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1.
Circulation ; 149(18): 1419-1434, 2024 Apr 30.
Artículo en Inglés | MEDLINE | ID: mdl-38357791

RESUMEN

BACKGROUND: Clonal hematopoiesis of indeterminate potential (CHIP), a common age-associated phenomenon, associates with increased risk of both hematological malignancy and cardiovascular disease. Although CHIP is known to increase the risk of myocardial infarction and heart failure, the influence of CHIP in cardiac arrhythmias, such as atrial fibrillation (AF), is less explored. METHODS: CHIP prevalence was determined in the UK Biobank, and incident AF analysis was stratified by CHIP status and clone size using Cox proportional hazard models. Lethally irradiated mice were transplanted with hematopoietic-specific loss of Tet2, hematopoietic-specific loss of Tet2 and Nlrp3, or wild-type control and fed a Western diet, compounded with or without NLRP3 (NLR [NACHT, LRR {leucine rich repeat}] family pyrin domain containing protein 3) inhibitor, NP3-361, for 6 to 9 weeks. Mice underwent in vivo invasive electrophysiology studies and ex vivo optical mapping. Cardiomyocytes from Ldlr-/- mice with hematopoietic-specific loss of Tet2 or wild-type control and fed a Western diet were isolated to evaluate calcium signaling dynamics and analysis. Cocultures of pluripotent stem cell-derived atrial cardiomyocytes were incubated with Tet2-deficient bone marrow-derived macrophages, wild-type control, or cytokines IL-1ß (interleukin 1ß) or IL-6 (interleukin 6). RESULTS: Analysis of the UK Biobank showed individuals with CHIP, in particular TET2 CHIP, have increased incident AF. Hematopoietic-specific inactivation of Tet2 increases AF propensity in atherogenic and nonatherogenic mouse models and is associated with increased Nlrp3 expression and CaMKII (Ca2+/calmodulin-dependent protein kinase II) activation, with AF susceptibility prevented by inactivation of Nlrp3. Cardiomyocytes isolated from Ldlr-/- mice with hematopoietic inactivation of Tet2 and fed a Western diet have impaired calcium release from the sarcoplasmic reticulum into the cytosol, contributing to atrial arrhythmogenesis. Abnormal sarcoplasmic reticulum calcium release was recapitulated in cocultures of cardiomyocytes with the addition of Tet2-deficient macrophages or cytokines IL-1ß or IL-6. CONCLUSIONS: We identified a modest association between CHIP, particularly TET2 CHIP, and incident AF in the UK Biobank population. In a mouse model of AF resulting from hematopoietic-specific inactivation of Tet2, we propose altered calcium handling as an arrhythmogenic mechanism, dependent on Nlrp3 inflammasome activation. Our data are in keeping with previous studies of CHIP in cardiovascular disease, and further studies into the therapeutic potential of NLRP3 inhibition for individuals with TET2 CHIP may be warranted.


Asunto(s)
Fibrilación Atrial , Hematopoyesis Clonal , Proteínas de Unión al ADN , Dioxigenasas , Inflamasomas , Proteína con Dominio Pirina 3 de la Familia NLR , Proteínas Proto-Oncogénicas , Animales , Dioxigenasas/metabolismo , Dioxigenasas/genética , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Fibrilación Atrial/metabolismo , Fibrilación Atrial/etiología , Fibrilación Atrial/genética , Fibrilación Atrial/patología , Inflamasomas/metabolismo , Humanos , Ratones , Hematopoyesis Clonal/genética , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas/genética , Masculino , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Femenino , Anciano , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Persona de Mediana Edad , Ratones Noqueados , Factores de Riesgo
2.
Circ Res ; 133(4): 313-329, 2023 08 04.
Artículo en Inglés | MEDLINE | ID: mdl-37449401

RESUMEN

BACKGROUND: ZFHX3 (zinc finger homeobox 3), a gene that encodes a large transcription factor, is at the second-most significantly associated locus with atrial fibrillation (AF), but its function in the heart is unknown. This study aims to identify causative genetic variation related to AF at the ZFHX3 locus and examine the impact of Zfhx3 loss on cardiac function in mice. METHODS: CRISPR-Cas9 genome editing, chromatin immunoprecipitation, and luciferase assays in pluripotent stem cell-derived cardiomyocytes were used to identify causative genetic variation related to AF at the ZFHX3 locus. Cardiac function was assessed by echocardiography, magnetic resonance imaging, electrophysiology studies, calcium imaging, and RNA sequencing in mice with heterozygous and homozygous cardiomyocyte-restricted Zfhx3 loss (Zfhx3 Het and knockout, respectively). Human cardiac single-nucleus ATAC (assay for transposase-accessible chromatin)-sequencing data was analyzed to determine which genes in atrial cardiomyocytes are directly regulated by ZFHX3. RESULTS: We found single-nucleotide polymorphism (SNP) rs12931021 modulates an enhancer regulating ZFHX3 expression, and the AF risk allele is associated with decreased ZFHX3 transcription. We observed a gene-dose response in AF susceptibility with Zfhx3 knockout mice having higher incidence, frequency, and burden of AF than Zfhx3 Het and wild-type mice, with alterations in conduction velocity, atrial action potential duration, calcium handling and the development of atrial enlargement and thrombus, and dilated cardiomyopathy. Zfhx3 loss results in atrial-specific differential effects on genes and signaling pathways involved in cardiac pathophysiology and AF. CONCLUSIONS: Our findings implicate ZFHX3 as the causative gene at the 16q22 locus for AF, and cardiac abnormalities caused by loss of cardiac Zfhx3 are due to atrial-specific dysregulation of pathways involved in AF susceptibility. Together, these data reveal a novel and important role for Zfhx3 in the control of cardiac genes and signaling pathways essential for normal atrial function.


Asunto(s)
Fibrilación Atrial , Proteínas de Homeodominio , Animales , Humanos , Ratones , Fibrilación Atrial/genética , Calcio/metabolismo , Dilatación , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Miocitos Cardíacos/metabolismo , Factores de Transcripción/genética
3.
Circ Res ; 127(1): 91-110, 2020 06 19.
Artículo en Inglés | MEDLINE | ID: mdl-32716814

RESUMEN

Atrial fibrillation (AF) is the most common sustained arrhythmia encountered in humans and is a significant source of morbidity and mortality. Despite its prevalence, our mechanistic understanding is incomplete, the therapeutic options have limited efficacy, and are often fraught with risks. A better biological understanding of AF is needed to spearhead novel therapeutic avenues. Although "natural" AF is nearly nonexistent in most species, animal models have contributed significantly to our understanding of AF and some therapeutic options. However, the impediments of animal models are also apparent and stem largely from the differences in basic physiology as well as the complexities underlying human AF; these preclude the creation of a "perfect" animal model and have obviated the translation of animal findings. Herein, we review the vast array of AF models available, spanning the mouse heart (weighing 1/1000th of a human heart) to the horse heart (10× heavier than the human heart). We attempt to highlight the features of each model that bring value to our understanding of AF but also the shortcomings and pitfalls. Finally, we borrowed the concept of a SWOT analysis from the business community (which stands for strengths, weaknesses, opportunities, and threats) and applied this introspective type of analysis to animal models for AF. We identify unmet needs and stress that is in the context of rapidly advancing technologies, these present opportunities for the future use of animal models.


Asunto(s)
Fibrilación Atrial/fisiopatología , Modelos Animales de Enfermedad , Animales , Animales de Laboratorio/anatomía & histología , Animales de Laboratorio/fisiología , Fibrilación Atrial/etiología , Fibrilación Atrial/patología , Humanos , Especificidad de la Especie
4.
Circulation ; 142(25): 2443-2455, 2020 12 22.
Artículo en Inglés | MEDLINE | ID: mdl-33092403

RESUMEN

BACKGROUND: Ibrutinib is a Bruton tyrosine kinase inhibitor with remarkable efficacy against B-cell cancers. Ibrutinib also increases the risk of atrial fibrillation (AF), which remains poorly understood. METHODS: We performed electrophysiology studies on mice treated with ibrutinib to assess inducibility of AF. Chemoproteomic analysis of cardiac lysates identified candidate ibrutinib targets, which were further evaluated in genetic mouse models and additional pharmacological experiments. The pharmacovigilance database, VigiBase, was queried to determine whether drug inhibition of an identified candidate kinase was associated with increased reporting of AF. RESULTS: We demonstrate that treatment of mice with ibrutinib for 4 weeks results in inducible AF, left atrial enlargement, myocardial fibrosis, and inflammation. This effect was reproduced in mice lacking Bruton tyrosine kinase, but not in mice treated with 4 weeks of acalabrutinib, a more specific Bruton tyrosine kinase inhibitor, demonstrating that AF is an off-target side effect. Chemoproteomic profiling identified a short list of candidate kinases that was narrowed by additional experimentation leaving CSK (C-terminal Src kinase) as the strongest candidate for ibrutinib-induced AF. Cardiac-specific Csk knockout in mice led to increased AF, left atrial enlargement, fibrosis, and inflammation, phenocopying ibrutinib treatment. Disproportionality analyses in VigiBase confirmed increased reporting of AF associated with kinase inhibitors blocking Csk versus non-Csk inhibitors, with a reporting odds ratio of 8.0 (95% CI, 7.3-8.7; P<0.0001). CONCLUSIONS: These data identify Csk inhibition as the mechanism through which ibrutinib leads to AF. Registration: URL: https://ww.clinicaltrials.gov; Unique identifier: NCT03530215.


Asunto(s)
Adenina/análogos & derivados , Antineoplásicos/toxicidad , Fibrilación Atrial/inducido químicamente , Función del Atrio Izquierdo/efectos de los fármacos , Proteína Tirosina Quinasa CSK/antagonistas & inhibidores , Atrios Cardíacos/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Piperidinas/toxicidad , Inhibidores de Proteínas Quinasas/toxicidad , Potenciales de Acción/efectos de los fármacos , Adenina/toxicidad , Agammaglobulinemia Tirosina Quinasa/deficiencia , Agammaglobulinemia Tirosina Quinasa/genética , Animales , Fibrilación Atrial/enzimología , Fibrilación Atrial/fisiopatología , Proteína Tirosina Quinasa CSK/genética , Proteína Tirosina Quinasa CSK/metabolismo , Bases de Datos Genéticas , Atrios Cardíacos/enzimología , Atrios Cardíacos/fisiopatología , Humanos , Ratones de la Cepa 129 , Ratones Endogámicos C57BL , Ratones Endogámicos CBA , Ratones Noqueados , Medición de Riesgo , Factores de Riesgo
5.
J Cardiovasc Electrophysiol ; 32(5): 1281-1289, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33625757

RESUMEN

INTRODUCTION: We previously introduced the inverse solution guidance algorithm (ISGA) methodology using a Single Equivalent Moving Dipole model of cardiac electrical activity to localize both the exit site of a re-entrant circuit and the tip of a radiofrequency (RF) ablation catheter. The purpose of this study was to investigate the use of ISGA for ablation catheter guidance in an animal model. METHODS: Ventricular tachycardia (VT) was simulated by rapid ventricular pacing at a target site in eleven Yorkshire swine. The ablation target was established using three different techniques: a pacing lead placed into the ventricular wall at the mid-myocardial level (Type-1), an intracardiac mapping catheter (Type-2), and an RF ablation catheter placed at a random position on the endocardial surface (Type-3). In each experiment, one operator placed the catheter/pacing lead at the target location, while another used the ISGA system to manipulate the RF ablation catheter starting from a random ventricular location to locate the target. RESULTS: The average localization error of the RF ablation catheter tip was 0.31 ± 0.08 cm. After analyzing approximately 35 cardiac cycles of simulated VT, the ISGA system's accuracy in locating the target was 0.4 cm after four catheter movements in the Type-1 experiment, 0.48 cm after six movements in the Type-2 experiment, and 0.67 cm after seven movements in the Type-3 experiment. CONCLUSION: We demonstrated the feasibility of using the ISGA method to guide an ablation catheter to the origin of a VT focus by analyzing a few beats of body surface potentials without electro-anatomic mapping.


Asunto(s)
Ablación por Catéter , Taquicardia Ventricular , Algoritmos , Animales , Catéteres , Corazón , Porcinos , Taquicardia Ventricular/diagnóstico , Taquicardia Ventricular/cirugía
6.
Pacing Clin Electrophysiol ; 44(5): 895-902, 2021 May.
Artículo en Inglés | MEDLINE | ID: mdl-33675073

RESUMEN

BACKGROUND: There are limited data on the comparative analyses of TightRail rotating dilator sheath (Philips) and laser sheath for lead extraction. OBJECTIVE: To evaluate the effectiveness and safety of the TightRail sheath as a primary or secondary tool for transvenous lead extraction (TLE). METHODS: Retrospective cohort analysis of 202 consecutive patients who underwent TLE using either TightRail sheath and/or GlideLight laser sheath (Philips) in our hospital. The study population was divided into three groups: Group A underwent TLE with laser sheath only (N = 157), Group B with TightRail sheath only (N = 22), and Group C with both sheaths (N = 23). RESULTS: During this period, 375 leads in 202 patients were extracted, including 297 leads extracted by laser sheath alone, 45 leads by TightRail sheath alone, and 33 by both TightRail sheath and laser sheaths. The most common indications included device infection (44.6%) and lead-related complications (44.1%). The median age of leads was 8.9 years. TightRail sheath (Group B) achieved similar efficacy as a primary extraction tool compared with laser sheath (Group A), with complete procedure success rate of 93.3% (vs. 96.6%, P = .263) and clinical success rate of 100.0% (vs. 98.1%, P = .513). Among 32 leads in which Tightrail was used after laser had failed (Group C), the complete procedure success rate was 75.8%. No significant difference in procedural adverse events was observed. CONCLUSION: Our single-center experience confirms that the TightRail system is an effective first-line and second-line method for TLE. Further investigation is required to guide the selection of mechanical and laser sheaths in lead extraction cases.


Asunto(s)
Remoción de Dispositivos/instrumentación , Electrodos Implantados , Desfibriladores Implantables , Diseño de Equipo , Femenino , Humanos , Rayos Láser , Masculino , Persona de Mediana Edad , Marcapaso Artificial , Estudios Retrospectivos
7.
Circ Res ; 123(11): 1208-1219, 2018 11 09.
Artículo en Inglés | MEDLINE | ID: mdl-30571465

RESUMEN

RATIONALE: Cardiac pacing is a critical technology for the treatment of arrhythmia and heart failure. The impact of specific pacing strategies on myocardial function is an area of intense research and high clinical significance. Mouse models have proven extremely useful for probing mechanisms of heart disease, but there is currently no reliable technology for long-term pacing in the mouse. OBJECTIVE: We sought to develop a device for long-term pacing studies in mice. We evaluated the device for (1) treating third-degree atrioventricular block after macrophage depletion, (2) ventricular pacing-induced cardiomyopathy, and (3) high-rate atrial pacing. METHODS AND RESULTS: We developed a mouse pacemaker by refashioning a 26 mm×6.7 mm clinical device powered by a miniaturized, highly efficient battery. The electrode was fitted with a single flexible lead, and custom software extended the pacing rate to up to 1200 bpm. The wirelessly programmable device was implanted in the dorsal subcutaneous space of 39 mice. The tunneled lead was passed through a left thoracotomy incision and attached to the epicardial surface of the apex (for ventricular pacing) or the left atrium (for atrial pacing). Mice tolerated the implantation and both long-term atrial and ventricular pacing over weeks. We then validated the pacemaker's suitability for the treatment of atrioventricular block after macrophage depletion in Cd11b DTR mice. Ventricular pacing increased the heart rate from 313±59 to 550 bpm ( P<0.05). In addition, we characterized tachypacing-induced cardiomyopathy in mice. Four weeks of ventricular pacing resulted in reduced left ventricular function, fibrosis, and an increased number of cardiac leukocytes and endothelial activation. Finally, we demonstrated the feasibility of chronic atrial pacing at 1200 bpm. CONCLUSIONS: Long-term pacing with a fully implantable, programmable, and battery-powered device enables previously impossible investigations of arrhythmia and heart failure in the mouse.


Asunto(s)
Arritmias Cardíacas/fisiopatología , Marcapaso Artificial , Telemetría/métodos , Animales , Electrodos Implantados , Diseño de Equipo , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Miniaturización , Programas Informáticos , Tiempo
9.
J Physiol ; 594(6): 1689-707, 2016 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-26775607

RESUMEN

Hypertension is a risk factor for sudden cardiac death caused by ventricular tachycardia and fibrillation (VT/VF). We hypothesized that, in early hypertension, the susceptibility to stress-induced VT/VF increases. We compared the susceptibility of 5- to 6-month-old male spontaneously hypertensive rats (SHR) and age/sex-matched normotensive rats (NR) to VT/VF during challenge with oxidative stress (H2 O2 ; 0.15 mmol l(-1) ). We found that only SHR hearts exhibited left ventricular fibrosis and hypertrophy. H2 O2 promoted VT in all 30 SHR but none of the NR hearts. In 33% of SHR cases, focal VT degenerated to VF within 3 s. Simultaneous voltage-calcium optical mapping of Langendorff-perfused SHR hearts revealed that H2 O2 -induced VT/VF arose spontaneously from focal activations at the base and mid left ventricular epicardium. Microelectrode recording of SHR hearts showed that VT was initiated by early afterdepolarization (EAD)-mediated triggered activity. However, despite the increased susceptibility of SHR hearts to VT/VF, patch clamped isolated SHR ventricular myocytes developed EADs and triggered activity to the same extent as NR ventricular myocytes, except with larger EAD amplitude. During the early stages of hypertension, when challenged with oxidative stress, SHR hearts showed an increased ventricular arrhythmogenicity that stems primarily from tissue remodelling (hypertrophy, fibrosis) rather than cellular electrophysiological changes. Our findings highlight the need for early hypertension treatment to minimize myocardial fibrosis, ventricular hypertrophy, and arrhythmias.


Asunto(s)
Hipertensión/fisiopatología , Taquicardia Ventricular/fisiopatología , Potenciales de Acción , Animales , Células Cultivadas , Fibrosis , Ventrículos Cardíacos/patología , Ventrículos Cardíacos/fisiopatología , Hipertensión/complicaciones , Masculino , Ratas , Ratas Wistar , Taquicardia Ventricular/etiología , Taquicardia Ventricular/patología
10.
Circulation ; 132(16): 1528-1537, 2015 Oct 20.
Artículo en Inglés | MEDLINE | ID: mdl-26269574

RESUMEN

BACKGROUND: Hypokalemia is known to promote ventricular arrhythmias, especially in combination with class III antiarrhythmic drugs like dofetilide. Here, we evaluated the underlying molecular mechanisms. METHODS AND RESULTS: Arrhythmias were recorded in isolated rabbit and rat hearts or patch-clamped ventricular myocytes exposed to hypokalemia (1.0-3.5 mmol/L) in the absence or presence of dofetilide (1 µmol/L). Spontaneous early afterdepolarizations (EADs) and ventricular tachycardia/fibrillation occurred in 50% of hearts at 2.7 mmol/L [K] in the absence of dofetilide and 3.3 mmol/L [K] in its presence. Pretreatment with the Ca-calmodulin kinase II (CaMKII) inhibitor KN-93, but not its inactive analogue KN-92, abolished EADs and hypokalemia-induced ventricular tachycardia/fibrillation, as did the selective late Na current (INa) blocker GS-967. In intact hearts, moderate hypokalemia (2.7 mmol/L) significantly increased tissue CaMKII activity. Computer modeling revealed that EAD generation by hypokalemia (with or without dofetilide) required Na-K pump inhibition to induce intracellular Na and Ca overload with consequent CaMKII activation enhancing late INa and the L-type Ca current. K current suppression by hypokalemia and dofetilide alone in the absence of CaMKII activation were ineffective at causing EADs. CONCLUSIONS: We conclude that Na-K pump inhibition by even moderate hypokalemia plays a critical role in promoting EAD-mediated arrhythmias by inducing a positive feedback cycle activating CaMKII and enhancing late INa. Class III antiarrhythmic drugs like dofetilide sensitize the heart to this positive feedback loop.


Asunto(s)
Hipopotasemia/complicaciones , Fibrilación Ventricular/etiología , Potenciales de Acción , Animales , Bencilaminas/uso terapéutico , Simulación por Computador , Masculino , Fenetilaminas/farmacología , Piridinas/uso terapéutico , Conejos , Ratas , Ratas Endogámicas F344 , ATPasa Intercambiadora de Sodio-Potasio/antagonistas & inhibidores , ATPasa Intercambiadora de Sodio-Potasio/fisiología , Sulfonamidas/farmacología , Sulfonamidas/uso terapéutico , Triazoles/uso terapéutico , Fibrilación Ventricular/prevención & control
11.
Res Sq ; 2023 Sep 26.
Artículo en Inglés | MEDLINE | ID: mdl-37841859

RESUMEN

Background: Lifestyle modification programs, such as cardiac rehabilitation, may reduce atrial fibrillation (AF) burden and improve quality of life (QOL), but remain unproven. The objective of this pilot study was to assess feasibility, acceptability, and preliminary effectiveness of an exercise and nutrition-based cardiac rehabilitation-like program for AF patients. Methods: We enrolled overweight adults aged ≥ 30 years with symptomatic AF in a 12-week cardiac lifestyle group program, including 6 virtual and 6 in-person visits. All visits included discussion and education about nutrition, exercise, and behavior modification. In-person visits included supervised aerobic exercise and strength training. Outcomes at baseline and 12 weeks included feasibility of participation, acceptability, change in weight and BMI, and changes in survey-based AF burden, symptoms, and QOL. Results: From 84 invitees, 11 (13.1%) were enrolled (mean age 64; baseline BMI 38 kg/m2); 9 (82%) completed the program. Patients attended an average of 9.7 (81%) visits (Range: 6-11). Mean weight loss was 9.1 pounds (Range: 0-16); mean BMI decrease was 1.4 kg/m2 (Range: 0-2.6). Patients found the program helpful overall: all reported making diet and exercise changes during the program. Compared to baseline, patients reported decreased AF burden (12.9 vs. 11.7, p = 0.03) and symptom (10.1 vs. 5.6, p = 0.003) scores at the conclusion of the program. Patients also reported increased QOL overall (68.9 vs. 86.4, p = 0.001). Conclusions: Participation in a cardiac rehab-like program was feasible and acceptable for overweight patients with symptomatic AF. Results suggest preliminary effectiveness of the program for reducing AF burden and symptoms and increasing QOL.

12.
Science ; 381(6654): 231-239, 2023 07 14.
Artículo en Inglés | MEDLINE | ID: mdl-37440641

RESUMEN

Atrial fibrillation disrupts contraction of the atria, leading to stroke and heart failure. We deciphered how immune and stromal cells contribute to atrial fibrillation. Single-cell transcriptomes from human atria documented inflammatory monocyte and SPP1+ macrophage expansion in atrial fibrillation. Combining hypertension, obesity, and mitral valve regurgitation (HOMER) in mice elicited enlarged, fibrosed, and fibrillation-prone atria. Single-cell transcriptomes from HOMER mouse atria recapitulated cell composition and transcriptome changes observed in patients. Inhibiting monocyte migration reduced arrhythmia in Ccr2-∕- HOMER mice. Cell-cell interaction analysis identified SPP1 as a pleiotropic signal that promotes atrial fibrillation through cross-talk with local immune and stromal cells. Deleting Spp1 reduced atrial fibrillation in HOMER mice. These results identify SPP1+ macrophages as targets for immunotherapy in atrial fibrillation.


Asunto(s)
Fibrilación Atrial , Macrófagos , Osteopontina , Animales , Humanos , Ratones , Fibrilación Atrial/genética , Fibrilación Atrial/inmunología , Atrios Cardíacos , Macrófagos/inmunología , Insuficiencia de la Válvula Mitral/genética , Osteopontina/genética , Eliminación de Gen , Movimiento Celular , Análisis de Expresión Génica de una Sola Célula
13.
Am J Physiol Heart Circ Physiol ; 302(11): H2331-40, 2012 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-22467308

RESUMEN

Unlike young hearts, aged hearts are highly susceptible to early afterdepolarization (EAD)-mediated ventricular fibrillation (VF). This differential may result from age-related structural remodeling (fibrosis) or electrical remodeling of ventricular myocytes or both. We used optical mapping and microelectrode recordings in Langendorff-perfused hearts and patch-clamp recordings in isolated ventricular myocytes from aged (24-26 mo) and young (3-4 mo) rats to assess susceptibility to EADs and VF during either oxidative stress with ANG II (2 µM) or ionic stress with hypokalemia (2.7 mM). ANG II caused EAD-mediated VF in 16 of 19 aged hearts (83%) after 32 ± 7 min but in 0 of 9 young hearts (0%). ANG II-mediated VF was suppressed with KN-93 (Ca(2+)/calmodulin-dependent kinase inhibitor) and the reducing agent N-acetylcysteine. Hypokalemia caused EAD-mediated VF in 11 of 11 aged hearts (100%) after 7.4 ± 0.4 min. In 14 young hearts, however, VF did not occur in 6 hearts (43%) or was delayed in onset (31 ± 22 min, P < 0.05) in 8 hearts (57%). In patch-clamped myocytes, ANG II and hypokalemia (n = 6) induced EADs and triggered activity in both age groups (P = not significant) at a cycle length of >0.5 s. When myocytes of either age group were coupled to a virtual fibroblast using the dynamic patch-clamp technique, EADs arose in both groups at a cycle length of <0.5 s. Aged ventricles had significantly greater fibrosis and reduced connexin43 gap junction density compared with young hearts. The lack of differential age-related sensitivity at the single cell level in EAD susceptibility indicates that increased ventricular fibrosis in the aged heart plays a key role in increasing vulnerability to VF induced by oxidative and ionic stress.


Asunto(s)
Envejecimiento/fisiología , Angiotensina II/efectos adversos , Arritmias Cardíacas/etiología , Corazón/fisiopatología , Hipopotasemia/complicaciones , Miocardio/patología , Fibrilación Ventricular/etiología , Angiotensina II/farmacología , Animales , Arritmias Cardíacas/fisiopatología , Modelos Animales de Enfermedad , Fibrosis , Corazón/efectos de los fármacos , Hipopotasemia/fisiopatología , Masculino , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , NADPH Oxidasas/metabolismo , Estrés Oxidativo/fisiología , Técnicas de Placa-Clamp , Ratas , Ratas Endogámicas F344 , Especies Reactivas de Oxígeno/metabolismo , Fibrilación Ventricular/fisiopatología
15.
Korean J Anesthesiol ; 75(3): 216-230, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-35350095

RESUMEN

Myocardial infarction (MI) is the leading cause of death from coronary heart disease and requires immediate reperfusion therapy with thrombolysis, primary percutaneous coronary intervention, or coronary artery bypass grafting. However, myocardial reperfusion therapy is often accompanied by cardiac ischemia/reperfusion (I/R) injury, which leads to myocardial injury with detrimental consequences. The causes of I/R injury are unclear, but are multifactorial, including free radicals, reactive oxygen species, calcium overload, mitochondria dysfunction, inflammation, and neutrophil-mediated vascular injury. Mild hypothermia has been introduced as one of the potential inhibitors of myocardial I/R injury. Although animal studies have demonstrated that mild hypothermia significantly reduces or delays I/R myocardium damage, human trials have not shown clinical benefits in acute MI (AMI). In addition, the practice of hypothermia treatment is increasing in various fields such as surgical anesthesia and intensive care units. Adequate sedation for anesthetic procedures and protection from body shivering has become essential during therapeutic hypothermia. Therefore, anesthesiologists should be aware of the effects of therapeutic hypothermia on the metabolism of anesthetic drugs. In this paper, we review the existing data on the use of therapeutic hypothermia for AMI in animal models and human clinical trials to better understand the discrepancy between perceived benefits in preclinical animal models and the absence thereof in clinical trials thus far.


Asunto(s)
Hipotermia Inducida , Hipotermia , Infarto del Miocardio , Daño por Reperfusión Miocárdica , Intervención Coronaria Percutánea , Animales , Humanos , Hipotermia Inducida/efectos adversos , Hipotermia Inducida/métodos , Infarto del Miocardio/complicaciones , Infarto del Miocardio/terapia , Daño por Reperfusión Miocárdica/prevención & control , Intervención Coronaria Percutánea/efectos adversos
16.
JCI Insight ; 7(19)2022 10 10.
Artículo en Inglés | MEDLINE | ID: mdl-35998035

RESUMEN

Obesity is an important risk factor for atrial fibrillation (AF), but a better mechanistic understanding of obesity-related atrial fibrillation is required. Serum glucocorticoid kinase 1 (SGK1) is a kinase positioned within multiple obesity-related pathways, and prior work has shown a pathologic role of SGK1 signaling in ventricular arrhythmias. We validated a mouse model of obesity-related AF using wild-type mice fed a high-fat diet. RNA sequencing of atrial tissue demonstrated substantial differences in gene expression, with enrichment of multiple SGK1-related pathways, and we showed upregulated of SGK1 transcription, activation, and signaling in obese atria. Mice expressing a cardiac specific dominant-negative SGK1 were protected from obesity-related AF, through effects on atrial electrophysiology, action potential characteristics, structural remodeling, inflammation, and sodium current. Overall, this study demonstrates the promise of targeting SGK1 in a mouse model of obesity-related AF.


Asunto(s)
Fibrilación Atrial , Proteínas Serina-Treonina Quinasas , Animales , Ratones , Fibrilación Atrial/genética , Fibrilación Atrial/prevención & control , Modelos Animales de Enfermedad , Glucocorticoides/metabolismo , Atrios Cardíacos/patología , Obesidad/complicaciones , Obesidad/genética , Obesidad/metabolismo , Sodio/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo
17.
Am J Physiol Heart Circ Physiol ; 301(1): H180-91, 2011 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-21478408

RESUMEN

Selective glycolytic inhibition (GI) promotes electromechanical alternans and triggered beats in isolated cardiac myocytes. We sought to determine whether GI promotes triggered activity by early afterdepolarization (EAD) or delayed afterdepolarizations in intact hearts isolated from adult and aged rats. Dual voltage and intracellular calcium ion (Ca(i)(2+)) fluorescent optical maps and single cell glass microelectrode recordings were made from the left ventricular (LV) epicardium of isolated Langendorff-perfused adult (∼4 mo) and aged (∼24 mo) rat hearts. GI was induced by replacing glucose with 10 mM pyruvate in oxygenated Tyrode's. Within 20 min, GI slowed Ca(i)(2+) transient decline rate and shortened action potential duration in both groups. These changes were associated with ventricular fibrillation (VF) in the aged hearts (64 out of 66) but not in adult hearts (0 out of 18; P < 0.001). VF was preceded by a transient period of focal ventricular tachycardia caused by EAD-mediated triggered activity leading to VF within seconds. The VF was suppressed by the ATP-sensitive K (K(ATP)) channel blocker glibenclamide (1 µM) but not (0 out of 7) by mitochondrial K(ATP) block. The Ca-calmodulin-dependent protein kinase II (CaMKII) blocker KN-93 (1 µM) prevented GI-mediated VF (P < 0.05). Block of Na-Ca exchanger (NCX) by SEA0400 (2 µM) prevented GI-mediated VF (3 out of 6), provided significant bradycardia did not occur. Aged hearts had significantly greater LV fibrosis and reduced connexin 43 than adult hearts (P < 0.05). We conclude that in aged fibrotic unlike in adult rat hearts, GI promotes EADs, triggered activity, and VF by activation of K(ATP) channels CaMKII and NCX.


Asunto(s)
Envejecimiento/fisiología , Glucólisis/efectos de los fármacos , Corazón/fisiopatología , Fibrilación Ventricular/inducido químicamente , Potenciales de Acción/fisiología , Adenosina Trifosfato/metabolismo , Animales , Arritmia Sinusal/fisiopatología , Calcio/metabolismo , Calcio/fisiología , Señalización del Calcio/fisiología , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/efectos de los fármacos , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Conexina 43/metabolismo , Fenómenos Electrofisiológicos/fisiología , Endocardio/fisiología , Fibrosis/patología , Colorantes Fluorescentes , Técnicas In Vitro , Canales KATP/efectos de los fármacos , Canales KATP/metabolismo , Masculino , Microelectrodos , Miocardio , Oxidación-Reducción , Ratas , Ratas Endogámicas F344 , Intercambiador de Sodio-Calcio/efectos de los fármacos , Intercambiador de Sodio-Calcio/metabolismo , Taquicardia Ventricular/fisiopatología , Fibrilación Ventricular/fisiopatología
18.
Front Cardiovasc Med ; 8: 651269, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34150864

RESUMEN

Chemotherapy is widely used in the treatment of cancer patients, but the cardiotoxicity induced by chemotherapy is still a major concern to most clinicians. Currently, genetic methods have been used to detect patients with high risk of chemotherapy-induced cardiotoxicity (CIC), and our study evaluated the correlation between genomic variants and CIC. The systematic literature search was performed in the PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), China Biology Medicine disc (CBMdisc), the Embase database, China National Knowledge Internet (CNKI) and Wanfang database from inception until June 2020. Forty-one studies were identified that examined the relationship between genetic variations and CIC. And these studies examined 88 different genes and 154 single nucleotide polymorphisms (SNPs). Our study indicated 6 variants obviously associated with the increased risk for CIC, including CYBA rs4673 (pooled odds ratio, 1.93; 95% CI, 1.13-3.30), RAC2 rs13058338 (2.05; 1.11-3.78), CYP3A5 rs776746 (2.15; 1.00-4.62) ABCC1 rs45511401 (1.46; 1.05-2.01), ABCC2 rs8187710 (2.19; 1.38-3.48), and HER2-Ile655Val rs1136201 (2.48; 1.53-4.02). Although further studies are required to validate the diagnostic and prognostic roles of these 6 variants in predicting CIC, our study emphasizes the promising benefits of pharmacogenomic screening before chemotherapy to minimize the CIC.

19.
Case Rep Cardiol ; 2020: 8842150, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32934848

RESUMEN

A 67-year-old female with prior medical history of HTN and asthma presented with acute-onset dyspnea and nausea for 4 days prior to admission. Upon initial encounter in the emergency room, she was found to have findings of abnormal pulmonary infiltrates and consequent workup revealed COVID-19. During further hospital course, the patient developed abnormal EKG and echocardiographic findings consistent with stress-induced cardiomyopathy.

20.
Heart ; 104(3): 201-206, 2018 02.
Artículo en Inglés | MEDLINE | ID: mdl-28893835

RESUMEN

Atrial fibrillation (AF) is a prevalent arrhythmia associated with substantial morbidity, mortality and costs. Available management strategies generally have limited efficacy and are associated with potential adverse effects. In part, the limited efficacy of approaches to managing AF reflect an incomplete understanding of the biological mechanisms underlying the arrhythmia, and only a partial understanding of how best to individualise management. Over the last several decades, a greater understanding of genome biology has led to recognition of a widespread genetic susceptibility to AF. Through genome-wide association studies, at least 30 genetic loci have been identified in association with AF, most of which implicate mechanisms not previously appreciated to be involved in the development of AF. We now recognise that AF is a polygenic condition, yet a great deal of work lies ahead to better understand the precise mechanisms by which genomic variation causes AF. Understanding the genetic basis of AF could provide a better understanding of AF mechanisms and cardiovascular biology, inform the management of patients through risk-guided approaches and facilitate the development of novel therapeutics.


Asunto(s)
Fibrilación Atrial/genética , Animales , Fibrilación Atrial/terapia , Mapeo Cromosómico/métodos , Sitios Genéticos , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Genómica , Humanos , Recurrencia
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