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Aims: Atrial fibrillation (AF) worsens the prognosis of patients with heart failure (HF). Successful treatments are still very scarce for those with permanent AF and preserved (HFpEF) or mildly reduced (HFmrEF) ejection fraction. In this study, the long-term benefits and safety profile of heart rate regularization through left-bundle branch pacing (LBBP) and atrioventricular node ablation (AVNA) will be explored in comparison with pharmacological rate-control strategy., Methods and Results: The PACE-FIB trial is a multicentre, prospective, open-label, randomized (1:1) clinical study that will take place between March 2022 and February 2027. A total of 334 patients with HFpEF/HFmrEF and permanent AF will receive either LBBP followed by AVNA (intervention arm) or optimal pharmacological treatment for heart rate control according to European guideline recommendations (control arm). All patients will be followed up for a minimum of 36 months. The primary outcome measure will be the composite of all-cause mortality, HF hospitalization, and worsening HF at 36 months. Other secondary efficacy and safety outcome measures such as echocardiographic parameters, functional status, and treatment-related adverse events, among others, will be analysed too., Conclusion: LBBP is a promising stimulation mode that may foster the clinical benefit of heart rate regularization through AV node ablation compared with pharmacological rate control. This is the first randomized trial specifically addressing the long-term efficacy and safety of this pace-and-ablate strategy in patients with HFpEF/HFmrEF and permanent AF., (© 2023 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: Cryoballoon pulmonary vein isolation (CB-PVI) offers similar efficacy to point-by-point radiofrequency PVI for patients with atrial fibrillation (AF), but generally with higher X-ray exposure. Strategies aimed at reducing fluoroscopy mostly rely on other costly imaging techniques, limiting their applicability. We designed a Systematic Workflow and Electrogram guidance to reduce X-ray Exposure Time during CB-PVI (SWEET-Cryo) strategy and analysed its impact on fluoroscopy use and acute procedural and clinical outcomes., Methods and Results: We enrolled 100 patients with paroxysmal or persistent AF undergoing CB-PVI by two operators with different levels of expertise. Patients treated with the SWEET-Cryo strategy (prospective cohort; n = 50) or conventional fluoroscopy (retrospective control cohort; n = 50) were compared. When applied by the senior operator, the SWEET-Cryo strategy significantly reduced the mean fluoroscopy time (FT) (2.6 ± 1.25 vs. 20.3 ± 10.8 min) and mean dose area product (DAP) (5.1 ± 3.8 vs. 35.3 ± 22.3 Gy cm2) compared with those of the control group, respectively (P < 0.001). Significant reductions in FT (6.4 ± 2.5 min vs. 32.5 ± 10.05) and DAP (13.9 ± 7.7 vs. 92.3 ± 63.8) were also achieved by the less experienced operator (P < 0.001). No difference was observed in acute and long-term complications or freedom from AF between fluoroscopy strategies during a 33-month median follow-up. Mean FT was maintained below 3 min in randomly selected cases performed during the follow-up period., Conclusion: In contrast to conventional protocols and regardless of the operator's experience, the optimized SWEET-Cryo strategy dramatically reduced fluoroscopy exposure during CB-PVI. The efficacy, safety, or added costs of the ablation procedure were not compromised., Competing Interests: Conflict of interest: D.R.M. and F.A.Y. have received honoraria for lectures and educational events from Medtronic. All remaining authors have declared no conflicts of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Metabolic reprogramming is required to fight infections and thyroid hormones are key regulators of metabolism. We have analyzed in hospitalized COVID-19 patients: 40 euthyroid and 39 levothyroxine (LT4)-treated patients in the ward and 29 euthyroid and 9 LT4-treated patients in the intensive care unit (ICU), the baseline characteristics, laboratory data, thyroid-stimulating hormone (TSH), free thyroxine (FT4), free triiodothyronine (FT3), the FT3/FT4 ratio, 11 antiviral cytokines and 74 metabolomic parameters. No evidence for significant differences between euthyroid and LT4-treated patients were found in the biochemical, metabolomic and cytokines parameters analyzed. Only TSH (p=0.009) and ferritin (p=0.031) showed significant differences between euthyroid and LT4-treated patients in the ward, and TSH (p=0.044) and FT4 (p=0.012) in the ICU. Accordingly, severity and mortality were similar in euthyroid and LT4-treated patients. On the other hand, FT3 was negatively related to age (p=0.012), independently of sex and body mass index in hospitalized COVID-19 patients. Patients with low FT3 and older age showed a worse prognosis and higher levels of the COVID-19 severity markers IL-6 and IL-10 than patients with high FT3. IL-6 negatively correlated with FT3 (p=0.023) independently of age, body mass index and sex, whereas IL-10 positively associated with age (p=0.035) independently of FT3, body mass index and sex. A metabolomic cluster of 6 parameters defined low FT3 ward patients. Two parameters, esterified cholesterol (p=4.1x10 -4 ) and small HDL particles (p=6.0x10 -5 ) correlated with FT3 independently of age, body mass index and sex, whereas 3-hydroxybutyrate (p=0.010), acetone (p=0.076), creatinine (p=0.017) and high-density-lipoprotein (HDL) diameter (p=8.3x10 -3 ) were associated to FT3 and also to age, with p-values of 0.030, 0.026, 0.017 and 8.3x10 -3 , respectively. In conclusion, no significant differences in FT3, cytokines, and metabolomic profile, or in severity and outcome of COVID-19, were found during hospitalization between euthyroid patients and hypothyroid patients treated with LT4. In addition, FT3 and age negatively correlate in COVID-19 patients and parameters that predict poor prognosis were associated with low FT3, and/or with age. A metabolomic cluster indicative of a high ketogenic profile defines non-critical hospitalized patients with low FT3 levels., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Amich, Anguita, Escribano-Serrat, Alvarez, Rodríguez-Muñoz, García, Bello, Peña-Pedrosa, Martínez-Micaelo, Amigó, Ortiz, Torrejón, Boscá, Martín-Sánchez, Aranda and Alemany.)

A 54-year-old woman with symptomatic premature ventricular contractions (PVC) was referred for electrophysiological study. The earliest activation was located at the parahisian area, so it was decided to ablate using cryoenergy. No AV conduction impairment was observed during cryomapping. PVCs were abolished after the first 15 seconds of cryoablation, without recurrence. However, after 354 seconds of cryoablation, a mild PR prolongation was followed by first degree and 2-to-1 AV block. Termination of cryoablation led to complete recovery without definitive damage and with elimination of the PVC. This case illustrates how lesion formation using cryoenergy can continue to evolve even after several minutes, highlighting the need of monitoring throughout the whole target duration., Competing Interests: Declaration of competing interest No conflict of interest exists for any of the authors., (Copyright © 2022 Indian Heart Rhythm Society. Published by Elsevier B.V. All rights reserved.)

Oncogene-immortalized bone marrow-derived macrophages are considered to be a good model for the study of immune cell functions, but the factors required for their survival and proliferation are still unknown. Although the effect of the thyroid hormones on global metabolic and transcriptional responses in macrophages has not yet been examined, there is increasing evidence that they could modulate macrophage functions. We show here that the thyroid hormone T3 is an absolute requirement for the growth of immortal macrophages. The hormone regulates the activity of the main signaling pathways required for proliferation and anabolic processes, including the phosphorylation of ERK and p38 MAPKs, AKT, ribosomal S6 protein, AMPK and Sirtuin-1. T3 also alters the levels of metabolites controlling transcriptional and post-transcriptional actions in macrophages, and causes widespread transcriptomic changes, up-regulating genes needed for protein synthesis and cell proliferation, while down-regulating genes involved in immune responses and endocytosis, among others. This is not observed in primary bone marrow-derived macrophages, where only p38 and AMPK activation is regulated by T3 and in which the metabolic and transcriptomic effects of the hormone are much weaker. However, the response to IFN-γ is reduced by T3 similarly in immortalized macrophages and in the primary cells, confirming previous results showing that the thyroid hormones can antagonize JAK/STAT-mediated signaling. These results provide new perspectives on the relevant pathways involved in proliferation and survival of macrophage cell culture models and on the crosstalk between the thyroid hormones and the immune system., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 López-Mateo, Rodríguez-Muñoz, de La Rosa, Castrillo, Alemany and Aranda.)

The coronavirus disease 2019 (COVID-19) pandemic has resulted in a deep restructuring of cardiovascular care, especially in the setting of cardiac arrhythmia units, which are characterized by a wide variety of clinical and interventional activities. We describe the experience of a large university hospital deeply hit during the COVID-19 health crisis (first outbreak of the pandemic), focusing on the exceptional measures implemented and their impact in terms of outcomes. We performed a retrospective study comparing the human and structural resources and the activity of a cardiac arrhythmia unit in a Spanish tertiary hospital for two consecutive periods: from January 12, 2020, to March 8, 2020 ("pre-COVID stage"), and from March 9, 2020, to May 2, 2020 ("COVID stage"). Data were contextualized within the number of confirmed COVID-19 cases in the region of Madrid. The measures implemented were promotion of non-face-to-face consultations, selection of urgent procedures, design of a "COVID-free" circuit for outpatient interventions, and protocolization for patients with COVID-19. A total of 3,526 consultations and 362 procedures were performed. During the COVID stage, the number of consultations remained stable, and the electrophysiology rooms' activity decreased by 55.2% with a relative increase in the number of urgent-hospitalized cases attended (11.8% COVID-19-positive patients). The electrophysiology rooms' activity returned to "normal" in the last week of the COVID stage, with no contagion being detected among patients or professionals. In conclusion, the measures implemented allowed us to respond safely and efficiently to the health care needs of patients with arrhythmias during the COVID-19 crisis and may be useful for other institutions facing similar situations., Competing Interests: The authors report no conflicts of interest for the published content., (Copyright: © 2021 Innovations in Cardiac Rhythm Management.)

Bone marrow erythropoiesis is mainly homeostatic and a demand of oxygen in tissues activates stress erythropoiesis in the spleen. Here, we show an increase in the number of circulating erythrocytes in apolipoprotein E -/- mice fed a Western high-fat diet, with similar number of circulating leukocytes and CD41 + events (platelets). Atherogenic conditions increase spleen erythropoiesis with no variations of this cell lineage in the bone marrow. Spleens from atherogenic mice show augmented number of late-stage erythroblasts and biased differentiation of progenitor cells towards the erythroid cell lineage, with an increase of CD71 + CD41CD34 - CD117 + Sca1 - Lin - cells (erythroid-primed megakaryocyte-erythroid progenitors), which is consistent with the way in which atherogenesis modifies the expression of pro-erythroid and pro-megakaryocytic genes in megakaryocyte-erythroid progenitors. These data explain the transiently improved response to an acute severe hemolytic anemia insult found in atherogenic mice in comparison to control mice, as well as the higher burst-forming unit-erythroid and colony forming unit-erythroid capacity of splenocytes from atherogenic mice. In conclusion, our work demonstrates that, along with the well stablished enhancement of monocytosis during atherogenesis, stress erythropoiesis in apolipoprotein E -/- mice fed a Western high fat diet results in increased numbers of circulating red blood cells.

Background: Left ventricular assist devices (LVAD) are increasingly used in patients with advanced heart failure, many of whom have been or will be implanted with an implantable cardioverter defibrillator (ICD). Interaction between both devices is a matter of concern. Subcutaneous ICD (S-ICD) obtains its signals through subcutaneous vectors, which poses special challenges with regards to adequate performance following LVAD implantation., Case Summary: We describe the case of a 24-year-old man implanted with an S-ICD because of idiopathic dilated cardiomyopathy, severe biventricular dysfunction, and self-limiting sustained ventricular tachycardias. After the implantation of a HeartMate 3™ (Left Ventricular Assist System, Abbott) several months later, the S-ICD became useless because of inappropriate sensing due to electromagnetic interference and attenuation of QRS voltage., Discussion: We reviewed the reported cases in PubMed about the concomitant use of S-ICD and LVAD. Seven case reports about the performance of S-ICD in patients with an LVAD were identified, with discordant results. From these articles, we analyse the potential causes for these differing results. Pump location and operating rates in LVAD, as well as changes in the subcutaneous-electrocardiogram detected by the S-ICD after LVAD implantation are related to sensing disturbances when used in the same patient., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Optimal atrioventricular delay (AVD) achieves maximum cardiac output in patients undergoing cardiac resynchronization therapy (CRT). Nonoptimal AVD decreases left ventricular (LV) end-diastolic volume and causes loss of flow momentum prior to LV ejection., Objective: We investigated the potential role of energy dissipation (ED) in these changes in cardiac output through the study of intraventricular flow. We hypothesized that short and long AVD increases ED when compared with optimal AVD by altering the physiologic flow mechanics that preserve kinetic energy in the LV., Methods: Forty-four patients under CRT underwent echocardiographic LV flow analysis under optimal, short, and long AVD. LV ED and vortical flow in the inflow-outflow tract were studied during the end-diastolic and early systolic period, and paired comparisons were obtained between optimal and nonoptimal values., Results: ED in the left ventricle was minimal in optimal AVD and significantly increased with nonoptimal values (79.1 ± 27.5 J/m·sec in optimal AVD vs 96.5 ± 34.7 J/m·sec in short AVD; n = 18, P = .006; 123.3 ± 67.6 J/m·sec in optimal AVD vs 292.4 ± 202.5 J/m·sec in long AVD; P < .001). Increase in ED occurred due to inadequate flow redirection toward the outflow tract in short AVD and due to both turbulence and prolonged ineffective flow rotation in long AVD., Conclusions: Optimal AVD in resynchronization therapy favors physiological vortex flow patterns in the left ventricle during the end-diastolic and early systolic period. These patterns are altered when nonoptimal values are programmed, increasing ED., (Copyright © 2019 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved.)

Background: Flow entering the left ventricle is reversed toward the outflow tract through rotating reversal flow around the mitral valve. This was thought to facilitate early ejection, but had not been proved to date. We hypothesized that perfect coupling between reversal and ejection flow would occur at optimal atrioventricular delay (AVD), contributing to its hemodynamic superiority, and evaluated its applicability for AVD optimization., Methods and Results: Forty consecutive patients with cardiac resynchronization therapy underwent intracardiac flow analysis and AVD optimization. Reversal and ejection flow curves were studied. The presence and duration of reversal-ejection discontinuity were assessed for all programmed AVD. Reproducibility of each optimization method was evaluated through interobserver variability. Discontinuity between reversal and ejection flow was observed in all patients with longer than optimal AVD, increasing linearly with excess duration in AVD (linear R 2 =0.976, P <0.001). Longer discontinuities implied progressive decreases in pre-ejection flow velocity in the left ventricular outflow tract, with consequent loss of flow momentum. The equation optimal AVD=programmed AVD-[1.2(discontinuity duration)]+4 accurately predicted optimal AVD. Short AVD systematically compromised reversal flow because of premature ejection. Agreement over optimal AVD was superior when assessed by flow reversal method (intraclass correlation coefficient =0.931; P <0.001) over both iterative and aortic velocity-time integral methods., Conclusions: Perfect coupling between mitral-aortic flow reversal and ejection flow in the left ventricle occurs at optimal AVD. As a result, full blood momentum in the outflow tract is used to facilitate early ejection. This can be measured and provides a new method for AVD optimization., (© 2017 American Heart Association, Inc.)

Ventricular wall rupture has become an infrequent complication of myocardial infarction due to widespread use of prompt reperfusion strategies. Patients suffering myocardial infarction with normal coronary arteries seldom develop severe mechanical complications. We present the case of a patient who developed a ventricular septal rupture following an anteroseptal myocardial infarction and who presented normal coronary arteries at the time of coronary angiography., (Copyright © 2015 Sociedade Portuguesa de Cardiologia. Published by Elsevier España. All rights reserved.)

Background: There is no consensus on which right ventricle (RV) strain parameter should be used in the clinical practice: four chamber RV longitudinal strain (4CH RV-LS) or free wall longitudinal strain (FWLS). The aim of this study was to analyze which RV strain parameter better predicts prognosis in patients with left heart disease., Methods: One hundred and three outpatients with several degrees of functional tricuspid regurgitation severity secondary to left heart disease were prospectively included. 4CH RV-LS and FWLS were assessed using speckle tracking. Left ventricular (LV) systolic function was determined using LV ejection fraction and RV systolic function using tricuspid annular plane systolic excursion (TAPSE). Patients were followed up for 23.1 ± 12.4 months for an endpoint of cardiac hospitalization due to heart failure., Results: The cutoff value related to RV dysfunction (TAPSE < 17 mm) was lower, in absolute value, for 4CH RV-LS (4CH RV-LS = -17.3%; FWLS = -19.5%). There were 33 adverse events during the follow-up. Patients with 4CH RV-LS > -17.3% (log rank [LR] = 22.033; p < 0.001); FWLS > -19.5% (LR = 12.2; p < 0.001), TAPSE < 17 mm (LR = 17.4; p < 0.001) and LV systolic dysfunction (LR = 13.3; p < 0.001) had lower event-free survival (Kaplan Meier). In Cox multivariate analysis, 4CH RV-LS > -17.3% (hazard ratio [HR] = 3.593; p < 0.002), TAPSE < 17 (HR = 2.093; p < 0.055) and LV systolic dysfunction (HR = 2.087; p < 0,054) had prognostic value, whereas FWLS did not reach significance., Conclusions: Although both 4CH RV-LS and FWLS have prognostic value, 4CH RV-LS is a better predictor of episodes of heart failure in patients with left heart disease, providing additional information to that obtained by TAPSE.