RESUMEN
BACKGROUND: Whether vigorous exercise increases risk of ventricular arrhythmias for individuals diagnosed and treated for congenital long QT syndrome (LQTS) remains unknown. METHODS: The National Institutes of Health-funded LIVE-LQTS study (Lifestyle and Exercise in the Long QT Syndrome) prospectively enrolled individuals 8 to 60 years of age with phenotypic and/or genotypic LQTS from 37 sites in 5 countries from May 2015 to February 2019. Participants (or parents) answered physical activity and clinical events surveys every 6 months for 3 years with follow-up completed in February 2022. Vigorous exercise was defined as ≥6 metabolic equivalents for >60 hours per year. A blinded Clinical Events Committee adjudicated the composite end point of sudden death, sudden cardiac arrest, ventricular arrhythmia treated by an implantable cardioverter defibrillator, and likely arrhythmic syncope. A National Death Index search ascertained vital status for those with incomplete follow-up. A noninferiority hypothesis (boundary of 1.5) between vigorous exercisers and others was tested with multivariable Cox regression analysis. RESULTS: Among the 1413 participants (13% <18 years of age, 35% 18-25 years of age, 67% female, 25% with implantable cardioverter defibrillators, 90% genotype positive, 49% with LQT1, 91% were treated with beta-blockers, left cardiac sympathetic denervation, and/or implantable cardioverter defibrillator), 52% participated in vigorous exercise (55% of these competitively). Thirty-seven individuals experienced the composite end point (including one sudden cardiac arrest and one sudden death in the nonvigorous group, one sudden cardiac arrest in the vigorous group) with overall event rates at 3 years of 2.6% in the vigorous and 2.7% in the nonvigorous exercise groups. The unadjusted hazard ratio for experience of events for the vigorous group compared with the nonvigorous group was 0.97 (90% CI, 0.57-1.67), with an adjusted hazard ratio of 1.17 (90% CI, 0.67-2.04). The upper 95% one-sided confidence level extended beyond the 1.5 boundary. Neither vigorous or nonvigorous exercise was found to be superior in any group or subgroup. CONCLUSIONS: Among individuals diagnosed with phenotypic and/or genotypic LQTS who were risk assessed and treated in experienced centers, LQTS-associated cardiac event rates were low and similar between those exercising vigorously and those not exercising vigorously. Consistent with the low event rate, CIs are wide, and noninferiority was not demonstrated. These data further inform shared decision-making discussions between patient and physician about exercise and competitive sports participation. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02549664.
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Ejercicio Físico , Síndrome de QT Prolongado , Humanos , Síndrome de QT Prolongado/terapia , Síndrome de QT Prolongado/congénito , Síndrome de QT Prolongado/diagnóstico , Síndrome de QT Prolongado/fisiopatología , Síndrome de QT Prolongado/mortalidad , Femenino , Masculino , Adolescente , Niño , Estudios Prospectivos , Adulto , Persona de Mediana Edad , Adulto Joven , Muerte Súbita Cardíaca/prevención & control , Muerte Súbita Cardíaca/epidemiología , Factores de RiesgoRESUMEN
In cardiomyocytes, NaV1.5 channels mediate initiation and fast propagation of action potentials. The Ca2+-binding protein calmodulin (CaM) serves as a de facto subunit of NaV1.5. Genetic studies and atomic structures suggest that this interaction is pathophysiologically critical, as human mutations within the NaV1.5 carboxy-terminus that disrupt CaM binding are linked to distinct forms of life-threatening arrhythmias, including long QT syndrome 3, a "gain-of-function" defect, and Brugada syndrome, a "loss-of-function" phenotype. Yet, how a common disruption in CaM binding engenders divergent effects on NaV1.5 gating is not fully understood, though vital for elucidating arrhythmogenic mechanisms and for developing new therapies. Here, using extensive single-channel analysis, we find that the disruption of Ca2+-free CaM preassociation with NaV1.5 exerts two disparate effects: 1) a decrease in the peak open probability and 2) an increase in persistent NaV openings. Mechanistically, these effects arise from a CaM-dependent switch in the NaV inactivation mechanism. Specifically, CaM-bound channels preferentially inactivate from the open state, while those devoid of CaM exhibit enhanced closed-state inactivation. Further enriching this scheme, for certain mutant NaV1.5, local Ca2+ fluctuations elicit a rapid recruitment of CaM that reverses the increase in persistent Na current, a factor that may promote beat-to-beat variability in late Na current. In all, these findings identify the elementary mechanism of CaM regulation of NaV1.5 and, in so doing, unravel a noncanonical role for CaM in tuning ion channel gating. Furthermore, our results furnish an in-depth molecular framework for understanding complex arrhythmogenic phenotypes of NaV1.5 channelopathies.
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Potenciales de Acción/genética , Calcio/metabolismo , Calmodulina/química , Miocitos Cardíacos/metabolismo , Canal de Sodio Activado por Voltaje NAV1.5/química , Arritmias Cardíacas/genética , Arritmias Cardíacas/metabolismo , Arritmias Cardíacas/patología , Sitios de Unión , Señalización del Calcio , Calmodulina/genética , Calmodulina/metabolismo , Transferencia Resonante de Energía de Fluorescencia , Expresión Génica , Células HEK293 , Humanos , Activación del Canal Iónico , Cinética , Modelos Moleculares , Mutación , Miocitos Cardíacos/citología , Canal de Sodio Activado por Voltaje NAV1.5/genética , Canal de Sodio Activado por Voltaje NAV1.5/metabolismo , Técnicas de Placa-Clamp , Unión Proteica , Conformación Proteica en Hélice alfa , Conformación Proteica en Lámina beta , Dominios y Motivos de Interacción de Proteínas , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Sodio/metabolismoRESUMEN
Voltage-gated sodium channels, NaVs, are responsible for the rapid rise of action potentials in excitable tissues. NaV channel mutations have been implicated in several human genetic diseases, such as hypokalemic periodic paralysis, myotonia, and long-QT and Brugada syndromes. Here, we generated high-affinity anti-NaV nanobodies (Nbs), Nb17 and Nb82, that recognize the NaV1.4 (skeletal muscle) and NaV1.5 (cardiac muscle) channel isoforms. These Nbs were raised in llama (Lama glama) and selected from a phage display library for high affinity to the C-terminal (CT) region of NaV1.4. The Nbs were expressed in Escherichia coli, purified, and biophysically characterized. Development of high-affinity Nbs specifically targeting a given human NaV isoform has been challenging because they usually show undesired crossreactivity for different NaV isoforms. Our results show, however, that Nb17 and Nb82 recognize the CTNaV1.4 or CTNaV1.5 over other CTNav isoforms. Kinetic experiments by biolayer interferometry determined that Nb17 and Nb82 bind to the CTNaV1.4 and CTNaV1.5 with high affinity (KD â¼ 40-60 nM). In addition, as proof of concept, we show that Nb82 could detect NaV1.4 and NaV1.5 channels in mammalian cells and tissues by Western blot. Furthermore, human embryonic kidney cells expressing holo NaV1.5 channels demonstrated a robust FRET-binding efficiency for Nb17 and Nb82. Our work lays the foundation for developing Nbs as anti-NaV reagents to capture NaVs from cell lysates and as molecular visualization agents for NaVs.
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Anticuerpos de Dominio Único , Canales de Sodio Activados por Voltaje , Animales , Células Cultivadas , Escherichia coli/genética , Humanos , Síndrome de QT Prolongado/metabolismo , Mamíferos/metabolismo , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Anticuerpos de Dominio Único/genética , Anticuerpos de Dominio Único/metabolismo , Canales de Sodio Activados por Voltaje/genética , Canales de Sodio Activados por Voltaje/metabolismoRESUMEN
Voltage gated Na channels (NaV) are essential for excitation of tissues. Mutations in NaVs cause a spectrum of human disease from autism and epilepsy to cardiac arrhythmias to skeletal myotonias. The carboxyl termini (CT) of NaV channels are hotspots for disease-causing mutations and are richly invested with protein interaction sites. We have focused on the regulation of NaV by two proteins that bind in this region: calmodulin (CaM) and non-secreted fibroblast growth factors (iFGF or FHF). CaM regulates NaV gating, mediating Ca2+-dependent inactivation (CDI) in a channel isoform-specific manner, while Ca2+-free CaM (apo-CaM) binding broadly regulates NaV opening and suppresses the arrhythmogenic late Na current (INa-L). FHFs inhibit CDI, in NaV isoforms that exhibit this property, and potently suppress INa-L, the latter requiring the amino terminus of the FHF. A peptide comprised of the first 39 amino acids of FHF1A is sufficient to inhibit INa-L, constituting a credible specific antiarrhythmic.
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Factores de Crecimiento de Fibroblastos , Canales de Sodio , Humanos , MutaciónRESUMEN
Calmodulin (CaM) regulation of voltage-gated calcium (CaV) channels is a powerful Ca2+ feedback mechanism that adjusts Ca2+ influx, affording rich mechanistic insights into Ca2+ decoding. CaM possesses a dual-lobed architecture, a salient feature of the myriad Ca2+-sensing proteins, where two homologous lobes that recognize similar targets hint at redundant signaling mechanisms. Here, by tethering CaM lobes, we demonstrate that bilobal architecture is obligatory for signaling to CaV channels. With one lobe bound, CaV carboxy tail rearranges itself, resulting in a preinhibited configuration precluded from Ca2+ feedback. Reconstitution of two lobes, even as separate molecules, relieves preinhibition and restores Ca2+ feedback. CaV channels thus detect the coincident binding of two Ca2+-free lobes to promote channel opening, a molecular implementation of a logical NOR operation that processes spatiotemporal Ca2+ signals bifurcated by CaM lobes. Overall, a unified scheme of CaV channel regulation by CaM now emerges, and our findings highlight the versatility of CaM to perform exquisite Ca2+ computations.
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Canales de Calcio/metabolismo , Señalización del Calcio , Calcio/metabolismo , Calmodulina/metabolismo , Activación del Canal Iónico/fisiología , Secuencia de Aminoácidos , Animales , Canales de Calcio/química , Calmodulina/química , Humanos , Modelos Moleculares , Unión Proteica , Conformación Proteica , Ratas , Homología de Secuencia , Transducción de SeñalRESUMEN
Recent advances in the understanding and use of pluripotent stem cells have produced major changes in approaches to the diagnosis and treatment of human disease. An obstacle to the use of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) for regenerative medicine, disease modeling and drug discovery is their immature state relative to adult myocardium. We show the effects of a combination of biochemical factors, thyroid hormone, dexamethasone, and insulin-like growth factor-1 (TDI) on the maturation of hiPSC-CMs in 3D cardiac microtissues (CMTs) that recapitulate aspects of the native myocardium. Based on a comparison of the gene expression profiles and the structural, ultrastructural, and electrophysiological properties of hiPSC-CMs in monolayers and CMTs, and measurements of the mechanical and pharmacological properties of CMTs, we find that TDI treatment in a 3D tissue context yields a higher fidelity adult cardiac phenotype, including sarcoplasmic reticulum function and contractile properties consistent with promotion of the maturation of hiPSC derived cardiomyocytes.
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Diferenciación Celular , Células Madre Pluripotentes Inducidas/citología , Miocitos Cardíacos/citología , Potenciales de Acción , Fenómenos Biomecánicos , Señalización del Calcio , Forma de la Célula , Regulación de la Expresión Génica , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Células Madre Pluripotentes Inducidas/ultraestructura , Contracción Miocárdica , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/ultraestructura , Proteoma/metabolismo , Ingeniería de Tejidos , Transcriptoma/genéticaRESUMEN
RATIONALE: Disrupted proteostasis is one major pathological trait that heart failure (HF) shares with other organ proteinopathies, such as Alzheimer and Parkinson diseases. Yet, differently from the latter, whether and how cardiac preamyloid oligomers (PAOs) develop in acquired forms of HF is unclear. OBJECTIVE: We previously reported a rise in monophosphorylated, aggregate-prone desmin in canine and human HF. We now tested whether monophosphorylated desmin acts as the seed nucleating PAOs formation and determined whether positron emission tomography is able to detect myocardial PAOs in nongenetic HF. METHODS AND RESULTS: Here, we first show that toxic cardiac PAOs accumulate in the myocardium of mice subjected to transverse aortic constriction and that PAOs comigrate with the cytoskeletal protein desmin in this well-established model of acquired HF. We confirm this evidence in cardiac extracts from human ischemic and nonischemic HF. We also demonstrate that Ser31 phosphorylated desmin aggregates extensively in cultured cardiomyocytes. Lastly, we were able to detect the in vivo accumulation of cardiac PAOs using positron emission tomography for the first time in acquired HF. CONCLUSIONS: Ser31 phosphorylated desmin is a likely candidate seed for the nucleation process leading to cardiac PAOs deposition. Desmin post-translational processing and misfolding constitute a new, attractive avenue for the diagnosis and treatment of the cardiac accumulation of toxic PAOs that can now be measured by positron emission tomography in acquired HF.
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Amiloide/metabolismo , Desmina/metabolismo , Insuficiencia Cardíaca/metabolismo , Miocitos Cardíacos/metabolismo , Procesamiento Proteico-Postraduccional , Amiloide/análisis , Amiloide/efectos de los fármacos , Animales , Catequina/análogos & derivados , Catequina/farmacología , Células Cultivadas , Desmina/genética , Femenino , Vectores Genéticos , Insuficiencia Cardíaca/etiología , Humanos , Masculino , Espectrometría de Masas/métodos , Ratones , Ratones Noqueados , Mutagénesis Sitio-Dirigida , Isquemia Miocárdica/complicaciones , Fosforilación , Polimorfismo de Nucleótido Simple , Tomografía de Emisión de Positrones/métodos , Presión , Agregado de Proteínas/efectos de los fármacos , Pliegue de Proteína , Ratas , Proteínas Recombinantes/metabolismo , alfa-Cristalinas/deficiencia , beta-Cristalinas/deficienciaRESUMEN
BACKGROUND: Pacemaker battery depletion triggers alert for replacement notification and results in automatic reprogramming, which has been shown to be associated with relevant cardiorespiratory symptoms and adverse clinical events. OBJECTIVE: Determine if electrocardiogram (ECG) pacing features may be predictive of pacemaker battery depletion and clinical risk. METHODS: This is an ECG substudy of a cohort analysis of 298 subjects referred for pacemaker generator replacement from 2006 to 2017. Electronic medical record review was performed; clinical, ECG, and pacemaker characteristics were abstracted. We applied two ECG prediction rules for pacemaker battery depletion that are relevant to all major pacemaker manufacturers except Boston Scientific and MicroPort: (1) atrial pacing not at a multiple of 10 and (2) nonsynchronous ventricular pacing not at a multiple of 10, to determine diagnostic sensitivity, specificity, and risk in applicable ECG subjects. RESULTS: We excluded 32 subjects not at replacement notification or duplicate surgeries. Overall, 176 of 266 subjects (66.2%) demonstrated atrial pacing or nonsynchronous ventricular pacing on preoperative ECG. When utilizing both rules, 139 of 176 preoperative ECGs and 12 of 163 postoperative ECGs met criteria for battery depletion yielding reasonable sensitivity (79.0%), high specificity (92.6%), and a positive likelihood ratio of 11.6:1. These rules were associated with significant increase in cardiorespiratory symptoms (P < .001) and adverse clinical events (P < .025). CONCLUSIONS: The "Rules of Ten" provided reasonable sensitivity and specificity for detecting replacement notification in pacemaker subjects with an applicable ECG. This ECG tool may help clinicians identify most patients with pacemaker battery depletion at significant clinical risk.
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Suministros de Energía Eléctrica , Electrocardiografía/métodos , Falla de Equipo , Marcapaso Artificial , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Valor Predictivo de las Pruebas , Estudios Retrospectivos , Sensibilidad y EspecificidadRESUMEN
On pathological stress, Wnt signaling is reactivated and induces genes associated with cardiac remodeling and fibrosis. We have previously shown that a cell surface receptor Cdon (cell-adhesion associated, oncogene regulated) suppresses Wnt signaling to promote neuronal differentiation however its role in heart is unknown. Here, we demonstrate a critical role of Cdon in cardiac function and remodeling. Cdon is expressed and predominantly localized at intercalated disk in both mouse and human hearts. Cdon-deficient mice develop cardiac dysfunction including reduced ejection fraction and ECG abnormalities. Cdon-/- hearts exhibit increased fibrosis and up-regulation of genes associated with cardiac remodeling and fibrosis. Electrical remodeling was demonstrated by up-regulation and mislocalization of the gap junction protein, Connexin 43 (Cx43) in Cdon-/- hearts. In agreement with altered Cx43 expression, functional analysis both using Cdon-/- cardiomyocytes and shRNA-mediated knockdown in rat cardiomyocytes shows aberrant gap junction activities. Analysis of the underlying mechanism reveals that Cdon-/- hearts exhibit hyperactive Wnt signaling as evident by ß-catenin accumulation and Axin2 up-regulation. On the other hand, the treatment of rat cardiomyocytes with a Wnt activator TWS119 reduces Cdon levels and aberrant Cx43 activities, similarly to Cdon-deficient cardiomyocytes, suggesting a negative feedback between Cdon and Wnt signaling. Finally, inhibition of Wnt/ß-catenin signaling by XAV939, IWP2 or dickkopf (DKK)1 prevented Cdon depletion-induced up-regulation of collagen 1a and Cx43. Taken together, these results demonstrate that Cdon deficiency causes hyperactive Wnt signaling leading to aberrant intercellular coupling and cardiac fibrosis. Cdon exhibits great potential as a target for the treatment of cardiac fibrosis and cardiomyopathy.
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Moléculas de Adhesión Celular/deficiencia , Corazón/fisiología , Remodelación Ventricular/fisiología , Vía de Señalización Wnt/fisiología , beta Catenina/metabolismo , Animales , Moléculas de Adhesión Celular/metabolismo , Conexina 43/metabolismo , Conexinas/metabolismo , Fibrosis/metabolismo , Uniones Comunicantes/metabolismo , Ratones , Ratones Endogámicos C57BL , Miocardio/metabolismo , Miocitos Cardíacos/metabolismo , Pirimidinas/metabolismo , Pirroles/metabolismo , Ratas , Ratas Sprague-Dawley , Regulación hacia Arriba/fisiologíaRESUMEN
RATIONALE: Calmodulinopathies comprise a new category of potentially life-threatening genetic arrhythmia syndromes capable of producing severe long-QT syndrome (LQTS) with mutations involving CALM1, CALM2, or CALM3. The underlying basis of this form of LQTS is a disruption of Ca2+/calmodulin (CaM)-dependent inactivation of L-type Ca2+ channels. OBJECTIVE: To gain insight into the mechanistic underpinnings of calmodulinopathies and devise new therapeutic strategies for the treatment of this form of LQTS. METHODS AND RESULTS: We generated and characterized the functional properties of induced pluripotent stem cell-derived cardiomyocytes from a patient with D130G-CALM2-mediated LQTS, thus creating a platform with which to devise and test novel therapeutic strategies. The patient-derived induced pluripotent stem cell-derived cardiomyocytes display (1) significantly prolonged action potentials, (2) disrupted Ca2+ cycling properties, and (3) diminished Ca2+/CaM-dependent inactivation of L-type Ca2+ channels. Next, taking advantage of the fact that calmodulinopathy patients harbor a mutation in only 1 of 6 redundant CaM-encoding alleles, we devised a strategy using CRISPR interference to selectively suppress the mutant gene while sparing the wild-type counterparts. Indeed, suppression of CALM2 expression produced a functional rescue in induced pluripotent stem cell-derived cardiomyocytes with D130G-CALM2, as shown by the normalization of action potential duration and Ca2+/CaM-dependent inactivation after treatment. Moreover, CRISPR interference can be designed to achieve selective knockdown of any of the 3 CALM genes, making it a generalizable therapeutic strategy for any calmodulinopathy. CONCLUSIONS: Overall, this therapeutic strategy holds great promise for calmodulinopathy patients as it represents a generalizable intervention capable of specifically altering CaM expression and potentially attenuating LQTS-triggered cardiac events, thus initiating a path toward precision medicine.
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Calmodulina/genética , Células Madre Pluripotentes Inducidas/fisiología , Síndrome de QT Prolongado/genética , Síndrome de QT Prolongado/terapia , Medicina de Precisión/métodos , Células Cultivadas , Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas/genética , Femenino , Humanos , Células Madre Pluripotentes Inducidas/trasplante , Síndrome de QT Prolongado/diagnóstico , Mutación Missense/genéticaRESUMEN
Aims: Historical studies of ablation of atrioventricular nodal re-entrant tachycardia (AVNRT) have shown high long-term success rates and low complication rates. The potential impact of several recent practice trends has not been described. This study aims to characterize recent clinical practice trends in AVNRT ablation and their associated success rates and complications. Methods and results: Patients undergoing initial ablation of AVNRT between 1 July 2005 and 30 June 2015 were included in this study. Patient demographics and procedural data were abstracted from procedure reports. Follow-up data, including AVNRT recurrence and complications, was evaluated through electronic medical record review. In total, 877 patients underwent catheter ablation for AVNRT. By the last recorded year, three-dimension (3D) electroanatomical mapping (EAM) was used in 36.2%, 43.2% included anaesthesia, and 23.1% utilized irrigated catheters. Long-term procedural success was 95.5%. The use of anaesthesia, 3D EAM, and irrigated ablation catheters were not associated with differences in success. The presence of an atrial 'echo' or 'AH' jump at the end of an acutely successful procedure was not associated with long-term recurrence (P = 0.18, P = 0.15, respectively). Complications, including AV block requiring a pacemaker (0.4%), were uncommon. Conclusion: In a large, contemporary cohort, catheter ablation for AVNRT remains highly successful with low complications rates. The increased use of anaesthesia as well as modern mapping and ablation tools were not associated with changes in clinical outcomes. Further prospective evaluation of such contemporary practices is warranted given the lack of evidence to support their escalating use.
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Ablación por Catéter , Taquicardia por Reentrada en el Nodo Atrioventricular/cirugía , Anestesia/métodos , Ablación por Catéter/efectos adversos , Ablación por Catéter/tendencias , Técnicas Electrofisiológicas Cardíacas , Humanos , Complicaciones Posoperatorias/etiología , Pautas de la Práctica en Medicina/tendencias , Recurrencia , Estudios Retrospectivos , Factores de Riesgo , Taquicardia por Reentrada en el Nodo Atrioventricular/diagnóstico , Taquicardia por Reentrada en el Nodo Atrioventricular/fisiopatología , Factores de Tiempo , Resultado del Tratamiento , Flujo de TrabajoRESUMEN
BACKGROUND: Pacemaker patients experience battery depletion that activates pacemaker's alert for replacement notification. Automatic reprogramming at replacement notification can result in loss of rate response and atrioventricular (AV) synchrony. OBJECTIVE: To determine if relevant symptoms or clinical events may be associated with automatic reprogramming at replacement notification. METHODS: Electronic medical record review was undertaken for 298 patients referred for pacemaker generator replacement. Primary endpoints were symptoms or clinical events during replacement notification period. RESULTS: Following elimination of duplicate pacemaker replacements (n = 12), "near-replacement notification" or "recalled" (n = 15) and pacemakers at "end of life" (n = 5), 266 subjects were included. Three distinct reprogramming cohorts were identified; those with no change (control) in pacing mode (n = 46), those with loss of rate response (n = 154), and those with loss of AV synchrony ± rate response (n = 66). In total, 83 subjects (31.2%) had symptoms with significant differences seen between groups (control = 4.3%, loss of rate response = 26.0%, loss of AV synchrony ± rate response = 62.1%, P < 0.001). Overall, 28 subjects (10.5%) experienced clinical events with significant differences seen between groups (control = 0.0%, loss of rate response = 6.5%, loss of AV synchrony ± rate response = 27.3%, P < 0.001). CONCLUSIONS: Automatic reprogramming at replacement notification was associated with significant symptoms in 26% of those who lost rate response and in 62% of those who lost AV synchrony ± rate response. Additionally, 27% of the latter cohort required nonelective clinical care.
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Suministros de Energía Eléctrica , Marcapaso Artificial , Anciano , Anciano de 80 o más Años , Remoción de Dispositivos , Electrodos Implantados , Falla de Equipo , Análisis de Falla de Equipo , Femenino , Humanos , Masculino , Estudios Retrospectivos , Factores de TiempoRESUMEN
BACKGROUND: Patients go without pacemaker, defibrillator, and cardiac resynchronization therapies (devices) each year due to the prohibitive costs of devices. OBJECTIVE: We sought to examine data available from studies regarding contemporary risks of reused devices in comparison with new devices. METHODS: We searched online indexing sites to identify recent studies. Peer-reviewed manuscripts reporting infection, malfunction, premature battery depletion, and device-related death with reused devices were included. The primary study outcome was the composite risk of infection, malfunction, premature battery depletion, and death. Secondary outcomes were the individual risks. RESULTS: Nine observational studies (published 2009-2017) were identified totaling 2,302 devices (2,017 pacemakers, 285 defibrillators). Five controlled trials were included in meta-analysis (2,114 devices; 1,258 new vs 856 reused). All device reuse protocols employed interrogation to confirm longevity and functionality, disinfectant therapy, and, usually, additional biocidal agents, packaging, and ethylene oxide gas sterilization. Demographic characteristics, indications for pacing, and median follow-up were similar. There were no device-related deaths reported and no statistically significant difference in risk between new versus reused devices for the primary outcome (2.23% vs 3.86% respectively, P = 0.807, odds ratio = 0.76). There were no significant differences seen in the secondary outcomes for the individual risks of infection, malfunction, and premature battery depletion. CONCLUSIONS: Device reuse utilizing modern protocols did not significantly increase risk of infection, malfunction, premature battery depletion, or device-related death in observational studies. These data provide rationale for proceeding with a prospective multicenter noninferiority randomized control trial.
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Desfibriladores Implantables , Equipo Reutilizado , Marcapaso Artificial , Remoción de Dispositivos , Falla de Equipo , Humanos , Factores de RiesgoRESUMEN
BDNF and its associated tropomyosin-related kinase receptor B (TrkB) nurture vessels and nerves serving the heart. However, the direct effect of BDNF/TrkB signaling on the myocardium is poorly understood. Here we report that cardiac-specific TrkB knockout mice (TrkB(-/-)) display impaired cardiac contraction and relaxation, showing that BDNF/TrkB signaling acts constitutively to sustain in vivo myocardial performance. BDNF enhances normal cardiomyocyte Ca(2+) cycling, contractility, and relaxation via Ca(2+)/calmodulin-dependent protein kinase II (CaMKII). Conversely, failing myocytes, which have increased truncated TrkB lacking tyrosine kinase activity and chronically activated CaMKII, are insensitive to BDNF. Thus, BDNF/TrkB signaling represents a previously unidentified pathway by which the peripheral nervous system directly and tonically influences myocardial function in parallel with ß-adrenergic control. Deficits in this system are likely additional contributors to acute and chronic cardiac dysfunction.
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Factor Neurotrófico Derivado del Encéfalo/metabolismo , Señalización del Calcio/fisiología , Diástole/fisiología , Contracción Miocárdica/fisiología , Receptor trkB/metabolismo , Análisis de Varianza , Animales , Calcio/metabolismo , Hemodinámica , Inmunohistoquímica , Ratones , Ratones Noqueados , Técnicas de Placa-ClampRESUMEN
QT interval variation is assumed to arise from variation in repolarization as evidenced from rare Na- and K-channel mutations in Mendelian QT prolongation syndromes. However, in the general population, common noncoding variants at a chromosome 1q locus are the most common genetic regulators of QT interval variation. In this study, we use multiple human genetic, molecular genetic, and cellular assays to identify a functional variant underlying trait association: a noncoding polymorphism (rs7539120) that maps within an enhancer of NOS1AP and affects cardiac function by increasing NOS1AP transcript expression. We further localized NOS1AP to cardiomyocyte intercalated discs (IDs) and demonstrate that overexpression of NOS1AP in cardiomyocytes leads to altered cellular electrophysiology. We advance the hypothesis that NOS1AP affects cardiac electrical conductance and coupling and thereby regulates the QT interval through propagation defects. As further evidence of an important role for propagation variation affecting QT interval in humans, we show that common polymorphisms mapping near a specific set of 170 genes encoding ID proteins are significantly enriched for association with the QT interval, as compared to genome-wide markers. These results suggest that focused studies of proteins within the cardiomyocyte ID are likely to provide insights into QT prolongation and its associated disorders.
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Proteínas Adaptadoras Transductoras de Señales/genética , Síndrome de QT Prolongado/genética , Miocitos Cardíacos/metabolismo , Sitios de Carácter Cuantitativo , Animales , Estudios de Cohortes , Electrocardiografía , Regulación de la Expresión Génica , Estudio de Asociación del Genoma Completo , Genotipo , Células HEK293 , Humanos , Lentivirus/genética , Ratones , Fenotipo , Polimorfismo de Nucleótido Simple , Pez Cebra/embriología , Pez Cebra/genéticaRESUMEN
OBJECTIVE: Circulating cardiac troponin has been associated with adverse prognosis in the acute respiratory distress syndrome in small and single-center studies; however, comprehensive studies of myocardial injury in acute respiratory distress syndrome using modern high-sensitivity troponin assays, which can detect troponin at much lower circulating concentrations, have not been performed. DESIGN: We performed a prospective cohort study. SETTING: We included patients enrolled in previously completed trials of acute respiratory distress syndrome. PATIENTS: One thousand fifty-seven acute respiratory distress syndrome patients were included. INTERVENTIONS: To determine the association of circulating high-sensitivity troponin I (Abbott ARCHITECT), with acute respiratory distress syndrome outcomes, we measured high-sensitivity troponin I within 24 hours of intubation. The primary outcome was 60-day mortality. MEASUREMENTS AND MAIN RESULTS: Detectable high-sensitivity troponin I was present in 94% of patients; 38% of patients had detectable levels below the 99th percentile of a healthy reference population (26 ng/L), whereas 56% of patients had levels above the 99th percentile cut point. After multivariable adjustment, age, cause of acute respiratory distress syndrome, temperature, heart rate, vasopressor use, Sequential Organ Failure Assessment score, creatinine, and PCO2 were associated with higher high-sensitivity troponin I concentration. After adjustment for age, sex, and randomized trial assignment, the hazard ratio for 60-day mortality comparing the fifth to the first quintiles of high-sensitivity troponin I was 1.61 (95% CI, 1.11-2.32; p trend = 0.003). Adjusting for Sequential Organ Failure Assessment score suggested that this association was not independent of disease severity (hazard ratio, 0.95; 95% CI, 0.64-1.39; p = 0.93). CONCLUSIONS: Circulating troponin is detectable in over 90% of patients with acute respiratory distress syndrome and is associated with degree of critical illness. The magnitude of myocardial injury correlated with mortality.
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Síndrome de Dificultad Respiratoria/sangre , Síndrome de Dificultad Respiratoria/mortalidad , Troponina I/sangre , Factores de Edad , Monóxido de Carbono/sangre , Estudios de Cohortes , Creatinina/sangre , Femenino , Fiebre/epidemiología , Frecuencia Cardíaca , Humanos , Masculino , Persona de Mediana Edad , Puntuaciones en la Disfunción de Órganos , Prevalencia , Pronóstico , Vasoconstrictores/uso terapéuticoRESUMEN
INTRODUCTION: Inappropriate implantable cardioverter-defibrillator (ICD) shocks, commonly caused by atrial fibrillation (AF), are associated with an increased mortality. Because impaired left atrial (LA) function predicts development of AF, we hypothesized that impaired LA function predicts inappropriate shocks beyond a history of AF. METHODS AND RESULTS: We prospectively analyzed the association between LA function and incident inappropriate shocks in primary prevention ICD candidates. In the Prospective Observational Study of ICD (PROSE-ICD), we assessed LA function using tissue-tracking cardiac magnetic resonance (CMR) prior to ICD implantation. A total of 162 patients (113 males, age 56 ± 15 years) were included. During the mean follow-up of 4.0 ± 2.9 years, 26 patients (16%) experienced inappropriate shocks due to AF (n = 19; 73%), supraventricular tachycardia (n = 5; 19%), and abnormal sensing (n = 2; 8%). In univariable analyses, inappropriate shocks were associated with AF history prior to ICD implantation, age below 70 years, QRS duration less than 120 milliseconds, larger LA minimum volume, lower LA stroke volume, lower LA emptying fraction, impaired LA maximum and preatrial contraction strains (Smax and SpreA ), and impaired LA strain rate during left ventricular systole and atrial contraction (SRs and SRa ). In multivariable analysis, impaired Smax (hazard ratio [HR]: 0.96, P = 0.044), SpreA (HR: 0.94, P = 0.030), and SRa (HR: 0.25, P < 0.001) were independently associated with inappropriate shocks. The receiver-operating characteristics curve showed that SRa improved the predictive value beyond the patient demographics including AF history (P = 0.033). CONCLUSION: Impaired LA function assessed by tissue-tracking CMR is an independent predictor of inappropriate shocks in primary prevention ICD candidates beyond AF history.
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Fibrilación Atrial/etiología , Fibrilación Atrial/fisiopatología , Función del Atrio Izquierdo/fisiología , Desfibriladores Implantables/efectos adversos , Prevención Primaria/métodos , Adulto , Anciano , Fibrilación Atrial/prevención & control , Desfibriladores Implantables/tendencias , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Prevención Primaria/tendencias , Estudios ProspectivosRESUMEN
Despite the revolutionary advancements in the past 3 decades in the treatment of ventricular tachyarrhythmias with device-based therapy, sudden cardiac death (SCD) remains an enormous public health burden. Survivors of SCD are generally at high risk for recurrent events. The clinical management of such patients requires a multidisciplinary approach from postresuscitative care to a thorough cardiovascular investigation in an attempt to identify the underlying substrate, with potential to eliminate or modify the triggers through catheter ablation and ultimately an implantable cardioverter-defibrillator (ICD) for prompt treatment of recurrences in those at risk. Early recognition of low left ventricular ejection fraction as a strong predictor of death and association of ventricular arrhythmias with sudden death led to significant investigation with antiarrhythmic drugs. The lack of efficacy and the proarrhythmic effects of drugs catalyzed the development and investigation of the ICD through several major clinical trials that proved the efficacy of ICD as a bedrock tool to detect and promptly treat life-threatening arrhythmias. The ICD therapy is routinely used for primary prevention of SCD in patients with cardiomyopathy and high risk inherited arrhythmic conditions and secondary prevention in survivors of sudden cardiac arrest. This compendium will review the clinical management of those surviving SCD and discuss landmark studies of antiarrhythmic drugs, ICD, and cardiac resynchronization therapy in the primary and secondary prevention of SCD.
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Muerte Súbita Cardíaca/prevención & control , Síndrome Coronario Agudo/prevención & control , Síndrome Coronario Agudo/terapia , Arritmias Cardíacas/complicaciones , Arritmias Cardíacas/fisiopatología , Arritmias Cardíacas/terapia , Terapia de Resincronización Cardíaca , Reanimación Cardiopulmonar , Fármacos Cardiovasculares/clasificación , Fármacos Cardiovasculares/uso terapéutico , Ablación por Catéter , Ensayos Clínicos como Asunto/métodos , Muerte Súbita Cardíaca/epidemiología , Muerte Súbita Cardíaca/etiología , Desfibriladores Implantables , Manejo de la Enfermedad , Cardioversión Eléctrica , Electrocardiografía , Paro Cardíaco/terapia , Humanos , Estudios Multicéntricos como Asunto , Prevención Primaria , Recurrencia , Prevención Secundaria , Sobrevivientes , SimpatectomíaRESUMEN
RATIONALE: Cardiac resynchronization therapy (CRT) is the only heart failure (HF) therapy documented to improve left ventricular function and reduce mortality. The underlying mechanisms are incompletely understood. Although ß-adrenergic signaling has been studied extensively, the effect of CRT on cholinergic signaling is unexplored. OBJECTIVE: We hypothesized that remodeling of cholinergic signaling plays an important role in the aberrant calcium signaling and depressed contractile and ß-adrenergic responsiveness in dyssynchronous HF that are restored by CRT. METHODS AND RESULTS: Canine tachypaced dyssynchronous HF and CRT models were generated to interrogate responses specific to dyssynchronous versus resynchronized ventricular contraction during hemodynamic decompensation. Echocardiographic, electrocardiographic, and invasive hemodynamic data were collected from normal controls, dyssynchronous HF and CRT models. Left ventricular tissue was used for biochemical analyses and functional measurements (calcium transient, sarcomere shortening) from isolated myocytes (n=42-104 myocytes per model; 6-9 hearts per model). Human left ventricular myocardium was obtained for biochemical analyses from explanted failing (n=18) and nonfailing (n=7) hearts. The M2 subtype of muscarinic acetylcholine receptors was upregulated in human and canine HF compared with nonfailing controls. CRT attenuated the increased M2 subtype of muscarinic acetylcholine receptor expression and Gαi coupling and enhanced M3 subtype of muscarinic acetylcholine receptor expression in association with enhanced calcium cycling, sarcomere shortening, and ß-adrenergic responsiveness. Despite model-dependent remodeling, cholinergic stimulation completely abolished isoproterenol-induced triggered activity in both dyssynchronous HF and CRT myocytes. CONCLUSIONS: Remodeling of cholinergic signaling is a critical pathological component of human and canine HF. Differential remodeling of cholinergic signaling represents a novel mechanism for enhancing sympathovagal balance with CRT and may identify new targets for treatment of systolic HF.
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Acetilcolina/metabolismo , Terapia de Resincronización Cardíaca , Insuficiencia Cardíaca/terapia , Corazón/inervación , Sistema Nervioso Simpático/metabolismo , Transmisión Sináptica , Nervio Vago/metabolismo , Disfunción Ventricular Izquierda/terapia , Agonistas Adrenérgicos beta/farmacología , Animales , Señalización del Calcio , Estudios de Casos y Controles , Modelos Animales de Enfermedad , Perros , Subunidades alfa de la Proteína de Unión al GTP Gi-Go/metabolismo , Insuficiencia Cardíaca/diagnóstico , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/fisiopatología , Humanos , Agonistas Muscarínicos/farmacología , Antagonistas Muscarínicos/farmacología , Contracción Miocárdica , Receptor Muscarínico M2/metabolismo , Receptor Muscarínico M3/metabolismo , Recuperación de la Función , Sistema Nervioso Simpático/efectos de los fármacos , Sistema Nervioso Simpático/fisiopatología , Transmisión Sináptica/efectos de los fármacos , Factores de Tiempo , Nervio Vago/efectos de los fármacos , Nervio Vago/fisiopatología , Disfunción Ventricular Izquierda/diagnóstico , Disfunción Ventricular Izquierda/metabolismo , Disfunción Ventricular Izquierda/fisiopatología , Función Ventricular IzquierdaRESUMEN
All contemporary pacemakers undergo automatic reprogramming upon reaching elective replacement indication due to battery depletion. The majority of such reprogramming will result in changes to both pacing mode and pacing rate. The exact software reprogramming varies considerably among pacemaker manufacturers and may even vary among models of the same manufacturer. Accordingly, it is essential for healthcare providers managing pacemaker patients to have a detailed understanding of the automatic reprogramming seen at elective replacement indication as well as their potential physiological and clinical consequences.