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BACKGROUND: Kawasaki disease (KD) is an acute febrile illness and systemic vasculitis often associated with cardiac sequelae, including arrhythmias. Abundant evidence indicates a central role for IL (interleukin)-1 and TNFα (tumor necrosis factor-alpha) signaling in the formation of arterial lesions in KD. We aimed to investigate the mechanisms underlying the development of electrophysiological abnormalities in a murine model of KD vasculitis. METHODS: Lactobacillus casei cell wall extract-induced KD vasculitis model was used to investigate the therapeutic efficacy of clinically relevant IL-1Ra (IL-1 receptor antagonist) and TNFα neutralization. Echocardiography, in vivo electrophysiology, whole-heart optical mapping, and imaging were performed. RESULTS: KD vasculitis was associated with impaired ejection fraction, increased ventricular tachycardia, prolonged repolarization, and slowed conduction velocity. Since our transcriptomic analysis of human patients showed elevated levels of both IL-1ß and TNFα, we asked whether either cytokine was linked to the development of myocardial dysfunction. Remarkably, only inhibition of IL-1 signaling by IL-1Ra but not TNFα neutralization was able to prevent changes in ejection fraction and arrhythmias, whereas both IL-1Ra and TNFα neutralization significantly improved vasculitis and heart vessel inflammation. The treatment of L casei cell wall extract-injected mice with IL-1Ra also restored conduction velocity and improved the organization of Cx43 (connexin 43) at the intercalated disk. In contrast, in mice with gain of function of the IL-1 signaling pathway, L casei cell wall extract induced spontaneous ventricular tachycardia and premature deaths. CONCLUSIONS: Our results characterize the electrophysiological abnormalities associated with L casei cell wall extract-induced KD and show that IL-1Ra is more effective in preventing KD-induced myocardial dysfunction and arrhythmias than anti-TNFα therapy. These findings support the advancement of clinical trials using IL-1Ra in patients with KD.
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Cardiomiopatías , Síndrome Mucocutáneo Linfonodular , Taquicardia Ventricular , Vasculitis , Humanos , Animales , Ratones , Síndrome Mucocutáneo Linfonodular/complicaciones , Síndrome Mucocutáneo Linfonodular/tratamiento farmacológico , Proteína Antagonista del Receptor de Interleucina 1/farmacología , Proteína Antagonista del Receptor de Interleucina 1/uso terapéutico , Factor de Necrosis Tumoral alfa , Modelos Animales de Enfermedad , Interleucina-1beta/metabolismo , Arritmias Cardíacas/etiología , Arritmias Cardíacas/prevención & control , Taquicardia Ventricular/prevención & control , Taquicardia Ventricular/complicacionesRESUMEN
BACKGROUND: The ability to increase heart rate during exercise and other stressors is a key homeostatic feature of the sinoatrial node (SAN). When the physiological heart rate response is blunted, chronotropic incompetence limits exercise capacity, a common problem in patients with heart failure with preserved ejection fraction (HFpEF). Despite its clinical relevance, the mechanisms of chronotropic incompetence remain unknown. METHODS: Dahl salt-sensitive rats fed a high-salt diet and C57Bl6 mice fed a high-fat diet and an inhibitor of constitutive nitric oxide synthase (Nω-nitro-L-arginine methyl ester [L-NAME]; 2-hit) were used as models of HFpEF. Myocardial infarction was created to induce HF with reduced ejection fraction. Rats and mice fed with a normal diet or those that had a sham surgery served as respective controls. A comprehensive characterization of SAN function and chronotropic response was conducted by in vivo, ex vivo, and single-cell electrophysiologic studies. RNA sequencing of SAN was performed to identify transcriptomic changes. Computational modeling of biophysically-detailed human HFpEF SAN was created. RESULTS: Rats with phenotypically-verified HFpEF exhibited limited chronotropic response associated with intrinsic SAN dysfunction, including impaired ß-adrenergic responsiveness and an alternating leading pacemaker within the SAN. Prolonged SAN recovery time and reduced SAN sensitivity to isoproterenol were confirmed in the 2-hit mouse model. Adenosine challenge unmasked conduction blocks within the SAN, which were associated with structural remodeling. Chronotropic incompetence and SAN dysfunction were also found in rats with HF with reduced ejection fraction. Single-cell studies and transcriptomic profiling revealed HFpEF-related alterations in both the "membrane clock" (ion channels) and the "Ca2+ clock" (spontaneous Ca2+ release events). The physiologic impairments were reproduced in silico by empirically-constrained quantitative modeling of human SAN function. CONCLUSIONS: Chronotropic incompetence and SAN dysfunction were seen in both models of HF. We identified that intrinsic abnormalities of SAN structure and function underlie the chronotropic response in HFpEF.
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Insuficiencia Cardíaca/fisiopatología , Nodo Sinoatrial/anomalías , Volumen Sistólico/fisiología , Animales , Humanos , RatasRESUMEN
AIMS: Cardiomyopathy patients are prone to ventricular arrhythmias (VA) and sudden cardiac death. Current therapies to prevent VA include radiofrequency ablation to destroy slowly conducting pathways of viable myocardium which support re-entry. Here, we tested the reverse concept, namely that boosting local tissue viability in zones of slow conduction might eliminate slow conduction and suppress VA in ischaemic cardiomyopathy. METHODS AND RESULTS: Exosomes are extracellular vesicles laden with bioactive cargo. Exosomes secreted by cardiosphere-derived cells (CDCEXO) reduce scar and improve heart function after intramyocardial delivery. In a VA-prone porcine model of ischaemic cardiomyopathy, we injected CDCEXO or vehicle into zones of delayed conduction defined by electroanatomic mapping. Up to 1-month post-injection, CDCEXO, but not the vehicle, decreased myocardial scar, suppressed slowly conducting electrical pathways, and inhibited VA induction by programmed electrical stimulation. In silico reconstruction of electrical activity based on magnetic resonance images accurately reproduced the suppression of VA inducibility by CDCEXO. Strong anti-fibrotic effects of CDCEXO, evident histologically and by proteomic analysis from pig hearts, were confirmed in a co-culture assay of cardiomyocytes and fibroblasts. CONCLUSION: Biological substrate modification by exosome injection may be worth developing as a non-destructive alternative to conventional ablation for the prevention of recurrent ventricular tachyarrhythmias.
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Cardiomiopatías , Ablación por Catéter , Isquemia Miocárdica , Taquicardia Ventricular , Animales , Arritmias Cardíacas/etiología , Arritmias Cardíacas/prevención & control , Cardiomiopatías/cirugía , Ablación por Catéter/métodos , Cicatriz/prevención & control , Humanos , Isquemia Miocárdica/cirugía , Isquemia Miocárdica/terapia , Proteómica , Porcinos , Taquicardia Ventricular/etiología , Taquicardia Ventricular/prevención & controlRESUMEN
Ventricular arrhythmias (VAs) represent a major cause of sudden cardiac death and afflict patients with heart failure from both ischaemic and non-ischaemic origins, and inherited cardiomyopathies. Current VA management, including anti-arrhythmic medications, autonomic modulation, implantable cardioverter-defibrillator implantation, and catheter ablation, remains suboptimal. Catheter ablation may even cause significant cardiomyocyte loss. Cell-based therapies and exosome treatment have been proposed as promising strategies to lessen cardiomyocyte death, modulate immune reaction, and reduce myocardial scarring, and, therefore, are potentially beneficial in treating VAs. In this review, we summarise the current cornerstones of VA management. We also discuss recent advances and ongoing evidence regarding cell-based and exosome therapy, with special attention to VA treatment.
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Cardiomiopatías , Ablación por Catéter , Desfibriladores Implantables , Taquicardia Ventricular , Humanos , Desfibriladores Implantables/efectos adversos , Arritmias Cardíacas/terapia , Muerte Súbita Cardíaca/etiología , Cardiomiopatías/complicaciones , Antiarrítmicos , Ablación por Catéter/efectos adversos , Taquicardia Ventricular/cirugíaRESUMEN
Heart failure with preserved ejection fraction (HFpEF) is defined by increased left ventricular (LV) stiffness, impaired vascular compliance, and fibrosis. Although systemic inflammation, driven by comorbidities, has been proposed to play a key role, the precise pathogenesis remains elusive. To test the hypothesis that inflammation drives endothelial dysfunction in HFpEF, we used cardiosphere-derived cells (CDCs), which reduce inflammation and fibrosis, improving function, structure, and survival in HFpEF rats. Dahl salt-sensitive rats fed a high-salt diet developed HFpEF, as manifested by diastolic dysfunction, systemic inflammation, and accelerated mortality. Rats were randomly allocated to receive intracoronary infusion of CDCs or vehicle. Two weeks later, inflammation, oxidative stress, and endothelial function were analyzed. Single-cell RNA sequencing of heart tissue was used to assay transcriptomic changes. CDCs improved endothelial-dependent vasodilation while reducing oxidative stress and restoring endothelial nitric oxide synthase (eNOS) expression. RNA sequencing revealed CDC-induced attenuation of pathways underlying endothelial cell leukocyte binding and innate immunity. Exposure of endothelial cells to CDC-secreted extracellular vesicles in vitro reduced VCAM-1 protein expression and attenuated monocyte adhesion and transmigration. Cell therapy with CDCs corrects diastolic dysfunction, reduces oxidative stress, and restores vascular reactivity. These findings lend credence to the hypothesis that inflammatory changes of the vascular endothelium are important, if not central, to HFpEF pathogenesis.NEW & NOTEWORTHY We tested the concept that inflammation of endothelial cells is a major pathogenic factor in HFpEF. CDCs are heart-derived cell products with verified anti-inflammatory therapeutic properties. Infusion of CDCs reduced oxidative stress, restored eNOS abundance, lowered monocyte levels, and rescued the expression of multiple disease-associated genes, thereby restoring vascular reactivity. The salutary effects of CDCs support the hypothesis that inflammation of endothelial cells is a proximate driver of HFpEF.
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Insuficiencia Cardíaca , Hipertensión , Animales , Antiinflamatorios/farmacología , Tratamiento Basado en Trasplante de Células y Tejidos/efectos adversos , Células Endoteliales/metabolismo , Fibrosis , Inflamación/patología , Óxido Nítrico Sintasa de Tipo III , Ratas , Ratas Endogámicas Dahl , Volumen Sistólico , Molécula 1 de Adhesión Celular VascularRESUMEN
AIMS: Arrhythmogenic cardiomyopathy (ACM) is characterized by progressive loss of cardiomyocytes, and fibrofatty tissue replacement. Extracellular vesicles (EVs) secreted by cardiosphere-derived cells, immortalized, and engineered to express high levels of ß-catenin, exert anti-inflammatory, and anti-fibrotic effects. The aim of the current study was to assess efficacy of EVs in an ACM murine model. METHODS AND RESULTS: Four-week-old homozygous knock-in mutant desmoglein-2 (Dsg2mt/mt) were randomized to receive weekly EVs or vehicle for 4 weeks. After 4 weeks, DSG2mt/mt mice receiving EVs showed improved biventricular function (left, P < 0.0001; right, P = 0.0037) and less left ventricular dilation (P < 0.0179). Electrocardiography revealed abbreviated QRS duration (P = 0.0003) and QTc interval (P = 0.0006) in EV-treated DSG2mt/mt mice. Further electrophysiology testing in the EV group showed decreased burden (P = 0.0042) and inducibility of ventricular arrhythmias (P = 0.0037). Optical mapping demonstrated accelerated repolarization (P = 0.0290) and faster conduction (P = 0.0274) in Dsg2mt/mt mice receiving EVs. DSG2mt/mt hearts exhibited reduced fibrosis, less cell death, and preserved connexin 43 expression after EV treatment. Hearts of Dsg2mt/mt mice expressed markedly increased levels of inflammatory cytokines that were, in part, attenuated by EV therapy. The pan-inflammatory transcription factor nuclear factor-κB (NF-κB), the inflammasome sensor NLRP3, and the macrophage marker CD68 were all reduced in EV-treated animals. Blocking EV hsa-miR-4488 in vitro and in vivo reactivates NF-κB and blunts the beneficial effects of EVs. CONCLUSIONS: Extracellular vesicle treatment improved cardiac function, reduced cardiac inflammation, and suppressed arrhythmogenesis in ACM. Further studies are needed prior to translating the present findings to human forms of this heterogenous disease.
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Cardiomiopatías , Vesículas Extracelulares , Animales , Arritmias Cardíacas , Desmogleínas , Ratones , Miocitos CardíacosRESUMEN
Arrhythmogenic cardiomyopathy (AC) is an inherited disease characterized by progressive breakdown of heart muscle, myocardial tissue death, and fibrofatty replacement. In most cases of AC, the primary lesion occurs in one of the genes encoding desmosomal proteins, disruption of which increases membrane fragility at the intercalated disc. Disrupted, exposed desmosomal proteins also serve as epitopes that can trigger an autoimmune reaction. Damage to cell membranes and autoimmunity provoke myocardial inflammation, a key feature in early stages of the disease. In several preclinical models, targeting inflammation has been shown to blunt disease progression, but translation to the clinic has been sparse. Here we review current understanding of inflammatory pathways and how they interact with injured tissue and the immune system in AC. We further discuss the potential role of immunomodulatory therapies in AC.
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Displasia Ventricular Derecha Arritmogénica/metabolismo , Desmosomas/metabolismo , Mediadores de Inflamación/metabolismo , Inflamación/metabolismo , Miocardio/metabolismo , Animales , Antiinflamatorios/farmacología , Displasia Ventricular Derecha Arritmogénica/inmunología , Displasia Ventricular Derecha Arritmogénica/patología , Displasia Ventricular Derecha Arritmogénica/terapia , Tratamiento Basado en Trasplante de Células y Tejidos , Desmosomas/efectos de los fármacos , Desmosomas/inmunología , Desmosomas/patología , Terapia Genética , Humanos , Agentes Inmunomoduladores/farmacología , Inmunoterapia , Inflamación/inmunología , Inflamación/patología , Inflamación/terapia , Mediadores de Inflamación/antagonistas & inhibidores , Miocardio/inmunología , Miocardio/patología , Transducción de SeñalRESUMEN
BACKGROUND: Extracellular volume fraction (ECV) quantification with cardiovascular magnetic resonance (CMR) T1 mapping is a powerful tool for the characterization of focal or diffuse myocardial fibrosis. However, it is technically challenging to acquire high-quality T1 and ECV maps in small animals for preclinical research because of high heart rates and high respiration rates. In this work, we developed an electrocardiogram (ECG)-less, free-breathing ECV mapping method using motion-resolved CMR Multitasking on a 9.4 T small animal CMR system. The feasibility of characterizing diffuse myocardial fibrosis was tested in a rat heart failure model with preserved ejection fraction (HFpEF). METHODS: High-salt fed rats diagnosed with HFpEF (n = 9) and control rats (n = 9) were imaged with the proposed ECV Multitasking technique. A 25-min exam, including two 4-min T1 Multitasking scans before and after gadolinium injection, were performed on each rat. It allows a cardiac temporal resolution of 20 ms for a heart rate of ~ 300 bpm. Myocardial ECV was calculated from the hematocrit (HCT) and fitted T1 values of the myocardium and the blood pool. Masson's trichrome stain was used to measure the extent of fibrosis. Welch's t-test was performed between control and HFpEF groups. RESULTS: ECV was significantly higher in the HFpEF group (22.4% ± 2.5% vs. 18.0% ± 2.1%, P = 0.0010). A moderate correlation between the ECV and the extent of fibrosis was found (R = 0.59, P = 0.0098). CONCLUSIONS: Motion-resolved ECV Multitasking CMR can quantify ECV in the rat myocardium at high heart rates without ECG triggering or respiratory gating. Elevated ECV found in the HFpEF group is consistent with previous human studies and well correlated with histological data. This technique has the potential to be a viable imaging tool for myocardial tissue characterization in small animal models.
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Técnicas de Imagen Sincronizada Cardíacas , Insuficiencia Cardíaca/diagnóstico por imagen , Frecuencia Cardíaca , Imagen por Resonancia Magnética , Respiración , Volumen Sistólico , Función Ventricular Izquierda , Animales , Modelos Animales de Enfermedad , Estudios de Factibilidad , Fibrosis , Insuficiencia Cardíaca/etiología , Insuficiencia Cardíaca/fisiopatología , Hipertensión/etiología , Hipertensión/fisiopatología , Masculino , Miocardio/patología , Valor Predictivo de las Pruebas , Ratas Endogámicas Dahl , Cloruro de Sodio DietéticoRESUMEN
KEY POINTS: Heart failure (HF), the leading cause of death in developed countries, occurs in the setting of reduced (HFrEF) or preserved (HFpEF) ejection fraction. Unlike HFrEF, there are no effective treatments for HFpEF, which accounts for â¼50% of heart failure. Abnormal intracellular calcium dynamics in cardiomyocytes have major implications for contractility and rhythm, but compared to HFrEF, very little is known about calcium cycling in HFpEF. We used rat models of HFpEF and HFrEF to reveal distinct differences in intracellular calcium regulation and excitation-contraction (EC) coupling. While HFrEF is characterized by defective EC coupling at baseline, HFpEF exhibits enhanced coupling fidelity, further aggravated by a reduction in ß-adrenergic sensitivity. These differences in EC coupling and ß-adrenergic sensitivity may help explain why therapies that work in HFrEF are ineffective in HFpEF. ABSTRACT: Heart failure with reduced or preserved ejection fraction (respectively, HFrEF and HFpEF) is the leading cause of death in developed countries. Although numerous therapies improve outcomes in HFrEF, there are no effective treatments for HFpEF. We studied phenotypically verified rat models of HFrEF and HFpEF to compare excitation-contraction (EC) coupling and protein expression in these two forms of heart failure. Dahl salt-sensitive rats were fed a high-salt diet (8% NaCl) from 7 weeks of age to induce HFpEF. Impaired diastolic relaxation and preserved ejection fraction were confirmed in each animal echocardiographically, and clinical signs of heart failure were documented. To generate HFrEF, Sprague-Dawley (SD) rats underwent permanent left anterior descending coronary artery ligation which, 8-10 weeks later, led to systolic dysfunction (verified echocardiographically) and clinical signs of heart failure. Calcium (Ca2+ ) transients were measured in isolated cardiomyocytes under field stimulation or patch clamp. Ultra-high-speed laser scanning confocal imaging captured Ca2+ sparks evoked by voltage steps. Western blotting and PCR were used to assay changes in EC coupling protein and RNA expression. Cardiomyocytes from rats with HFrEF exhibited impaired EC coupling, including decreased Ca2+ transient (CaT) amplitude and defective couplon recruitment, associated with transverse (t)-tubule disruption. In stark contrast, HFpEF cardiomyocytes showed saturated EC coupling (increased ICa , high probability of couplon recruitment with greater Ca2+ release synchrony, increased CaT) and preserved t-tubule integrity. ß-Adrenergic stimulation of HFpEF myocytes with isoprenaline (isoproterenol) failed to elicit robust increases in ICa or CaT and relaxation kinetics. Fundamental differences in EC coupling distinguish HFrEF from HFpEF.
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Insuficiencia Cardíaca , Adrenérgicos , Animales , Calcio , Pronóstico , Ratas , Ratas Endogámicas Dahl , Ratas Sprague-Dawley , Volumen SistólicoRESUMEN
BACKGROUND: Esophageal injury is related to a reduction in luminal esophageal temperature (LET) in second-generation cryoballoon (CB) ablation; however, methods to prevent these reductions in temperature have not been well characterized. METHODS: Esophageal temperature was continuously monitored using a LET probe in patients undergoing pulmonary vein (PV) isolation using the second-generation CB. A rotational maneuver of the CB was performed if the initial ablation resulted in a decrease of more than 4â in LET. The refrigerant injector near the distal CB pole was used as a fluoroscopic marker to measure the nearest distance between the CB and the LET probe. RESULTS: A total of 52 consecutive patients were enrolled in this study. The rotation was applied in 19 patients and 20 PVs (seven left superior pulmonary veins [LSPVs], seven left inferior PVs [LIPVs], and six right inferior PVs [RIPVs]) with a reduction in LET of more than 4â during freezing. The nadir temperature of CB applications was similar before and after CB rotation in all PVs. There was significant difference in the minimum LET before and after rotation during freezing in LSPVs (28.4 ± 3.7 vs 32.4 ± 2.3â, P = .02), LIPVs (28.4 ± 1.4 vs 32.6 ± 2.7, P = .01) and RIPVs (26.1 ± 4.3 vs 34.0 ± 1.3â, P = .002). The differences in mean balloon to LET distance were measured for all veins before and after rotation; LSPV (right anterior oblique [RAO], 11.0 ± 1.7 vs 13.8 ± 4.5 mm, P = .05); LIPV (RAO, 10.7 ± 4.3 vs 14.6 ± 6.1 mm, P = .03); RIPV (LAO, 11.8 ± 5.5 vs 14.2 ± 5.7 mm, P = .01). CONCLUSIONS: CB rotational maneuvers during ablation can prevent significant reduction in LET and may prevent esophageal injury during the procedure.
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Fibrilación Atrial/cirugía , Ablación por Catéter , Criocirugía/instrumentación , Criocirugía/métodos , Esófago/lesiones , Complicaciones Intraoperatorias/prevención & control , Anciano , Frío , Criocirugía/efectos adversos , Femenino , Humanos , Complicaciones Intraoperatorias/etiología , Masculino , Persona de Mediana Edad , Monitoreo Intraoperatorio , Estudios Prospectivos , Venas Pulmonares/cirugíaRESUMEN
BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) represents approximately half of heart failure, and its incidence continues to increase. The leading cause of mortality in HFpEF is sudden death, but little is known about the underlying mechanisms. METHODS: Dahl salt-sensitive rats were fed a high-salt diet (8% NaCl) from 7 weeks of age to induce HFpEF (n=38). Rats fed a normal-salt diet (0.3% NaCl) served as controls (n=13). Echocardiograms were performed to assess systolic and diastolic function from 14 weeks of age. HFpEF-verified and control rats underwent programmed electrical stimulation. Corrected QT interval was measured by surface ECG. The mechanisms of ventricular arrhythmias (VA) were probed by optical mapping, whole-cell patch clamp to measure action potential duration and ionic currents, and quantitative polymerase chain reaction and Western blotting to investigate changes in ion channel expression. RESULTS: After 7 weeks of a high-salt diet, 31 of 38 rats showed diastolic dysfunction and preserved ejection fraction along with signs of heart failure and hence were diagnosed with HFpEF. Programmed electric stimulation demonstrated increased susceptibility to VA in HFpEF rats (P<0.001 versus controls). The arrhythmogenicity index was increased (P<0.001) and the corrected QT interval on ECG was prolonged (P<0.001) in HFpEF rats. Optical mapping of HFpEF hearts demonstrated prolonged action potentials (P<0.05) and multiple reentry circuits during induced VA. Single-cell recordings of cardiomyocytes isolated from HFpEF rats confirmed a delay of repolarization (P=0.001) and revealed downregulation of transient outward potassium current (Ito; P<0.05). The rapid components of the delayed rectifier potassium current (IKr) and the inward rectifier potassium current (IK1) were also downregulated (P<0.05), but the current densities were much lower than for Ito. In accordance with the reduction of Ito, both Kcnd3 transcript and Kv4.3 protein levels were decreased in HFpEF rat hearts. CONCLUSIONS: Susceptibility to VA was markedly increased in rats with HFpEF. Underlying abnormalities include QT prolongation, delayed repolarization from downregulation of potassium currents, and multiple reentry circuits during VA. Our findings are consistent with the hypothesis that potassium current downregulation leads to abnormal repolarization in HFpEF, which in turn predisposes to VA and sudden cardiac death.
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Potenciales de Acción , Arritmias Cardíacas/etiología , Insuficiencia Cardíaca/etiología , Frecuencia Cardíaca , Ventrículos Cardíacos/fisiopatología , Disfunción Ventricular Izquierda/etiología , Función Ventricular Izquierda , Animales , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/metabolismo , Arritmias Cardíacas/fisiopatología , Estimulación Cardíaca Artificial , Modelos Animales de Enfermedad , Electrocardiografía , Fibrosis , Insuficiencia Cardíaca/diagnóstico , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/fisiopatología , Ventrículos Cardíacos/metabolismo , Ventrículos Cardíacos/patología , Preparación de Corazón Aislado , Masculino , Técnicas de Placa-Clamp , Potasio/metabolismo , Ratas Endogámicas Dahl , Canales de Potasio Shal/genética , Canales de Potasio Shal/metabolismo , Cloruro de Sodio Dietético , Volumen Sistólico , Factores de Tiempo , Disfunción Ventricular Izquierda/diagnóstico , Disfunción Ventricular Izquierda/metabolismo , Disfunción Ventricular Izquierda/fisiopatología , Imagen de Colorante Sensible al VoltajeAsunto(s)
Arritmias Cardíacas/fisiopatología , Arritmias Cardíacas/cirugía , Fascículo Atrioventricular/fisiopatología , Fascículo Atrioventricular/cirugía , Ablación por Catéter , Técnicas Electrofisiológicas Cardíacas , Mapeo Epicárdico , Ventrículos Cardíacos/fisiopatología , Ventrículos Cardíacos/cirugía , HumanosRESUMEN
Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiac condition characterized by cardiac remodeling and life-threatening ventricular arrhythmias. In this issue of the JCI, Chelko, Penna, and colleagues mechanistically addressed the intricate contribution of immune-mediated injury in ACM pathogenesis. Inhibition of nuclear factor κ-B (NF-κB) and infiltration of monocyte-derived macrophages expressing C-C motif chemokine receptor-2 (CCR2) alleviated the phenotypic ACM features (i.e., fibrofatty replacement, contractile dysfunction, and ventricular arrhythmias) in desmoglein 2-mutant (Dsg2mut/mut) mice. These findings pave the way for efficacious and targetable immune therapy for patients with ACM.
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Desmogleína 2 , Macrófagos , Receptores CCR2 , Animales , Macrófagos/metabolismo , Macrófagos/inmunología , Macrófagos/patología , Ratones , Humanos , Desmogleína 2/genética , Desmogleína 2/metabolismo , Desmogleína 2/inmunología , Receptores CCR2/genética , Receptores CCR2/metabolismo , Receptores CCR2/antagonistas & inhibidores , FN-kappa B/metabolismo , FN-kappa B/genética , Arritmias Cardíacas/patología , Arritmias Cardíacas/inmunología , Arritmias Cardíacas/genética , Arritmias Cardíacas/metabolismo , Displasia Ventricular Derecha Arritmogénica/genética , Displasia Ventricular Derecha Arritmogénica/patología , Displasia Ventricular Derecha Arritmogénica/metabolismo , Cardiomiopatías/genética , Cardiomiopatías/patología , Cardiomiopatías/inmunología , Cardiomiopatías/metabolismoRESUMEN
PURPOSE: Micropeptides are an emerging class of proteins that play critical roles in cell signaling. Here, we describe the discovery of a novel micropeptide, dubbed slitharin (Slt), in conditioned media from Cardiosphere-derived cells (CDCs), a therapeutic cardiac stromal cell type. EXPERIMENTAL DESIGN: We performed mass spectrometry of peptide-enriched fractions from the conditioned media of CDCs and a therapeutically inert cell type (human dermal fibrobasts). We then evaluated the therapeutic capacity of the candidate peptide using an in vitro model of cardiomyocyte injury and a rat model of myocardial infarction. RESULTS: We identified a novel 24-amino acid micropeptide (dubbed Slitharin [Slt]) with a non-canonical leucine start codon, arising from long intergenic non-coding (LINC) RNA 2099. Neonatal rat ventricular myocytes (NRVMs) exposed to Slt were protected from hypoxic injury in vitro compared to a vehicle or scrambled control. Transcriptomic analysis of cardiomyocytes exposed to Slt reveals cytoprotective capacity, putatively through regulation of stress-induced MAPK-ERK. Slt also exerted cardioprotective effects in rats with myocardial infarction as shown by reduced infarct size 48 h post-injury. Conclusions and clinical relavance: Thus, Slt is a non-coding RNA-derived micropeptide, identified in the extracellular space, with a potential cardioprotective function.
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BACKGROUND: Late potential (LP) elimination has been proposed as a surrogate endpoint for scar-related ventricular tachycardia (VT) ablation procedures. The characteristics, distribution, and predictors of persistent late potentials (pLPs) after ablation have not been studied. OBJECTIVE: The purpose of this study was to characterize the spatial distribution and features of pLP after catheter ablation of VT substrate with high-resolution mapping. METHODS: Cases of scar-related VT ablation with adequate pre- and postablation electroanatomic maps (EAMs) acquired exclusively using a high-density grid catheter were reviewed from 2021 to 2023. RESULTS: A total of 62 EAMs (pre- and postablation) from 31 cases using a high-density grid catheter were reviewed. pLPs were observed in 19 cases (61%) after ablation. New LP, spatially distinct from preablation LP, at the periphery of the ablation area comprised the majority of pLPs (16/19 [84%]). Isolated pLPs were more prevalent than fractionated pLPs, with a median amplitude of 0.26 mV (0.09-0.59 mV). The presence of pLP was associated with a significantly lower left ventricular ejection fraction (LVEF) and septal ablation but not low voltage, LP, or ablation area compared to absence of pLP (22.8% ± 7.8% vs 31.5% ± 8.0%, P = .008 for LVEF; 83% vs 44%, P = .033 for septal ablation). CONCLUSION: Formation of spatially distinct new LP after targeted VT ablation is common, especially in patients with lower LVEF and septal substrate independent of ablation burden. This finding highlights the limitations of complete LP elimination as an endpoint to VT ablation procedures.
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BACKGROUND: Autonomic nerve activity is important in the mechanisms of paroxysmal atrial fibrillation (PAF). OBJECTIVE: The purpose of this study was to test the hypothesis that a single burst of skin sympathetic nerve activity (SKNA) can toggle on and off PAF or premature atrial contraction (PAC) clusters. METHODS: Simultaneous recording of SKNA and electrocardiogram (neuECG) recording was performed over 7 days in patients with PAF. RESULTS: In study 1, 8 patients (7 men and 1 woman; age 62 ± 8 years) had 124 episodes of PAF. An SKNA burst toggled both on and off PAF in 8 episodes (6.5%) (type 1), toggled on but not off in 12 episodes (9.7%) (type 2), and toggled on a PAC cluster followed by PAF in 4 episodes (3.2%) (type 3). The duration of these PAF episodes was <10 minutes. The remaining 100 episodes (80.6%) were associated with active SKNA bursts throughout PAF (type 4) and lasted longer than type 1 (P = .0185) and type 2 (P = .0027) PAF. There were 47 PAC clusters. Among them, 24 (51.1%) were toggled on and off, and 23 (48.9%) were toggled on but not off by an SKNA burst. In study 2, 17 patients (9 men and 8 women; age 58 ± 12 years) had <10 minutes of PAF (4, 8, 0, and 31 of types 1, 2, 3, and 4, respectively). There were significant circadian variations of all types of PAF. CONCLUSION: A single SKNA burst can toggle short-duration PAF and PAC cluster episodes on and off. The absence of continued SKNA after the onset might have affected the maintenance of these arrhythmias.
Asunto(s)
Fibrilación Atrial , Complejos Atriales Prematuros , Electrocardiografía , Sistema Nervioso Simpático , Humanos , Femenino , Masculino , Fibrilación Atrial/fisiopatología , Fibrilación Atrial/diagnóstico , Persona de Mediana Edad , Complejos Atriales Prematuros/fisiopatología , Complejos Atriales Prematuros/diagnóstico , Sistema Nervioso Simpático/fisiopatología , Anciano , Recurrencia , Frecuencia Cardíaca/fisiología , Piel/inervación , Estudios de SeguimientoRESUMEN
In order for bloodborne stem cells to be effective in tissue regeneration, cells must cross vessel walls and enter the parenchyma. Although such transmigration does occur, the mechanism remains elusive. Leukocytes invade tissue by diapedesis; stem cells are commonly assumed to do likewise, but evidence is lacking. Cardiac-derived regenerative cells and multicellular cardiospheres (CSPs) were infused into the coronary vessels of rat hearts. Serial histology revealed a novel mechanism of cell transmigration, "active vascular expulsion," which underlies the extravasation of infused cells and cell aggregates. In this mechanism, the vascular barrier undergoes extensive remodeling, while the cells themselves are relatively passive. The mechanism was confirmed in vivo by serial intravital microscopy of CSP extravasation in a dorsal skin flap model. Integrins and matrix metalloproteinases play critical roles in active vascular expulsion. In vitro models revealed that active vascular expulsion is generalizable to other stem cell types and to breast cancer cells. Recognition of active vascular expulsion as a mechanism for transvascular cell migration opens new opportunities to enhance the efficacy of vascularly delivered cell therapy.