Prevention Of Fibrillation Research Articles

Mineralocorticoid receptor antagonists for atrial fibrillation prevention: effective solution or empty promise?

Mineralocorticoid receptor antagonists for atrial fibrillation prevention: effective solution or empty promise?

Current Strategies for Atrial Fibrillation Prevention and Management: Taming the Commonest Cardiac Arrhythmia.

Atrial fibrillation (AF) is the commonest cardiac arrhythmia, constituting a major cause of morbidity and mortality, with an age-dependent incidence and prevalence ranging from 1-2% in the general population to ~10% in persons aged >60 years. The global prevalence of AF is rapidly increasing, mostly due to the aging population. If not properly and timely managed, this arrhythmia adversely affects left ventricular function, increases the risk of stroke five-fold, impairs quality of life, and shortens longevity. There is a genetic, hence non-modifiable, predisposition to the arrhythmia, while several life-style and cardiometabolic inciting factors, such as hypertension, heart failure, coronary disease, metabolic syndrome, alcohol use, and thyroid disorders, can be addressed, attesting to the importance of a holistic approach to its management. Thromboembolism is a serious consequence of AF, which could lead to a disabling stroke or have a lethal outcome. The risk of a thromboembolic complication can be estimated as based on a scoring system that takes into consideration the patient's age, previous thromboembolic events, and clinical comorbidities. In addition, rapid AF could affect cardiac performance, leading to an elusive type of arrhythmia-induced cardiomyopathy and heart failure with grave consequences if undetected and untreated. Furthermore, AF may cause silent brain infarcts and/or its hemodynamic perturbations can account for a type of dementia that needs to be taken into account, emphasizing the need for AF screening and prevention strategies. All these issues are herein detailed, the causes of the arrhythmia are tabulated, and an algorithm illustrates our current approach to its management.

Antihypertensive Drugs for the Prevention of Atrial Fibrillation: A Drug Target Mendelian Randomization Study.

We investigated the potential impact of antihypertensive drugs for atrial fibrillation (AF) prevention through a drug target Mendelian randomization study to avoid the potential limitations of clinical studies. Validated published single-nucleotide polymorphisms (SNPs) that mimic the action of 12 antihypertensive drug classes, including alpha-adrenoceptor blockers, adrenergic neuron blockers, angiotensin-converting enzyme inhibitors, angiotensin-II receptor blockers, beta-adrenoceptor blockers, centrally acting antihypertensive drugs, calcium channel blockers, loop diuretics, potassium-sparing diuretics and mineralocorticoid receptor antagonists, renin inhibitors, thiazides and related diuretic agents, and vasodilators were used. We estimated, via their corresponding gene and protein targets, the downstream effect of these drug classes to prevent AF via systolic blood pressure using 2-sample Mendelian randomization analyses. The SNPs were extracted from 2 European genome-wide association studies for the drug classes (n=317 754; n=757 601) and 1 European genome-wide association study for AF (n=1 030 836). Drug target Mendelian randomization analyses supported the significant preventive causal effects of lowering systolic blood pressure per 10 mm Hg via alpha-adrenoceptor blockers (n=11 SNPs; odds ratio [OR], 0.34 [95% CI, 0.21-0.56]; P=2.74×10-05), beta-adrenoceptor blockers (n=17 SNPs; OR, 0.52 [95% CI, 0.35-0.78]; P=1.62×10-03), calcium channel blockers (n=49 SNPs; OR, 0.50 [95% CI, 0.36-0.70]; P=4.51×10-05), vasodilators (n=19 SNPs; OR, 0.53 [95% CI, 0.34-0.84]; P=7.03×10-03), and all 12 antihypertensive drug classes combined (n=158 SNPs; OR, 0.64 [95% CI, 0.54-0.77]; P=8.50×10-07) on AF risk. Our results indicated that lowering systolic blood pressure via protein targets of various antihypertensive drugs seems promising for AF prevention. Our findings inform future clinical trials and have implications for repurposing antihypertensive drugs for AF prevention.

Efficacy and safety of colchicine for atrial fibrillation prevention: An updated meta-analysis of randomized controlled trials

BackgroundAtrial fibrillation (AF), the most common arrhythmia, is closely related to inflammation. Colchicine has the potent anti-inflammatory effects. Several randomized clinical trials (RCTs) have evaluated the efficacy and safety of colchicine in the prevention of AF but the results are inconsistent. ObjectiveThe purpose of our study was to evaluate the impact of colchicine on AF. Method and resultsPubMed, EMBASE, Web of Science, Cochrane Library and ClinicalTrials.gov were searched for related studies until Jan 8, 2024. A total of 17 studies including 16,238 participants were included. Compared to the placebo group, there were fewer incidences of AF in the colchicine group (RR: 0.75, 95%CI: 0.68–0.83, P < 0.001). The incidence of overall adverse events and overall gastrointestinal intolerance did not differ significantly between the two groups. However, diarrhea, nausea, and discontinuation occurred more frequently in patients treated with colchicine. ConclusionColchicine can prevent patients from the incidence of AF, regardless of the mean age of patients, type of atrial fibrillation, maintenance dose, duration of colchicine use, cumulative daily dose, and follow-up time with more diarrhea, nausea and discontinuation. These adverse events can be avoided by low doses (0.5 mg once daily) and long period time of colchicine use.

Atrial Fibrosis and Inflammation in Postoperative Atrial Fibrillation: Comparative Effects of Amiodarone, Colchicine, or Exosomes

BackgroundExtracellular vesicles (EVs) isolated from human heart-derived cells have shown promise in suppressing inflammation and fibroblast proliferation. However, their precise benefits in atrial fibrillation (AF) prevention and the role of their antifibrotic/anti-inflammatory properties remain unclear. ObjectivesThe purpose of this study was to conduct a head-to-head comparison of antiarrhythmic strategies to prevent postoperative AF using a rat model of sterile pericarditis. Specifically, we aimed to assess the efficacy of amiodarone (a classic antiarrhythmic drug), colchicine (an anti-inflammatory agent), and EVs derived from human heart-derived cells, which possess anti-inflammatory and antifibrotic properties, on AF induction, inflammation, and fibrosis progression. MethodsHeart-derived cells were cultured from human atrial appendages under serum-free xenogen-free conditions. Middle-aged Sprague Dawley rats were randomized into different groups, including sham operation, sterile pericarditis with amiodarone treatment, sterile pericarditis with colchicine treatment (2 dose levels), and sterile pericarditis with intra-atrial injection of EVs or vehicle. Invasive electrophysiological testing was performed 3 days after surgery before sacrifice. ResultsSterile pericarditis increased the likelihood of inducing AF. Colchicine and EVs exhibited anti-inflammatory effects, but only EV treatment significantly reduced AF probability, whereas colchicine showed a positive trend without statistical significance. EVs and high-dose colchicine reduced atrial fibrosis by 46% ± 2% and 26% ± 2%, respectively. Amiodarone prevented AF induction but had no effect on inflammation or fibrosis. ConclusionsIn this study, both amiodarone and EVs prevented AF, whereas treatment with colchicine was ineffective. The additional anti-inflammatory and antifibrotic effects of EVs suggest their potential as a comprehensive therapeutic approach for AF prevention, surpassing the effects of amiodarone or colchicine.

Exploring Patient Viewpoints to Optimize Implementation of a Biological Therapy for Atrial Fibrillation Prevention

BackgroundEmbracing patient viewpoints can enhance the translation of novel therapeutics to clinical settings. This study evaluated the acceptability of using extracellular vesicles (EVs) as a biological therapy for preventing postoperative atrial fibrillation (AF), through engagement with patients, providing insights into their attitudes and information needs. MethodsPatients participated in prerecorded presentations, virtual focus groups, and surveys to assess their perspectives on EV therapy and determine the factors influencing their acceptance of the intervention. ResultsParticipants with postoperative AF experienced prolonged intensive care unit and hospital stays, compared to those of patients with normal heart rhythm. Prior to the presentation, a number of participants were unfamiliar with postoperative AF and biological therapies. However, postpresentation and post–focus group activities resulted in enhanced understanding of the research, with high levels of comprehension reported by all participants. The level of acceptance of EV therapy tended to increase, with a majority expressing willingness to participate in clinical trials and accept the therapy. The focus groups identified and addressed common questions regarding the potential risks and side effects of EVs, their source, dosing, utility for patients with preexisting AF, and the risk of human immunodeficiency virus (HIV) contraction or allergic reactions. ConclusionsThe study highlights the importance of providing education, involving the patient's circle of care, and addressing patient concerns, to promote acceptance of therapies such as EV therapy for postoperative AF. Clinical Trial RegistrationNCT05032495.

Postoperative Atrial Fibrillation Prevention in Patients Undergoing Coronary Artery Bypass Grafting by Using Perioperative HCN Channel Blockers and Selective Beta Blockers

Postoperative Atrial Fibrillation Prevention in Patients Undergoing Coronary Artery Bypass Grafting by Using Perioperative HCN Channel Blockers and Selective Beta Blockers

Abstract P502: Lifestyle Modification for Secondary Prevention of Atrial Fibrillation: A Pilot Study

Background: Addressing modifiable cardiovascular risk factors through lifestyle interventions may be effective for secondary atrial fibrillation (AF) prevention. Aims: To assess feasibility, acceptability, and preliminary effectiveness of an exercise and nutrition-based cardiac rehabilitation-like program for patients with symptomatic AF. Methods: We enrolled overweight (body mass index [BMI] ≥ 28 kg/m 2 ) adults aged ≥ 30 years with symptomatic AF in a 12-week cardiac lifestyle group program, which included 6 virtual and 6 in-person visits. All visits included discussion and education about nutrition, exercise, and behavior modification. In-person visits included supervised aerobic exercise and strength training. Patients were evaluated to assess health history, diet, and baseline cardiac risk factors. Outcomes at baseline and 12 weeks included feasibility of participation, change in weight and BMI, acceptability, and changes in survey-based AF burden and symptoms, and AF-related quality of life (QOL). Results: From 84 invitees, 11 (13.1%) were enrolled (mean age 64; baseline BMI 38 kg/m 2 ; 45% female); 9 (82%) completed the program. Patients attended an average of 9.7 (81%) visits (Range: 6-11). Mean weight loss was 9.1 pounds (Range: 0-16) and mean BMI decrease was 1.4 kg/m 2 (Range: 0-2.6). Nine of 11 patients completed baseline and follow-up surveys (Table) . Patients found the program helpful overall: all reported making diet and exercise changes during the program; 8 (89%) were confident in continuing dietary changes and 7 (77%) were confident in continuing exercise changes after the program. Patients reported decreased AF burden and symptoms, and increased QOL at the conclusion of the program (Table) . Conclusions: Participation in a cardiac rehab-like program was feasible and acceptable for overweight patients with symptomatic AF. Results suggest preliminary effectiveness of the program for reducing AF burden and symptoms and increasing quality of life.

Beta-blockers in Hypertensive Left Ventricular Hypertrophy and Atrial Fibrillation Prevention.

Hypertensive left ventricular hypertrophy (HTN LVH) is a key risk factor for atrial fibrillation (AF). To evaluate the possible role of beta-blockers (BBs) in addition to a renin-angiotensinaldosterone system (RAAS) blocker in AF prevention in patients with HTN LVH. We performed a PubMed, Elsevier, SAGE, Oxford, and Google Scholar search with the search items 'beta blocker hypertension left ventricular hypertrophy patient' from 2013-2023. In the end, a 'snowball search', based on the references of relevant papers as well as from papers that cited them was performed. HTN LVH is a risk factor for AF. In turn, AF substantially complicates HTN LVH and contributes to the genesis of heart failure (HF) with preserved ejection fraction (HFpEF). The prognosis of HFpEF is comparable with that of HF with reduced EF (HFrEF), and, regardless of the type, HF is associated with five-year mortality of 50-75%. The antiarrhythmic properties of BBs are wellrecognized, and BBs as a class of drugs are - in general - recommended to decrease the incidence of AF in HTN. BBs are recommended (as a class) for AF prevention in several contemporary guidelines for HTN. LVH regression in HTN - used as a single criterion for the choice of antihypertensive medication - does not capture this protective effect. Consequently, it is worth studying how meaningful this antiarrhythmic action (to prevent AF) of BBs is in patients with HTN LVH in addition to a RAAS blocker.

Synergetic construction of color and multifunction for sustainable lyocell fabric by microbial nano pigment

As a kind of low-carbon, environmentally friendly and high-quality regenerated cellulose fiber derived from nature plant, the promotion and application of lyocell fiber is attracting much attention. In this paper, for the first time, microbial pigment was applied for color and multifunction construction of lyocell fabric. The size change of the pigment nano-particles during the color construction process was explored to verify the dyeing mechanism of nano-suspension system, and the optimal dyeing condition was obtained. In order to improve the dyeing effect and functionality of fabric, 1,2,3,4-butanetetracarboxylic acid (BTCA) was used to realize the anionic modification of lyocell fabric with high strength retention rate. Under optimal color construction condition, the color depth of the modified fabric was 298.5% higher than that of the unmodified one, and the dyed fabric possessed excellent dyeing uniformity and permeability. Moreover, the crosslinking reaction between BTCA and cellulose macromolecules, as well as the pigment deposition inside the fibers were helpful to the fibrillation prevention function of lyocell fibers. Dyed fabrics inherited the antibacterial and ultraviolet absorption properties of prodigiosins. The bacteriostatic rate against Staphylococcus aureus was above than 98.5%, and the UV protection performance was obviously improved. This technology successfully realized the color and multi-functional construction of the lyocell fabric in one step by natural pigment from microorganism.

2023 ACC/AHA/ACCP/HRS Guideline for the Diagnosis and Management of Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines.

The "2023 ACC/AHA/ACCP/HRS Guideline for the Diagnosis and Management of Atrial Fibrillation" provides recommendations to guide clinicians in the treatment of patients with atrial fibrillation. A comprehensive literature search was conducted from May 12, 2022, to November 3, 2022, encompassing studies, reviews, and other evidence conducted on human subjects that were published in English from PubMed, EMBASE, the Cochrane Library, the Agency for Healthcare Research and Quality, and other selected databases relevant to this guideline. Additional relevant studies, published through November 2022, during the guideline writing process, were also considered by the writing committee and added to the evidence tables, where appropriate. Atrial fibrillation is the most sustained common arrhythmia, and its incidence and prevalence are increasing in the United States and globally. Recommendations from the "2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation" and the "2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation" have been updated with new evidence to guide clinicians. In addition, new recommendations addressing atrial fibrillation and thromboembolic risk assessment, anticoagulation, left atrial appendage occlusion, atrial fibrillation catheter or surgical ablation, and risk factor modification and atrial fibrillation prevention have been developed.

Comparison of amiodarone and esmolol for prevention of reperfusion ventricular fibrillation in individuals undergoing heart valve or aortic surgery: a study protocol for a randomized controlled clinical trial

BackgroundAmiodarone and esmolol can help to prevent and treat post-cardiac surgery reperfusion ventricular fibrillation. However, the relative efficacies of these two drugs remain unknown. The aim of the current trial is to compare the performances of amiodarone and esmolol for preventing reperfusion ventricular fibrillation following open heart surgery.Methods/designThis is a single-center, prospective, double-blind, controlled clinical trial. A total of 260 patients undergoing heart valve or aortic surgery will be assigned randomly to treatment with prophylactic esmolol (intervention group) or amiodarone (control group). The main outcome is the incidence of reperfusion ventricular fibrillation following aortic opening during extracorporeal circulation. The secondary outcomes are the rate of automatic cardiac resuscitation, energy and frequency of electrical defibrillation, number of electrical defibrillations, and pacemaker use in the two groups of patients. Information on the patients’ general condition and the durations of anesthesia, extracorporeal circulation, aortic occlusion, and operation time will be recorded. We will also compare the heart rate, mean arterial pressure, and central venous pressure between the two groups of patients at induction of anesthesia (T1), start of surgery (T2), start of extracorporeal circulation (T3), aortic block (T4), aortic opening (T5), after opening for 10 (T6), 20 (T7), and 30 min (T8), at cessation of extracorporeal circulation (T9), and at the end of surgery (T10) and compare blood gas analysis results at T1, T5, T9, and T10.DiscussionThis study will determine if prophylactic esmolol is more effective than amiodarone for reducing the incidence of reperfusion ventricular fibrillation in patients undergoing heart valve or aortic surgery.Trial registrationChina Clinical Trials Registry ChiCTR1900026429. Registered on 2019.10.9.

Impact of Limited Enhanced Recovery Pathway for Cardiac Surgery: A Single-Institution Experience

ObjectivesEnhanced Recovery Pathway (ERP) refers to extensive multidisciplinary evidence-based pathways utilized to facilitate recovery after surgery. We assess the impact that limited ERP protocols had on outcomes in patients undergoing cardiac surgery at our institution. DesignRetrospective cohort study. SettingThis study was a single-institution study conducted at a university hospital. ParticipantsPatients undergoing open adult cardiac surgery. InterventionsERP pathways limited to pre-operative, intra-operative, and post-operative management of pain control, atrial fibrillation prevention, and nutrition optimization were implemented. Measurements and Main Results1,058 patients were included in this study. There were 374 patients in each pre and post ERP cohort after propensity matching with no significant baseline differences between the two cohorts. Compared to the matched patients in the pre-ERP group, patients in the post-ERP group had decreased total ventilation hours (6.8 vs 7.8, p = 0.006), less use of postoperative opioid analgesics as determined by total morphine milligram equivalent (32.5 vs 47.5, p < 0.001), and a decreased rate of postoperative atrial fibrillation (23.3% vs. 30.5%, p = 0.032). Post-ERP patients also experienced less subjective pain and postoperative nausea and drowsiness as compared to their matched pre-ERP cohorts. ConclusionsLimited ERP implementation resulted in significantly improved perioperative outcomes. Patients additionally experienced less postoperative pain despite decreased opioid utilization. Implementation of ERP, even in a limited format, is a promising approach to improving outcomes in patients undergoing cardiac surgery.

Interaction enhancement of Lyocell cellulose chains for controlled fibrillation behavior with greener application in eco-textiles

Lyocell is treated as a biodegradable, sustainable, and low-carbon emission cellulose fiber, but it possesses a high fibrillation tendency in the dyeing process which is generally conducted at alkaline, wet and high-temperature conditions. The fibrillation phenomenon seriously reduces the product quality and affects its application in eco-textiles. In response to the problem, a greener and simple fibrillation prevention treatment was innovatively conducted before the coloration process to enhance the interaction of Lyocell cellulose macromolecular chains. A nonionic crosslinker with isocyanate reactive groups was applied for the fibrillation control. The mechanism of the reaction between the nonionic crosslinker and Lyocell cellulose chains was determined through the measurements of fiber swelling, dynamic surface tension, Fourier transform infrared spectroscopy (FTIR), and X-ray diffraction (XRD). It was found that the fibril interaction was significantly enhanced with reduced lateral swelling of Lyocell fibers. The fibrillation tendency was greatly reduced at the treatment condition of 20 g/L, 175 °C, and 80 s. Moreover, the interaction between cellulose chains was further improved after dyed with bifunctional reactive dyes. In comparison to commercial cationic and anionic crosslinkers, the nonionic sample not only showed little effect on the dye fixation, but also added good wrinkle resistance to Lyocell fabrics. The method showed the advantages of a shorter process and low chemical consumption compared to the conventional Lyocell dyeing process. Therefore, this work may promote the development of Lyocell fabric in high-quality and eco-friendly textiles.

Prevention of insulin fibrillation by biocompatible choline-amino acid based ionic liquids: Biophysical insights

We have synthesized biocompatible ionic liquids (ILs) with choline as cation and amino acids as anions to explore their potential towards prevention of fibrillation in insulin and the obtain corresponding mechanistic insights. This has been achieved by examining the effect of these ILs on insulin at the nucleation, elongation and maturation stages of the fibrillation process. A combination of high sensitivity isothermal titration calorimetry (ITC) and differential scanning calorimetry (DSC) have been employed along with spectroscopy and microscopy to evaluate interaction of the ILs at each stage of fibrillation quantitatively. Choline glycinate is observed to provide maximum stabilization to insulin compared to that provided by choline prolinate, choline leucinate, and choline valinate. This increased thermal stabilization has direct correlation with the extent of reduction in the fibrillation of insulin by ILs determined using Thioflavin T and 8-anilinonaphthalene sulfonate based fluorescence assays. ITC has permitted understanding nature of interaction of the ILs with the protein at different fibrillation stages in terms of standard molar enthalpy of interaction whereas DSC has enabled understanding the extent of reduction in thermal stability of the protein at these stages. These ILs are able to completely inhibit formation of insulin aggregates at a concentration of 50 mM. Stabilization of proteins by ILs could be explained based on involvement of preferential hydration process. The work provides biocompatible IL based approach in achieving stability and prevention of fibrillation in insulin.

Comparison of Amiodarone with Combined Doses of Magnesium Sulphate and Lidocaine for Prevention of Ventricular Fibrillation Following Coronary Clamp Release During Coronary Artery Bypass Graft Surgery

Objective: To compare the effects of amiodarone with effects of combined doses of magnesium sulphate and lidocaine for prevention of ventricular fibrillation following coronary clamp release during (coronary artery bypass grafting) CABG.&#x0D; Study Design: Comparative cross sectional study.&#x0D; Place and Duration of Study: Army Cardiac Centre, Lahore Pakistan, from Jun 2021 to Dec 2021.&#x0D; Methodology: One hundred patients who reported at Army Cardiac Centre Lahore, Pakistan for coronary artery bypass grafting surgery, were involved in comparative study. Patients satisfying the inclusion criteria were allocated into the LM(Lidocaine Magnesium) and A (Amiodarone) groups. Following aortic cross clamp release, the incidence of ventricular fibrillation (VF) and other arrhythmias was calculated in first 30 minutes and up to 24 hours later. The ionotropic agent used was epinephrine at a rate of 0.05 to 0.1 micrograms/kg/minute. Within 15 minutes of anesthetic induction and 15 minutes after the CPB pump was removed, hemodynamic parameters were assessed and recorded.&#x0D; Results: Arrhythmias within 30 minutes and up to 24 hours after aortic cross clamp ACC release in A and LM group were compared. The difference between two groups, having arrhythmias and no arrhythmias was statistically insignificant (p≥0.050) except VF up to 24 hours after ACC release. The highest voltage for defibrillation was used in Group-A n=20 (40.0%) and n=27 (54.0%) in L.M group, (p=0.004). The average electrical defibrillations in group-A was less than that of group L.M,(p=0.000). While, the use of ionotropic agent was almost equal in both the groups, (p=0.975).&#x0D; Conclusion: Overall, the amiodarone group had a decreased incidence of VF when the ACC was released, while the difference was not statistically significant.

Inhibition of α-Synuclein fibrillation by natural polyphenols: Thermodynamic and biophysical aspects

α-Synuclein (α-Syn) is a presynaptic neuronal protein whose fibrillar aggregates accumulate in the form of Lewy bodies in dopaminogenic neurons. This leads to dysfunctionality and death of neurons in the affected brain and is one of the major causes of Parkinson’s disease (PD). Preventing the fibrillation of the α-Syn by natural compounds can contribute to the development of new therapeutic strategies. In this work, we have reported the inhibition of α-Syn fibrillation by two natural polyphenols Epigallocatechin gallete (EGCG), and Epicatechin (EC). The fluorescence microscopy and isothermal titration calorimetry (ITC) suggest that both EGCG and EC bind to α-Syn with moderate affinity (104–103 mol−1·kg) via a combination of H-bonding/polar and hydrophobic interactions. ThT binding and light scattering assays showed that both polyphenols delay and inhibit α-Syn fibrillation which is also confirmed by transmission electron microscopy. Both polyphenols are found to be effective even if they are added after the onset of fibrillation and also the seeds formed in the presence of EGCG and EC do not further enhance fibrillation. Circular dichroism (CD) spectroscopy revealed that EGCG and EC bind and delay the alteration of α-Syn into cross β-amyloid fibrillar structures. The results will provide deep insights into the EGCG and EC mediated prevention of α-Syn fibrillation and unlock the potential of natural products as therapeutic candidates against PD.

PMON181 RGS4 Is Essential For The Sympathetic Regulation of The Short-chain Fatty Acid Receptor FFAR3 In The Heart

Abstract Background Free fatty acids (FFAs) are essential cell nutrients but also important signaling molecules regulating various cellular processes. Short-chain fatty acids (SCFAs), like propionate and butyrate, activate two different types of G protein-coupled receptors (GPCRs), FFAR2 and FFAR3. FFAR3 (also known as GPR41) couples to Gi/o proteins lowering cyclic 3', 5'-adenosine monophosphate (cAMP) levels and activating mitogen-activated protein kinases (MAPKs). In addition to adipose tissue, FFAR3 is highly expressed in peripheral sympathetic ganglia augmenting sympathetic nervous system (SNS) outflow. Regulator of G protein Signaling (RGS)-4 belongs to the RGS superfamily of proteins and inactivates (terminates) both Gi/o- and Gq-protein signaling. Cardiac RGS4 has been implicated in atrial fibrillation (AFib) prevention via calcium signaling attenuation. Finally, β-adrenergic receptors (ARs), the major mediators of catecholaminergic and SNS actions in cardiac myocytes, stimulate cAMP synthesis and activate protein kinase A (PKA), which is known to activate RGS4 via phosphorylation. Objective We examined whether RGS4 regulates cardiac FFAR3 signaling. Methods We used H9c2 cardiomyocytes transfected to express the human FFAR3. After treatment with catecholaminergic agonists and/or propionic acid plus various pharmacological inhibitors and siRNA to deplete RGS4, we performed signaling assays (western blotting, cAMP accumulation, GTP binding, ELISA) to delineate the precise involvement of RGS4 in the cardiac βAR-FFAR3 signaling crosstalk. Results RGS4 is essential for the dampening of propionate/FFAR3-dependent signaling in H9c2 cardiomyocytes since siRNA-mediated RGS4 depletion significantly enhances the effect of propionic acid on cAMP lowering, Gi/o activation, and p38 MAPK activation. Notably, concomitant isoproterenol or salbutamol treatment blocks propionic acid-induced signaling via the FFAR3 in H9c2 cardiomyocytes, indicating negative regulation of FFAR3 by catecholamines via the β2AR. Mechanistically, this is mediated by RGS4, since neither isoproterenol, nor salbutamol can inhibit propionate signaling upon siRNA-mediated RGS4 depletion. Finally, β2AR inhibition of FFAR3 signaling via RGS4 is dependent on β2AR-activated PKA, because pre-treatment with the PKA inhibitor H89 abrogates the catecholaminergic inhibition of FFAR3 signaling in H9c2 cardiomyocytes, as measured by cAMP lowering, downstream p38 MAPK activation, and interleukin (IL)-6 production. Conclusion Catecholamine-activated RGS4 abrogates SCFA/FFAR3 signaling and function in cardiac myocytes. This may represent part of the mechanism via which RGS4 protects against both AFib pathogenesis and FFAR3-promoted SNS hyperactivity and inflammation in the myocardium. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Regulation of oxaliplatin and carboplatin on the assembly behavior and cytotoxicity of human islet amyloid polypeptide

Human islet amyloid polypeptide (hIAPP) is associated with the pathology of Type II diabetes (T2DM) due to its misfolding and amyloid deposition. The peptide is widely concerned as a potential drug target, and the prevention of hIAPP fibrillation is a rational therapeutic strategy for T2DM. Platinum complexes are promising anticancer agents with good biocompatibility, they can resist the aggregation of amyloid peptides, while the effects of oxaliplatin and carboplatin on hIAPP fibrillation are unknown. In the present work, we selected the two platinum drugs to reveal their inhibition and disaggregation against hIAPP fibrillation by various biophysical methods. The two complexes impeded hIAPP fibril formation and dispersed the aggregates into small oligomers and most monomers. They also reduced peptides oligomerization and promoted rat insulinoma β-cells viability. They bound to hIAPP mainly through metal coordination and hydrophobic interactions. Moreover, oxaliplatin showed better inhibition and regulation on peptides aggregation and cytotoxicity than carboplatin. This work is of important biomedical values for clinical platinum drugs against T2DM and other amyloidosis related diseases.

Statin and Postcardiac Surgery Atrial Fibrillation Prevention: A Systematic Review and Meta-Analysis.

Postoperative atrial fibrillation (POAF) is a frequently reported postcardiac surgery complication leading to increased in-hospital and long-term mortality rates. Many randomized controlled trials (RCTs) have recently suggested using statins to protect against POAF. Therefore, we performed a systematic literature search and meta-analysis in electronic databases for eligible studies published between January 2006 and January 2022. The principal inclusion criteria were as follows: RCTs' study design, statin-naive patients, total study participants ≥50 units, and statin pretreatment started no more than 21 days before cardiac surgery. In the primary analysis, statin pretreatment reduced the incidence of POAF compared with placebo. Analyzing different molecules, atorvastatin was associated with lower incidence of POAF but rosuvastatin was not. We therefore performed a sensitivity analysis excluding RCTs affected by important risk of biases. Thus, studies whose participants were ≥199 were those eligible for the secondary analysis. No statistically significant difference between statin pretreatment and placebo (OR 0.87; 95% CI: 0.71-1.07, P = 0.18) as well as for atorvastatin (OR 0.88; 95% CI: 0.61-1.28; P = 0.48; I 2 = 84%) and rosuvastatin (OR 0.87; 95% CI: 0.68-1.12, P = 0.29) was observed. To conclude, statin pretreatment before cardiac surgery is not associated with a significant reduction in POAF occurrence.