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Chu-Pak Lau

Publications and source records attributed to Chu-Pak Lau.

At least 19 recordsLinked to original sources
PubMed2006

Regulation of voltage-gated cardiac sodium current by epidermal growth factor receptor kinase in guinea pig ventricular myocytes.

Voltage-gated cardiac fast sodium channel current (I(Na)) plays a critical role in the initiation and propagation of the myocardial action potential, and regulation of cardiac I(Na) by protein tyrosine kinases (PTKs) is not well documented, though it is known that ion channels are among the targets of PTKs. The present study was therefore designed to investigate whether/how cardiac I(Na) was modulated by PTKs in guinea pig ventricular myocytes using whole-cell patch clamp and immunoprecipitation and Western blotting approaches. It was found that cardiac I(Na) was enhanced by epidermal growth factor (EGF), and the effect was antagonized by the selective epidermal growth factor receptor (EGFR) kinase inhibitor tyrphostin AG556 while potentiated by orthovanadate (a protein tyrosine phosphatase (PTP) inhibitor). In addition, AG556 inhibited, while orthovanadate increased I(Na), and the inhibition of I(Na) by AG556 was antagonized by orthovanadate. Immunoprecipitation and Western blotting analysis demonstrated that tyrosine phosphorylation level of cardiac sodium channels was enhanced by EGF or orthovanadate, and reduced by AG556. The AG556-induced reduction of phosphorylation level was significantly reversed by orthovanadate. Our results demonstrate the novel information that EGFR kinase enhances, and PTPs reduce native cardiac I(Na) in guinea pig ventricular myocytes.

Animals↗
PubMed2006

Impaired nitrate-mediated dilatation could reflect nitrate tolerance in patients with coronary artery disease.

AIM: To investigate whether nitrate-mediated dilatation (NMD) of the brachial artery could be impaired by the use of nitrates and reflect nitrate tolerance in coronary artery disease (CAD) patients. METHODS: A total of 243 patients (mean age 61+/-12 years, 146 male) were recruited before coronary angiography. Gensini score was calculated to assess the severity of CAD. Flow-mediated dilatation (FMD) and NMD of the brachial artery were measured. RESULTS: NMD progressively decreased from subjects without CAD (control group, n=71) to non-nitrate users (n=64) and nitrate users (n=108) with CAD (16.2+/-6.01% versus 13.4+/-5.57% versus 9.57+/-4.52%, P<0.001 for all). Multiple linear regression analysis showed that age, FMD, diameter of the brachial artery, hypertension, and nitrate use were independent determinants of NMD. In subgroup analysis of patients with high Gensini score (>10), nitrate users (n=56, 9.00+/-4.00%) had a significant lower NMD than non-users (n=28, 12.4+/-5.45%, P<0.001), but no difference in other parameters including age, prevalence of hypertension, FMD, Gensini score and use of other medications. CONCLUSIONS: The use of nitrates independently impaired NMD in CAD patients. An impaired NMD could be a comprehensive index of nitrate tolerance in patients with CAD.

Adult↗
PubMed2006

Evidence for cystic fibrosis transmembrane conductance regulator chloride current in swine ventricular myocytes.

The present study investigated whether cAMP-dependent cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channel current (i.e., I(Cl.CFTR) or I(Cl.cAMP)) would be expressed in pig cardiac myocytes using whole-cell patch technique and reverse transcription polymerase chain reaction (RT-PCR). It was found that the beta-adrenoceptor agonist isoproterenol activated a time-independent current in myocytes from the ventricle, but not the atrium of pig heart. Histamine and forskolin (an adenylate cyclase activator) induced a similar current in pig ventricular cells. The current induced by isoproterenol was blocked by the PKA inhibitor H-7, reduced by the replacement of external Cl(-) ion, and inhibited by the application of 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB), but not 4'-diisothiocynatostilbene-2,2'-disulfonic acid (DIDS), typical of I(Cl.CFTR). I(Cl.CFTR) showed a small difference in regional myocytes across the left ventricular wall from epicardium to endocardium. Isoproterenol-induced current was 3.1+/-0.2 (n=33), 2.8+/-0.2 (n=25) and 2.3+/-0.2 pA/pF (n=31) respectively in subepicardial, midmyocardial, and subendocardial myocytes (P<0.05, subepicardium vs. subendocardium). RT-PCR and Western blotting analysis revealed that significant differences in CFTR channel mRNA and protein levels were present in atrial and ventricular cells, but not in regional ventricular cells across the ventricular wall from subepicardium to subendocardium. These results indicate that the functional CFTR channel (i.e., I(Cl.CFTR)) is present in ventricular myocytes, but not in atrial cells of pig heart.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed2006

Emerging trends of community acquired infective endocarditis.

BACKGROUND: To obtain epidemiological information and to evaluate the emerging trend of incidence and clinical features of community acquired infective endocarditis (IE) in Hong Kong. METHODS: Population-based survey in a regional hospital in Hong Kong which served 0.55 million population over an 11-year period was conducted. 172 patients diagnosed to have IE between 1995 and 2005 were analyzed. Incidence, underlying heart disease, causative microorganisms and clinical outcomes of IE were studied. RESULTS: The standardized annual incidence of community acquired IE was 2.8 cases per 100,000 person-year and remain stable over the past 10 years in Hong Kong (P=0.57 for trends). The most common underlying heart diseases for IE were intravenous drug addict (30%), followed by chronic rheumatic heart disease (18%). There was a time trend of increasing age in patients suffered from IE, both in patients with or without intravenous drug abuse (overall P=0.004). Although there were no significant changes in the overall proportion of IE patients with different underlying etiologies, site of IE involvement and types of microorganisms, non-addict patients showed an increasing trend of staphylococcal IE during the study period (P=0.01). The adverse clinical outcome of IE during the study period remained unchanged (P=0.71). CONCLUSIONS: The results of this study have demonstrated that IE continued to be an important disease with stable incidence and high morbidity and mortality over time in Asia. Furthermore, our study also highlighted that IE is an emerging disease with continuously changing clinical and microbiologic patterns, and significant differences are still present between different countries.

Community-Acquired Infections↗
PubMed2006

A patient with relapsing pacemaker infection due to "Gram-positive bacilli".

Mycobacterium fortuitum infection of pacemaker system is rarely encountered in clinical practice. We reported a case of relapsing M. fortuitum infection of pacemaker system associated with endocarditis which had been erroneously diagnosed to be Gram-positive bacilli. The diagnosis was finally confirmed by detail histological and microbiological examination. This case clearly demonstrated that incomplete removal of pacemaker system resulted in relapsing infection despite appropriate antibiotic therapy.

Aged↗
PubMed2006

Incidence, clinical characteristics and outcome of congestive heart failure as the initial presentation in patients with primary hyperthyroidism.

BACKGROUND: There are limited systematic data on the incidence, clinical characteristics and outcomes of congestive heart failure (CHF) in patients with hyperthyroidism. The aim of this study was to investigate the incidence, clinical characteristics and outcome of CHF as the initial presentation in patients with primary hyperthyroidism. METHODS: The prevalence, clinical characteristics and outcome of CHF was studied in 591 consecutive patients (mean (SD) age 45 (1) years, 140 men) who presented with primary hyperthyroidism. RESULTS: CHF was the presenting condition in 34 patients (5.8%) with hyperthyroidism. The presence of atrial fibrillation at presentation (OR 37.4, 95% CI 9.72 to 144.0, p<0.001) was an independent predictor for the occurrence of CHF. Of the 34 patients with CHF, 16 (47%) had systolic left ventricular dysfunction with left ventricular ejection fraction (LVEF)<50%. They were predominantly male (OR 26.6, 95% CI 2.6 to 272.5, p = 0.006) and had a lower serum thyroxine level (OR 0.93, 95% CI 0.87 to 0.99, p = 0.044) than patients with preserved left ventricular systolic function. In these patients, LVEF (55 (4)% vs 30 (2)%, p<0.001) and New York Heart Association functional class (1.2 (0.1) vs 2.5 (0.2), p<0.001) improved significantly 3 months after achieving euthyroid status. Systolic left ventricular dysfunction (mean (SD) LVEF 38 (4)%) persisted on long-term follow-up in five PATIENTS: no clinical parameter could be identified to predict the occurrence of this persistent cardiomyopathy (p>0.05). CONCLUSION: CHF was the initial clinical presentation in approximately 6% of patients with hyperthyroidism, and half of them had left ventricular systolic dysfunction. Symptoms of CHF subsided and LVEF improved after treatment for hyperthyroidism. Nonetheless, one-third of these patients developed persistent dilated cardiomyopathy.

Adolescent↗
PubMed2006

Bioartificial sinus node constructed via in vivo gene transfer of an engineered pacemaker HCN Channel reduces the dependence on electronic pacemaker in a sick-sinus syndrome model.

BACKGROUND: The normal cardiac rhythm originates in the sinoatrial (SA) node that anatomically resides in the right atrium. Malfunction of the SA node leads to various forms of arrhythmias that necessitate the implantation of electronic pacemakers. We hypothesized that overexpression of an engineered HCN construct via somatic gene transfer offers a flexible approach for fine-tuning cardiac pacing in vivo. METHODS AND RESULTS: Using various electrophysiological and mapping techniques, we examined the effects of in situ focal expression of HCN1-DeltaDeltaDelta, the S3-S4 linker of which has been shortened to favor channel opening, on impulse generation and conduction. Single left ventricular cardiomyocytes isolated from guinea pig hearts preinjected with the recombinant adenovirus Ad-CMV-GFP-IRES-HCN1-DeltaDeltaDelta in vivo uniquely exhibited automaticity with a normal firing rate (237+/-12 bpm). High-resolution ex vivo optical mapping of Ad-CGI-HCN1-DeltaDeltaDelta-injected Langendorff-perfused hearts revealed the generation of spontaneous action potentials from the transduced region in the left ventricle. To evaluate the efficacy of our approach for reliable atrial pacing, we generated a porcine model of sick-sinus syndrome by guided radiofrequency ablation of the native SA node, followed by implantation of a dual-chamber electronic pacemaker to prevent bradycardia-induced hemodynamic collapse. Interestingly, focal transduction of Ad-CGI-HCN1-DeltaDeltaDelta in the left atrium of animals with sick-sinus syndrome reproducibly induced a stable, catecholamine-responsive in vivo "bioartificial node" that exhibited a physiological heart rate and was capable of reliably pacing the myocardium, substantially reducing electronic pacing. CONCLUSIONS: The results of the present study provide important functional and mechanistic insights into cardiac automaticity and have further refined an HCN gene-based therapy for correcting defects in cardiac impulse generation.

Animals↗
PubMed2006

Characterization of recombinant human cardiac KCNQ1/KCNE1 channels (I (Ks)) stably expressed in HEK 293 cells.

The present study was designed to characterize pharmacological, biophysical and electrophysiological properties of the recombinant human cardiac I (Ks) (KCNQ1/KCNE1) channels at physiological temperature. Human cardiac KCNQ1 and KCNE1 genes were cotransfected into HEK 293 cells, and a cell clone stably expressing both genes was selected. Membrane currents were recorded using a perforated patch-clamp technique. The typical I (Ks) was slowly activated upon depolarization voltages in HEK 293 cells stably expressing human cardiac KCNQ1 and KCNE1 genes, and the current was inhibited by I (Ks) blockers HMR 1556 and chromanol 293B, with 50% inhibitory concentrations (IC(50)s) of 83.8 nM: and 9.2 muM: , respectively. I (Ks) showed a significant temperature-dependent increase in its magnitude upon elevating bath temperature to 36 degrees C from room temperature (21 degrees C). The current was upregulated by the beta-adrenoceptor agonist isoproterenol, and the effect was reversed by H89. In addition, I (Ks) was inhibited by Ba(2+) in a concentration-dependent manner (IC(50) = 1.4 mM). Action potential clamp revealed a "bell-shaped" time course of I (Ks) during the action potential, and maximal peak current was seen at the plateau of the action potential. A significant use- and frequency-dependent increase of I (Ks) was observed during a train of action potential clamp. These results indicate that the recombinant human cardiac I (Ks) stably expressed in HEK 293 cells is similar to native I (Ks) in drug sensitivity and regulated by Ba(2+) and beta-adrenoceptor via the cyclic adenosine monophosphate/protein kinase A pathway. Importantly, the current exhibits significant temperature dependence, a bell-shaped time course during action potential and prominent use- or frequency-dependent accumulation during a train of action potentials.

Action Potentials↗
PubMed2006

Properties of ion channels in rabbit mesenchymal stem cells from bone marrow.

The present study was designed to investigate properties of ion channels in undifferentiated rabbit mesenchymal stem cells (MSCs) from bone marrow using whole-cell patch-clamp and RT-PCR techniques. It was found that three types of outward currents were present in rabbit MSCs, including an inward rectifier K(+) current (I(Kir)), a noise-like Ca(2+)-activated K(+) current (I(KCa)) co-present with delayed rectifier K(+) current (IK(DR)). I(Kir) was inhibited by Ba(2+), while I(KCa) was inhibited by paxilline (a blocker of big conductance I(KCa) channels) and clotrimazole (an inhibitor of intermediate conductance I(KCa) channels). IK(DR) exhibited a slow inactivation, "U-shaped" voltage-dependent inactivation, and slow recovery from inactivation, and the current was inhibited by tetraethylammonium or 4-aminopyridine. RT-PCR revealed the molecular identities for the functional ionic currents, including Kir1.1 (possibly responsible for I(Kir)), KCa1.1 and KCa3.1 (possibly responsible for I(KCa)), and Kv1.2, Kv2.1, and Kv2.2 (possibly responsible for IK(DR)). These results demonstrate for the first time that three types of functional ion channel currents (i.e., I(Kir), I(KCa), and IK(DR)) are present in rabbit MSCs from bone marrow.

Animals↗
PubMed2006

Incidence and predictors of upper gastrointestinal bleeding in patients receiving low-dose aspirin for secondary prevention of cardiovascular events in patients with coronary artery disease.

AIM: The use of low-dose aspirin to prevent cardiovascular disease events is well established. However, the incidence and predictors of upper gastrointestinal bleeding (UGIB) with its use are unknown. We studied prospectively the incidence and outcome of peptic ulceration in low-dose aspirin users. METHODS: A total of 991 patients with coronary artery disease (CAD) on low-dose aspirin were prospectively followed-up for two years for the occurrence and clinical features of first hospitalized episode of UGIB. RESULTS: UGIB had a bimodal presentation with 45% occurring within four months of aspirin initiation and had an overall prevalence of 1.5% per year. There was no UGIB-related death. Hypertension (OR = 4.6, 95%CI 1.5-14.7, P = 0.009), history of peptic ulceration (OR = 3.1, 95%CI 1.1-9.0, P = 0.039), tertiary education (OR = 3.08, 95%CI 1.1-9.0, P = 0.039) and higher lean body mass (P = 0.016) were independent factors associated with UGIB. Use of nitrate did not reduce UGIB. CONCLUSION: The incidence of UGIB in patients with CAD on long-term low-dose aspirin is low, but is accompanied with significant morbidity. With prolonged use of aspirin, UGIB continues to be a problem for those with risk factors and especially in patients with a history of peptic ulcers, in which UGIB tends to occur early after aspirin therapy.

Aged↗
PubMed2006

Safety of catheter-based intramyocardial autologous bone marrow cells implantation for therapeutic angiogenesis.

The long-term safety and efficacy of autologous bone marrow cell implantation into the myocardium remains undefined. We studied the long-term clinical outcome of 12 patients with severe coronary artery disease who underwent electromechanical mapping-guided catheter-based autologous bone marrow cell implantation. Magnetic resonance imaging at 3 and 6 months showed no evidence of intramyocardial tumor formation, myocardial damage, or worsening of left ventricular ejection fraction. No sustained arrhythmia was detected on 24-hour Holter monitoring. After 44 +/- 10 months of follow-up, 1 patient had died of stroke at 8 months and another patient had died of myocardial infarction at 20 months. Computed tomography at 36 months or postmortem examination showed no tumor formation or intramyocardial calcification at the treated sites, and no sustained ventricular arrhythmia or sudden death was observed. Autologous bone marrow cell implantation into the ischemic human myocardium was not associated with long-term major adverse events regarding tumor, scar, or calcification formation, and the arrhythmogenic risk was low.

Aged↗
PubMed2006

Effects of oral arsenic trioxide therapy on QT intervals in patients with acute promyelocytic leukemia: implications for long-term cardiac safety.

Ventricular tachyarrhythmias may occur during intravenous arsenic trioxide (As2O3). This has not happened during oral As2O3. Sixteen patients were studied by electrocardiography and 24-hour Holter monitoring at baseline, during and after oral As2O3 (As2O3-ON, As2O3-OFF). QT and corrected QT (QTc) were significantly longer during As2O3-ON than in As2O3-OFF, but QT and QTc dispersions were comparable. The patients' 24-hour heart rates were higher during As2O3-ON than in As2O3-OFF. QTc intervals at each hour were longer during As2O3-ON than in As2O3-OFF. However, QTc prolongation of more than 30 milliseconds only occurred at one time point (2 hours) after oral As2O3, resulting in QTc of more than 500 milliseconds in 3 of 16 patients, all within 4 hours of oral As2O3. Although the standard deviation of normal RR interval was lower during As2O3-ON, ratios of low frequency to high frequency power for As2O3-ON and As2O3-OFF were comparable. No ventricular proarrhythmias were observed. These observations, due to the lower peak plasma arsenic reached during oral As2O3, may explain the relative cardiac safety of oral As2O3.

Administration, Oral↗
PubMed2006

Ion channels in mesenchymal stem cells from rat bone marrow.

Mesenchymal stem cells (MSCs) from bone marrow are believed to be an ideal cell source for cardiomyoplasty; however, cellular electrophysiology is not understood. The present study was designed to investigate ion channels in undifferentiated rat MSCs. It was found that three types of outward currents were present in rat MSCs, including a small portion of Ca(2+)-activated K(+) channel (I(KCa)) sensitive to inhibition by iberiotoxin and/or clotromazole, a delayed rectifier K(+) current (IK(DR)), and a transient outward K(+) current (I(to)). In addition, tetrodotoxin (TTX)-sensitive sodium current (I(Na.TTX)) and nifedipine-sensitive L-type Ca(2+) current (I(Ca.L)) were found in a small population of rat MSCs. Moreover, reverse transcription-polymerase chain reaction revealed the molecular evidence of mRNA for the functional ionic currents, including Slo and KCNN4 for I(KCa); Kv1.4 for I(to); Kv1.2 and Kv2.1 for IK(DR); SCN2a1 for I(Na.TTX); and CCHL2a for I(Ca.L). These results demonstrate for the first time that multiple functional ion channel currents (i.e., I(KCa), I(to), IK(DR), I(Na.TTX), and I(Ca.L)) are present in rat MSCs from bone marrow; however, physiological roles of these ion channels remain to be studied.

Adipogenesis↗
PubMed2006

Prognostic implications of PR-segment depression in inferior leads in acute inferior myocardial infarction.

BACKGROUND: Concurrent atrial ischemia is usually overlooked in acute myocardial infarction (MI) due to its subtle electrocardiographic (ECG) changes, lack of clear-cut clinical picture, and prognostic significance. PR-segment depression in the inferior leads is a simplified ECG sign for detecting possible underlying atrial ischemia. HYPOTHESIS: The purpose of this study was to document the incidence, clinical characteristics, and prognostic implications of this ECG sign in the setting of acute inferior MI. METHODS: Demographics, clinical characteristics, and outcomes of 463 consecutive patients presenting with acute inferior MI were reviewed. The in-hospital ECG was examined by two independent reviewers. The results were then compared between those with and without ECG sign. RESULTS: Profound PR-segment depression > or = 1.2 mm in inferior leads was found in 9 of 463 (1.9%) patients. Patients with atrial ischemia tended to present earlier (2.4 +/- 2.6 vs. 7.0 +/- 8.2 h, p = 0.000) and had a higher frequency of first-degree atrioventricular block (77.8 vs. 30.6%, p = 0.028) and supraventricular arrhythmias (55.5 vs. 20.2%, p = 0.022). Of greater importance, it was significantly associated with an increased rate of cardiac free-wall rupture (33.3 vs. 2.0%, p = 0.001) and in-hospital mortality (44.4 vs. 11.7%, p = 0.015). CONCLUSION: Profound PR-segment depression > or = 1.2 mm in inferior leads was associated with a complicated hospital course and poor short-term outcome in acute inferior MI. These patients were at high risk for the development of atrioventricular block, supraventricular arrhythmias, and cardiac free-wall rupture.

Aged↗
PubMed2006

Effects of the antifungal antibiotic clotrimazole on human cardiac repolarization potassium currents.

The antifungal antibiotic clotrimazole (CLT) shows therapeutic effects on cancer, sickle cell disease, malaria, etc. by inhibiting membrane intermediate-conductance Ca2+ -activated K+ channels (IKCa). However, it is unclear whether this drug would affect human cardiac K+ currents. The present study was therefore designed to investigate the effects of CLT on transient outward K+ current (Ito1), and ultra-rapid delayed rectifier K+ current (IKur) in isolated human atrial myocytes, and cloned hERG channel current (IhERG) and recombinant human cardiac KCNQ1/KCNE1 channel current (IKs) expressed in HEK 293 cells. It was found that CLT inhibited Ito1 with an IC50 of 29.5 microM, accelerated Ito1 inactivation, and decreased recovery of Ito1 from inactivation. In addition, CLT inhibited human atrial I(Kur) in a concentration-dependent manner (IC50 = 7.6 microM). CLT substantially suppressed IhERG (IC50 = 3.6 microM), and negatively shifted the activation conductance of IhERG. Moreover, CLT inhibited IKs (IC50 = 15.1 microM), and positively shifted the activation conductance of the current. These results indicate that the antifungal antibiotic CLT substantially inhibits human cardiac repolarization K+ currents including Ito1, IKur, IhERG, and IKs. However, caution is recommended when correlating the observed in vitro effects on cardiac ion currents to the clinical relevance.

Adult↗