Pharmacological inhibition of I-K1 by PA-6 in isolated rat hearts affects ventricular repolarization and refractoriness

The inwardly rectifying potassium current (I(K) (1)) conducted through K(ir)2.X channels contribute to repolarization of the cardiac action potential and to stabilization of the resting membrane potential in cardiomyocytes. Our aim was to investigate the effect of the recently discovered I(K) (1) inhibitor PA‐6 on action potential repolarization and refractoriness in isolated rat hearts. Transiently transfected HEK‐293 cells expressing I(K) (1) were voltage‐clamped with ramp protocols. Langendorff‐perfused heart experiments were performed on male Sprague–Dawley rats, effective refractory period, Wenckebach cycle length, and ventricular effective refractory period were determined following 200 nmol/L PA‐6 perfusion. 200 nmol/L PA‐6 resulted in a significant time‐latency in drug effect on the I(K) (1) current expressed in HEK‐293 cells, giving rise to a maximal effect at 20 min. In the Langendorff‐perfused heart experiments, PA‐6 prolonged the ventricular action potential duration at 90% repolarization (from 41.8 ± 6.5 msec to 72.6 ± 21.1 msec, 74% compared to baseline, P < 0.01, n = 6). In parallel, PA‐6 significantly prolonged the ventricular effective refractory period compared to baseline (from 34.8 ± 4.6 msec to 58.1 ± 14.7 msec, 67%, P < 0.01, n = 6). PA‐6 increased the short‐term beat‐to‐beat variability and ventricular fibrillation was observed in two of six hearts. Neither atrial ERP nor duration of atrial fibrillation was altered following PA‐6 application. The results show that pharmacological inhibition of cardiac I(K) (1) affects ventricular action potential repolarization and refractoriness and increases the risk of ventricular arrhythmia in isolated rat hearts

Appropriate threshold levels of cardiac beat-to-beat variation in semi-automatic analysis of equine ECG recordings

BACKGROUND: Although premature beats are a matter of concern in horses, the interpretation of equine ECG recordings is complicated by a lack of standardized analysis criteria and a limited knowledge of the normal beat-to-beat variation of equine cardiac rhythm. The purpose of this study was to determine the appropriate threshold levels of maximum acceptable deviation of RR intervals in equine ECG analysis, and to evaluate a novel two-step timing algorithm by quantifying the frequency of arrhythmias in a cohort of healthy adult endurance horses. RESULTS: Beat-to-beat variation differed considerably with heart rate (HR), and an adaptable model consisting of three different HR ranges with separate threshold levels of maximum acceptable RR deviation was consequently defined. For resting HRs <60 beats/min (bpm) the threshold level of RR deviation was set at 20%, for HRs in the intermediate range between 60 and 100 bpm the threshold was 10%, and for exercising HRs >100 bpm, the threshold level was 4%. Supraventricular premature beats represented the most prevalent arrhythmia category with varying frequencies in seven horses at rest (median 7, range 2–86) and six horses during exercise (median 2, range 1–24). CONCLUSIONS: Beat-to-beat variation of equine cardiac rhythm varies according to HR, and threshold levels in equine ECG analysis should be adjusted accordingly. Standardization of the analysis criteria will enable comparisons of studies and follow-up examinations of patients. A small number of supraventricular premature beats appears to be a normal finding in endurance horses. Further studies are required to validate the findings and determine the clinical significance of premature beats in horses

Antiarrhythmic and electrophysiologic effects of flecainide on acutely induced atrial fibrillation in healthy horses

BACKGROUND: Only few pharmacologic compounds have been validated for treatment of atrial fibrillation (AF) in horses. Studies investigating the utility and safety of flecainide to treat AF in horses have produced conflicting results, and the antiarrhythmic mechanisms of flecainide are not fully understood. OBJECTIVES: To study the potential of flecainide to terminate acutely induced AF of short duration (≥15 minutes), to examine flecainide‐induced changes in AF duration and AF vulnerability, and to investigate the in vivo effects of flecainide on right atrial effective refractory period, AF cycle length, and ventricular depolarization and repolarization. ANIMALS: Nine Standardbred horses. Eight received flecainide, 3 were used as time‐matched controls, 2 of which also received flecainide. METHODS: Prospective study. The antiarrhythmic and electrophysiologic effects of flecainide were based on 5 parameters: ability to terminate acute pacing‐induced AF (≥15 minutes), and drug‐induced changes in atrial effective refractory period, AF duration, AF vulnerability, and ventricular depolarization and repolarization times. Parameters were assessed at baseline and after flecainide by programmed electrical stimulation methods. RESULTS: Flecainide terminated all acutely induced AF episodes (n = 7); (AF duration, 21 ± 5 minutes) and significantly decreased the AF duration, but neither altered atrial effective refractory period nor AF vulnerability significantly. Ventricular repolarization time was prolonged between 8 and 20 minutes after initiation of flecainide infusion, but no ventricular arrhythmias were detected. CONCLUSIONS AND CLINICAL IMPORTANCE: Flecainide had clear antiarrhythmic properties in terminating acute pacing‐induced AF, but showed no protective properties against immediate reinduction of AF. Flecainide caused temporary prolongation in the ventricular repolarization, which may be a proarrhythmic effect

Atrial fibrillatory rate as predictor of recurrence of atrial fibrillation in horses treated medically or with electrical cardioversion

Background The recurrence rate of atrial fibrillation (AF) in horses after cardioversion to sinus rhythm (SR) is relatively high. Atrial fibrillatory rate (AFR) derived from surface ECG is considered a biomarker for electrical remodelling and could potentially be used for the prediction of successful AF cardioversion and AF recurrence. Objectives Evaluate if AFR was associated with successful treatment and could predict AF recurrence in horses. Study design Retrospective multicentre study. Methods Electrocardiograms (ECG) from horses with persistent AF admitted for cardioversion with either medical treatment (quinidine) or transvenous electrical cardioversion (TVEC) were included. Bipolar surface ECG recordings were analysed by spatiotemporal cancellation of QRST complexes and calculation of AFR from the remaining atrial signal. Kaplan-Meier survival curve and Cox regression analyses were performed to assess the relationship between AFR and the risk of AF recurrence. Results Of the 195 horses included, 74 received quinidine treatment and 121 were treated with TVEC. Ten horses did not cardiovert to SR after quinidine treatment and AFR was higher in these, compared with the horses that successfully cardioverted to SR (median [interquartile range]), (383 [367-422] vs 351 [332-389] fibrillations per minute (fpm), P < .01). Within the first 180 days following AF cardioversion, 12% of the quinidine and 34% of TVEC horses had AF recurrence. For the horses successfully cardioverted with TVEC, AFR above 380 fpm was significantly associated with AF recurrence (hazard ratio = 2.4, 95% confidence interval 1.2-4.8, P = .01). Main limitations The treatment groups were different and not randomly allocated, therefore the two treatments cannot be compared. Medical records and the follow-up strategy varied between the centres. Conclusions High AFR is associated with failure of quinidine cardioversion and AF recurrence after successful TVEC. As a noninvasive marker that can be retrieved from surface ECG, AFR can be clinically useful in predicting the probability of responding to quinidine treatment as well as maintaining SR after electrical cardioversion

Time‐dependent antiarrhythmic effects of flecainide on induced atrial fibrillation in horses

Background, Objective: Pharmacological treatment of atrial fibrillation (AF) in horses can be challenging because of low efficacy and adverse effects. Flecainide has been tested with variable efficacy. To test whether the efficacy of flecainide is dependent on AF duration. Animals and Methods: Nine Standardbred mares. Factorial study design. All horses were instrumented with a pacemaker and assigned to a control or an AF group. On day 0, all horses were in sinus rhythm and received 2 mg/kg flecainide IV. Atrial fibrillation subsequently was induced in the AF group by pacemaker stimulation. On days 3, 9, 27, and 55, flecainide was administered to all horses, regardless of heart rhythm. Results: Conclusions and Clinical ImportanceAll horses in AF cardioverted to sinus rhythm on days 3 and 9. On day 27, 5/6 horses cardioverted, whereas only 2/6 cardioverted on day 55. The time from the start of flecainide infusion to cardioversion (range, 3-185min, log transformed) showed linear correlation with the cumulative duration of AF (r(2)=.80, P<.0001). Flecainide induced abnormal QRS complexes in 4/6 AF horses and 1/3 controls. A positive correlation was found between heart rate before flecainide infusion and number of abnormal QRS complexes (0.14, P<.05). One horse suffered from cardiac arrest and died after flecainide infusion. Flecainide is effective for cardioversion of short-term induced AF, but the effect decreases with AF duration. Controlling heart rate may minimize adverse effects caused by flecainide, but the drug should be used with great caution

SCORE2-Diabetes: 10-year cardiovascular risk estimation in type 2 diabetes in Europe

Aims: To develop and validate a recalibrated prediction model (SCORE2-Diabetes) to estimate the 10-year risk of cardiovascular disease (CVD) in individuals with type 2 diabetes in Europe. Methods and results: SCORE2-Diabetes was developed by extending SCORE2 algorithms using individual-participant data from four large-scale datasets comprising 229 460 participants (43 706 CVD events) with type 2 diabetes and without previous CVD. Sex-specific competing risk-adjusted models were used including conventional risk factors (i.e. age, smoking, systolic blood pressure, total, and HDL-cholesterol), as well as diabetes-related variables (i.e. age at diabetes diagnosis, glycated haemoglobin [HbA1c] and creatinine-based estimated glomerular filtration rate [eGFR]). Models were recalibrated to CVD incidence in four European risk regions. External validation included 217 036 further individuals (38 602 CVD events), and showed good discrimination, and improvement over SCORE2 (C-index change from 0.009 to 0.031). Regional calibration was satisfactory. SCORE2-Diabetes risk predictions varied several-fold, depending on individuals' levels of diabetes-related factors. For example, in the moderate-risk region, the estimated 10-year CVD risk was 11% for a 60-year-old man, non-smoker, with type 2 diabetes, average conventional risk factors, HbA1c of 50 mmol/mol, eGFR of 90 mL/min/1.73 m2, and age at diabetes diagnosis of 60 years. By contrast, the estimated risk was 17% in a similar man, with HbA1c of 70 mmol/mol, eGFR of 60 mL/min/1.73 m2, and age at diabetes diagnosis of 50 years. For a woman with the same characteristics, the risk was 8% and 13%, respectively. Conclusion: SCORE2-Diabetes, a new algorithm developed, calibrated, and validated to predict 10-year risk of CVD in individuals with type 2 diabetes, enhances identification of individuals at higher risk of developing CVD across Europe

Формирование эмоциональной культуры как компонента инновационной культуры студентов

Homozygosity has long been associated with rare, often devastating, Mendelian disorders1 and Darwin was one of the first to recognise that inbreeding reduces evolutionary fitness2. However, the effect of the more distant parental relatedness common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity, ROH), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power3,4. Here we use ROH to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts and find statistically significant associations between summed runs of homozygosity (SROH) and four complex traits: height, forced expiratory lung volume in 1 second (FEV1), general cognitive ability (g) and educational attainment (nominal p<1 × 10−300, 2.1 × 10−6, 2.5 × 10−10, 1.8 × 10−10). In each case increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing convincing evidence for the first time that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples5,6, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein (LDL) cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection7, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been