Adverse Cardiovascular Effects of COVID-19 Vaccination: A Systematic Review.

Several vaccines against coronavirus disease 2019 (COVID-19)-caused by the novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-have been developed since the COVID-19 pandemic began. Of these, 7 have been approved in the World Health Organization's Emergency Use Listing. However, these vaccines have been reported to have rare or serious adverse cardiovascular effects. This review presents updated information on the adverse cardiovascular effects of the approved COVID-19 vaccines-including inactivated vaccines, protein subunit vaccines, virus-like particles, nucleic acid vaccines, and viral vector vaccines-and the underlying mechanisms.

Ventricular response as a predictor of the termination of sustained paroxysmal atrial fibrillation.

BACKGROUND: Atrial fibrillation (AF) is the most common sustained atrial arrhythmia. Accurate detection of the timing and possibility of AF termination is vital for optimizing rhythm and rate control strategies. The present study evaluated whether the ventricular response (VR) in AF offers a distinctive electrocardiographic indicator for predicting AF termination. METHODS: Patients experiencing sustained paroxysmal AF for more than 3 h were observed using 24-h ambulatory Holter monitoring. VR within 5 min before AF termination (VR 0-5 min, BAFT) was compared with VR observed during the 60th to 65th min (VR 60-65 min, BAFT) and the 120th to 125th min (VR 120-125 min, BAFT) before AF termination. Maximum and minimum VRs were calculated on the basis of the average of the highest and lowest VRs across 10 consecutive heartbeats. RESULTS: Data from 37 episodes of paroxysmal AF revealed that the minimum VR0-5 min, BAFT (64 ± 20 bpm) was significantly faster than both the minimum VR120-125 min, BAFT (56 ± 15 bpm) and the minimum VR60-65 min, BAFT (57 ± 16 bpm, p < .05). Similarly, the maximum VR0-5 min, BAFT (158 ± 49 bpm) was significantly faster than the maximum VR120-125 min, BAFT (148 ± 45 bpm, p < .05). In the daytime, the minimum VR0-5 min, BAFT (66 ± 20 bpm) was significantly faster than both the minimum VR60-65 min, BAFT (58 ± 17 bpm) and minimum VR120-125 min, BAFT (57 ± 15 bpm, p < .05). However, the mean and maximum VR0-5 min, BAFT in the daytime were similar to the mean and maximum VR120-125 min in the daytime, respectively. At night, the minimum, mean, and maximum VR0-5 min, BAFT were similar to the minimum, mean, and maximum VR120-125 min, respectively. CONCLUSIONS: Elevated VR rates during AF episodes may be predictors for the termination of AF, especially during the daytime and in patients with nondilated left atria. These findings may guide the development of clinical approaches to rhythm control in AF.

Correlation between short- and mid-term hemoglobin A1c and glycemic control determined by continuous glucose monitoring.

BACKGROUND: Glucose monitoring is vital for glycemic control in patients with diabetes mellitus (DM). Continuous glucose monitoring (CGM) measures whole-day glucose levels. Hemoglobin A1c (HbA1c) is a vital outcome predictor in patients with DM. METHODS: This study investigated the relationship between HbA1c and CGM, which remained unclear hitherto. Data of patients with DM (n = 91) who received CGM and HbA1c testing (1-3 months before and after CGM) were retrospectively analyzed. Diurnal and nocturnal glucose, highest CGM data (10%, 25%, and 50%), mean amplitude of glycemic excursions (MAGE), percent coefficient of variation (%CV), and continuous overlapping net glycemic action were compared with HbA1c values before and after CGM. RESULTS: The CGM results were significantly correlated with HbA1c values measured 1 (r = 0.69) and 2 (r = 0.39) months after CGM and 1 month (r = 0.35) before CGM. However, glucose levels recorded in CGM did not correlate with the HbA1c values 3 months after and 2-3 months before CGM. MAGE and %CV were strongly correlated with HbA1c values 1 and 2 months after CGM, respectively. Diurnal blood glucose levels were significantly correlated with HbA1c values 1-2 months before and 1 month after CGM. The nocturnal blood glucose levels were significantly correlated with HbA1c values 1-3 months before and 1-2 months after CGM. CONCLUSIONS: CGM can predict HbA1c values within 1 month after CGM in patients with DM.

Effects of phosphodiesterase-1 inhibitor on pulmonary vein electrophysiology and arrhythmogenesis.

INTRODUCTION: Phosphodiesterase (PDE) isoform inhibitors have mechanical and electrical effects on the heart. Inhibition of PDE-1 enzymes is a novel strategy for treating heart failure. However, the electrophysiological effects of PDE-1 inhibition on the heart remain unclear. This study explored the effects of PDE-1 inhibition using ITI-214 on electrical activity in the pulmonary vein (PV), the most common trigger of atrial fibrillation, and investigated the underlying ionic mechanisms. METHODS: Conventional microelectrodes or whole-cell patch clamps were employed to study the effects of ITI-214 (0.1-10 µM) on PV electrical activity, mechanical responses and ionic currents in isolated rabbit PV tissue specimens and isolated single PV cardiomyocytes. RESULTS: ITI-214 at 1 µM and 10 µM (but not 0.1 µM) significantly reduced PV spontaneous beating rate (10 ± 2% and 10 ± 3%, respectively) and PV diastolic tension (11 ± 3% and 17 ± 3%, respectively). ITI-24 (1 µM) significantly reduced late sodium current (INa-Late ), L-type calcium current (ICa-L ) and the reverse mode of the sodium-calcium exchanger (NCX), but it did not affect peak sodium currents. CONCLUSIONS: ITI-214 reduces PV spontaneous activity and PV diastolic tension by reducing INa-Late , ICa-L and NCX current. Considering its therapeutic potential in heart failure, targeting PDE-1 inhibition may provide a novel strategy for managing atrial arrhythmogenesis.

Circulating level of microRNA-142-5p is a potential biomarker for predicting in-stent restenosis: a case-control study.

BACKGROUND: Patients who receive percutaneous coronary intervention (PCI) have different chances of developing in-stent restenosis (ISR). To date, no predictable biomarker can be applied in the clinic. MicroRNAs (miRNAs or miRs) play critical roles in transcription regulation, and their circulating levels were reported to have potential as clinical biomarkers. METHODS: In total, 93 coronary stent-implanted patients without pregnancy, liver or renal dysfunction, malignancy, hemophilia, or autoimmune diseases were recruited in this clinical study. All recruited participants were divided into an ISR group (n = 45) and a non-ISR group (n = 48) based on their restenotic status as confirmed by cardiologists at the first follow-up visit (6 months after surgery). Blood samples of all participants were harvested to measure circulating levels of miRNA candidates (miR-132, miR-142-5p, miR-15b, miR-24-2, and miR-424) to evaluate whether these circulating miRNAs can be applied as predictive biomarkers of ISR. RESULTS: Our data indicated that circulating levels of miR-142-5p were significantly higher in the ISR population, and results from the receiver operating characteristic (ROC) curve analysis also demonstrated superior discriminatory ability of miR-142-5p in predicting patients' restenotic status. In addition, circulating levels of miR-15b, miR-24-2, and miR-424 had differential expressions in participants with diabetes, hyperlipidemia, and hypertension, respectively. CONCLUSIONS: The current study revealed that the circulating level of miR-142-5p has potential application as a clinical biomarker for predicting the development of ISR in stent-implanted patients.

The AMP-activated protein kinase modulates hypothermia-induced J wave.

BACKGROUND: The mechanism underlying the occurrence of the J wave in low temperature remains unclear. However, low temperature is associated with metabolic disorder and 5' AMP-activated protein kinase (AMPK), which modulates ionic currents and cardiac metabolism. This study investigated whether AMPK regulation can modulate the occurrence of the J wave at low temperature. METHODS: Unipolar and bipolar leads were used to record monophasic action potential (the endocardium and epicardium) and pseudo-electrocardiograms (inferior leads) to study the cardiac electrical activity. Measurements were taken in isolated Langendorff rabbit hearts at both 30℃ and 37℃ before and after administration of 4-aminopyridine (an ultrarapid delayed rectifier potassium current inhibitor, IKur , 50 µmol L-1 ), PF06409577 (an AMPK activator, 1 µmol L-1 ), compound C (an AMPK inhibitor, 10 µmol L-1 ) and glibenclamide (an ATP-sensitive inward rectifier potassium channel inhibitor, IKATP , 20 µmol L-1 ). RESULTS: The amplitude of the J wave (2.46 ± 0.34 mV vs. 1.11 ± 0.23 mV, P < .01) at 30℃ (n = 15) was larger than that at 37℃ (n = 15). PF06409577 (1 µmol L-1 ) increased the J waves at both 30℃ and 37℃. In contrast, compound C (10 µmol L-1 ) reduced J wave at both 37℃ and 30℃. Low-temperature-induced J waves were individually suppressed by 4-AP (50 µmol L-1 ) and glibenclamide (20 µmol L-1 ). CONCLUSIONS: AMPK inhibition reduces low-temperature-induced J waves and possible ventricular arrhythmogenesis by modulating IKATP and IKur channels.

Various subtypes of phosphodiesterase inhibitors differentially regulate pulmonary vein and sinoatrial node electrical activities.

Phosphodiesterase (PDE)3-5 are expressed in cardiac tissue and play critical roles in the pathogenesis of heart failure and atrial fibrillation. PDE inhibitors are widely used in the clinic, but their effects on the electrical activity of the heart are not well understood. The aim of the present study was to examine the effects of various PDE inhibitors on spontaneous cardiac activity and compare those effects between sinoatrial nodes (SANs) and pulmonary veins (PVs). Conventional microelectrodes were used to record action potentials in isolated rabbit SAN and PV tissue preparations, before and after administration of different concentrations (0.1, 1 and 10 µM) of milrinone (PDE3 inhibitor), rolipram (PDE4 inhibitor) and sildenafil (PDE5 inhibitor), with or without the application of isoproterenol (cAMP and PKA activator), KT5823 (PKG inhibitor) or H89 (PKA inhibitor). Milrinone (1 and 10 µM) increased the spontaneous activity in PVs by 10.6±4.9 and 16.7±5.3% and in SANs by 9.3±4.3 and 20.7±4.6%, respectively. In addition, milrinone (1 and 10 µM) induced the occurrence of triggered activity (0/8 vs. 5/8; P<0.005) in PVs. Rolipram increased PV spontaneous activity by 7.5±1.3-9.5±4.0%, although this was not significant, and did not alter SAN spontaneous activity. Sildenafil reduced spontaneous activity in PVs to a greater extent than that seen in SANs. Both KT5823 and H89 suppressed milrinone-increased PV spontaneous activity. In the presence of isoproterenol, milrinone did not alter isoproterenol-induced PV arrhythmogenesis, suggesting that the effects of PDE3 are mediated by the protein kinase G and protein kinase A signaling pathways. In conclusion, inhibitors of different PDE subtypes exert diverse electrophysiological effects on PV and SAN activities.

Arginine vasopressin modulates electrical activity and calcium homeostasis in pulmonary vein cardiomyocytes.

BACKGROUND: Atrial fibrillation (AF) frequently coexists with congestive heart failure (HF) and arginine vasopressin (AVP) V1 receptor antagonists are used to treat hyponatremia in HF. However, the role of AVP in HF-induced AF still remains unclear. Pulmonary veins (PVs) are central in the genesis of AF. The purpose of this study was to determine if AVP is directly involved in the regulation of PV electrophysiological properties and calcium (Ca2+) homeostasis as well as the identification of the underlying mechanisms. METHODS: Patch clamp, confocal microscopy with Fluo-3 fluorescence, and Western blot analyses were used to evaluate the electrophysiological characteristics, Ca2+ homeostasis, and Ca2+ regulatory proteins in isolated rabbit single PV cardiomyocytes incubated with and without AVP (1 µM), OPC 21268 (0.1 µM, AVP V1 antagonist), or OPC 41061 (10 nM, AVP V2 antagonist) for 4-6 h. RESULTS: AVP (0.1 and 1 µM)-treated PV cardiomyocytes had a faster beating rate (108 to 152%) than the control cells. AVP (1 µM) treated PV cardiomyocytes had higher late sodium (Na+) and Na+/Ca2+ exchanger (NCX) currents than control PV cardiomyocytes. AVP (1 µM) treated PV cardiomyocytes had smaller Ca2+i transients, and sarcoplasmic reticulum (SR) Ca2+ content as well as higher Ca2+ leak. However, combined AVP (1 µM) and OPC 21268 (0.1 µM) treated PV cardiomyocytes had a slower PV beating rate, larger Ca2+i transients and SR Ca2+ content, smaller late Na+ and NCX currents than AVP (1 µM)-treated PV cardiomyocytes. Western blot experiments showed that AVP (1 µM) treated PV cardiomyocytes had higher expression of NCX and p-CaMKII, and a higher ratio of p-CaMKII/CaMKII. CONCLUSIONS: AVP increases PV arrhythmogenesis with dysregulated Ca2+ homeostasis through vasopressin V1 signaling.

Vitamin D and bisphosphonates therapies for osteoporosis are associated with different risks of atrial fibrillation in women: A nationwide population-based analysis.

Osteoporosis and atrial fibrillation (AF) are common in post-menopausal women. Vitamin D and bisphosphonates are widely used to treat osteoporosis, and these may have different effects on the risk of AF.The goal of this study was to evaluate whether different agents for treating osteoporosis modulate the risk of AF in a population-based database.We identified 20,788 female patients suffering from osteoporosis who were or were not treated with vitamin D or bisphosphonates using the Taiwan National Health Insurance nationwide database from 2000 to 2008 and followed them up for 5 consecutive years to determine if they had a new diagnosis of AF after the diagnosis of osteoporosis.There were 14 (2.67%) new AF diagnoses in osteoporosis patients treated with bisphosphonates, one (0.28%) new AF diagnosis in patients treated with vitamin D, and 279 (1.40%) new AF diagnoses in patients who were not treated with vitamin D or bisphosphonates (neither group). Osteoporosis patients who received bisphosphonates showed a higher incidence of AF occurrence than those that were not treated with bisphosphonates (P = .015). In contrast, 1 patient who received vitamin D had a new diagnosis of AF during the study period; thus, the incidence was significantly lower than that in the patients treated with bisphosphonates (P = .007). In addition, the patients who were treated with vitamin D had a lower incidence of AF than did those who were not treated with either vitamin D or bisphosphonates (P = .074). Kaplan-Meier analysis also showed a significant difference in AF occurrence in different groups during the 5-year follow-up (P = .010).Different treatment for osteoporosis may carry diverse risks of AF occurrence. Vitamin D may have potential beneficial effects of reducing AF occurrence in osteoporosis patients.

Factors That Determine the Prothrombin Time in Patients With Atrial Fibrillation Receiving Rivaroxaban.

Rivaroxaban, a direct factor Xa inhibitor, is widely used to reduce the chance of stroke in patients with atrial fibrillation (AF). It is not clear why the prothrombin time (PT) of the international normalized ratio (INR) fails to correlate with treatment using rivaroxaban in patients with AF. In this study, patient characteristics, the rivaroxaban dosage, AF type, drug history, biochemical properties, and hematological profiles were assessed in patients treated with rivaroxaban. In 69 patients with AF receiving rivaroxaban, 27 (39.1%) patients had a normal INR (≤1.1, group 1), 27 (39.1%) patients had a slightly prolonged INR (1.1∼1.5, group 2), and 15 (21.7%) patients had a significantly prolonged INR (>1.5, group 3). Group 1 patients had a higher incidence of a stroke history than did patients in group 2 (P = .026) and group 3 (P = .032). We scored patients with a persistent AF pattern (1 point), paroxysmal AF pattern (0 point), renal function (ie, the creatinine clearance rate in mL/min/1.73 m2 of >60 as 0 points, of 30∼60 as 1 point, and of <30 as 2 points), and no history of stroke (1 point), and we found that group 3 had a higher score than groups 2 or 1 (2.9 ± 0.8, 2.4 ± 0.7, and 2 ± 0.7, respectively; P < .05). There were similar incidences of bleeding, stroke, and unexpected hospitalizations among the 3 groups. The PT of the INR is determined by multiple variables in patients with AF receiving rivaroxaban. Rivaroxaban-treated patients with AF having different INR values may have similar clinical outcomes.

Factor Xa inhibitors differently modulate electrical activities in pulmonary veins and the sinoatrial node.

Factor Xa inhibitors reduce stroke in patients with atrial fibrillation. Pulmonary veins (PVs) and the sinoatrial node (SAN) are crucial for genesis of atrial fibrillation. However, the electrophysiological effects of factor Xa inhibitors (edoxaban and rivaroxaban) on PVs and the SAN remain unclear. Conventional microelectrodes were used to record the action potential in isolated rabbit PVs and SAN preparations before and after administration of edoxaban (0.1, 0.3, and 1 µM) or rivaroxaban (0.01, 0.03, 0.1, and 0.3 µM). A whole-cell patch-clamp was used to record the late sodium current (INa-late) in isolated single rabbit PV cardiomyocytes. Edoxaban significantly reduced PV spontaneous beating rates at 0.3 and 1 µM (N = 6 rabbits, P < 0.05), and reduced SAN beating rates at 1 µM (N = 6, P < 0.05). Similarly, rivaroxaban reduced PV spontaneous beating rates at 0.1 and 0.3 µM (N = 7, P < 0.05), and reduced SAN beating rates at 0.3 µM (N = 6, P < 0.05). However, neither edoxaban (1 µM) nor rivaroxaban (0.3 µM) reduced PV spontaneous beating rates in the presence of 1 µM BMS200261 (an inhibitor of protease-activated receptors type 1, PAR1 inhibitor) or 10 µM ranolazine (an inhibitor of late sodium current, INa-late inhibitor). Edoxaban (0.3 and 1 µM) and rivaroxaban (0.1 and 0.3 µM) respectively decreased the INa-late by 47%, 47%, 36%, and 49% (n = 9 PV cardiomyocytes from 5 rabbits, P < 0.05). In conclusion, Factor Xa inhibitors reduce PV spontaneous activities and may modulate occurrence of atrial fibrillation by inhibiting PAR1 and reducing the INa-late in PVs.

Levosimendan differentially modulates electrophysiological activities of sinoatrial nodes, pulmonary veins, and the left and right atria.

INTRODUCTION: Calcium overload increases the risk of atrial fibrillation (AF). Levosimendan, a calcium sensitizer, increases myofilament contractility. Clinical reports suggested that levosimendan might increase AF occurrence, but the electrophysiological effects of levosimendan on AF substrates and triggers (pulmonary veins, PVs) are not clear. METHODS AND RESULTS: Conventional microelectrodes were used to record action potentials (APs) in isolated rabbit PVs, sinoatrial nodes (SANs), the left atrium (LA), and right atrium (RA) before and after application of different concentrations of levosimendan with or without milrinone (a phosphodiesterase [PDE] III inhibitor), and glibenclamide (an ATP-sensitive potassium channel [KATP ] inhibitor). Levosimendan (0.03, 0.1, 0.3, and 1 µM) significantly increased spontaneous rates from 2.1 ± 0.2 to 2.5 ± 0.2, 2.5 ± 0.2, 2.5 ± 0.1, and 2.7 ± 0.2 Hz, respectively, in PVs (n = 10), but had no effects on denudated PVs (n = 9). Additionally, levosimendan significantly induced burst firing and/or triggered beats in intact PVs, but not in denudated PVs. In contrast, levosimendan at 0.3 and 1 µM increased the SAN spontaneous rate. In the presence of milrinone (10 µM), levosimendan (1 µM) did not increase the PV spontaneous activity. Moreover, glibenclamide (100 µM) prevented acceleration of the levosimendan-induced SAN and PV rates. In the LA, levosimendan at 0.3 and 1 µM shortened the AP duration, and increased contractility at 0.03, 0.1, 0.3, and 1 µM. In contrast, levosimendan did not change the RA contractility, and shortened the AP duration only at 1 µM. CONCLUSIONS: Levosimendan increased PV arrhythmogenesis through activating endothelial PDE III and the KATP , and modulating PV tension.

Modulation of Autonomic Nervous Activity in the Termination of Paroxysmal Atrial Fibrillation.

BACKGROUND: Autonomic nervous activity plays a critical role in the genesis of paroxysmal atrial fibrillation (AF, PAF). However, the role of autonomic nervous activity on AF termination has not been elucidated. Heart rate variability (HRV) is widely used to evaluate autonomic nervous activity in humans. The purpose of this study was to assess whether autonomic nervous activity assessed by HRV contributes to AF termination. METHODS: Electrocardiograms (ECGs) and HRV were studied in patients with termination of sustained (>30 s) PAF by 24-hour ambulatory Holter monitoring. The 20-minute interval after termination of AF was divided into four segments of 5 minutes each, and a frequency analysis was applied to each 5-minute segment. RESULTS: In 52 AF episodes, the ultra-low-frequency power, very-low-frequency power, low-frequency power (LF), high-frequency power (HF), and total power significantly decreased with time after episodes of AF termination. The LF/HF (L/H) ratio, normalized LF (LFnu), and normalized HF (HFnu) significantly changed after AF termination. Eighteen (35%) episodes had decreased LFnu and increased HFnu (sympathetic withdrawal and vagal activation), which had slower average AF ventricular responses (92 ± 16 beats/min vs 105 ± 24 beats/min, P < 0.05) than the AF termination episodes (n = 34, 65%) with increased LFnu and decreased HFnu (sympathetic activation and vagal withdrawal). Moreover, older patients (aged >65 years) had a higher incidence (n = 27, 75%) of AF termination with increased LFnu and decreased HFnu than did younger patients (aged ≤65 years, n = 7, 44%, P < 0.05). CONCLUSION: Autonomic changes critically regulate termination of PAF, which is modulated by aging.

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. METHODS AND RESULTS: 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).

Cloud-based BP system integrated with CPOE improves self-management of the hypertensive patients: A randomized controlled trial.

BACKGROUND: Less than 50% of patients with hypertensive disease manage to maintain their blood pressure (BP) within normal levels. OBJECTIVE: The aim of this study is to evaluate whether cloud BP system integrated with computerized physician order entry (CPOE) can improve BP management as compared with traditional care. METHODS: A randomized controlled trial done on a random sample of 382 adults recruited from 786 patients who had been diagnosed with hypertension and receiving treatment for hypertension in two district hospitals in the north of Taiwan. Physicians had access to cloud BP data from CPOE. Neither patients nor physicians were blinded to group assignment. The study was conducted over a period of seven months. RESULTS: At baseline, the enrollees were 50% male with a mean (SD) age of 58.18 (10.83) years. The mean sitting BP of both arms was no different. The proportion of patients with BP control at two, four and six months was significantly greater in the intervention group than in the control group. The average capture rates of blood pressure in the intervention group were also significantly higher than the control group in all three check-points. CONCLUSIONS: Cloud-based BP system integrated with CPOE at the point of care achieved better BP control compared to traditional care. This system does not require any technical skills and is therefore suitable for every age group. The praise and assurance to the patients from the physicians after reviewing the Cloud BP records positively reinforced both BP measuring and medication adherence behaviors.

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, ß 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.