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DddA-derived cytosine base editors (DdCBEs) and transcription activator-like effector (TALE)-linked deaminases (TALEDs) catalyze targeted base editing of mitochondrial DNA (mtDNA) in eukaryotic cells, a method useful for modeling of mitochondrial genetic disorders and developing novel therapeutic modalities. Here, we report that A-to-G-editing TALEDs but not C-to-T-editing DdCBEs induce tens of thousands of transcriptome-wide off-target edits in human cells. To avoid these unwanted RNA edits, we engineered the substrate-binding site in TadA8e, the deoxy-adenine deaminase in TALEDs, and created TALED variants with fine-tuned deaminase activity. Our engineered TALED variants not only reduced RNA off-target edits by >99% but also minimized off-target mtDNA mutations and bystander edits at a target site. Unlike wild-type versions, our TALED variants were not cytotoxic and did not cause developmental arrest of mouse embryos. As a result, we obtained mice with pathogenic mtDNA mutations, associated with Leigh syndrome, which showed reduced heart rates.
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DNA Mitocondrial , Efetores Semelhantes a Ativadores de Transcrição , Animais , Humanos , Camundongos , Adenina , Citosina , DNA Mitocondrial/genética , Edição de Genes , RNA , Efetores Semelhantes a Ativadores de Transcrição/metabolismo , Engenharia de ProteínasRESUMO
Mitochondrial DNA (mtDNA) editing paves the way for disease modeling of mitochondrial genetic disorders in cell lines and animals and also for the treatment of these diseases in the future. Bacterial cytidine deaminase DddA-derived cytosine base editors (DdCBEs) enabling mtDNA editing, however, are largely limited to C-to-T conversions in the 5'-TC context (e.g., TC-to-TT conversions), suitable for generating merely 1/8 of all possible transition (purine-to-purine and pyrimidine-to-pyrimidine) mutations. Here, we present transcription-activator-like effector (TALE)-linked deaminases (TALEDs), composed of custom-designed TALE DNA-binding arrays, a catalytically impaired, full-length DddA variant or split DddA originated from Burkholderia cenocepacia, and an engineered deoxyadenosine deaminase derived from the E. coli TadA protein, which induce targeted A-to-G editing in human mitochondria. Custom-designed TALEDs were highly efficient in human cells, catalyzing A-to-G conversions at a total of 17 target sites in various mitochondrial genes with editing frequencies of up to 49%.
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DNA Mitocondrial , Doenças Mitocondriais , Animais , Sistemas CRISPR-Cas , Citosina/metabolismo , DNA Mitocondrial/genética , Escherichia coli/genética , Escherichia coli/metabolismo , Edição de Genes , Humanos , Mitocôndrias/genética , Mitocôndrias/metabolismo , Doenças Mitocondriais/genética , PurinasRESUMO
BACKGROUND: Continuous automatic optimisation of cardiac resynchronisation therapy (CRT), stimulating only the left ventricle to fuse with intrinsic right bundle conduction (synchronised left ventricular stimulation), might offer better outcomes than conventional CRT in patients with heart failure, left bundle branch block, and normal atrioventricular conduction. This study aimed to compare clinical outcomes of adaptive CRT versus conventional CRT in patients with heart failure with intact atrioventricular conduction and left bundle branch block. METHODS: This global, prospective, randomised controlled trial was done in 227 hospitals in 27 countries across Asia, Australia, Europe, and North America. Eligible patients were aged 18 years or older with class 2-4 heart failure, an ejection fraction of 35% or less, left bundle branch block with QRS duration of 140 ms or more (male patients) or 130 ms or more (female patients), and a baseline PR interval 200 ms or less. Patients were randomly assigned (1:1) via block permutation to adaptive CRT (an algorithm providing synchronised left ventricular stimulation) or conventional biventricular CRT using a device programmer. All patients received device programming but were masked until procedures were completed. Site staff were not masked to group assignment. The primary outcome was a composite of all-cause death or intervention for heart failure decompensation and was assessed in the intention-to-treat population. Safety events were collected and reported in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT02205359, and is closed to accrual. FINDINGS: Between Aug 5, 2014, and Jan 31, 2019, of 3797 patients enrolled, 3617 (95·3%) were randomly assigned (1810 to adaptive CRT and 1807 to conventional CRT). The futility boundary was crossed at the third interim analysis on June 23, 2022, when the decision was made to stop the trial early. 1568 (43·4%) of 3617 patients were female and 2049 (56·6%) were male. Median follow-up was 59·0 months (IQR 45-72). A primary outcome event occurred in 430 of 1810 patients (Kaplan-Meier occurrence rate 23·5% [95% CI 21·3-25·5] at 60 months) in the adaptive CRT group and in 470 of 1807 patients (25·7% [23·5-27·8] at 60 months) in the conventional CRT group (hazard ratio 0·89, 95% CI 0·78-1·01; p=0·077). System-related adverse events were reported in 452 (25·0%) of 1810 patients in the adaptive CRT group and 440 (24·3%) of 1807 patients in the conventional CRT group. INTERPRETATION: Compared with conventional CRT, adaptive CRT did not significantly reduce the incidence of all-cause death or intervention for heart failure decompensation in the included population of patients with heart failure, left bundle branch block, and intact AV conduction. Death and heart failure decompensation rates were low with both CRT therapies, suggesting a greater response to CRT occurred in this population than in patients in previous trials. FUNDING: Medtronic.
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Terapia de Ressincronização Cardíaca , Insuficiência Cardíaca , Humanos , Masculino , Feminino , Bloqueio de Ramo/etiologia , Bloqueio de Ramo/terapia , Estudos Prospectivos , Resultado do Tratamento , Terapia de Ressincronização Cardíaca/efeitos adversos , Terapia de Ressincronização Cardíaca/métodos , Volume Sistólico , EletrocardiografiaRESUMO
OBJECTIVES: To assess the association between the use of adaptive pacing on clinical and economic outcomes of cardiac resynchronization therapy (CRT) recipients in a real-world analysis. BACKGROUND: The adaptivCRT (aCRT) algorithm was shown in prior subgroup analyses of prospective trials to achieve clinical benefits, but a large prospective trial showed nonsignificant changes in the endpoint of mortality or hospitalizations due to heart failure. METHODS: CRT-implanted patients from the Optum Clinformatics database with ≥ 90 days of follow-up were included. Remote monitoring data were used to classify patients based on CRT setting-adaptive biventricular and left ventricular pacing (aCRT) vs standard biventricular pacing (Standard CRT). Inverse probability of treatment weighting was used to adjust for baseline differences between groups. Mortality, 30-day readmissions, health care use, and payer and patients' costs were evaluated post-implantation. RESULTS: This study included 2412 aCRT and 1638 Standard CRT patients (mean follow-up: 2.4 ± 1.4 years), with balanced baseline characteristics after adjustment. The aCRT group was associated with lower all-cause mortality rates (adjusted hazard ratioâ¯=â¯0.88 [95% confidence interval (CI):0.80, 0.96]), fewer all-cause 30-day readmissions (adjusted incidence rate ratioâ¯=â¯0.87 [CI:0.81, 0.94]), and fewer all-cause and HF-related inpatient, outpatient and emergency department visits. The aCRT cohort was also associated with lower all-cause outpatient payer-paid amounts and lower all-cause and HF-related inpatient and emergency department patient-paid amounts. CONCLUSIONS: In this retrospective analysis of a large real-world cohort, the use of an adaptive CRT algorithm was associated with lower mortality rates, reduced health care resource use and lower payer and patient costs.
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INTRODUCTION: Atrioventricular nodal reentrant tachycardia (AVNRT) is the most common supraventricular tachycardia referred for ablation. Periprocedural conduction system damage was a primary concern during AVNRT ablation. This study aimed to assess the incidence of permanent atrioventricular (AV) block and the success rate associated with different types of catheters in slow pathway ablation. METHOD: A literature search was performed to identify studies that compared various techniques, including types of radiofrequency ablation (irrigated and nonirrigated) and different sizes of catheter tip cryoablation (4, 6, and 8-mm), in terms of their outcomes related to permanent atrioventricular block and success rate. To assess and rank the treatments for the different outcomes, a random-effects model of network meta-analysis, along with p-scores, was employed. RESULTS: A total of 27 studies with 5110 patients were included in the analysis. Overall success rates ranged from 89.78% to 100%. Point estimation showed 4-mm cryoablation exhibited an odds ratio of 0.649 (95%CI: 0.202-2.087) when compared to nonirrigated RFA. Similarly, 6-mm cryoablation had an odds ratio of 0.944 (95%CI: 0.307-2.905), 8-mm cryoablation had an odds ratio of 0.848 (95%CI: 0.089-8.107), and irrigated RFA had an odds ratio of 0.424 (95%CI: 0.058-3.121) compared to nonirrigated RFA. CONCLUSION: Our study found no significant difference in the incidence of permanent AV block between the types of catheters. The success rates were consistently high across all groups. These findings emphasize the potential of both RF ablation (irrigated and nonirrigated catheter) and cryoablation as viable options for the treatment of AVNRT, with similar safety and efficacy profile.
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Criocirurgia , Taquicardia por Reentrada no Nó Atrioventricular , Criocirurgia/métodos , Humanos , Taquicardia por Reentrada no Nó Atrioventricular/cirurgia , Ablação por Radiofrequência , Metanálise em Rede , Resultado do Tratamento , Bloqueio Atrioventricular , Ablação por Cateter/métodos , Desenho de EquipamentoRESUMO
OBJECTIVE: COVID-19 has been associated with myocardial involvement in collegiate athletes. The first report from the Big Ten COVID-19 Cardiac Registry (Registry) was an ecological study that reported myocarditis in 37 of 1597 athletes (2.3%) based on local clinical diagnosis. Our objective was to assess the relationship between athlete and clinical characteristics and myocardial involvement. DESIGN: Cross-sectional study. SETTING: We analyzed data from 1218 COVID-19 positive Big Ten collegiate athletes who provided informed consent to participate in the Registry. PARTICIPANTS: 1218 athletes with a COVID-19-positive PCR test before June 1, 2021. ASSESSMENT OF INDEPENDENT VARIABLES: Demographic and clinical characteristics of athletes were obtained from the medical record. MAIN OUTCOME MEASURES: Myocardial involvement was diagnosed based on local clinical, cardiac magnetic resonance (CMR), electrocardiography, troponin assay, and echocardiography. We assessed the association of clinical factors with myocardial involvement using logistic regression and estimated the area under the receiver operating characteristic (ROC) curve. RESULTS: 25 of 1218 (2.0%) athletes met criteria for myocardial involvement. The logistic regression model used to predict myocardial involvement contained indicator variables for chest pain, new exercise intolerance, abnormal echocardiogram (echo), and abnormal troponin. The area under the ROC curve for these indicators was 0.714. The presence of any of these 4 factors in a collegiate athlete who tested positive for COVID-19 would capture 55.6% of cases. Among noncases without missing data, 86.9% would not be flagged for possible myocardial involvement. CONCLUSION: Myocardial involvement was infrequent. We predicted case status with good specificity but deficient sensitivity. A diagnostic approach for myocardial involvement based exclusively on symptoms would be less sensitive than one based on symptoms, echo, and troponin level evaluations. Abnormality of any of these evaluations would be an indication for CMR.
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BACKGROUND: Placement of an interatrial shunt device reduces pulmonary capillary wedge pressure during exercise in patients with heart failure and preserved or mildly reduced ejection fraction. We aimed to investigate whether an interatrial shunt can reduce heart failure events or improve health status in these patients. METHODS: In this randomised, international, blinded, sham-controlled trial performed at 89 health-care centres, we included patients (aged ≥40 years) with symptomatic heart failure, an ejection fraction of at least 40%, and pulmonary capillary wedge pressure during exercise of at least 25 mm Hg while exceeding right atrial pressure by at least 5 mm Hg. Patients were randomly assigned (1:1) to receive either a shunt device or sham procedure. Patients and outcome assessors were masked to randomisation. The primary endpoint was a hierarchical composite of cardiovascular death or non-fatal ischemic stroke at 12 months, rate of total heart failure events up to 24 months, and change in Kansas City Cardiomyopathy Questionnaire overall summary score at 12 months. Pre-specified subgroup analyses were conducted for the heart failure event endpoint. Analysis of the primary endpoint, all other efficacy endpoints, and safety endpoints was conducted in the modified intention-to-treat population, defined as all patients randomly allocated to receive treatment, excluding those found to be ineligible after randomisation and therefore not treated. This study is registered with ClinicalTrials.gov, NCT03088033. FINDINGS: Between May 25, 2017, and July 24, 2020, 1072 participants were enrolled, of whom 626 were randomly assigned to either the atrial shunt device (n=314) or sham procedure (n=312). There were no differences between groups in the primary composite endpoint (win ratio 1·0 [95% CI 0·8-1·2]; p=0·85) or in the individual components of the primary endpoint. The prespecified subgroups demonstrating a differential effect of atrial shunt device treatment on heart failure events were pulmonary artery systolic pressure at 20W of exercise (pinteraction=0·002 [>70 mm Hg associated with worse outcomes]), right atrial volume index (pinteraction=0·012 [≥29·7 mL/m2, worse outcomes]), and sex (pinteraction=0·02 [men, worse outcomes]). There were no differences in the composite safety endpoint between the two groups (n=116 [38%] for shunt device vs n=97 [31%] for sham procedure; p=0·11). INTERPRETATION: Placement of an atrial shunt device did not reduce the total rate of heart failure events or improve health status in the overall population of patients with heart failure and ejection fraction of greater than or equal to 40%. FUNDING: Corvia Medical.
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Cateterismo Cardíaco , Insuficiência Cardíaca , Adulto , Cateterismo Cardíaco/instrumentação , Flavinas , Átrios do Coração/cirurgia , Insuficiência Cardíaca/fisiopatologia , Humanos , Luciferases , Masculino , Volume SistólicoRESUMO
INTRODUCTION: Transseptal puncture (TSP) is routinely performed for left atrial ablation procedures. The use of a three-dimensional (3D) mapping system or intracardiac echocardiography (ICE) is useful in localizing the fossa ovalis and reducing fluoroscopy use. We aimed to compare the safety and efficacy between 3D mapping system-guided TSP and ICE-guided TSP techniques. METHODS: We conducted a prospective observational study of patients undergoing TSP for left atrial catheter ablation procedures (mostly atrial fibrillation ablation). Propensity scoring was used to match patients undergoing 3D-guided TSP with patients undergoing ICE-guided TSP. Logistic regression was used to compare the clinical data, procedural data, fluoroscopy time, success rate, and complications between the groups. RESULTS: Sixty-five patients underwent 3D-guided TSP, and 151 propensity score-matched patients underwent ICE-guided TSP. The TSP success rate was 100% in both the 3D-guided and ICE-guided groups. Median needle time was 4.00 min (interquartile range [IQR]: 2.57-5.08) in patients with 3D-guided TSP compared to 4.02 min (IQR: 2.83-6.95) in those with ICE-guided TSP (p = .22). Mean fluoroscopy time was 0.2 min (IQR: 0.1-0.4) in patients with 3D-guided TSP compared to 1.2 min (IQR: 0.7-2.2) in those with ICE-guided TSP (p < .001). There were no complications related to TSP in both group. CONCLUSIONS: Three-dimensional mapping-guided TSP is as safe and effective as ICE-guided TSP without additional cost.
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Fibrilação Atrial , Ablação por Cateter , Humanos , Fibrilação Atrial/diagnóstico por imagem , Fibrilação Atrial/cirurgia , Pontuação de Propensão , Átrios do Coração , Punções , Ablação por Cateter/efeitos adversos , Ablação por Cateter/métodos , Fluoroscopia , Resultado do TratamentoRESUMO
The specificity loop of Matrix Metalloproteinases (MMPs) is known to regulate recognition of their substrates, and the S1'-site surrounded by the loop is a unique place to address the selectivity of ligands toward each MMP. Molecular dynamics (MD) simulations of apo-MMP-13 and its complex forms with various ligands were conducted to identify the role of the specificity loop for the ligand binding to MMP-13. The MD simulations showed the dual role of T247 as a hydrogen bond donor to the ligand, as well as a contributor to the formation of the van der Waal surface area, with T245 and K249 on the S1'-site. The hydrophobic surface area mediated by T247 blocks the access of water molecules to the S1'-site of MMP-13 and stabilizes the ligand in the site. The F252 residue is flexible in order to search for the optimum location in the S1'-site of the apo-MMP-13, but once a ligand binds to the S1'-site, it can form offset π-π or edge-to-π stacking interactions with the ligand. Lastly, H222 and Y244 provide the offset π-π and π-CH(Cß) interactions on each side of the phenyl ring of the ligand, and this sandwiched interaction could be critical for the ligand binding to MMP-13.
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Inibidores de Metaloproteinases de Matriz , Simulação de Dinâmica Molecular , Metaloproteinase 13 da Matriz/metabolismo , Ligantes , Inibidores de Metaloproteinases de Matriz/química , Metaloproteinase 2 da Matriz/metabolismo , Sítios de LigaçãoRESUMO
The interplay of COVID-19 and heart failure is complex and involves direct and indirect effects. Patients with existing heart failure develop more severe COVID-19 symptoms and have worse clinical outcomes. Pandemic-related policies and protocols have negatively affected care for cardiovascular conditions and established hospital protocols, which is particularly important for patients with heart failure.
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COVID-19 , Doenças Cardiovasculares , Insuficiência Cardíaca , Humanos , COVID-19/complicações , COVID-19/epidemiologia , SARS-CoV-2 , Insuficiência Cardíaca/epidemiologia , Insuficiência Cardíaca/terapiaRESUMO
Serological assessment of cardiac troponins (cTn) is the gold standard to assess myocardial injury in clinical practice. A greater magnitude of acutely or chronically elevated cTn concentrations is associated with lower event-free survival in patients and the general population. Exercise training is known to improve cardiovascular function and promote longevity, but exercise can produce an acute rise in cTn concentrations, which may exceed the upper reference limit in a substantial number of individuals. Whether exercise-induced cTn elevations are attributable to a physiological or pathological response and if they are clinically relevant has been debated for decades. Thus far, exercise-induced cTn elevations have been viewed as the only benign form of cTn elevations. However, recent studies report intriguing findings that shed new light on the underlying mechanisms and clinical relevance of exercise-induced cTn elevations. We will review the biochemical characteristics of cTn assays, key factors determining the magnitude of postexercise cTn concentrations, the release kinetics, underlying mechanisms causing and contributing to exercise-induced cTn release, and the clinical relevance of exercise-induced cTn elevations. We will also explain the association with cardiac function, correlates with (subclinical) cardiovascular diseases and exercise-induced cTn elevations predictive value for future cardiovascular events. Last, we will provide recommendations for interpretation of these findings and provide direction for future research in this field.
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Doenças Cardiovasculares/metabolismo , Exercício Físico , Troponina/metabolismo , Humanos , CinéticaRESUMO
Dystrophinopathy is caused by mutations in the dystrophin gene, which lead to progressive muscle degeneration, necrosis, and finally, death. Recently, golden retrievers have been suggested as a useful animal model for studying human dystrophinopathy, but the model has limitations due to difficulty in maintaining the genetic background using conventional breeding. In this study, we successfully generated a dystrophin mutant dog using the CRISPR/Cas9 system and somatic cell nuclear transfer. The dystrophin mutant dog displayed phenotypes such as elevated serum creatine kinase, dystrophin deficiency, skeletal muscle defects, an abnormal electrocardiogram, and avoidance of ambulation. These results indicate that donor cells with CRISPR/Cas9 for a specific gene combined with the somatic cell nuclear transfer technique can efficiently produce a dystrophin mutant dog, which will help in the successful development of gene therapy drugs for dogs and humans.
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Distrofina , Distrofia Muscular de Duchenne , Animais , Sistemas CRISPR-Cas/genética , Cães , Distrofina/genética , Distrofina/metabolismo , Edição de Genes , Músculo Esquelético/metabolismo , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/terapia , Técnicas de Transferência NuclearRESUMO
BACKGROUND: Despite the high rate of sudden death after myocardial infarction among patients with a low ejection fraction, implantable cardioverter-defibrillators are contraindicated until 40 to 90 days after myocardial infarction. Whether a wearable cardioverter-defibrillator would reduce the incidence of sudden death during this high-risk period is unclear. METHODS: We randomly assigned (in a 2:1 ratio) patients with acute myocardial infarction and an ejection fraction of 35% or less to receive a wearable cardioverter-defibrillator plus guideline-directed therapy (the device group) or to receive only guideline-directed therapy (the control group). The primary outcome was the composite of sudden death or death from ventricular tachyarrhythmia at 90 days (arrhythmic death). Secondary outcomes included death from any cause and nonarrhythmic death. RESULTS: Of 2302 participants, 1524 were randomly assigned to the device group and 778 to the control group. Participants in the device group wore the device for a median of 18.0 hours per day (interquartile range, 3.8 to 22.7). Arrhythmic death occurred in 1.6% of the participants in the device group and in 2.4% of those in the control group (relative risk, 0.67; 95% confidence interval [CI], 0.37 to 1.21; P=0.18). Death from any cause occurred in 3.1% of the participants in the device group and in 4.9% of those in the control group (relative risk, 0.64; 95% CI, 0.43 to 0.98; uncorrected P=0.04), and nonarrhythmic death in 1.4% and 2.2%, respectively (relative risk, 0.63; 95% CI, 0.33 to 1.19; uncorrected P=0.15). Of the 48 participants in the device group who died, 12 were wearing the device at the time of death. A total of 20 participants in the device group (1.3%) received an appropriate shock, and 9 (0.6%) received an inappropriate shock. CONCLUSIONS: Among patients with a recent myocardial infarction and an ejection fraction of 35% or less, the wearable cardioverter-defibrillator did not lead to a significantly lower rate of the primary outcome of arrhythmic death than control. (Funded by the National Institutes of Health and Zoll Medical; VEST ClinicalTrials.gov number, NCT01446965 .).
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Morte Súbita Cardíaca/prevenção & controle , Desfibriladores , Infarto do Miocárdio/terapia , Taquicardia Ventricular/prevenção & controle , Dispositivos Eletrônicos Vestíveis , Idoso , Morte Súbita Cardíaca/etiologia , Desfibriladores/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/complicações , Infarto do Miocárdio/mortalidade , Volume Sistólico , Taquicardia Ventricular/mortalidade , Resultado do Tratamento , Dispositivos Eletrônicos Vestíveis/efeitos adversosRESUMO
BACKGROUND: Diabetes mellitus (DM) is a risk factor for atrial fibrillation (AF). The effect of antidiabetic medications on AF or the outcomes of catheter ablation (CA) has not been well described. We sought to determine whether metformin treatment is associated with a lower risk of atrial arrhythmias after CA in patients with DM and AF. METHODS AND RESULTS: A first CA was performed in 271 consecutive patients with DM and AF (age: 65 ± 9 years, women: 34%; and paroxysmal AF: 51%). At a median of 13 months after CA (interquartile range: 6-30), 100/182 patients (55%) treated with metformin remained in sinus rhythm without antiarrhythmic drug therapy, compared with 36/89 patients (40%) not receiving metformin (p = .03). There was a significant association between metformin therapy and freedom from recurrent atrial arrhythmias after CA in multivariable Cox hazards models (hazard ratio [HR]: 0.66; ±95% confidence interval [CI]: 0.44-0.98; p = .04) that adjusted for age, sex, body mass index, AF type (paroxysmal vs. nonparoxysmal), antiarrhythmic medication, obstructive sleep apnea, chronic kidney disease, coronary artery disease, left ventricular ejection fraction, and left atrial diameter. A Cox model that also incorporated other antidiabetic agents and fasting blood glucose demonstrated a similar reduction in the risk of recurrent atrial arrhythmias with metformin treatment (HR: 0.63; ±95% CI: 0.42-0.96; p = .03). CONCLUSIONS: In patients with DM, treatment with metformin appears to be independently associated with a significant reduction in the risk of recurrent atrial arrhythmias after CA for AF. Whether this effect is due to glycemic control or pleiotropic effects on electroanatomical mechanisms of AF remains to be determined.
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Fibrilação Atrial , Ablação por Cateter , Metformina , Idoso , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/tratamento farmacológico , Fibrilação Atrial/cirurgia , Ablação por Cateter/efeitos adversos , Feminino , Humanos , Metformina/efeitos adversos , Pessoa de Meia-Idade , Recidiva , Fatores de Risco , Volume Sistólico , Resultado do Tratamento , Função Ventricular EsquerdaRESUMO
BACKGROUND: An accurate assessment of permanent pacemaker implantation (PPI) risk following transcatheter aortic valve replacement (TAVR) is important for clinical decision making. The aims of this study were to investigate the significance and utility of pre- and post-TAVR ECG data and compare machine learning approaches with traditional logistic regression in predicting pacemaker risk following TAVR. METHODS: Five hundred fifity seven patients in sinus rhythm undergoing TAVR for severe aortic stenosis (AS) were included in the analysis. Baseline demographics, clinical, pre-TAVR ECG, post-TAVR data, post-TAVR ECGs (24 h following TAVR and before PPI), and echocardiographic data were recorded. A Random Forest (RF) algorithm and logistic regression were used to train models for assessing the likelihood of PPI following TAVR. RESULTS: Average age was 80 ± 9 years, with 52% male. PPI after TAVR occurred in 95 patients (17.1%). The optimal cutoff of delta PR (difference between post and pre TAVR PR intervals) to predict PPI was 20 ms with a sensitivity of 0.82, a specificity of 0.66. With regard to delta QRS, the optimal cutoff was 13 ms with a sensitivity of 0.68 and a specificity of 0.59. The RF model that incorporated post-TAVR ECG data (AUC 0.81) more accurately predicted PPI risk compared to the RF model without post-TAVR ECG data (AUC 0.72). Moreover, the RF model performed better than logistic regression model in predicting PPI risk (AUC: 0.81 vs. 0.69). CONCLUSIONS: Machine learning using RF methodology is significantly more powerful than traditional logistic regression in predicting PPI risk following TAVR.
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Estenose da Valva Aórtica/cirurgia , Arritmias Cardíacas/cirurgia , Aprendizado de Máquina , Marca-Passo Artificial , Complicações Pós-Operatórias/cirurgia , Substituição da Valva Aórtica Transcateter , Idoso , Idoso de 80 Anos ou mais , Feminino , Previsões , Humanos , Modelos Logísticos , Masculino , Implantação de Prótese/estatística & dados numéricos , Estudos Retrospectivos , Medição de RiscoRESUMO
CRISPR-Cas12a represents a class 2/type V CRISPR RNA-guided endonuclease, holding promise as a precise genome-editing tool in vitro and in vivo. For efficient delivery of the CRISPR-Cas system into cancer, oncolytic adenovirus (oAd) has been recognized as a promising alternative vehicle to conventional cancer therapy, owing to its cancer specificity; however, to our knowledge, it has not been used for genome editing. In this study, we show that CRISPR-Cas12a mediated by oAd disrupts the oncogenic signaling pathway with excellent cancer specificity. The intratumoral delivery of a single oAd co-expressing a Cas12a and a CRISPR RNA (crRNA) targeting the epidermal growth factor receptor (EGFR) gene (oAd/Cas12a/crEGFR) induces efficient and precise editing of the targeted EGFR gene in a cancer-specific manner, without detectable off-target nuclease activity. Importantly, oAd/Cas12a/crEGFR elicits a potent antitumor effect via robust induction of apoptosis and inhibition of tumor cell proliferation, ultimately leading to complete tumor regression in a subset of treated mice. Collectively, in this study we show precise genomic reprogramming via a single oAd vector-mediated CRISPR-Cas system and the feasibility of such system as an alternative cancer therapy.
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Sistemas CRISPR-Cas , Receptores ErbB/genética , Edição de Genes , Vetores Genéticos/genética , Terapia Viral Oncolítica , Vírus Oncolíticos/genética , RNA Guia de Cinetoplastídeos/genética , Humanos , Neoplasias/genética , Neoplasias/terapiaRESUMO
BACKGROUND: Prehospital electrocardiogram(s) (ECG) can improve early detection of acute coronary syndrome (ST-segment elevation myocardial infarction [STEMI], non-STEMI, and unstable angina) and inform prehospital activation of cardiac catheterization lab; thus, reducing total ischemic time and improving patient outcomes. Less is known, however, about the association of prehospital ECG ischemic findings and long term adverse clinical events. With this in mind, this study was designed to examine the: 1) frequency of prehospital ECGs for acute myocardial ischemia (ST-elevation, ST-depression, and/or T-wave inversion); and, 2) whether any of these specific ECG features are associated with adverse clinical events within 30 day of initial presentation to the emergency department (ED). METHODS: We included consecutive patients ≥ 21 years during a five-year period (2013-2017), who were transported by ambulance to the ED with non-traumatic chest pain and/or anginal equivalent(s) and had a prehospital 12lead ECG. Two cardiologists (LG, EC), blinded to clinical data, interpreted the 12lead ECGs applying current guideline based ischemia criteria. Adverse clinical events, return to ED, and rehospitalization evaluated at 30-days. RESULTS: We identified 3646 patients (mean age, 59.7 years ±15.7; 45% female) with ECGs, of which N = 3587 had data on the three ischemic markers of interest. Of these, 1762 (49.1%) had ECG evidence of ischemia. In adjusted logistic regression models, those with T-wave inversion had a higher odds (OR = 1.59) of new onset heart failure, while ST-elevation was associated with lower odds (OR = 0.69). Patients with ST-depression had higher odds of new onset heart failure and death within 30 days (OR = 1.29, 1.49 respectively), but this association attenuated after controlling for other ECG features. CONCLUSIONS: ST-depression and/or T-wave inversion are independent predictors of new onset heart failure, within 30 days of initial ED presentation. Our study in a large cohort of patients, suggests that using ECG ST-elevation alone may not capture patients with ischemia who may benefit from aggressive anti-ischemic therapies to reduce myocardial damage with resultant heart failure.
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Síndrome Coronariana Aguda , Serviços Médicos de Emergência , Insuficiência Cardíaca , Síndrome Coronariana Aguda/diagnóstico , Ambulâncias , Depressão , Eletrocardiografia , Feminino , Insuficiência Cardíaca/diagnóstico , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: The AdaptivCRT (aCRT) algorithm continuously adjusts cardiac resynchronization therapy (CRT) according to intrinsic atrioventricular conduction, providing synchronized left ventricular pacing in patients with normal PR interval and adaptive BiV pacing in patients with prolonged PR interval. Previous analyses demonstrated an association between aCRT and clinical benefit. We evaluated the incidence of patient mortality and atrial fibrillation (AF) with aCRT compared with standard CRT in a real-world population. METHODS AND RESULTS: Patients enrolled in the Medtronic Personalized CRT Registry and implanted with a CRT from 2013-2018 were divided into aCRT ON or standard CRT groups based upon device-stored data. A Frailty survival model was used to evaluate the potential survival benefit of aCRT, accounting for patient heterogeneity and center variability. Daily AF burden and first device-detected AF episodes of various durations were recorded by the device during follow-up. A total of 1814 CRT patients with no reported long-standing AF history at implant were included. Mean follow-up time was 26.1 ± 16.5 months and 1162 patients (64.1%) had aCRT ON. Patient survival probability at 36 months was 88.3% for aCRT ON and 83.7% for standard CRT (covariate-adjusted hazard ratio [HR] = 0.71, 95% CI: 0.53-0.96, P = .028). Mean AF burden during follow-up was consistently lower in aCRT ON patients compared with standard CRT. At 36 months, the probability of AF was lower in patients with aCRT ON, regardless of which AF definition threshold was applied (6 minutes-30 days, all P < .001). CONCLUSION: Use of the AdaptivCRT algorithm was associated with improved patient survival and lower incidence of AF in a real-world, prospective, nonrandomized registry.
Assuntos
Algoritmos , Fibrilação Atrial/epidemiologia , Dispositivos de Terapia de Ressincronização Cardíaca , Terapia de Ressincronização Cardíaca/efeitos adversos , Insuficiência Cardíaca/terapia , Terapia Assistida por Computador/instrumentação , Idoso , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/mortalidade , Terapia de Ressincronização Cardíaca/mortalidade , Feminino , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/mortalidade , Insuficiência Cardíaca/fisiopatologia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Sistema de Registros , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do TratamentoRESUMO
INTRODUCTION: Brugada syndrome (BrS) is associated with ventricular arrhythmia leading to sudden cardiac death. Risk stratification is challenging, as major arrhythmic events (MAEs) are rare. We assessed the utility of drug challenge testing in BrS by a systematic review and meta-analysis. METHODS AND RESULTS: We comprehensively searched the databases of MEDLINE and EMBASE from inception to May 2019. Included studies compared the incidence of MAE between spontaneous and drug challenge-induced Type 1. Mixed-effects Poisson regression was used to calculate the incidence rate ratio (IRR). Eighteen studies from 2006 to 2018 were included (4099 patients, mean follow-up: 4.5 years). Pooled annual incidences of MAE in spontaneous, drug challenge induced (regardless of symptoms), asymptomatic drug challenge induced, and symptomatic drug challenge-induced Type 1 were 23.8 (95% confidence interval [CI]: 19.8-27.8), 6.5 (95% CI: 3.9-9.1), 2.1 (95% CI: -0.3 to 4.4), and 19.6 (95% CI: 9.9-29.3) per 1000 person-years, respectively. The incidence of MAE between symptomatic drug challenge induced and asymptomatic spontaneous Type 1 was not statistically different (IRR = 1.0; 95% CI: 0.6-1.7). CONCLUSIONS: The incidence of MAE in drug challenge-induced Type 1 in asymptomatic patients is low. The incidence of MAE between symptomatic drug challenge induced and asymptomatic spontaneous Type 1 was similar.
Assuntos
Síndrome de Brugada , Preparações Farmacêuticas , Síndrome de Brugada/diagnóstico , Síndrome de Brugada/epidemiologia , Morte Súbita Cardíaca/epidemiologia , Morte Súbita Cardíaca/prevenção & controle , Eletrocardiografia , Humanos , Medição de RiscoRESUMO
BACKGROUND: Vest Prevention of Early Sudden Death Trial did not demonstrate a significant reduction in arrhythmic death with the wearable cardioverter-defibrillator (WCD), but compliance with the device may have substantially affected the results. ThePletcher influence of WCD compliance on outcomes has not yet been fully evaluated. METHODS: Using linear and pooled logistic models, we performed as-treated analyses omitting person-time in the hospital and adjusted for correlates of WCD compliance. To assess the impact of early stopping of WCD, we performed a per-protocol Kaplan-Meier analysis, censoring after the last day the WCD was worn. Interactions of potential effect modifiers with treatment assignment and WCD compliance on outcomes were investigated. Finally, we used linear models to identify predictors of WCD compliance. RESULTS: A per-protocol analysis demonstrated a significant reduction in total (P < .001) and arrhythmic (P = .001) mortality. Better WCD compliance was independently predicted by cardiac arrest during index myocardial infarction (MI), higher Cr, diabetes, prior heart failure, EF ≤ 25%, Polish enrolling center and number of WCD alarms, while worse compliance was predicted by being divorced, Asian race, higher body mass index, prior percutaneous coronary intervention, or any WCD shock. Neither excluding time in hospital from the as-treated analysis nor adjustment for factors affecting WCD compliance materially changed the results. No variable demonstrated a significant interaction in either the intention-to-treat or as-treated analysis. CONCLUSION: Robust sensitivity analyses of as-treated and per-protocol analyses suggest that the WCD is protective in compliant patients with ejection fraction less than or equal to 35% during the first 3 months post-MI.