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1.
Circulation ; 141(12): 1001-1026, 2020 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-32202936

RESUMO

Heart failure with preserved ejection fraction (HFpEF), a major public health problem that is rising in prevalence, is associated with high morbidity and mortality and is considered to be the greatest unmet need in cardiovascular medicine today because of a general lack of effective treatments. To address this challenging syndrome, the National Heart, Lung, and Blood Institute convened a working group made up of experts in HFpEF and novel research methodologies to discuss research gaps and to prioritize research directions over the next decade. Here, we summarize the discussion of the working group, followed by key recommendations for future research priorities. There was uniform recognition that HFpEF is a highly integrated, multiorgan, systemic disorder requiring a multipronged investigative approach in both humans and animal models to improve understanding of mechanisms and treatment of HFpEF. It was recognized that advances in the understanding of basic mechanisms and the roles of inflammation, macrovascular and microvascular dysfunction, fibrosis, and tissue remodeling are needed and ideally would be obtained from (1) improved animal models, including large animal models, which incorporate the effects of aging and associated comorbid conditions; (2) repositories of deeply phenotyped physiological data and human tissue, made accessible to researchers to enhance collaboration and research advances; and (3) novel research methods that take advantage of computational advances and multiscale modeling for the analysis of complex, high-density data across multiple domains. The working group emphasized the need for interactions among basic, translational, clinical, and epidemiological scientists and across organ systems and cell types, leveraging different areas or research focus, and between research centers. A network of collaborative centers to accelerate basic, translational, and clinical research of pathobiological mechanisms and treatment strategies in HFpEF was discussed as an example of a strategy to advance research progress. This resource would facilitate comprehensive, deep phenotyping of a multicenter HFpEF patient cohort with standardized protocols and a robust biorepository. The research priorities outlined in this document are meant to stimulate scientific advances in HFpEF by providing a road map for future collaborative investigations among a diverse group of scientists across multiple domains.

2.
Circulation ; 141(1): 21-33, 2020 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-31779467

RESUMO

BACKGROUND: Cardiac dysfunction and cardiovascular events are prevalent among patients with chronic kidney disease without overt obstructive coronary artery disease, but the mechanisms remain poorly understood. Coronary microvascular dysfunction has been proposed as a link between abnormal renal function and impairment of cardiac function and cardiovascular events. We aimed to investigate the relations between chronic kidney disease, coronary microvascular dysfunction, cardiac dysfunction, and adverse cardiovascular outcomes. METHODS: Patients undergoing cardiac stress positron emission tomography, echocardiogram, and renal function ascertainment at Brigham and Women's Hospital were studied longitudinally. Patients free of overt coronary (summed stress score <3 and without a history of ischemic heart disease), valvular, and end-organ disease were followed up for the adverse composite outcome of death or hospitalization for myocardial infarction or heart failure. Coronary flow reserve (CFR) was determined from positron emission tomography. Echocardiograms were used to measure cardiac mechanics: diastolic (lateral and septal E/e') and systolic (global longitudinal, radial, and circumferential strain). Image analyses and event adjudication were blinded. The associations between estimated glomerular filtration rate (eGFR), CFR, diastolic and systolic indices, and adverse cardiovascular outcomes were assessed in adjusted models and mediation analyses. RESULTS: Of the 352 patients (median age, 65 years; 63% female; 22% black) studied, 35% had an eGFR <60 mL·min-1·1.73 m-2, a median left ventricular ejection fraction of 62%, and a median CFR of 1.8. eGFR and CFR were associated with diastolic and systolic indices, as well as future cardiovascular events (all P<0.05). In multivariable models, CFR, but not eGFR, was independently associated with cardiac mechanics and cardiovascular events. The associations between eGFR, cardiac mechanics, and cardiovascular events were partly mediated via CFR. CONCLUSIONS: Coronary microvascular dysfunction, but not eGFR, was independently associated with abnormal cardiac mechanics and an increased risk of cardiovascular events. Coronary microvascular dysfunction may mediate the effect of chronic kidney disease on abnormal cardiac function and cardiovascular events in those without overt coronary artery disease.

3.
Circ Cardiovasc Qual Outcomes ; 12(9): e005289, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31525078

RESUMO

BACKGROUND: The ECG remains the most widely used diagnostic test for characterization of cardiac structure and electrical activity. We hypothesized that parallel advances in computing power, machine learning algorithms, and availability of large-scale data could substantially expand the clinical inferences derived from the ECG while at the same time preserving interpretability for medical decision-making. METHODS AND RESULTS: We identified 36 186 ECGs from the University of California, San Francisco database that would enable training of models for estimation of cardiac structure or function or detection of disease. We segmented the ECG into standard component waveforms and intervals using a novel combination of convolutional neural networks and hidden Markov models and evaluated this segmentation by comparing resulting electrical intervals against 141 864 measurements produced during the clinical workflow. We then built a patient-level ECG profile, a 725-element feature vector and used this profile to train and interpret machine learning models for examples of cardiac structure (left ventricular mass, left atrial volume, and mitral annulus e-prime) and disease (pulmonary arterial hypertension, hypertrophic cardiomyopathy, cardiac amyloid, and mitral valve prolapse). ECG measurements derived from the convolutional neural network-hidden Markov model segmentation agreed with clinical estimates, with median absolute deviations as a fraction of observed value of 0.6% for heart rate and 4% for QT interval. Models trained using patient-level ECG profiles enabled surprising quantitative estimates of left ventricular mass and mitral annulus e' velocity (median absolute deviation of 16% and 19%, respectively) with good discrimination for left ventricular hypertrophy and diastolic dysfunction as binary traits. Model performance using our approach for disease detection demonstrated areas under the receiver operating characteristic curve of 0.94 for pulmonary arterial hypertension, 0.91 for hypertrophic cardiomyopathy, 0.86 for cardiac amyloid, and 0.77 for mitral valve prolapse. CONCLUSIONS: Modern machine learning methods can extend the 12-lead ECG to quantitative applications well beyond its current uses while preserving the transparency that is so fundamental to clinical care.

5.
Circulation ; 138(16): 1623-1635, 2018 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-30354459

RESUMO

BACKGROUND: Automated cardiac image interpretation has the potential to transform clinical practice in multiple ways, including enabling serial assessment of cardiac function by nonexperts in primary care and rural settings. We hypothesized that advances in computer vision could enable building a fully automated, scalable analysis pipeline for echocardiogram interpretation, including (1) view identification, (2) image segmentation, (3) quantification of structure and function, and (4) disease detection. METHODS: Using 14 035 echocardiograms spanning a 10-year period, we trained and evaluated convolutional neural network models for multiple tasks, including automated identification of 23 viewpoints and segmentation of cardiac chambers across 5 common views. The segmentation output was used to quantify chamber volumes and left ventricular mass, determine ejection fraction, and facilitate automated determination of longitudinal strain through speckle tracking. Results were evaluated through comparison to manual segmentation and measurements from 8666 echocardiograms obtained during the routine clinical workflow. Finally, we developed models to detect 3 diseases: hypertrophic cardiomyopathy, cardiac amyloid, and pulmonary arterial hypertension. RESULTS: Convolutional neural networks accurately identified views (eg, 96% for parasternal long axis), including flagging partially obscured cardiac chambers, and enabled the segmentation of individual cardiac chambers. The resulting cardiac structure measurements agreed with study report values (eg, median absolute deviations of 15% to 17% of observed values for left ventricular mass, left ventricular diastolic volume, and left atrial volume). In terms of function, we computed automated ejection fraction and longitudinal strain measurements (within 2 cohorts), which agreed with commercial software-derived values (for ejection fraction, median absolute deviation=9.7% of observed, N=6407 studies; for strain, median absolute deviation=7.5%, n=419, and 9.0%, n=110) and demonstrated applicability to serial monitoring of patients with breast cancer for trastuzumab cardiotoxicity. Overall, we found automated measurements to be comparable or superior to manual measurements across 11 internal consistency metrics (eg, the correlation of left atrial and ventricular volumes). Finally, we trained convolutional neural networks to detect hypertrophic cardiomyopathy, cardiac amyloidosis, and pulmonary arterial hypertension with C statistics of 0.93, 0.87, and 0.85, respectively. CONCLUSIONS: Our pipeline lays the groundwork for using automated interpretation to support serial patient tracking and scalable analysis of millions of echocardiograms archived within healthcare systems.


Assuntos
Amiloidose/diagnóstico por imagem , Cardiomiopatia Hipertrófica/diagnóstico por imagem , Aprendizado Profundo , Ecocardiografia/métodos , Hipertensão Pulmonar/diagnóstico por imagem , Interpretação de Imagem Assistida por Computador/métodos , Amiloidose/fisiopatologia , Automação , Cardiomiopatia Hipertrófica/fisiopatologia , Humanos , Hipertensão Pulmonar/fisiopatologia , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Volume Sistólico , Função Ventricular Esquerda
7.
Dev Cell ; 46(1): 112-125.e4, 2018 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-29974860

RESUMO

Zebrafish is a powerful model for forward genetics. Reverse genetic approaches are limited by the time required to generate stable mutant lines. We describe a system for gene knockout that consistently produces null phenotypes in G0 zebrafish. Yolk injection of sets of four CRISPR/Cas9 ribonucleoprotein complexes redundantly targeting a single gene recapitulated germline-transmitted knockout phenotypes in >90% of G0 embryos for each of 8 test genes. Early embryonic (6 hpf) and stable adult phenotypes were produced. Simultaneous multi-gene knockout was feasible but associated with toxicity in some cases. To facilitate use, we generated a lookup table of four-guide sets for 21,386 zebrafish genes and validated several. Using this resource, we targeted 50 cardiomyocyte transcriptional regulators and uncovered a role of zbtb16a in cardiac development. This system provides a platform for rapid screening of genes of interest in development, physiology, and disease models in zebrafish.


Assuntos
Técnicas de Inativação de Genes/métodos , Coração/embriologia , Proteína com Dedos de Zinco da Leucemia Promielocítica/genética , Proteínas de Peixe-Zebra/genética , Peixe-Zebra/genética , Animais , Sequência de Bases , Sistemas CRISPR-Cas/genética , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas/genética , Subunidades alfa G12-G13 de Proteínas de Ligação ao GTP/genética , Engenharia Genética/métodos , Morfolinos/genética , Miócitos Cardíacos/citologia , Transcrição Genética/genética , Peixe-Zebra/embriologia
8.
Diabetes ; 67(2): 208-221, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29203511

RESUMO

Disruption of hepatocyte growth hormone (GH) signaling through disruption of Jak2 (JAK2L) leads to fatty liver. Previously, we demonstrated that development of fatty liver depends on adipocyte GH signaling. We sought to determine the individual roles of hepatocyte and adipocyte Jak2 on whole-body and tissue insulin sensitivity and liver metabolism. On chow, JAK2L mice had hepatic steatosis and severe whole-body and hepatic insulin resistance. However, concomitant deletion of Jak2 in hepatocytes and adipocytes (JAK2LA) completely normalized insulin sensitivity while reducing liver lipid content. On high-fat diet, JAK2L mice had hepatic steatosis and insulin resistance despite protection from diet-induced obesity. JAK2LA mice had higher liver lipid content and no protection from obesity but retained exquisite hepatic insulin sensitivity. AKT activity was selectively attenuated in JAK2L adipose tissue, whereas hepatic insulin signaling remained intact despite profound hepatic insulin resistance. Therefore, JAK2 in adipose tissue is epistatic to liver with regard to insulin sensitivity and responsiveness, despite fatty liver and obesity. However, hepatocyte autonomous JAK2 signaling regulates liver lipid deposition under conditions of excess dietary fat. This work demonstrates how various tissues integrate JAK2 signals to regulate insulin/glucose and lipid metabolism.


Assuntos
Tecido Adiposo/enzimologia , Resistência à Insulina , Janus Quinase 2/metabolismo , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/etiologia , Obesidade/metabolismo , Tecido Adiposo/metabolismo , Adiposidade , Animais , Dieta Hiperlipídica/efeitos adversos , Janus Quinase 2/genética , Metabolismo dos Lipídeos , Fígado/enzimologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Obesidade/etiologia , Obesidade/fisiopatologia , Especificidade de Órgãos , Fosfoproteínas/metabolismo , Fosforilação , Processamento de Proteína Pós-Traducional , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Treonina/metabolismo
10.
Cell Stem Cell ; 20(4): 547-557.e7, 2017 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-28388431

RESUMO

Genome-wide association studies (GWAS) have highlighted a large number of genetic variants with potential disease association, but functional analysis remains a challenge. Here we describe an approach to functionally validate identified variants through differentiation of induced pluripotent stem cells (iPSCs) to study cellular pathophysiology. We collected peripheral blood cells from Framingham Heart Study participants and reprogrammed them to iPSCs. We then differentiated 68 iPSC lines into hepatocytes and adipocytes to investigate the effect of the 1p13 rs12740374 variant on cardiometabolic disease phenotypes via transcriptomics and metabolomic signatures. We observed a clear association between rs12740374 and lipid accumulation and gene expression in differentiated hepatocytes, in particular, expression of SORT1, CELSR2, and PSRC1, consistent with previous analyses of this variant using other approaches. Initial investigation of additional SNPs also highlighted correlations with gene expression. These findings suggest that iPSC-based population studies hold promise as tools for the functional validation of GWAS variants.


Assuntos
Diferenciação Celular/genética , Estudo de Associação Genômica Ampla , Células-Tronco Pluripotentes Induzidas/citologia , Doenças Metabólicas/genética , Adipócitos Brancos/citologia , Adipócitos Brancos/metabolismo , Reprogramação Celular/genética , Cromossomos Humanos Par 1/genética , Estudos de Coortes , Regulação para Baixo/genética , Genótipo , Hepatócitos/citologia , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Leucócitos Mononucleares/metabolismo , Metabolismo dos Lipídeos/genética , Metabolômica , Modelos Genéticos , Fenótipo , Locos de Características Quantitativas/genética , Reprodutibilidade dos Testes , Análise de Sequência de RNA , Doadores de Tecidos , Transcriptoma/genética
11.
Stem Cell Reports ; 8(5): 1164-1173, 2017 05 09.
Artigo em Inglês | MEDLINE | ID: mdl-28416283

RESUMO

The striking rise of obesity-related metabolic disorders has focused attention on adipocytes as critical mediators of disease phenotypes. To better understand the role played by excess adipose in metabolic dysfunction it is crucial to decipher the transcriptional underpinnings of the low-grade adipose inflammation characteristic of diseases such as type 2 diabetes. Through employing a comparative transcriptomics approach, we identified IRF1 as differentially regulated between primary and in vitro-derived genetically matched adipocytes. This suggests a role as a mediator of adipocyte inflammatory phenotypes, similar to its function in other tissues. Utilizing adipose-derived mesenchymal progenitors we subsequently demonstrated that expression of IRF1 in adipocytes indeed contributes to upregulation of inflammatory processes, both in vitro and in vivo. This highlights IRF1's relevance to obesity-related inflammation and the resultant metabolic dysregulation.


Assuntos
Adipócitos/metabolismo , Fator Regulador 1 de Interferon/genética , Obesidade/metabolismo , Fenótipo , Adipócitos/citologia , Animais , Células Cultivadas , Feminino , Humanos , Inflamação/genética , Inflamação/metabolismo , Fator Regulador 1 de Interferon/metabolismo , Transplante de Células-Tronco Mesenquimais/efeitos adversos , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Camundongos , Camundongos Nus , Obesidade/genética , Transcriptoma , Regulação para Cima
12.
J Cardiovasc Transl Res ; 10(3): 275-284, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28258421

RESUMO

We sought to evaluate whether unbiased machine learning of dense phenotypic data ("phenomapping") could identify distinct hypertension subgroups that are associated with the myocardial substrate (i.e., abnormal cardiac mechanics) for heart failure with preserved ejection fraction (HFpEF). In the HyperGEN study, a population- and family-based study of hypertension, we studied 1273 hypertensive patients utilizing clinical, laboratory, and conventional echocardiographic phenotyping of the study participants. We used machine learning analysis of 47 continuous phenotypic variables to identify mutually exclusive groups constituting a novel classification of hypertension. The phenomapping analysis classified study participants into 2 distinct groups that differed markedly in clinical characteristics, cardiac structure/function, and indices of cardiac mechanics (e.g., phenogroup #2 had a decreased absolute longitudinal strain [12.8 ± 4.1 vs. 14.6 ± 3.5%] even after adjustment for traditional comorbidities [p < 0.001]). The 2 hypertension phenogroups may represent distinct subtypes that may benefit from targeted therapies for the prevention of HFpEF.


Assuntos
Pressão Sanguínea , Insuficiência Cardíaca/etiologia , Hipertensão/complicações , Aprendizado de Máquina , Volume Sistólico , Adulto , Idoso , Fenômenos Biomecânicos , Análise por Conglomerados , Estudos Transversais , Ecocardiografia Doppler , Feminino , Insuficiência Cardíaca/diagnóstico por imagem , Insuficiência Cardíaca/fisiopatologia , Humanos , Hipertensão/classificação , Hipertensão/diagnóstico por imagem , Hipertensão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Reconhecimento Automatizado de Padrão , Fenótipo , Valor Preditivo dos Testes , Prognóstico , Medição de Risco , Fatores de Risco , Estresse Mecânico , Estados Unidos
13.
JACC Clin Electrophysiol ; 3(3): 276-288, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-29759522

RESUMO

OBJECTIVES: This study sought to investigate for an underlying genetic etiology in cases of apparent idiopathic bundle branch re-entrant ventricular tachycardia (BBRVT). BACKGROUND: BBRVT is a life-threatening arrhythmia occurring secondary to macro-re-entry within the His-Purkinje system. Although classically associated with dilated cardiomyopathy, BBRVT may also occur in the setting of isolated, unexplained conduction system disease. METHODS: Cases of BBRVT with normal biventricular size and function were recruited from 6 North American centers. Enrollment required a clinically documented wide complex tachycardia and BBRVT proven during invasive electrophysiology study. Study participants were screened for mutations within genes associated with cardiac conduction system disease. Pathogenicity of identified mutations was evaluated using in silico phylogenetic and physicochemical analyses and in vitro biophysical studies. RESULTS: Among 6 cases of idiopathic BBRVT, each presented with hemodynamic compromise and 2 suffered cardiac arrests requiring resuscitation. Putative culprit mutations were identified in 3 of 6 cases, including 2 in SCN5A (Ala1905Gly [novel] and c.4719C>T [splice site mutation]) and 1 in LMNA (Leu327Val [novel]). Biophysical analysis of mutant Ala1905Gly Nav1.5 channels in tsA201 cells revealed significantly reduced peak current density and positive shifts in the voltage-dependence of activation, consistent with a loss-of-function. The SCN5A c.4719C>T splice site mutation has previously been reported as disease-causing in 3 cases of Brugada syndrome, whereas the novel LMNA Leu327Val mutation was associated with a classic laminopathy phenotype. Following catheter ablation, BBRVT was noninducible in all cases and none experienced a clinical recurrence during follow-up. CONCLUSIONS: Our investigation into apparent idiopathic BBRVT has identified the first genetic culprits for this life-threatening arrhythmia, providing further insight into its underlying pathophysiology and emphasizing a potential role for genetic testing in this condition. Our findings also highlight BBRVT as a novel genetic etiology of unexplained sudden cardiac death that can be cured with catheter ablation.


Assuntos
Arritmias Cardíacas/complicações , Cardiomiopatia Dilatada/complicações , Morte Súbita Cardíaca/prevenção & controle , Taquicardia Ventricular/genética , Adolescente , Adulto , Arritmias Cardíacas/fisiopatologia , Síndrome de Brugada/genética , Cardiomiopatia Dilatada/fisiopatologia , Ablação por Cateter/efeitos adversos , Morte Súbita Cardíaca/etiologia , Eletrocardiografia , Técnicas Eletrofisiológicas Cardíacas/métodos , Feminino , Humanos , Lamina Tipo A/genética , Masculino , Mutação/genética , Canal de Sódio Disparado por Voltagem NAV1.5/genética , Taquicardia Ventricular/fisiopatologia , Taquicardia Ventricular/terapia , Adulto Jovem
14.
Circ Cardiovasc Genet ; 9(5): 419-425, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27625338

RESUMO

BACKGROUND: Truncating mutations in the giant sarcomeric gene Titin are the most common type of genetic alteration in dilated cardiomyopathy. Detailed studies have amassed a wealth of information about truncating variant position in cases and controls. Nonetheless, considerable confusion exists as to how to interpret the pathogenicity of these variants, hindering our ability to make useful recommendations to patients. METHODS AND RESULTS: Building on our recent discovery of a conserved internal promoter within the Titin gene, we sought to develop an integrative statistical model to explain the observed pattern of Titin truncation variants in patients with dilated cardiomyopathy and population controls. We amassed Titin truncation mutation information from 1714 human dilated cardiomyopathy cases and >69 000 controls and found 3 factors explaining the distribution of Titin mutations: (1) alternative splicing, (2) whether the internal promoter Cronos isoform was disrupted, and (3) whether the distal C terminus was targeted (in keeping with the observation that truncation variants in this region escape nonsense-mediated decay and continue to be incorporated in the sarcomere). A model using these 3 factors had strong predictive performance with an area under the receiver operating characteristic curve of 0.81. Accordingly, individuals with either the most severe form of dilated cardiomyopathy or whose mutations demonstrated clear family segregation experienced the highest risk profile across all 3 components. CONCLUSIONS: We conclude that quantitative models derived from large-scale human genetic and phenotypic data can be applied to help overcome the ever-growing challenges of genetic data interpretation. Results of our approach can be found at http://cvri.ucsf.edu/~deo/TTNtruncationvariant.html.


Assuntos
Processamento Alternativo , Cardiomiopatia Dilatada/genética , Conectina/genética , Mutação , Degradação do RNAm Mediada por Códon sem Sentido , Regiões Promotoras Genéticas , Área Sob a Curva , Cardiomiopatia Dilatada/diagnóstico , Cardiomiopatia Dilatada/metabolismo , Estudos de Casos e Controles , Biologia Computacional , Conectina/metabolismo , Bases de Dados Genéticas , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Modelos Genéticos , Modelos Estatísticos , Fenótipo , Curva ROC , Fatores de Risco
15.
Cell ; 166(4): 841-854, 2016 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-27453471

RESUMO

For placental mammals, the transition from the in utero maternal environment to postnatal life requires the activation of thermogenesis to maintain their core temperature. This is primarily accomplished by induction of uncoupling protein 1 (UCP1) in brown and beige adipocytes, the principal sites for uncoupled respiration. Despite its importance, how placental mammals license their thermogenic adipocytes to participate in postnatal uncoupled respiration is not known. Here, we provide evidence that the "alarmin" IL-33, a nuclear cytokine that activates type 2 immune responses, licenses brown and beige adipocytes for uncoupled respiration. We find that, in absence of IL-33 or ST2, beige and brown adipocytes develop normally but fail to express an appropriately spliced form of Ucp1 mRNA, resulting in absence of UCP1 protein and impairment in uncoupled respiration and thermoregulation. Together, these data suggest that IL-33 and ST2 function as a developmental switch to license thermogenesis during the perinatal period. PAPERCLIP.


Assuntos
Proteína 1 Semelhante a Receptor de Interleucina-1/metabolismo , Interleucina-33/metabolismo , Parto , Termogênese , Adipócitos/metabolismo , Animais , Animais Recém-Nascidos , Respiração Celular , Temperatura Baixa , Feminino , Interleucina-33/genética , Linfócitos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL
18.
Circulation ; 132(20): 1920-30, 2015 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-26572668

RESUMO

Spurred by advances in processing power, memory, storage, and an unprecedented wealth of data, computers are being asked to tackle increasingly complex learning tasks, often with astonishing success. Computers have now mastered a popular variant of poker, learned the laws of physics from experimental data, and become experts in video games - tasks that would have been deemed impossible not too long ago. In parallel, the number of companies centered on applying complex data analysis to varying industries has exploded, and it is thus unsurprising that some analytic companies are turning attention to problems in health care. The purpose of this review is to explore what problems in medicine might benefit from such learning approaches and use examples from the literature to introduce basic concepts in machine learning. It is important to note that seemingly large enough medical data sets and adequate learning algorithms have been available for many decades, and yet, although there are thousands of papers applying machine learning algorithms to medical data, very few have contributed meaningfully to clinical care. This lack of impact stands in stark contrast to the enormous relevance of machine learning to many other industries. Thus, part of my effort will be to identify what obstacles there may be to changing the practice of medicine through statistical learning approaches, and discuss how these might be overcome.


Assuntos
Algoritmos , Aprendizado de Máquina/tendências , Medicina/tendências , Humanos
19.
Elife ; 4: e09406, 2015 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-26473617

RESUMO

Truncating mutations in the giant sarcomeric protein Titin result in dilated cardiomyopathy and skeletal myopathy. The most severely affected dilated cardiomyopathy patients harbor Titin truncations in the C-terminal two-thirds of the protein, suggesting that mutation position might influence disease mechanism. Using CRISPR/Cas9 technology, we generated six zebrafish lines with Titin truncations in the N-terminal and C-terminal regions. Although all exons were constitutive, C-terminal mutations caused severe myopathy whereas N-terminal mutations demonstrated mild phenotypes. Surprisingly, neither mutation type acted as a dominant negative. Instead, we found a conserved internal promoter at the precise position where divergence in disease severity occurs, with the resulting protein product partially rescuing N-terminal truncations. In addition to its clinical implications, our work may shed light on a long-standing mystery regarding the architecture of the sarcomere.


Assuntos
Cardiomiopatia Dilatada/patologia , Conectina/genética , Doenças Musculares/patologia , Regiões Promotoras Genéticas , Deleção de Sequência , Animais , Conectina/metabolismo , Modelos Animais de Doenças , Humanos , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Peixe-Zebra
20.
Circ Res ; 116(5): 797-803, 2015 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-25623957

RESUMO

RATIONALE: Treatment of sinus node disease with regenerative or cell-based therapies will require a detailed understanding of gene regulatory networks in cardiac pacemaker cells (PCs). OBJECTIVE: To characterize the transcriptome of PCs using RNA sequencing and to identify transcriptional networks responsible for PC gene expression. METHODS AND RESULTS: We used laser capture microdissection on a sinus node reporter mouse line to isolate RNA from PCs for RNA sequencing. Differential expression and network analysis identified novel sinoatrial node-enriched genes and predicted that the transcription factor Islet-1 is active in developing PCs. RNA sequencing on sinoatrial node tissue lacking Islet-1 established that Islet-1 is an important transcriptional regulator within the developing sinoatrial node. CONCLUSIONS: (1) The PC transcriptome diverges sharply from other cardiomyocytes; (2) Islet-1 is a positive transcriptional regulator of the PC gene expression program.


Assuntos
Regulação da Expressão Gênica no Desenvolvimento , Proteínas com Homeodomínio LIM/fisiologia , Miócitos Cardíacos/metabolismo , RNA Mensageiro/biossíntese , Nó Sinoatrial/citologia , Fatores de Transcrição/fisiologia , Animais , Feminino , Coração Fetal/citologia , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Genes Reporter , Átrios do Coração/citologia , Átrios do Coração/embriologia , Átrios do Coração/metabolismo , Sequenciamento de Nucleotídeos em Larga Escala , Proteínas com Homeodomínio LIM/deficiência , Proteínas com Homeodomínio LIM/genética , Microdissecção e Captura a Laser , Masculino , Camundongos , Dados de Sequência Molecular , Contração Miocárdica , RNA Mensageiro/genética , RNA Mensageiro/isolamento & purificação , Nó Sinoatrial/embriologia , Nó Sinoatrial/metabolismo , Técnica de Subtração , Fatores de Transcrição/deficiência , Fatores de Transcrição/genética , Transcrição Genética , Transcriptoma
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