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BACKGROUND: The low-voltage area detected by electroanatomic mapping (EAM) is a surrogate marker of left atrial fibrosis. However, the correlation between the EAM and late gadolinium enhancement magnetic resonance imaging (LGE-MRI) has been inconsistent among studies. This study aimed to investigate how LA size affects the correlation between EAM and LGE-MRI. METHODS: High-density EAMs of the LA during sinus rhythm were collected in 22 patients undergoing AF ablation. The EAMs were co-registered with pre-ablation LGE-MRI models. Voltages in the areas with and without LGE were recorded. Left atrial volume index (LAVI) was calculated from MRI, and LAVI > 62 ml/m2 was defined as significant LA enlargement (LAE). RESULTS: Atrial bipolar voltage negatively correlates with the left atrial volume index. The median voltages in areas without LGE were 1.1 mV vs 2.0 mV in patients with vs without significant LAE (p = 0.002). In areas of LGE, median voltages were 0.4 mV vs 0.8 mV in patients with vs without significant LAE (p = 0.02). A voltage threshold of 1.7 mV predicted atrial LGE in patients with normal or mildly enlarged LA (sensitivity and specificity of 74% and 59%, respectively). In contrast, areas of voltage less than 0.75 mV correlated with LGE in patients with significant LA enlargement (sensitivity 68% and specificity 66%). CONCLUSIONS: LAVI affects left atrial bipolar voltage, and the correlation between low-voltage areas and LGE-MRI. Distinct voltage thresholds according to the LAVI value might be considered to identify atrial scar by EAM.
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Fibrilação Atrial , Ablação por Cateter , Humanos , Fibrilação Atrial/diagnóstico por imagem , Fibrilação Atrial/cirurgia , Meios de Contraste , Gadolínio , Átrios do Coração/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Fibrose , Ablação por Cateter/métodosRESUMO
Purpose: To characterize global and segmental circumferential systolic strain (CS) measured by cardiac MRI in athletes after SARS-CoV-2 infection. Materials and Methods: This retrospective observational cohort study included 188 soldiers and collegiate athletes referred for cardiac MRI after SARS-CoV-2 infection (C19+) between July 2020 and February 2021 and a control group of 72 soldiers, collegiate, and high school athletes who underwent cardiac MRI from May 2019 to February 2020, prior to the first SARS-CoV-2 case detected in our region (C19-). Global and segmental CS were measured by feature tracking, then compared between each group using unadjusted and multivariable- adjusted models. Acute myocarditis was diagnosed according to the modified Lake Louise criteria and the location of pathologic late gadolinium enhancement (LGE) was ascertained. Results: Among the 188 C19+ athletes (median age, 25 years [IQR, 23-30]; 131 men), the majority had mild illness. Global CS significantly differed between C19+ and C19- groups, with a median of -24.0 (IQR -25.8, -21.4) versus. -25.0 (-28.0, -22.4), respectively (p = .009). This difference in CS persisted following adjustment for age, sex, body mass index, heart rate, and systolic blood pressure ß coefficient 1.29 [95% CI: 0.20, 2.38], p = .02). In segmental analysis, the basal- and mid- inferoseptal, septal and inferolateral segments were significantly different (p < .05), which had a higher frequency of post-COVID late gadolinium enhancement. The global and segmental differences were similar after exclusion of athletes with myocarditis. Conclusion: Among athletes, SARS-CoV-2 infection was associated with a small but statistically significant reduced CS.
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BACKGROUND: Patients with COVID-19 have increased sleep disturbances and decreased sleep quality during and after the infection. The current published literature focuses mainly on qualitative analyses based on surveys and subjective measurements rather than quantitative data. OBJECTIVE: In this paper, we assessed the long-term effects of COVID-19 through sleep patterns from continuous signals collected via wearable wristbands. METHODS: Patients with a history of COVID-19 were compared to a control arm of individuals who never had COVID-19. Baseline demographics were collected for each subject. Linear correlations among the mean duration of each sleep phase and the mean daily biometrics were performed. The average duration for each subject's total sleep time and sleep phases per night was calculated and compared between the 2 groups. RESULTS: This study includes 122 patients with COVID-19 and 588 controls (N=710). Total sleep time was positively correlated with respiratory rate (RR) and oxygen saturation (SpO2). Increased awake sleep phase was correlated with increased heart rate, decreased RR, heart rate variability (HRV), and SpO2. Increased light sleep time was correlated with increased RR and SpO2 in the group with COVID-19. Deep sleep duration was correlated with decreased heart rate as well as increased RR and SpO2. When comparing different sleep phases, patients with long COVID-19 had decreased light sleep (244, SD 67 vs 258, SD 67; P=.003) and decreased deep sleep time (123, SD 66 vs 128, SD 58; P=.02). CONCLUSIONS: Regardless of the demographic background and symptom levels, patients with a history of COVID-19 infection demonstrated altered sleep architecture when compared to matched controls. The sleep of patients with COVID-19 was characterized by decreased total sleep and deep sleep.
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COVID-19 , Dispositivos Eletrônicos Vestíveis , COVID-19/complicações , COVID-19/epidemiologia , Humanos , Polissonografia , Sono/fisiologia , Qualidade do Sono , Síndrome de COVID-19 Pós-AgudaRESUMO
INTRODUCTION: To target posterior wall isolation (PWI) in atrial fibrillation (AF) ablation, diffuse ablation theoretically confers a lower risk of conduction recovery compared to box set. We sought to assess the safety and efficacy of diffuse PWI with low-flow, medium-power, and short-duration (LF-MPSD) ablation, and evaluate the durability of pulmonary vein isolation (PVI) and PWI among patients undergoing repeat ablations. METHODS: We retrospectively studied patients undergoing LF-MPSD ablation for AF (PVI + diffuse PWI) between August 2017 and December 2019. Clinical characteristics were collected. Kaplan-Meier survival analysis was performed to study AF/atrial flutter (AFL) recurrence. Ablation data were analyzed in patients who underwent a repeat AF/AFL ablation. RESULTS: Of the 463 patients undergoing LF-MPSD AF ablation (PVI alone, or PVI + diffuse PWI), 137 patients had PVI + diffuse PWI. Acute PWI with complete electrocardiogram elimination was achieved in 134 (97.8%) patients. Among the 126 patients with consistent follow-up, 38 (30.2%) patients had AF/AFL recurrence during a median duration of 14 months. Eighteen patients underwent a repeat AF/AFL ablation after PVI + diffuse PWI, and 16 (88.9%) patients had durable PVI, in contrast to 10 of 45 (23.9%) patients who had redo ablation after LF-MPSD PVI alone. Seven patients (38.9%) had durable PWI, while 11 patients had partial electrical recovery at the posterior wall. The median percentage of area without electrical activity at the posterior wall was 70.7%. Conduction block across the posterior wall was maintained in 16 (88.9%) patients. CONCLUSION: There was a high rate of PVI durability in patients undergoing diffuse PWI and PVI. Partial posterior wall electrical recovery was common but conduction block across the posterior wall was maintained in most patients.
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Fibrilação Atrial , Flutter Atrial , Ablação por Cateter , Veias Pulmonares , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/etiologia , Fibrilação Atrial/cirurgia , Flutter Atrial/diagnóstico , Flutter Atrial/etiologia , Flutter Atrial/cirurgia , Ablação por Cateter/efeitos adversos , Humanos , Veias Pulmonares/cirurgia , Recidiva , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND: Myocarditis is a potential complication after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and a known cause of sudden cardiac death. Given the athletic demands of soldiers, identification of myocarditis and characterization of post-acute sequelae of SARS-CoV-2 infection with cardiovascular symptoms (CV PASC) may be critical to guide return-to-service. This study sought to evaluate the spectrum of cardiac involvement among soldiers with cardiopulmonary symptoms in the late convalescent phase of recovery from SARS-CoV-2 compared to a healthy soldier control group, and to determine the rate of progression to CV PASC. METHODS: All soldiers referred for cardiovascular magnetic resonance (CMR) imaging for cardiopulmonary symptoms following COVID-19 were enrolled and matched by age, gender, and athletic phenotype 1:1 to soldiers undergoing CMR in the year prior to the first case of COVID-19 at our institution. Demographic, clinical, laboratory, and imaging parameters were compared between groups. The diagnosis of acute myocarditis was made using modified Lake Louise criteria. Wilcoxon rank sum and chi-squared tests were used for comparison of continuous and categorical variables, respectively. RESULTS: Fifty soldier cases and 50 healthy soldier controls were included. The median time from SARS-CoV-2 detection to CMR was 71 days. The majority of cases experienced moderate symptoms (N = 43, 86%), while only 10% required hospitalization. The right ventricular (RV) ejection fraction (RVEF) was reduced in soldier cases compared to controls (51.0% vs. 53.2%, p = 0.012). Four cases were diagnosed with myocarditis (8%), 1 (2%) was diagnosed with Takotsubo cardiomyopathy, and 1 (2%) had new biventricular systolic dysfunction of unclear etiology. Isolated inferior RV septal insertion late gadolinium enhancement (LGE) was present in 8 cases and 8 controls (16% vs. 24%, p = 0.09). Seven of the 19 (37%) cases that completed an intermediate-term follow-up survey reported CV PASC at a median of 139 days of follow-up. Two of the 7 soldiers (29%) with CV PASC had a pathological clinical diagnosis (myocarditis) on CMR. CONCLUSIONS: Cardiovascular pathology was diagnosed in 6 symptomatic soldiers (12%) after recovery from SARS-CoV-2, with myocarditis found in 4 (8%). RVEF was reduced in soldier cases compared to controls. CV PASC occurred in over one-third of soldiers surveyed, but did not occur in any soldiers with asymptomatic acute SARS-CoV-2 infection.
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COVID-19 , Militares , Miocardite , COVID-19/complicações , Estudos de Casos e Controles , Meios de Contraste , Gadolínio , Humanos , Espectroscopia de Ressonância Magnética , Miocardite/diagnóstico por imagem , Miocardite/etiologia , Valor Preditivo dos Testes , SARS-CoV-2 , Síndrome de COVID-19 Pós-AgudaRESUMO
OBJECTIVES: This study aimed to review the utility of quinidine in patients presenting with recurrent sustained ventricular arrhythmia (VA) and limited antiarrhythmic drug (AAD) options. BACKGROUND: Therapeutic options are often limited in patients with structural heart disease and recurrent VAs. Quinidine has an established role in rare arrhythmic syndromes, but its potential use in other difficult VAs has not been assessed in the present era. METHODS: We performed a retrospective analysis of 37 patients who had in-hospital quinidine initiation after multiple other therapies failed for VA suppression at our tertiary referral center. Clinical data and outcomes were obtained from the medical record. RESULTS: Of 30 patients with in-hospital quantifiable VA episodes, quinidine reduced acute VA from a median of 3 episodes (interquartile range [IQR]: 2 to 7.5) to 0 (IQR: 0 to 0.5) during medians of 3 days before and 4 days after quinidine initiation (p < 0.001). VA events decreased from a median of 10.5 episodes per day (IQR: 5 to 15) to 0.5 episodes (IQR: 0 to 4) after quinidine initiation in the 12 patients presenting with electrical storm (p = 0.004). Among the 24 patients discharged on quinidine, 13 (54.2%) had VA recurrence during a median of 138 days. Adverse effects in 9 of the 37 patients (24.3%) led to drug discontinuation, most commonly gastrointestinal intolerance. CONCLUSIONS: In patients with recurrent VAs and structural heart disease who have limited treatment options, quinidine can be useful, particularly as a short-term therapy.
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Quinidina , Fibrilação Ventricular , Antiarrítmicos/uso terapêutico , Arritmias Cardíacas/tratamento farmacológico , Humanos , Quinidina/uso terapêutico , Estudos Retrospectivos , Fibrilação Ventricular/tratamento farmacológicoRESUMO
[Figure: see text].
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Autofagia , Proteína Beclina-1/farmacologia , Traumatismo por Reperfusão Miocárdica/metabolismo , Miócitos Cardíacos/metabolismo , Animais , Proteína 7 Relacionada à Autofagia/genética , Proteína 7 Relacionada à Autofagia/metabolismo , Proteína Beclina-1/uso terapêutico , Células Cultivadas , Camundongos , Camundongos Endogâmicos C57BL , Contração Miocárdica , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/fisiologia , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Proteínas Recombinantes/farmacologia , Proteínas Recombinantes/uso terapêuticoRESUMO
Coronary artery disease is a leading cause of morbidity and mortality worldwide. Noninvasive imaging tests play a significant role in diagnosing coronary artery disease, as well as risk stratification and guidance for revascularization. Myocardial perfusion imaging, including single photon emission computed tomography and positron emission tomography, has been widely employed. In this review, we will review test accuracy and clinical significance of these methods for diagnosing and managing coronary artery disease. We will further discuss the comparative usefulness of other noninvasive tests-stress echocardiography, coronary computed tomography angiography, and cardiac magnetic resonance imaging-in the evaluation of ischemia and myocardial viability.
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Doença da Artéria Coronariana/diagnóstico por imagem , Imagem de Perfusão do Miocárdio , Técnicas de Imagem Cardíaca , Doença da Artéria Coronariana/fisiopatologia , Doença da Artéria Coronariana/terapia , Humanos , PrognósticoRESUMO
INTRODUCTION: Clinical trials and observational studies of pacing-induced cardiomyopathy (PICM) have largely included elderly patients with mean age >70 years. The prevalence and predictors of PICM in younger patients (age < 60 years) after pacemaker implantation are not known. METHODS: Adults (18-59 years) who received single-chamber ventricular or dual-chamber pacemakers at Vanderbilt University Medical Center from 1986 to 2015 were included. Patients without documented ventricular pacing burden and patients with baseline left ventricular ejection fraction (LVEF) <35% were excluded. PICM was defined as LVEF decrease of ≥ 10% and LVEF < 50% during follow-up with right ventricular pacing ≥20%, and without alternative explanations for cardiomyopathy. RESULTS: A total of 325 patients were included in the study. During a median follow-up duration of 11.5 (Interquartile range 7-17) years, 38 patients (11.7%) developed PICM (1.3 per 100 patient-year). Older age (HR 2.5 for age ≥50 years, p = .013), reduced baseline LVEF (HR 2.4, p = .022), and preimplant AVB (HR 2.7, p = .007) were associated with an increased risk of PICM in the multivariate analysis. Furthermore, baseline AF conferred an increased risk of PICM only in patients without preimplant AVB but not patients with pre-implant AVB. CONCLUSIONS: The incidence of PICM in young patients was low, but PICM could occur more than a decade after pacemaker implantation. Older age, baseline reduced LVEF, and preimplant AVB were associated with an increased risk of PICM in the young patient cohort.
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Cardiomiopatias , Marca-Passo Artificial , Idoso , Estimulação Cardíaca Artificial/efeitos adversos , Cardiomiopatias/epidemiologia , Humanos , Pessoa de Meia-Idade , Prevalência , Estudos Retrospectivos , Volume Sistólico , Função Ventricular Esquerda , Adulto JovemRESUMO
Forkhead box O (FoxO) proteins and thyroid hormone (TH) have well established roles in cardiovascular morphogenesis and remodeling. However, specific role(s) of individual FoxO family members in stress-induced growth and remodeling of cardiomyocytes remains unknown. Here, we report that FoxO1, but not FoxO3, activity is essential for reciprocal regulation of types II and III iodothyronine deiodinases (Dio2 and Dio3, respectively), key enzymes involved in intracellular TH metabolism. We further show that Dio2 is a direct transcriptional target of FoxO1, and the FoxO1-Dio2 axis governs TH-induced hypertrophic growth of neonatal cardiomyocytes in vitro and in vivo. Utilizing transverse aortic constriction as a model of hemodynamic stress in wild-type and cardiomyocyte-restricted FoxO1 knockout mice, we unveil an essential role for the FoxO1-Dio2 axis in afterload-induced pathological cardiac remodeling and activation of TRα1. These findings demonstrate a previously unrecognized FoxO1-Dio2 signaling axis in stress-induced cardiomyocyte growth and remodeling and intracellular TH homeostasis.
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Proteína Forkhead Box O1/metabolismo , Iodeto Peroxidase/metabolismo , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Hormônios Tireóideos/metabolismo , Animais , Animais Recém-Nascidos , Cardiomegalia/metabolismo , Cardiomegalia/patologia , Cardiomegalia/fisiopatologia , Células Cultivadas , Proteína Forkhead Box O1/genética , Regulação da Expressão Gênica , Iodeto Peroxidase/antagonistas & inibidores , Iodeto Peroxidase/genética , Camundongos , Camundongos Knockout , Ratos , Transdução de Sinais , Remodelação Ventricular , Iodotironina Desiodinase Tipo IIRESUMO
BACKGROUND: The unfolded protein response plays versatile roles in physiology and pathophysiology. Its connection to cell growth, however, remains elusive. Here, we sought to define the role of unfolded protein response in the regulation of cardiomyocyte growth in the heart. METHODS: We used both gain- and loss-of-function approaches to genetically manipulate XBP1s (spliced X-box binding protein 1), the most conserved signaling branch of the unfolded protein response, in the heart. In addition, primary cardiomyocyte culture was used to address the role of XBP1s in cell growth in a cell-autonomous manner. RESULTS: We found that XBP1s expression is reduced in both human and rodent cardiac tissues under heart failure. Furthermore, deficiency of XBP1s leads to decompensation and exacerbation of heart failure progression under pressure overload. On the other hand, cardiac-restricted overexpression of XBP1s prevents the development of cardiac dysfunction. Mechanistically, we found that XBP1s stimulates adaptive cardiac growth through activation of the mechanistic target of rapamycin signaling, which is mediated via FKBP11 (FK506-binding protein 11), a novel transcriptional target of XBP1s. Moreover, silencing of FKBP11 significantly diminishes XBP1s-induced mechanistic target of rapamycin activation and adaptive cell growth. CONCLUSIONS: Our results reveal a critical role of the XBP1s-FKBP11-mechanistic target of rapamycin axis in coupling of the unfolded protein response and cardiac cell growth regulation.
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Proliferação de Células/fisiologia , DNA Recombinante/biossíntese , Miócitos Cardíacos/metabolismo , Serina-Treonina Quinases TOR/biossíntese , Proteína 1 de Ligação a X-Box/biossíntese , Adolescente , Adulto , Animais , Animais Recém-Nascidos , Células Cultivadas , DNA Recombinante/genética , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Pessoa de Meia-Idade , Ratos , Ratos Sprague-Dawley , Serina-Treonina Quinases TOR/genética , Proteína 1 de Ligação a X-Box/genética , Adulto JovemRESUMO
BACKGROUND: Information on the clinical and echocardiographic characteristics of young patients with heart failure with reduced ejection fraction is scant, especially among racially diverse populations. METHODS: Patients admitted to Montefiore Medical Center between 2000 and 2016 with heart failure and ejection fraction of <40% were categorized as young (18-39 years), middle-aged (40-64 years), and elderly (≥65 years). Multivariable Cox regression models were used to evaluate mortality risk. RESULTS: A total of 1032 young, 8336 middle-aged, and 13,315 elderly patients were included. Median follow-up was 36 (14-69) months. The young group had more black individuals, lower socioeconomic scores, larger left ventricular chambers, but lower N-terminal pro b-type natriuretic peptide levels (P < 0.001). Better survival outcomes were observed in the young compared to the middle-aged [hazard ratio (HR), 1.52; 95% confidence interval (CI), 1.31-1.77] and elderly (HR, 3.19; 95% CI, 2.75-3.70). After multivariable adjustments, only ß-blockers were associated with a significant reduction of mortality in young patients (HR, 0.33; 95% CI, 0.22-0.51). CONCLUSION: In conclusion, young patients with heart failure with reduced ejection fraction have distinct demographic, clinical, and echocardiographic characteristics. They had lower socioeconomic status yet received more aggressive treatments and had lower mortality rates. Only ß-blockers were associated with improved survival in young patients from our cohort.
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Antagonistas Adrenérgicos beta/uso terapêutico , Insuficiência Cardíaca , Volume Sistólico , Adulto , Distribuição por Idade , Idoso , População Negra/estatística & dados numéricos , Ecocardiografia/métodos , Ecocardiografia/estatística & dados numéricos , Feminino , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/etnologia , Insuficiência Cardíaca/fisiopatologia , Insuficiência Cardíaca/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Mortalidade , Peptídeo Natriurético Encefálico/análise , Fragmentos de Peptídeos/análise , Modelos de Riscos Proporcionais , Fatores Socioeconômicos , Estados Unidos/epidemiologiaRESUMO
Brugada syndrome (BrS) is one of the most common causes of sudden cardiac death in normal structural heart individuals. First characterised in 1992, the global prevalence of BrS is unclear, with estimates placing it at around 0.05% and presenting most frequently in southeast Asian countries. This review aims to summarise the development in the understanding of BrS and, importantly, progress in its management, underpinned by knowledge regarding its genetics and molecular mechanisms. It also provides update on risk stratification and promising new therapies for BrS, including epicardial ablation. Future studies are required to increase understanding of the pathogenesis of this disease and to guide clinical practice.
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BACKGROUND: Left ventricular diastolic dysfunction has been shown to associate with increased risk of atrial fibrillation (AF). We aimed to examine the predictors of AF in individuals with preclinical diastolic dysfunction (PDD) - diastolic dysfunction without clinical heart failure - and develop a risk score in this population. METHODS: Patients underwent echocardiogram from December 2009 to December 2015 showing left ventricular ejection fraction (LVEF) ≥ 50% and grade 1 diastolic dysfunction, without clinical heart failure, valvular heart disease or AF were included. Outcome was defined as new onset AF. Cumulative probabilities were estimated and multivariable adjusted competing-risks regression analysis was performed to examine predictors of incident AF. A predictive score model was constructed. RESULTS: A total of 9591 PDD patients (mean age 66, 41% men) of racial/ethnical diversity were included in the study. During a median follow-up of 54 months, 455 (4.7%) patients developed AF. Independent predictors of AF included advanced age, male sex, race, hypertension, diabetes, and peripheral artery disease. A risk score including these factors showed a Wolber's concordance index of 0.65 (0.63-0.68, p < 0.001), suggesting a good discrimination. CONCLUSIONS: Our study revealed a set of predictors of AF in PDD patients. A simple risk score predicting AF in PDD was developed and internally validated. The scoring system could help clinical risk stratification, which may lead to prevention and early treatment strategies.
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Fibrilação Atrial/epidemiologia , Ecocardiografia , Indicadores Básicos de Saúde , Saúde da População Urbana , Disfunção Ventricular Esquerda/diagnóstico por imagem , Função Ventricular Esquerda , Idoso , Idoso de 80 Anos ou mais , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/fisiopatologia , Diástole , Eletrocardiografia , Feminino , Nível de Saúde , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Cidade de Nova Iorque/epidemiologia , Valor Preditivo dos Testes , Prognóstico , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Disfunção Ventricular Esquerda/epidemiologia , Disfunção Ventricular Esquerda/fisiopatologiaRESUMO
AIMS: Considerable evidence points to critical roles of intracellular Ca2+ homeostasis in the modulation and control of autophagic activity. Yet, underlying molecular mechanisms remain unknown. Mutations in the gene (pkd2) encoding polycystin-2 (PC2) are associated with autosomal dominant polycystic kidney disease (ADPKD), the most common inherited nephropathy. PC2 has been associated with impaired Ca2+ handling in cardiomyocytes and indirect evidence suggests that this protein may be involved in autophagic control. Here, we investigated the role for PC2 as an essential regulator of Ca2+ homeostasis and autophagy. METHODS AND RESULTS: Activation of autophagic flux triggered by mTOR inhibition either pharmacologically (rapamycin) or by means of nutrient depletion was suppressed in cells depleted of PC2. Moreover, cardiomyocyte-specific PC2 knockout mice (αMhc-cre;Pkd2F/F mice) manifested impaired autophagic flux in the setting of nutrient deprivation. Stress-induced autophagy was blunted by intracellular Ca2+ chelation using BAPTA-AM, whereas removal of extracellular Ca2+ had no effect, pointing to a role of intracellular Ca2+ homeostasis in stress-induced cardiomyocyte autophagy. To determine the link between stress-induced autophagy and PC2-induced Ca2+ mobilization, we over-expressed either wild-type PC2 (WT) or a Ca2+-channel deficient PC2 mutant (PC2-D509V). PC2 over-expression increased autophagic flux, whereas PC2-D509V expression did not. Importantly, autophagy induction triggered by PC2 over-expression was attenuated by BAPTA-AM, supporting a model of PC2-dependent control of autophagy through intracellular Ca2+. Furthermore, PC2 ablation was associated with impaired Ca2+ handling in cardiomyocytes marked by partial depletion of sarcoplasmic reticulum Ca2+ stores. Finally, we provide evidence that Ca2+-mediated autophagy elicited by PC2 is a mechanism conserved across multiple cell types. CONCLUSION: Together, this study unveils PC2 as a novel regulator of autophagy acting through control of intracellular Ca2+ homeostasis.
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Autofagia , Miócitos Cardíacos/metabolismo , Canais de Cátion TRPP/metabolismo , Animais , Autofagia/efeitos dos fármacos , Proteínas Relacionadas à Autofagia/genética , Proteínas Relacionadas à Autofagia/metabolismo , Cálcio/metabolismo , Células HeLa , Humanos , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Camundongos Knockout , Miócitos Cardíacos/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Retículo Sarcoplasmático/efeitos dos fármacos , Retículo Sarcoplasmático/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sirolimo/farmacologia , Estresse MecânicoRESUMO
Altering chromatin structure through histone posttranslational modifications has emerged as a key driver of transcriptional responses in cells. Modulation of these transcriptional responses by pharmacological inhibition of class I histone deacetylases (HDACs), a group of chromatin remodeling enzymes, has been successful in blocking the growth of some cancer cell types. These inhibitors also attenuate the pathogenesis of pathological cardiac remodeling by blunting and even reversing pathological hypertrophy. The mechanistic target of rapamycin (mTOR) is a critical sensor and regulator of cell growth that, as part of mTOR complex 1 (mTORC1), drives changes in protein synthesis and metabolism in both pathological and physiological hypertrophy. We demonstrated through pharmacological and genetic methods that inhibition of class I HDACs suppressed pathological cardiac hypertrophy through inhibition of mTOR activity. Mice genetically silenced for HDAC1 and HDAC2 had a reduced hypertrophic response to thoracic aortic constriction (TAC) and showed reduced mTOR activity. We determined that the abundance of tuberous sclerosis complex 2 (TSC2), an mTOR inhibitor, was increased through a transcriptional mechanism in cardiomyocytes when class I HDACs were inhibited. In neonatal rat cardiomyocytes, loss of TSC2 abolished HDAC-dependent inhibition of mTOR activity, and increased expression of TSC2 was sufficient to reduce hypertrophy in response to phenylephrine. These findings point to mTOR and TSC2-dependent control of mTOR as critical components of the mechanism by which HDAC inhibitors blunt pathological cardiac growth. These results also suggest a strategy to modulate mTOR activity and facilitate the translational exploitation of HDAC inhibitors in heart disease.
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Cardiomegalia/metabolismo , Histona Desacetilase 1/metabolismo , Histona Desacetilase 2/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Animais , Animais Recém-Nascidos , Western Blotting , Cardiomegalia/genética , Linhagem Celular , Células Cultivadas , Histona Desacetilase 1/genética , Histona Desacetilase 2/genética , Inibidores de Histona Desacetilases/farmacologia , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Peptídeos Cíclicos/farmacologia , Interferência de RNA , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/genética , Proteína 2 do Complexo Esclerose Tuberosa , Proteínas Supressoras de Tumor/genéticaRESUMO
BACKGROUND: The clinical use of doxorubicin is limited by cardiotoxicity. Histopathological changes include interstitial myocardial fibrosis and the appearance of vacuolated cardiomyocytes. Whereas dysregulation of autophagy in the myocardium has been implicated in a variety of cardiovascular diseases, the role of autophagy in doxorubicin cardiomyopathy remains poorly defined. METHODS AND RESULTS: Most models of doxorubicin cardiotoxicity involve intraperitoneal injection of high-dose drug, which elicits lethargy, anorexia, weight loss, and peritoneal fibrosis, all of which confound the interpretation of autophagy. Given this, we first established a model that provokes modest and progressive cardiotoxicity without constitutional symptoms, reminiscent of the effects seen in patients. We report that doxorubicin blocks cardiomyocyte autophagic flux in vivo and in cardiomyocytes in culture. This block was accompanied by robust accumulation of undegraded autolysosomes. We go on to localize the site of block as a defect in lysosome acidification. To test the functional relevance of doxorubicin-triggered autolysosome accumulation, we studied animals with diminished autophagic activity resulting from haploinsufficiency for Beclin 1. Beclin 1(+/-) mice exposed to doxorubicin were protected in terms of structural and functional changes within the myocardium. Conversely, animals overexpressing Beclin 1 manifested an amplified cardiotoxic response. CONCLUSIONS: Doxorubicin blocks autophagic flux in cardiomyocytes by impairing lysosome acidification and lysosomal function. Reducing autophagy initiation protects against doxorubicin cardiotoxicity.
Assuntos
Autofagia/efeitos dos fármacos , Doxorrubicina/farmacologia , Lisossomos/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Animais , Antibióticos Antineoplásicos , Autofagia/fisiologia , Linhagem Celular , Células Cultivadas , Humanos , Concentração de Íons de Hidrogênio , Lisossomos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
High-fat diets (HFDs) lead to obesity and inflammation in the central nervous system (CNS). Estrogens and estrogen receptor α (ERα) protect premenopausal females from the metabolic complications of inflammation and obesity-related disease. Here, we demonstrate that hypothalamic PGC-1α regulates ERα and inflammation in vivo. HFD significantly increased palmitic acid (PA) and sphingolipids in the CNS of male mice when compared to female mice. PA, in vitro, and HFD, in vivo, reduced PGC-1α and ERα in hypothalamic neurons and astrocytes of male mice and promoted inflammation. PGC-1α depletion with ERα overexpression significantly inhibited PA-induced inflammation, confirming that ERα is a critical determinant of the anti-inflammatory response. Physiologic relevance of ERα-regulated inflammation was demonstrated by reduced myocardial function in male, but not female, mice following chronic HFD exposure. Our findings show that HFD/PA reduces PGC-1α and ERα, promoting inflammation and decrements in myocardial function in a sex-specific way.
Assuntos
Dieta Hiperlipídica/efeitos adversos , Receptor alfa de Estrogênio/metabolismo , Hipotálamo/metabolismo , Fatores de Transcrição/metabolismo , Animais , Astrócitos/metabolismo , Linhagem Celular , Receptor alfa de Estrogênio/genética , Feminino , Hipotálamo/citologia , Hipotálamo/efeitos dos fármacos , Inflamação/etiologia , Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/metabolismo , Ácido Palmítico/efeitos adversos , Ácido Palmítico/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Fatores Sexuais , Esfingolipídeos/metabolismo , Fatores de Transcrição/genética , Disfunção Ventricular/etiologia , Disfunção Ventricular/metabolismoRESUMO
The hexosamine biosynthetic pathway (HBP) generates uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) for glycan synthesis and O-linked GlcNAc (O-GlcNAc) protein modifications. Despite the established role of the HBP in metabolism and multiple diseases, regulation of the HBP remains largely undefined. Here, we show that spliced X-box binding protein 1 (Xbp1s), the most conserved signal transducer of the unfolded protein response (UPR), is a direct transcriptional activator of the HBP. We demonstrate that the UPR triggers HBP activation via Xbp1s-dependent transcription of genes coding for key, rate-limiting enzymes. We further establish that this previously unrecognized UPR-HBP axis is triggered in a variety of stress conditions. Finally, we demonstrate a physiologic role for the UPR-HBP axis by showing that acute stimulation of Xbp1s in heart by ischemia/reperfusion confers robust cardioprotection in part through induction of the HBP. Collectively, these studies reveal that Xbp1s couples the UPR to the HBP to protect cells under stress.
Assuntos
Vias Biossintéticas , Proteínas de Ligação a DNA/metabolismo , Hexosaminas/metabolismo , Fatores de Transcrição/metabolismo , Resposta a Proteínas não Dobradas , Animais , Glutamina-Frutose-6-Fosfato Transaminase (Isomerizante) , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Isquemia Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/metabolismo , Miócitos Cardíacos/metabolismo , Transferases de Grupos Nitrogenados/genética , Fatores de Transcrição de Fator Regulador X , Proteína 1 de Ligação a X-BoxRESUMO
Heart failure is a leading cause of morbidity and mortality worldwide, currently affecting 5 million Americans. A syndrome defined on clinical terms, heart failure is the end result of events occurring in multiple heart diseases, including hypertension, myocardial infarction, genetic mutations and diabetes, and metabolic dysregulation, is a hallmark feature. Mounting evidence from clinical and preclinical studies suggests strongly that fatty acid uptake and oxidation are adversely affected, especially in end-stage heart failure. Moreover, metabolic flexibility, the heart's ability to move freely among diverse energy substrates, is impaired in heart failure. Indeed, impairment of the heart's ability to adapt to its metabolic milieu and associated metabolic derangement are important contributing factors in the heart failure pathogenesis. Elucidation of molecular mechanisms governing metabolic control in heart failure will provide critical insights into disease initiation and progression, raising the prospect of advances with clinical relevance.