Shenfu Administration Improves Cardiac Fibrosis in Rats With Myocardial Ischemia-Reperfusion Through Adenosine A2a Receptor Activation.

OBJECTIVE: Shenfu injection (SFI) is commonly used for cardiac dysfunction in China. Adenosine receptors have been reported to exert anti-fibrosis effects. The intent of this study was to evaluate that SFI attenuates cardiac fibrosis through activating of adenosine A2a receptor (A2aR) in rats with myocardial ischemia-reperfusion (MI/R). METHODS: Sprague Dawley male rats were randomly divided into five groups, nine rats in each group. Injections in all rat groups were carried out prior to reperfusion, and in the sham and MI/R groups, only vehicle was injected. Injections in the remaining group were as follows: 5 mL/kg in the SFI group; 15 mg/kg nicorandil in the A2R agonist group; and 5 mL/kg SFI plus 5 mg/kg MSX-3 in the SFI + A2aR antagonist group. Changes in cyclic adenosine monophosphate (cAMP) and the development of myocardial infarction and cardiac fibrosis were documented among the groups. Additionally, the levels of A2aR, collagen Ⅰ, collagen Ⅲ, fibronectin, and matrix metalloproteinase-9 (MMP-9) were measured. RESULTS: Following injection with SFI or nicorandil, the cAMP concentration, infarct area, and cardiac fibrosis induced by MI/R injury were significantly decreased (p < 0.05). Additionally, the levels of collagen Ⅰ, collagen Ⅲ, fibronectin, and MMP-9 were clearly suppressed by SFI or nicorandil when compared with the MI/R group (p<0.01). However, the protective effects of SFI were counteracted by MSX-3. A negative correlation between A2aR and collagen I and collagen III was found (p = 0.00). CONCLUSION: SFI activated the A2aR to reduce myocardial fibrosis caused by MI/R injury, which provided an underlying mechanism of action of SFI.

Characterization of Preclinical Pharmacokinetic Properties and Prediction of Human PK Using a Physiologically Based Pharmacokinetic Model for a Novel Anti-Arrhythmic Agent Sulcardine Sulfate.

PURPOSE: Sulcardine sulfate (Sul) is a novel antiarrhythmic agent with promising pharmacological properties, which is currently being evaluated in several clinical trials as an oral formulation. To meet the medication needs of patients with acute conditions, the injection formulation of Sul has been developed. The objective of this study was to systemically investigate the pharmacokinetic profiles of Sul after intravenous infusion. METHODS: This research included the plasma protein binding and metabolic stability studies in vitro, plasma pharmacokinetics, biodistribution, excretion studies in animals, and the prediction of the clinical PK of Sul injection using a physiologically based pharmacokinetics (PBPK) model. RESULTS: The metabolic stability was similarly in dogs and humans but lower in rats. The plasma protein binding rates showed a concentration-dependent manner and species differences. The pharmacokinetic behavior after intravenous administration was linear in rats within the dose range of 30-90 mg/kg, but nonlinear in dogs within 30-60 mg/kg. Sul could be rapidly and widely distributed in multiple tissues after intravenous administration. About 12% of the parent compound were excreted via the urine and only a small fraction via bile and feces,and eight metabolites were found and identified in the rat excretion. The PBPK models were developed and simulated the observed PK date well in both rats and dogs. The PBPK model refined with human data predicted the PK characteristics of the first intravenous infusion of Sul in human. CONCLUSIONS: Our study systematically explored the pharmacokinetic characteristics of Sul and successfully developed the PBPK model to predict of its clinical PK.

Low-dose oral propranolol for treatment of thyrotoxic periodic paralysis with hypokalaemia in the emergency department: A case report.

WHAT IS KNOWN AND OBJECTIVE: Thyrotoxic periodic paralysis (TPP) with hypokalaemia is a rare acute phenomenon. Reports of the use of high-dose non-selective ß-blockers describe symptom resolution, but often administration does not occur promptly enough in the treatment course and patients may experience overcorrection and hyperkalaemia. CASE DESCRIPTION: A 37-year-old Hispanic male developed TPP. Patient was successfully treated with low-dose oral propranolol and potassium supplementation with no overcorrection. WHAT IS NEW AND CONCLUSION: Delay in the administration of non-selective ß-blockers may lead to overcorrection of potassium with exogenous supplementation. Low-dose propranolol administered in the Emergency Department was successful in preventing overcorrection of potassium.

Safety and Effectiveness of Rivaroxaban in Combination with Various Antiarrhythmic Drugs in Patients with Non-Permanent Atrial Fibrillation.

INTRODUCTION: Rivaroxaban reduces the risk of thromboembolism in atrial fibrillation (AF) patients, who often also receive antiarrhythmic drugs (AADs) to maintain sinus rhythm. Current guidelines contraindicate concomitant use of rivaroxaban with the popular AAD dronedarone, despite little data demonstrating interactions with AADs. This study investigates the outcomes of concomitant rivaroxaban and AAD drug use in a real-world cohort. METHODS: This retrospective study included 1777 non-permanent AF patients taking rivaroxaban for ≥ 1 month between 2011 and 2016 from a multicenter cohort in Taiwan, and compared concomitant AAD use against clinical outcome endpoints for safety, effectiveness, and major adverse cardiac events (MACE). Multivariate Cox proportional hazard analyses were used to evaluate the association between concomitant AAD use and outcomes. RESULTS: Patients were divided into rivaroxaban alone (n = 1205) and with concomitant amiodarone (n = 177), dronedarone (n = 231), or propafenone (n = 164) groups. The proportion of patients using rivaroxaban 10 mg was highest in the concomitant dronedarone group: rivaroxaban alone, 53.6%; with amiodarone, 57.6%; with dronedarone, 77.1%; and with propafenone, 46.3% (p < 0.001). The cumulative incidences of safety (p = 0.892), effectiveness (p = 0.336), and MACE (p = 0.674) were similar between the four groups; however, there were significantly fewer new systemic thromboembolisms in the dronedarone group: rivaroxaban alone, 2.5%; with amiodarone, 0.6%; with dronedarone, 0%; and with propafenone, 1.2% (p = 0.029). The all-cause death rate was also lowest in the dronedarone group: rivaroxaban alone, 9.0%; with amiodarone, 9.6%; with dronedarone, 3.0%; and with propafenone: 6.1% (p = 0.013). After covariate adjustment, there were no differences in the safety, effectiveness, and MACE endpoints between patients receiving or not receiving AADs. CONCLUSION: Concomitant use of rivaroxaban with AADs appears to be well tolerated, warranting further investigation into the apparent benefits of a reduced dose of rivaroxaban combined with dronedarone.

[Clinical pathway for electrical storm treatment in a healthcare network modeling. A proposal from ANMCO Tuscany]. / Percorso clinico-assistenziale in rete per il trattamento del paziente con "storm" aritmico. La proposta dell'ANMCO Toscana.

Electrical storm (ES) is defined as three or more episodes of sustained ventricular tachycardia (VT) or fibrillation (VF) within 24 h, or an incessant VT/VF lasting more than 12 h. It usually occurs in implantable cardioverter-defibrillator (ICD) recipients, and three or more device interventions are typically used for the diagnosis. ES incidence is particularly high in case of ICD implanted in secondary prevention (10-30%), with recurrences occurring in up to 80% of patients. A comprehensive evaluation of triggers, predictive factors of high-risk patients and an appropriate management of the acute/subacute and chronic phases are pivotal to reduce mortality and recurrences. Medical therapy with antiarrhythmic and anesthetic drugs, with appropriate device reprogramming and neuroaxial modulation if needed, are used to cool down the ES, which should ultimately be treated with ablation therapy or, less often, with an alternative treatment, such as denervation or stereotactic radiosurgery. An optimization of the clinical pathway in a network modeling is crucial to achieve the best treatment, eventually addressing patients to centers with VT ablation programs, and identifying the most challenging procedures and the most critical patients that should be treated only in high-volume tertiary centers. In this paper, we present a proposal of healthcare network modeling for ES treatment in a regional setting.

Ibutilide with magnesium for conversion of atrial fibrillation or flutter in rheumatic heart disease patients: Ibutilide with magnesium for chemical cardioversion of atrial fibrillation or flutter.

BACKGROUND: Data on adjunctive use of magnesium with ibutilide for conversion of persistent rheumatic atrial fibrillation and flutter to sinus rhythm is lacking. AIM: We aimed to study the efficacy of adjunctive supplementation of intravenous magnesium with ibutilide for conversion of persistent rheumatic atrial fibrillation and flutter to sinus rhythm and to define a definite level of serum magnesium which leads to significant increase in rates of such conversion. METHODS AND RESULTS: This was a prospective study including 33 Rheumatic heart disease patients (13 males and 20 females) with mean age of 49.27 ± 11.4 years and persistent AF or AFl. All patients received intravenous magnesium to raise serum magnesium level in range of 4 mg/dl to 4.5 mg/dl prior to administration of Ibutilide. 25 out of 33 (76%) patients converted to sinus rhythm. Upon univariate analysis, presence of background beta blocker therapy, serum potassium and magnesium at time of Ibutilide injection were found to have significant relation with conversion to sinus rhythm. Upon multivariate analysis serum magnesium level at the time of Ibutilide injection was found to have significant contribution on post injection rhythm reversal (p-value = 0.006). The level of magnesium at 3.8 mg/dl was found to have maximum sensitivity of 96% and specificity of 62.5% for conversion to sinus rhythm by ibutilide with magnesium (p-value< 0.05). CONCLUSIONS: Ibutilide is highly effective in cardioversion of persistent rheumatic atrial fibrillation/flutter patients. Raising Serum Magnesium levels above 3.8 mg/dl significantly improves efficacy of ibutilide.

Use of an antiarrhythmic drug against acute selenium toxicity.

OBJECTIVE: Selenium is an essential trace element. But, selenium may have toxic effects in high doses. There are no proven antidotes or curative treatments for acut selenium toxicity. Treatment involves stopping the exposure and providing supportive care for symptoms. Therefore, it is necessary to find more effective substances in the treatment of selenium toxicity. The aim of this study was to increase the survival rate of animals by supporting the heart with amiodarone and to determine the effect of amiodarone on the pathological, hematological and biochemical parameters in acute selenium intoxication. METHODS: 64 Wistar-Albino rats were divided into four groups. Group I was given only distilled water, Group II was given 18 mg/kg dose of amiodarone, Group III was given 18 mg/kg amiodarone and 10 mg/kg sodium selenite and Group IV was given sodium selenite 10 mg/kg (LD50 dose)orally. RESULTS: 11 of the 16 animals in Group IV died within the first 48 h of drug administration. However, no deaths were observed in the rats in Group III. No hematological changes were observed. Biochemically, CK, CK-MB and LDH levels of Group IV were higher than the other groups on both the 2nd and 10th days. In Groups II and III, this serum level decreased, and vitamin B12 levels increased. In macroscopic inspections of the organs of Groups III and IV, slight paleness was detected. Histopathologically, degenerative changes in tissue were observed, especially in Group IV. CONCLUSION: This study shows that amiodarone application has a reducing effect on selenium toxicity. This was because amiodarone protected the heart by reducing CK and CK-MB levels and increased vitamin B12 levels, which play a role in the synthesis of S-adenosyl methionine that converts selenium into a nontoxic form.

The role of atrial sensing for new-onset atrial arrhythmias diagnosis and management in single-chamber implantable cardioverter-defibrillator recipients: Results from the THINGS registry.

INTRODUCTION: Atrial tachycardia/fibrillation (AT/AF) episodes are common in implantable cardioverter-defibrillator (ICD) recipients and can be undetected by standard single-chamber devices. This study aims to explore whether a single-lead ICD with an atrial dipole (ICD DX; BIOTRONIK SE & Co, Berlin, Germany) could improve the AT/AF diagnosis and management as compared to standard ICD (ICD VR). METHODS AND RESULTS: We selected patients without AT/AF history from the THINGS registry which included consecutive patients implanted with ICD for standard indications. The ICD VR and the ICD DX groups included 236 (62.8%) and 140 (37.2%) patients, respectively, and had no significant differences in baseline characteristics. During a median follow-up of 27 months, there were 7 AT/AF diagnoses in the ICD VR and 18 in the ICD DX group. The 2-year incidence of AT/AF diagnosis was 3.6% (95% confidence interval [CI]: 1.6%-9.6%) for the ICD VR and 11.4% (95% CI: 6.8%-18.9%) for the ICD DX group (adjusted hazard ratio [HR]: 3.85 [95% CI: 1.58-9.41]; P = .003). Initiation of oral anticoagulation (OAC) due to AT/AF diagnosis was reported in 15 patients. The 2-year incidence of OAC onset was 3.6% (95% CI: 1.6%-7.8%) for the ICD VR and 6.3% (95% CI: 3.0%-12.7%) for ICD DX group (adjusted HR: 1.99 [95% CI: 0.72-5.56]; P = .184). CONCLUSION: We observed that atrial sensing capability in single-chamber ICD patients without evidence of atrial arrhythmias at implant is associated with a greater likelihood of detecting AT/AF episodes. The management of these diagnosed arrhythmias often led to clinical interventions, mainly represented by initiation of OAC therapy.

Alleviation of arrhythmia burden in children with frequent idiopathic premature ventricular contractions by omega-3-fatty acid supplementation.

BACKGROUND: Patients at our pediatric outpatient clinic were offered 24-h Holter electrocardiogram (ECG) before and after 3-month period of dietary supplementation with omega-3 fatty acids to monitor the effect on heart rate variability (HRV) and arrhythmias. METHODS: The study included 17 children (mean age: 11.6 ±â€¯4.9 years) with >1% premature ventricular contractions (PVC) at baseline. 24-h Holter ECG monitoring was performed before and after omega-3 fatty acid supplementation (mean duration: 143 days). RESULTS: Compared with 86 age-matched healthy control children, baseline HRV was significantly reduced and mean heart rate was significantly increased in children with frequent PVC. After omega-3-fatty acid supplementation, the mean heart rate decreased from 92.6 ±â€¯3.4 bpm to 83.9 ±â€¯9.9 bpm (p = 0.001), while global HRV showed a significant increase [standard deviation of all NN intervals (SDNN): 148.1 ±â€¯34.4 ms vs. 126.5 ±â€¯39.3 ms, p = 0.022)]. Enhanced vagal activity was indicated by significantly higher square root of the mean of the sum of the squares of differences between adjacent NN intervals (rMSSD) (42.3 ±â€¯12.6 vs. 33.2 ±â€¯14.8; p = 0.0003). PVC percentage significantly decreased by 45% (6.9 ±â€¯7.0% vs. 12.1 ±â€¯8.2%; p = 0.014). CONCLUSIONS: Omega-3-fatty acid supplementation caused a 45% reduction in frequent PVC in children with structurally healthy hearts. This antiarrhythmic effect was likely attributable to improved autonomic function, which is consistent with previous findings in children with obesity, attention deficit disorder, and short stature.

Effect of Lidocaine Injection of Ganglionated Plexi in a Canine Model and Patients With Persistent and Long-Standing Persistent Atrial Fibrillation.

Background This study assessed the effect of blockading neural transmission in the ganglionated plexi by injecting lidocaine into fat pads in the vagal nerve stimulation canine model and patients with persistent atrial fibrillation ( AF ). Methods and Results An efficacy test of lidocaine injection was performed in 7 canines. During vagal nerve stimulation, AF was sustained for >5 minutes. The lidocaine was injected into ganglionated plexi during sinus rhythm and reinduction of AF was attempted. Six patients with persistent AF were studied at open heart surgery. Lidocaine was injected into ganglionated plexi. Atrial electrograms were recorded from 96 epicardial electrodes covering Bachmann's bundle and atrial appendages. In the canine vagal nerve stimulation AF model, AF was not inducible in 4 of 7 after lidocaine injection. In patients with persistent AF , during baseline AF , there was a left atrium ( LA )-to-right atrium ( RA ) frequency gradient ( LA , mean cycle length [ CL ] 175±17 ms; RA , mean CL 192±17 ms; P<0.01). After lidocaine injection, AF persisted in all patients, and the LA -to- RA frequency gradient disappeared ( LA , mean CL 186±13 ms; RA , mean CL 199±23 ms; P=0.08). Comparison of mean CL s before and after lidocaine demonstrated prolongation of LA CL s ( P<0.05) with no effect on RA CL s. Conclusions In the canine vagal nerve stimulation AF model, lidocaine injection decreased inducibility of AF . In patients with persistent AF , atrial electrograms from the LA had shorter CL s than RA , indicating an LA -to- RA frequency gradient. Lidocaine injection significantly prolonged only LA CL s, explaining disappearance of the LA -to- RA frequency gradient. The mechanism of localized atrial electrogram CL prolongation in patients with persistent AF is uncertain.

Predictors of left atrial appendage stunning after electrical cardioversion in patients with atrial fibrillation.

The transient left atrial appendage (LAA) dysfunction after electrical cardioversion (CV), which is called as LAA-stunning, was found to be an important etiology of thrombus formation. The aim of the present study was to investigate the risk factors of LAA-stunning. This study included 134 patients who underwent catheter ablation for non-paroxysmal, non-valvular, and symptomatic atrial fibrillation (AF). Internal-CV was performed, and LAA emptying fraction (LAA-EF) was assessed using LAA-angiogram before and just after CV. LAA-stunning (defined as 10% reduction of LAA-EF after CV) was observed in 45/134 patients (34%). Patients in LAA-stunning group had longer duration of AF prior to CV, higher brain natriuretic peptide (BNP), higher prevalence of patients taking calcium blocker, larger left atrial (LA) diameter, elevated E wave, and larger LA volume than those in non LAA-stunning group. Multivariate analysis showed that longer duration of AF prior to CV (p = 0.015, OR 1.033 for 1 month extend, 95% CI 1.006-1.073) and elevated BNP (p = 0.038, OR 1.041 for each 10 pg/mL increase, 95% CI 1.001-1.009) were associated with LAA-stunning. In addition, all patients were divided into four groups based on the combination between duration of AF prior to CV and BNP; group 1 (low BNP/short-lasting AF), group 2 (high BNP/short-lasting AF), group 3 (low BNP/long-lasting AF), and group 4 (high BNP/long-lasting AF). The rate of LAA-stunning was the highest in the group 4 (55.6%). Elevated BNP and long duration of AF were associated with LAA stunning after electrical cardioversion.

Amiodarone and acupuncture for cardiac arrhythmia: Study protocol for a systematic review.

BACKGROUND: Amiodarone and acupuncture (AA) are commonly used to treat cardiac arrhythmia (CA). The objective of this systematic review is to assess the efficacy and safety of AA for patients with CA. METHODS: Randomized controlled trials (RCTs) of AA for CC will be searched from 9 databases including PubMed, EMBASE, Cochrane Library, Web of Science, Scopus, Chinese Biomedical Literature Database, China National Knowledge Infrastructure, VIP Information, and Wanfang Data from inception to February 1, 2019 without any limitations. Two reviewers will independently screen the relevant papers, extract data, and evaluate the risk of bias for each included study. RevMan 5.3 software will be used for meta-analysis. The primary outcome includes arrhythmic episodes (including time and frequency domain parameters). The secondary outcomes consist of health-related quality of life, oxygen saturation, and safety. RESULTS: The protocol of this proposed study will provide evidence to judge whether AA is an effective treatment for patients with CA. CONCLUSION: The findings of this proposed study will summarize the up-to-date evidence of AA for CA. PROSPERO REGISTRATION NUMBER: PROSPERO CRD42019120962.

Low-dose Magnesium Sulfate Versus High Dose in the Early Management of Rapid Atrial Fibrillation: Randomized Controlled Double-blind Study (LOMAGHI Study).

OBJECTIVES: We aim to determine the benefit of two different doses magnesium sulfate (MgSO4 ) compared to placebo in rate control of rapid atrial fibrillation (AF) managed in the emergency department (ED). METHODS: We undertook a randomized, controlled, double-blind clinical trial in three university hospital EDs between August 2009 and December 2014. Patients > 18 years with rapid AF (>120 beats/min) were enrolled and randomized to 9 g of intravenous MgSO4 (high-dose group, n = 153), 4.5 g of intravenous MgSO4 (low-dose group, n = 148), or serum saline infusion (placebo group, n = 149), given in addition to atrioventricular (AV) nodal blocking agents. The primary outcome was the reduction of baseline ventricular rate (VR) to 90 beats/min or less or reduction of VR by 20% or greater from baseline (therapeutic response). Secondary outcome included resolution time (defined as the elapsed time from start of treatment to therapeutic response), sinus rhythm conversion rate, and adverse events within the first 24 hours. RESULTS: At 4 hours, therapeutic response rate was higher in low- and high-MgSO4 groups compared to placebo group; the absolute differences were, respectively, 20.5% (risk ratio [RR] = 2.31, 95% confidence interval [CI] = 1.45-3.69) and +15.8% (RR = 1.89, 95% CI = 1.20-2.99). At 24 hours, compared to placebo group, therapeutic response difference was +14.1% (RR = 9.74, 95% CI = 2.87-17.05) with low-dose MgSO4 and +10.3% (RR = 3.22, 95% CI = 1.45-7.17) with high-dose MgSO4 . The lowest resolution time was observed in the low-dose MgSO4 group (5.2 ± 2 hours) compared to 6.1 ± 1.9 hours in the high-dose MgSO4 group and 8.4 ± 2.5 hours in the placebo group. Rhythm control rate at 24 hours was significantly higher in the low-dose MgSO4 group (22.9%) compared to the high-dose MgSO4 group (13.0%, p = 0.03) and the placebo group (10.7%). Adverse effects were minor and significantly more frequent with high-dose MgSO4 . CONCLUSIONS: Intravenous MgSO4 appears to have a synergistic effect when combined with other AV nodal blockers resulting in improved rate control. Similar efficacy was observed with 4.5 and 9 g of MgSO4 but a dose of 9 g was associated with more side effects.

Tongguan capsule-derived herb reduces susceptibility to atrial fibrillation by inhibiting left atrial fibrosis via modulating cardiac fibroblasts.

Tongguan capsule is a compound Chinese medicine used to treat ischaemic heart diseases. This study aimed to investigate whether Tongguan capsule-derived herb (TGD) has a preventive effect on atrial fibrillation (AF) in post-myocardial infarction (MI) rats and to determine the underlying mechanisms. MI was induced by ligation of the left anterior descending coronary artery. TGD was administered to the post-MI rats over a 4-week period. The TGD-treated rats had lower rates of AF inducibility and shorter AF durations than the MI rats. TGD improved the left atrial (LA) conduction velocity and homogeneity. It reduced the fibrosis-positive areas and the protein levels of collagen types I and III in the left atrium. In vitro, it inhibited the expression of collagen types I and III by inhibiting the proliferation, migration, differentiation and cytokine secretion of cardiac fibroblasts (CFs). In conclusion, the current study demonstrated that TGD reduces susceptibility to AF and improves LA conduction function in rats with post-MI by inhibiting left atrial fibrosis and modulating CFs. Targeting the CF population may be a novel antiarrhythmic therapeutic approach.

Coexistence of Brugada and Wolff Parkinson White syndromes: A case report and review of the literature.

A 31-year-old male patient presented with complaints of palpitations, dizziness, and recurrent episodes of syncope. A 12-lead electrocardiogram (ECG) revealed manifest ventricular preexcitation, which suggested Wolff Parkinson White syndrome. In addition, an incomplete right bundle branch block and a 3-mm ST segment elevation ending with inverted T-waves in V2 were consistent with coved-type (type 1) Brugada pattern. An electrophysiological study was performed, and during the mapping, the earliest ventricular activation with the shortest A-V interval was found on the mitral annulus posterolateral site. After successful radiofrequency catheter ablation of the accessory pathway, the Brugada pattern on the ECG changed, which prompted an ajmaline provocation test. A type 1 Brugada ECG pattern occurred following the administration of ajmaline. Considering the probable symptom combinations of these 2 coexisting syndromes and the presence of recurrent episodes of syncope, programmed ventricular stimulation was performed and subsequently, ventricular fibrillation was induced. An implantable cardioverter-defibrillator was implanted soon after.