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The environment is a strong determinant of cardiovascular health. Environmental cardiology studies the contribution of environmental exposures with the aim of minimizing the harmful influences of pollution and promoting cardiovascular health through specific preventive or therapeutic strategies. The present review focuses on particulate matter and metals, which are the pollutants with the strongest level of scientific evidence, and includes possible interventions. Legislation, mitigation and control of pollutants in air, water and food, as well as environmental policies for heart-healthy spaces, are key measures for cardiovascular health. Individual strategies include the chelation of divalent metals such as lead and cadmium, metals that can only be removed from the body via chelation. The TACT (Trial to Assess Chelation Therapy, NCT00044213) clinical trial demonstrated cardiovascular benefit in patients with a previous myocardial infarction, especially in those with diabetes. Currently, the TACT2 trial (NCT02733185) is replicating the TACT results in people with diabetes. Data from the United States and Argentina have also shown the potential usefulness of chelation in severe peripheral arterial disease. More research and action in environmental cardiology could substantially help to improve the prevention and treatment of cardiovascular disease.

Identifying biomarkers of subclinical atrial fibrillation (AF) is of most interest in patients with cryptogenic stroke (CrS). We sought to evaluate the circulating microRNA (miRNA) profile of patients with CrS and AF compared with those in persistent sinus rhythm.Among 64 consecutive patients with CrS under continuous monitoring by a predischarge insertable monitor, 18 patients (9 with AF and 9 in persistent sinus rhythm) were selected for high-throughput determination of 754 miRNAs. Nine patients with concomitant stroke and AF were also screened to improve the yield of miRNA selection. Differentially expressed miRNAs were replicated in an independent cohort (n=46). Biological markers were stratified by the median and included in logistic regression analyses to evaluate their association with AF at 6 and 12 months.Eight miRNAs were differentially expressed between patients with and without AF. In the replication cohort, miR-1-3p, a gene regulator involved in cardiac arrhythmogenesis, was the only miRNA to remain significantly higher in patients with CrS and AF vs those in sinus rhythm and showed a modest association with AF burden. High (= above the median) miR-1-3p plasma values, together with a low left atrial ejection fraction, were independently associated with the presence of AF at 6 and 12 months.In this cohort, plasma levels of miR-1-3p were elevated in CrS patients with subsequent AF. Our results preliminarily suggest that miR-1-3p could be a novel biomarker that, together with clinical parameters, could help identify patients with CrS and a high risk of occult AF.

Objective: To determine patient difficulties and concerns when performing IBC (Intermittent Bladder Catheterisation), as well as the evolution of adherence, quality of life, and emotional state of patients one year after starting IBC. Method: A prospective, observational, multicentre study conducted in 20 Spanish hospitals with a one-year follow-up. Data sources were patient records and the King’s Health Questionnaire on quality of life, the Mini-Mental State Examination (MMSE), and the Hospital Anxiety and Depression Scale (HADS). Perceived adherence was measured using the ICAS (Intermittent Catheterization Adherence Scale) and perceived difficulties with IBC were assessed using the ICDQ (Intermittent Catheterization Difficulty Questionnaire). For data analysis, descriptive and bivariate statistics were performed for paired data at three points in time (T1: one month, T2: three months, T3: one year). Results: A total of 134 subjects initially participated in the study (T0), becoming 104 subjects at T1, 91 at T2, and 88 at T3, with a mean age of 39 years (standard deviation = 22.16 years). Actual IBC adherence ranged from 84.8% at T1 to 84.1% at T3. After one year of follow-up, a statistically significant improvement in quality of life (p ≤ 0.05) was observed in all dimensions with the exception of personal relationships. However, there were no changes in the levels of anxiety (p = 0.190) or depression (p = 0.682) at T3 compared to T0. Conclusions: Patients requiring IBC exhibit good treatment adherence, with a significant proportion of them performing self-catheterisation. After one year of IBC, a significant improvement in quality of life was noted, albeit with a significant impact on their daily lives and their personal and social relationships. Patient support programmes could be implemented to improve their ability to cope with difficulties and thus enhance both their quality of life and the maintenance of their adherence.

Resumen Introduccion y objetivos La evaluacion del riesgo de arritmias ventriculares en pacientes con tetralogia de Fallot reparada (TFr) es compleja. Este estudio pretende identificar las caracteristicas electrofisiologicas del ventriculo derecho (VD) asociadas con un mayor riesgo de arritmias ventriculares en pacientes con TFr. Metodos Se incluyo a todos los pacientes consecutivos con TFr sometidos a mapeo electroanatomico del VD en un centro terciario. Mediante modelos de regresion logistica, se identificaron los factores asociados con mayor riesgo de taquicardia ventricular (TV) clinica o inducida y, secundariamente, solo de TV clinica. Resultados De los 56 pacientes incluidos, 21 presentaron TV clinica o inducida. Los factores asociados con TV clinica o inducida fueron: extrasistolia ventricular (EV) frecuente/TV no sostenida en el Holter de 24 h (OR = 11,34; IC95%, 1,50-85,97; p = 0,019), intervalo HV > 55 ms (OR = 21,20; IC95%, 3,12-144,14; p = 0,002) y tiempo de activacion del VD (por cada 10 ms, OR = 1,34; IC95%, 1,02-1,75; p = 0,035). El modelo que incluia dichas variables mostro una buena capacidad de discriminacion, con un area bajo la curva de 0,884 (IC95%, 0,79-0,97; p 55 ms (OR = 9,65; IC95%, 1,41-66,14; p = 0,021) y la EV frecuente/TV no sostenida (OR = 13,14; IC95%, 1,95-88,54; p = 0,008) (area bajo de la curva = 0,836; IC95%, 0,663-1,000; p = 0,002). Conclusiones La EV frecuente/TV no sostenida, el intervalo HV > 55 ms y el tiempo de activacion del VD son factores asociados con mayor riesgo de arritmias ventriculares en pacientes con TFr.

Introduction and objectives Risk stratification of ventricular arrhythmias in patients with repaired tetralogy of Fallot (rTOF) remains unresolved. We aimed to identify right ventricular (RV) electrophysiological parameters potentially associated with a higher risk of ventricular arrhythmias in patients with rTOF. Methods We included all consecutive patients with rTOF who underwent RV electroanatomical mapping at a single tertiary center. We used logistic regression modeling to identify those variables associated with an increased risk of clinical or induced ventricular tachycardia (VT), or clinical VT exclusively. Results Twenty-one of the 56 patients included had clinical or induced VT. A high-frequency of premature ventricular contractions/nonsustained VT (OR, 11.34; 95%CI, 1.50-85.97; P = .019), an HV interval > 55 ms (OR, 21.20; 95%CI, 3.12-144.14; P = .002), and RV activation time (ms) (OR [per 10 ms intervals], 1.34; 95%CI, 1.02-1.75; P = .035) proved to be associated with clinical or induced VT. The model including this information had good discrimination ability, with an area under the curve of 0.884 (95%CI, 0.79-0.97; P 55 ms (OR, 9.65; 95%CI, 1.41-66.14; P = .021) and high-frequency of premature ventricular contractions/nonsustained VT (OR, 13.14; 95%CI, 1.95-88.54; P = .008) were independently associated (area under the curve of 0.836 [95%CI, 0.663-1.000; P = .002]). Conclusions High-frequency of premature ventricular contractions/nonsustained VT, an HV interval > 55 ms and RV activation time are factors associated with an increased risk of ventricular arrhythmias in patients with rTOF.

Williams-Beuren syndrome (WBS) is a rare genetic multisystemic disorder characterized by mild-to-moderate intellectual disability and hypersocial phenotype, while the most life-threatening features are cardiovascular abnormalities. Nowadays, there are no pharmacological treatments to directly ameliorate the main traits of WBS. The endocannabinoid system (ECS), given its relevance for both cognitive and cardiovascular function, could be a potential druggable target in this syndrome. We analyzed the components of the ECS in the complete deletion (CD) mouse model of WBS and assessed the impact of its pharmacological modulation in key phenotypes relevant for WBS. CD mice showed the characteristic hypersociable phenotype with no preference for social novelty and poor short-term object-recognition performance. Brain cannabinoid type-1 receptor (CB1R) in CD male mice showed alterations in density and coupling with no detectable change in main endocannabinoids. Endocannabinoid signaling modulation with subchronic (10 days) JZL184, a selective inhibitor of monoacylglycerol lipase, specifically normalized the social and cognitive phenotype of CD mice. Notably, JZL184 treatment improved cardiovascular function and restored gene expression patterns in cardiac tissue. These results reveal the modulation of the ECS as a promising novel therapeutic approach to improve key phenotypic alterations in WBS. Ministerio de Ciencia, Innovacion y Universidades FPU13/01867 Alba Navarro-Romero Ministerio de Ciencia e Innovacion BES-2016-077950 Lorena Galera-Lopez Ministerio de Ciencia e Innovacion RTI2018-099282-B-I00 Andres Ozaita Ministerio de Ciencia e Innovacion SAF2017-84060-R Rafael Maldonado Generalitat de Catalunya 2017SGR-669 Rafael Maldonado Ministerio de Ciencia e Innovacion SAF2016-78508-R Victoria Campuzano Basque Country Government IT1454-22 Rafael Rodriguez-Puertas Instituto de Salud Carlos III PI20/00153, co-funded by the European Union (ERDF "A way to make Europe") Rafael Rodriguez-Puertas Institucio Catalana de Recerca i Estudis Avancats Rafael Maldonado Ministerio de Economia y Competitividad #MDM-2014-0370 Alba Navarro-Romero Ministerio de Economia y Competitividad #MDM-2014-0370 Eduardo Eyras Ministerio de Ciencia e Innovacion PRE2019-087644 Lucia de los Reyes-Ramirez Ministerio de Ciencia e Innovacion AEI/MINEICO/FEDER Andres Ozaita Ministerio de Ciencia e Innovacion AEI/MINEICO/FEDER Rafael Maldonado Ministerio de Ciencia e Innovacion AEI/MINEICO/FEDER Victoria Campuzano Ministerio de Economia y Competitividad FEDER Alba Navarro-Romero Ministerio de Economia y Competitividad FEDER Eduardo Eyras Ministerio de Economia y Competitividad IPEP MdM-2017 Eduardo Eyras Ministerio de Ciencia e Innovacion UE Andres Ozaita Ministerio de Ciencia e Innovacion UE Rafael Maldonado Ministerio de Economia y Competitividad UE Alba Navarro-Romero Ministerio de Ciencia e Innovacion UE Victoria Campuzano Ministerio de Economia y Competitividad EU Eduardo Eyras FRAXA Research Foundation Lorena Galera-Lopez The funders had no role in study design, data collection, and interpretation, or the decision to submit the work for publication.

Patients with a single syncopal episode (SSE) and complete bundle branch block (cBBB) are frequently managed more conservatively than patients with recurrent episodes (RSE). The objective of this study was to analyze if there are differences between patients with single or recurrent unexplained syncope and cBBB in arrhythmic risk, the diagnostic yield of tests, and clinical outcomes.Cohort study of consecutive patients with unexplained syncope and cBBB with a median follow-up time of 3 years. The patients were evaluated via a stepwise workup protocol based on electrophysiological study (EPS) and long-term follow-up with an implantable cardiac monitor.Of the 503 patients included in the study, 238 (47.3%) had had only 1 syncopal episode. The risk of an arrhythmic syncope was similar in both groups (58.8% in SSE vs 57.0% in RSE; P = .68), also after adjustment for possible confounding variables (HR, 1.06; 95%CI, 0.81-1.38; P = .674). No significant differences between the groups were found in the EPS results and implantable cardiac monitor diagnostic yield. A total of 141 (59.2%) patients with SSE and 154 (58.1%) patients with RSE required cardiac device implantation (P = .797). After appropriate treatment, 35 (6.7%) patients had recurrence of syncope. The recurrence rate and mortality were also similar in both groups.Patients with cBBB and unexplained syncope are at high risk of an arrhythmic etiology, even after the first syncopal episode. Patients with SSE and RSE have a similar arrhythmic risk and similar outcomes, and therefore there is no clinical justification for not managing them in the same manner.

The aim of this work was to study the association of potential biomarkers with fast aortic stenosis (AS) progression. Patients with moderate-to-severe AS were classified as very fast progressors (VFP) if exhibited an annualized change in peak velocity (aΔVmax) ≥0.45m/s/year and/or in aortic valve area (aΔAVA) ≥-0.2cm2/year. Respective cut-off values of ≥0.3m/s/year and ≥-0.1cm2/year defined fast progressors (FP), whereas the remaining patients were non-fast progressors (non-FP). Baseline markers of lipid metabolism, inflammation, and cardiac overload were determined. Two hundred and nine patients (97 non-FP, 38 FP, and 74 VFP) were included. PCSK9 levels were significantly associated with VFP (OR 1.014 [95%CI 1.005-1.024], for every 10 ng/mL), as were active smoking (OR 3.48) and body mass index (BMI, OR 1.09), with an AUC of 0.704 for the model. PCSK9 levels, active smoking, and BMI were associated with very fast AS progression in our series, suggesting that inflammation and calcification participate in disease progression.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have proven to delay diabetic kidney disease (DKD) progression on top of the standard of care with the renin–angiotensin system (RAS) blockade. The molecular mechanisms underlying the synergistic effect of SGLT2i and RAS blockers is poorly understood. We gave a SGLT2i (empagliflozin), an angiotensin-converting enzyme inhibitor (ramipril), or a combination of both drugs for 8 weeks to diabetic (db/db) mice. Vehicle-treated db/db and db/m mice were used as controls. At the end of the experiment, mice were killed, and the kidneys were saved to perform a differential high-throughput proteomic analysis by mass spectrometry using isobaric tandem mass tags (TMT labeling) that allow relative quantification of the identified proteins. The differential proteomic analysis revealed 203 proteins differentially expressed in one or more experimental groups (false discovery rate < 0.05 and Log2 fold change ≥ ±1). Fourteen were differentially expressed in the kidneys from the db/db mice treated with empagliflozin with ramipril. Among them, MAP17 was up-regulated. These findings were subsequently validated by Western blot. The combined therapy of empagliflozin and ramipril up-regulated MAP17 in the kidney of a diabetic mice model. MAP17 is a major scaffolding protein of the proximal tubular cells that places transporters together, namely SGLT2 and NHE3. Our results suggest that SGLT2i on top of RAS blockade may protect the kidney by boosting the inactivation of NHE3 via the up-regulation of key scaffolder proteins such as MAP17.

Aim To assess the changes induced by the COVID-19 lockdown on cardiac biometric variables recorded using an implantable cardiac monitor (ICM) in a patient population monitored for syncope work-up, as well to assess whether there has been an effect on arrhythmic events among the patients. Methods Longitudinal cohort study. We included 245 adult patients monitored with an ICM indicated for the investigation of syncope. The records from days 1 to 12 March 2020 (prior to the institution of lockdown by the state government) with days 16 to 28 March 2020 were compared. Results Daily physical exercise reduced markedly after the imposition of lockdown (132 [55–233] minutes vs. 78 [21–154] minutes). The mean daytime HR prior to lockdown was 77 [69–85] bpm, whereas during lockdown it was 74 [66–81] bpm. During the lockdown period, a drop in the variability in heart rate (114 [94–136] ms vs. 111 [92–133] ms) was observed. Although the incidence of AF was similar over both periods, the daily AF burden was significantly higher post-lockdown (405 [391–425] minutes vs. 423 [423–537] minutes). No differences in the number of other arrhythmias were found. Conclusions The establishment of mandatory lockdown has led to a marked drop in daily physical activity in this population which probably explains changes observed in other cardiac biometric variables. Although, in the short term, we have not documented an increased risk of arrhythmia, we cannot rule out an effect in the medium to long term or in other populations of at-risk patients.

Background Syncope in patients with mid-range left ventricular ejection fraction (LVEF) can be due to potentially serious arrhythmic causes. However, there is no clear consensus on the best way to manage these patients. Objectives The objectives of this study were to determine the causes of syncope and assess the diagnostic yield and safety of a stepwise workup protocol in this population. Methods This was a prospective observational study. A stepwise workup protocol was applied to patients with LVEF 35%–50% and unexplained syncope after the initial assessment (step 1). Results One hundred four patients were included {median age 75.6 years; (interquartile range [IQR] 67.6–81.2 years); median LVEF 45% (IQR 40%–48%); median follow-up 2.0 years (IQR 0.7–3.3 years). In 71 patients (68.3%), a diagnosis was reached: 55 (77.5%) in step 2 (hospital admission and electrophysiology study) and 16 (36.5%) in step 3 (implantable cardiac monitor). Arrhythmic causes were the most common etiology (45.2% auriculoventricular block and 9.6% ventricular tachycardia). Sixty patients (57.7%) required the implantation of a cardiac device and 11 had a defibrillation function. Patients diagnosed in step 3 had a higher global risk of recurrence of syncope (hazard ratio 6.5; 95% confidence interval 2.3–18.0). The mortality rate was 8.1 per 100 person-years, and the sudden or unknown death rate was 0.9 per 100 person-years. Conclusion In patients with mid-range left ventricular dysfunction and syncope of unknown cause, a systematic diagnostic strategy based on electrophysiology study and/or implantable cardiac monitor implantation allows a diagnosis to be reached in a high proportion of cases and guides the treatment. Arrhythmia is the most common cause of syncope in this population, particularly auriculoventricular block.

BACKGROUND AND AIMS sodium-glucose 2 cotransporter inhibitors (SGLT2i) prevent cardiovascular events in diabetic patients. Moreover, their diuretic effect could attenuate the adverse events of endothelin receptor antagonists (ERA), which have also shown kidney protective effects in diabetes. The present study aimed to evaluate the beneficial cardiorenal impact of the combination of SGLT2i, ERA and ramipril versus treatment with ramipril alone in experimental diabetes. METHOD Twelve-week-old db/db mice were treated for 8 weeks with different combinations of an SGLT2i (empagliflozin, 10 mg/Kg/day), an ERA (atrasentan, 7 mg/Kg/day) and an RAS blocker (ramipril, 8 mg/Kg/day). Vehicle-treated diabetic and nondiabetic mice were included as controls. During the experiment, blood pressure (BP), glomerular filtration rate (GFR) and echocardiographic parameters were measured. Kidney and heart were collected at the end for histological studies. RESULTS The triple therapy with empagliflozin, atrasentan and ramipril was superior to ramipril alone in reducing BP (mean BP 61.0 mmHg versus 67.10 mmHg in the ramipril group), preventing diabetic hyperfiltration (214.3 μL/100 g/min GFR decrease versus 34.7 μL/100 g/min decrease in the ramipril group) (Figure 1), and improving echocardiographic parameters of diastolic dysfunction, including left atrium diameter and isovolumetric relaxation time. Moreover, the combined therapy offered protection against diabetic injury in kidney and heart by a reduction of mesangial matrix expansion (46.0% of glomerular mesangial matrix versus 46.9% in the ramipril group), as well as left ventricle cardiomyocyte hypertrophy (mean cardiomyocyte area 125 μm2 versus 131 μm2 in the ramipril group) and heart collagen deposition (Figure 1). CONCLUSION In experimental diabetes, combined therapy of ramipril, empagliflozin and atrasentan promotes both heart and kidney protective effects that outweigh the beneficial effects of ramipril alone.

Aging; Dicarbonyl stress; Mitochondria Envelliment; Estrès dicarbonílic; Mitocondris Envejecimiento; Estrés dicarbonílico; Mitocondrias Aged cardiomyocytes develop a mismatch between energy demand and supply, the severity of which determines the onset of heart failure, and become prone to undergo cell death. The FoF1-ATP synthase is the molecular machine that provides >90% of the ATP consumed by healthy cardiomyocytes and is proposed to form the mitochondrial permeability transition pore (mPTP), an energy-dissipating channel involved in cell death. We investigated whether aging alters FoF1-ATP synthase self-assembly, a fundamental biological process involved in mitochondrial cristae morphology and energy efficiency, and the functional consequences this may have. Purified heart mitochondria and cardiomyocytes from aging mice displayed an impaired dimerization of FoF1-ATP synthase (blue native and proximity ligation assay), associated with abnormal mitochondrial cristae tip curvature (TEM). Defective dimerization did not modify the in vitro hydrolase activity of FoF1-ATP synthase but reduced the efficiency of oxidative phosphorylation in intact mitochondria (in which membrane architecture plays a fundamental role) and increased cardiomyocytes’ susceptibility to undergo energy collapse by mPTP. High throughput proteomics and fluorescence immunolabeling identified glycation of 5 subunits of FoF1-ATP synthase as the causative mechanism of the altered dimerization. In vitro induction of FoF1-ATP synthase glycation in H9c2 myoblasts recapitulated the age-related defective FoF1-ATP synthase assembly, reduced the relative contribution of oxidative phosphorylation to cell energy metabolism, and increased mPTP susceptibility. These results identify altered dimerization of FoF1-ATP synthase secondary to enzyme glycation as a novel pathophysiological mechanism involved in mitochondrial cristae remodeling, energy deficiency, and increased vulnerability of cardiomyocytes to undergo mitochondrial failure during aging. This work was supported by the Instituto de Salud Carlos III of the Spanish Ministry of Health (FIS-PI19-01196) and a grant from the Sociedad Española de Cardiología (SEC/FEC-INV-BAS 217003)

Objective The use of implantable cardiac monitors (ICM) is highly useful in syncope workup. Latest-generation devices can detect asymptomatic episodes of atrial fibrillation. The main objective of this study was to determine the incidence of subclinical atrial fibrillation (AF) detected in a patient population undergoing prolonged electrocardiographic monitoring with an ICM for the etiological workup of syncope. Methods Prospective observational study carried out in a tertiary hospital from April 2014 to October 2019. All consecutive adult patients monitored with a latest-generation ICM for syncope with no prior history of AF were included in the analysis. Results Of a total of 509 ICMs implanted during the study period, 208 patients fulfilled the inclusion criteria. 42 patients (20.2%) were found to have AF on ICM. The incidence of AF was 11.7 cases per 100 person-years (95% CI: 8.7–15.9 per 100 person-years). The median burden of AF was 0.2% (IQR 0–0.8%). Age, the presence of hypertension, chronic kidney disease, the size of the septum and left atrium on electrocardiogram and the presence of broad QRS on baseline electrocardiogram were predictors for the appearance of AF in the univariate analysis. Conclusion The incidental finding of atrial fibrillation in patients with syncope monitored with ICM is common. The burden of AF is low, and it is generally subclinical. These findings create added value for the use of ICM in the workup for syncope, although further studies are needed to determine the clinical benefit of documenting subclinical AF.

Background: Pulmonary veins isolation (PVI) is a standard treatment for recurrent atrial fibrillation (AF). Uninterrupted anticoagulation for minimum 3 weeks before the ablation and exclusion of left atrial (LA) thrombus with transesophageal echography (TEE) immediately before or during the procedure minimize peri-procedural risk. We aimed to demonstrate the utility of cardiac tomography (CT) and cardiac magnetic resonance (CMR) to rule out LA thrombus prior to PVI. Methods: Patients undergoing PVI for recurrent AF were retrospectively evaluated. Only patients that started anticoagulation at least 3 weeks prior to the CT/CMR and subsequently uninterrupted until the ablation procedure were selected. An intracardiac echo (ICE) catheter was used in all patients to evaluate LA thrombus. The results of CT/CMR were compared to ICE imaging. Results: We included 272 consecutive patients averaging 54.5 years (71% male; 30% persistent AF). Average CHA2DS2VASC Score was 0.9 and mean LA diameter was 43 mm, 111 patients on Acenocumarol and 161 on direct oral anticoagulants. Anticoagulation was started 227±392 days before the CT/CMR, and 291±416 days before the ablation procedure. CT/CMR diagnosed intracardiac thrombus in 2 cases, both in the LA appendage. A new CT/CMR revealed resolution of thrombus after 6 additional months of uninterrupted anticoagulation. No macroscopic thrombus was observed in any patients with ICE (negative predictive value of 100%; pConclusions: CT and MRI are excellent surrogates to TEE and ICE to rule out intracardiac thrombus in patients adequately anticoagulated prior AF ablation. This is true even for delayed procedures as long as anticoagulation is uninterrupted.

To analyze if there are sex-related differences in patients with unexplained syncope and bundle branch block (BBB). Despite increasing awareness that sex is a major determinant of the incidence, etiology, and the outcomes of different arrhythmias, no studies have examined differences in presentation and outcomes between men and women with syncope and BBB. Cohort study of consecutive patients with unexplained syncope and BBB was included from January 2010 to January 2021 with a median follow-up time of 3.4 years [interquartile range (IQR) 1.7-6.0 years]. They were evaluated by a stepwise workup protocol based on electrophysiological study (EPS) and long-term follow-up with an implantable cardiac monitor (ICM). Of the 443 patients included in the study, 165 (37.2%) were women. Compared with men, women had less diabetes (25.5 vs. 39.9%, p = 0.002) and less history of ischemic heart disease (IHD; 13.3 vs. 25.9%, p = 0.002). Left bundle branch block (LBBB) was more frequent in women (55.2 vs. 27.7%, p < 0.001) while right bundle branch block (RBBB) was more frequent in men (41.5 vs. 67.7%, p < 0.001). His to ventricle (HV) interval in the EPS was shorter in women (58 ms [IQR 52-71] vs. 60 ms [IQR 52-73], p = 0.035) and less women had an HV interval longer than 70 ms (28.5 vs. 38.1%, p = 0.039), however, EPS and ICM offered a similar diagnostic yield in both sexes (40.6 vs. 48.9% and 48.4% vs. 51.1%, respectively). Women had a lower risk of developing atrioventricular block (AVB) (adjusted odds ratio [OR] 0.44-95% CI 0.26-0.74, p = 0.002) and of requiring permanent pacemaker implantation (adjusted hazard ratio [HR] 0.72-95% CI: 0.52-0.99, p = 0.046). The mortality rate was lower in women (4.5 per 100 person-years [95% CI 3.1-6.4 per 100 person-years] vs. 7.3 per 100 person-years [95% CI 5.9-9.1 per 100 person-years]). Compared to men, women with unexplained syncope and BBB have a lower risk of AVB and of requiring cardiac pacing. A stepwise diagnostic approach has a similar diagnostic yield in both sexes, and it seems appropriate to guide the treatment and avoid unnecessary pacemaker implantation, especially in women. Risk of AVB and need for cardiac pacing. Left: Percentage of patients diagnosed with aAVB/sCD in both sexes. Right-top: Multivariate logistic regression analyses for risk of aAVB/sCD. Odds ratio and 95% CI are plotted. Right-bottom: Kaplan-Meier pacemaker-free survival estimates curves in both sexes. aAVB/sCD, advanced atrio-ventricular block or severe conduction disturbances; HR, hazard ratio; CI, confidence interval; y.o, years old; IHD, ischemic heart disease; LVEF, left ventricular ejection fraction; BBB, bundle branch block; LBBB, left bundle branch block; RBBB, right bundle branch block; LAFB, left anterior fascicular block.

Monitoreo cardíaco; Grabadora de bucle; Palpitación Cardiac monitoring; Loop recorder; Palpitation Monitorització cardíaca; Gravadora de bucle; Palpitació Palpitations are one of the most common reasons for medical consultation. They tend to worry patients and can affect their quality of life. They are often a symptom associated with cardiac rhythm disorders, although there are other etiologies. For diagnosis, it is essential to be able to reliably correlate the symptoms with an electrocardiographic record allowing the identification or ruling out of a possible rhythm disorder. However, reaching a diagnosis is not always simple, given that they tend to be transitory symptoms and the patient is frequently asymptomatic at the time of assessment. In recent years, electrocardiographic monitoring systems have incorporated many technical improvements that solve several of the 24-h Holter monitor limitations. The objective of this review is to provide an update on the different monitoring methods currently available, remarking their indications and limitations, to help healthcare professionals to appropriately select and use them in the work-up of patients with palpitations.

Background In the last years a substantial effort has been made to improve the understanding of the sex-differences in cardiovascular disease. However, no studies have examined differences in presentation and outcomes between men and women presenting with syncope and bundle branch block (BBB). Aim To determinate if there are sex-specific differences in the characteristics and outcomes of syncope in patients with BBB Methods Cohort study carried out in a tertiary hospital that is a reference center for syncope from January 2008 to February 2021. Patients (p.) with BBB and syncope of unknown origin after the initial evaluation without direct indication of an ICD were included. They were managed according to the current ESC guidelines. All patients underwent to an EPS and an ILR was implanted if it was not diagnostic. Results 374p. were included (75±1 y. o; 135 (36%) female). Mean follow up was 2.3±1.6 y.o. No differences in baseline characteristics where found comparing both groups, except that LBBB was more prevalent in female and RBBB in male (Figure 1A). EPS and ILR diagnostic yield was 44%/44% respectively in females and 50% /40% in males (p=ns). However, basal HV interval in EPS was significant shorter in females (Figure 2A). In the multivariate analyses female sex was associated with a significant lower risk of AV block (Figure 1B), and with a trend of less need of a pacemaker implantation (PM) (53% in females, 60% in males) (Log-rank 0.1) (Figure 2B). No significant differences in recurrences neither in mortality rate were found. Conclusions Female patients with syncope and BBB have lower risk of AV block compared to males, and only half of them required a pacemaker implantation. A strategy of direct PM implantation should be avoided, specially in woman. Funding Acknowledgement Type of funding sources: None. Figure 1Figure 2

HL-1 cells; L-type calcium channels; Calcium regulation Células HL-1; Canales de calcio tipo L; Regulación del calcio Cel·lules HL-1; Canals de calci tipus L; Regulació del calci MicroRNAs (miRNAs) participate in atrial remodeling and atrial fibrillation (AF) promotion. We determined the circulating miRNA profile in patients with AF and heart failure with reduced ejection fraction (HFrEF), and its potential role in promoting the arrhythmia. In plasma of 98 patients with HFrEF (49 with AF and 49 in sinus rhythm, SR), differential miRNA expression was determined by high-throughput microarray analysis followed by replication of selected candidates. Validated miRNAs were determined in human atrial samples, and potential arrhythmogenic mechanisms studied in HL-1 cells. Circulating miR-199a-5p and miR-22-5p were significantly increased in HFrEF patients with AF versus those with HFrEF in SR. Both miRNAs, but particularly miR-199a-5p, were increased in atrial samples of patients with AF. Overexpression of both miRNAs in HL-1 cells resulted in decreased protein levels of L-type Ca2+ channel, NCX and connexin-40, leading to lower basal intracellular Ca2+ levels, fewer inward currents, a moderate reduction in Ca2+ buffering post-caffeine exposure, and a deficient cell-to-cell communication. In conclusion, circulating miR-199a-5p and miR-22-5p are higher in HFrEF patients with AF, with similar findings in human atrial samples of AF patients. Cells exposed to both miRNAs exhibited altered Ca2+ handling and defective cell-to-cell communication, both findings being potential arrhythmogenic mechanisms. This work was funded by the following grants, awarded to B.B.: Sociedad Española de Cardiología, Sección de Arritmias y Electrofisiología 2012; Sociedad Española de Cardiología, Sección de Insuficiencia Cardíaca 2013; Fondo Investigación Sanitaria (FIS)—Instituto Carlos III 2013 (PI13/01830); and Societat Catalana de Cardiologia 2016. Awarded to K.W.A-A. and S.R.: British Heart Foundation (BHF) Intermediate Research Fellowship. Awarded to J.M.F.F.: grant from the Spanish Ministry of Science and Innovation (RTI2018-094809-B-I00). “María de Maeztu” Programme for Units of Excellence in R&D to the Departament de Ciències Experimentals i de la Salut (MDM-2014-0370) and FEDER (Fondo Europeo de Desarrollo Regional) also contributed to this work.

Chronic kidney disease; Diabetic nephropathy; Endothelin receptor antagonists Enfermedad renal crónica; Nefropatía diabética; Antagonistas de los receptores de endotelina Malaltia renal crònica; Nefropatia diabètica; Antagonistes dels receptors d'endotelina Treatments with sodium–glucose 2 cotransporter inhibitors (SGLT2i) or endothelin receptor antagonists (ERA) have shown cardiorenal protective effects. The present study aimed to evaluate the cardiorenal beneficial effects of the combination of SGLT2i and ERA on top of renin–angiotensin system (RAS) blockade. Type 2 diabetic mice (db/db) were treated with different combinations of an SGLT2i (empagliflozin), an ERA (atrasentan), and an angiotensin-converting enzyme inhibitor (ramipril) for 8 weeks. Vehicle-treated diabetic mice and non-diabetic mice were included as controls. Weight, blood glucose, blood pressure, and kidney and heart function were monitored during the study. Kidneys and heart were collected for histological examination and to study the intrarenal RAS. Treatment with empagliflozin alone or combined significantly decreased blood glucose compared to vehicle-treated db/db. The dual and triple therapies achieved significantly greater reductions in diastolic blood pressure than ramipril alone. Compared to vehicle-treated db/db, empagliflozin combined with ramipril or in triple therapy significantly prevented GFR increase, but only the triple combination exerted greater protection against podocyte loss. In the heart, empagliflozin alone or combined reduced cardiac isovolumetric relaxation time (IVRT) and left atrium (LA) diameter as compared to vehicle-treated db/db. However, only the triple therapy was able to reduce cardiomyocyte area. Importantly, the add-on triple therapy further enhanced the intrarenal ACE2/Ang(1-7)/Mas protective arm of the RAS. These data suggest that triple therapy with empagliflozin, atrasentan and ramipril show synergistic cardiorenal protective effects in a type 2 diabetic mouse model. The following study was funded with Spanish government grants (FONDO DE INVESTIGACIÓN SANITARIA-FEDER, ISCIII (PI17/00257 and RICORS RD21/0005/0016)) and with financial support from Boehringer Ingelheim Pharma GmbH. The funders had no role in study design, analyses, interpretation of the data, drafting of the manuscript, or decision to submit the manuscript for publication. The funders were allowed to comment on the manuscript prior to publication; however, the final wording was at the full discretion of the investigators.

Purpose Patients undergoing cavotricuspid isthmus (CTI) ablation for typical flutter (AFL) have a high incidence of new onset atrial fibrillation (AF). We aimed to analyze the influence of PACE score to predict new onset AF in this subset of patients to stratify thromboembolic risk. Methods Between 2017 and 2019, patients undergoing CTI ablation for AFL and without history of AF were prospectively included. All patients were monitored continuously by implantable loop recorder and followed by remote monitoring. Results Overall 48 patients were included. New onset AF rate at 12 months was 56.3%. We observed two very strong independent predictors for new onset AF: a PACE score ≥ 30 (HR:6.9; 95% CI:1.71–27.91; p = 0.007) and an HV interval ≥ 55 (HR:11.86; 95% CI:2.57–54.8; p = 0.002). Conclusions The incidence of newly diagnosed AF is high in patients with AFL after CTI ablation, and can occur early. A high PACE score and/or long HV interval predict even higher risk, and may be useful in the decision for empiric long-term anticoagulation.