Histone deacetylase 1 controls cardiomyocyte proliferation during embryonic heart development and cardiac regeneration in zebrafish.

In contrast to mammals, the zebrafish maintains its cardiomyocyte proliferation capacity throughout adulthood. However, neither the molecular mechanisms that orchestrate the proliferation of cardiomyocytes during developmental heart growth nor in the context of regeneration in the adult are sufficiently defined yet. We identified in a forward genetic N-ethyl-N-nitrosourea (ENU) mutagenesis screen the recessive, embryonic-lethal zebrafish mutant baldrian (bal), which shows severely impaired developmental heart growth due to diminished cardiomyocyte proliferation. By positional cloning, we identified a missense mutation in the zebrafish histone deacetylase 1 (hdac1) gene leading to severe protein instability and the loss of Hdac1 function in vivo. Hdac1 inhibition significantly reduces cardiomyocyte proliferation, indicating a role of Hdac1 during developmental heart growth in zebrafish. To evaluate whether developmental and regenerative Hdac1-associated mechanisms of cardiomyocyte proliferation are conserved, we analyzed regenerative cardiomyocyte proliferation after Hdac1 inhibition at the wound border zone in cryoinjured adult zebrafish hearts and we found that Hdac1 is also essential to orchestrate regenerative cardiomyocyte proliferation in the adult vertebrate heart. In summary, our findings suggest an important and conserved role of Histone deacetylase 1 (Hdac1) in developmental and adult regenerative cardiomyocyte proliferation in the vertebrate heart.

Impact of cryoballoon application abortion due to phrenic nerve injury on reconnection rates: a YETI subgroup analysis.

AIMS: Cryoballoon (CB)-based pulmonary vein isolation (PVI) is an effective treatment for atrial fibrillation (AF). The most frequent complication during CB-based PVI is right-sided phrenic nerve injury (PNI) which is leading to premature abortion of the freeze cycle. Here, we analysed reconnection rates after CB-based PVI and PNI in a large-scale population during repeat procedures. METHODS AND RESULTS: In the YETI registry, a total of 17 356 patients underwent CB-based PVI in 33 centres, and 731 (4.2%) patients experienced PNI. A total of 111/731 (15.2%) patients received a repeat procedure for treatment of recurrent AF. In 94/111 (84.7%) patients data on repeat procedures were available. A total of 89/94 (94.7%) index pulmonary veins (PVs) have been isolated during the initial PVI. During repeat procedures, 22 (24.7%) of initially isolated index PVs showed reconnection. The use of a double stop technique did non influence the PV reconnection rate (P = 0.464). The time to PNI was 140.5 ± 45.1 s in patients with persistent PVI and 133.5 ± 53.8 s in patients with reconnection (P = 0.559). No differences were noted between the two populations in terms of CB temperature at the time of PNI (P = 0.362). The only parameter associated with isolation durability was CB temperature after 30 s of freezing. The PV reconnection did not influence the time to AF recurrence. CONCLUSION: In patients with cryoballon application abortion due to PNI, a high rate of persistent PVI rate was found at repeat procedures. Our data may help to identify the optimal dosing protocol in CB-based PVI procedures. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT03645577?term=YETI&cntry=DE&draw=2&rank=1 ClinicalTrials.gov Identifier: NCT03645577.

Novel cryoballoon ablation system for pulmonary vein isolation: multicenter assessment of efficacy and safety-ANTARCTICA study.

AIMS: Pulmonary vein isolation (PVI) either by balloon devices or radiofrequency forms the cornerstone of invasive atrial fibrillation (AF) treatment. Although equally effective cryoballoon (CB)-based PVI offers shorter procedure duration and a better safety profile. Beside the worldwide established Arctic Front Advance system, a novel CB device, POLARx, was recently introduced. This CB incorporates unique features, which may translate into improved efficacy and safety. However, multicentre assessment of periprocedural efficacy and safety is lacking up to date. METHODS AND RESULTS: A total of 317 patients with paroxysmal or persistent AF were included and underwent POLARx CB-based PVI in 6 centres from Germany and Italy. Acute efficacy and safety were assessed in this prospective multicenter observational study. In 317 patients [mean age: 64 ± 12 years, 209 of 317 (66%) paroxysmal AF], a total of 1256 pulmonary veins (PVs) were identified and 1252 (99,7%) PVs were successfully isolated utilizing mainly the short tip POLARx CB (82%). The mean minimal CB temperature was -57.9 ± 7°C. Real-time PVI was registered in 72% of PVs. The rate of serious adverse events was 6.0% which was significantly reduced after a learning curve of 25 cases (9.3% vs. 3.0%, P = 0.018). The rate of recurrence-free survival after mean follow-up of 226 ± 115 days including a 90-day blanking period was 86.1%. CONCLUSION: In this large multicentre assessment, the novel POLARx CB shows a promising efficacy and safety profile after a short learning curve.

Catheter ablation for atrial fibrillation in HFpEF patients-A propensity-score-matched analysis.

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) and atrial fibrillation (AF) are both common conditions associated with high morbidity and mortality, especially if they coexist. Catheter ablation (CA) for AF has been shown recently to induce reverse remodeling and improve symptoms in HFpEF patients. The aim of this study was to compare outcomes of AF patients with HFpEF, who either underwent CA for AF or received medical therapy only. METHODS AND RESULTS: We included all AF patients with HFpEF according to current guidelines treated at our hospital between 2013 and 2018. Out of 6614 AF patients, we identified 127 with confirmed HFpEF. After applying propensity score matching to balance patient groups, 43 patients treated by CA and 43 patients receiving medical treatment were compared. Patients in the CA group underwent a mean of 1.5 ± 0.8 ablation procedures. Arrhythmia recurrence occurred significantly less frequently in the CA group (hazard ratio [HR]: 0.47; 95% CI: 0.25-0.87; p = .016). The primary endpoint, a composite of heart failure hospitalization and death, was reduced significantly by CA compared to medical therapy (HR: 0.30; 95% CI: 0.13-0.67; p = .003). This was driven by a decrease in heart failure hospitalization. Clinical and echocardiographic parameters of HFpEF improved significantly only after CA. Remarkably, reassessment of diagnostic HFpEF criteria at the end of follow-up demonstrated HFpEF resolution in 15 out of 43 patients (35%) treated by CA and only 4 out of 43 patients (9%) treated medically (p = .008). CONCLUSION: Catheter ablation for AF in HFpEF patients in comparison to medical therapy decreases heart failure hospitalization, heart failure symptoms, and improves diastolic function. AF ablation should be considered in patients with HFpEF and concomitant AF.

Intraventricular Thrombus Formation and Embolism in Takotsubo Syndrome: Insights From the International Takotsubo Registry.

OBJECTIVE: Takotsubo syndrome (TTS) is characterized by acute left ventricular dysfunction, which can contribute to intraventricular thrombus and embolism. Still, prevalence and clinical impact of thrombus formation and embolic events on outcome of TTS patients remain unclear. This study aimed to investigate clinical features and outcomes of patients with and without intraventricular thrombus or embolism. Additionally, factors associated with thrombus formation or embolism, as well as predictors for mortality, were identified. Approach and Results: TTS patients enrolled in the International Takotsubo Registry at 28 centers in Australia, Europe, and the United States were dichotomized according to the occurrence/absence of intraventricular thrombus or embolism. Patients with intraventricular thrombus or embolism were defined as the ThrombEmb group. Of 1676 TTS patients, 56 (3.3%) patients developed intraventricular thrombus and/or embolism following TTS diagnosis (median time interval, 2.0 days [range, 0-38 days]). Patients in the ThrombEmb group had a different clinical profile including lower left ventricular ejection fraction, higher prevalence of the apical type, elevated levels of troponin and inflammatory markers, and higher prevalence of vascular disease. In a Firth bias-reduced penalized-likelihood logistic regression model apical type, left ventricular ejection fraction ≤30%, previous vascular disease, and a white blood cell count on admission >10×103 cells/µL emerged as independent predictors for thrombus formation or embolism. CONCLUSIONS: Intraventricular thrombus or embolism occur in 3.3% of patients in the acute phase of TTS. A simple risk score including clinical parameters associated with intraventricular thrombus formation or embolism identifies patients at increased risk. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01947621.

Safety of conscious sedation in electroanatomical mapping procedures and cryoballoon pulmonary vein isolation.

Immobilization of patients during electrophysiological procedures, to avoid complications by patients' unexpected bodily motion, is achieved by moderate to deep conscious sedation using benzodiazepines and propofol for sedation and opioids for analgesia. Our aim was to compare respiratory and hemodynamic safety endpoints of cryoballoon pulmonary vein isolation (PVI) and electroanatomical mapping (EAM) procedures. Included patients underwent either cryoballoon PVI or EAM procedures. Sedation monitoring included non-invasive blood pressure measurements, transcutaneous oxygen saturation (tSpO2) and transcutaneous carbon-dioxide (tpCO2) measurements. We enrolled 125 consecutive patients, 67 patients underwent cryoballoon atrial fibrillation ablation and 58 patients had an EAM and radiofrequency ablation procedure. Mean procedure duration of EAM procedures was significantly longer (p < 0.001) and propofol doses as well as morphine equivalent doses of administered opioids were significantly higher in EAM patients compared to cryoballoon patients (p < 0.001). Cryoballoon patients display higher tpCO2 levels compared to EAM patients at 30 min (cryoballoon: 51.1 ± 7.0 mmHg vs. EAM: 48.6 ± 6.2 mmHg, p = 0.009) and at 60 min (cryoballoon: 51.4 ± 7.3 mmHg vs. EAM: 48.9 ± 6.6 mmHg, p = 0.07) procedure duration. Mean arterial pressure was significantly higher after 60 min (cryoballoon: 84.7 ± 16.7 mmHg vs. EAM: 76.7 ± 13.3 mmHg, p = 0.017) in cryoballoon PVI compared to EAM procedures. Regarding respiratory and hemodynamic safety endpoints, no significant difference was detected regarding hypercapnia, hypoxia and episodes of hypotension. Despite longer procedure duration and deeper sedation requirement, conscious sedation in EAM procedures appears to be as safe as conscious sedation in cryoballoon ablation procedures regarding hemodynamic and respiratory safety endpoints.

Coexistence and outcome of coronary artery disease in Takotsubo syndrome.

AIMS: Takotsubo syndrome (TTS) is an acute heart failure syndrome, which shares many features with acute coronary syndrome (ACS). Although TTS was initially described with angiographically normal coronary arteries, smaller studies recently indicated a potential coexistence of coronary artery disease (CAD) in TTS patients. This study aimed to determine the coexistence, features, and prognostic role of CAD in a large cohort of patients with TTS. METHODS AND RESULTS: Coronary anatomy and CAD were studied in patients diagnosed with TTS. Inclusion criteria were compliance with the International Takotsubo Diagnostic Criteria for TTS, and availability of original coronary angiographies with ventriculography performed during the acute phase. Exclusion criteria were missing views, poor quality of angiography loops, and angiography without ventriculography. A total of 1016 TTS patients were studied. Of those, 23.0% had obstructive CAD, 41.2% had non-obstructive CAD, and 35.7% had angiographically normal coronary arteries. A total of 47 patients (4.6%) underwent percutaneous coronary intervention, and 3 patients had acute and 8 had chronic coronary artery occlusion concomitant with TTS, respectively. The presence of CAD was associated with increased incidence of shock, ventilation, and death from any cause. After adjusting for confounders, the presence of obstructive CAD was associated with mortality at 30 days. Takotsubo syndrome patients with obstructive CAD were at comparable risk for shock and death and nearly at twice the risk for ventilation compared to an age- and sex-matched ACS cohort. CONCLUSIONS: Coronary artery disease frequently coexists in TTS patients, presents with the whole spectrum of coronary pathology including acute coronary occlusion, and is associated with adverse outcome. TRIAL REGISTRATION: ClinicalTrials.gov number: NCT01947621.

Restoration of sinus rhythm by pulmonary vein isolation improves heart failure with preserved ejection fraction in atrial fibrillation patients.

AIMS: Atrial fibrillation (AF) in patients suffering from heart failure with preserved ejection fraction (HFpEF) is associated with increased symptoms and higher morbidity and mortality. Effective treatment strategies for this patient population have not yet been established. METHODS AND RESULTS: We analysed clinical outcomes and echocardiographic parameters of patients with AF and HFpEF who underwent pulmonary vein isolation (PVI). Out of 374 PVI patients, we identified 35 patients suffering from concomitant HFpEF. Freedom from atrial tachyarrhythmia (AT) after 1 year was 80%. Heart failure symptoms assessed by New York Heart Association class significantly improved from 2.7 ± 0.7 to 1.7 ± 0.9 (P < 0.001). We observed regression of diastolic dysfunction by echocardiography 12 months after the index procedure. Moreover, 15 patients (42.9%) experienced complete resolution of HFpEF after a single ablation procedure. Multivariate logistic regression revealed absence of AT recurrence as an independent predictor of recovery from HFpEF (hazard ratio 11.37, 95% confidence interval 1.70-75.84, P = 0.009). Furthermore, resolution of HFpEF by achieving freedom from AT recurrence by PVI, including multiple procedures, led to a significant reduction of hospitalizations. CONCLUSION: Our results suggest that restoration of sinus rhythm by PVI in HFpEF patients with concomitant AF induces reverse remodelling, improvement of symptoms, resolution of HFpEF and subsequently decrease of hospitalizations. Randomized controlled trials are warranted to confirm our results.

Novel spiral mapping catheter facilitates observation of the time-to-pulmonary vein isolation during cryoballoon ablation.

Observation of the time-to-pulmonary vein isolation (TTI) by a spiral mapping catheter has emerged as a valuable procedural parameter in cryoballoon pulmonary vein isolation (PVI). The 1st generation spiral mapping catheter (Achieve, SMC1) has been available as an 8-polar catheter with a distal loop diameter of 15 or 20 mm. The novel spiral mapping catheter (Achieve Advance, SMC2) was designed as a true guidewire and is available, in addition to the sizes of the SMC1, as a 10-polar mapping catheter with a distal loop diameter of 25 mm. Whether these novel features of SMC2 influence procedural characteristics of Cryo-PVI in comparison to SMC1 has not been reported. In this prospective cohort study 158 patients (age 65.1 ± 12.4 years, female 39%, paroxysmal AF 60%) undergoing PVI with the 2nd generation cryoballoon were included. SMC1 was used in 57 patients (36%), whereas 101 patients (64%) underwent Cryo-PVI with the SMC2. All PVs (623/623, 100%) were isolated successfully. Mean procedure duration was 72.0 ± 18.9 min in the SMC1 group and 74.4 ± 19.1 min in the SMC2 group (p = 0.432). Mean fluoroscopy time was also not different between both study groups (SMC1 15.7 ± 6.6 min, SMC2 15.7 ± 7.3 min, p = 0.593). TTI was observed in 68.6% of pulmonary veins in the SMC1 group, whereas TTI observation rate was 82.6% in the SMC2 group (p < 0.001). Number of freezes (5.5 ± 1.5 vs. 6.5 ± 1.9; p = 0.001) and total freeze duration (14.1 ± 4.5 vs. 17.6 ± 5.6; p < 0.001) were increased in the SMC2 group. SMC2 significantly increases TTI observation rate during Cryo-PVI. Procedure duration and fluoroscopy time are similar and number of freezes and total freeze duration are increased compared to PVI with SMC1 due to decreased stability and maneuverability of SMC2.

Mutation of the Na+/K+-ATPase Atp1a1a.1 causes QT interval prolongation and bradycardia in zebrafish.

The genetic underpinnings that orchestrate the vertebrate heart rate are not fully understood yet, but of high clinical importance, since diseases of cardiac impulse formation and propagation are common and severe human arrhythmias. To identify novel regulators of the vertebrate heart rate, we deciphered the pathogenesis of the bradycardia in the homozygous zebrafish mutant hiphop (hip) and identified a missense-mutation (N851K) in Na+/K+-ATPase α1-subunit (atp1a1a.1). N851K affects zebrafish Na+/K+-ATPase ion transport capacity, as revealed by in vitro pump current measurements. Inhibition of the Na+/K+-ATPase in vivo indicates that hip rather acts as a hypomorph than being a null allele. Consequently, reduced Na+/K+-ATPase function leads to prolonged QT interval and refractoriness in the hip mutant heart, as shown by electrocardiogram and in vivo electrical stimulation experiments. We here demonstrate for the first time that Na+/K+-ATPase plays an essential role in heart rate regulation by prolonging myocardial repolarization.

Atrial Fibrillation Ablation with a Novel Fully 3D-Mapping-Integrated Multi-Electrode Radiofrequency Balloon Catheter.

Pulmonary vein isolation (PVI), as the cornerstone of atrial fibrillation (AF) ablation, has emerged a widely used therapy for patients suffering from AF. To improve PVI efficiency, single-shot catheters (SSCs) have been developed. Regrettably, SSCs are not integrated into 3D-mapping technology. In that regard, a novel radiofrequency balloon catheter (RFBC, Heliostar, Biosense Webster) with full integration into 3D-mapping technology has been developed. The aim of this study was to assess operative and follow-up outcomes of the RFBC in AF patients. In this monocentric prospective registry, patients with a first-time PVI using the RFBC were included. Follow-up visits were scheduled 3, 6, 12 and 24 months after ablation and in case of symptoms. A total of 171 patients (36.8% female) were included, with a mean age of 68.5 ± 10.2 years. Among them, 63 patients (36.8%) presented with persistent AF. Notably, no major periprocedural complications were observed. The mean follow-up period was 287 ± 157 days. In the Kaplan-Meier analysis, the estimated recurrence-free survival after 12 months was 81.8%. Based on our data, PVI with the fully 3D-mapping-integrated RFBC seems to be safe and effective and to have a favorable 12-month outcome in patients with paroxysmal and persistent AF.

Incidence of premature battery depletion in subcutaneous cardioverter-defibrillator patients: insights from a multicenter registry.

BACKGROUND: The subcutaneous ICD established its role in the prevention of sudden cardiac death in recent years. The occurrence of premature battery depletion in a large subset of potentially affected devices has been a cause of concern. The incidence of premature battery depletion has not been studied systematically beyond manufacturer-reported data. METHODS: Retrospective data and the most recent follow-up data on S-ICD devices from fourteen centers in Europe, the US, and Canada was studied. The incidence of generator removal or failure was reported to investigate the incidence of premature S-ICD battery depletion, defined as battery failure within 60 months or less. RESULTS: Data from 1054 devices was analyzed. Premature battery depletion occurred in 3.5% of potentially affected devices over an observation period of 49 months. CONCLUSIONS: The incidence of premature battery depletion of S-ICD potentially affected by a battery advisory was around 3.5% after 4 years in this study. Premature depletion occurred exclusively in devices under advisory. This is in line with the most recently published reports from the manufacturer. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04767516 .

Machine learning-based prediction of in-hospital death for patients with takotsubo syndrome: The InterTAK-ML model.

AIMS: Takotsubo syndrome (TTS) is associated with a substantial rate of adverse events. We sought to design a machine learning (ML)-based model to predict the risk of in-hospital death and to perform a clustering of TTS patients to identify different risk profiles. METHODS AND RESULTS: A ridge logistic regression-based ML model for predicting in-hospital death was developed on 3482 TTS patients from the International Takotsubo (InterTAK) Registry, randomly split in a train and an internal validation cohort (75% and 25% of the sample size, respectively) and evaluated in an external validation cohort (1037 patients). Thirty-one clinically relevant variables were included in the prediction model. Model performance represented the primary endpoint and was assessed according to area under the curve (AUC), sensitivity and specificity. As secondary endpoint, a K-medoids clustering algorithm was designed to stratify patients into phenotypic groups based on the 10 most relevant features emerging from the main model. The overall incidence of in-hospital death was 5.2%. The InterTAK-ML model showed an AUC of 0.89 (0.85-0.92), a sensitivity of 0.85 (0.78-0.95) and a specificity of 0.76 (0.74-0.79) in the internal validation cohort and an AUC of 0.82 (0.73-0.91), a sensitivity of 0.74 (0.61-0.87) and a specificity of 0.79 (0.77-0.81) in the external cohort for in-hospital death prediction. By exploiting the 10 variables showing the highest feature importance, TTS patients were clustered into six groups associated with different risks of in-hospital death (28.8% vs. 15.5% vs. 5.4% vs. 1.0.8% vs. 0.5%) which were consistent also in the external cohort. CONCLUSION: A ML-based approach for the identification of TTS patients at risk of adverse short-term prognosis is feasible and effective. The InterTAK-ML model showed unprecedented discriminative capability for the prediction of in-hospital death.

Real-Time Spiral CMR Is Superior to Conventional Segmented Cine-Imaging for Left-Ventricular Functional Assessment in Patients with Arrhythmia.

(1) Background: Segmented Cartesian Cardiovascular magnetic resonance (CMR) often fails to deliver robust assessment of cardiac function in patients with arrhythmia. We aimed to assess the performance of a tiny golden-angle spiral real-time CMR sequence at 1.5 T for left-ventricular (LV) volumetry in patients with irregular heart rhythm; (2) Methods: We validated the real-time sequence against the standard breath-hold segmented Cartesian sequence in 32 patients, of whom 11 presented with arrhythmia. End-diastolic volume (EDV), end-systolic volume (ESV), stroke volume (SV), and ejection fraction (EF) were assessed. In arrhythmic patients, real-time and standard Cartesian acquisitions were compared against a reference echocardiographic modality; (3) Results: In patients with sinus rhythm, good agreements and correlations were found between the segmented and real-time methods, with only minor, non-significant underestimation of EDV for the real-time sequence (135.95 ± 30 mL vs. 137.15 ± 31, p = 0.164). In patients with arrhythmia, spiral real-time CMR yielded superior image quality to the conventional segmented imaging, allowing for excellent agreement with the reference echocardiographic volumetry. In contrast, in this cohort, standard Cartesian CMR showed significant underestimation of LV-ESV (106.72 ± 63.51 mL vs. 125.47 ± 72.41 mL, p = 0.026) and overestimation of LVEF (42.96 ± 10.81% vs. 39.02 ± 11.72%, p = 0.039); (4) Conclusions: Real-time spiral CMR improves image quality in arrhythmic patients, allowing reliable assessment of LV volumetry.

Substrate-based ablation of atypical atrial flutter in patients with atrial cardiomyopathy.

Background: Standard therapy of atypical atrial flutter (AFL) aims at deploying ablation lines between two non-conducting anatomical structures, thereby creating a line of block within the re-entry circuit. We have developed an ablation strategy, where we incorporate voltage information as a surrogate for atrial fibrosis from the electro-anatomical map (EAM) during AFL ablation procedures to create individualized, substrate-based ablation lines along the area of most pronounced low-voltage within the reentry-circuit. Objective: The aim of this study was to evaluate acute procedural success and long-term outcome of a substrate-based ablation (SBA) strategy in comparison to a standard anatomically based ablation (ABA) strategy for the ablation of atypical AFL. Methods: Patients that underwent ablation for AFL at our institution were included. SBA procedures were compared to ABA procedures. Endpoints were acute termination of AFL and recurrence of the index AFL or any other AFL during follow-up. Results: We included 47 patients, 24 individuals (51.1%) in the SBA group and 23 patients (48.9%) in the ABA group. Most patients had signs of atrial cardiomyopathy, namely enlarged left atrial diameter (LAD) and extended amount of left atrial low-voltage areas (LVA). Termination of AFL occurred in 27 of 29 (93.1%) AFL in the SBA group and in 28 of 31 (90.3%) AFL in the ABA group (p = 0.99). Freedom from recurrence of any atypical AFL after 2.5 years was 21.5% in the ABA group compared to 48.8% in the SBA group (p = 0.047). Conclusion: Substrate-based ablation is as effective as an anatomically-based ablation in the acute termination of AFL but yields better rhythm outcome with less recurrence of AFL in patients with atrial cardiomyopathy.

Incidence of Long-Term Pulmonary Vein Reconnection after a 2-Minute Cryoballoon Freeze for Pulmonary Vein Isolation-Invasive Insights of TTI-Dependent Cryoenergy Titration.

INTRODUCTION: The optimal freeze duration in cryoballoon pulmonary vein isolation (PVI) is unknown. TTI-based titration of cryoenergy allows individualized freeze duration and has emerged as a favorable ablation strategy in PV cryoablation. In a recent study, we demonstrated that omission of a bonus freeze and reduction in freeze duration to a minimum of 2 min in the case of short TTI led to comparable arrhythmia recurrence rates. Whereas clinical outcome seems to be comparable to fixed freeze duration, evidence of long-term PV reconnection rates in patients undergoing TTI-based cryoballoon ablation is sparse. AIM OF THE STUDY: To evaluate the procedural efficacy of a single 2-min freeze for PVI, we assessed PV conduction recovery after cryoballoon PVI with a TTI-guided titration of freeze duration compared to a fixed ablation protocol. METHODS AND RESULTS: We included consecutive patients with atrial fibrillation (AF) recurrence undergoing a second ablation procedure after the initial cryoballoon procedure. The second AF ablation procedure was performed by the 3D-mapping system and radiofrequency ablation technique. A total of 219 patients (age: 66.2 ± 10.8 years, 53% female, paroxysmal AF: 53%) treated with the TTI-guided protocol (174 patients, 685 PV) or fixed protocol (45 patients, 179 PV) showed comparable total reconnection rates (TTI: 36.9% vs. fixed: 31.8%, p = 0.21). The PV reconnection rate was not statistically different for PVs treated with a 2-min freeze in case of short TTI, compared to longer freeze duration. Interestingly, the PV reconnection rate was lower in LIPVs treated with the fixed protocol (13% vs. 31%, p = 0.029). In the TTI group, 17 out of 127 patients (15%) had durable isolation of all PVs, whereas in 8 out of 40 patients (20%) in the fixed group, all PVs were still isolated (p = 0.31). CONCLUSIONS: overall reconnection rate was not different using a TTI-guided ablation protocol compared to a fixed ablation protocol, whereas the LIPV reconnection rate was significantly lower in patients treated with a fixed ablation protocol.

Deferral of non-emergency cardiac procedures is associated with increased early emergency cardiovascular hospitalizations.

BACKGROUND: During the COVID-19 pandemic, in anticipation of a demand surge for high-care hospital beds, many hospitals postponed non-emergency interventions of cardiac patients. AIM: The aim of this study was to assess the outcomes of cardiac patients whose non-emergency interventions had been deferred during the COVID-19 pandemic. METHODS: Patients whose non-emergency cardiac intervention had been cancelled between March 19th and April 30th, 2020 were included (study group). All patients were considered as deferrable according to current recommendations. Patients' outcomes after 12 months were compared to a seasonal control group who underwent non-emergency interventions in 2019 as scheduled. The primary endpoint was a composite of emergency cardiovascular hospitalization and death. Secondary endpoints were levels of symptoms and cardiac biomarkers. RESULTS: Outcomes of 193 consecutive patients in the study group were assessed and compared to 216 controls. The primary endpoint occurred significantly more often in the study group (HR 2.42, 95%CI 1.63-3.61, p < 0.001). This was driven by an increase in hospitalizations. Subgroup analyses showed that especially patients with a deferred transcatheter heart valve intervention experienced early emergency hospitalization (HR 9.55, 95%CI 3.70-24.62, p < 0.001). These findings were accompanied by more pronounced symptoms and higher biomarker levels. CONCLUSIONS: Deferral of non-emergency cardiac interventions to meet the higher demand for hospital beds during the COVID-19 crisis is associated with early emergency cardiovascular hospitalizations. Patients suffering from valvular heart disease especially constitute a vulnerable group. Consequently, our results suggest that current recommendations on the management of cardiovascular disease during the COVID-19 pandemic need revision.

Phrenic Nerve Injury During Cryoballoon-Based Pulmonary Vein Isolation: Results of the Worldwide YETI Registry.

BACKGROUND: Cryoballoon-based pulmonary vein isolation (PVI) has emerged as an effective treatment for atrial fibrillation. The most frequent complication during cryoballoon-based PVI is phrenic nerve injury (PNI). However, data on PNI are scarce. METHODS: The YETI registry is a retrospective, multicenter, and multinational registry evaluating the incidence, characteristics, prognostic factors for PNI recovery and follow-up data of patients with PNI during cryoballoon-based PVI. Experienced electrophysiological centers were invited to participate. All patients with PNI during CB2 or third (CB3) and fourth-generation cryoballoon (CB4)-based PVI were eligible. RESULTS: A total of 17 356 patients underwent cryoballoon-based PVI in 33 centers from 10 countries. A total of 731 (4.2%) patients experienced PNI. The mean time to PNI was 127.7±50.4 seconds, and the mean temperature at the time of PNI was -49±8°C. At the end of the procedure, PNI recovered in 394/731 patients (53.9%). Recovery of PNI at 12 months of follow-up was found in 97.0% of patients (682/703, with 28 patients lost to follow-up). A total of 16/703 (2.3%) reported symptomatic PNI. Only 0.06% of the overall population showed symptomatic and permanent PNI. Prognostic factors improving PNI recovery are immediate stop at PNI by double-stop technique and utilization of a bonus-freeze protocol. Age, cryoballoon temperature at PNI, and compound motor action potential amplitude loss >30% were identified as factors decreasing PNI recovery. Based on these parameters, a score was calculated. The YETI score has a numerical value that will directly represent the probability of a specific patient of recovering from PNI within 12 months. CONCLUSIONS: The incidence of PNI during cryoballoon-based PVI was 4.2%. Overall 97% of PNI recovered within 12 months. Symptomatic and permanent PNI is exceedingly rare in patients after cryoballoon-based PVI. The YETI score estimates the prognosis after iatrogenic cryoballoon-derived PNI. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03645577. Graphic Abstract: A graphic abstract is available for this article.

Predicting Phrenic Nerve Palsy in Patients Undergoing Atrial Fibrillation Ablation With the Cryoballoon-Does Sex Matter?

Background: Phrenicus nerve palsy (PNP) is a typical complication during pulmonary vein isolation (PVI) using the cryoballoon with the ominous potential to counteract the clinical benefit of restored sinus rhythm. According to current evidence incidence of PNP is about 5-10% of patients undergoing Cryo-PVI and is more frequent during ablation of the RSPV compared to the RIPV. However, information on patient specific characteristics predicting PNP and long-term outcome of patients suffering from this adverse event is sparse. Aim of the Study: To evaluate procedural and clinical characteristics of AF patients with PNP during cryoballoon PVI compared to patients without PNP. Methods and Results: Between 2013 and 2019 we included 632 consecutive AF patients undergoing PVI with the cryoballoon in our study. 84/632 (13.3%) patients experienced a total number of 89 PNP during the ablation procedure. 75/89 (84%) cryothermal induced PNP recovered until the end of the procedure (transient PNP, tPNP), whereas 14/89 (16%) PNP hold beyond the end of the procedure (non-transient PNP, ntPNP). Using multivariate logistic regression, we found that sex and BMI are strong and independent predictors of cryothermal induced non-transient PNP during cryoballoon PVI with an odds ratio of 3.9 (CI: 95%, 1.1-14.8, p = 0.04) for female gender. Interestingly, all patients (14/14, 100%) with a non-transient PNP experienced complete PNP resolution after a mean recovery time of 68 ± 79 days. Conclusion: Our data indicate for the first time, that female sex and lower BMI are independent predictors for non-transient PNP caused by cryoballoon PVI. Fortunately, during follow up all PNP patients resolved completely with a median recovery time of 35 days.