Jen Hung Huang

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.

Apamin modulates electrophysiological characteristics of the pulmonary vein and the Sinoatrial Node

Small‐conductance calcium‐activated potassium (SK) channels play an important role in atrial electrophysiology. Blocking SK channels prolongs action potential (AP) duration and attenuate electrical remodelling. The effects of SK blocking on the pulmonary vein (PV) and the sinoatrial node (SAN) remain unclear.

Rivaroxaban modulates electrical and mechanical characteristics of left atrium

BackgroundRivaroxaban reduces stroke in patients with atrial fibrillation (AF). Left atrium (LA) plays a critical role in the pathophysiology of AF. However, the electromechanical effects of rivaroxaban on LA are not clear.ResultsConventional microelectrodes and a whole-cell patch-clamp were used to record the action potentials (APs) and ionic currents in rabbit LA preparations and isolated single LA cardiomyocytes before and after the administration of rivaroxaban. Rivaroxaban (10, 30, 100, and 300 nM) concentration-dependently reduced LA (n = 7) AP durations at 90% repolarization (APD90) from 76 ± 2 to 79 ± 3, 67 ± 4 (P < 0.05, vs. control), 59 ± 5, (P < 0.01, vs. control), and 56 ± 4 ms (P < 0.005, vs. control), respectively. Rivaroxaban (10, 30, 100, and 300 nM) concentration-dependently increased the LA (n = 7) diastolic tension by 351 ± 69 (P < 0.05, vs. control), 563 ± 136 (P < 0.05, vs. control), 582 ± 119 (P < 0.05, vs. control), and 603 ± 108 mg (P < 0.005, vs. control), respectively, but did not change LA contractility. In the presence of L-NAME (100 μM) and indomethacin (10 μM), additional rivaroxaban (300 nM) treatment did not significantly further increase the LA (n = 7) diastolic tension, but shortened the APD90 from 73 ± 2 to 60 ± 6 ms (P < 0.05, vs. control). Rivaroxaban (100 nM) increased the L-type calcium current and ultra-rapid delayed rectifier potassium current, but did not change the transient outward potassium current in isolated LA cardiomyocytes.ConclusionsRivaroxaban modulates LA electrical and mechanical characteristics with direct ionic current effects.

Gender differences and the trend in the acute myocardial infarction: a 10-year nationwide population-based analysis.

It is not clear whether gender is associated with different hospitalization cost and lengths for acute myocardial infarction (AMI). We identified patients hospitalized for primary diagnosis of AMI with (STEMI) or without (NSTEMI) ST elevation from 1999 to 2008 through a national database containing 1,000,000 subjects. As compared to that in 1999~2000, total (0.35‰  versus 0.06‰, P < 0.001) and male (0.59‰  versus 0.07‰, P < 0.001) STEMI hospitalization percentages were decreased in 2007~2008, but female STEMI hospitalization percentages were not different from 1999 to 2008. However, NSTEMI hospitalization percentages were similar over the 10-year period. The hospitalization age for AMI, STEMI, and NSTEMI was increased over the 10-year period by 14, 9, and 7 years in male, and by 18, 18, and 21 years in female. The female and male hospitalization cost and lengths were similar in the period. As compared to nonmedical center, the hospitalization cost for STEMI in medical center was higher in male patients, but not in female patients, and the hospitalization cost for NSTEMI was higher in both male and female gender. We found significant differences between male and female, medical center and non-medical center, or STEMI and NSTEMI on medical care over the 10-year period.

Extremely high coronary artery calcium score is associated with a high cancer incidence

Calcium score, obtained by computed tomographic coronary angiography, can estimate the severity of coronary atherosclerosis [1–3]. Although the severity of atherosclerosis may not be directly related to the stenosis of coronary arteries [4], calcium score had been proved to improve the classification of coronary heart disease (CHD) risks [5–8]. CHD risks can be evaluated by classifying the calcium score to 0, 1–10, 11–100, 101–400, and larger than 400 [9,10]. However, calcium score can be much larger than 400, and has been reported to be more than 5000 [11]. The patient characteristics with extreme high calcium score are not clear. Older age, white race, male gender, diabetes, lipid profile and smoking may produce high calcium score [11–13]. However, it is not clear whether the above mentioned factors also cause extreme high calcium score. It is either unclear if there is any other factor contributing to the extreme high calcium score. From 1st Jan, 2006 to 31th Dec, 2008, 1453 patients in a medical center received cardiac computed tomography to obtain calcium score for evaluation of coronary artery diseases. Among them, 198 patients had calcium scoremore than 100 (from 101 to 3907).We reviewed the medical records of all patients. Only the patients (n=130) with follow-up more than one year were included in this study. Gender, age, smoking history, systolic blood pressure, height, body weight, the drug history for angiotensin-converting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARB), or lipid lowering agents, laboratory studies and history of diabetes or cancerswere obtained. Only the results checked three months before or after the coronary computed tomography were used for statistical analysis. The patients with positive malignancy were defined as pathologically provenmalignancy before or after the coronary computed angiography. We also calculated Framingham coronary heart disease risk scores. The entire study was conducted with the approval of institutional review board. Continuous variables were expressed as mean±SD. Comparisons among the differences in different calcium score groups were analyzed, using one-way ANOVA analysis with Scheffe post-hoc analysis. Categorical variables were reported as frequencies and compared using the Chi-squared analysis or the Fishers exact test. A two-tailed Pb0.05 was considered statistically significant. The Odds ratios of systolic blood pressure, uric acid, prescription rate of ACEI/ARB and cancer incidence were calculated by multivariable logistic regression. Each character was analyzed with the rest three characters controlled. The statistical analyses were performed using SPSS (version 15.0). Table 1 shows the patient characteristics among the calcium scores within 100–400, 400–1000, and N1000. There are significant differences in systolic blood pressure, Framingham risk score, uric acid, and the prescription rate of ACEI/ARB. The patients with calcium score N1000 had a higher incidence of cancer than the other two groups. The patientswith calcium scorewithin 400–1000 had a higher prescription rate of ACEI/ARB and a higher Framingham risk score. The multivariable analysis (Table 2) shows that the systolic blood pressure, uric acid, and cancer incidence are independent risk factors for the patients with calcium score N1000. The cell types and involved organs of the cancers varied, including lung squamous cell carcinoma, colon adenocarcinoma, prostate cancer, hepatocellular carcinoma, urothelial carcinoma, skin basal cell carcinoma and gastrointestinal stromal tumor. Except one patient with gastrointestinal stromal tumor, all the other patients had cancer diagnosed after the cardiac computed tomography. We compared the patients with and without cancer (Table 3) and found that patients with cancer had poorer renal function, higher serum level of uric acid, and insignificantly higher calcium scores. Moreover, the cancer patients had 50% (5/10) incidence of high calcium score N1000, which is significantly higher than the incidence 14% (17/120) of non-cancer patients (P=0.014). We found the systolic blood pressure would increase as the calcium score is getting higher. However, different from the previous studies [14–17], this study did not find a higher prevalence of dyslipidemia, diabetes, old age, male gender and smoking in the patients with higher calcium score, which may be caused by different

Glucagon-like peptide-1 regulates calcium homeostasis and electrophysiological activities of HL-1 cardiomyocytes.

Glucagon like-peptide-1 (GLP-1) is an incretin hormone with antidiabetic effects through stimulating insulin secretion, β cell neogenesis, satiety sensation, and inhibiting glucagon secretion. Administration of GLP-1 provides cardioprotective effects through attenuating cardiac inflammation and insulin resistance. GLP-1 also modulates the heart rate and systolic pressure, which suggests that GLP-1 may have cardiac electrical effects. Therefore, the purposes of this study were to evaluate whether GLP-1 has direct cardiac effects and identify the underlying mechanisms. Patch clamp, confocal microscopy with Fluo-3 fluorescence, and Western blot analyses were used to evaluate the electrophysiological characteristics, calcium homeostasis, and calcium regulatory proteins in HL-1 atrial myocytes with and without GLP-1 (1 and 10nM) incubation for 24h. GLP-1 (1 and 10nM) and control cells had similar action potential durations. However, GLP-1 at 10nM significantly increased calcium transients and sarcoplasmic reticular Ca(2+) contents. Compared to the control, GLP-1 (10nM)-treated cells significantly decreased phosphorylation of the ryanodine receptor at S2814 and total phospholamban, but there were similar protein levels of sarcoplasmic reticular Ca(2+)-ATPase and the sodium-calcium exchanger. Moreover, exendin (9-39) amide (a GLP-1 receptor antagonist, 10nM) attenuated GLP-1-mediated effects on total SR content and phosphorylated ryanodine receptor S2814. This study demonstrates GLP-1 may regulate HL-1 cell arrhythmogenesis through modulating calcium handling proteins.

Amyloid peptide regulates calcium homoeostasis and arrhythmogenesis in pulmonary vein cardiomyocytes

Eur J Clin Invest 2012; 42 (6): 589–598

Distinctive electrophysiological characteristics of right ventricular out-flow tract cardiomyocytes

Ventricular arrhythmias commonly originate from the right ventricular out‐flow tract (RVOT). However, the electrophysiological characteristics and Ca2+ homoeostasis of RVOT cardiomyocytes remain unclear. Whole‐cell patch clamp and indo‐1 fluorometric ratio techniques were used to investigate action potentials, Ca2+ homoeostasis and ionic currents in isolated cardiomyocytes from the rabbit RVOT and right ventricular apex (RVA). Conventional microelectrodes were used to record the electrical activity before and after (KN‐93, a Ca2+/calmodulin‐dependent kinase II inhibitor, or ranolazine, a late sodium current inhibitor) treatment in RVOT and RVA tissue preparations under electrical pacing and ouabain (Na+/K+ ATPase inhibitor) administration. In contrast to RVA cardiomyocytes, RVOT cardiomyocytes were characterized by longer action potential duration measured at 90% and 50% repolarization, larger Ca2+ transients, higher Ca2+ stores, higher late Na+ and transient outward K+ currents, but smaller delayed rectifier K+, L‐type Ca2+ currents and Na+‐Ca2+ exchanger currents. RVOT cardiomyocytes showed significantly more pacing‐induced delayed afterdepolarizations (22% versus 0%, P < 0.05) and ouabain‐induced ventricular arrhythmias (94% versus 61%, P < 0.05) than RVA cardiomyocytes. Consistently, it took longer time (9 ± 1 versus 4 ± 1 min., P < 0.05) to eliminate ouabain‐induced ventricular arrhythmias after application of KN‐93 (but not ranolazine) in the RVOT in comparison with the RVA. These results indicate that RVOT cardiomyocytes have distinct electrophysiological characteristics with longer AP duration and greater Ca2+ content, which could contribute to the high RVOT arrhythmogenic activity.

Gender differences in trend of hospital management for atrial fibrillation: A nationwide population-based analysis

nationwide population-based analysis Jen-Hung Huang , Hung-Yu Yang , Chien-Yeh Hsu , Yung-Kuo Lin , Shih-Ann Chen , Yi-Jen Chen a,c,⁎ a Division of Cardiovascular Medicine, Wan Fang Hospital, Taipei Medical University, Taiwan b Graduate Institute of Biomedical Informatics, Taipei Medical University, Taiwan c Graduate Institute of Clinical Medicine, Taipei Medical University, Taiwan d Division of Cardiology and Cardiovascular Research Center, Taipei Veterans General Hospital, Taipei, Taiwan

Pericardial fat is associated with the risk of ventricular arrhythmia in asian patients

BACKGROUND Pericardial fat is correlated with the occurrence of atrial fibrillation or coronary atherosclerosis. However, the role of pericardial fat in ventricular arrhythmia remains unclear. METHODSANDRESULTS Patients who had undergone dual-source computed tomography and 24-h Holter ECG were retrospectively enrolled. Quantification of the volume of pericardial fat surrounding the ventricles was analyzed using threshold attenuation of dual-source CT. The volume of pericardial fat was significantly different among those without ventricular premature beats (VPBs) in 24 h (n=28), those with occasional VPBs (n=54) and those with frequent VPBs (n=34) (12.5±6.1 cm(3)vs. 14±8.9 cm(3)vs. 29.9±17.3 cm(3), P<0.001). In addition, the number of VPBs strongly correlated with the volume of total pericardial fat (R=0.501, P<0.001), right ventricular (RV) pericardial fat (R=0.539, P<0.001), and left ventricular pericardial fat (R=0.376, P<0.001). Multivariate logistic regression analysis showed that quartiles of RV localized pericardial fat significantly increased the risk of frequent VPBs (OR=3.2, P=0.047). Moreover, the number of VPBs in 24 h was significantly different among the patients with a fat volume within the 25th percentile, 25-75th percentile and 75th percentile. CONCLUSIONS Pericardial fat (especially RV pericardial fat) was associated with the frequency of VPBs, which suggests the arrhythmogenic potential of ventricular pericardial fat. (Circ J 2016; 80: 1726-1733).