RESUMEN
Prolyl hydroxylase (PHD) inhibitors are in clinical development for anaemia in chronic kidney disease. Epidemiological studies have reported conflicting results regarding safety of long-term therapeutic haemoglobin (Hgb) rises through PHD inhibition on risk of cardiovascular disease. Genetic variation in genes encoding PHDs can be used as partial proxies to investigate the potential effects of long-term Hgb rises. We used Mendelian randomization to investigate the effect of long-term Hgb level rises through genetically proxied PHD inhibition on coronary artery disease (CAD: 60 801 cases; 123 504 controls), myocardial infarction (MI: 42 561 cases; 123 504 controls) or stroke (40 585 cases; 406 111 controls). To further characterize long-term effects of Hgb level rises, we performed a phenome-wide association study (PheWAS) in up to 451 099 UK Biobank individuals. Genetically proxied therapeutic PHD inhibition, equivalent to a 1.00 g/dl increase in Hgb levels, was not associated (at P < 0.05) with increased odds of CAD; odd ratio (OR) [95% confidence intervals (CI)] = 1.06 (0.84, 1.35), MI [OR (95% CI) = 1.02 (0.79, 1.33)] or stroke [OR (95% CI) = 0.91 (0.66, 1.24)]. PheWAS revealed associations with blood related phenotypes consistent with EGLN's role, relevant kidney- and liver-related biomarkers like estimated glomerular filtration rate and microalbuminuria, and non-alcoholic fatty liver disease (Bonferroni-adjusted P < 5.42E-05) but these were not clinically meaningful. These findings suggest that long-term alterations in Hgb through PHD inhibition are unlikely to substantially increase cardiovascular disease risk; using large disease genome-wide association study data, we could exclude ORs of 1.35 for cardiovascular risk with a 1.00 g/dl increase in Hgb.
Asunto(s)
Enfermedades Cardiovasculares , Accidente Cerebrovascular , Humanos , Enfermedades Cardiovasculares/genética , Estudio de Asociación del Genoma Completo , Factores de Riesgo , Prolil Hidroxilasas/genética , Predisposición Genética a la Enfermedad , Factores de Riesgo de Enfermedad Cardiaca , Accidente Cerebrovascular/genética , Análisis de la Aleatorización MendelianaRESUMEN
Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are currently under clinical development for treating anemia in chronic kidney disease (CKD), but it is important to monitor their cardiovascular safety. Genetic variants can be used as predictors to help inform the potential risk of adverse effects associated with drug treatments. We therefore aimed to use human genetics to help assess the risk of adverse cardiovascular events associated with therapeutically altered EPO levels to help inform clinical trials studying the safety of HIF-PHIs. By performing a genome-wide association meta-analysis of EPO (n = 6,127), we identified a cis-EPO variant (rs1617640) lying in the EPO promoter region. We validated this variant as most likely causal in controlling EPO levels by using genetic and functional approaches, including single-base gene editing. Using this variant as a partial predictor for therapeutic modulation of EPO and large genome-wide association data in Mendelian randomization tests, we found no evidence (at p < 0.05) that genetically predicted long-term rises in endogenous EPO, equivalent to a 2.2-unit increase, increased risk of coronary artery disease (CAD, OR [95% CI] = 1.01 [0.93, 1.07]), myocardial infarction (MI, OR [95% CI] = 0.99 [0.87, 1.15]), or stroke (OR [95% CI] = 0.97 [0.87, 1.07]). We could exclude increased odds of 1.15 for cardiovascular disease for a 2.2-unit EPO increase. A combination of genetic and functional studies provides a powerful approach to investigate the potential therapeutic profile of EPO-increasing therapies for treating anemia in CKD.
Asunto(s)
Anemia , Enfermedad de la Arteria Coronaria , Infarto del Miocardio , Insuficiencia Renal Crónica , Anemia/tratamiento farmacológico , Anemia/genética , Enfermedad de la Arteria Coronaria/genética , Estudio de Asociación del Genoma Completo , Humanos , Análisis de la Aleatorización Mendeliana , Infarto del Miocardio/genética , Insuficiencia Renal Crónica/genéticaRESUMEN
RATIONALE: The heartbeat is organized by the cardiac conduction system (CCS), a specialized network of cardiomyocytes. Patterning of the CCS into atrial node versus ventricular conduction system (VCS) components with distinct physiology is essential for the normal heartbeat. Distinct node versus VCS physiology has been recognized for more than a century, but the molecular basis of this regional patterning is not well understood. OBJECTIVE: To study the genetic and genomic mechanisms underlying node versus VCS distinction and investigate rhythm consequences of failed VCS patterning. METHODS AND RESULTS: Using mouse genetics, we found that the balance between T-box transcriptional activator, Tbx5, and T-box transcriptional repressor, Tbx3, determined the molecular and functional output of VCS myocytes. Adult VCS-specific removal of Tbx5 or overexpression of Tbx3 re-patterned the fast VCS into slow, nodal-like cells based on molecular and functional criteria. In these cases, gene expression profiling showed diminished expression of genes required for VCS-specific fast conduction but maintenance of expression of genes required for nodal slow conduction physiology. Action potentials of Tbx5-deficient VCS myocytes adopted nodal-specific characteristics, including increased action potential duration and cellular automaticity. Removal of Tbx5 in vivo precipitated inappropriate depolarizations in the atrioventricular (His)-bundle associated with lethal ventricular arrhythmias. TBX5 bound and directly activated cis-regulatory elements at fast conduction channel genes required for fast physiological characteristics of the VCS action potential, defining the identity of the adult VCS. CONCLUSIONS: The CCS is patterned entirely as a slow, nodal ground state, with a T-box dependent, physiologically dominant, fast conduction network driven specifically in the VCS. Disruption of the fast VCS gene regulatory network allowed nodal physiology to emerge, providing a plausible molecular mechanism for some lethal ventricular arrhythmias.
Asunto(s)
Arritmias Cardíacas/metabolismo , Nodo Atrioventricular/metabolismo , Ventrículos Cardíacos/metabolismo , Proteínas de Dominio T Box/metabolismo , Transcripción Genética , Potenciales de Acción , Animales , Arritmias Cardíacas/genética , Arritmias Cardíacas/fisiopatología , Nodo Atrioventricular/fisiopatología , Tipificación del Cuerpo , Femenino , Regulación del Desarrollo de la Expresión Génica , Células HEK293 , Frecuencia Cardíaca , Ventrículos Cardíacos/fisiopatología , Humanos , Masculino , Ratones Noqueados , Proteínas de Dominio T Box/deficiencia , Proteínas de Dominio T Box/genética , Factores de TiempoRESUMEN
BACKGROUND: Daprodustat is a hypoxia-inducible factor-prolyl hydroxylase inhibitor currently being investigated as a treatment for anemia of chronic kidney disease (CKD) in both dialysis and nondialysis patients. In clinical studies to date, daprodustat has been administered orally as a once-daily regimen. This randomized, double-blind, placebo-controlled study characterized the initial dose-hemoglobin response as well as the efficacy and safety of three times weekly (TIW) daprodustat in hemodialysis patients switched from stable recombinant human erythropoietin (rhEPO), in accordance with a TIW hemodialysis schedule. METHODS: 103 patients on hemodialysis with baseline hemoglobin of 9.0 to 11.5 g/dL and previously receiving a stable dose of rhEPO or its analogs were randomized 1:1:1:1:1 to receive daprodustat 10, 15, 25, or 30 mg or placebo TIW over 29 days. RESULTS: Mean baseline hemoglobin was 10.6 g/dL for the placebo group and each daprodustat cohort. Daprodustat produced dose-dependent changes in mean hemoglobin from baseline to day 29. Using a Bayesian approach, the estimated dose conversion ratio between once-daily and TIW daprodustat was ~ 2.0 across the evaluated dose range using an Emax model. Daprodustat was generally well tolerated, with an adverse event (AE) profile consistent with the hemodialysis population. CONCLUSIONS: These data help inform the appropriate dose conversion ratio to be applied to daily doses to obtain equivalent daprodustat TIW doses and suggest TIW treatment with daprodustat can treat anemia of CKD safely, supporting future long-term studies for this indication using a TIW dosing regimen. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02689206 ; date registered: 02/11/2016.
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Anemia/sangre , Anemia/tratamiento farmacológico , Barbitúricos/administración & dosificación , Inhibidores Enzimáticos/administración & dosificación , Glicina/análogos & derivados , Hemoglobinas/metabolismo , Anciano , Anciano de 80 o más Años , Anemia/etiología , Barbitúricos/efectos adversos , Barbitúricos/farmacocinética , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Esquema de Medicación , Inhibidores Enzimáticos/efectos adversos , Inhibidores Enzimáticos/farmacocinética , Eritropoyetina/sangre , Eritropoyetina/uso terapéutico , Femenino , Ferritinas/sangre , Glicina/administración & dosificación , Glicina/efectos adversos , Glicina/farmacocinética , Hematínicos/uso terapéutico , Hematopoyesis/efectos de los fármacos , Hepcidinas/sangre , Humanos , Prolina Dioxigenasas del Factor Inducible por Hipoxia/antagonistas & inhibidores , Masculino , Persona de Mediana Edad , Diálisis Renal , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/terapia , Transferrina/metabolismo , Factor A de Crecimiento Endotelial Vascular/sangreRESUMEN
Current therapies are less effective for treating sustained/permanent versus paroxysmal atrial fibrillation (AF). We and others have previously shown that histone deacetylase (HDAC) inhibition reverses structural and electrical atrial remodeling in mice with inducible, paroxysmal-like AF. Here, we hypothesize an important, specific role for class I HDACs in determining structural atrial alterations during sustained AF. The class I HDAC inhibitor N-acetyldinaline [4-(acetylamino)-N-(2-amino-phenyl) benzamide] (CI-994) was administered for 2 weeks (1 mg/kg/day) to Hopx transgenic mice with atrial remodeling and inducible AF and to dogs with atrial tachypacing-induced sustained AF. Class I HDAC inhibition prevented atrial fibrosis and arrhythmia inducibility in mice. Dogs were divided into three groups: 1) sinus rhythm, 2) sustained AF plus vehicle, and 3) sustained AF plus CI-994. In group 3, the time in AF over 2 weeks was reduced by 30% compared with group 2, along with attenuated atrial fibrosis and intra-atrial adipocyte infiltration. Moreover, group 2 dogs had higher atrial and serum inflammatory cytokines, adipokines, and atrial immune cells and adipocytes compared with groups 1 and 3. On the other hand, groups 2 and 3 displayed similar left atrial size, ventricular function, and mitral regurgitation. Importantly, the same histologic alterations found in dogs with sustained AF and reversed by CI-994 were also present in atrial tissue from transplanted patients with chronic AF. This is the first evidence that, in sustained AF, class I HDAC inhibition can reduce the total time of fibrillation, atrial fibrosis, intra-atrial adipocytes, and immune cell infiltration without significant effects on cardiac function.
Asunto(s)
Fibrilación Atrial/tratamiento farmacológico , Inhibidores de Histona Desacetilasas/farmacología , Fenilendiaminas/farmacología , Adipocitos/efectos de los fármacos , Adipocitos/patología , Animales , Fibrilación Atrial/inmunología , Fibrilación Atrial/metabolismo , Fibrilación Atrial/patología , Remodelación Atrial/efectos de los fármacos , Linfocitos B/efectos de los fármacos , Linfocitos B/metabolismo , Benzamidas , Biomarcadores/metabolismo , Citocinas/sangre , Citocinas/metabolismo , Perros , Atrios Cardíacos/efectos de los fármacos , Atrios Cardíacos/metabolismo , Atrios Cardíacos/patología , Inhibidores de Histona Desacetilasas/uso terapéutico , Ratones , Fenilendiaminas/uso terapéuticoRESUMEN
We show that the transfer of the adult ventricular myocyte (AVM) transcriptome into either a fibroblast or an astrocyte converts the host cell into a cardiomyocyte. Transcriptome-effected cardiomyocytes (tCardiomyocytes) display morphologies, immunocytochemical properties, and expression profiles of postnatal cardiomyocytes. Cell morphology analysis shows that tCardiomyoctes are elongated and have a similar length-to-width ratio as AVMs. These global phenotypic changes occur in a time-dependent manner and confer electroexcitability to the tCardiomyocytes. tCardiomyocyte generation does not require continuous overexpression of specific transcription factors; for example, the expression level of transcription factor Mef2c is higher in tCardiomyocytes than in fibroblasts, but similar in tCardiomyocytes and AVMs. These data highlight the dominant role of the gene expression profile in developing and maintaining cellular phenotype. The transcriptome-induced phenotype remodeling-generated tCardiomyocyte has significant implications for understanding and modulating cardiac disease development.
Asunto(s)
Fibroblastos/citología , Perfilación de la Expresión Génica , Miocitos Cardíacos/citología , Miocitos Cardíacos/metabolismo , Fenotipo , ARN/genética , Transfección/métodos , Animales , Astrocitos/citología , Astrocitos/metabolismo , Forma de la Célula , Tamaño de la Célula , Células Cultivadas , Biología Computacional , Inmunohistoquímica , Ratones , Ratones Endogámicos C57BL , Análisis por Micromatrices , Microscopía Confocal , Técnicas de Placa-Clamp , Poli A/genéticaRESUMEN
BACKGROUND: Notch signaling has previously been shown to play an essential role in regulating cell fate decisions and differentiation during cardiogenesis in many systems including Drosophila, Xenopus, and mammals. We hypothesized that Notch may also be involved in directing the progressive lineage restriction of cardiomyocytes into specialized conduction cells. METHODS AND RESULTS: In hearts where Notch signaling is activated within the myocardium from early development onward, Notch promotes a conduction-like phenotype based on ectopic expression of conduction system-specific genes and cell autonomous changes in electrophysiology. With the use of an in vitro assay to activate Notch in newborn cardiomyocytes, we observed global changes in the transcriptome, and in action potential characteristics, consistent with reprogramming to a conduction-like phenotype. CONCLUSIONS: Notch can instruct the differentiation of chamber cardiac progenitors into specialized conduction-like cells. Plasticity remains in late-stage cardiomyocytes, which has potential implications for engineering of specialized cardiovascular tissues.
Asunto(s)
Nodo Atrioventricular/citología , Regulación del Desarrollo de la Expresión Génica , Miocardio/metabolismo , Miocitos Cardíacos/metabolismo , Receptor Notch1/fisiología , Potenciales de Acción , Adenoviridae/genética , Animales , Animales Recién Nacidos , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/biosíntesis , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Linaje de la Célula , Contactina 2/biosíntesis , Contactina 2/genética , Proteína Homeótica Nkx-2.5 , Proteínas de Homeodominio/biosíntesis , Proteínas de Homeodominio/genética , Ratones , Miocitos Cardíacos/ultraestructura , Canal de Sodio Activado por Voltaje NAV1.5 , Plasticidad Neuronal , Técnicas de Placa-Clamp , Fenotipo , Ramos Subendocárdicos/citología , Receptor Notch1/genética , Proteínas Recombinantes de Fusión/fisiología , Transducción de Señal/fisiología , Canales de Sodio/biosíntesis , Canales de Sodio/genética , Proteínas de Dominio T Box/biosíntesis , Proteínas de Dominio T Box/genética , Factor de Transcripción HES-1 , Factores de Transcripción/biosíntesis , Factores de Transcripción/genéticaRESUMEN
INTRODUCTION: Arrhythmia monitoring in patients undergoing atrial fibrillation (AF) ablation is challenging. Transtelephonic monitors (TTMs) are cumbersome to use and provide limited temporal assessment. Implantable loop recorders (ILRs) may overcome these limitations. We sought to evaluate the utility of ILRs versus conventional monitoring (CM) in patients undergoing AF ablation. METHODS AND RESULTS: Forty-four patients undergoing AF ablation received ILRs and CM (30-day TTM at discharge and months 5 and 11 postablation). Over the initial 6 months, clinical decisions were made based on CM. Subjects were then randomized for the remaining 6 months to arrhythmia assessment and management by ILR versus CM. The primary endpoint was arrhythmia recurrence. The secondary endpoint was actionable clinical events (change of antiarrhythmic drugs [AADs], anticoagulation, non-AF arrhythmia events, etc.) due to either monitoring strategy. Over the study period, 6 patients withdrew. In the first 6 months, AF recurred in 18 patients (7 noted by CM, 18 by ILR; P = 0.002). Five patients in the CM (28%) and 5 in the ILR arm (25%; P = NS) had AF recurrence during the latter 6 months. AF was falsely diagnosed frequently by ILR (730 of 1,421 episodes; 51%). In more patients in the ILR compared with the CM arm, rate control agents (60% vs 39%, P = 0.02) and AADs (71% vs 44%, P = 0.04) were discontinued. CONCLUSION: In AF ablation patients, ILR can detect more arrhythmias than CM. However, false detection remains a challenge. With adequate oversight, ILRs may be useful in monitoring these patients after ablation.
Asunto(s)
Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/fisiopatología , Fibrilación Atrial/fisiopatología , Fibrilación Atrial/cirugía , Ablación por Catéter/métodos , Electrocardiografía Ambulatoria/instrumentación , Distribución de Chi-Cuadrado , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Recurrencia , Resultado del TratamientoRESUMEN
T-wave oversensing can be a serious problem that often results in inappropriate device therapy. We report here a patient with binge alcohol use who received multiple, inappropriate ICD shocks due to T-wave oversensing from repolarization changes induced by acute alcohol intoxication and no other relevant metabolic derangements. Following recovery from his alcohol intoxication a few days later, the T-wave amplitude decreased so the device no longer inappropriately sensed or delivered therapies. This case represents an uncommon, but reversible, cause of T-wave oversensing that should be considered before more aggressive measures are taken to correct the abnormality.
Asunto(s)
Intoxicación Alcohólica/complicaciones , Desfibriladores Implantables/efectos adversos , Traumatismos por Electricidad/etiología , Electrocardiografía , Errores Médicos/prevención & control , Anciano , Humanos , MasculinoRESUMEN
Nonsteroidal anti-inflammatory drugs selective for inhibition of COX-2 increase heart failure and elevate blood pressure. The COX-2 gene was floxed and crossed into merCremer mice under the alpha-myosin heavy-chain promoter. Tamoxifen induced selective deletion of COX-2 in cardiomyocytes depressed cardiac output, and resulted in weight loss, diminished exercise tolerance, and enhanced susceptibility to induced arrhythmogenesis. The cardiac dysfunction subsequent to pressure overload recovered progressively in the knockouts coincident with increasing cardiomyocyte hypertrophy and interstitial and perivascular fibrosis. Inhibition of COX-2 in cardiomyocytes may contribute to heart failure in patients receiving nonsteroidal anti-inflammatory drugs specific for inhibition of COX-2.
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Ciclooxigenasa 2/fisiología , Frecuencia Cardíaca , Miocitos Cardíacos/patología , Miocitos Cardíacos/fisiología , Animales , Antiinflamatorios no Esteroideos/efectos adversos , Ciclooxigenasa 2/genética , Eliminación de Gen , Frecuencia Cardíaca/genética , Hipertrofia/inducido químicamente , Hipertrofia/enzimología , Ratones , Ratones Noqueados , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/enzimologíaRESUMEN
Mitochondrial membrane potential loss has severe bioenergetic consequences and contributes to many human diseases including myocardial infarction, stroke, cancer, and neurodegeneration. However, despite its prominence and importance in cellular energy production, the basic mechanism whereby the mitochondrial membrane potential is established remains unclear. Our studies elucidate that complex II-driven electron flow is the primary means by which the mitochondrial membrane is polarized under hypoxic conditions and that lack of the complex II substrate succinate resulted in reversible membrane potential loss that could be restored rapidly by succinate supplementation. Inhibition of mitochondrial complex I and F(0)F(1)-ATP synthase induced mitochondrial depolarization that was independent of the mitochondrial permeability transition pore, Bcl-2 (B-cell lymphoma 2) family proteins, or high amplitude swelling and could not be reversed by succinate. Importantly, succinate metabolism under hypoxic conditions restores membrane potential and ATP levels. Furthermore, a reliance on complex II-mediated electron flow allows cells from mitochondrial disease patients devoid of a functional complex I to maintain a mitochondrial membrane potential that conveys both a mitochondrial structure and the ability to sequester agonist-induced calcium similar to that of normal cells. This finding is important as it sets the stage for complex II functional preservation as an attractive therapy to maintain mitochondrial function during hypoxia.
Asunto(s)
Calcio/fisiología , Complejo II de Transporte de Electrones/fisiología , Hipoxia , Potencial de la Membrana Mitocondrial , Proteínas Proto-Oncogénicas c-bcl-2/fisiología , Adenosina Trifosfato , Animales , Humanos , Ratones , Proteínas de Transporte de Membrana Mitocondrial , Poro de Transición de la Permeabilidad Mitocondrial , ATPasas de Translocación de Protón/fisiología , Ratas , Ácido Succínico/farmacologíaAsunto(s)
Fibrilación Atrial/fisiopatología , Sistema de Conducción Cardíaco/fisiopatología , Corazón/inervación , Animales , Fibrilación Atrial/patología , Fibrilación Atrial/cirugía , Sistema Nervioso Autónomo/anatomía & histología , Sistema Nervioso Autónomo/fisiopatología , Tronco Encefálico/fisiología , Estimulación Cardíaca Artificial , Ablación por Catéter , Cromogranina A/uso terapéutico , Variación Genética , Atrios Cardíacos/inervación , Sistema de Conducción Cardíaco/patología , Humanos , Células Intersticiales de Cajal/fisiología , Modelos Cardiovasculares , Miocitos Cardíacos/fisiología , Fragmentos de Péptidos/uso terapéutico , Venas Pulmonares/anatomía & histología , Receptor Muscarínico M2/fisiología , Receptores Adrenérgicos beta/fisiología , Terapias en Investigación , Vagotomía , Nervio Vago/fisiología , Venas Cavas/anatomía & histologíaRESUMEN
Cardiac-specific deletion of the murine gene (Cdh2) encoding the cell adhesion molecule, N-cadherin, results in disassembly of the intercalated disc (ICD) structure and sudden arrhythmic death. Connexin 43 (Cx43)-containing gap junctions are significantly reduced in the heart after depleting N-cadherin, therefore we hypothesized that animals expressing half the normal levels of N-cadherin would exhibit an intermediate phenotype. We examined the effect of N-cadherin haploinsufficiency on Cx43 expression and susceptibility to induced arrhythmias in mice either wild-type or heterozygous for the Cx43 (Gja1)-null allele. An increase in hypophosphorylated Cx43 accompanied by a modest decrease in total Cx43 protein levels was observed in the N-cadherin heterozygous mice. Consistent with these findings N-cadherin heterozygotes exhibited increased susceptibility to ventricular arrhythmias compared to wild-type mice. Quantitative immunofluorescence microscopy revealed a reduction in size of large Cx43-containing plaques in the N-cadherin heterozygous animals compared to wild-type. Gap junctions were further decreased in number and size in the N-cad/Cx43 compound heterozygous mice with increased arrhythmic susceptibility compared to the single mutants. The scaffold protein, ZO-1, was reduced at the ICD in N-cadherin heterozygous cardiomyocytes providing a possible explanation for the reduction in Cx43 plaque size. These data provide further support for the intimate relationship between N-cadherin and Cx43 in the heart, and suggest that germline mutations in the human N-cadherin (Cdh2) gene may predispose patients to increased risk of cardiac arrhythmias.
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Arritmias Cardíacas/metabolismo , Cadherinas/metabolismo , Conexina 43/metabolismo , Uniones Comunicantes/metabolismo , Animales , Arritmias Cardíacas/genética , Arritmias Cardíacas/fisiopatología , Western Blotting , Cadherinas/genética , Comunicación Celular/genética , Células Cultivadas , Conexina 43/genética , Electrofisiología , Técnica del Anticuerpo Fluorescente , Heterocigoto , Proteínas de la Membrana/metabolismo , Ratones , Células Musculares/metabolismo , Mutación , Miocardio/metabolismo , Miocardio/patología , Fosfoproteínas/metabolismo , Proteína de la Zonula Occludens-1 , beta Catenina/metabolismoRESUMEN
Atrial fibrosis influences the development of atrial fibrillation (AF), particularly in the setting of structural heart disease where angiotensin-inhibition is partially effective for reducing atrial fibrosis and AF. Histone-deacetylase inhibition reduces cardiac hypertrophy and fibrosis, so we sought to determine if the HDAC inhibitor trichostatin A (TSA) could reduce atrial fibrosis and arrhythmias. Mice over-expressing homeodomain-only protein (HopX(Tg)), which recruits HDAC activity to induce cardiac hypertrophy were investigated in 4 groups (aged 14-18 weeks): wild-type (WT), HopX(Tg), HopX(Tg) mice treated with TSA for 2 weeks (TSA-HopX) and wild-type mice treated with TSA for 2 weeks (TSA-WT). These groups were characterized using invasive electrophysiology, atrial fibrosis measurements, atrial connexin immunocytochemistry and myocardial angiotensin II measurements. Invasive electrophysiologic stimulation, using the same attempts in each group, induced more atrial arrhythmias in HopX(Tg) mice (48 episodes in 13 of 15 HopX(Tg) mice versus 5 episodes in 2 of 15 TSA-HopX mice, P<0.001; versus 9 episodes in 2 of 15 WT mice, P<0.001; versus no episodes in any TSA-WT mice, P<0.001). TSA reduced atrial arrhythmia duration in HopX(Tg) mice (1307+/-289 ms versus 148+/-110 ms, P<0.01) and atrial fibrosis (8.1+/-1.5% versus 3.9+/-0.4%, P<0.001). Atrial connexin40 was lower in HopX(Tg) compared to WT mice, and TSA normalized the expression and size distribution of connexin40 gap junctions. Myocardial angiotensin II levels were similar between WT and HopX(Tg) mice (76.3+/-26.0 versus 69.7+/-16.6 pg/mg protein, P=NS). Therefore, it appears HDAC-inhibition reverses atrial fibrosis, connexin40 remodeling and atrial arrhythmia vulnerability independent of angiotensin II in cardiac hypertrophy.
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Arritmias Cardíacas/enzimología , Inhibidores Enzimáticos/efectos adversos , Inhibidores de Histona Desacetilasas , Histona Desacetilasas/metabolismo , Proteínas de Homeodominio/biosíntesis , Ácidos Hidroxámicos/efectos adversos , Angiotensina II/genética , Angiotensina II/metabolismo , Animales , Arritmias Cardíacas/inducido químicamente , Arritmias Cardíacas/genética , Arritmias Cardíacas/patología , Cardiomegalia/congénito , Cardiomegalia/enzimología , Cardiomegalia/genética , Cardiomegalia/patología , Conexinas/genética , Conexinas/metabolismo , Inhibidores Enzimáticos/farmacología , Fibrosis , Proteínas de Homeodominio/genética , Ácidos Hidroxámicos/farmacología , Ratones , Ratones Transgénicos , Factores de Tiempo , Proteína alfa-5 de Unión ComunicanteRESUMEN
BACKGROUND: Current atrial fibrillation (AF) ablation involves isolation of all pulmonary veins (PVs) with or without additional linear lesions. However, whether such extensive ablation is necessary is unclear. OBJECTIVE: The purpose of this study was to assess the efficacy of different ablation strategies on long-term AF control. METHODS: We prospectively randomized patients to undergo isolation of all versus arrhythmogenic PVs (identified by standardized stimulation protocol). PV isolation was guided by circular mapping catheter. The endpoint was entry/exit block persisting for > or = 20 minutes. Patients were evaluated at three clinic visits (at 6 weeks, 6 months, and 1 year) and multiple transtelephonic monitoring periods. Antiarrhythmic drugs were discontinued at 6 weeks. Primary study endpoint was long-term AF control (freedom or >90% reduction in AF burden off or on previously ineffective antiarrhythmic drugs at 1 year after a single ablation procedure). RESULTS: Over a 20-month period, 105 patients (76 men and 29 women, age 57 +/- 9 years; paroxysmal AF = 77) were randomized, and 103 patients completed 1-year follow-up (51 patients in all-PV arm, 52 patients in arrhythmogenic PV arm). The primary endpoint was achieved in 75 (73%) patients and was similar in patients randomized to all-PV arm versus arrhythmogenic PV arm [38 (75%) patients vs 37 (71%) patients, respectively; odds ratio 1.18, 95% confidence interval 0.50, 2.83, P = .70]. Secondary study endpoints, including freedom from AF off antiarrhythmic drugs, total procedure/fluoroscopy times, and occurrence of serious adverse events, were not different between the two groups. CONCLUSION: In a randomized comparison, isolation of arrhythmogenic veins was as efficacious as empiric isolation of all veins in achieving long-term AF control.
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Fibrilación Atrial/cirugía , Ablación por Catéter , Venas Pulmonares/patología , Fibrilación Atrial/fisiopatología , Fibrilación Atrial/prevención & control , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Factores de Tiempo , Resultado del TratamientoRESUMEN
The structural integrity of the heart is maintained by the end-to-end connection between the myocytes called the intercalated disc. The intercalated disc contains different junctional complexes that enable the myocardium to function as a syncytium. One of the junctional complexes, the zonula adherens or adherens junction, consists of the cell adhesion molecule, N-cadherin, which mediates strong homophilic cell-cell adhesion via linkage to the actin cytoskeleton. To determine the function of N-cadherin in the working myocardium, we generated a conditional knockout containing loxP sites flanking exon 1 of the N-cadherin (Cdh2) gene. Using a cardiac-specific tamoxifen-inducible Cre transgene, N-cadherin was deleted in the adult myocardium. Loss of N-cadherin resulted in disassembly of the intercalated disc structure, including adherens junctions and desmosomes. The mutant mice exhibited modest dilated cardiomyopathy and impaired cardiac function, with most animals dying within two months after tamoxifen administration. Decreased sarcomere length and increased Z-line thickness were observed in the mutant hearts consistent with loss of muscle tension because N-cadherin was no longer available to anchor myofibrils at the plasma membrane. Ambulatory electrocardiogram monitoring captured the abrupt onset of spontaneous ventricular tachycardia, confirming that the deaths were arrhythmic in nature. A significant decrease in the gap junction protein, connexin 43, was observed in the N-cadherin-depleted hearts. This animal model provides the first demonstration of the hierarchical relationship of the structural components of the intercalated disc in the working myocardium, thus establishing N-cadherin's paramount importance in maintaining the structural integrity of the heart.
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Cadherinas/genética , Miocardio/química , Miocardio/metabolismo , Miocitos Cardíacos/química , Miocitos Cardíacos/metabolismo , Uniones Adherentes/genética , Animales , Arritmias Cardíacas/etiología , Arritmias Cardíacas/mortalidad , Cruzamiento/métodos , Causas de Muerte , Adhesión Celular/genética , Desmosomas/genética , Eliminación de Gen , Corazón/fisiopatología , Integrina beta1/biosíntesis , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos , Ratones Noqueados , Mutación/genética , Miocardio/patología , Miocitos Cardíacos/patologíaRESUMEN
The remodeling of ventricular gap junctions, as defined by changes in size, distribution, or function, is a prominent feature of diseased myocardium. However, the regulation of assembly and maintenance of gap junctions remains poorly understood. To investigate N-cadherin function in the adult myocardium, we used a floxed N-cadherin gene in conjunction with a cardiac-specific tamoxifen-inducible Cre transgene. The mutant animals appeared active and healthy until their sudden death approximately 2 months after deleting N-cadherin from the heart. Electrophysiologic analysis revealed abnormal conduction in the ventricles of mutant animals, including diminished QRS complex amplitude consistent with loss of electrical coupling in the myocardium. A significant decrease in the gap junction proteins, connexin-43 and connexin-40, was observed in N-cadherin-depleted myocytes. Perturbation of connexin function resulted in decreased ventricular conduction velocity, as determined by optical mapping. Our data suggest that perturbation of the N-cadherin/catenin complex in heart disease may be an underlying cause, leading to the establishment of the arrythmogenic substrate by destabilizing gap junctions at the cell surface.
Asunto(s)
Arritmias Cardíacas/etiología , Cadherinas/fisiología , Conexina 43/análisis , Conexinas/análisis , Miocitos Cardíacos/química , Animales , Conexina 43/fisiología , Conexinas/fisiología , Muerte Súbita Cardíaca/etiología , Electrocardiografía , Uniones Comunicantes/fisiología , Ratones , Ratones Noqueados , Proteína alfa-5 de Unión ComunicanteRESUMEN
Hop is an unusual homeobox gene expressed in the embryonic and adult heart. Hop acts downstream of Nkx2-5 during development, and Nkx2-5 mutations are associated with cardiac conduction system (CCS) defects. Inactivation of Hop in the mouse is lethal in half of the expected null embryos. Here, we show that Hop is expressed strongly in the adult CCS. Hop-/- adult mice display conduction defects below the atrioventricular node (AVN) as determined by invasive electrophysiological testing. These defects are associated with decreased expression of connexin40. Our results suggest that Hop functions in the adult CCS and demonstrate conservation of molecular hierarchies between embryonic myocardium and the specialized conduction tissue of the mature heart.
Asunto(s)
Sistema de Conducción Cardíaco/fisiología , Proteínas de Homeodominio/fisiología , Animales , Conexinas/análisis , Electrocardiografía , Proteína Homeótica Nkx-2.5 , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Factores de Transcripción/fisiología , Proteína alfa-5 de Unión ComunicanteRESUMEN
Diseases of the cardiac conduction system (CCS) are a significant health issue in adult patients where few therapeutic options exist outside of expensive, device-based procedures. An evolving paradigm pointing toward several key transcription factors required for CCS development and maintenance may be a group of potential targets for reversing or treating degenerative conduction system disease. Recently, a small homeodomain-only protein (Hop) involved with regulating cardiac development has been identified, which is highly expressed in the adult murine CCS. Targeted disruption of the Hop locus leads to infra-nodal conduction defects with downregulation of connexin40 expression within the confines of the CCS. Loss of Hop does not appear to affect the size or distribution of the mature murine CCS and further studies will be required to determine whether Hop is associated with conduction system disease in humans.
Asunto(s)
Sistema de Conducción Cardíaco/efectos de los fármacos , Proteínas de Homeodominio/fisiología , Proteínas de Homeodominio/uso terapéutico , Proteínas Supresoras de Tumor/fisiología , Proteínas Supresoras de Tumor/uso terapéutico , Animales , Conexinas/efectos de los fármacos , Regulación hacia Abajo/efectos de los fármacos , Sistema de Conducción Cardíaco/metabolismo , Sistema de Conducción Cardíaco/fisiopatología , Proteínas de Homeodominio/biosíntesis , Humanos , Proteínas Supresoras de Tumor/biosíntesis , Proteína alfa-5 de Unión ComunicanteRESUMEN
OBJECTIVE: To compare safety and efficacy of 8-mm versus cooled tip catheter in achieving electrical isolation (EI) of pulmonary veins (PV) for long-term control of atrial fibrillation (AF). BACKGROUND: There is paucity of studies comparing safety/efficacy of 8-mm and cooled tip catheters in patients undergoing AF ablation. METHODS AND RESULTS: This was a randomized and patient-blinded study. Subjects were followed by clinic visits (at 6 weeks and 6 months) and transtelephonic monitoring (3-week duration) done around each visit. Primary endpoints were: (1) long-term AF control (complete freedom and/or >90% reduction in AF burden on or off antiarrhythmic drugs at 6 months after a single ablation), and (2) occurrence of serious adverse events (cardiac tamponade, stroke, LA-esophageal fistula, and/or death). Eighty-two patients (age 56 +/- 9 years, 60 males, paroxysmal AF = 59) were randomized (42 patients to 8-mm tip and 40 patients to cooled tip). EI of PVs was achieved in shorter time by the 8-mm tip as compared with cooled tip catheter (40 +/- 23 minutes vs 50 +/- 30 minutes; P < 0.05) but long-term AF control was not different between the two (32 patients [78%] vs 28 patients [70%], respectively; P = NS). One serious adverse event occurred in each group (LA-esophageal fistula and stroke, respectively) and no significant PV stenosis was observed in either. CONCLUSION: EI of PVs using either 8-mm or cooled tip catheter results in long-term AF control in the majority after a single ablation procedure, with comparable efficacy and safety.