Spatial Distribution of Calcium Sparks Determines Their Ability to Induce Afterdepolarizations in Human Atrial Myocytes.

Analysis of the spatio-temporal distribution of calcium sparks showed a preferential increase in sparks near the sarcolemma in atrial myocytes from patients with atrial fibrillation (AF), linked to higher ryanodine receptor (RyR2) phosphorylation at s2808 and lower calsequestrin-2 levels. Mathematical modeling, incorporating modulation of RyR2 gating, showed that only the observed combinations of RyR2 phosphorylation and calsequestrin-2 levels can account for the spatio-temporal distribution of sparks in patients with and without AF. Furthermore, we demonstrate that preferential calcium release near the sarcolemma is key to a higher incidence and amplitude of afterdepolarizations in atrial myocytes from patients with AF.

Beta-blocker treatment of patients with atrial fibrillation attenuates spontaneous calcium release-induced electrical activity.

AIMS: Atrial fibrillation (AF) has been associated with excessive spontaneous calcium release, linked to cyclic AMP (cAMP)-dependent phosphorylation of calcium regulatory proteins. Because ß-blockers are expected to attenuate cAMP-dependent signaling, we aimed to examine whether the treatment of patients with ß-blockers affected the incidence of spontaneous calcium release events or transient inward currents (ITI). METHODS: The impact of treatment with commonly used ß-blockers was analyzed in human atrial myocytes from 371 patients using patch-clamp technique, confocal calcium imaging or immunofluorescent labeling. Data were analyzed using multivariate regression analysis taking into account potentially confounding effects of relevant clinical factors RESULTS: The L-type calcium current (ICa) density was diminished significantly in patients with chronic but not paroxysmal AF and the treatment of patients with ß-blockers did not affect ICa density in any group. By contrast, the ITI frequency was elevated in patients with either paroxysmal or chronic AF that did not receive treatment, and ß-blocker treatment reduced the frequency to levels observed in patients without AF. Confocal calcium imaging showed that ß-blocker treatment also reduced the calcium spark frequency in patients with AF to levels observed in those without AF. Furthermore, phosphorylation of the ryanodine receptor (RyR2) at Ser-2808 and phospholamban at Ser-16 was significantly lower in patients with AF that received ß-blockers. CONCLUSION: Together, our findings demonstrate that ß-blocker treatment may be of therapeutic utility to prevent spontaneous calcium release-induced atrial electrical activity; especially in patients with a history of paroxysmal AF displaying preserved ICa density.

Time course, factors related to, and prognostic impact of venoarterial extracorporeal membrane flow in cardiogenic shock.

AIMS: Venoarterial extracorporeal membrane oxygenation (VA-ECMO) is currently one of the most used devices in refractory cardiogenic shock. However, there is a lack of evidence on how to set the 'optimal' flow. We aimed to describe the evolution of VA-ECMO flows in a cardiogenic shock population and determine the risk factors of 'high-ECMO flow'. METHODS AND RESULTS: A 7 year database of patients supported with VA-ECMO was used. Based on the median flow during the first 48 h of the VA-ECMO run, patients were classified as 'high-flow' or 'low-flow', respectively, when median ECMO flow was ≥3.6 or <3.6 L/min. Outcomes included rates of ventilator-associated pneumonia, ECMO-related complications, days on ECMO, days on mechanical ventilation, intensive care unit and hospitalization lengths of stay, and in-hospital and 60 day mortality. Risk factors of high-ECMO flow were assessed using univariate and multivariate cox regression. The study population included 209 patients on VA-ECMO, median age was 51 (40-59) years, and 78% were males. The most frequent aetiology leading to cardiogenic shock was end-stage dilated cardiomyopathy (57%), followed by acute myocardial infarction (23%) and fulminant myocarditis (17%). Among the 209 patients, 105 (50%) were classified as 'high-flow'. This group had a higher rate of ischaemic aetiology (16% vs. 30%, P = 0.023) and was sicker at admission, in terms of worse Simplified Acute Physiology Score II score [40 (26-58) vs. 56 (42-74), P < 0.001], higher lactate [3.6 (2.2-5.8) mmol/L vs. 5.2 (3-9.7) mmol/L, P < 0.001], and higher aspartate aminotransferase [97 (41-375) U/L vs. 309 (85-939) U/L, P < 0.001], among others. The 'low-flow' group had less ventilator-associated pneumonia (40% vs. 59%, P = 0.007) and less days on mechanical ventilation [4 (1.5-7.5) vs. 6 (3-12) days, P = 0.009]. No differences were found in lengths of stay or survival according to the ECMO flow. The multivariate analysis showed that risk factors independently associated with 'high-flow' were mechanical ventilation at cannulation [odds ratio (OR) 3.9, 95% confidence interval (CI) 2.1-7.1] and pre-ECMO lactate (OR 1.1, 95% CI 1.0-1.2). CONCLUSIONS: In patients with refractory cardiogenic shock supported with VA-ECMO, sicker patients had higher support since early phases, presenting thereafter higher rates of ventilator-associated pneumonia but similar survival compared with patients with lower flows.

Incremental prognostic value of lung ultrasound on contemporary heart failure risk scores.

Introduction: Over the last decades, several scores have been developed to aid clinicians in assessing prognosis in patients with heart failure (HF) based on clinical data, medications and, ultimately, biomarkers. Lung ultrasound (LUS) has emerged as a promising prognostic tool for patients when assessed at discharge after a HF hospitalization. We hypothesized that contemporary HF risk scores can be improved upon by the inclusion of the number of B-lines detected by LUS at discharge to predict death, urgent visit, or HF readmission at 6- month follow-up. Methods: We evaluated the discrimination improvement of adding the number of B-lines to 4 contemporary HF risk scores (Get with the Guidelines -GWTG-, MAGGIC, Redin-SCORE, and BCN Bio-HF) by comparing the change in the area under the receiver operating curve (AUC), the net reclassification index (NRI), and the integrated discrimination improvement (IDI). The population of the study was constituted by the 123 patients enrolled in the LUS-HF trial, adjusting the analyses by the intervention. Results: The AUC of the GWTG score increased from 0.682 to 0.789 (p = 0.02), resulting in a NRI of 0.608 and an IDI of 0.136 (p < 0.05). Similar results were observed when adding the number of B-lines to the MAGGIC score, with an AUC that increased from 0.705 to 0.787 (p < 0.05). This increase translated into a NRI of 0.608 and an IDI of 0.038 (p < 0.05). Regarding Redin-SCORE at 1-month and 1-year, the AUC increased from 0.714 to 0.773 and from 0.681 to 0.757, although it did not reach statistical significance (p = 0.08 and p = 0.06 respectively). Both IDI and NRI were significantly improved (0.093 and 0.509 in the 1-month score, p < 0.05; 0.056 and 0.111 in the 1-year score, p < 0.05). Lastly, the AUC for the BCN Bio-HF score increased from 0.733 to 0.772, which was statistically non-significant, with a NRI value of 0.363 (p = 0.06) and an IDI of 0.092 (p < 0.05). Conclusion: Adding the results of LUS evaluated at discharge improved the predictive value of most of the contemporary HF risk scores. As it is a simple, fast, and non-invasive test it may be recommended to assess prognosis at discharge in HF patients.

Electrophysiological and histological characterization of atrial scarring in a model of isolated atrial myocardial infarction.

Background: Characterization of atrial myocardial infarction is hampered by the frequent concurrence of ventricular infarction. Theoretically, atrial infarct scarring could be recognized by multifrequency tissue impedance, like in ventricular infarction, but this remains to be proven. Objective: This study aimed at developing a model of atrial infarction to assess the potential of multifrequency impedance to recognize areas of atrial infarct scar. Methods: Seven anesthetized pigs were submitted to transcatheter occlusion of atrial coronary branches arising from the left coronary circumflex artery. Six weeks later the animals were anesthetized and underwent atrial voltage mapping and multifrequency impedance recordings. The hearts were thereafter extracted for anatomopathological study. Two additional pigs not submitted to atrial branch occlusion were used as controls. Results: Selective occlusion of the atrial branches induced areas of healed infarction in the left atrium in 6 of the 7 cases. Endocardial mapping of the left atrium showed reduced multi-frequency impedance (Phase angle at 307 kHz: from -17.1° ± 5.0° to -8.9° ± 2.6°, p < .01) and low-voltage of bipolar electrograms (.2 ± 0.1 mV vs. 1.9 ± 1.5 mV vs., p < .01) in areas affected by the infarction. Data variability of the impedance phase angle was lower than that of bipolar voltage (coefficient of variability of phase angle at307 kHz vs. bipolar voltage: .30 vs. .77). Histological analysis excluded the presence of ventricular infarction. Conclusion: Selective occlusion of atrial coronary branches permits to set up a model of selective atrial infarction. Atrial multifrequency impedance mapping allowed recognition of atrial infarct scarring with lesser data variability than local bipolar voltage mapping. Our model may have potential applicability on the study of atrial arrhythmia mechanisms.

ß2-adrenergic stimulation potentiates spontaneous calcium release by increasing signal mass and co-activation of ryanodine receptor clusters.

AIMS: It is unknown how ß-adrenergic stimulation affects calcium dynamics in individual RyR2 clusters and leads to the induction of spontaneous calcium waves. To address this, we analysed spontaneous calcium release events in green fluorescent protein (GFP)-tagged RyR2 clusters. METHODS: Cardiomyocytes from mice with GFP-tagged RyR2 or human right atrial tissue were subjected to immunofluorescent labelling or confocal calcium imaging. RESULTS: Spontaneous calcium release from single RyR2 clusters induced 91.4% ± 2.0% of all calcium sparks while 8.0% ± 1.6% were caused by release from two neighbouring clusters. Sparks with two RyR2 clusters had 40% bigger amplitude, were 26% wider, and lasted 35% longer at half maximum. Consequently, the spark mass was larger in two- than one-cluster sparks with a median and interquartile range for the cumulative distribution of 15.7 ± 20.1 vs 7.6 ± 5.7 a.u. (P < .01). ß2-adrenergic stimulation increased RyR2 phosphorylation at s2809 and s2815, tripled the fraction of two- and three-cluster sparks, and significantly increased the spark mass. Interestingly, the amplitude and mass of the calcium released from a RyR2 cluster were proportional to the SR calcium load, but the firing rate was not. The spark mass was also higher in 33 patients with atrial fibrillation than in 36 without (22.9 ± 23.4 a.u. vs 10.7 ± 10.9; P = .015). CONCLUSIONS: Most sparks are caused by activation of a single RyR2 cluster at baseline while ß-adrenergic stimulation doubles the mass and the number of clusters per spark. This mimics the shift in the cumulative spark mass distribution observed in myocytes from patients with atrial fibrillation.

Influence of sex on intracellular calcium homoeostasis in patients with atrial fibrillation.

AIMS: Atrial fibrillation (AF) has been associated with intracellular calcium disturbances in human atrial myocytes, but little is known about the potential influence of sex and we here aimed to address this issue. METHODS AND RESULTS: Alterations in calcium regulatory mechanisms were assessed in human atrial myocytes from patients without AF or with long-standing persistent or permanent AF. Patch-clamp measurements revealed that L-type calcium current (ICa) density was significantly smaller in males with than without AF (-1.15 ± 0.37 vs. -2.06 ± 0.29 pA/pF) but not in females with AF (-1.88 ± 0.40 vs. -2.21 ± 0.0.30 pA/pF). In contrast, transient inward currents (ITi) were more frequent in females with than without AF (1.92 ± 0.36 vs. 1.10 ± 0.19 events/min) but not in males with AF. Moreover, confocal calcium imaging showed that females with AF had more calcium spark sites than those without AF (9.8 ± 1.8 vs. 2.2 ± 1.9 sites/µm2) and sparks were wider (3.0 ± 0.3 vs. 2.2 ± 0.3 µm) and lasted longer (79 ± 6 vs. 55 ± 8 ms), favouring their fusion into calcium waves that triggers ITIs and afterdepolarizations. This was linked to higher ryanodine receptor phosphorylation at s2808 in women with AF, and inhibition of adenosine A2A or beta-adrenergic receptors that modulate s2808 phosphorylation was able to reduce the higher incidence of ITI in women with AF. CONCLUSION: Perturbations of the calcium homoeostasis in AF is sex-dependent, concurring with increased spontaneous SR calcium release-induced electrical activity in women but not in men, and with diminished ICa density in men only.

A 3-Biomarker 2-Point-Based Risk Stratification Strategy in Acute Heart Failure.

Introduction and Objectives: Most multi-biomarker strategies in acute heart failure (HF) have only measured biomarkers in a single-point time. This study aimed to evaluate the prognostic yielding of NT-proBNP, hsTnT, Cys-C, hs-CRP, GDF15, and GAL-3 in HF patients both at admission and discharge. Methods: We included 830 patients enrolled consecutively in a prospective multicenter registry. Primary outcome was 12-month mortality. The gain in the C-index, calibration, net reclassification improvement (NRI), and integrated discrimination improvement (IDI) was calculated after adding each individual biomarker value or their combination on top of the best clinical model developed in this study (C-index 0.752, 0.715-0.789) and also on top of 4 currently used scores (MAGGIC, GWTG-HF, Redin-SCORE, BCN-bioHF). Results: After 12-month, death occurred in 154 (18.5%) cases. On top of the best clinical model, the addition of NT-proBNP, hs-CRP, and GDF-15 above the respective cutoff point at admission and discharge and their delta during compensation improved the C-index to 0.782 (0.747-0.817), IDI by 5% (p < 0.001), and NRI by 57% (p < 0.001) for 12-month mortality. A 4-risk grading categories for 12-month mortality (11.7, 19.2, 26.7, and 39.4%, respectively; p < 0.001) were obtained using combination of these biomarkers. Conclusion: A model including NT-proBNP, hs-CRP, and GDF-15 measured at admission and discharge afforded a mortality risk prediction greater than our clinical model and also better than the most currently used scores. In addition, this 3-biomarker panel defined 4-risk categories for 12-month mortality.

Awake venoarterial extracorporeal membrane oxygenation for refractory cardiogenic shock.

BACKGROUND: Venoarterial-extracorporeal membrane oxygenation (VA-ECMO) is currently one of the first-line therapies for refractory cardiogenic shock (CS), but its applicability is undermined by the high morbidity associated with its complications, especially those related to mechanical ventilation (MV). We aimed to assess the prognostic impact of keeping patients in refractory CS awake at cannulation and during the VA-ECMO run. METHODS: A 7-year database of patients given peripheral VA-ECMO support was used to conduct a propensity-score (PS)-matched analysis to balance their clinical profiles. Patients were classified as 'awake ECMO' or 'non-awake ECMO', respectively, if invasive MV was used during ≤50% or >50% of the VA-ECMO run. Primary outcomes included ventilator-associated pneumonia and ECMO-related complication rates, and secondary outcomes were 60-day and 1-year mortality. A multivariate logistic-regression analysis was used to identify whether MV at cannulation was independently associated with 60-day mortality. RESULTS: Among 231 patients included, 91 (39%) were 'awake' and 140 (61%) 'non-awake'. After PS-matching adjustment, the 'awake ECMO' group had significantly lower rates of pneumonia (35% vs. 59%, P = 0.017), tracheostomy, renal replacement therapy, and less antibiotic and sedative consumption. This strategy was also associated with reduced 60-day (20% vs. 41%, P = 0.018) and 1-year mortality rates (31% vs. 54%, P = 0.021) compared to the 'non-awake' group, respectively. Lastly, MV at ECMO cannulation was independently associated with 60-day mortality. CONCLUSION: An 'awake ECMO' management in VA-ECMO-supported CS patients is feasible, safe, and associated with improved short- and long-term outcomes.

Differentiation of athlete's heart and hypertrophic cardiomyopathy by the fractal dimension of left ventricular trabeculae.

BACKGROUND: Differentiation between exercise induced adaptive myocardial hypertrophy (athlete's heart) and hypertrophic cardiomyopathy (HCM) is currently based on echocardiographic and cardiac magnetic resonance (CMR) criteria, but these may be insufficient in patients with subtle phenotype expression. This study aimed to assess whether left ventricular (LV) fractal pattern could permit to differentiate athlete's heart from HCM. METHODS: We recruited retrospectively 61 elite marathon runners, 67 patients with HCM, and 33 healthy subjects. A CMR study was performed in all subjects and the LV trabeculae fractal dimension (FD) was measured in end-diastolic frames of each short-axis cine sequence. For group comparison, the ratio of maximal myocardial wall thickness (mMWT)/indexed LV end-diastolic volume (LVED) was determined. RESULTS: As compared with athletes, patients with HCM had significantly (p < 0.001) greater FD in the LV basal (1.30 ± 0.07 vs. 1.23 ± 0.05) and apical (1.38 ± 0.06 vs. 1.30 ± 0.07) regions and in the whole heart (1.34 ± 0.05 vs. 1.27 ± 0.05). FD increased with age, left atrial area and indexed left ventricular mass (p < 0.05 for all) and correlated negatively with LV and RV end-diastolic volumes (p < 0.05 each). The addition of whole heart FD to the ratio of maximal myocardial wall thickness/indexed LVEDV lead to an improvement in the ability to discriminate HCM with a net reclassification index (NRI) of 71%. CONCLUSIONS: The FD regional distribution of the LV trabeculae differentiates patients with athlete's heart from patients with HCM. The addition of whole heart FD to the mMWT/indexed LVEDV ratio improves the predictive capacity of the model to differentiate both entities.

Prognostic impact of hyponatraemia and hypernatraemia at admission and discharge in heart failure patients with preserved, mid-range and reduced ejection fraction.

BACKGROUND: Hyponatraemia is common in patients with acute heart failure (HF). AIMS: To determine the impact of sodium disturbances on mortality and readmissions in HF with reduced left ventricular ejection fraction (HFrEF), preserved ejection fraction (HFpEF) and mid-range ejection fraction (HFmrEF). METHODS: This study was a prospective multicentre consecutive registry in 20 hospitals, including patients admitted due to acute HF in cardiology departments. Sodium <135 mmol/L was considered hyponatraemia, >145 mmol/L hypernatraemia and 135-145 mmol/L normal. RESULTS: A total of 1309 patients was included. Mean age was 72.0 ± 11.9 years, and 810 (61.9%) were male. Mean serum sodium level was 138.6 ± 4.7 mmol/L at hospital admission and 138.1 ± 4.1 mmol/L at discharge. The evolution of sodium levels was: normal-at-admission/normal-at-discharge 941 (71.9%), abnormal-at-admission/normal-at-discharge 127 (9.7%), normal-at-admission/abnormal-at-discharge 155 (11.8%) and abnormal-at-admission/abnormal-at-discharge 86 (6.6%). Hyponatraemia at discharge was more common in HFrEF (109 (20.7%)) than in HFpEF (79 (13.9%)) and HFmrEF (27 (12%)), P = 0.003. The prevalence of hypernatraemia at discharge was similar in the three groups: HFrEF (10 (1.9%)), HFpEF (12 (2.1%)) and HFmrEF (4 (1.9%)), P = 0.96. In multivariate analysis, abnormal sodium concentrations at hospital admission (hazard ratio (HR) 1.42, 95% confidence interval (CI) 1.15-1.76, P = 0.001) and discharge (HR 1.33, 95% CI 1.08-1.64, P = 0.007) were both independently associated with increased mortality and readmissions at 12 months. CONCLUSIONS: Hyponatraemia and hypernatraemia at admission and discharge predict a poor outcome in patients with acute HF regardless of left ventricular ejection fraction. Hyponatraemia at discharge is more frequent in HFrEF than in the other groups.

Modes of death in heart failure according to age, sex and left ventricular ejection fraction.

Modes of death in patients with heart failure (HF) have been well characterized in randomized studies, but data from real-life are scarce, especially in the elderly, women and in HF with mid-range or preserved left ventricular ejection fraction (LVEF). Our purpose was to examine modes of death in HF patients according to age, sex and LVEF. We analysed the mode of death of HF patients from two prospective multicentre contemporary Spanish registries conducted by cardiologists (REDINSCOR, n = 2150) and by internists (RICA, n = 1396). Mode of death was pre-specified. Out of 3546 patients, 485 (13.7%) died during the 9-month follow-up. Cardiovascular (CV) causes were the most frequent, regardless of the age, sex and LVEF. More than half of patients died due to worsening HF in both groups of patients, followed by other non-CV causes in those attended by internists, and sudden cardiac death in those cared by cardiologists. Stroke was more common among elderly patients, women and HF with preserved LVEF. Non-CV causes, particularly infectious diseases, accounted for a remarkable proportion of deaths, especially in the elderly and in HF patients with preserved LVEF. Functional class, age and anaemia had a strong influence on both CV and non-CV death. CV death due to refractory HF was the most prevalent among our population, irrespective of age, sex or LVEF. However, a significant proportion of HF patients died from non-CV causes, particularly elderly with mid-range and preserved LVEF. These patients could benefit significantly from a multidisciplinary follow-up.

New Electrocardiographic Algorithm for the Diagnosis of Acute Myocardial Infarction in Patients With Left Bundle Branch Block.

Background Current electrocardiographic algorithms lack sensitivity to diagnose acute myocardial infarction (AMI) in the presence of left bundle branch block. Methods and Results A multicenter retrospective cohort study including consecutive patients with suspected AMI and left bundle branch block, referred for primary percutaneous coronary intervention between 2009 and 2018. Pre-2015 patients formed the derivation cohort (n=163, 61 with AMI); patients between 2015 and 2018 formed the validation cohort (n=107, 40 with AMI). A control group of patients without suspected AMI was also studied (n=214). Different electrocardiographic criteria were tested. A total of 484 patients were studied. A new electrocardiographic algorithm (BARCELONA algorithm) was derived and validated. The algorithm is positive in the presence of ST deviation ≥1 mm (0.1 mV) concordant with QRS polarity, in any lead, or ST deviation ≥1 mm (0.1 mV) discordant with the QRS, in leads with max (R|S) voltage (the voltage of the largest deflection of the QRS, ie, R or S wave) ≤6 mm (0.6 mV). In both the derivation and the validation cohort, the BARCELONA algorithm achieved the highest sensitivity (93%-95%), negative predictive value (96%-97%), efficiency (91%-94%) and area under the receiver operating characteristic curve (0.92-0.93), significantly higher than previous electrocardiographic rules (P<0.01); the specificity was good in both groups (89%-94%) as well as the control group (90%). Conclusions In patients with left bundle branch block referred for primary percutaneous coronary intervention, the BARCELONA algorithm was specific and highly sensitive for the diagnosis of AMI, leading to a diagnostic accuracy comparable to that obtained by ECG in patients without left bundle branch block.

Estimated Population Prevalence of Heart Failure with Reduced Ejection Fraction in Spain, According to DAPA-HF Study Criteria.

Heart failure (HF) is one of the main causes of morbidity, mortality, and high healthcare costs. Dapagliflozin, a sodium-glucose cotransporter-2 (SGLT2) inhibitor, reduced cardiovascular mortality and hospitalization for HF compared to placebo in patients with chronic HF, and reduced ejection fraction (EF) in the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) study. Our aim was to estimate the number of patients with DAPA-HF characteristics in Spain. Our literature review identified epidemiological studies whose objective was to quantify the prevalence of HF and its comorbidities in Spain. We estimated the prevalence of HF with reduced EF, of New York Heart Association (NYHA) functional class II-IV, and with a glomerular filtration rate (GFR) ≥ 30 mL/min/1.73 m². In this population, we analysed the prevalence of diabetes using data from the REDINSCOR (Spanish Network for Heart Failure) registry. Our estimations indicate there are 594,684 patients ≥45 years old with HF in Spain (2.6% of this population age group), of which 52.4%, 84.0%, and 93.9% have reduced EF, are NYHA II-IV, and have a GFR ≥ 30 mL/min/1.73 m², respectively. By our calculations, approximately 245,789 Spanish patients would meet the DAPA-HF patient profile, and therefore could benefit from the protective cardiovascular effects of dapagliflozin.

Prevalence and prognostic impact of subclinical pulmonary congestion at discharge in patients with acute heart failure.

AIMS: Residual pulmonary congestion at hospital discharge can worsen the outcomes in patients with heart failure (HF) and can be detected by lung ultrasound (LUS). The aim of this study was to analyse the prevalence of subclinical pulmonary congestion at discharge and its impact on prognosis in patients admitted for acute HF. METHODS AND RESULTS: This is a post-hoc analysis of the LUS-HF trial. LUS was performed by the investigators in eight chest zones with a pocket device. Physical exam was subsequently performed by the treating physicians. Primary outcome was a combined endpoint of rehospitalization, unexpected visit for HF worsening or death at 6- month follow-up. Subclinical pulmonary congestion at discharge was defined as the presence of ≥5 B-lines in LUS in absence of rales in the auscultation employing the area under the ROC curve. At discharge, 100 patients (81%) did not show clinical signs of pulmonary congestion. Of these, 41 had ≥5 B-lines. Independent factors related with the presence of subclinical pulmonary congestion were anaemia, higher New York Heart Association (NYHA) class, and N terminal pro brain natriuretic peptide (NT-proBNP). After adjusting by propensity score analysis including age, renal insufficiency, atrial fibrillation, NYHA class, NT-proBNP levels, clinical congestion, and the trial intervention, the presence of subclinical pulmonary congestion at discharge was a risk factor for the occurrence of the primary outcome (hazard ratio 2.63; 95% confidence interval: 1.08-6.41; P = 0.033). CONCLUSIONS: Up to 40% of patients considered 'dry' according to pulmonary auscultation presents subclinical congestion at hospital discharge that can be detected by LUS and implies a worse prognosis at 6- month follow-up. Comorbidities, high values of natriuretic peptides, and higher NYHA class are the factors related with its presence.

Cambio en la causa de muerte e influencia de la mejora terapéutica con el tiempo en pacientes con insuficiencia cardiaca y fracción de eyección reducida / Changes in causes of death and influence of therapeutic improvement over time in patients with heart failure and reduced ejection fraction

INTRODUCCIÓN Y OBJETIVOS: En pacientes con insuficiencia cardiaca y fracción de eyección reducida (IC-FEr), se ha demostrado en ensayos clínicos que diferentes terapias reducen la mortalidad, pero hay pocos datos de la práctica real acerca del efecto en los distintos tipos de muerte. MÉTODOS: Se estudió a 2.351 pacientes ambulatorios con IC-FEr (FE <40%) procedentes de los registros prospectivos multicéntricos MUSIC (n=641, años 2003-2004) y REDINSCOR I (n=1.710, años 2007-2011). Las variables se registraron a la inclusión, y el seguimiento fue de 4 años. Un comité independiente adjudicó la mortalidad y sus causas. RESULTADOS: Los pacientes en el registro más contemporáneo recibieron con mayor frecuencia bloqueadores beta (el 85 frente al 71%; p <0,001), antialdosterónicos (el 64 frente al 44%; p <0,001), desfibrilador automático implantable (el 19 frente al 2%; p <0,001) y resincronización (el 7,2 frente al 4,8%; p = 0,04). La población más contemporánea presentó menos muerte súbita (el 6,8 frente al 11,4%; p <0,001). Tras emparejar por puntuación de propensión, se obtuvieron 2 poblaciones comparables que solo diferían en los tratamientos (575 frente a 575 pacientes): la población más contemporánea presentó menor riesgo de muerte total (HR=0,70; IC95%, 0,57-0,87; p = 0,001) y de muerte súbita (sHR=0,46; IC95%, 0,30-0,70; p <0,001), con una tendencia de muerte por IC (sHR=0,73; IC95%, 0,53-1,01; p = 0,059) y sin diferencias por otras causas (sHR=1,17; IC95%, 0,78-1,75; p = 0,445), independientemente de la clase funcional. CONCLUSIONES: En pacientes ambulatorios con IC-FEr, la mejora terapéutica se asoció con un menor riesgo de muerte, principalmente debido a la significativa reducción de las muertes súbitas

INTRODUCTION AND OBJECTIVES: In patients with heart failure and reduced ejection fraction (HFrEF), several therapies have been proven to reduce mortality in clinical trials. However, there are few data on the effect of the use of evidence-based therapies on causes of death in clinical practice. METHODS: This study included 2351 outpatients with HFrEF (< 40%) from 2 multicenter prospective registries: MUSIC (n=641, period: 2003-2004) and REDINSCOR I (n=1710, period: 2007-2011). Variables were recorded at inclusion and all patients were followed-up for 4 years. Causes of death were validated by an independent committee. RESULTS: Patients in REDINSCOR I more frequently received beta-blockers (85% vs 71%; P <.001), mineralocorticoid antagonists (64% vs 44%; P <.001), implantable cardioverter-defibrillators (19% vs 2%; P <.001), and resynchronization therapy (7.2% vs 4.8%; P=.04). In these patients, sudden cardiac death was less frequent than in those in MUSIC (6.8% vs 11.4%; P <.001). After propensity score matching, we obtained 2 comparable populations differing only in treatments (575 vs 575 patients). In patients in REDINSCOR I, we found a lower risk of total mortality (HR, 0.70; 95%CI, 0.57-0.87; P=.001) and sudden cardiac death (sHR, 0.46; 95%CI, 0.30-0.70; P <.001), and a trend toward lower mortality due to end-stage HF (sHR, 0.73; 95%CI, 0.53-1.01; P=.059), without differences in other causes of death (sHR, 1.17; 95%CI, 0.78-1.75; P=.445), regardless of functional class. CONCLUSIONS: In ambulatory patients with HFrEF, implementation of evidence-based therapies was associated with a lower risk of death, mainly due to a significant reduction in sudden cardiac death

Changes in Local Atrial Electrograms and Surface ECG Induced by Acute Atrial Myocardial Infarction.

BACKGROUND: Atrial coronary branch occlusion is a hardly recognizable clinical entity that can promote atrial fibrillation. The low diagnostic accuracy of the ECG could deal with the characteristics of the ischemia-induced changes in local atrial electrograms, but these have not been described. OBJECTIVES: We analyzed the effects of selective acute atrial branch occlusion on local myocardial structure, atrial electrograms, and surface ECG in an experimental model close to human cardiac anatomy and electrophysiology. METHODS: Six anesthetized open-chest anesthetized pigs underwent surgical occlusion of an atrial coronary branch arising from the right coronary artery during 4 h. Atrial electrograms and ECG were simultaneously recorded. One additional pig acted as sham control. In all cases, the hearts were processed for anatomopathological analysis. RESULTS: Atrial branch occlusion induced patchy atrial necrosis with sharp border zone. During the first 30 min of occlusion, atrial electrograms showed progressive R wave enlargement (1.8 ± 0.6 mV vs. 2.5 ± 1.1 mV, p < 0.01), delayed local activation times (28.5 ± 8.9 ms vs. 36.1 ± 16.4 ms, p < 0.01), ST segment elevation (-0.3 ± 0.3 mV vs. 1.0 ± 1.0 mV, p < 0.01), and presence of monophasic potentials. Atrial ST segment elevation decreased after 2 h of occlusion. The electrical border zone was ∼1 mm and expanded over time. After 2 h of occlusion, the ECG showed a decrease in P wave amplitude (from 0.09 ± 0.04 mV to 0.05 ± 0.04 mV after 165 min occlusion, p < 0.05) and duration (64.4 ± 8.0 ms vs. 80.9 ± 12.6 ms, p < 0.01). CONCLUSION: Selective atrial branch occlusion induces patchy atrial infarction and characteristic changes in atrial activation, R/S wave, and ST segment that are not discernible at the ECG. Only indirect changes in P wave amplitude and duration were appreciated in advanced stages of acute coronary occlusion.

Changes in causes of death and influence of therapeutic improvement over time in patients with heart failure and reduced ejection fraction.

INTRODUCTION AND OBJECTIVES: In patients with heart failure and reduced ejection fraction (HFrEF), several therapies have been proven to reduce mortality in clinical trials. However, there are few data on the effect of the use of evidence-based therapies on causes of death in clinical practice. METHODS: This study included 2351 outpatients with HFrEF (< 40%) from 2 multicenter prospective registries: MUSIC (n=641, period: 2003-2004) and REDINSCOR I (n=1710, period: 2007-2011). Variables were recorded at inclusion and all patients were followed-up for 4 years. Causes of death were validated by an independent committee. RESULTS: Patients in REDINSCOR I more frequently received beta-blockers (85% vs 71%; P <.001), mineralocorticoid antagonists (64% vs 44%; P <.001), implantable cardioverter-defibrillators (19% vs 2%; P <.001), and resynchronization therapy (7.2% vs 4.8%; P=.04). In these patients, sudden cardiac death was less frequent than in those in MUSIC (6.8% vs 11.4%; P <.001). After propensity score matching, we obtained 2 comparable populations differing only in treatments (575 vs 575 patients). In patients in REDINSCOR I, we found a lower risk of total mortality (HR, 0.70; 95%CI, 0.57-0.87; P=.001) and sudden cardiac death (sHR, 0.46; 95%CI, 0.30-0.70; P <.001), and a trend toward lower mortality due to end-stage HF (sHR, 0.73; 95%CI, 0.53-1.01; P=.059), without differences in other causes of death (sHR, 1.17; 95%CI, 0.78-1.75; P=.445), regardless of functional class. CONCLUSIONS: In ambulatory patients with HFrEF, implementation of evidence-based therapies was associated with a lower risk of death, mainly due to a significant reduction in sudden cardiac death.