identified three classes of mXinα-interacting proteins: catenins, actin regulators/modulators, and ion-channel subunits. Thus, mXinα acts as a scaffolding protein modulating the N-cadherin-mediated adhesion and ion-channel surface expression. Xin expression is significantly upregulated in early stages of stressed hearts, whereas Xin expression is downregulated in failing hearts from various human cardiomyopathies. Thus, mutations in these Xin loci may lead to diverse cardiomyopathies and heart failure.

Antiarrhythmic effects of (-)-epicatechin-3-gallate, a novel sodium channel agonist in cultured neonatal rat ventricular myocytes.

(-)-Epicatechin-3-gallate (ECG), a polyphenol extracted from green tea, has been proposed as an effective compound for improving cardiac contractility. However, the therapeutic potential of ECG on the treatment of arrhythmia remains unknown. We investigated the direct actions of ECG on the modulation of ion currents and cardiac cell excitability in the primary culture of neonatal rat ventricular myocyte (NRVM), which is considered a hypertrophic model for analysis of myocardial arrhythmias. By using the whole-cell patch-clamp configurations, we found ECG enhanced the slowly inactivating component of voltage-gated Na(+) currents (I(Na)) in a concentration-dependent manner (0.1-100 µM) with an EC(50) value of 3.8 µM. ECG not only shifted the current-voltage relationship of peak I(Na) to the hyperpolarizing direction but also accelerated I(Na) recovery kinetics. Working at a concentration level of I(Na) enhancement, ECG has no notable effect on voltage-gated K(+) currents and L-type Ca(2+) currents. With culture time increment, the firing rate of spontaneous action potential (sAP) in NRVMs was gradually decreased until spontaneous early after-depolarization (EAD) was observed after about one week culture. ECG increased the firing rate of normal sAP about two-fold without waveform alteration. Interestingly, the bradycardia-dependent EAD could be significantly restored by ECG in fast firing rate to normal sAP waveform. The expression of dominant cardiac sodium channel subunit, Nav1.5, was consistently detected throughout the culture periods. Our results reveal how ECG, the novel I(Na) agonist, may act as a promising candidate in clinical applications on cardiac arrhythmias.

Xin proteins and intercalated disc maturation, signaling and diseases.

Intercalated discs (ICDs) are cardiac-specific structures responsible for mechanical and electrical communication among adjacent cardiomyocytes and are implicated in signal transduction. The striated muscle-specific Xin repeat-containing proteins localize to ICDs and play critical roles in ICD formation and cardiac function. Knocking down the Xin gene in chicken embryos collapses the wall of developing heart chambers and leads to abnormal cardiac morphogenesis. In mammals, a pair of paralogous genes, Xinalpha and Xinbeta exist. Ablation of the mouse Xinalpha (mXinalpha) does not affect heart development. Instead, mXinalpha-deficient mice show adult late-onset cardiac hypertrophy and cardiomyopathy with conduction defects. The mXinalpha-deficient hearts up-regulate mouse Xinbeta (mXinbeta, suggesting a partial compensatory role of mXinbeta. Complete loss of mXinbeta however, leads to failure of forming ICD, mis-localization of mXinalpha, and early postnatal lethality. In this review, we will briefly discuss recent advances in the anatomy and function of ICDs. We will then review what we know about Xin repeat-containing proteins and how this protein family promotes ICD maturation and stability for normal cardiac function.

Clinical analysis of macrophage activation syndrome in pediatric patients with autoimmune diseases.

Macrophage activation syndrome (MAS) belongs to secondary hemophagocytic lymphohistiocytosis (HLH) syndrome. It is usually associated with rheumatic diseases. We retrospectively reviewed our hospital's medical records of 102 HLH/MAS patients from the past 20 years. Demographics, clinical data, treatment, and outcomes were analyzed. Among 102 patients, eight patients with underlying juvenile systemic lupus erythematous (two patients), mixed connective tissue disease (one patient), primary anti-phospholipid syndrome (one patient), and systemic type juvenile rheumatoid arthritis (sJRA; four patients) with 13 episodes of MAS were studied. Clinical manifestations of MAS included fever (100 %), hepatosplenomegaly (77 %), lymphadenopathy (38 %), skin rash (62 %), and neurological involvement (31 %). Laboratory features included leukopenia (54 %), anemia (46 %), thrombocytopenia (77 %), jaundice (27 %), hypofibrinogenemia (40 %), decreased erythrocyte sedimentation rate (67 %), and elevated liver enzymes (77 %), lactate dehydrogenase (100 %), ferritin (88 %), triglycerides (91 %), C-reactive protein (85 %), plasma D-dimer (50 %), and hemophagocytosis in bone marrow (83 %). The Epstein-Barr virus and adenovirus infection triggered MAS in two patients with sJRA. Methylprednisolone pulse therapy was effective in two out of three patients, and high-dose intravenous immunoglobulin (IVIG) was effective in two out of six patients. Patients with sJRA responded well to corticosteroids and cyclosporine. Complications included opportunistic infection with Pneumocystis jiroveci, multiple organ failure, and intensive care unit myopathy. The mortality rate was one out of eight (12.5 %). Our results showed that MAS could be fatal and complicate various pediatric autoimmune diseases. It generally has a good response to corticosteroids and IVIG. Prompt recognition and timely treatment can result in good outcomes.

Effect of docosahexaenoic acid on hypoxia/reoxygenation injury in human coronary arterial smooth muscle cells.

PURPOSE: Hypoxia and reoxygenation (H/R) occur in a wide variety of important clinical conditions such as myocardial infarction. H/R injury is a complex phenomenon involving not only intracellular damage processes but also an injurious inflammatory response. Docosahexaenoic acid (DHA), an n-3 polyunsaturated fatty acid, has long been proved to be protective against several types of cardiovascular disease. However, its beneficial effect during H/R is inconclusive. In this study, we employed an in vitro model to examine whether DHA is protective against H/R-induced cell damage in human coronary artery smooth muscle cells (HCASMCs). METHODS: HCASMCs in the absence or presence of DHA (1, 3, 10, and 30 µM) were subjected to control or H/R treatment using a modular incubator chamber to create hypoxic condition. Cell viability was evaluated by MTT assay. Spectrophotometric and spectrofluorometric assays were used to measure the generation of nitric oxide (NO) and reactive oxygen species (ROS), respectively. Inflammatory cytokines were determined by enzyme-linked immunosorbent assay. Intracellular calcium mobilization was estimated microfluorimetrically using calcium indicator dye, fura 2-acetomethyl ester. RESULTS: Hypoxia/reoxygenation caused significant injury in cultured HCASMCs. DHA at low concentrations (1, 3, and 10 µM) did not afford protection, whereas at 30 µM, it caused deleterious effects, presumably by enhancing the production of NO, ROS, IL-1ß, and IL-6 and altering the intracellular calcium dynamics. CONCLUSIONS: Our results do not support the protective function of DHA in H/R-injured coronary arterial smooth muscle cells.

Hypoxia and reoxygenation modulate the arrhythmogenic activity of the pulmonary vein and atrium.

Ischaemia and reperfusion contribute to the genesis of AF (atrial fibrillation). PVs (pulmonary veins) and the atria are important foci for AF initiation and maintenance. However, the effect of ischaemia and reperfusion on PVs and the atria has not yet been fully elucidated. In the present study, conventional microelectrodes were used to record the APs (action potentials) in isolated rabbit PV, LA (left atrium) and RA (right atrium) specimens during hypoxia and reoxygenation, and pharmacological interventions. Hypoxia reduced the PV beating rates from 1.8±0.1 to 1.3±0.2 and 0.8±0.1 Hz at 30 and 60 min respectively (n=8, P<0.005), and induced EAD (early after depolarization) in three (37.5%) of the PVs and DAD (delayed after depolarization) in one (12.5%) of the PVs. Reoxygenation increased the PV spontaneous rate to 1.4±0.2 Hz (P<0.05) and induced PV burst firings (3.5±0.1 Hz, P<0.001) in six (75%) of the PVs. Hypoxia shortened the AP duration in the LA and PVs, but not in the RA. Pretreatment with glibenclamide attenuated hypoxia-induced decreases in the PV spontaneous activity and the shortening of the LA and PV AP duration. Similar to those in hypoxia, the K(ATP) (ATP-sensitive potassium) channel opener pinacidil (30 µM) decreased PV spontaneous activity and shortened the AP duration. Pretreatment with 5 mM N-MPG [N-(mercaptopropionyl)glycine; a hydroxyl (•OH) free-radical scavenger] or 300 µM chloramphenicol [a cytochrome P450 inhibitor that reduces ROS (reactive oxygen species)] attenuated the rate changes induced by hypoxia and reoxygenation, and also decreased the burst firing incidence. In conclusion, hypoxia and reoxygenation significantly increased PV arrhythmogenesis and induced different electrophysiological responses in the RA and LA, which may play a role in the pathophysiology of AF.

Heart failure enhanced pulmonary vein arrhythmogenesis and dysregulated sodium and calcium homeostasis with increased calcium sparks.

UNLABELLED: Late sodium currents and intracellular Ca(2+) (Ca(2+) (i)) dynamics play an important role in arrhythmogenesis of pulmonary vein (PV) and heart failure (HF). It is not clear whether HF enhances PV arrhythmogenesis through modulation of Ca(2+) homeostasis and increased late sodium currents. The aim of this study was to investigate the sodium and calcium homeostasis in PV cardiomyocytes with HF. METHODS AND RESULTS: Whole-cell patch clamp was used to investigate the action potentials and ionic currents in isolated rabbit single PV cardiomyocytes with and without rapid pacing induced HF. The Ca(2+) (i) dynamics were evaluated through fluorescence and confocal microscopy. As compared to control PV cardiomyocytes (n = 18), HF PV cardiomyocytes (n = 13) had a higher incidence of delayed afterdepolarization (45% vs 13%, P < 0.05) and faster spontaneous activity (3.0 ± 0.2 vs 2.1 ± 0.2 Hz, P < 0.05). HF PV cardiomyocytes had increased late Na(+) currents, Na(+) /Ca(2+) exchanger currents, and transient inward currents, but had decreased Na(+) currents or L-type calcium currents. HF PV cardiomyocytes with pacemaker activity had larger Ca(2+) (i) transients (R410/485, 0.18 ± 0.04 vs 0.11 ± 0.02, P < 0.05), and sarcoplasmic reticulum Ca(2+) stores. Moreover, HF PV cardiomyocytes with pacemaker activity (n = 18) had higher incidence (95% vs 70%, P < 0.05), frequency (7.8 ± 3.1 vs 2.3 ± 1.2 spark/mm/s, P < 0.05), amplitude (F/F(0) , 3.2 ± 0.8 vs 1.9 ± 0.5, P < 0.05), and longer decay time (65 ± 3 vs 48 ± 4 ms, P < 0.05) of Ca(2+) sparks than control PV cardiomyocytes with pacemaker activity (n = 18). CONCLUSIONS: Dysregulated sodium and calcium homeostasis, and enhanced calcium sparks promote arrhythmogenesis of PV cardiomyocytes in HF, which may play an important role in the development of atrial fibrillation.

Slow conduction and gap junction remodeling in murine ventricle after chronic alcohol ingestion.

BACKGROUND: Long-term heavy alcohol drinkers are prone to the development of cardiac arrhythmia. To understand the mechanisms, we evaluated the cardiac structural and electrophysiological changes in mice chronically drinking excessive alcohol. RESULTS: Male C57BL/6J mice were given 36% alcohol in the drinking water. Those given blank water were used as control. Twelve weeks later, the phenotypic characteristics of the heart, including gap junctions and electrical properties were examined. In the alcohol group the ventricles contained a smaller size of cardiomyocytes and a higher density of capillary networks, compared to the control. Western blots showed that, after drinking alcohol, the content of connexin43 (Cx43) protein in the left ventricle was increased by 18% (p < 0.05). Consistently, immunoconfocal microscopy demonstrated that Cx43 gap junctions were up-regulated in the alcohol group with a disorganized distribution, compared to the control. Optical mapping showed that the alcohol group had a reduced conduction velocity (40 ± 18 vs 60 ± 7 cm/sec, p < 0.05) and a higher incidence of ventricular tachyarrhythmia (62% vs 30%, p < 0.05). CONCLUSION: Long-term excessive alcohol intake resulted in extensive cardiac remodeling, including changes in expression and distribution of gap junctions, growth of capillary network, reduction of cardiomyocyte size, and decrease of myocardial conduction.

Heart failure enhances arrhythmogenesis in pulmonary veins.

1. Heart failure (HF) predisposes to atrial fibrillation (AF) as a result of substrate remodelling. The present study aimed to investigate the impact of HF on the electrical remodelling of the pulmonary veins (PV) and left atrium (LA). 2. The electrical activity was recorded in LA and PV from control rabbits and rabbits with rapid ventricular pacing-induced HF, using a multi-electrode array system and conventional microelectrodes. 3. Compared with the control-PV (n = 21), the HF-PV (n = 13) had a higher incidence and frequency of rapid pacing-induced spontaneous activity (85 vs 29%, P = 0.005; 3.5 ± 0.2 vs 1.7 ± 0.1 Hz, P < 0.001) and high-frequency irregular electrical activity (92 vs 38%, P = 0.01; 23 ± 1 vs 19 ± 1 Hz, P = 0.003), greater depolarized resting membrane potential (-59 ± 1 vs -70 ± 2 mV, P < 0.001), higher incidence of early afterdepolarizations (EAD; 69 vs 6%, P = 0.001) and delayed afterdepolarizations (DAD; 92 vs 25%, P = 0.001), and slower conduction velocity (38 ± 2 vs 63 ± 2 cm/s, P < 0.05). In comparison to the HF-LA, the HF-PV had a higher incidence of spontaneous activity and high-frequency irregular electrical activity (85 vs 39%, P = 0.04; 92 vs 46%, P = 0.03), and higher incidence of EAD and DAD, and those differences were not found between the control-LA and control-PV. The control-PV with high-frequency irregular electrical activity had a higher incidence of DAD and spontaneous activity as compared with those without it. 4. HF contributed to an increased automaticity, triggered activity and conduction disturbance in the PV. The PV possessed more arrhythmogenic properties, which might play an important role in the genesis of AF in HF.

Intercalated disc-associated protein, mXin-alpha, influences surface expression of ITO currents in ventricular myocytes.

Mouse Xin-alpha (mXin-alpha) encodes a Xin repeat-containing, actin-binding protein localized to the intercalated disc (ICD). Ablation of mXin-alpha progressively leads to disrupted ICD structure, cardiac hypertrophy and cardiomyopathy with conduction defects during adulthood. Such conduction defects could be due to ICD structural defects and/or cell electrophysiological property changes. Here, we showed that despite the normal ICD structure, juvenile mXina-null cardiomyocytes (from 3~4-week-old mice) exhibited a significant reduction in the transient outward K+ current (ITO), similar to adult mutant cells. Juvenile but not adult mutant cardiomyocytes also had a significant reduction in the delayed rectifier K+ current. In contrast, the mutant adult ventricular myocytes had a significant reduction in the inward rectifier K+ current (IK1) on hyperpolarization. These together could account for the prolongation of action potential duration (APD) and the ease of developing early afterdepolarization observed in juvenile mXin-alpha-null cells. Interestingly, juvenile mXin-alpha-null cardiomyocytes had a notable decrease in the amplitude of intracellular Ca2+ transient and no change in the L-type Ca2+ current, suggesting that the prolonged APD did not promote an increase in intracellular Ca2+ for cardiac hypertrophy. Juvenile mXin-alpha-null ventricles had reduced levels of membrane-associated Kv channel interacting protein 2, an auxiliary subunit of ITO, and filamin, an actin cross-linking protein. We further showed that mXin-alpha interacted with both proteins, providing a novel mechanism for ITO surface expression.

Diverse cell morphology and intracellular calcium dynamics in pulmonary vein cardiomyocytes.

Pulmonary veins (PVs) contain cardiomyocytes with a complex cellular morphology and high arrhythmogenesis. Ca(2+) regulation and Ca(2+) sparks play a pivotal role in the electrical activity of cardiomyocytes. The purpose of this study was to investigate whether the cell morphology can determine the PV electrical activity and Ca(2+) homeostasis. Through confocal microscopy with fluo-3 Ca(2+) fluorescence, Ca(2+) sparks and Ca(2+) transients were evaluated in isolated single rabbit left atria (LA) and PV cardiomyocytes according to the cell morphology (rod, rod-spindle and spindle/bifurcated). Twenty-two (20%) rod, 49 (43%) rod-spindle and 41 (37%) spindle/bifurcated cardiomyocytes were identified in the LA (n = 29) and PV (n = 83) cardiomyocytes. The PV cardiomyocytes with pacemaker activity had a higher incidence of spindle/bifurcated morphology than LA and PV cardiomyocytes without pacemaker activity. As compared to those in the rod or rod-spindle cardiomyocytes, spindle/bifurcated cardiomyocytes had a larger Ca(2+) transient amplitude and higher frequency of the Ca(2+) sparks with larger amplitude and longer duration. In contrast, rod-spindle and rod cardiomyocytes had similar Ca(2+) transients and Ca(2+) sparks. The cell length correlated well with the amplitude of the Ca(2+) transient and Ca(2+) spark duration with a linear regression. In conclusion, cell morphology and cell length play a potential role in the Ca(2+) homeostasis and Ca(2+) spark. The large Ca(2+) transients and high frequency of Ca(2+) sparks in spindle/bifurcated cardiomyocytes may cause a high arrhythmogenesis in the PV cardiomyocytes with pacemaker activity.

Oxidative stress on pulmonary vein and left atrium arrhythmogenesis.

BACKGROUND: Oxidative stress and pulmonary veins (PVs) play critical roles in the pathophysiology of atrial fibrillation. The purpose of the present study was to investigate whether oxidative stress and antioxidant agents can change the electrophysiological characteristics of the left atrium (LA) and PVs. METHODS AND RESULTS: Conventional microelectrodes were used to record the action potentials (APs) in isolated rabbit PV and LA specimens before and after H(2)O(2) administration with or without ascorbic acid or N-mercaptopropionyl-glycine (N-MPG, a free radical .OH scavenger). H(2)O(2) (0.02 and 0.2 mmol/L) decreased the PV spontaneous rates from 2.0+/-0.1 Hz to 1.6+/-0.1 Hz, and 1.7+/-0.1 Hz (n=10, P<0.05), but H(2)O(2) (2 mmol/L) increased PV spontaneous rates from 2.0+/-0.1 Hz to 2.8+/-0.2 Hz. H(2)O(2) easily induced PV burst firing and early afterdepolarizations, but not in the LA. H(2)O(2) shortened the AP duration and increased the contractile force to a greater extent in the LA than in PVs. In addition, the H(2)O(2)-induced PV burst firing and increasing spontaneous rates were suppressed or attenuated by pretreatment with ascorbic acid (1 mmol/L) or N-MPG (10 mmol/L). CONCLUSIONS: H(2)O(2) significantly changed the electrophysiological characteristics of PV and LA through activation of free radicals and may facilitate the occurrence of atrial fibrillation.

Essential roles of an intercalated disc protein, mXinbeta, in postnatal heart growth and survival.

RATIONALE: The Xin repeat-containing proteins mXinalpha and mXinbeta localize to the intercalated disc of mouse heart and are implicated in cardiac development and function. The mXinalpha directly interacts with beta-catenin, p120-catenin, and actin filaments. Ablation of mXinalpha results in adult late-onset cardiomyopathy with conduction defects. An upregulation of the mXinbeta in mXinalpha-deficient hearts suggests a partial compensation. OBJECTIVE: The essential roles of mXinbeta in cardiac development and intercalated disc maturation were investigated. METHODS AND RESULTS: Ablation of mXinbeta led to abnormal heart shape, ventricular septal defects, severe growth retardation, and postnatal lethality with no upregulation of the mXinalpha. Postnatal upregulation of mXinbeta in wild-type hearts, as well as altered apoptosis and proliferation in mXinbeta-null hearts, suggests that mXinbeta is required for postnatal heart remodeling. The mXinbeta-null hearts exhibited a misorganized myocardium as detected by histological and electron microscopic studies and an impaired diastolic function, as suggested by echocardiography and a delay in switching off the slow skeletal troponin I. Loss of mXinbeta resulted in the failure of forming mature intercalated discs and the mislocalization of mXinalpha and N-cadherin. The mXinbeta-null hearts showed upregulation of active Stat3 (signal transducer and activator of transcription 3) and downregulation of the activities of Rac1, insulin-like growth factor 1 receptor, protein kinase B, and extracellular signal-regulated kinases 1 and 2. CONCLUSIONS: These findings identify not only an essential role of mXinbeta in the intercalated disc maturation but also mechanisms of mXinbeta modulating N-cadherin-mediated adhesion signaling and its crosstalk signaling for postnatal heart growth and animal survival.

Reduced Ca2+ transport across sarcolemma but enhanced spontaneous activity in cardiomyocytes isolated from left atrium-pulmonary veins tissue of myopathic hamster.

BACKGROUND: Several lines of evidence point to a particularly important role of the left atrium (LA) in initiating and maintaining atrial fibrillation (AF). This role may be related to the location of pulmonary veins (PVs) in the LA. The aim of the present study was to investigate the action potential (AP) and ionic currents in LA-PV cardiomyocytes isolated from Bio14.6 myopathic Syrian hamsters (36-57 week-old) versus age-matched F1B healthy control hamsters. METHODS AND RESULTS: Whole-cell patch-clamp techniques were used to record AP in current-clamp mode and ionic currents in voltage-clamp mode. The results obtained show that in both healthy and myopathic LA-PV tissue spontaneously discharging cardiomyocytes can be found, but they are more numerous in myopathic (9/29) than in healthy hamsters (4/42, p < 0.05 by chi2 analysis). Myopathic myocytes have shorter AP duration (APD) with smaller ICa,L and INCX than the healthy control. The currents ITO, IK, IK1 and ICa,T are not significantly different in myopathic versus healthy cells. CONCLUSIONS: Our results indicate that in myopathic Syrian hamsters LA-PV cardiomyocytes are more prone to automatic rhythms. Also, they show altered electrophysiologic properties, which may be due to abnormal Ca2+ channels and may account for contractile dysfunction.