ECMELLA as a bridge to heart transplantation in refractory ventricular fibrillation: A case report.

Background: Extracorporeal membrane oxygenation (ECMO) is an effective cardiorespiratory support technique in refractory cardiac arrest (CA). In patients under veno-arterial ECMO, the use of an Impella device, a microaxial pump inserted percutaneously, is a valuable strategy through a left ventricular unloading approach. ECMELLA, a combination of ECMO with Impella, seems to be a promising method to support end-organ perfusion while unloading the left ventricle. Case summary: The present case report describes the clinical course of a patient with ischemic and dilated cardiomyopathy who presented with refractory ventricular fibrillation (VF) leading to CA in the late postmyocardial infarction (MI) period, and who was successfully treated with ECMO and IMPELLA as a bridge to heart transplantation. Discussion: In the case of CA on VF refractory to conventional resuscitation maneuvers, early extracorporeal cardiopulmonary resuscitation (ECPR) associated with an Impella seems to be the best strategy. It provides organ perfusion, left ventricular unloading, and ability for neurological evaluation and VF catheter ablation before allowing heart transplantation. It is the treatment of choice in cases of end-stage ischaemic cardiomyopathy and recurrent malignant arrhythmias.

Early and Late Postoperative Tachyarrhythmias in Children and Young Adults Undergoing Congenital Heart Disease Surgery.

The population of patients with congenital heart disease is constantly growing with an increasing number of individuals reaching adulthood. A significant proportion of these children and young adults will suffer from tachyarrhythmias due to the abnormal anatomy, the hemodynamic burden, or as a sequela of surgical treatment. Depending on the underlying mechanism, arrhythmias may arise in the early postoperative period (hours to days after surgery) or in the late postoperative period (usually years after surgery). A good understanding of the electrophysiological characteristics and pathophysiological mechanisms is therefore crucial to guide the therapeutic approach. Here, we synthesize the current state of knowledge on epidemiological features, risk factors, pathophysiological insights, electrophysiological features, and therapy regarding tachyarrhythmias in children and young adults undergoing reparative surgery for congenital heart disease. The evolution and latest data on treatment options, including pharmacological therapy, ablation procedures, device therapy decision, and thromboprophylaxis, are summarized. Finally, throughout this comprehensive review, knowledge gaps and areas for future research are also identified.

Recognition of pre-hypertrophic cardiac involvement in Fabry Disease based on automated electrocardiographic measures.

BACKGROUND: Various electrocardiographic (ECG) indices have been shown to be useful for early recognition and staging of cardiac involvement in Fabry Disease (FD). However, many of them lack acceptable sensitivity and specificity. We assessed the value of automated ECG measures to discriminate between pre-hypertrophic FD and healthy individuals. METHODS AND RESULTS: Normal ECGs from 1496 healthy individuals (57.4% male, age 37.4 ± 13 years) were compared to those of 142 FD patients without LVH (37.3% male, age 41.5 ± 18 years). All ECGs were analyzed centrally and a total of 429 automated ECG measures per individual were included for step-wise analysis. The Cramer V statistic was first used to pick out those parameters which were helpful in discriminating between the two groups and a final selection was made by using two models, namely the FLD (Fisher Linear Discrimination) and the Logistic model, to optimise diagnostic performance for the detection of cardiac involvement in FD patients vs. specificity in healthy individuals. The three-step statistical analysis identified 9 ECG parameters as most significant for the discrimination between the groups. The combined discriminant score yielded 64% sensitivity and 97% specificity for correct classification of FD patients in the test sample with a logistic area under curve of the ROC analysis of 0.97. CONCLUSION: The combination of automated ECG measures identified via a stepwise statistical approach may be useful for detection of FD patients in the pre-hypertrophic stage. These data are promising for screening purposes in the very early stages of FD cardiomyopathy and warrant prospective confirmation.

Novel bleeding risk score for patients with atrial fibrillation on oral anticoagulants, including direct oral anticoagulants.

OBJECTIVE: Balancing bleeding risk and stroke risk in patients with atrial fibrillation (AF) is a common challenge. Though several bleeding risk scores exist, most have not included patients on direct oral anticoagulants (DOACs). We aimed at developing a novel bleeding risk score for patients with AF on oral anticoagulants (OAC) including both vitamin K antagonists (VKA) and DOACs. METHODS: We included patients with AF on OACs from a prospective multicenter cohort study in Switzerland (SWISS-AF). The outcome was time to first bleeding. Bleeding events were defined as major or clinically relevant non-major bleeding. We used backward elimination to identify bleeding risk variables. We derived the score using a point score system based on the ß-coefficients from the multivariable model. We used the Brier score for model calibration (<0.25 indicating good calibration), and Harrel's c-statistics for model discrimination. RESULTS: We included 2147 patients with AF on OAC (72.5% male, mean age 73.4 ± 8.2 years), of whom 1209 (56.3%) took DOACs. After a follow-up of 4.4 years, a total of 255 (11.9%) bleeding events occurred. After backward elimination, age > 75 years, history of cancer, prior major hemorrhage, and arterial hypertension remained in the final prediction model. The Brier score was 0.23 (95% confidence interval [CI] 0.19-0.27), the c-statistic at 12 months was 0.71 (95% CI 0.63-0.80). CONCLUSION: In this prospective cohort study of AF patients and predominantly DOAC users, we successfully derived a bleeding risk prediction model with good calibration and discrimination.

The myocardial phenotype of Fabry disease pre-hypertrophy and pre-detectable storage.

AIMS: Cardiac involvement in Fabry disease (FD) occurs prior to left ventricular hypertrophy (LVH) and is characterized by low myocardial native T1 with sphingolipid storage reflected by cardiovascular magnetic resonance (CMR) and electrocardiogram (ECG) changes. We hypothesize that a pre-storage myocardial phenotype might occur even earlier, prior to T1 lowering. METHODS AND RESULTS: FD patients and age-, sex-, and heart rate-matched healthy controls underwent same-day ECG with advanced analysis and multiparametric CMR [cines, global longitudinal strain (GLS), T1 and T2 mapping, stress perfusion (myocardial blood flow, MBF), and late gadolinium enhancement (LGE)]. One hundred and fourteen Fabry patients (46 ± 13 years, 61% female) and 76 controls (49 ± 15 years, 50% female) were included. In pre-LVH FD (n = 72, 63%), a low T1 (n = 32/72, 44%) was associated with a constellation of ECG and functional abnormalities compared to normal T1 FD patients and controls. However, pre-LVH FD with normal T1 (n = 40/72, 56%) also had abnormalities compared to controls: reduced GLS (-18 ± 2 vs. -20 ± 2%, P < 0.001), microvascular changes (lower MBF 2.5 ± 0.7 vs. 3.0 ± 0.8 mL/g/min, P = 0.028), subtle T2 elevation (50 ± 4 vs. 48 ± 2 ms, P = 0.027), and limited LGE (%LGE 0.3 ± 1.1 vs. 0%, P = 0.004). ECG abnormalities included shorter P-wave duration (88 ± 12 vs. 94 ± 15 ms, P = 0.010) and T-wave peak time (Tonset - Tpeak; 104 ± 28 vs. 115 ± 20 ms, P = 0.015), resulting in a more symmetric T wave with lower T-wave time ratio (Tonset - Tpeak)/(Tpeak - Tend) (1.5 ± 0.4 vs. 1.8 ± 0.4, P < 0.001) compared to controls. CONCLUSION: FD has a measurable myocardial phenotype pre-LVH and pre-detectable myocyte storage with microvascular dysfunction, subtly impaired GLS and altered atrial depolarization and ventricular repolarization intervals.

The value of ECG parameters as markers of treatment response in Fabry cardiomyopathy.

OBJECTIVE: Best treatment outcomes in Fabry disease (FD) associated cardiomyopathy can be obtained when treatment is started as early as possible. The rationale of this study was to assess the role of ECG changes for identification of cardiac involvement and patients at an earlier stage of the disease more likely deriving a benefit from enzyme replacement therapy (ERT). METHODS: A retrospective analysis of patient data was performed from an observational, longitudinal, prospective cohort. Treatment response was defined as absence or presence of disease progression, defined as new onset or increase in left ventricular (LV) mass >10%. Demographic, clinical, ECG and echocardiographic parameters at baseline were tested for their value in determining absence or presence of disease progression under ERT at 5-year follow-up. RESULTS: The study population consisted of a total of 38 patients (25 men, mean age 36±13 years, overall median follow-up duration 6.4±1.2 years). Patients in the progression group (14 men, 4 women) had a longer QRS duration (99±11 ms vs 84±13 ms, p<0.05 for men, 93±9 years vs 81±5 years, p<0.05 for women) and QTc interval (401±15 ms vs 372±10 ms, p<0.005 for men) and a higher amount of ECG abnormalities (86% vs 18%, p<0.005 for men and 100% vs 0%, p<0.005 for women) at the time of ERT initiation. An abnormal baseline ECG was significantly associated with disease progression (sensitivity 94.1%, specificity 88.9%, positive likelihood ratio of 8.47, p<0.005). CONCLUSIONS: An abnormal ECG at the time of treatment initiation is significantly associated with cardiac disease progression in FD. This effect seems to be independent of age, gender or LV mass at baseline and suggests maximal treatment benefit when ERT is initiated before ECG abnormalities develop.

Contact Force in Atrial Fibrillation: Role of Atrial Rhythm and Ventricular Contractions: Co-Force Atrial Fibrillation Study.

BACKGROUND: In an experimental model, variable and intermittent contact force (CF) resulted in a significant decrease in lesion volume. In humans, variability of CF during pulmonary vein isolation has not been characterized. METHODS AND RESULTS: In 20 consecutive patients undergoing CF-guided circumferential pulmonary vein isolation, 914 radiofrequency applications (530 in sinus rhythm and 384 in atrial fibrillation) were analyzed. The variability of the 60% CF range (CF(60%)) was 17±9.6 g. Hundred seventy-one (19%) applications were delivered with constant, 717 (78%) with variable, and 26 (3%) with intermittent CF. The mean CF and force-time integral were significantly higher during applications with variable than with intermittent or constant CF. There was no significant difference in CF variability, CF(60%) variability, and force-time integral between applications delivered in sinus rhythm and atrial fibrillation. The main reasons for CF variability were systolo-diastolic heart movement (29%) and respiration (27%). In 10 additional patients, during adenosine-induced atrioventricular block, the minimum CF significantly increased at 19 sites (5.3±4.4 versus 13.4±5.9 g; P<0.001) and at 16 sites intermittent or variable CF became constant. At only 1 site systolo-diastolic movement remained the main reason for variable CF. CONCLUSIONS: CF during pulmonary vein isolation remains highly variable despite efforts to optimize contact. CF and CF parameters were similar during sinus rhythm and atrial fibrillation. The main reasons for CF variability are systolo-diastolic heart movement and respiration. The systolo-diastolic peaks and nadirs of CF are because of ventricular contractions at the large majority of pulmonary vein isolation sites.

Electrocardiographic Screening for Prolonged QT Interval to Reduce Sudden Cardiac Death in Psychiatric Patients: A Cost-Effectiveness Analysis.

IMPORTANCE: Sudden cardiac death is a leading cause of mortality in psychiatric patients. Long QT (LQT) is common in this population and predisposes to Torsades-de-Pointes (TdP) and subsequent mortality. OBJECTIVE: To estimate the cost-effectiveness of electrocardiographic screening to detect LQT in psychiatric inpatients. DESIGN, SETTING, AND PARTICIPANTS: We built a decision analytic model based on a decision tree to evaluate the cost-effectiveness and utility of LQT screening from a health care perspective. LQT proportion parameters were derived from an in-hospital cross-sectional study. We performed experts' elicitation to estimate the risk of TdP, given extent of QT prolongation. A TdP reduction of 65% after LQT detection was based on positive drug dechallenge rate and through adequate treatment and electrolyte adjustments. The base-case model uncertainty was assessed with one-way and probabilistic sensitivity analyses. Finally, the TdP related mortality and TdP avoidance parameters were varied in a two-way sensitivity analysis to assess their effect on the Incremental Cost-Effectiveness Ratio (ICER). MAIN OUTCOMES AND MEASURES: Costs, Quality Ajusted Life Year (QALY), ICER, and probability of cost effectiveness thresholds ($ 10,000, $25,000, and $50,000 per QALY). RESULTS: In the base-case scenario, the numbers of patients needed to screen were 1128 and 2817 to avoid one TdP and one death, respectively. The ICER of systematic ECG screening was $8644 (95%CI, 3144-82 498) per QALY. The probability of cost-effectiveness was 96% at a willingness-to-pay of $50,000 for one QALY. In sensitivity analyses, results were sensitive to the case-fatality of TdP episodes and to the TdP reduction following the diagnosis of LQT. CONCLUSION AND RELEVANCE: In psychiatric hospitals, performing systematic ECG screening at admission help reduce the number of sudden cardiac deaths in a cost-effective fashion.

Prospective European survey on atrial fibrillation ablation: clinical characteristics of patients and ablation strategies used in different countries.

BACKGROUND: Atrial fibrillation (AF) ablation is widely adopted. Our aim was to conduct a prospective multicenter survey to verify patients' characteristics, approaches, and technologies adopted across Europe. METHODS AND RESULTS: A total of 35 centers in 12 countries actively participated in the study and 940 patients (median age 60 years) were enrolled. AF was paroxysmal, persistent, and long-lasting persistent in 52.4%, 36%, and 11.6% of patients, respectively; 95.5% of patients were symptomatic and 91.4% were refractory to antiarrhythmic therapy. Redo procedures were performed in 20.9%. Pulmonary vein isolation (PVI) emerged as the cornerstone of ablative therapy and has been performed in 98.7% of procedures, with confirmation of PVI in 92.9% of cases. The ablation of nonparoxysmal AF was not generally limited to isolating the PVs and several adjunctive approaches are adopted, particularly in the case of long-lasting persistent AF. Linear lesions or elimination of complex fractionated atrial electrograms were more frequently added. Circular mapping catheters and imaging techniques were seen to be used in about two-thirds of cases. Radiofrequency energy was delivered through open irrigated catheters in 68% of cases. CONCLUSIONS: European centers are largely following the recommendations of the guidelines and the expert consensus documents for AF ablation. AF ablation is mainly performed in relatively young patients with symptomatic drug refractory AF and no or minimal heart disease. Patients with paroxysmal AF are the most frequently treated with a quite uniform ablative approach across Europe. A less standardized approach was observed in nonparoxysmal AF patients.

Enhanced efficiency of a novel porous tip irrigated RF ablation catheter for pulmonary vein isolation.

INTRODUCTION: Irrigated tip radiofrequency (RF) catheter ablation is the most frequently used technology for pulmonary vein isolation (PVI). The purpose of this study was to compare the efficiency and the safety of 2 different open irrigated tip RF ablation catheters. METHODS AND RESULTS: A total of 160 patients with symptomatic AF (29% persistent, 68% male, 61 ± 10 years) were randomized to circumferential PVI using 2 different irrigated tip catheters: (1) the novel Thermocool SF(®) with a porous tip (56 holes) or (2) the Thermocool(®) catheter with 6 irrigation holes at the distal tip in both power- and temperature-controlled modes. PVI procedural time and RF duration were significantly shorter with SF(®) versus Thermocool(®) catheter: 104.5 versus 114 minutes (P = 0.023) and 35.4 minutes versus 39.9 minutes (P < 0.001), respectively. Similarly, the total fluoroscopy time and dose were shorter with SF(®) versus. Thermocool(®) catheter: 21 minutes versus 24 minutes (P = 0.02) and 1014.5 µGy*m(2) versus 1377 µGy*m(2) (P < 0.0001), respectively. Irrigation volume was lower with SF(®): 600 mL versus 1100 mL, (P < 0.0001) and the rates of complications were not significantly different (0.6% vs 0.49%, P = 0.66). At 20.5 ± 7.5 months follow-up, there were no significant differences with regard to arrhythmia freedom between SF(®) (59.2%) and TC® groups (59.3%), (P = 0.61). CONCLUSIONS: Using the novel irrigated tip SF catheter, PVI is achieved within a shorter ablation and procedural durations. The underlying mechanisms and potential differences in RF lesion size remain to be elucidated.

Rapid protein-ligand costructures from sparse NOE data.

An efficient way to rapidly generate protein-ligand costructures based on solution-NMR using sparse NOE data combined with selective isotope labeling is presented. A docked model of the 27 kDa N-terminal ATPase domain of Hsp90 bound to a small molecule ligand was generated using only 21 intermolecular NOEs, which uniquely defined both the binding site and the orientation of the ligand. The approach can prove valuable for the early stages of fragment-based drug discovery.

The Rev1 translesion synthesis polymerase has multiple distinct DNA binding modes.

Rev1 is a eukaryotic DNA polymerase of the Y family involved in translesion synthesis (TLS), a major damage tolerance pathway that allows DNA replication at damaged templates. Uniquely amongst the Y family polymerases, the N-terminal part of Rev1, dubbed the BRCA1 C-terminal homology (BRCT) region, includes a BRCT domain. While most BRCT domains mediate protein-protein interactions, Rev1 contains a predicted α-helix N-terminal to the BRCT domain and in human Replication Factor C (RFC) such a BRCT region endows the protein with DNA binding capacity. Here, we studied the DNA binding properties of yeast and mouse Rev1. Our results show that the BRCT region of Rev1 specifically binds to a 5' phosphorylated, recessed, primer-template junction. This DNA binding depends on the extra α-helix, N-terminal to the BRCT domain. Surprisingly, a stretch of 20 amino acids N-terminal to the predicted α-helix is also critical for high-affinity DNA binding. In addition to 5' primer-template junction binding, Rev1 efficiently binds to a recessed 3' primer-template junction. These dual DNA binding characteristics are discussed in view of the proposed recruitment of Rev1 by 5' primer-template junctions, downstream of stalled replication forks.

Electrophysiological evaluation of pulmonary vein isolation.

Electrophysiologically demonstrated complete conduction block at the level of the veno-atrial junction is preferable as the endpoint of pulmonary vein (PV) ablation rather than circumferential periostial radiofrequency delivery. Knowledge of the individual anatomy of the PVs and the left atrium (LA), appropriate positioning of circular mapping catheters, and the electrophysiology of PV activation in addition to effective ablation tools is necessary to achieve this endpoint. Additional unnecessary ablation and possibly complications can be avoided by the recognition of non-PV myocardial contributions to PV electrograms. The posterior wall of the LA appendage contributes far-field electrograms to recordings from all left superior PVs (LSPV), the low lateral LA to 80% of left inferior PV (LIPV) recordings and the superior vena cava to 23% of right superior PV (RSPV) recordings. Each of these far-field components can be recognized in sinus rhythm as well as during ongoing atrial fibrillation. Finally, the creation of temporally stable and definitive PV isolation remains a currently unsolved problem.

Why can pulmonary vein stenoses created by radiofrequency catheter ablation worsen during and after follow-up? A potential explanation.

BACKGROUND: Radiofrequency catheter ablation of excitation foci inside pulmonary veins (PV) generates stenoses that can become quite severe during or after the follow-up period. Since severe PV stenoses have most often disastrous consequences, it would be important to know the underlying mechanism of this temporal evolution. The present study proposes a potential explanation based on mechanical considerations. METHODS: we have used a mathematical-physical model to examine the cyclic increase in axial wall stress induced in the proximal (= upstream), non-stenosed segment of a stenosed pulmonary vein during the forward flow phases. In a representative example, the value of this increase at peak flow was calculated for diameter stenoses (DS) ranging from 1 to 99%. RESULTS: The increase becomes appreciable at a DS of roughly 30% and rise then strongly with further increasing DS value. At high DS values (e.g. > 90%) the increase is approximately twice the value of the axial stress present in the PV during the zero-flow phase. CONCLUSION: Since abnormal wall stresses are known to induce damages and abnormal biological processes (e.g., endothelium tears, elastic membrane fragmentations, matrix secretion, myofibroblast generation, etc) in the vessel wall, it seems plausible that the supplementary axial stress experienced cyclically by the stenotic and the proximal segments of the PV is responsible for the often observed progressive reduction of the vessel lumen after healing of the ablation injury. In the light of this model, the only potentially effective therapy in these cases would be to reduce the DS as strongly as possible. This implies most probably stenting or surgery.

Linear cryoablation of the left atrium versus pulmonary vein cryoisolation in patients with permanent atrial fibrillation and valvular heart disease: correlation of electroanatomic mapping and long-term clinical results.

BACKGROUND: The aim of this study was to clarify the role of pulmonary vein isolation (PVI) alone versus left atrial linear lesions in the treatment of permanent atrial fibrillation (AF) in patients with left atrial dilatation and valvular disease. The primary end point was to assess the persistence of sinus rhythm (SR) off antiarrhythmic drugs (AADs) at 2-year follow-up and to correlate clinical outcome with surgical results validated with electroanatomic mapping (EAM). METHODS AND RESULTS: A total of 105 patients with permanent AF undergoing valve surgery were assigned to 3 different groups: in groups "U" and "7," left atrial linear cryoablation was performed, whereas in group "PV" patients, anatomic cryoisolation of pulmonary veins only was performed. In groups U and 7, SR was achieved in 57% of patients, whereas it was achieved in 20% of PV patients during 2-year follow-up. In the first 51 patients, the ablation schemes were validated with EAM. The EAM showed that the U lesion was never obtained: in 59% of these patients, a complete 7 lesion was achieved instead; in the 7 group, a complete 7 lesion was present in 65% of patients, whereas a complete PVI was obtained in 71% of patients. Considering patients in whom a complete 7 lesion was demonstrated with the EAM, SR without AADs was achieved in 86% of patients, whereas only 25% of patients with complete PVI were in SR without AADs. CONCLUSIONS: In patients with permanent AF, left atrial dilatation and valvular heart disease linear lesions in the posterior region of the left atrium are more effective than PVI alone. With cryoablation, the surgical intent is fulfilled in only approximately 65% of the cases. Knowing the real anatomic and electrophysiological effects of surgical ablation is necessary to correctly interpret the clinical outcome.

Catheter ablation for atrial fibrillation: mechanism-based curative treatment.

The considerable cumulative morbidity and mortality burden resulting from atrial fibrillation has prompted renewed efforts to seek curative and widely applicable therapies. Currently used drugs are not only frequently ineffective at eliminating fibrillation, but may actually be life threatening. Extensive surgery involving both atria has shown that atrial fibrillation can be eliminated in most, if not all, patients, but at a significant cost. The recent discovery of the pivotal role that myocardial extensions into the pulmonary veins play in the initiation, and probably also the maintenance, of atrial fibrillation, has provided a relatively limited target conducive to catheter-based interventions. In experienced hands, paroxysmal atrial fibrillation can be eliminated in more than 85% of patients by a percutaneous intervention lasting less than 3 h with an attendant nonlethal complication risk of 1 to 2%. Thromboembolic complications and pulmonary vein stenosis are the principal complications that may result from this treatment, but their incidence is decreasing. Success rates in patients with persistent or permanent atrial fibrillation are lower, and it is anticipated that increased understanding of the underlying mechanisms will allow doctors to identify those subsets with the greatest potential for benefit from percutaneous catheter-based interventions. Such progress may allow doctors to extend the benefits of eliminating atrial fibrillation to the widest possible range of patients with this recalcitrant disorder.