Vascular endothelial growth factor modulates pulmonary vein arrhythmogenesis via vascular endothelial growth factor receptor 1/NOS pathway.

Atrial fibrillation (AF) is a common form of arrhythmia with serious public health impacts, but its underlying mechanisms are not yet fully understood. Vascular endothelial growth factor (VEGF) is highly expressed in the atrium of patients with AF, but whether VEGF affects AF pathogenesis remains unclear. Pulmonary veins (PVs) are important sources for the genesis of atrial tachycardia or AF. Therefore, this study assessed the effects of VEGF on PV electrophysiological properties and evaluated its underlying mechanisms. Conventional microelectrodes and whole-cell patch clamps were performed using isolated rabbit PV preparations or single isolated PV cardiomyocytes before and after VEGF or VEGF receptor (VEGFR), Akt, NOS inhibitor administration. We found that VEGF (0.1, 1, and 10 ng/mL) reduced the PV beating rate in a dose-dependent manner. Furthermore, VEGF (10 ng/mL) reduced late diastolic depolarization and diastolic tension. Isoproterenol increased PV beating and burst firing, which was attenuated by VEGF (1 ng/mL). In the presence of VEGFR-1 inhibition (ZM306416 at 10 µM) and L-NAME (100 µM), VEGF (1 ng/mL) did not alter PV spontaneous activity. In isolated PV cardiomyocytes, VEGF (1 ng/mL) decreased L-type calcium, sodium/calcium exchanger, and late sodium currents. In conclusion, we found that VEGF reduces PV arrhythmogenesis by modulating sodium/calcium homeostasis through VEGFR-1/NOS signaling pathway.

Trastuzumab increases pulmonary vein arrhythmogenesis through modulating pulmonary vein electrical and conduction properties via phosphatidylinositol 3-kinase signaling.

OBJECTIVES: Drug-induced atrial fibrillation (AF) is considered an adverse effect of chemotherapeutic drugs. AF is a crucial risk factor for stroke, heart failure, myocardial infarction, and mortality. Pulmonary veins (PVs) are considered triggers inducing AF, and the sinoatrial node (SAN) may modulate PV activity and participate in AF genesis. AF was associated with early discontinuation of trastuzumab in patients with breast cancer. However, whether trastuzumab directly modulates the electrophysiological characteristics of PV and SAN remains unclear. MATERIALS AND METHODS: ECG and conventional microelectrode system were used to record rabbit heart rhythm in vivo and electrical activities in vitro from isolated SAN, PV, and SAN-PV preparations. RESULTS: Trastuzumab reduced the beating rate in isolated PV and SAN preparations at 1, 10, and 30 µM (particularly in isolated SAN preparations) and induced burst firings in isolated PV preparations at 10 µΜ. In addition, trastuzumab (10 µM) induced SAN-PV conduction block and burst firings, which were blocked by wortmannin (a PI3K inhibitor, 100 nM). Similarly, ECG recordings showed that acute intravenous administration of trastuzumab (10 mg/kg) reduced rabbit heart rates. CONCLUSION: Trastuzumab increased PV arrhythmogenesis through interfering with PI3K signaling, which may contribute to the genesis of AF.

Epigallocatechin-3-gallate modulates arrhythmogenic activity and calcium homeostasis of left atrium.

BACKGROUND: Atrial fibrillation (AF) is the commonest sustained arrhythmia, and increases the risk of stroke, heart failure, and mortality. Calcium (Ca2+) overload and oxidative stress are thought to participate in the pathogenesis of AF. Epigallocatechin-3-gallate (EGCG) has an antioxidative effect and been shown to be beneficial in promoting cardiovascular health. However, it is not clear if EGCG directly modulates the electrophysiological characteristics and Ca2+ homeostasis of the left atrium (LA). METHODS AND RESULTS: Conventional microelectrodes, whole-cell patch-clamp, and Fluo-3 fluorometric ratio technique were performed using the isolated rabbit LA preparations or isolated single LA cardiomyocytes before and after EGCG treatment. EGCG (0.01, 0.1, 1, and 10µM) which concentration-dependently decreased the APD20 by 13±8%, 25±5%, 31±6%, and 37±5%, APD50 by 9±8%, 22±6%, 32±7%, and 40±4%, and APD90 by 2±12%, 9±8%, 24±10%, and 34±5% in LA preparations. EGCG (0.1µM) decreased the late sodium (Na+) current, L-type Ca2+ current, nickel-sensitive Na+-Ca2+ exchanger current, and transient outward current, but did not change the Na+ current and ultra-rapid delayed rectifier potassium current in LA cardiomyocytes. EGCG decreased intracellular Ca2+ transient and sarcoplasmic reticulum Ca2+ content in LA cardiomyocytes. Furthermore, EGCG decreased isoproterenol (ISO, 1µM)-induced burst firing. KT5823 (1µM) or KN93 (1µM) decreased the incidences of ISO-induced LA burst firing, which became lower with EGCG treatment. H89 (10µM) and KN92 (1µM) did not suppress the incidence of ISO-induced LA burst firing. However, EGCG decreased the incidences of ISO-induced LA burst firing in the presence of H89 or KN92. CONCLUSION: EGCG directly regulates LA electrophysiological characteristics and Ca2+ homeostasis, and suppresses ISO-induced atrial arrhythmogenesis through inhibiting Ca2+/calmodulin or cGMP-dependent protein kinases.

Effects of Acetaminophen on Left Atrial Contractility.

BACKGROUND: It has been observed that acetaminophen shows cardioprotective efficacy in mammals. In this study, we investigated the electromechanical effects of acetaminophen on the left atrium (LA). METHODS: Conventional microelectrodes were used to record the action potentials (AP) in rabbit LA preparations. The action potential duration (APD) at repolarization levels of 90%, 50% and 20% of the AP amplitude (APD90, APD50, and APD20, respectively), resting membrane potential, and contractile force were measured during 2 Hz electrical stimulation before and after sequential acetaminophen administration to the LA. RESULTS: Acetaminophen (0.1, 0.3, 1, and 3 mM) reduced APD20 from 9.4 ± 1.2 to 8.0 ± 1.1 (p < 0.05), 7.1 ± 0.8 (p < 0.05), 7.8 ± 1.1, and 6.8 ± 1.2 ms (p < 0.05), respectively, and APD50 from 20.2 ± 1.9 to 17.4 ± 2.0, 15.6 ± 1.8 (p < 0.05), 15.8 ± 2.2 (p < 0.05), and 14.1 ± 2.4 ms (p < 0.05), respectively, in a concentration-dependent manner. APD90 was reduced from 72.0 ± 3.6 to 64.7 ± 4.2, 61.9 ± 4.3, 60.5 ± 3.7, and 53.4 ± 4.4 ms (p < 0.05), respectively. Acetaminophen increased LA contractility from 45 ± 9 to 52 ± 10 (p < 0.05), 55 ± 9 (p < 0.01), 58 ± 9 (p < 0.01), and 60 ± 9 mg (p < 0.01), respectively, in a concentration-dependent manner. In the presence of the NOS inhibitor L-NAME or PKG-I inhibitor DT-2, additional acetaminophen treatment did not significantly increase LA contractility. CONCLUSIONS: Acetaminophen modulated the electromechanical characteristics of LA by inhibiting the NOS and PKG I pathway, and then contributed to the positive inotropic effect.

Case report: hexachloroethane smoke inhalation: a rare cause of severe hepatic injuries.

CONTEXT: We report on two patients, a 23-year-old man and a 24-year-old man, who had chemical pneumonitis and respiratory distress after inhaling hexachloroethane/zinc oxide (HC/ZnO) smoke during military training. CASE PRESENTATION: The patients had been healthy previously and denied any history of alcohol or drug abuse. Hematologic tests revealed leukocytosis with neutrophils predominant. The respiratory conditions of both patients improved after steroid therapy and oxygen support, but deterioration of liver function was found. The laboratory results showed that alanine aminotransferase (ALT) and gamma-glutamyl transpeptidase levels were elevated about 1.5-fold the normal limits and that aspartate aminotransferase (AST) levels were marginally elevated. The elevation of liver aminotransferase started from day 1 and day 2 and peaked from day 18 to day 22. ALT/AST levels then returned to normal in 6 weeks. Common viral hepatitis was ruled out after serologic tests. Abdominal sonography and physical examination failed to show any specific findings. DISCUSSION: The hepatotoxic effect was attributed to inhalation of high-concentration HC/ZnO smoke in an enclosed area, where several hepatotoxicants, including ZnCl2, HC, and chlorinated vapors, could have been generated and mixed in the smoke. RELEVANCE TO CLINICAL PRACTICE: These case reports elaborate the hepatic effects that may occur in addition to pulmonary effects of HC/ZnO smoke.