Imaging, biomarker and invasive assessment of diffuse left ventricular myocardial fibrosis in atrial fibrillation.

BACKGROUND: Using cardiovascular magnetic resonance imaging (CMR), it is possible to detect diffuse fibrosis of the left ventricle (LV) in patients with atrial fibrillation (AF), which may be independently associated with recurrence of AF after ablation. By conducting CMR, clinical, electrophysiology and biomarker assessment we planned to investigate LV myocardial fibrosis in patients undergoing AF ablation. METHODS: LV fibrosis was assessed by T1 mapping in 31 patients undergoing percutaneous ablation for AF. Galectin-3, coronary sinus type I collagen C terminal telopeptide (ICTP), and type III procollagen N terminal peptide were measured with ELISA. Comparison was made between groups above and below the median for LV extracellular volume fraction (ECV), followed by regression analysis. RESULTS: On linear regression analysis LV ECV had significant associations with invasive left atrial pressure (Beta 0.49, P = 0.008) and coronary sinus ICTP (Beta 0.75, P < 0.001), which remained significant on multivariable regression. CONCLUSION: LV fibrosis in patients with AF is associated with left atrial pressure and invasively measured levels of ICTP turnover biomarker.

A novel approach to mapping the atrial ganglionated plexus network by generating a distribution probability atlas.

INTRODUCTION: The ganglionated plexuses (GPs) of the intrinsic cardiac autonomic system are implicated in arrhythmogenesis. GP localization by stimulation of the epicardial fat pads to produce atrioventricular dissociating (AVD) effects is well described. We determined the anatomical distribution of the left atrial GPs that influence atrioventricular (AV) dissociation. METHODS AND RESULTS: High frequency stimulation was delivered through a Smart-Touch catheter in the left atrium of patients undergoing atrial fibrillation (AF) ablation. Three dimensional locations of points tested throughout the entire chamber were recorded on the CARTO™ system. Impact on the AV conduction was categorized as ventricular asystole, bradycardia, or no effect. CARTO maps were exported, registered, and transformed onto a reference left atrial geometry using a custom software, enabling data from multiple patients to be overlaid. In 28 patients, 2108 locations were tested and 283 sites (13%) demonstrated (AVD-GP) effects. There were 10 AVD-GPs (interquartile range, 11.5) per patient. Eighty percent (226) produced asystole and 20% (57) showed bradycardia. The distribution of the two groups was very similar. Highest probability of AVD-GPs (>20%) was identified in: inferoseptal portion (41%) and right inferior pulmonary vein base (30%) of the posterior wall, right superior pulmonary vein antrum (31%). CONCLUSION: It is feasible to map the entire left atrium for AVD-GPs before AF ablation. Aggregated data from multiple patients, producing a distribution probability atlas of AVD-GPs, identified three regions with a higher likelihood for finding AVD-GPs and these matched the histological descriptions. This approach could be used to better characterize the autonomic network.

Intra-cardiac and peripheral levels of biochemical markers of fibrosis in patients undergoing catheter ablation for atrial fibrillation.

AIMS: Measurement of circulating biomarkers of fibrosis may have a role in selecting patients and treatment strategy for catheter ablation. Pro-collagen type III N-terminal pro-peptide (PIIINP), C-telopeptide of type I collagen (ICTP), fibroblast growth factor 23 (FGF-23), and galectin 3 (gal-3) have all been suggested as possible biomarkers for this indication, but studies assessing whether peripheral levels reflect intra-cardiac levels are scarce. METHODS AND RESULTS: We studied 93 patients undergoing ablation for paroxysmal atrial fibrillation (AF) (n = 63) or non-paroxysmal AF (n = 30). Femoral venous, left and right atrial, and coronary sinus blood were analysed using ELISA to determine biomarker levels. Levels were compared with control patients (n = 36) and baseline characteristics, including left atrial voltage mapping data. C-telopeptide of type I collagen levels were higher in AF than in non-AF patients (P = 0.007). Peripheral ICTP levels were higher than all intra-cardiac levels (P < 0.001). Peripheral gal-3 levels were higher than left atrial levels (P = 0.001). Peripheral levels of FGF-23 and PIIINP were not significantly different from intra-cardiac levels. CS levels of ICTP were higher than right and left atrial levels (P < 0.001). gal-3 was higher in women vs. men (P ≤ 0.001) and with higher body mass index (P ≤ 0.001). ICTP levels increased with reducing ejection fraction (P ≤ 0.012). CONCLUSIONS: Atrial fibrillation patients have higher levels of circulating ICTP than matched non-AF controls. In AF ablation patients, intra-cardiac sampling of FGF-23 or PIIINP gives no further information over peripheral sampling. For gal-3 and ICTP, intra-cardiac sampling may be necessary to assess their association with intra-cardiac processes. None of the biomarkers is related to fibrosis assessed by left atrial voltage.

Unusual fluoroscopic finding during atrial fibrillation cryoablation.

QUESTION: What is the next most appropriate course of action?Embolectomy.Usual postprocedural care.Thrombolytic therapy.Start aspirin.

Phase Entrainment of Induced Ventricular Fibrillation: A Human Feasibility and Proof of Concept Study.

Cardioversion and defibrillation by a single high energy shock applied by myocardial or body surface electrodes is painful, causes long term tissue damage, and is associated with worsening long term outcomes, but is almost always required for treatment of ventricular fibrillation . As a initial step towards developing methods that can terminate ventricular arrhythmias painlessly, we aim to determine if pacing stimuli at a rate of 5/s applied via an implantable cardiac defibrillator (ICD) can modify human ventricular fibrillation. In 8 patients undergoing defibrillation testing of a new/exchanged intracardiac defibrillator, five seconds of pacing at five stimuli per second was applied during the 10-20 seconds of induced ventricular fibrillation before the defibrillation shock was automatically applied, and the cardiac electrograms recorded and analyzed. The high frequency pacing did not entrain the ventricular fibrillation, but altered the dominant frequency in all 8 patients, and modulated the phase computed via the Hilbert Transform, in four of the patients. In this pilot study we demonstrate that high frequency pacing applied via ICD electrodes during VF can alter the dominant frequency and modulate the probability density of the phase of the electrogram of the ventricular fibrillation.

Multicentre randomised trial comparing contact force with electrical coupling index in atrial flutter ablation (VERISMART trial).

INTRODUCTION: Electrical coupling index (ECI) and contact force (CF) have been developed to aid lesion formation during catheter ablation. ECI measures tissue impedance and capacitance whilst CF measures direct contact. The aim was to determine whether the presence of catheter / tissue interaction information, such as ECI and CF, reduce time to achieve bidirectional cavotricuspid isthmus block during atrial flutter (AFL) ablation. METHODS: Patients with paroxysmal or persistent AFL were randomised to CF visible (range 5-40g), CF not visible, ECI visible (change of 12%) or ECI not visible. Follow-up occurred at 3 and 6 months and included a 7 day ECG recording. The primary endpoint was time to bidirectional cavotricuspid isthmus block. RESULTS: 114 patients were randomised, 16 were excluded. Time to bidirectional block was significantly shorter when ECI was visible (median 30.0 mins (IQR 31) to median 10.5mins (IQR 12) p 0.023) versus ECI not visible. There was a trend towards a shorter time to bidirectional block when CF was visible. Higher force was applied when CF was visible (median 9.03g (IQR 7.4) vs. 11.3g (5.5) p 0.017). There was no difference in the acute recurrence of conduction between groups. The complication rate was 2%, AFL recurrence was 1.1% and at 6 month follow-up, 12% had atrial fibrillation. CONCLUSION: The use of tissue contact information during AFL ablation was associated with reduced time taken to achieve bidirectional block when ECI was visible. Contact force data improved contact when visible with a trend towards a reduction in the procedural endpoint. ClinicalTrials.gov trial identifier: NCT02490033.

Left atrial voltage, circulating biomarkers of fibrosis, and atrial fibrillation ablation. A prospective cohort study.

AIMS: To test the ability of four circulating biomarkers of fibrosis, and of low left atrial voltage, to predict recurrence of atrial fibrillation after catheter ablation. BACKGROUND: Circulating biomarkers potentially may be used to improve patient selection for atrial fibrillation ablation. Low voltage areas in the left atrium predict arrhythmia recurrence when mapped in sinus rhythm. This study tested type III procollagen N terminal peptide (PIIINP), galectin-3 (gal-3), fibroblast growth factor 23 (FGF-23), and type I collagen C terminal telopeptide (ICTP), and whether low voltage areas in the left atrium predicted atrial fibrillation recurrence, irrespective of the rhythm during mapping. METHODS: 92 atrial fibrillation ablation patients were studied. Biomarker levels in peripheral and intra-cardiac blood were measured with enzyme-linked immunosorbent assay. Low voltage (<0.5mV) was expressed as a proportion of the mapped left atrial surface area. Follow-up was one year. The primary endpoint was recurrence of arrhythmia. The secondary endpoint was a composite of recurrence despite two procedures, or after one procedure if no second procedure was undertaken. RESULTS: The biomarkers were not predictive of either endpoint. After multivariate Cox regression analysis, high proportion of low voltage area in the left atrium was found to predict the primary endpoint in sinus rhythm mapping (hazard ratio 4.323, 95% confidence interval 1.337-13.982, p = 0.014) and atrial fibrillation mapping (hazard ratio 5.195, 95% confidence interval 1.032-26.141, p = 0.046). This effect was also apparent for the secondary endpoint. CONCLUSION: The studied biomarkers do not predict arrhythmia recurrence after catheter ablation. Left atrial voltage is an independent predictor of recurrence, whether the left atrium is mapped in atrial fibrillation or sinus rhythm.

Circulating biomarkers of fibrosis and cardioversion of atrial fibrillation: A prospective, controlled cohort study.

INTRODUCTION: External direct current cardioversion (DCCV) is an established treatment for AF but is associated with procedural risk and high AF recurrence rates. Cardiac fibrosis has been associated with AF, and circulating biomarkers have been suggested as a method of its assessment, but which biomarkers are suitable is yet to be determined. This study examines the differences between levels of procollagen type III N terminal peptide (PIIINP), type I collagen carboxyl telopeptide (ICTP), galectin-3 (gal-3) and fibroblast growth factor 23 (FGF-23) in DCCV patients, and disease-and-age-matched controls. Their predictive value for AF recurrence was analysed. METHODS: 79 patients undergoing DCCV and 40 age-and-disease-matched controls were included. Biomarkers were analysed using ELISA. Linear regression was used to examine relationships between biomarker levels and baseline characteristics, including echocardiographic measurements. Cox regression was used to assess relationships between baseline characteristics, including biomarker levels, and AF recurrence. RESULTS: There was no statistically significant difference between biomarker levels in the DCCV and control groups. Diabetes mellitus was related to higher FGF-23 (p=0.007) and PIIINP (p=0.027). Female sex (p=0.014), hypertension (p=0.001), and higher body mass index (p≤0.001) were related to higher gal-3 levels. FGF-23 was weakly predictive of AF recurrence (HR 1.003 p=0.012). CONCLUSION: PIIINP, ICTP, and Gal-3 are not predictive of AF recurrence after DCCV. FGF-23 may be associated with arrhythmia recurrence, but further work is required to clarify this. The presence of AF has no effect on levels of these biomarkers when compared to age and disease-matched controls.

Electrocardiogram interpretation and arrhythmia management: a primary and secondary care survey.

BACKGROUND: There is increasing desire among service commissioners to treat arrhythmia in primary care. Accurate interpretation of the electrocardiogram (ECG) is fundamental to this. ECG interpretation has previously been shown to vary widely but there is little recent data. AIM: To examine the interpretation of ECGs in primary and secondary care. DESIGN AND SETTING: A cross-sectional survey of participants' interpretation of six ECGs and hypothetical management of patients based on those ECGs, at primary care educational events, and a cardiology department in Leeds. METHOD: A total of 262 primary care clinicians and 20 cardiology clinicians were surveyed via questionnaire. Answers were compared with expert electrophysiologist opinion. RESULTS: In primary care, abnormal ECGs were interpreted as normal by 23% of responders. ST elevation and prolonged QT were incorrectly interpreted as normal by 1% and 22%, respectively. In cardiology, abnormal ECGs were interpreted as normal by 3%. CONCLUSION: ECG provision and interpretation remains inconsistent in both primary and secondary care. Primary care practitioners are less experienced and less confident with ECG interpretation than cardiologists, and require support in this area.

Assessment of atrial fibrosis for the rhythm control of atrial fibrillation.

Rhythm control of atrial fibrillation (AF) remains challenging, with modest long-term success rates. Atrial fibrosis has been associated with AF, but the clinical utility of assessment of this fibrosis has yet to be fully elucidated. In this paper we review the current state of understanding of the pathophysiology of atrial fibrosis in AF, and its impact upon the instigation and propagation of the arrhythmia. Fibrosis causes an increase in volume of dysfunctional extracellular matrix, and is associated with cellular alterations such as hypertrophy, apoptosis and membrane dysfunction within the atrial myocardium. In turn, these cause pathological alterations to atrial conduction, such as increased anisotropy, conduction block and re-entry, which can lead to AF. We review current methods of assessing atrial fibrosis and their impact upon the prediction of success of interventional rhythm control strategies such as ablation and cardioversion. We focus particularly on circulating biomarkers of fibrosis and scar formation; their role in the fibrotic process, and their value in the prediction of rhythm control success. We also review imaging and invasive electrocardiographic mapping techniques that may identify fibrosis, and again assess their potential predictive value. In this area there exist many unanswered questions, but further work will help to refine techniques to reliably identify and treat those patients who are most likely to benefit from rhythm control treatment strategies.

Early Repolarization Syndrome; Mechanistic Theories and Clinical Correlates.

The early repolarization (ER) pattern on the 12-lead electrocardiogram is characterized by J point elevation in the inferior and/or lateral leads. The ER pattern is associated with an increased risk of ventricular arrhythmias and sudden cardiac death (SCD). Based on studies in animal models and genetic studies, it has been proposed that J point elevation in ER is a manifestation of augmented dispersion of repolarization which creates a substrate for ventricular arrhythmia. A competing theory regarding early repolarization syndrome (ERS) proposes that the syndrome arises as a consequence of abnormal depolarization. In recent years, multiple clinical studies have described the characteristics of ER patients with VF in more detail. The majority of these studies have provided evidence to support basic science observations. However, not all clinical observations correlate with basic science findings. This review will provide an overview of basic science and genetic research in ER and correlate basic science evidence with the clinical phenotype.

A novel cardiopulmonary exercise test protocol and criterion to determine maximal oxygen uptake in chronic heart failure.

Cardiopulmonary exercise testing for peak oxygen uptake (Vo(2peak)) can evaluate prognosis in chronic heart failure (CHF) patients, with the peak respiratory exchange ratio (RER(peak)) commonly used to confirm maximal effort and maximal oxygen uptake (Vo(2max)). We determined the precision of RER(peak) in confirming Vo(2max), and whether a novel ramp-incremental (RI) step-exercise (SE) (RISE) test could better determine Vo(2max) in CHF. Male CHF patients (n = 24; NYHA class I-III) performed a symptom-limited RISE-95 cycle ergometer test in the format: RI (4-18 W/min; ∼10 min); 5 min recovery (10 W); SE (95% peak RI work rate). Patients (n = 18) then performed RISE-95 tests using slow (3-8 W/min; ∼15 min) and fast (10-30 W/min; ∼6 min) ramp rates. Pulmonary gas exchange was measured breath-by-breath. Vo(2peak) was compared within patients by unpaired t-test of the highest 12 breaths during RI and SE phases to confirm Vo(2max) and its 95% confidence limits (CI(95)). RER(peak) was significantly influenced by ramp rate (fast, medium, slow: 1.21 ± 0.1 vs. 1.15 ± 0.1 vs. 1.09 ± 0.1; P = 0.001), unlike Vo(2peak) (mean n = 18; 14.4 ± 2.6 ml·kg(-1)·min(-1); P = 0.476). Group Vo(2peak) was similar between RI and SE (n = 24; 14.5 ± 3.0 vs. 14.7 ± 3.1 ml·kg(-1)·min(-1); P = 0.407); however, within-subject comparisons confirmed Vo(2max) in only 14 of 24 patients (CI(95) for Vo(2max) estimation averaged 1.4 ± 0.8 ml·kg(-1)·min(-1)). The RER(peak) in CHF was significantly influenced by ramp rate, suggesting its use to determine maximal effort and Vo(2max) be abandoned. In contrast, the RISE-95 test had high precision for Vo(2max) confirmation with patient-specific CI(95) (without secondary criteria), and showed that Vo(2max) is commonly underestimated in CHF. The RISE-95 test was well tolerated by CHF patients, supporting its use for Vo(2max) confirmation.