Comprehensive analysis of same day discharge after atrial fibrillation ablation: Clinical, cost, and patient reported outcomes.

BACKGROUND: Same day discharge (SDD) following atrial fibrillation (AF) ablation procedure has emerged as routine practice, and primarily driven by operator discretion. However, the impacts of SDD on clinical outcomes, healthcare system costs, and patient reported outcomes (PROs) have not been systematically studied. METHODS: We retrospectively analyzed patients undergoing routine AF ablation procedures with SDD versus overnight observation (NSDD). After propensity adjustment we compared postprocedure adverse events (AEs), healthcare system costs, and changes in PROs. RESULTS: We identified 310 cases, with 159 undergoing SDD and 151 staying at least one midnight in the hospital (NSDD). Compared with NSDD, SDD patients were similar age (mean 64 vs. 66, p = 0.3), sex (26% female vs. 27%, p = 0.8), and with lower mean CHADS2-VA2Sc scores (2.0 vs. 2.7; p < 0.011). The primary outcome of AEs was noninferior in SDD versus NSDD patients (odds ratio 0.45, 95% confidence interval 0.21-0.99; noninferiority margin of 10%). There were also no differences in overall cost to the healthcare system between SDD and NSDD (p = 0.11). PROs numerically favored SDD (p = NS for all scores). CONCLUSIONS: Physician selection for SDD appears at least as safe as NSDD with respect to clinical outcomes and SDD is not significantly less costly to the health system. There is a trend towards more favorable, general PROs among SDD patients. Routine SDD should be strongly considered for patients undergoing routine AF ablation procedures.

Cardiac myosin-binding protein C N-terminal interactions with myosin and actin filaments: Opposite effects of phosphorylation and M-domain mutations.

N-terminal cardiac myosin-binding protein C (cMyBP-C) domains (C0-C2) bind to thick (myosin) and thin (actin) filaments to coordinate contraction and relaxation of the heart. These interactions are regulated by phosphorylation of the M-domain situated between domains C1 and C2. In cardiomyopathies and heart failure, phosphorylation of cMyBP-C is significantly altered. We aimed to investigate how cMyBP-C interacts with myosin and actin. We developed complementary, high-throughput, C0-C2 FRET-based binding assays for myosin and actin to characterize the effects due to 5 HCM-linked variants or functional mutations in unphosphorylated and phosphorylated C0-C2. The assays indicated that phosphorylation decreases binding to both myosin and actin, whereas the HCM mutations in M-domain generally increase binding. The effects of mutations were greatest in phosphorylated C0-C2, and some mutations had a larger effect on actin than myosin binding. Phosphorylation also altered the spatial relationship of the probes on C0-C2 and actin. The magnitude of these structural changes was dependent on C0-C2 probe location (C0, C1, or M-domain). We conclude that binding can differ between myosin and actin due to phosphorylation or mutations. Additionally, these variables can change the mode of binding, affecting which of the interactions in cMyBP-C N-terminal domains with myosin or actin take place. The opposite effects of phosphorylation and M-domain mutations is consistent with the idea that cMyBP-C phosphorylation is critical for normal cardiac function. The precision of these assays is indicative of their usefulness in high-throughput screening of drug libraries for targeting cMyBP-C as therapy.

Mortality benefit with AF ablation: Impact of normal sinus rhythm seen in CABANA and EAST AFnet.

Atrial fibrillation (AF) is significantly associated with morbidity and mortality and erodes the quality and quantity of life. It is standard of care to treat patients with AF and an increased risk of stroke with oral anticoagulation therapy, but the more daunting question many clinicians face is whether to pursue a "rate-only" or "rhythm" control strategy. Historical studies over the years have sought to answer this question but have found no significant difference in major clinical outcomes between the two strategies. There are opportunities based on new data to improve the natural history of the disease. The EAST AFnet trial for the first time revealed a significant morbidity and mortality advantage to rhythm control therapy when performed early in the disease process of AF and in the setting of comprehensive medical management that was maintained. The CABANA trial clearly demonstrated that catheter ablation was a more effective long-term treatment of AF in general and significantly lowers risk of AF progression compared to medical therapy. Like multiple prior trials of rhythm management strategies, when rhythm control was effective in these trials, independent of therapy assignment, there was a significantly lower risk of adverse outcomes and death. These contemporary data provide optimism that the pervasive mortality risk in patients with AF observed over the past 50 years may be improved by the timing, use, and efficacy of use of therapeutic interventions.

Drug discovery for heart failure targeting myosin-binding protein C.

Cardiac MyBP-C (cMyBP-C) interacts with actin and myosin to fine-tune cardiac muscle contractility. Phosphorylation of cMyBP-C, which reduces the binding of cMyBP-C to actin and myosin, is often decreased in patients with heart failure (HF) and is cardioprotective in model systems of HF. Therefore, cMyBP-C is a potential target for HF drugs that mimic its phosphorylation and/or perturb its interactions with actin or myosin. We labeled actin with fluorescein-5-maleimide (FMAL) and the C0-C2 fragment of cMyBP-C (cC0-C2) with tetramethylrhodamine (TMR). We performed two complementary high-throughput screens (HTS) on an FDA-approved drug library, to discover small molecules that specifically bind to cMyBP-C and affect its interactions with actin or myosin, using fluorescence lifetime (FLT) detection. We first excited FMAL and detected its FLT, to measure changes in fluorescence resonance energy transfer (FRET) from FMAL (donor) to TMR (acceptor), indicating binding. Using the same samples, we then excited TMR directly, using a longer wavelength laser, to detect the effects of compounds on the environmentally sensitive FLT of TMR, to identify compounds that bind directly to cC0-C2. Secondary assays, performed on selected modulators with the most promising effects in the primary HTS assays, characterized the specificity of these compounds for phosphorylated versus unphosphorylated cC0-C2 and for cC0-C2 versus C1-C2 of fast skeletal muscle (fC1-C2). A subset of identified compounds modulated ATPase activity in cardiac and/or skeletal myofibrils. These assays establish the feasibility of the discovery of small-molecule modulators of the cMyBP-C-actin/myosin interaction, with the ultimate goal of developing therapies for HF.

Drug discovery for heart failure targeting myosin-binding protein C.

Cardiac MyBP-C (cMyBP-C) interacts with actin-myosin to fine-tune cardiac muscle contractility. Phosphorylation of cMyBP-C, which reduces binding of cMyBP-C to actin or myosin, is often decreased in heart failure (HF) patients, and is cardioprotective in model systems for HF. Therefore, cMyBP-C is a potential target for HF drugs that mimic phosphorylation and/or perturb its interactions with actin or myosin. We labeled actin with fluorescein-5-maleimide (FMAL), and the C0-C2 fragment of cMyBP-C (cC0-C2) with tetramethyl rhodamine (TMR). We performed two complementary high-throughput screens (HTS) on an FDA-approved drug library, to discover small molecules that specifically bind to cMyBP-C and affect its interactions with actin or myosin, using fluorescence lifetime (FLT) detection. We first excited FMAL and detected its FLT, to measure changes in fluorescence resonance energy transfer (FRET) from FMAL (donor) to TMR (acceptor), indicating binding and/or structural changes in the protein complex. Using the same samples, we then excited TMR directly, using a longer wavelength laser, to detect the effects of compounds on the environmentally sensitive FLT of TMR, to identify compounds that bind directly to cC0-C2. Secondary assays, performed on selected modulators with the most promising effects in the primary HTS assays, characterized specificity of these compounds for phosphorylated versus unphosphorylated cC0-C2 and for cC0-C2 versus C1-C2 of fast skeletal muscle (fskC1-C2). A subset of identified compounds modulated ATPase activity in cardiac and/or skeletal myofibrils. These assays establish feasibility for discovery of small-molecule modulators of the cMyBP-C-actin/myosin interaction, with the ultimate goal of developing therapies for HF.

Increasing time between first diagnosis of atrial fibrillation and catheter ablation adversely affects long-term outcomes in patients with and without structural heart disease.

INTRODUCTION: Atrial Fibrillation (AF) is a common arrhythmia often comorbid with systolic or diastolic heart failure (HF). Catheter ablation is a more effective treatment for AF with concurrent left ventricular dysfunction, however, the optimal timing of use in these patients is unknown. METHODS: All patients that received a catheter ablation for AF(n = 9979) with 1 year of follow-up within the Intermountain Healthcare system were included. Patients with were identified by the presence of structural disease by ejection fraction (EF): EF ≤ 35% (n = 1024) and EF > 35% (n = 8955). Recursive partitioning categories were used to separate patients into clinically meaningful strata based upon time from initial AF diagnosis until ablation: 30-180(n = 2689), 2:181-545(n = 1747), 3:546-1825(n = 2941), and 4:>1825(n = 2602) days. RESULTS: The mean days from AF diagnosis to first ablation was 3.5 ± 3.8 years (EF > 35%: 3.5 ± 3.8 years, EF ≤ 35%: 3.4 ± 3.8 years, p = .66). In the EF > 35% group, delays in treatment (181-545 vs. 30-180, 546-1825 vs. 30-180, >1825 vs. 30-180 days) increased the risk of death with a hazard ratio (HR) of 2.02(p < .0001), 2.62(p < .0001), and 4.39(p < .0001) respectively with significant risks for HF hospitalization (HR:1.44-3.69), stroke (HR:1.11-2.14), and AF recurrence (HR:1.42-1.81). In patients with an EF ≤ 35%, treatment delays also significantly increased risk of death (HR 2.07-3.77) with similar trends in HF hospitalization (HR:1.63-1.09) and AF recurrence (HR:0.79-1.24). CONCLUSION: Delays in catheter ablation for AF resulted in increased all-cause mortality in all patients with differential impact observed on HF hospitalization, stroke, and AF recurrence risks by baseline EF. These data favor earlier use of ablation for AF in patients with and without structural heart disease.

Fluorescence lifetime-based assay reports structural changes in cardiac muscle mediated by effectors of contractile regulation.

Cardiac muscle contraction is regulated by Ca2+-induced structural changes of the thin filaments to permit myosin cross-bridge cycling driven by ATP hydrolysis in the sarcomere. In congestive heart failure, contraction is weakened, and thus targeting the contractile proteins of the sarcomere is a promising approach to therapy. However, development of novel therapeutic interventions has been challenging due to a lack of precise discovery tools. We have developed a fluorescence lifetime-based assay using an existing site-directed probe, N,N'-dimethyl-N-(iodoacetyl)-N'-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)ethylenediamine (IANBD) attached to human cardiac troponin C (cTnC) mutant cTnCT53C, exchanged into porcine cardiac myofibrils. We hypothesized that IANBD-cTnCT53C fluorescence lifetime measurements provide insight into the activation state of the thin filament. The sensitivity and precision of detecting structural changes in cTnC due to physiological and therapeutic modulators of thick and thin filament functions were determined. The effects of Ca2+ binding to cTnC and myosin binding to the thin filament were readily detected by this assay in mock high-throughput screen tests using a fluorescence lifetime plate reader. We then evaluated known effectors of altered cTnC-Ca2+ binding, W7 and pimobendan, and myosin-binding drugs, mavacamten and omecamtiv mecarbil, used to treat cardiac diseases. Screening assays were determined to be of high quality as indicated by the Z' factor. We conclude that cTnC lifetime-based probes allow for precise evaluation of the thin filament activation in functioning myofibrils that can be used in future high-throughput screens of small-molecule modulators of function of the thin and thick filaments.

Novel methodology for the evaluation of symptoms reported by patients with newly diagnosed atrial fibrillation: Application of natural language processing to electronic medical records data.

INTRODUCTION: Understanding symptom patterns in atrial fibrillation (AF) can help in disease management. We report on the application of natural language processing (NLP) to electronic medical records (EMRs) to capture symptom reports in patients with newly diagnosed (incident) AF. METHODS AND RESULTS: This observational retrospective study included adult patients with an index diagnosis of incident AF during January 1, 2016 through June 30, 2018, in the Optum datasets. The baseline and follow-up periods were 1 year before/after the index date, respectively. The primary objective was identification of the following predefined symptom reports: dyspnea or shortness of breath; syncope, presyncope, lightheadedness, or dizziness; chest pain; fatigue; and palpitations. In an exploratory analysis, the incidence rates of symptom reports and cardiovascular hospitalization were assessed in propensity-matched patient cohorts with incident AF receiving first-line dronedarone or sotalol. Among 30 447 patients with an index AF diagnosis, the NLP algorithm identified at least 1 predefined symptom in 9734 (31.9%) patients. The incidence rate of symptom reports was highest at 0-3 months post-diagnosis and lower at >3-6 and >6-12 months (pre-defined timepoints). Across all time periods, the most common symptoms were dyspnea or shortness of breath, followed by syncope, presyncope, lightheadedness, or dizziness. Similar temporal patterns of symptom reports were observed among patients with prescriptions for dronedarone or sotalol as first-line treatment. CONCLUSION: This study illustrates that NLP can be applied to EMR data to characterize symptom reports in patients with incident AF, and the potential for these methods to inform comparative effectiveness.

Impact of anticoagulation therapy on the cognitive decline and dementia in patients with non-valvular atrial fibrillation (cognitive decline and dementia in patients with non-valvular atrial fibrillation [CAF] trial).

Background: Atrial fibrillation (AF) is associated with a risk for cognitive impairment and dementia, which is more pronounced in patients with a history of clinical stroke. Anticoagulation use and efficacy impact long-term risk of dementia in AF patients in observational trials. Methods: The cognitive decline and dementia in patients with non-valvular atrial fibrillation (CAF) Trial was a randomized, prospective, open-label vanguard clinical study with blinded endpoint assessment involving patients with moderate- to high-risk (CHADS2 or CHA2DS2-Vasc scores of ≥2) non-valvular AF assigned to dabigatran etexilate or warfarin. The primary endpoint was incident dementia or moderate cognitive decline at 24 months. Results: A total of 101 patients were enrolled [mean age:73.7 ± 6.0 years, male: 54(53.5%)]. Prior stroke and stroke risk factors were similar between groups. Average INR over the study was 2.41 ± 0.68 in the warfarin group. No patient experienced a stroke or developed dementia. Mini-Mental Status Evaluation, Hachinski Ischemic scale, cognitive subscale of the Alzheimer's Disease Assessment Scale, Disability Assessment for Dementia, Quality of Life Improvement as assessed by Minnesota Living with Heart Failure Scale and the Anti-Clot Treatment Scale Quality of Life Survey scores did not vary at baseline or change over 2 years. Biomarker analysis indicated a similar efficacy of anticoagulation strategies. Conclusion: Use of dabigatran and well-managed warfarin therapy were associated with similar risks of stroke, cognitive decline, and dementia at 2 years, suggestive that either strategy is acceptable. The results of this Vanguard study did not support the pursuit of a larger formally powered study.

Catheter ablation for atrial fibrillation in the elderly >75 years old: Systematic review and meta-analysis.

INTRODUCTION: Atrial fibrillation (AF) ablation is increasingly performed worldwide. As comfort with AF ablation increases, the procedure is increasingly used in patients that are older and in those with more comorbidities. However, it is not well established whether AF ablation in the elderly, especially those >75 years old, has comparable safety and efficacy to younger populations. OBJECTIVE: To compare the efficacy and safety profiles in patients older than 75 years undergoing AF ablation with younger patients. METHODS: Databases from EMBASE, Medline, PubMed, and Cochrane, were searched from inception through September 2021. Studies that compared the success rates in AF catheter ablation and all complications rates between patients who were older vs under 75 years were included. Effect estimates from the individual studies were extracted and combined using random effect, generic inverse variance method of DerSimonian and Laird. RESULTS: Twenty-seven observational studies were included in the analysis consisting of 363,542 patients who underwent AF ablation. Comparing patients older than 75 years old to younger patients, there was no difference in the success of ablation rates between elderly and younger patients (pooled OR 0.85: 95% CI:0.69-1.05, p = .131). On the other hand, AF ablation in the elderly was associated with higher complication rates (pooled OR 1.42: 95% CI:1.21-1.68, p < .001). CONCLUSION: As AF ablation is expanded to elderly populations, our study found that AF ablation success rates were similar in both elderly and younger patients. However, older patients experience higher rates of complications that should be considered when offering the procedure and as a means to improve outcomes with future innovations.

In-situ characterization of porcine fibroblasts in response to silver ions by Raman spectroscopy and liquid scanning transmission electron microscopy.

Since silver ion is known for its antimicrobial function, most of the research has focused mainly on toxicity effects rather than the role of silver ion in general biology and the behind mechanism of actions of silver ion in mammalian cells. Moreover, a conventional in vitro approach to estimate the effects of silver ion on cells does not provide information about the biochemical changes and might accompany artifacts due to invasive and destructive sample preparation processes. In the present study, in-situ real time approaches were applied to evaluate the impact of silver ion (0.57, 1.34, 1.96, 2.33 mg/L) on fibroblast cells. Raman spectroscopy analysis showed that Raman peak intensities of proteins and nucleic acids significantly increased in the cells after exposure to silver ion for 21 h, especially at relatively higher levels 1.34, 1.96, and 2.33 mg/L. Raman peak at 1585 cm-1 and liquid scanning transmission electron microscopy energy-dispersive x-ray spectroscopy (STEM-EDS) analysis revealed the fate of silver ion that was taken up by the cell and reduced into metallic silver accumulating in the cell as silver nanoparticles. These results suggest cells were undergoing different activities such as enhanced metabolic activities rather than cell apoptosis or cell death. Additionally, Raman spectroscopy predicted the level of silver ion exposed to the cell at 2.11 ± 0.38 and 1.73 ± 0.26 mg/L by the PLS prediction model, compared with the results measured by inductively coupled plasma mass spectrometry (ICP-MS), 2.14 ± 0.07 and 1.87 ± 0.07 mg/L respectively, suggesting Raman spectroscopy can provide a new and fast approach to determine and measure the concentration of silver ion or probably other tested molecules treated to the cell for the future research.

Human cardiac myosin-binding protein C phosphorylation- and mutation-dependent structural dynamics monitored by time-resolved FRET.

Cardiac myosin-binding protein C (cMyBP-C) is a thick filament-associated protein of the sarcomere and a potential therapeutic target for treating contractile dysfunction in heart failure. Mimicking the structural dynamics of phosphorylated cMyBP-C by small-molecule drug binding could lead to therapies that modulate cMyBP-C conformational states, and thereby function, to improve contractility. We have developed a human cMyBP-C biosensor capable of detecting intramolecular structural changes due to phosphorylation and mutation. Using site-directed mutagenesis and time-resolved fluorescence resonance energy transfer (TR-FRET), we substituted cysteines in cMyBP-C N-terminal domains C0 through C2 (C0-C2) for thiol-reactive fluorescent probe labeling to examine C0-C2 structure. We identified a cysteine pair that upon donor-acceptor labeling reports phosphorylation-sensitive structural changes between the C1 domain and the tri-helix bundle of the M-domain that links C1 to C2. Phosphorylation reduced FRET efficiency by ~18%, corresponding to a ~11% increase in the distance between probes and a ~30% increase in disorder between them. The magnitude and precision of phosphorylation-mediated TR-FRET changes, as quantified by the Z'-factor, demonstrate the assay's potential for structure-based high-throughput screening of compounds for cMyBP-C-targeted therapies to improve cardiac performance in heart failure. Additionally, by probing C1's spatial positioning relative to the tri-helix bundle, these findings provide new molecular insight into the structural dynamics of phosphoregulation as well as mutations in cMyBP-C. Biosensor sensitivity to disease-relevant mutations in C0-C2 was demonstrated by examination of the hypertrophic cardiomyopathy mutation R282W. The results presented here support a screening platform to identify small molecules that regulate N-terminal cMyBP-C conformational states.

The ENHANCE-AF clinical trial to evaluate an atrial fibrillation shared decision-making pathway: Rationale and study design.

INTRODUCTION: Shared decision making (SDM) may result in treatment plans that best reflect the goals and wishes of patients, increasing patient satisfaction with the decision-making process. There is a knowledge gap to support the use of decision aids in SDM for anticoagulation therapy in patients with atrial fibrillation (AF). We describe the development and testing of a new decision aid, including a multicenter, randomized, controlled, 2-arm, open-label ENHANCE-AF clinical trial (Engaging Patients to Help Achieve Increased Patient Choice and Engagement for AF Stroke Prevention) to evaluate its effectiveness in 1,200 participants. METHODS: Participants will be randomized to either usual care or to a SDM pathway incorporating a digital tool designed to simplify the complex concepts surrounding AF in conjunction with a clinician tool and a non-clinician navigator to guide the participants through each step of the tool. The participant-determined primary outcome for this study is the Decisional Conflict Scale, measured at 1 month after the index visit during which a decision was made regarding anticoagulation use. Secondary outcomes at both 1 and 6 months will include other decision making related scales as well as participant and clinician satisfaction, oral anticoagulation adherence, and a composite rate of major bleeding, death, stroke, or transient ischemic attack. The study will be conducted at four sites selected for their ability to enroll participants of varying racial and ethnic backgrounds, health literacy, and language skills. Participants will be followed in the study for 6 months. CONCLUSIONS: The results of the ENHANCE-AF trial will determine whether a decision aid facilitates high quality shared decision making in anticoagulation discussions for stroke reduction in AF. An improved shared decision-making experience may allow patients to make decisions better aligned with their personal values and preferences, while improving overall AF care.

Bayesian network meta-analysis comparing cryoablation, radiofrequency ablation, and antiarrhythmic drugs as initial therapies for atrial fibrillation.

BACKGROUND: Antiarrhythmic drugs (AADs) and catheter ablation are first line treatments of paroxysmal atrial fibrillation (PAF), however, there exists a paucity of data regarding the potential benefit of different catheter ablation technologies versus AADs as an early rhythm strategy. OBJECTIVE: To assess the safety and efficacy of cryoablation versus radiofrequency ablation (RFA) versus AADs as a first line therapy of PAF. METHODS: MEDLINE, Embase, Scopus and CENTRAL were searched to retrieve randomized clinical trials (RCTs) comparing cryoablation, RFA or AADs to one another as first line therapies for atrial fibrillation (AF). The primary outcome was overall freedom from arrhythmia recurrence (AF, atrial flutter [AFL], atrial tachycardia). Secondary outcomes included freedom from symptomatic arrhythmia recurrence, hospitalization, and serious adverse events. A random-effects Bayesian network meta-analysis was used to calculate odds ratios (OR) and 95% credible intervals (CrI). RESULTS: Six RCTs (N = 1212) met the inclusion criteria (605 AADs, 365 Cryoablation, and 245 RFA). Compared with AADs, overall recurrence was reduced with RFA (OR: 0.31; 95% CrI: 0.10-0.71) and cryoablation (OR: 0.39; 95% CrI: 0.16-1.00). Comparing ablation (cryoablation and RFA) with AADs in respect to freedom from symptomatic AF recurrence, neither cryoablation (OR: 0.35; 95% CrI: 0.06-1.96) nor RFA (OR: 0.34; 95% CrI: 0.07-1.27) resulted in statistically significant reductions individually compared to AADs, though pooled ablation with both technologies showed lower odds of arrhythmia recurrence (OR: 0.35; 95% CrI: 0.13-0.79). In terms of serious adverse events rates, neither cryoablation (OR: 0.77; 95% CrI: 0.44-1.39) nor RFA (OR: 1.45; 95% CrI: 0.67-3.23) were significantly different to AADs. RFA resulted in a statistically significant reduction in hospitalizations compared to AAD (OR: 0.08; 95% CrI: 0.01-0.99), whereas cryoablation did not (OR: 0.77; 95% CrI: 0.44-1.39). The surface under the cumulative ranking curve showed RFA to be the most effective treatment at reducing overall rates of recurrence, symptomatic recurrence and hospitalizations; whereas cryoablation was most likely to reduce serious adverse events. CONCLUSION: Cryoablation and RFA are both effective and safe first line therapies for AF compared to AADs, with RFA being the most effective at reducing recurrences.

Economics and outcomes of sotalol in-patient dosing approaches in patients with atrial fibrillation.

INTRODUCTION: There exists variability in the administration of in-patient sotalol therapy for symptomatic atrial fibrillation (AF). The impact of this variability on patient in-hospital and 30-day posthospitalization costs and outcomes is not known. Also, the cost impact of intravenous sotalol, which can accelerate drug loading to therapeutic levels, is unknown. METHODS: One hundred and thirty-three AF patients admitted for oral sotalol initiation at an Intermountain Healthcare Hospital from January 2017 to December 2018 were included. Patient and dosing characteristics were described descriptively and the impact of dosing schedule was correlated with daily hospital costs/clinical outcomes during the index hospitalization and for 30 days. The Centers for Medicare and Medicaid Services reimbursement for 3-day sotalol initiation is $9263.51. Projections of cost savings were made considering a 1-day load using intravenous sotalol that costs $2500.00 to administer. RESULTS: The average age was 70.3 ± 12.3 years and 60.2% were male with comorbidities of hypertension (83%), diabetes (36%), and coronary artery disease (53%). The mean ejection fraction was 59.9 ± 7.8% and the median corrected QT interval was 453.7 ± 37.6 ms before sotalol dosing. No ventricular arrhythmias developed, but bradycardia (<60 bpm) was observed in 37.6% of patients. The average length of stay was 3.9 ± 4.6 (median: 2.2) days. Postdischarge outcomes and rehospitalization rates stratified by length of stay were similar. The cost per day was estimated at $2931.55 (1. $2931.55, 2. $5863.10, 3. $8794.65, 4. $11 726.20). CONCLUSIONS: In-patient oral sotalol dosing is markedly variable and results in the potential of both cost gain and loss to a hospital. In consideration of estimated costs, there is the potential for $871.55 cost savings compared to a 2-day oral load and $3803.10 compared to a 3-day oral load.

Ablation versus medication as initial therapy for paroxysmal atrial fibrillation: An updated meta-analysis of randomized controlled trials.

BACKGROUND: Recent randomized controlled trials (RCTs) suggest that ablation is superior to antiarrhythmic drugs (AADs) as an initial therapy for paroxysmal atrial fibrillation (pAF) to prevent arrhythmia recurrences. We performed an updated meta-analysis of RCTs, to include recent data from cryoballoon-based ablation and to compare arrhythmia-free survival and adverse events between ablation and AADs. METHODS: We searched MEDLINE and EMBASE from inception to December 2020. We included RCT comparing patients with pAF undergoing ablation or receiving AADs as an initial therapy. We combined data using the random-effects model to calculate hazards ratio (HR) for arrhythmia-free survival and odds ratio (OR) for adverse events. RESULTS: Five studies from 2005 to 2020 involving 985 patients were included (495 patients and 490 patients underwent ablation and medication as initial therapy, respectively). Patients who underwent ablation had higher freedom from atrial tachyarrhythmias (ATs) during the 12-24 months follow-up period (pooled HR = 0.48, 95% CI: 0.40-0.59, P < .001). In a subgroup analysis of ablation method used, both cryoablation group (pooled HR = 0.49, 95% CI: 0.38-0.64, P < .001) and radiofrequency ablation group (pooled HR = 0.47, 95%CI: 0.35-0.64, P < .001) showed reduction in AT recurrence compared with AAD group. There were no differences in adverse events including cerebrovascular accident, pericardial effusion or tamponade, pulmonary vein stenosis, acute coronary syndrome, deep vein thrombosis and pulmonary embolism, and bradycardia requiring a pacemaker. CONCLUSION: Catheter ablation (both cryoablation and radiofrequency ablation) is superior to AAD as an initial therapy for pAF in efficacy for reducing AT recurrences without a compromise in adverse events.

Absent or Mild Coronary Calcium Predicts Low-Risk Stress Test Results and Outcomes in Patients Considered for Flecainide Therapy.

BACKGROUND: Flecainide is a useful antiarrhythmic for atrial fibrillation (AF). However, because of ventricular proarrhythmia risk, a history of myocardial infarction (MI) or coronary artery disease (CAD) is a flecainide exclusion, and stress testing is used to exclude ischemia. We assessed whether absent/mild coronary artery calcium (CAC) can supplement or avoid the need for stress testing. METHODS: We assessed ischemic burden using regadenoson Rb-82 PET/CT in 1372 AF patients ≥50 years old without symptoms or signs of clinical CAD. CAC was determined qualitatively by low dose attenuation computed tomography (CT) (n = 816) or by quantitative CT (n = 556). Ischemic burden and clinical outcomes were compared by CAC burden. RESULTS: Patients with CAC absent or mild (n = 766, 57.2%) were younger, more frequently female, and had higher BMI but lower rates of diabetes, hypertension, and dyslipidemia. Average ischemic burden was lower in CAC-absent/mild patients, and CAC-absent/mild patients showed greater coronary flow reserve, had fewer referrals for coronary angiography, and less often had obstructive CAD. Revascularization at 90 days was lower, and the rate of longer-term major adverse cardiovascular events was favorable. CONCLUSIONS: An easily administered, inexpensive, low radiation CAC scan can identify a subset of flecainide candidates with a low ischemic burden on PET stress testing that rarely needs coronary angiography/intervention and has favorable outcomes. Absent or mild CAC-burden combined with other clinical information may avoid or complement routine stress testing. However, additional, ideally randomized and multicenter trials are indicated to confirm these findings before replacing stress testing with CAC screening in selecting patients for flecainide therapy in clinical practice.

Cardiac myosin-binding protein C interaction with actin is inhibited by compounds identified in a high-throughput fluorescence lifetime screen.

Cardiac myosin-binding protein C (cMyBP-C) interacts with actin and myosin to modulate cardiac muscle contractility. These interactions are disfavored by cMyBP-C phosphorylation. Heart failure patients often display decreased cMyBP-C phosphorylation, and phosphorylation in model systems has been shown to be cardioprotective against heart failure. Therefore, cMyBP-C is a potential target for heart failure drugs that mimic phosphorylation or perturb its interactions with actin/myosin. Here we have used a novel fluorescence lifetime-based assay to identify small-molecule inhibitors of actin-cMyBP-C binding. Actin was labeled with a fluorescent dye (Alexa Fluor 568, AF568) near its cMyBP-C binding sites; when combined with the cMyBP-C N-terminal fragment, C0-C2, the fluorescence lifetime of AF568-actin decreases. Using this reduction in lifetime as a readout of actin binding, a high-throughput screen of a 1280-compound library identified three reproducible hit compounds (suramin, NF023, and aurintricarboxylic acid) that reduced C0-C2 binding to actin in the micromolar range. Binding of phosphorylated C0-C2 was also blocked by these compounds. That they specifically block binding was confirmed by an actin-C0-C2 time-resolved FRET (TR-FRET) binding assay. Isothermal titration calorimetry (ITC) and transient phosphorescence anisotropy (TPA) confirmed that these compounds bind to cMyBP-C, but not to actin. TPA results were also consistent with these compounds inhibiting C0-C2 binding to actin. We conclude that the actin-cMyBP-C fluorescence lifetime assay permits detection of pharmacologically active compounds that affect cMyBP-C-actin binding. We now have, for the first time, a validated high-throughput screen focused on cMyBP-C, a regulator of cardiac muscle contractility and known key factor in heart failure.

A high-throughput fluorescence lifetime-based assay to detect binding of myosin-binding protein C to F-actin.

Binding properties of actin-binding proteins are typically evaluated by cosedimentation assays. However, this method is time-consuming, involves multiple steps, and has a limited throughput. These shortcomings preclude its use in screening for drugs that modulate actin-binding proteins relevant to human disease. To develop a simple, quantitative, and scalable F-actin-binding assay, we attached fluorescent probes to actin's Cys-374 and assessed changes in fluorescence lifetime upon binding to the N-terminal region (domains C0-C2) of human cardiac myosin-binding protein C (cMyBP-C). The lifetime of all five probes tested decreased upon incubation with cMyBP-C C0-C2, as measured by time-resolved fluorescence (TR-F), with IAEDANS being the most sensitive probe that yielded the smallest errors. The TR-F assay was compared with cosedimentation to evaluate in vitro changes in binding to actin and actin-tropomyosin arising from cMyBP-C mutations associated with hypertrophic cardiomyopathy (HCM) and tropomyosin binding. Lifetime changes of labeled actin with added C0-C2 were consistent with cosedimentation results. The HCM mutation L352P was confirmed to enhance actin binding, whereas PKA phosphorylation reduced binding. The HCM mutation R282W, predicted to disrupt a PKA recognition sequence, led to deficits in C0-C2 phosphorylation and altered binding. Lastly, C0-C2 binding was found to be enhanced by tropomyosin and binding capacity to be altered by mutations in a tropomyosin-binding region. These findings suggest that the TR-F assay is suitable for rapidly and accurately determining quantitative binding and for screening physiological conditions and compounds that affect cMyBP-C binding to F-actin for therapeutic discovery.

Effects of electrical biostimulation and silver ions on porcine fibroblast cells.

The medical applications of electrical biostimulation and silver ions have been evaluated in laboratory experiments and clinical studies for more than two decades. Their effects on preventing infection and promoting wound healing have been described. However, little is known about the role of electrical biostimulation and/or silver ion on changes in cellular transcriptome dynamics. To our knowledge, few studies have been conducted to investigate the potential of electrical biostimulation and silver ions in cell reprogramming. Besides, it is essential to assess any possible adverse effects or potential benefits of the silver ions on mammalian cells to address its safety concerns and to improve silver medical products. In this study, we investigated transcriptomic changes in porcine fibroblast cells in response to electrical biostimulation in the presence of silver ions. Exposed cells presented distinct morphological changes after treatment, which was mainly due to the exposure of silver ions rather than the electrical current itself. Gene expression analyses suggested that electrical biostimulation and silver ions did not increase the expression of pluripotency genes. Interestingly, a set of genes related to cellular metabolic processes were differentially expressed after cells were exposed to electrically generated silver ions for 21 hours. We found that 2.00 mg/L of electrically generated silver ion caused an increase of ATP generation and an increase of the total pool of NAD+ and NADH, while ROS production did not change. Aside from toxic effects, the results reported herein demonstrate the alternative effects of silver ions on mammalian cells, especially an oxidative phosphorylation burst. To our knowledge, this response of mammalian cells to silver ions has not been described previously. Although the function of this burst is not understood, it may lead to alterations in cellular activities such as metabolic remodeling and cell reprogramming, and/or serve an as-yet unknown function in neutralization or detoxification of the silver ions within the cells.