Virus Evolution on Fitness Landscapes.

The landscape paradigm is revisited in the light of evolution in simple systems. A brief overview of different classes of fitness landscapes is followed by a more detailed discussion of the RNA model, which is currently the only evolutionary model that allows for a comprehensive molecular analysis of a fitness landscape. Neutral networks of genotypes are indispensable for the success of evolution. Important insights into the evolutionary mechanism are gained by considering the topology of sequence and shape spaces. The dynamic concept of molecular quasispecies is viewed in the light of the landscape paradigm. The distribution of fitness values in state space is mirrored by the population structures of mutant distributions. Two classes of thresholds for replication error or mutations are important: (i) the-conventional-genotypic error threshold, which separates ordered replication from random drift on neutral networks, and (ii) a phenotypic error threshold above which the molecular phenotype is lost. Empirical landscapes are reviewed and finally, the implications of the landscape concept for virus evolution are discussed.

Cryoballoon vs. radiofrequency catheter ablation: insights from NOrwegian randomized study of PERSistent Atrial Fibrillation (NO-PERSAF study).

AIMS: Pulmonary vein isolation (PVI) is still regarded as a cornerstone for treatment of persistent atrial fibrillation (AF). This study evaluated the effectiveness of PVI performed with cryoballoon ablation (CBA) in comparison with radiofrequency ablation (RFA) in patients with persistent AF. METHODS AND RESULTS: A total of 101 patients with symptomatic persistent AF were enrolled and randomized (1:1) to CBA or RFA groups and followed up for 12 months. The primary endpoint was any documented recurrent atrial tachyarrhythmia (ATA) lasting longer than 30 s following a 3-month blanking period. Secondary endpoints were procedure-related complications, procedure and ablation duration, and fluoroscopy time. The ATA-free survival curves were estimated by Kaplan-Meier method and analysed by the log-rank test. According to intention-to-treat analysis, freedom from ATA was achieved in 36 out of 52 patients in the CBA group and 30 out of 49 patients in the RFA group (69.2% vs. 61.2%, P = 0.393). No difference in AF recurrence was found between the two groups (27.5% in CBA vs. 38.0% in RFA, P = 0.258), and less atrial flutter recurrence was documented in the CBA group compared with the RFA group (3.9% vs. 18.0%, P = 0.020). The procedure and ablation duration were significantly shorter in the CBA group (160 ± 31 vs. 197 ± 38 min, P < 0.0001; 36.7 ± 9.5 vs. 55.3 ± 16.7 min, P < 0.0001). There was no difference regarding fluoroscopy time (21.5 ± 7.8 vs. 23.4 ± 11.2 min, P > 0.05). CONCLUSION: Compared with RFA, PVI performed by CBA led to shorter procedure and ablation duration, with less atrial flutter recurrence and similar freedom from ATA at 12-month follow-up.

Clinical outcome of cardiac resynchronization therapy in patients randomized to an active fixation bipolar left ventricular lead versus a passive quadripolar lead.

Objectives: To compare the clinical outcome of cardiac resynchronization therapy (CRT) in patients receiving a bipolar left ventricular (LV) lead with a side helix for active fixation to the outcome in patients receiving a quadripolar passive fixation LV lead.Design: Sixty-two patients (mean age 72 ± 11 years) were blindly and randomly assigned to the active fixation bipolar lead group (n = 31) or to the quadripolar lead group (n= 31). The LV leads were targeted to the basal LV segment in a vein concordant to the LV segment with the latest mechanical contraction chosen on the basis of preoperative radial strain (RS) echocardiography.Results: At the 6-month follow-up (FU), the reduction in LV end-systolic volume and LV reverse remodelling responder rate, defined as LV end-systolic volume reduction >15%, was 77% in the active fixation group and 83% in the quadripolar group, which was not significantly different. At the 12-month FU, the LV ejection fraction (LVEF) did not differ between the groups. There were no significant differences between the two groups in changes in New York Heart Association (NYHA) functional class or Minnesota Living with Heart Failure Questionnaire score. The occurrence of phrenic nerve stimulation (PNS) was 19% in the active fixation group versus 10% in the quadripolar group (p=.30), and all cases were resolved by reprogramming the device. All patients were alive at the 12-month FU. There was no device infection.Conclusions: There were no significant differences between the active fixation group of patients and the quadripolar group of patients concerning improvement in echocardiographic parameters or clinical symptoms.ClinicalTrials.gov number, NCT04632472.

Accuracy and usability of single-lead ECG from smartphones - A clinical study.

BACKGROUND: Several wireless ECG devices are commercially available for possible screening, monitoring and diagnosis of rhythms. The field is rapidly expanding, and some devices have demonstrated acceptable qualities. The objective was to evaluate the accuracy, usability and diagnostic capabilities of smartphone ECG in both patients and healthy controls. METHODS: We used a commercially available smartphone ECG device, connected wirelessly to a tablet, to record a 30-s lead I ECG in 144 subjects-20 of whom repeated the test after vigorous exercise. The subjects included 94 patients under standard calculated 12-lead ECG surveillance; transcripts were obtained shortly after the smartphone ECG was acquired. RESULTS: No significant differences were found in the QRS, frequency and QT intervals between the two modalities. Smartphone ECG recordings separated pathologic rhythms (atrial fibrillation (AF)/flutter, atrioventricular block, regular supraventricular rhythm, and pacing) from sinus rhythms with a sensitivity of 0.75 and a specificity of 0.97. The specific diagnosis of AF appeared in 11 patients and was detected with a sensitivity of 1 and a specificity of 0.94. There was a marginal decrease in the interpretability of the smartphone ECG after exercise. Inter- and intraobserver variability was low. CONCLUSIONS: Smartphone ECG accurately measures most baseline intervals and has acceptable sensitivity and specificity for pathological rhythms, especially for AF. Vigorous activity has a minor influence on the readability of the PR interval. Elderly patients may face challenges in recording a smartphone ECG correctly without assistance. According to our findings, the smartphone ECG would be applicable as a screening device for pathological rhythms.

Molecular evolution between chemistry and biology : The interplay of competition, cooperation, and mutation.

Biological evolution is reduced to three fundamental processes in the spirit of a minimal model: (i) Competition caused by differential fitness, (ii) cooperation of competitors in the sense of symbiosis, and (iii) variation introduced by mutation understood as error-prone reproduction. The three combinations of two fundamental processes each, ([Formula: see text]) competition and mutation, ([Formula: see text]) cooperation and competition, and ([Formula: see text]) cooperation and mutation, are analyzed. Changes in population dynamics that are induced by bifurcations and threshold phenomena are discussed.

Troponin T release comparing manually or magnetically guided radiofrequency ablation for AVNRT- a MAGMA AVNRT substudy.

OBJECTIVES: Catheter ablation is regarded as first-line therapy for symptomatic atrioventricular nodal reentry tachycardia (AVNRT). Ablation induces intended myocardial damage and the extent of myocardial damage may differ between ablation methods. The objective of this MAGMA AVNRT(NCT00875914) substudy was to compare high-sensitive cardiac troponin T (hs-cTnT) levels as a surrogate marker for myocardial damage after manually guided (MAN) AVNRT ablation versus AVNRT ablation using remote magnetic navigation (RMN). DESIGN: In total, 70 patients (mean age 44 ± 14 years, 26% male) undergoing catheter ablation for AVNRT in the MagMa-AVNRT-Trial were randomized to remote magnetic navigation (n = 34, 49%) or manually guided catheter ablation (n = 36, 51%). hs-cTnT was measured the day after the procedure. RESULTS: The median follow-up time was 6.2 ± 1.1 years. Acute success was 100% in both groups. hs-cTnT release was significantly lower in the remote magnetic navigation group (52 ng/L versus 95 ng/L, p < .01), even though the ablation time was longer and number of applications was higher with remote magnetic navigation (4.2 min vs 2.8 min, p = .017; 4.9 vs 3.3 applications, p = .01). hs-cTnT released per minute ablation time was also lower with remote magnetic navigation (12 ng/L versus 34 ng/L, p < .01). Both groups exhibited similar clinical long-term follow up regarding recurrence and complications. CONCLUSION: Remote magnetic navigation controlled catheter ablation of AVNRT has similar clinical outcome, but leads to less hs-cTnT release than manually guided catheter ablation. This might correspond to less unintended myocardial damage with RMN, which might be advantageous in complex ablation procedures.

Quasispecies on Fitness Landscapes.

Selection-mutation dynamics is studied as adaptation and neutral drift on abstract fitness landscapes. Various models of fitness landscapes are introduced and analyzed with respect to the stationary mutant distributions adopted by populations upon them. The concept of quasispecies is introduced, and the error threshold phenomenon is analyzed. Complex fitness landscapes with large scatter of fitness values are shown to sustain error thresholds. The phenomenological theory of the quasispecies introduced in 1971 by Eigen is compared to approximation-free numerical computations. The concept of strong quasispecies understood as mutant distributions, which are especially stable against changes in mutations rates, is presented. The role of fitness neutral genotypes in quasispecies is discussed.

What Is a Quasispecies? Historical Origins and Current Scope.

The quasispecies concept is introduced by means of a simple theoretical model that uses as little chemical kinetics and mathematics as possible but fully in the spirit of Albert Einstein who said: "Things should be made as simple as possible but not simpler." More elaborate treatments follow in the forthcoming chapters. It is shown that the most important results of the theory, in particular the existence of error thresholds, are not dependent on simplifying assumptions concerning the distribution of fitness values. Error thresholds are regularly found on landscapes with large and irregular scatter of fitness. After the introduction to theory, it will be shown how experimental data on the evolution of molecules or viruses may be fit to the theoretical model.

Atrioventricular nodal ablation in patients with resynchronization therapy and atrial fibrillation - long term results.

OBJECTIVES: Atrioventricular nodal ablation (AVNA) is recommended for patients (pts) with cardiac resynchronization therapy (CRT) having atrial fibrillation (AF) and incomplete ventricular capture (Class IIa, level B). AVNA reduces mortality and improves the New York Heart Association (NYHA) functional class during intermediate term follow-up. The objectives were to study the long-term outcome regarding quality of life (QoL) and survival of our CRT pts after AVNA. DESIGN: 37 CRT-pts undergoing AVNA due to inadequate biventricular pacing were included in the study. Data were retrospectively obtained from clinical records and through telephone interviews. RESULTS: Twenty pts died during the follow-up period of average 30.6 ± 24 months. After AVNA the ventricular capture improved significantly from 68.4 ± 23% to 98.5 ± 2% (p < 0.001). A significant and sustained improvement of average 0.3 ± 0.5 (p = 0.001) in NYHA functional class was found. Additionally a large percentage of pts discontinued taking rate reducing drugs with potential severe side effects. CONCLUSION: AVNA in CRT pts was safe and effective. The treatment resulted in a sustained improvement in QoL, including long-term improvement in NYHA functional class.

Incidence and clinical predictors of subsequent atrial fibrillation requiring additional ablation after cavotricuspid isthmus ablation for typical atrial flutter.

OBJECTIVES: We sought to investigate the incidence of atrial fibrillation after catheter ablation for typical atrial flutter and to determine the predictors for symptomatic atrial fibrillation that required a further additional dedicated ablation procedure. DESIGN: 127 patients underwent elective cavotricuspid isthmus ablation with the indication of symptomatic, typical atrial flutter. The occurrence of atrial flutter, atrial fibrillation, cerebrovascular events and the need for additional ablation procedures for symptomatic atrial fibrillation was assessed during long-term follow-up. RESULTS: The majority of patients (70%) manifested atrial fibrillation during a follow-up period of 68 ± 24 months, and a significant proportion (42%) underwent one or multiple atrial fibrillation ablation procedures after an average of 26 months from the index procedure. Recurrence of typical atrial flutter was rare. Ten patients (8%) suffered cerebrovascular events. Earlier documentation of atrial fibrillation (OR 3.53), previous use of flecainide (OR 3.33) and left atrial diameter (OR 2.96) independently predicted occurrence of atrial fibrillation during the follow-up. A combination of pre- and intra-procedural documentation of atrial fibrillation (OR 3.81) and previous use of flecainide (OR 2.43) independently predicted additional atrial fibrillation ablation. DISCUSSION: Atrial fibrillation occurred in the majority of patients after ablation for typical atrial flutter and 42% of them required an additional dedicated ablation procedure. Pre- and intraprocedural documentation of atrial fibrillation together with previous use of flecainide independently predicted atrial fibrillation occurrence and a need for additional ablation. Anticoagulation treatment should be continued in high-risk patients in spite of clinical disappearance of atrial flutter.

10-year follow-up after radiofrequency ablation of idiopathic ventricular arrhythmias from right ventricular outflow tract.

BACKGROUND: The aim of this study was to examine the effect of radiofrequency ablation (RFA) of ventricular arrhythmias from right ventricular outflow tract (RVOT) during long-term follow-up. METHODS: A follow-up analysis was conducted using an in-house questionnaire, as well as a qualitative assessment of the patients' medical records. The study population of 34 patients had a previous diagnosis of idiopathic VT or frequent PVCs from the RVOT, and received RFA treatment between 2002 and 2005. RESULTS: The main symptoms prior to RFA were palpitations (82.4%) and dizziness (76.5%). A reduction in symptoms following RFA was reported by 91.2% of patients (p < 0.001). Furthermore, there was a reduced use of antiarrhythmic medication after RFA (p < 0.001). General health perception classified on a scale of 1 (poor) to 4 (excellent), improved from median class 1 to 3 (p < 0.001) during long-term follow-up. The fitness to work increased from median class 3 to class 5 (1 = incapacitated, 5 = full time employment, p = 0.038), while the rate of patients in full time employment increased from 26.5% to 55.9% after RFA (p = 0.02). CONCLUSIONS: A reduction of symptoms and use of antiarrhythmic medication, as well as an improvement in the general health perception and fitness to work after RFA of idiopathic ventricular arrhythmias can be demonstrated at ten-year follow-up.

Transference-focused psychotherapy for borderline personality disorder: change in reflective function.

Borderline personality disorder is associated with deficits in personality functioning and mentalisation. In a randomised controlled trial 104 people with borderline personality disorder received either transference-focused psychotherapy (TFP) or treatment by experienced community therapists. Among other outcome variables, mentalisation was assessed by means of the Reflective Functioning Scale (RF Scale). Findings revealed only significant improvements in reflective function in the TFP group within 1 year of treatment. The between-group effect was of medium size (d = 0.45). Improvements in reflective function were significantly correlated with improvements in personality organisation.

Premedication and preoperative information reduces pain intensity and increases satisfaction in patients undergoing ablation for atrial fibrillation. A randomised controlled study.

BACKGROUND: Pain and discomfort are common during radiofrequency ablation (RFA) for atrial fibrillation. AIMS: To compare and evaluate the effect of premedication, standardised preoperative information and preoperative anxiety on pain intensity, drug consumption and patients' satisfaction. METHODS: Preoperative anxiety at baseline, pain intensity during RFA, and patient satisfaction after the procedure were measured in 3 random groups. Group A (n=20) received standard pain management, group B (n=20) received premedication and group C (n=20) received premedication and standardised preoperative information. RESULTS: Patients in groups B and C experienced less pain intensity (p<0.001) and needed fewer anxiolytics (p=0.023) and analgesics (p=0.031) compared to group A. Patient satisfaction was higher in group C (p=0.005) compared to group A. Increased preoperative anxiety is related to elevated drug demand (p<0.05). CONCLUSION: Premedication alone or combined with preoperative information reduces and higher preoperative anxiety increases pain intensity and drug consumption during RFA. Preoperative information improves patient satisfaction.

Ablation effect indicated by impedance fall is correlated with contact force level during ablation for atrial fibrillation.

INTRODUCTION: Previous studies have validated the use of impedance fall as a measure of the effects of ablation. We investigated whether catheter-to-tissue contact force correlated with impedance fall during atrial fibrillation ablation. METHODS AND RESULTS: A total of 394 ablation points from 35 patients who underwent atrial fibrillation ablation were selected and analyzed in terms of the presence of stable catheter contact in non-ablated areas in the left atrium. A fixed power output (30 W) was applied for 60 seconds. Contact force, impedance fall, and force-direction angle were retrieved and exported for off-line analysis. Qualified points were divided into 5 groups according to the level of contact force (1-5 g, 6-10 g, 11-15 g, 16-20 g, and >20 g). An acute impedance fall was observed in the first 10 seconds followed by a plateau in group I and by a further fall in the other groups. Group V showed a rise in impedance during the last 20 seconds of ablation. Levels of impedance fall at each time point were significantly different among all the groups (P<0.001) except between groups III and IV. There was a significant correlation between contact force and maximum impedance fall (rho = 0.54, P<0.01). Lesions with a force-direction angle of 0-30° had significantly lower contact force and maximum impedance fall than those with angles of 30-60° and 60-135° (P<0.01). CONCLUSIONS: Under stable catheter conditions, contact force correlates with impedance fall during 60 seconds of ablation. Contact force exceeding 5 g produces greater impedance fall, which probably indicates adequate lesion formation. A contact force greater than 20 g may lead to late tissue overheating.

Thawing plateau time indicating the duration of phase transition from ice to water is the strongest predictor for long-term durable pulmonary vein isolation after cryoballoon ablation for atrial fibrillation-Data from the index and repeat procedures.

Introduction: This study aimed to clarify the relationship between the durability of pulmonary vein (PV) isolation and the time of phase transition from ice to water indicated by thawing plateau time in a cryoballoon ablation for atrial fibrillation (AF). Methods and results: In this retrospective study, 241 PVs from 71 patients who underwent a repeat AF ablation 526 (IQR: 412, 675) days after a cryoballoon ablation were analyzed. Reconnection was observed in 101 (41.9%) PVs of 53 patients (74.6%). Thawing plateau time (TimeTP) was defined as the time from 0°C to 10°C inside the balloon in the thawing period. Durable PV isolation was associated with significantly longer TimeTP compared with PV reconnection (26.0 vs. 11.0 s, P < 0.001). The proportion of durable PV isolations increased with TimeTP in a dose-proportional manner. The cut point for PV reconnection was TimeTP <15 s with a positive predictive value of 82.1% (sensitivity = 63.4%, specificity = 90.0%) while for durable PV isolation the cut point was TimeTP >25 s with a positive predictive value of 84.6% (sensitivity = 55.0%, specificity = 86.1%). In the analysis of multivariable logistic regression, location of PV reconnection (P < 0.01), TimeTP (P < 0.05) and thawing plateau integral (P < 0.01) were shown as independent predictors for durable PV isolation. Conclusion: TimeTP is an independent predictor for the durability of PV isolation, and it presents in a dose-proportional manner. TimeTP <15 s predicts long-term reconnection while TimeTP >25 s predicts durable PV isolation.

Ventricular arrhythmias originating from the aortomitral continuity: an uncommon variant of left ventricular outflow tract tachycardia.

AIMS: Ventricular arrhythmias arising from the fibrous rings have been demonstrated, but knowledge about the aortomitral continuity (AMC) as a source of the arrhytmias is still limited. The objective is to describe the characteristics of ventricular arrhythmias originating from the AMC in patients without structural heart disease. METHODS AND RESULTS: Ten patients with ventricular tachycardia (VT) and/or premature ventricular contractions, who had been successfully treated by catheter ablation at the AMC beneath the aortic valve, were enrolled. Clinical data and electrocardiographic characteristics were analysed. Three of the 10 patients had previously registered episodes of supraventricular tachycardia and had undergone catheter ablation of atrioventricular nodal reentrant tachycardia (AVNRT). In four patients with anterior AMC location, early R/S wave transition was found in the precordial leads, with equal R and S amplitudes in V2, rS in V1, and R in V3. In six patients whose VT arose from the middle part of the AMC, we demonstrated a special ('rebound') transition pattern, with which equal R and S amplitudes occurred in V2, and high R waves in V1 and V3. In the anterior AMC location, the S/R ratios in leads V1 and V2 were >1 and statistically significantly higher than those located in the middle (V1: 1.59 vs. 0.23, P< 0.001; V2: 1.52 vs. 0.41, P< 0.01). CONCLUSIONS: We report a series of ventricular arrhythmias arising from the AMC with different R/S wave transition patterns in the precordial leads on the electrocardiogram. There may be a relationship between ventricular arrhythmias from AMC and AVNRT.

The impacts of contact force, power and application time on ablation effect indicated by serial measurements of impedance drop in both conventional and high-power short-duration ablation settings of atrial fibrillation.

BACKGROUND: This study aimed to clarify the interrelationship and additive effects of contact force (CF), power and application time in both conventional and high-power short-duration (HPSD) settings. METHODS: Among 38 patients with paroxysmal atrial fibrillation who underwent first-time pulmonary vein isolation, 787 ablation points were collected at the beginning of the procedure at separate sites. Energy was applied for 60 s under power outputs of 25, 30 or 35 W (conventional group), or 10 s when using 50 W (HPSD group). An impedance drop (ID) of 10 Ω was regarded as a marker of adequate lesion formation. RESULTS: ID ≥ 10 Ω could not be achieved with CF < 5 g under any power setting. With CF ≥ 5 g, ID could be enhanced by increasing power output or prolonging ablation time. ID for 30 and 35 W was greater than for 25 W (p < 0.05). Ablation with 35 W resulted in greater ID than with 30 W only when CF of 10-20 g was applied for 20-40 s (p < 0.05). Under the same power output, ID increased with CF level at different time points. The higher the CF, the shorter the time needed to reach ID of 10 Ω and maximal ID. ID correlated well with ablation index under each power, except for lower ID values at 25 W. ID with 50 W for 10 s was equivalent to that with 25 W for 40 s, but lower than that with 30 W for 40 s or 35 W for 30 s. CONCLUSIONS: CF of at least 5 g is required for adequate ablation effect. With CF ≥ 5g, CF, power output, and ablation time can compensate for each other. Time to reach maximal ablation effect can be shortened by increasing CF or power. The effect of HPSD ablation with 50 W for 10 s is equivalent to conventional ablation with 25 W for 40 s and 30-35 W for 20-30 s in terms of ID.