Left Atrium Assessment by Speckle Tracking Echocardiography in Cryptogenic Stroke: Seeking Silent Atrial Fibrillation

Enfermedad auricular; Fibrilación auricular; EcocardiografíaMalaltia auricular; Fibril·lació auricular; EcocardiografiaAtrial disease; Atrial fibrillation; EchocardiographySilent atrial fibrillation (AF) may be the cause of some cryptogenic strokes (CrS). The aim of the study was to analyse atrial size and function by speckle tracking echocardiography in CrS patients to detect atrial disease. Patients admitted to the hospital due to CrS were included prospectively. Echocardiogram analysis included left atrial ejection fraction (LAEF) and atrial strain. Insertable cardiac monitor was implanted, and AF was defined as an episode of ≥1 min in the first year after stroke. Left atrial enlargement was defined as indexed volume > 34 mL/m2. Seventy-five consecutive patients were included, aged 76 ± 9 years (arterial hypertension 75%). AF was diagnosed in 49% of cases. The AF group had higher atrial volume and worse atrial function: peak atrial longitudinal strain (PALs) 19.6 ± 5.7% vs. 29.5 ± 7.2%, peak atrial contraction strain (PACs) 8.9 ± 3.9% vs. 16.5 ± 6%, LAEF 46.8 ± 11.5% vs. 60.6 ± 5.2%; p < 0.001. AF was diagnosed in 20 of 53 patients with non-enlarged atrium, and in 18 of them, atrial dysfunction was present. The multivariate logistic regression analysis demonstrated an independent association between detection of AF and atrial volume, LAEF, and strain. Cut-off values were obtained: LAEF < 55%, PALs < 21.4%, and PACs < 12.9%. In conclusion, speckle tracking echocardiography in CrS patients improves silent atrial disease diagnosis, with or without atrial enlargement.This research was funded by Instituto de Salud Carlos III-FIS (Fondo de Investigación Sanitaria, PI13/01830)

Serum Metabolomic Analysis Suggests Impairment of Myocardial Energy Production in Takotsubo Syndrome

Acute coronary syndromes; Takotsubo syndromeSíndromes coronarios agudos; Síndrome de TakotsuboSíndromes coronaris aguts; Síndrome de TakotsuboIntroduction: Takotsubo syndrome is a complex entity that, although it usually has a good prognosis, can be life threatening. While recent advances have improved the knowledge of takotsubo syndrome, many aspects of its etiology still remain uncertain. Metabolomics, a hypothesis generating approach, could provide novel pathophysiology information about this disease. Methods and Results: Serum samples were obtained from takotsubo (n = 19) and acute myocardial infarction patients (n = 8) at the cath lab and, in the case of takotsubo, again once the patient had recovered, 3 months after the main event. 1H NMR spectra of the serum were acquired at 9.4T using a CPMG pulse sequence (32 ms effective delay). Supervised and unsupervised pattern recognition approaches where applied to the data. Pattern recognition was able to differentiate between takotsubo and acute myocardial infarction during the acute phase with 95% accuracy. Myocardial infarction patients showed an increase in lipid signals, a known risk factor for the disease while takotsubo patients showed a relative increase in acetate that could suggest a reduced turnover of the Krebs cycle. When comparing acute and recovered phases, we could detect an increase in alanine and creatine once patients recovered. Conclusions: Our results demonstrate that takotsubo syndrome is metabolically different than AMI, showing limited myocardial energy production capacity during the acute phase. We achieved high classification success against AMI; however, this study should be considered as a proof of concept regarding clinical application of metabolic profiling in takotsubo cardiomyopathy.This work was supported by the Spanish Ministry of Economy and Competitiveness, Instituto de Salud Carlos III (Grants PI14/01431 and PI17/01397, SGR-1807, CIBER-CV, and CIBERESP), co-financed by the European Regional Development Fund (ERDF-FEDER, a way to build Europe)

Atrial Fibrillation in Heart Failure Is Associated with High Levels of Circulating microRNA-199a-5p and 22–5p and a Defective Regulation of Intracellular Calcium and Cell-to-Cell Communication

HL-1 cells; L-type calcium channels; Calcium regulationCélulas HL-1; Canales de calcio tipo L; Regulación del calcioCel·lules HL-1; Canals de calci tipus L; Regulació del calciMicroRNAs (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

Neurohormonal activation induces intracellular iron deficiency and mitochondrial dysfunction in cardiac cells

Cèl·lula cardíaca; Deficiència de ferro; Activació neurohormonalCardiac cell; Iron deficiency; Neurohormonal activationCélula cardíaca; Deficiencia de hierro; Activación neurohormonalBackground Iron deficiency (ID) is common in patients with heart failure (HF) and is associated with poor outcomes, yet its role in the pathophysiology of HF is not well-defined. We sought to determine the consequences of HF neurohormonal activation in iron homeostasis and mitochondrial function in cardiac cells. Methods HF was induced in C57BL/6 mice by using isoproterenol osmotic pumps and embryonic rat heart-derived H9c2 cells were subsequently challenged with Angiotensin II and/or Norepinephrine. The expression of several genes and proteins related to intracellular iron metabolism were assessed by Real time-PCR and immunoblotting, respectively. The intracellular iron levels were also determined. Mitochondrial function was analyzed by studying the mitochondrial membrane potential, the accumulation of radical oxygen species (ROS) and the adenosine triphosphate (ATP) production. Results Hearts from isoproterenol-stimulated mice showed a decreased in both mRNA and protein levels of iron regulatory proteins, transferrin receptor 1, ferroportin 1 and hepcidin compared to control mice. Furthermore, mitoferrin 2 and mitochondrial ferritin were also downregulated in the hearts from HF mice. Similar data regarding these key iron regulatory molecules were found in the H9c2 cells challenged with neurohormonal stimuli. Accordingly, a depletion of intracellular iron levels was found in the stimulated cells compared to non-stimulated cells, as well as in the hearts from the isoproterenol-induced HF mice. Finally, neurohormonal activation impaired mitochondrial function as indicated by the accumulation of ROS, the impaired mitochondrial membrane potential and the decrease in the ATP levels in the cardiac cells. Conclusions HF characteristic neurohormonal activation induced changes in the regulation of key molecules involved in iron homeostasis, reduced intracellular iron levels and impaired mitochondrial function. The current results suggest that iron could be involved in the pathophysiology of HF.This work was funded by the following Grants: unrestricted grant from Vifor Pharma and Basic Research Competitive Grant in Cardiology from the Spanish Society of Cardiology 2015

Cardiac monitoring for patients with palpitations

Monitoreo cardíaco; Grabadora de bucle; PalpitaciónCardiac monitoring; Loop recorder; PalpitationMonitorització cardíaca; Gravadora de bucle; PalpitacióPalpitations 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

Defective dimerization of FoF1-ATP synthase secondary to glycation favors mitochondrial energy deficiency in cardiomyocytes during aging

Aging; Dicarbonyl stress; MitochondriaEnvelliment; Estrès dicarbonílic; MitocondrisEnvejecimiento; Estrés dicarbonílico; MitocondriasAged 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

Enhanced Cardiorenal Protective Effects of Combining SGLT2 Inhibition, Endothelin Receptor Antagonism and RAS Blockade in Type 2 Diabetic Mice

Chronic kidney disease; Diabetic nephropathy; Endothelin receptor antagonistsEnfermedad renal crónica; Nefropatía diabética; Antagonistas de los receptores de endotelinaMalaltia renal crònica; Nefropatia diabètica; Antagonistes dels receptors d'endotelinaTreatments 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

Not enough QRS shortening? Keep calm and add another lead

Cardiac resynchronization therapy (CRT) diminishes symptoms and reduces hospitalization and mortality in patients with heart failure, LV dysfunction and left bundle branch block. However, up to one third of patients do not respond to CRT. In that regard, few initial studies presenting multisite pacing have shown encouraging results, demonstrating both feasibility and safety in placing a second CS lead in >80% of patients intended, with further QRS shortening, which is the most powerful predictor of LV reverse remodelling

The conventional isoproterenol-induced heart failure model does not consistently mimic the diaphragmatic dysfunction observed in patients

Heart failure (HF) impairs diaphragm function. Animal models realistically mimicking HF should feature both the cardiac alterations and the diaphragmatic dysfunction characterizing this disease. The isoproterenol-induced HF model is widely used, but whether it presents diaphragmatic dysfunction is unknown. However, indirect data from research in other fields suggest that isoproterenol could increase diaphragm function. The aim of this study was to test the hypothesis that the widespread rodent model of isoproterenol-induced HF results in increased diaphragmatic contractility. Forty C57BL/6J male mice were randomized into 2 groups: HF and healthy controls. After 30 days of isoproterenol infusion to establish HF, in vivo diaphragmatic excursion and ex vivo isolated diaphragm contractibility were measured. As compared with healthy controls, mice with isoproterenol-induced HF showed the expected changes in structural and functional echocardiographic parameters and lung edema. isoproterenol-induced HF increased in vivo diaphragm excursion (by ≈30%, p<0.01) and increased by ≈50% both ex vivo peak specific force (p<0.05) and tetanic force (p<0.05) at almost all 10-100 Hz frequencies (p<0.05), with reduced fatigue resistance (p<0.01) when compared with healthy controls. Expression of myosin genes encoding the main muscle fiber types revealed that Myh4 was higher in isoproterenol-induced HF than in healthy controls (p<0.05), suggesting greater distribution of type IIb fibers. These results show that the conventional isoproterenol-induced HF model increases diaphragm contraction, a finding contrary to what is observed in patients with HF. Therefore, this specific model seems limited for translational an integrative HF research, especially when cardio-respiratory interactions are investigated

Left atrium assessment by speckle tracking echocardiography in cryptogenic stroke: seeking silent atrial fibrillation

Silent atrial fibrillation (AF) may be the cause of some cryptogenic strokes (CrS). The aim of the study was to analyse atrial size and function by speckle tracking echocardiography in CrS patients to detect atrial disease. Patients admitted to the hospital due to CrS were included prospectively. Echocardiogram analysis included left atrial ejection fraction (LAEF) and atrial strain. Insertable cardiac monitor was implanted, and AF was defined as an episode of ≥1 min in the first year after stroke. Left atrial enlargement was defined as indexed volume > 34 mL/m2. Seventy-five consecutive patients were included, aged 76 ± 9 years (arterial hypertension 75%). AF was diagnosed in 49% of cases. The AF group had higher atrial volume and worse atrial function: peak atrial longitudinal strain (PALs) 19.6 ± 5.7% vs. 29.5 ± 7.2%, peak atrial contraction strain (PACs) 8.9 ± 3.9% vs. 16.5 ± 6%, LAEF 46.8 ± 11.5% vs. 60.6 ± 5.2%; p < 0.001. AF was diagnosed in 20 of 53 patients with non-enlarged atrium, and in 18 of them, atrial dysfunction was present. The multivariate logistic regression analysis demonstrated an independent association between detection of AF and atrial volume, LAEF, and strain. Cut-off values were obtained: LAEF < 55%, PALs < 21.4%, and PACs < 12.9%. In conclusion, speckle tracking echocardiography in CrS patients improves silent atrial disease diagnosis, with or without atrial enlargement