RESUMEN
Brugada syndrome (BrS), early repolarization syndrome (ERS), and idiopathic ventricular fibrillation (iVF) have long been considered primary electrical disorders associated with malignant ventricular arrhythmia and sudden cardiac death. However, recent studies have revealed the presence of subtle microstructural abnormalities of the extracellular matrix in some cases of BrS, ERS, and iVF, particularly within right ventricular subepicardial myocardium. Substrate-based ablation within this region has been shown to ameliorate the electrocardiographic phenotype and to reduce arrhythmia frequency in BrS. Patients with ERS and iVF may also exhibit low-voltage and fractionated electrograms in the ventricular subepicardial myocardium, which can be treated with ablation. A significant proportion of patients with BrS and ERS, as well as some iVF survivors, harbor pathogenic variants in the voltage-gated sodium channel gene, SCN5A, but the majority of genetic susceptibility of these disorders is likely to be polygenic. Here, we postulate that BrS, ERS, and iVF may form part of a spectrum of subtle subepicardial cardiomyopathy. We propose that impaired sodium current, along with genetic and environmental susceptibility, precipitates a reduction in epicardial conduction reserve, facilitating current-to-load mismatch at sites of structural discontinuity, giving rise to electrocardiographic changes and the arrhythmogenic substrate.
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Síndrome de Brugada , Cardiomiopatías , Humanos , Arritmias Cardíacas , Fibrilación Ventricular/etiología , Fibrilación Ventricular/genética , Síndrome de Brugada/complicaciones , Síndrome de Brugada/diagnóstico , Síndrome de Brugada/genética , Electrocardiografía , Cardiomiopatías/diagnóstico , Cardiomiopatías/genéticaRESUMEN
Multielectrode arrays (MEAs) are the method of choice for electrophysiological characterization of cardiomyocyte monolayers. The field potentials recorded using an MEA are like extracellular electrograms recorded from the myocardium using conventional electrodes. Nevertheless, different criteria are used to interpret field potentials and extracellular electrograms, which hamper correct interpretation and translation to the patient. To validate the criteria for interpretation of field potentials, we used neonatal rat cardiomyocytes to generate monolayers. We recorded field potentials using an MEA and simultaneously recorded action potentials using sharp microelectrodes. In parallel, we recreated our experimental setting in silico and performed simulations. We show that the amplitude of the local RS complex of a field potential correlated with conduction velocity in silico but not in vitro. The peak time of the T wave in field potentials exhibited a strong correlation with APD90 while the steepest upslope correlated well with APD50. However, this relationship only holds when the T wave displayed a biphasic pattern. Next, we simulated local extracellular action potentials (LEAPs). The shape of the LEAP differed markedly from the shape of the local action potential, but the final duration of the LEAP coincided with APD90. Criteria for interpretation of extracellular electrograms should be applied to field potentials. This will provide a strong basis for the analysis of heterogeneity in conduction velocity and repolarization in cultured monolayers of cardiomyocytes. Finally, a LEAP is not a recording of the local action potential but is generated by intracellular current provided by neighboring cardiomyocytes and is superior to field potential duration in estimating APD90.NEW & NOTEWORTHY We present a physiological basis for the interpretation of multielectrode array-derived, extracellular, electrical signals.
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Miocardio , Miocitos Cardíacos , Humanos , Ratas , Animales , Miocitos Cardíacos/fisiología , Arritmias Cardíacas , Microelectrodos , Potenciales de Acción/fisiologíaRESUMEN
Sodium glucose cotransporter 2 inhibitors (SGLT2i) constitute the only medication class that consistently prevents or attenuates human heart failure (HF) independent of ejection fraction. We have suggested earlier that the protective mechanisms of the SGLT2i Empagliflozin (EMPA) are mediated through reductions in the sodium hydrogen exchanger 1 (NHE1)-nitric oxide (NO) pathway, independent of SGLT2. Here, we examined the role of SGLT2, NHE1 and NO in a murine TAC/DOCA model of HF. SGLT2 knockout mice only showed attenuated systolic dysfunction without having an effect on other signs of HF. EMPA protected against systolic and diastolic dysfunction, hypertrophy, fibrosis, increased Nppa/Nppb mRNA expression and lung/liver edema. In addition, EMPA prevented increases in oxidative stress, sodium calcium exchanger expression and calcium/calmodulin-dependent protein kinase II activation to an equal degree in WT and SGLT2 KO animals. In particular, while NHE1 activity was increased in isolated cardiomyocytes from untreated HF, EMPA treatment prevented this. Since SGLT2 is not required for the protective effects of EMPA, the pathway between NHE1 and NO was further explored in SGLT2 KO animals. In vivo treatment with the specific NHE1-inhibitor Cariporide mimicked the protection by EMPA, without additional protection by EMPA. On the other hand, in vivo inhibition of NOS with L-NAME deteriorated HF and prevented protection by EMPA. In conclusion, the data support that the beneficial effects of EMPA are mediated through the NHE1-NO pathway in TAC/DOCA-induced heart failure and not through SGLT2 inhibition.
RESUMEN
Genome-wide association studies have identified noncoding variants near TBX3 that are associated with PR interval and QRS duration, suggesting that subtle changes in TBX3 expression affect atrioventricular conduction system function. To explore whether and to what extent the atrioventricular conduction system is affected by Tbx3 dose reduction, we first characterized electrophysiological properties and morphology of heterozygous Tbx3 mutant (Tbx3+/-) mouse hearts. We found PR interval shortening and prolonged QRS duration, as well as atrioventricular bundle hypoplasia after birth in heterozygous mice. The atrioventricular node size was unaffected. Transcriptomic analysis of atrioventricular nodes isolated by laser capture microdissection revealed hundreds of deregulated genes in Tbx3+/- mutants. Notably, Tbx3+/- atrioventricular nodes showed increased expression of working myocardial gene programs (mitochondrial and metabolic processes, muscle contractility) and reduced expression of pacemaker gene programs (neuronal, Wnt signaling, calcium/ion channel activity). By integrating chromatin accessibility profiles (ATAC sequencing) of atrioventricular tissue and other epigenetic data, we identified Tbx3-dependent atrioventricular regulatory DNA elements (REs) on a genome-wide scale. We used transgenic reporter assays to determine the functionality of candidate REs near Ryr2, an up-regulated chamber-enriched gene, and in Cacna1g, a down-regulated conduction system-specific gene. Using genome editing to delete candidate REs, we showed that a strong intronic bipartite RE selectively governs Cacna1g expression in the conduction system in vivo. Our data provide insights into the multifactorial Tbx3-dependent transcriptional network that regulates the structure and function of the cardiac conduction system, which may underlie the differences in PR duration and QRS interval between individuals carrying variants in the TBX3 locus.
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Nodo Atrioventricular , Proteínas de Dominio T Box , Transcriptoma/genética , Animales , Arritmias Cardíacas , Nodo Atrioventricular/metabolismo , Nodo Atrioventricular/fisiología , Canales de Calcio Tipo T/genética , Canales de Calcio Tipo T/metabolismo , Ratones , Ratones Transgénicos , Mutación/genética , Canal Liberador de Calcio Receptor de Rianodina/genética , Canal Liberador de Calcio Receptor de Rianodina/metabolismo , Proteínas de Dominio T Box/genética , Proteínas de Dominio T Box/metabolismoRESUMEN
Sodium glucose cotransporter 2 inhibitors (SGLT2i) constitute a promising drug treatment for heart failure patients with either preserved or reduced ejection fraction. Whereas SGLT2i were originally developed to target SGLT2 in the kidney to facilitate glucosuria in diabetic patients, it is becoming increasingly clear that these drugs also have important effects outside of the kidney. In this review we summarize the literature on cardiac effects of SGLT2i, focussing on pro-inflammatory and oxidative stress processes, ion transport mechanisms controlling sodium and calcium homeostasis and metabolic/mitochondrial pathways. These mechanisms are particularly important as disturbances in these pathways result in endothelial dysfunction, diastolic dysfunction, cardiac stiffness, and cardiac arrhythmias that together contribute to heart failure. We review the findings that support the concept that SGLT2i directly and beneficially interfere with inflammation, oxidative stress, ionic homeostasis, and metabolism within the cardiac cell. However, given the very low levels of SGLT2 in cardiac cells, the evidence suggests that SGLT2-independent effects of this class of drugs likely occurs via off-target effects in the myocardium. Thus, while there is still much to be understood about the various factors which determine how SGLT2i affect cardiac cells, much of the research clearly demonstrates that direct cardiac effects of these SGLT2i exist, albeit mediated via SGLT2-independent pathways, and these pathways may play a role in explaining the beneficial effects of SGLT2 inhibitors in heart failure.
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Diabetes Mellitus Tipo 2 , Insuficiencia Cardíaca , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Humanos , Miocardio/metabolismo , Transportador 2 de Sodio-Glucosa/metabolismo , Transportador 2 de Sodio-Glucosa/uso terapéutico , Inhibidores del Cotransportador de Sodio-Glucosa 2/efectos adversosRESUMEN
Sodium-glucose-cotransporter 2 inhibitors (SGLT2is) demonstrate large cardiovascular benefit in both diabetic and non-diabetic, acute and chronic heart failure patients. These inhibitors have on-target (SGLT2 inhibition in the kidney) and off-target effects that likely both contribute to the reported cardiovascular benefit. Here we review the literature on direct effects of SGLT2is on various cardiac cells and derive at an unifying working hypothesis. SGLT2is acutely and directly (1) inhibit cardiac sodium transporters and alter ion homeostasis, (2) reduce inflammation and oxidative stress, (3) influence metabolism, and (4) improve cardiac function. We postulate that cardiac benefit modulated by SGLT2i's can be commonly attributed to their inhibition of sodium-loaders in the plasma membrane (NHE-1, Nav1.5, SGLT) affecting intracellular sodium-homeostasis (the sodium-interactome), thereby providing a unifying view on the various effects reported in separate studies. The SGLT2is effects are most apparent when cells or hearts are subjected to pathological conditions (reactive oxygen species, inflammation, acidosis, hypoxia, high saturated fatty acids, hypertension, hyperglycemia, and heart failure sympathetic stimulation) that are known to prime these plasmalemmal sodium-loaders. In conclusion, the cardiac sodium-interactome provides a unifying testable working hypothesis and a possible, at least partly, explanation to the clinical benefits of SGLT2is observed in the diseased patient.
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Diabetes Mellitus Tipo 2 , Insuficiencia Cardíaca , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Compuestos de Bencidrilo/farmacología , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Glucósidos/farmacología , Insuficiencia Cardíaca/tratamiento farmacológico , Humanos , Inflamación , Sodio/metabolismo , Inhibidores del Cotransportador de Sodio-Glucosa 2/efectos adversosRESUMEN
The pig is commonly used as an experimental model of human heart disease, including for the study of mechanisms of arrhythmia. However, there exist differences between human and porcine cellular electrophysiology: The pig action potential (AP) has a deeper phase-1 notch, a longer duration at 50% repolarization, and higher plateau potentials than human. Ionic differences underlying the AP include larger rapid delayed-rectifier and smaller inward-rectifier K+-currents (IKr and IK1 respectively) in humans. AP steady-state rate-dependence and restitution is steeper in pigs. Porcine Ca2+ transients can have two components, unlike human. Although a reliable computational model for human ventricular myocytes exists, one for pigs is lacking. This hampers translation from results obtained in pigs to human myocardium. Here, we developed a computational model of the pig ventricular cardiomyocyte AP using experimental datasets of the relevant ionic currents, Ca2+-handling, AP shape, AP duration restitution, and inducibility of triggered activity and alternans. To properly capture porcine Ca2+ transients, we introduced a two-step process with a faster release in the t-tubular region, followed by a slower diffusion-induced release from a non t-tubular subcellular region. The pig model behavior was compared with that of a human ventricular cardiomyocyte (O'Hara-Rudy) model. The pig, but not the human model, developed early afterdepolarizations (EADs) under block of IK1, while IKr block led to EADs in the human but not in the pig model. At fast rates (pacing cycle length = 400 ms), the human cell model was more susceptible to spontaneous Ca2+ release-mediated delayed afterdepolarizations (DADs) and triggered activity than pig. Fast pacing led to alternans in human but not pig. Developing species-specific models incorporating electrophysiology and Ca2+-handling provides a tool to aid translating antiarrhythmic and arrhythmogenic assessment from the bench to the clinic.
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Modelos Cardiovasculares , Miocitos Cardíacos/fisiología , Potenciales de Acción , Animales , Arritmias Cardíacas/fisiopatología , Señalización del Calcio , Biología Computacional , Simulación por Computador , Fenómenos Electrofisiológicos , Ventrículos Cardíacos/citología , Humanos , Técnicas In Vitro , Modelos Animales , Técnicas de Placa-Clamp , Sus scrofa , Investigación Biomédica TraslacionalRESUMEN
BACKGROUND: The T wave of the electrocardiogram (ECG) reflects ventricular repolarization. Repolarization heterogeneity is associated with reentrant arrhythmias. Several T-wave markers (including QT interval) have been associated with ventricular arrhythmias, but studies linking such markers to underlying local repolarization time (RT) inhomogeneities are lacking. We aimed to investigate the relation of several T-wave markers to controlled drug-induced regional RT gradients in intact pig hearts. METHODS: Repolarization time gradients were created by regional infusion of dofetilide and pinacidil in four atrially paced porcine Langendorff-perfused hearts placed inside a torso tank. From the 12-lead ECG on the torso tank, the mean, maximum, and dispersion (max-min) of QTtime , JTtime , Tpeak-end , Twidth , TQratio , dV/dtmax , Tarea , Tamp , and T-upslope duration were determined, as well as upslope end difference between leads V1 and V6 . RESULTS: Temporal T-wave parameters Tpeak-end , Twidth, and TQratio show a significant and high correlation with RT gradient, best reflected by mean value. Tarea (mean, max and dispersion) and dV/dtmax dispersion show only a moderate significant correlation. T-upslope duration shows a significant correlation in particular for mean values. Mean, maximum, or dispersion of QTtime and V1 -V6 upslope end difference were not significantly correlated with RT gradient. CONCLUSION: Composite 12-lead ECG T-wave parameters Tpeak-end , Twidth , TQratio , upslope duration, and Tarea show a good correlation with underlying RT heterogeneity, whereas standard clinical metrics such as QTtime do not reflect local RT heterogeneity. The composite T-wave metrics may thus provide better insights in arrhythmia susceptibility than traditional QTtime metrics.
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Arritmias Cardíacas , Electrocardiografía , Humanos , Porcinos , Animales , Corazón , PinacidiloRESUMEN
Brugada syndrome and early repolarization syndrome are both classified as J-wave syndromes, with a similar mechanism of arrhythmogenesis and with the same basis for genesis of the characteristic electrocardiographic features. The Brugada syndrome is now considered a conduction disorder based on subtle structural abnormalities in the right ventricular outflow tract. Recent evidence suggests structural substrate in patients with the early repolarization syndrome as well. We propose a unifying mechanism based on these structural abnormalities explaining both arrhythmogenesis and the electrocardiographic changes. In addition, we speculate that, with increasing technical advances in imaging techniques and their spatial resolution, these syndromes will be reclassified as structural heart diseases or cardiomyopathies.
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Arritmias Cardíacas/patología , Síndrome de Brugada/patología , Trastorno del Sistema de Conducción Cardíaco/patología , Fibrosis/fisiopatología , Sistema de Conducción Cardíaco/anomalías , Animales , Arritmias Cardíacas/etiología , Síndrome de Brugada/etiología , Trastorno del Sistema de Conducción Cardíaco/etiología , HumanosRESUMEN
Repolarization reserve, the robustness of a cell to repolarize even when one of the repolarization mechanisms is failing, has been described qualitatively in terms of ionic currents, but has not been quantified by a generic metric that is applicable to drug screening. Prolonged repolarization leading to repolarization failure is highly arrhythmogenic. It may lead to ventricular tachycardia caused by triggered activity from early afterdepolarizations (EADs), or it may promote the occurrence of unidirectional conduction block and reentry. Both types of arrhythmia may deteriorate into ventricular fibrillation (VF) and death. We define the Repolarization Reserve Current (RRC) as the minimum constant current necessary to prevent normal repolarization of a cell. After developing and testing RRC for nine computational ionic models of various species, we applied it experimentally to atrial and ventricular human induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM), and isolated guinea-pig ventricular cardiomyocytes. In simulations, repolarization was all-or-none with a precise, model-dependent critical RRC, resulting in a discrete shift in the Action Potential Duration (APD) - RRC relation, in the occurrence of EADs and repolarization failure. These data were faithfully reproduced in cellular experiments. RRC allows simple, fast, unambiguous quantification of the arrhythmogenic propensity in cardiac cells of various origins and species without the need of prior knowledge of underlying currents and is suitable for high throughput applications, and personalized medicine applications.
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Potenciales de Acción/fisiología , Arritmias Cardíacas/inducido químicamente , Arritmias Cardíacas/fisiopatología , Biomarcadores/metabolismo , Animales , Simulación por Computador , Cobayas , Ventrículos Cardíacos/patología , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Iones , Miocitos Cardíacos/metabolismo , Preparaciones Farmacéuticas , Conejos , Factores de RiesgoRESUMEN
BACKGROUND: We conducted a multicenter study to evaluate mapping and ablation of ventricular fibrillation (VF) substrates or VF triggers in early repolarization syndromes (ERS) or J-wave syndrome (JWS). METHODS: We studied 52 patients with ERS (4 women; median age, 35 years) with recurrent VF episodes. Body surface electrocardiographic imaging and endocardial and epicardial electroanatomical mapping of both ventricles were performed during sinus rhythm and VF for localization of triggers, substrates, and drivers. Ablations were performed on VF substrates, defined as areas that had late depolarization abnormalities characterized by low-voltage fractionated late potentials, and VF triggers. RESULTS: Fifty-one of the 52 patients had detailed mapping that revealed 2 phenotypes: group 1 had late depolarization abnormalities predominantly at the right ventricular (RV) epicardium (n=40), and group 2 had no depolarization abnormalities (n=11). Group 1 can be subcategorized into 2 groups: Group 1A included 33 patients with ERS with Brugada electrocardiographic pattern, and group 1B included 7 patients with ERS without Brugada electrocardiographic pattern. Late depolarization areas colocalize with VF driver areas. The anterior RV outflow tract/RV epicardium and the RV inferior epicardium are the major substrate sites for group 1. The Purkinje network is the leading underlying VF trigger in group 2 that had no substrates. Ablations were performed in 43 patients: 31 and 5 group 1 patients had only VF substrate ablation and VF substrates plus VF trigger, respectively (mean, 1.4±0.6 sessions); 6 group 2 patients and 1 patient without group classification had only Purkinje VF trigger ablation (mean, 1.2±0.4 sessions). Ablations were successful in reducing VF recurrences (P<0.0001). After follow-up of 31±26 months, 39 (91%) had no VF recurrences. CONCLUSIONS: There are 2 phenotypes of ERS/J-wave syndrome: one with late depolarization abnormality as the underlying mechanism of high-amplitude J-wave elevation that predominantly resides in the RV outflow tract and RV inferolateral epicardium, serving as an excellent target for ablation, and the other with pure ERS devoid of VF substrates but with VF triggers that are associated with Purkinje sites. Ablation is effective in treating symptomatic patients with ERS/J-wave syndrome with frequent VF episodes.
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Síndrome de Brugada/fisiopatología , Endocardio/fisiopatología , Taquicardia Ventricular/fisiopatología , Fibrilación Ventricular/fisiopatología , Adulto , Ablación por Catéter/métodos , Electrocardiografía/métodos , Técnicas Electrofisiológicas Cardíacas/métodos , Mapeo Epicárdico/métodos , Femenino , Ventrículos Cardíacos/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
INTRODUCTION: To improve the mechanistic understanding of spontaneous initiation of ventricular fibrillation (VF), we characterized the patterns of premature ventricular complex (PVC) preceding spontaneous VF in primary and secondary implantable cardioverter-defibrillator (ICD) recipients. METHODS AND RESULTS: A single-center, cross-sectional analysis of 1209 patients with primary and secondary prevention ICD identified 190 patients who received ICD therapy (firing or antitachycardia pacing) for VF or monomorphic ventricular tachycardia (MMVT). Initiation was quantified by the coupling interval (CI), the cycle length immediately preceding the CI (CL(-1)), the CI corrected by CL(-1) using Fridericia's formula (CIc), and the prematurity index (PI). In both VF (n = 44; 23%) and MMVT (n = 134; 71%), the most common pattern of initiation was late-coupled PVC, followed by the short-long-short pattern. The parameters such as pre-initiation median CL, CL(-1), CI, and PI were not significantly different between VF and MMVT for any patterns. At least some events (45% of VF and 63% of MMVT) had extremely long CIs beyond the QTc cut-off estimated from the CL(-1), suggestive of initiation by a train of multiple PVCs or nonsustained VT instead of a single PVC. CONCLUSION: Some spontaneous VF events in ICD recipients appear to be initiated by a train of multiple PVC or nonsustained VT rather than a single PVC. This finding indicates that patterns of a single PVC are not an important determinant of VF initiation and thus account for conflicting results in previous studies.
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Desfibriladores Implantables , Fibrilación Ventricular , Estudios Transversales , Humanos , Taquicardia Ventricular/diagnóstico , Taquicardia Ventricular/terapia , Fibrilación Ventricular/diagnóstico , Fibrilación Ventricular/terapia , Complejos Prematuros Ventriculares/diagnósticoRESUMEN
Patients with very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) can present with life-threatening cardiac arrhythmias. The pathophysiological mechanism is unknown. We reprogrammed fibroblasts from one mildly and one severely affected VLCADD patient, into human induced pluripotent stem cells (hiPSCs) and differentiated these into cardiomyocytes (VLCADD-CMs). VLCADD-CMs displayed shorter action potentials (APs), more delayed afterdepolarizations (DADs) and higher systolic and diastolic intracellular Ca2+ concentration ([Ca2+]i) than control CMs. The mitochondrial booster resveratrol mitigated the biochemical, electrophysiological and [Ca2+]i changes in the mild but not in the severe VLCADD-CMs. Accumulation of potentially toxic intermediates of fatty acid oxidation was blocked by substrate reduction with etomoxir. Incubation with etomoxir led to marked prolongation of AP duration and reduced DADs and [Ca2+]i in both VLCADD-CMs. These results provide compelling evidence that reduced accumulation of fatty acid oxidation intermediates, either by enhanced fatty acid oxidation flux through increased mitochondria biogenesis (resveratrol) or by inhibition of fatty acid transport into the mitochondria (etomoxir), rescues pro-arrhythmia defects in VLCADD-CMs and open doors for new treatments.
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Acil-CoA Deshidrogenasa de Cadena Larga/deficiencia , Arritmias Cardíacas/prevención & control , Síndromes Congénitos de Insuficiencia de la Médula Ósea/fisiopatología , Compuestos Epoxi/farmacología , Ácidos Grasos/química , Errores Innatos del Metabolismo Lipídico/fisiopatología , Mitocondrias/fisiología , Enfermedades Mitocondriales/fisiopatología , Enfermedades Musculares/fisiopatología , Miocitos Cardíacos/fisiología , Resveratrol/farmacología , Potenciales de Acción , Arritmias Cardíacas/etiología , Electrofisiología Cardíaca , Síndromes Congénitos de Insuficiencia de la Médula Ósea/complicaciones , Ácidos Grasos/metabolismo , Humanos , Células Madre Pluripotentes Inducidas , Errores Innatos del Metabolismo Lipídico/complicaciones , Enfermedades Mitocondriales/complicaciones , Enfermedades Musculares/complicaciones , Miocitos Cardíacos/efectos de los fármacos , Oxidación-ReducciónAsunto(s)
Diabetes Mellitus Tipo 2 , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Humanos , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Hipoglucemiantes/farmacología , Hipoglucemiantes/uso terapéutico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Compuestos de Bencidrilo/farmacología , Compuestos de Bencidrilo/uso terapéutico , GlucosaRESUMEN
RATIONALE: Genome-wide association studies previously identified an association of rs9388451 at chromosome 6q22.3 (near HEY2) with Brugada syndrome. The causal gene and underlying mechanism remain unresolved. OBJECTIVE: We used an integrative approach entailing transcriptomic studies in human hearts and electrophysiological studies in Hey2+/- (Hey2 heterozygous knockout) mice to dissect the underpinnings of the 6q22.31 association with Brugada syndrome. METHODS AND RESULTS: We queried expression quantitative trait locus data acquired in 190 human left ventricular samples from the genotype-tissue expression consortium for cis-expression quantitative trait locus effects of rs9388451, which revealed an association between Brugada syndrome risk allele dosage and HEY2 expression (ß=+0.159; P=0.0036). In the same transcriptomic data, we conducted genome-wide coexpression analysis for HEY2, which uncovered KCNIP2, encoding the ß-subunit of the channel underlying the transient outward current (Ito), as the transcript most robustly correlating with HEY2 expression (ß=+1.47; P=2×10-34). Transcript abundance of Hey2 and the Ito subunits Kcnip2 and Kcnd2, assessed by quantitative reverse transcription-polymerase chain reaction, was higher in subepicardium versus subendocardium in both left and right ventricles, with lower levels in Hey2+/- mice compared with wild type. Surface ECG measurements showed less prominent J waves in Hey2+/- mice compared with wild-type. In wild-type mice, patch-clamp electrophysiological studies on cardiomyocytes from right ventricle demonstrated a shorter action potential duration and a lower Vmax in subepicardium compared with subendocardium cardiomyocytes, which was paralleled by a higher Ito and a lower sodium current (INa) density in subepicardium versus subendocardium. These transmural differences were diminished in Hey2+/- mice because of changes in subepicardial cardiomyocytes. CONCLUSIONS: This study uncovers a role of HEY2 in the normal transmural electrophysiological gradient in the ventricle and provides compelling evidence that genetic variation at 6q22.31 (rs9388451) is associated with Brugada syndrome through a HEY2-dependent alteration of ion channel expression across the cardiac ventricular wall.
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Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/biosíntesis , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Síndrome de Brugada/genética , Síndrome de Brugada/metabolismo , Predisposición Genética a la Enfermedad/genética , Ventrículos Cardíacos/metabolismo , Proteínas Represoras/biosíntesis , Proteínas Represoras/genética , Animales , Síndrome de Brugada/fisiopatología , Electrocardiografía/métodos , Femenino , Estudio de Asociación del Genoma Completo/métodos , Ventrículos Cardíacos/fisiopatología , Humanos , Canales Iónicos/biosíntesis , Canales Iónicos/genética , Masculino , Ratones , Ratones Noqueados , Ratones TransgénicosRESUMEN
BACKGROUND: With increasing clinical use of Electrocardiographic Imaging (ECGI), it is imperative to understand the limits of this technique. The objective of this study is to evaluate a potential-based ECGI approach for activation and repolarization mapping in sinus rhythm. METHOD: Langendorff-perfused pig hearts were suspended in a human-shaped torso tank. Electrograms were recorded with a 108-electrode sock and ECGs with 256 electrodes embedded in the tank surface. Left bundle branch block (LBBB) was developed in 4 hearts through ablation, and repolarization abnormalities in another 4 hearts through regional perfusion of dofetilide and pinacidil. Electrograms were noninvasively reconstructed and reconstructed activation and repolarization features were compared to those recorded. RESULTS: Visual consistency between ECGI and recorded activation and repolarization maps was high. While reconstructed repolarization times showed significantly more error than activation times quantitatively, patterns were reconstructed with a similar level of accuracy. The number of epicardial breakthrough sites was underestimated by ECGI and these were misplaced (>20â¯mm) in location. Likewise, ECGI reconstructed activation maps demonstrated artificial lines of block resulting from a W-shaped QRS waveform that were not present in recorded maps. Nevertheless, ECGI allowed identification of regions of abnormal repolarization reasonably accurately in terms of size, location and timing. CONCLUSIONS: This study validates a potential-based ECGI approach to noninvasively image activation and recovery in sinus rhythm. Despite inaccuracies in epicardial breakthroughs and lines of conduction block, other important clinical features such as regions of abnormal repolarization can be accurately derived making ECGI a valuable clinical tool.
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Arritmias Cardíacas , Mapeo del Potencial de Superficie Corporal , Electrocardiografía , Animales , Arritmias Cardíacas/diagnóstico , Diagnóstico por Imagen , Pruebas Diagnósticas de Rutina , PorcinosRESUMEN
AIMS/HYPOTHESIS: Sodium-glucose cotransporter 2 (SGLT2) inhibitors (SGLT2i) constitute a novel class of glucose-lowering (type 2) kidney-targeted agents. We recently reported that the SGLT2i empagliflozin (EMPA) reduced cardiac cytosolic Na+ ([Na+]c) and cytosolic Ca2+ ([Ca2+]c) concentrations through inhibition of Na+/H+ exchanger (NHE). Here, we examine (1) whether the SGLT2i dapagliflozin (DAPA) and canagliflozin (CANA) also inhibit NHE and reduce [Na+]c; (2) a structural model for the interaction of SGLT2i to NHE; (3) to what extent SGLT2i affect the haemodynamic and metabolic performance of isolated hearts of healthy mice. METHODS: Cardiac NHE activity and [Na+]c in mouse cardiomyocytes were measured in the presence of clinically relevant concentrations of EMPA (1 µmol/l), DAPA (1 µmol/l), CANA (3 µmol/l) or vehicle. NHE docking simulation studies were applied to explore potential binding sites for SGTL2i. Constant-flow Langendorff-perfused mouse hearts were subjected to SGLT2i for 30 min, and cardiovascular function, O2 consumption and energetics (phosphocreatine (PCr)/ATP) were determined. RESULTS: EMPA, DAPA and CANA inhibited NHE activity (measured through low pH recovery after NH4+ pulse: EMPA 6.69 ± 0.09, DAPA 6.77 ± 0.12 and CANA 6.80 ± 0.18 vs vehicle 7.09 ± 0.09; p < 0.001 for all three comparisons) and reduced [Na+]c (in mmol/l: EMPA 10.0 ± 0.5, DAPA 10.7 ± 0.7 and CANA 11.0 ± 0.9 vs vehicle 12.7 ± 0.7; p < 0.001). Docking studies provided high binding affinity of all three SGLT2i with the extracellular Na+-binding site of NHE. EMPA and CANA, but not DAPA, induced coronary vasodilation of the intact heart. PCr/ATP remained unaffected. CONCLUSIONS/INTERPRETATION: EMPA, DAPA and CANA directly inhibit cardiac NHE flux and reduce [Na+]c, possibly by binding with the Na+-binding site of NHE-1. Furthermore, EMPA and CANA affect the healthy heart by inducing vasodilation. The [Na+]c-lowering class effect of SGLT2i is a potential approach to combat elevated [Na+]c that is known to occur in heart failure and diabetes.
Asunto(s)
Citosol/metabolismo , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Transportador 2 de Sodio-Glucosa/metabolismo , Intercambiadores de Sodio-Hidrógeno/efectos de los fármacos , Intercambiadores de Sodio-Hidrógeno/metabolismo , Sodio/metabolismo , Aminopiridinas/farmacología , Animales , Compuestos de Bencidrilo/farmacología , Canagliflozina/farmacología , Glucósidos/farmacología , Masculino , Ratones , Sulfonamidas/farmacologíaRESUMEN
INTRODUCTION: Chronic total coronary occlusions (CTOs) have been associated with a higher prevalence of ventricular arrhythmias compared to patients without a CTO. We evaluated the effect of CTO revascularization on electrocardiographic (ECG) variables. METHODS: We studied a selection of ST-elevation myocardial infarction patients with a concomitant CTO enrolled in the EXPLORE trial. ECG variables and cardiac function were analysed at baseline and at 4â¯months follow-up. RESULTS: Patients were randomized to percutaneous coronary intervention (PCI) of their CTO (nâ¯=â¯77) or to no-CTO PCI (nâ¯=â¯81). At follow-up, median QT dispersion was significantly lower in the CTO PCI group compared to the no-CTO PCI group (46â¯ms [33-58] vs. 54â¯ms [37-68], Pâ¯=â¯0.043). No independent association was observed between ECG variables and cardiac function. CONCLUSION: Revascularization of a CTO after STEMI significantly shortened QT dispersion at 4â¯months follow-up. These findings support the hypothesis that CTO revascularization reduces the pro-arrhythmic substrate in CTO patients.
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Oclusión Coronaria/terapia , Electrocardiografía , Intervención Coronaria Percutánea , Infarto del Miocardio con Elevación del ST/fisiopatología , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/etiología , Oclusión Coronaria/complicaciones , Oclusión Coronaria/fisiopatología , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Estudios Retrospectivos , Infarto del Miocardio con Elevación del ST/complicaciones , Infarto del Miocardio con Elevación del ST/terapiaRESUMEN
AIMS/HYPOTHESIS: Empagliflozin (EMPA), an inhibitor of the renal sodium-glucose cotransporter (SGLT) 2, reduces the risk of cardiovascular death in patients with type 2 diabetes. The underlying mechanism of this effect is unknown. Elevated cardiac cytoplasmic Na+ ([Na+]c) and Ca2+ ([Ca2+]c) concentrations and decreased mitochondrial Ca2+ concentration ([Ca2+]m) are drivers of heart failure and cardiac death. We therefore hypothesised that EMPA would directly modify [Na+]c, [Ca2+]c and [Ca2+]m in cardiomyocytes. METHODS: [Na+]c, [Ca2+]c, [Ca 2+]m and Na+/H+ exchanger (NHE) activity were measured fluorometrically in isolated ventricular myocytes from rabbits and rats. RESULTS: An increase in extracellular glucose, from 5.5 mmol/l to 11 mmol/l, resulted in increased [Na+]c and [Ca2+]c levels. EMPA treatment directly inhibited NHE flux, caused a reduction in [Na+]c and [Ca2+]c and increased [Ca2+]m. After pretreatment with the NHE inhibitor, Cariporide, these effects of EMPA were strongly reduced. EMPA also affected [Na+]c and NHE flux in the absence of extracellular glucose. CONCLUSIONS/INTERPRETATION: The glucose lowering kidney-targeted agent, EMPA, demonstrates direct cardiac effects by lowering myocardial [Na+]c and [Ca2+]c and enhancing [Ca2+]m, through impairment of myocardial NHE flux, independent of SGLT2 activity.