Sympathetic response following unannounced loss of balance during walking in young adults: laboratory study.

An unannounced balance loss during walking, i.e., balance perturbation, is a stressful event, which changes the activity of the sympathetic nervous system (SNS). We examined SNS response to unannounced balance perturbation during walking, simulating real-life condition of balance loss. We asked: do laboratory-induced unannounced balance losses during walking cause a sympathetic response, and-if so-does it habituate after a series of perturbations? Thirty-four young adults underwent a series of six successive unannounced balance perturbations while walking on a treadmill. Sympathetic activity was monitored continuously using electrodermal activity and compared before and immediately after each unannounced perturbation. All perturbations elicited a significant increase of electrodermal activity (P < 0.001), indicating a phasic increase in the sympathetic drive. The relative phasic increase of electrodermal activity caused by the first perturbation was significantly higher than the last perturbation (P < 0.05). Three different types of electrodermal activity behavior were observed: steady-level tonic SNS activity, increased SNS activity, and decreased SNS activity. Balance loss during walking triggers phasic SNS response, this response habituates after a series of unannounced balance perturbations. In addition, three distinct patterns of tonic sympathetic activity may imply variations in the ability of the SNS response to habituate across individuals.NEW & NOTEWORTHY Up to date, the literature typically provides information about sympathetic nervous system activity and relatively static balance. We believe that exposing participants to a balance loss during walking, i.e., unexpected perturbation, provides a more ecologically valid situation to measure sympathetic nervous system response; this provides new and vital knowledge that can have a significant impact and understanding of how the SNS responds to a loss of balance in a real-life situation.

An objective tool for quantifying atrial fibrillation substrate in rats.

The utility of rodents for research related to atrial fibrillation (AF) is growing exponentially. However, the obtained arrhythmic waveforms are often mixed with ventricular signals and the ability to analyze regularity and complexity of such events is limited. Recently, we introduced an implantable quadripolar electrode adapted for advanced atrial electrophysiology in ambulatory rats. Notably, we have found that the implantation itself leads to progressive atrial remodeling, presumably because of mechanical loading of the atria. In the present study, we developed an algorithm to clean the atrial signals from ventricular mixing and thereafter quantify the AF substrate in an objective manner based on waveform complexity. Rats were sequentially examined 1-, 4-, and 8-wk postelectrode implantation using a standard AF triggering protocol. Preburst ventricular mixing was sampled and automatically subtracted based on QRS detection in the ECG. Thereafter, the "pure" atrial signals were analyzed by Lempel-Ziv complexity algorithm and a complexity ratio (CR) was defined for each signal by normalizing the postburst to the preburst values. Receiver operating characteristic (ROC) curve analysis indicated an optimal CR cutoff of 1.236 that detected irregular arrhythmic events with high sensitivity (94.5%), specificity (93.1%), and area under the curve (AUC) (0.96, 95% confidence interval, 0.945-0.976). Automated and unbiased analysis indicated a gradual increase in signal complexity over time with augmentation of high frequencies in power spectrum analysis. Our findings indicate that CR algorithm detects irregularity in a highly efficient manner and can also detect the atrial remodeling induced by electrode implantation. Thus, CR analysis can strongly facilitate standardized AF research in rodents.NEW & NOTEWORTHY Rodents are increasingly used in AF research. However, because of technical difficulties including atrial waveform mixing by ventricular signals, most studies do not discriminate between irregular (i.e., AF) and regular atrial arrhythmias. Here, we develop an unbiased computerized tool to "pure" the atrial signals from ventricular mixing and thereafter analyze AF substrate based on the level of irregularity in an objective manner. This novel tool can facilitate standardized AF research in rodents.

The roles of personal interview and cognitive abilities at admission to medical school in predicting performance of medical students in their internal medicine sub-internship.

BACKGROUND: The medical school admission process is complicated, perhaps reflecting unresolved debates concerning the most important skills necessary to become an ideal physician. The Goldman Medical School at Ben-Gurion University in Israel is known for placing great emphasis on the personal attributes of candidates in addition to their academic excellence. To this end, 1-h consecutive interviews are embedded in the admission process. This study aims to determine whether there is an association between candidates' personal interview ratings and the ratings assigned to these students at the conclusion of their 6th year internal medicine sub-internship. METHODS: Our study sample included 136 students who were admitted to the medical school in 2015, and who completed their 6th year internal medicine sub-internship in 2019-2020. Our data were derived from the admissions information for each candidate and from structured interviews concerning medical competence and personal traits, which were completed by medical personnel who were in contact with these students during their clinical rounds. RESULTS: Higher interview ratings of candidates during the admission process were associated with a higher probability that students would be evaluated as top-rated internists 6 years later (Odds Ratio (OR) = 9.4, p-value = 0.049), independent of gender (OR for male vs female = 0.2, p-value = 0.025) and age (OR = 1.3 per each year, p-value = 0.115). Although significant, the numeric difference in interview rating was relatively small (median 9.5 and 9.4 for top-rated and not top-rated internists, respectively). CONCLUSIONS: Our study shows that high personal interview ratings assigned to candidates as part of the medical school admission process are predictive of high performance ratings of students after they complete their 6th year internal medicine sub-internships. These findings demonstrate the value and importance of using semi-structured personal interviews in the medical school admission process.

Shifting from vitamin K antagonists to non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation: predictors, patterns and temporal trends.

BACKGROUND: Non-Vitamin K antagonist oral anticoagulants (NOACs) emerged as an alternative with comparable or superior efficacy and safety to vitamin K antagonists (VKAs) for stroke prevention in patients with non-valvular atrial fibrillation (AF). OBJECTIVES: The aim of the current study was to investigate the patterns, predictors, timelines and temporal trends of shifting from VKAs to NOACs. METHODS: In this retrospective observational study, the computerized database of a large healthcare provider in Israel, Maccabi Healthcare Services, was searched to identify patients with AF for whom either a VKA or NOAC was prescribed between 2012 and 2015. Time from diagnosis to therapy initiation and to shifting between therapies was evaluated. RESULTS: Out of 6987 eligible AF incident patients, 2338 (33.4%) initiated treatment with a VKA and 2221 (31.7%) with a NOAC. In addition, 5259 prevalent patients were analyzed. During the study period, NOAC prescriptions proportion among the newly diagnosed cases increased from 32 to 68.4% (p for trend <  0.001). The median time from diagnosis to first dispensing was greater in NOAC than VKA and decreased among patients treated with NOAC during the study period (2012: 1.9 and 0.3 months, 2015: 0.7 and 0.2 months, respectively). During follow-up, 3737 (49%) patients (54.3% and 47.1% of the incident and prevalent cases, respectively), shifted from a VKA to a NOAC, after a median of 22 months and 39 months in the incident and prevalent cases, respectively, decreasing throughout the study period. Female gender, younger age, southern district, higher CHADS2 and CHA2DS2-VASC score, non-smoking, and treatment with antiplatelets were associated with a greater likelihood for therapy shift. Shifting from a NOAC to a VKA decreased over time from 8 to 4.5% in 2012 to 0.5% and 0.7% in 2015 in the incident and prevalent groups, p <  0.001 respectively. CONCLUSIONS: Shifting from VKA to NOAC occurred in 50% of the cases, more frequently among incident cases, and younger patients with greater stroke risk. Shifting from a NOAC to a VKA was much less frequent, yet it occurred more often in incident cases and decreased over time. A socially and economically sensitive program to optimize the initiation of OAC therapy upon diagnosis is warranted.

"Preventive" pacing in patients with tachy-brady syndrome (TBS): Confirming a common practice.

AIMS: Many tachy-brady syndrome (TBS) patients, are implanted a permanent pacemaker (PPM) to allow continuation of anti-arrhythmic drug (AAD) therapy to maintain sinus rhythm. Many of these PPM's are implanted as a preventive measure, in absence of symptomatic bradycardia. Our primary aim was to evaluate pacing use among these patients and find predictors for PPM use. Our secondary aim was to appreciate the portion of these patients who progress to permanent atrial fibrillation (AF). METHODS: Retrospective study of TBS patients implanted a PPM as preventive measure, dividing cases into defined categories regarding highest percent atrial and ventricular pacing documented in PPM clinic visits during 3 year follow-up (F/U) period. Patients' baseline characteristics and AAD therapy were compared between cases with a major (>90%) pacing use and cases with <90% pacing use to find predictors for pacing use. Multivariable logistic regression was applied to identify independent variables associated with major pacing use. RESULTS: Our study included 119 TBS patients. Most (86.5%) TBS patients had a moderate (>50%) pacing use and 58% had a major pacing use. Significant association was found between pre-implant severe sinus bradycardia (<40 bpm), first degree atrioventricular block and amiodarone treatment to major pacing use on univariate analysis and severe sinus bradycardia was significantly associated with major pacing on multivariate analysis as well. Only minority (16.8%) of TBS patients progressed to permanent AF during the study F/U period. CONCLUSION: Our study reveals most TBS patients succeed to maintain sinus rhythm using an AAD with a significant pacing use, suggesting preventive PPM implantation might be advantageous in these cases. Pre-implant severe sinus bradycardia (<40 bpm) is a possible predictor for major pacing use in this population.

Cardiopoietic cell therapy for advanced ischaemic heart failure: results at 39 weeks of the prospective, randomized, double blind, sham-controlled CHART-1 clinical trial.

AIMS: Cardiopoietic cells, produced through cardiogenic conditioning of patients' mesenchymal stem cells, have shown preliminary efficacy. The Congestive Heart Failure Cardiopoietic Regenerative Therapy (CHART-1) trial aimed to validate cardiopoiesis-based biotherapy in a larger heart failure cohort. METHODS AND RESULTS: This multinational, randomized, double-blind, sham-controlled study was conducted in 39 hospitals. Patients with symptomatic ischaemic heart failure on guideline-directed therapy (n = 484) were screened; n = 348 underwent bone marrow harvest and mesenchymal stem cell expansion. Those achieving > 24 million mesenchymal stem cells (n = 315) were randomized to cardiopoietic cells delivered endomyocardially with a retention-enhanced catheter (n = 157) or sham procedure (n = 158). Procedures were performed as randomized in 271 patients (n = 120 cardiopoietic cells, n = 151 sham). The primary efficacy endpoint was a Finkelstein-Schoenfeld hierarchical composite (all-cause mortality, worsening heart failure, Minnesota Living with Heart Failure Questionnaire score, 6-min walk distance, left ventricular end-systolic volume, and ejection fraction) at 39 weeks. The primary outcome was neutral (Mann-Whitney estimator 0.54, 95% confidence interval [CI] 0.47-0.61 [value > 0.5 favours cell treatment], P = 0.27). Exploratory analyses suggested a benefit of cell treatment on the primary composite in patients with baseline left ventricular end-diastolic volume 200-370 mL (60% of patients) (Mann-Whitney estimator 0.61, 95% CI 0.52-0.70, P = 0.015). No difference was observed in serious adverse events. One (0.9%) cardiopoietic cell patient and 9 (5.4%) sham patients experienced aborted or sudden cardiac death. CONCLUSION: The primary endpoint was neutral, with safety demonstrated across the cohort. Further evaluation of cardiopoietic cell therapy in patients with elevated end-diastolic volume is warranted.

Ablation-Induced Change in the Course of Fascicular Tachycardia.

BACKGROUND: Multiform fascicular tachycardia (FT) was recently described as a ventricular tachycardia (VT) that has a reentrant mechanism using multiple fascicular branches and produces alternate fascicular VT forms. Ablating the respective fascicle may cause a change in the reentrant circuit resulting in a change in morphology. Ablation of the septal fascicle is crucial for successful treatment. OBJECTIVES: To describe four cases of FT in which ablation induced a change in QRS morphologies and aggravated clinical course. METHODS: Four out of 57 consecutive FT cases at three institutions were retrospectively analyzed and found to involve multiform FT. These cases underwent electrophysiological study, fascicular potential mapping, and electroanatomical mapping. All patients initially had FT with right bundle branch block (RBBB) and superior axis morphology. RESULTS: Radiofrequency catheter ablation (RFCA) targeting the distal left posterior fascicle (LPF) resulted in a second VT with an RBBB-inferior axis morphology that sometimes became faster and/or incessant and/or verapamil-refractory in characteristics. RFCA in the upper septum abolished the second VT with no complications and uneventful long-term follow-up. CONCLUSIONS: The change in FT morphology during ablation may be associated with a change in clinical course when shifting from one route to another and may aggravate symptoms. Targeting of the proximal conduction system (such as bifurcation, LPF, left anterior fascicle, high septal/auxiliary pathway) may serve to solve this problem.

Morbidity and mortality with cardiac resynchronization therapy with pacing vs. with defibrillation in octogenarian patients in a real-world setting.

AIMS: Cardiac resynchronization therapy (CRT) with a defibrillator (CRT-D) has downsides of high cost and inappropriate shocks compared to CRT without a defibrillator (CRT-P). Recent data suggest that the survival benefit of implantable cardioverter defibrillator (ICD) therapy is attenuated in the older age group. We hypothesized that, among octogenarians eligible for cardiac resynchronization therapy, CRT-P confers similar morbidity and mortality benefits as CRT-D. METHODS AND RESULTS: We compared morbidity and mortality outcomes between consecutive octogenarian patients eligible for CRT therapy who underwent CRT-P implantation at Barzilai MC (n = 142) vs. those implanted with CRT-D for primary prevention indication who were prospectively enrolled in the Israeli ICD Registry (n = 104). Among the 246 study patients, mean age was 84 ± 3 years, 74% were males, and 66% had ischaemic cardiomyopathy. Kaplan-Meier survival analysis showed that at 5 years of follow-up the rate of all-cause mortality was 43% in CRT-P vs. 57% in the CRT-D group [log-rank P = 0.13; adjusted hazard ratio (HR) = 0.79, 95% CI 0.46-1.35, P = 0.37]. Kaplan-Meier analysis also showed no significant difference in the rates of the combined endpoint of heart failure or death (46 vs. 60%, respectively, log-rank P = 0.36; adjusted HR was 0.85, 95% CI 0.51-1.44, P = 0.55). A Cox proportional hazard with competing risk model showed that re-hospitalizations for cardiac cause were not different for the two groups (adjusted HR 1.35, 95% CI 0.7-2.6, P = 0.37). CONCLUSION: Our data suggest that, in octogenarians with systolic heart failure, CRT-P therapy is associated with similar morbidity and mortality outcomes as CRT-D therapy.

Safety, efficacy, and clinical applicability of pulmonary vein isolation with circular multi-electrode ablation systems: PVAC® vs. nMARQ™ for atrial fibrillation ablation.

AIMS: We compare our experience with available circular multi-electrode catheters for atrial fibrillation (AF) ablation: PVAC(®), a phased radiofrequency system, and nMARQ™, an irrigated tip-CARTO-based technology. METHODS AND RESULTS: Prospective observational study of 175 consecutive patients with follow-up duration of at least 5 months who underwent pulmonary vein isolation (PVI) for symptomatic AF using PVAC(®) (n = 93, age 61.4 ± 9.8 years; 60% male, 13% persistent AF) vs. nMARQ™ (n = 82, age 63.2 ± 10.6 years; 67% male, 24% persistent AF). Procedure and radiation times were 94 ± 27 and 33 ± 13 min for PVAC(®) and 81 ± 18 and 30 ± 8.5 for nMARQ™ (P = 0.0008 and P = 0.18), respectively. The number of applications and the total burning time (min) were 20 ± 7 and 19 ± 6.7 for PVAC(®) and 16 ± 5.6 and 11 ± 4 for nMARQ™ (P < 0.0001 for both), respectively. In two nMARQ™ patients with small atria and pulmonary veins (PVs) and in two PVAC(®) patients with large PVs, the procedure failed; switching to the alternative technology was successful. Acute success rate was 97% for PVAC(®) and 95% for nMARQ™. There was one tamponade in nMARQ™ group and non-significant different minor complications for both techniques. One-year freedom from AF was 79 and 80.7% with PVAC(®) vs. nMARQ™, after one PVI, and 88 vs. 87.7% after two PVIs. CONCLUSION: Both technologies have short procedure and fluoroscopy times, comparable complication rates, and comparable acute and 1-year success rates. The number of applications and total procedure and burning times were shorter with nMARQ™. nMARQ™ was more suitable for larger atria and PVs. Thus, a patient-based pre-ablation anatomy definition is probably warranted for appropriate selection of technology type.

Rotational method simplifies 3-dimensional measurement of left atrial appendage dimensions during transesophageal echocardiography.

BACKGROUND: Not all echo laboratories have the capability of measuring direct online 3D images, but do have the capability of turning 3D images into 2D ones "online" for bedside measurements. Thus, we hypothesized that a simple and rapid rotation of the sagittal view (green box, x-plane) that shows all needed left atrial appendage (LAA) number of lobes, orifice area, maximal and minimal diameters and depth parameters on the 3D transesophageal echocardiography (3DTEE) image and LAA measurements after turning the images into 2D (Rotational 3DTEE/"Yosefy Rotation") is as accurate as the direct measurement on real-time-3D image (RT3DTEE). METHODS: We prospectively studied 41 consecutive patients who underwent a routine TEE exam, using QLAB 10 Application on EPIQ7 and IE33 3D-Echo machine (BORTHEL Phillips) between 01/2013 and 12/2015. All patients underwent 64-slice CT before pulmonary vein isolation or for workup of pulmonary embolism. LAA measurements were compared between RT3DTEE and Rotational 3DTEE versus CT. RESULTS: Rotational 3DTEE measurements of LAA were not statistically different from RT3DTEE and from CT regarding: number of lobes (1.6 ± 0.7, 1.6 ± 0.6, and 1.4 ± 0.6, respectively, p = NS for all); internal area of orifice (3.1 ± 0.6, 3.0 ± 0.7, and 3.3 ± 1.5 cm(2), respectively, p = NS for all); maximal LAA diameter (24.8 ± 4.5, 24.6 ± 5.0, and 24.9 ± 5.8 mm, respectively, p = NS for all); minimal LAA diameter (16.4 ± 3.4, 16.7 ± 3.3, and 17.0 ± 4.4 mm, respectively, p = NS for all), and LAA depth (20.0 ± 2.1, 19.8 ± 2.2, and 21.7 ± 6.9 mm, respectively, p = NS for all). CONCLUSION: Rotational 3DTEE method for assessing LAA is a simple, rapid and feasible method that has accuracy similar to that of RT3DTEE and CT. Thus, rotational 3DTEE ("Yosefy rotation") may facilitate LAA closure procedure by choosing the appropriate device size.

A New Method for Direct Three-Dimensional Measurement of Left Atrial Appendage Dimensions during Transesophageal Echocardiography.

AIMS: Currently, two-dimensional transesophageal echocardiography (2DTEE) at a cut-plane angulation of 135° is the recommended method to size maximal left atrial appendage (LAA) orifice diameter before introducing a percutaneous LAA closure device. We compared real time three-dimensional TEE (RT3DTEE) and 2DTEE for measuring LAA dimensions versus computed tomography (CT) as gold standard. METHODS AND RESULTS: We prospectively studied 30 consecutive patients who underwent a routine TEE examination, using QLAB 10.0 Application on EPIQ7 iE33 3D echo machine between December 2012 and December 2013. All patients underwent 64-slice CT before pulmonary vein isolation or for workup of pulmonary embolism. LAA measurements were compared between 135 2DTEE and RT3DTEE. Results were compared with CT measurements. Using RT3DTEE, larger LAA diameters were measured versus 2DTEE (23.5 ± 3.9 vs. 24.5 ± 4.7 mm). In seven patients (23.3%), the measurements in 135° 2DTEE were smaller than the cut-plane angulation with maximal orifice diameter. RT3DTEE measurements of LAA were not different from CT regarding number of lobes, area of orifice, and maximal diameter. LAA volume could not be measured directly using RT3DTEE. No difference was found between LAA depth using RT3DTEE (19.5 ± 2.3 mm) vs. CT (19.6 ± 2.3, P = NS) and 2DTEE (19.4 ± 2.2 mm) vs. CT (P = NS). However, RT3DTEE (24.5 ± 4.7 mm) vs. CT (24.6 ± 5, P = NS) was more accurate in measuring maximal LAA diameter compared to 2DTEE (23.5 ± 3.9 mm) vs. CT (P < 0.01). CONCLUSION: RT3DTEE method is more accurate than 2DTEE for assessment of maximal LAA orifice diameter. Bedsides, RT3DTEE LAA measurements are not statistically different from CT. Thus, RT3DTEE may facilitate LAA closure procedure by choosing the appropriate device size.

Implant-based multiparameter telemonitoring of patients with heart failure (IN-TIME): a randomised controlled trial.

BACKGROUND: An increasing number of patients with heart failure receive implantable cardioverter-defibrillators (ICDs) or cardiac resynchronisation defibrillators (CRT-Ds) with telemonitoring function. Early detection of worsening heart failure, or upstream factors predisposing to worsening heart failure, by implant-based telemonitoring might enable pre-emptive intervention and improve outcomes, but the evidence is weak. We investigated this possibility in IN-TIME, a clinical trial. METHODS: We did this randomised, controlled trial at 36 tertiary clinical centres and hospitals in Australia, Europe, and Israel. We enrolled patients with chronic heart failure, NYHA class II-III symptoms, ejection fraction of no more than 35%, optimal drug treatment, no permanent atrial fibrillation, and a recent dual-chamber ICD or CRT-D implantation. After a 1 month run-in phase, patients were randomly assigned (1:1) to either automatic, daily, implant-based, multiparameter telemonitoring in addition to standard care or standard care without telemonitoring. Investigators were not masked to treatment allocation. Patients were masked to allocation unless they were contacted because of telemonitoring findings. Follow-up was 1 year. The primary outcome measure was a composite clinical score combining all-cause death, overnight hospital admission for heart failure, change in NYHA class, and change in patient global self-assessment, for the intention-to-treat population. The trial is registered with ClinicalTrials.gov, number NCT00538356. FINDINGS: We enrolled 716 patients, of whom 664 were randomly assigned (333 to telemonitoring, 331 to control). Mean age was 65·5 years and mean ejection fraction was 26%. 285 (43%) of patients had NYHA functional class II and 378 (57%) had NYHA class III. Most patients received CRT-Ds (390; 58·7%). At 1 year, 63 (18·9%) of 333 patients in the telemonitoring group versus 90 (27·2%) of 331 in the control group (p=0·013) had worsened composite score (odds ratio 0·63, 95% CI 0·43-0·90). Ten versus 27 patients died during follow-up. INTERPRETATION: Automatic, daily, implant-based, multiparameter telemonitoring can significantly improve clinical outcomes for patients with heart failure. Such telemonitoring is feasible and should be used in clinical practice. FUNDING: Biotronik SE & Co. KG.

Intravenous methylphenidate: an unusual way to provoke ST-elevation myocardial infarction.

Acute ST-T elevation is a sign of myocardial ischemia or infarction usually due to coronary artery atherosclerosis or coronary spasm. Coronary spasm may be spontaneous or can occur as a result of a drug that causes arterial spam. Ritalin, Novartis Pharmaceut. Corporation, USA (methylphenidate hydrochloride), a dopamine reuptake inhibitor,is an oral drug used to treat attention-deficit/hyperactivity disorder and narcolepsy. Sudden deaths, stroke, and myocardial infarction have been reported in adults taking stimulant drugs at usual dose for attention-deficit/hyperactivity disorder [1]. This drug is not supplied as solution for injection [2]. We report here, what we believe to be, the first case report of a 40-year-old male patient who was admitted for acute chest pain and ST-elevation myocardial infarction after intravenous self-injection of Ritalin. His coronary angiogram demonstrated nonobstructive coronary disease.

[New treatments for stroke and thromboembolism prevention in atrial fibrillation].

Atrial fibrillation (AF) is the most common sustained arrhythmia in Western countries (prevalence 1-2%). Patients with AF have a 5-fold increased risk of stroke, and 15%-20% of all strokes are attributable to AF. Moreover, mortality, morbidity and economic burden from stroke complicating AF are particularly high. Thus, preventing stroke and thromboembolism is the cornerstone in AF management, with the vitamin K antagonist (VKA) - warfarin as the leading drug for many years. Although warfarin is effective in stroke reduction, only 55% of eligible patients with AF received it, 28% of patients discontinue it by 1-year, rates of major bleeding are higher that 20% and patients remain in the therapeutic range (INR 2-3) only 58% of the time. Warfarin underuse results from its pharmacological properties including: genetic variability in metabolism, multiple drug and food interactions, unpredictable anticoagulant effects, narrow therapeutic window, and the resulting need for inconvenient monitoring. The combination of aspirin and clopidogrel was found to be less effective than warfarin. Hence, new treatments were recently evaluated for AF-related stroke and thromboembolic prevention including: direct thrombin inhibitors (dabigatran etexilate), oral selective factor Xa inhibitors (rivaroxaban and apixaban), and percutaneous left atrial appendage closure. Some of these drugs have demonstrated promising results in clinical studies, they are convenient to use and do not require monitoring. The downsides are lack of antidotes or specific blood assays to monitor the anticoagulant effect and the need for invasive procedure for installation. Herein, we review the new treatments and the available clinical evidence for their use in AF.

[From treating to curing--new era in the approach to patients with atrial fibrillation].

Atrial fibrillation is the most common arrhythmia and its incidence and prevalence are growing steadily. It causes increased morbidity and mortality, while keeping patients in sinus rhythm was proven to decrease mortality rate. Nevertheless, antiarrhythmic drugs are limited in efficacy and have life-threatening adverse effects, thus neutralizing their benefits. Over the last years, ablation of pulmonary vein antrum has proven to be efficient in treating patients with atrial fibrillation. It has a success rate of 60-93% and overall complication rate of 6%. Recently, new ablation technologies entered the market and there has been improved understanding of the pathogenesis of atrial fibrillation. These improvements have led to better results and lower complication rates for atrial fibrillation ablation as a treatment option. In addition, new data was published regarding ablation treatment in the relatively healthy" elderly population. In the recent European Society of Cardiology (ESC) guidelines, ablation treatment for atrial fibrillation was graded as Class IA for patients who failed one antiarrhythmic drug and as Class IIA for patients who preferred ablation as their first treatment option. The field of atrial fibrillation ablation is evolving rapidly. The novel ablation catheters (the circular ones: PVAC and nMARQ, and the CryoCath balloon catheter) provide better tools for treating atrial fibrillation by reducing procedure time, making it possible to avoid general anesthesia and they are safer for use even in low-volume centers. These developments may enlarge the population that could be treated with ablation. It seems that we are in the middle of a process of change in the concept of treating atrial fibrillation.

INO-8875, a highly selective A1 adenosine receptor agonist: evaluation of chronotropic, dromotropic, and hemodynamic effects in rats.

Selective pharmacological activation of the adenosine 1 receptor (A(1)R) is a promising new approach to achieve a potent block of atrioventricular (A-V)-nodal conduction without significant cardiovascular side effects. The purpose of the present study was to evaluate the cardiovascular profile of INO-8875, a highly selective A(1)R agonist, and to compare its properties with N-[3(R)-tetrahydrofuranyl]-6-aminopurine riboside (CVT-510), which has already been shown to induce negative dromotropic effects with minimal cardiovascular side effects in animals and in clinical studies. Dose-response experiments in the isolated hearts of rats were used to evaluate the functional selectivity of INO-8875 for the slowing of A-V-nodal conduction. Ventilated adult rats were used to study the effects of INO-8875, in vivo, on arterial blood pressure as well as on supraventricular electrophysiology. Ex vivo, INO-8875 (100 nM to 3 µM) progressively prolonged A-V-nodal conduction without reducing left ventricular function or coronary resistance. In vivo, INO-8875 up to a dose of 50 µg/kg did not reduce the carotid arterial blood pressure (n = 4). INO-8875 (1-50 µg/kg) and CVT-510 (20 and 50 µg/kg) both induced a dose-dependent decrease in heart rate and atrial refractoriness, as well as slowing of A-V-nodal conduction. However, compared with CVT-510, the activity of INO-8875 was more pronounced in A-V-nodal function. INO-8875 exhibited a greater duration of action, lasting up to 2.5 hours post dosing, whereas the effects of CVT-510 dissipated over 1 hour. INO-8875 demonstrates functional properties of a highly selective A(1)R agonist. INO-8875 exhibits an increased dromotropic effect and greater duration of action compared with CVT-510.

[Sitting and cardiovascular morbidity and mortality].

Prolonged sitting and sedentary behavior comprises a major part of the modern lifestyle: at work, leisure (watching television, Internet) and commuting/traveling. Studies have shown that adults spend about half of their time at work and even more sitting. Similarly, a significant part of the leisure time is spent doing sedentary activities usually in front of a screen (TV or a computer). However, current recommendations focus on increasing moderate-to-vigorous physical activity with almost no recommendations relating to sedentary activities. Recent evidence from several research papers showed deleterious relationships of sedentary behavior with cardiovascular risk factors (e.g., obesity, type 2 diabetes mellitus and waist circumference). Furthermore, consistent independent associations have been observed between sitting time/sedentary behaviors and elevated all-cause and cardiovascular disease mortality risk. Generally, these associations have persisted following adjustment for physical activity. Recent emerging findings have shown that breaking up sedentary time potentially has a beneficial impact on cardiovascular health (independent of total sedentary time and moderate-to-vigorous intensity activity). In this article, we review the association between the time spent in various sedentary activities (occupational, leisure and commuting/transportation) and cardiovascular risk factors and cardiovascular morbidity and mortality. In addition, we review the suggested mechanisms that explain the empiric associations.

ZnT1 induces a crosstalk between T-type and L-type calcium channels through interactions with Raf-1 kinase and the calcium channel ß2 subunit.

ZnT1 is a major zinc transporter that regulates cellular zinc homeostasis. We have previously shown that ZnT1 has additional functions that are independent of its activity as a Zn2+ extruder. These include inhibition of the L-type calcium channel (LTCC) through interaction with the auxiliary ß-subunit of the LTCC and activation of the Raf-ERK signaling leading to augmented activity of the T-type calcium channel (TTCC). Our findings indicate that ZnT1 increases TTCC activity by enhancing the trafficking of the channel to the plasma membrane. LTCC and TTCC are co-expressed in many tissues and have different functions in a variety of tissues. In the current work, we investigated the effect of the voltage-gated calcium channel (VGCC) ß-subunit and ZnT1 on the crosstalk between LTCC and TTCC and their functions. Our results indicate that the ß-subunit inhibits the ZnT1-induced augmentation of TTCC function. This inhibition correlates with the VGCC ß-subunit-dependent reduction in ZnT1-induced activation of Ras-ERK signaling. The effect of ZnT1 is specific, as the presence of the ß-subunit did not change the effect of endothelin-1 (ET-1) on TTCC surface expression. These findings document a novel regulatory function of ZnT1 serving as a mediator in the crosstalk between TTCC and LTCC. Overall, we demonstrate that ZnT1 binds and regulates the activity of the ß-subunit of VGCC and Raf-1 kinase and modulates surface expression of the LTCC and TTCC catalytic subunits, consequently modulating the activity of these channels.

ZnT-1 enhances the activity and surface expression of T-type calcium channels through activation of Ras-ERK signaling.

Zinc transporter-1 (ZnT-1) is a putative zinc transporter that confers cellular resistance from zinc toxicity. In addition, ZnT-1 has important regulatory functions, including inhibition of L-type calcium channels and activation of Raf-1 kinase. Here we studied the effects of ZnT-1 on the expression and function of T-type calcium channels. In Xenopus oocytes expressing voltage-gated calcium channel (CaV) 3.1 or CaV3.2, ZnT-1 enhanced the low-threshold calcium currents (I(caT)) to 182 ± 15 and 167.95 ± 9.27% of control, respectively (P < 0.005 for both channels). As expected, ZnT-1 also enhanced ERK phosphorylation. Coexpression of ZnT-1 and nonactive Raf-1 blocked the ZnT-1-mediated ERK phosphorylation and abolished the ZnT-1-induced augmentation of I(caT). In mammalian cells (Chinese hamster ovary), coexpression of CaV3.1 and ZnT-1 increased the I(caT) to 166.37 ± 6.37% compared with cells expressing CaV3.1 alone (P < 0.01). Interestingly, surface expression measurements using biotinylation or total internal reflection fluorescence microscopy indicated marked ZnT-1-induced enhancement of CaV3.1 surface expression. The MEK inhibitor PD-98059 abolished the ZnT-1-induced augmentation of surface expression of CaV3.1. In cultured murine cardiomyocytes (HL-1 cells), transient exposure to zinc, leading to enhanced ZnT-1 expression, also enhanced the surface expression of endogenous CaV3.1 channels. Consistently, in these cells, endothelin-1, a potent activator of Ras-ERK signaling, enhanced the surface expression of CaV3.1 channels in a PD-98059-sensitive manner. Our findings indicate that ZnT-1 enhances the activity of CaV3.1 and CaV3.2 through activation of Ras-ERK signaling. The augmentation of CaV3.1 currents by Ras-ERK activation is associated with enhanced trafficking of the channel to the plasma membrane.