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BACKGROUND AND AIMS: Patients with atrial fibrillation (AF) are at increased risks of cardiovascular diseases and mortality, but risks according to age at diagnosis have not been reported. This study investigated age-specific risks of outcomes among patients with AF and the background population. METHODS: This nationwide population-based cohort study included patients with AF and controls without outcomes by the application of exposure density matching on the basis of sex, year of birth, and index date. The absolute risks and hazard rates were stratified by age groups and assessed using competing risk survival analyses and Cox regression models, respectively. The expected differences in residual life years among participants were estimated. RESULTS: The study included 216 579 AF patients from year 2000 to 2020 and 866 316 controls. The mean follow-up time was 7.9 years. Comparing AF patients with matched controls, the hazard ratios among individuals ≤50 years was 8.90 [95% confidence interval (CI), 7.17-11.0] for cardiomyopathy, 8.64 (95% CI, 7.74-9.64) for heart failure, 2.18 (95% CI, 1.89-2.52) for ischaemic stroke, and 2.74 (95% CI, 2.53-2.96) for mortality. The expected average loss of life years among individuals ≤50 years was 9.2 years (95% CI, 9.0-9.3) years. The estimates decreased with older age. CONCLUSIONS: The findings show that earlier diagnosis of AF is associated with a higher hazard ratio of subsequent myocardial disease and shorter life expectancy. Further studies are needed to determine causality and whether AF could be used as a risk marker among particularly younger patients.
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Fibrilação Atrial , Humanos , Fibrilação Atrial/mortalidade , Fibrilação Atrial/epidemiologia , Fibrilação Atrial/complicações , Fibrilação Atrial/diagnóstico , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Adulto , Fatores Etários , Insuficiência Cardíaca/mortalidade , Insuficiência Cardíaca/epidemiologia , Incidência , Fatores de Risco , Idoso de 80 Anos ou mais , Cardiomiopatias/mortalidade , Cardiomiopatias/epidemiologia , Cardiomiopatias/diagnóstico , AVC Isquêmico/epidemiologia , AVC Isquêmico/mortalidade , Estudos de Casos e ControlesRESUMO
AIMS: To search for sequence variants associated with ACEi discontinuation and to test their association with ACEi-associated adverse drug reactions (ADRs). METHODS AND RESULTS: A genome-wide association study (GWAS) on ACEi discontinuation was conducted, including 33 959 ACEi-discontinuers and 44 041 controls. Cases were defined as persons who switched from an ACEi treatment to an angiotensin receptor blocker. Controls were defined as persons who continued ACEi treatment for at least 1 year. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were computed for ACEi discontinuation risk by mixed model regression analysis. Summary statistics from the individual cohorts were meta-analyzed with a fixed-effects model. To test for association with specific ACEi-associated ADRs, any genome-wide significant (P < 5 × 10-8) ACEi discontinuation variants was tested for association with ACEi-associated cough and angioedema. A polygenetic risk score (PRS) based on ACEi discontinuation GWAS data was constructed and tested for association with ACEi-associated cough and angioedema in two population-based samples. In total, seven genetic genome-wide loci were identified, of which six were previously unreported. The strongest association with ACEi discontinuation was at 20q13.3 (NTSR1; OR: 1.21; 95% CI: 1.17-1.24; P = 2.1 × 10-34). Five of seven lead variants were associated with ACEi-associated cough, whereas none were associated with ACEi-associated angioedema. The ACEi discontinuation PRS was associated with ACEi-associated cough in a dose-response manner but not with ACEi-associated angioedema. ACEi discontinuation was genetically correlated with important causes for cough, including gastro-esophageal reflux disease, allergic rhinitis, hay fever, and asthma, which indicates partly shared genetic underpinning between these traits. CONCLUSION: This study showed the advantage of using prescription patterns to discover genetic links with ADRs. In total, seven genetic loci that associated with ACEi discontinuation were identified. There was evidence of a strong association between our ADR phenotype and ACEi-associated cough. Taken together, these findings increase insight into the pathophysiological processes that underlie ACEi-associated ADRs.
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Angioedema , Inibidores da Enzima Conversora de Angiotensina , Humanos , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Tosse/induzido quimicamente , Tosse/genética , Tosse/tratamento farmacológico , Estudo de Associação Genômica Ampla , Angioedema/induzido quimicamente , Loci Gênicos , Fatores de RiscoRESUMO
AIMS: Left atrial (LA) volume and function impose significant impact on cardiovascular pathogenesis if compromised. We aimed at investigating the genetic architecture of LA volume and function using cardiac magnetic resonance imaging data. METHODS AND RESULTS: We used the UK Biobank, which is a large prospective population study with available phenotypic and genetic data. On a subset of 35 658 European individuals, we performed genome-wide association studies on five volumetric and functional LA variables, generated using a machine learning algorithm. In total, we identified 18 novel genetic loci, mapped to genes with known roles in cardiomyopathy (e.g. MYO18B, TTN, DSP, ANKRD1) and arrhythmia (e.g. TTN, CASQ2, MYO18B, C9orf3). We observed high genetic correlation between LA volume and function and stroke, which was most pronounced for LA passive emptying fraction (rg = 0.40, P = 4 × 10-6). To investigate whether the genetic risk of atrial fibrillation (AF) is associated with LA traits that precede overt AF, we produced a polygenetic risk score for AF. We found that polygenetic risk for AF is associated with increased LA volume and decreased LA function in participants without AF [LAmax 0.25 (mL/m2)/standard deviation (SD), 95% confidence interval (CI) (0.15; 0.36), P = 5.13 × 10-6; LAmin 0.21 (mL/m2)/SD, 95% CI (0.15; 0.28), P = 1.86 × 10-10; LA active emptying fraction -0.35%/SD, 95% CI (-0.43; -0.26), P = 3.14 × 10-14]. CONCLUSION: We report on 18 genetic loci associated with LA volume and function and show evidence for several plausible candidate genes important for LA structure.
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Apêndice Atrial , Fibrilação Atrial , Fibrilação Atrial/genética , Função do Átrio Esquerdo , Estudo de Associação Genômica Ampla , Átrios do Coração/diagnóstico por imagem , Humanos , Estudos ProspectivosRESUMO
PURPOSE: We investigated whether Brugada syndrome (BrS)-associated variants identified in the general population have an effect on J-point elevation as well as whether carriers of BrS variants were more prone to experience syncope and malignant ventricular arrhythmia and had increased mortality compared with noncarriers. METHODS: All BrS-associated variants were identified using the Human Gene Mutation Database (HGMD). Individuals were randomly selected from a general population study using whole-exome sequencing data (n = 870) and genotype array data (n = 6,161) and screened for BrS-associated variants. Electrocardiograms (ECG) were analyzed electronically, and data on syncope, ventricular arrhythmias, and mortality were obtained from administrative health-care registries. RESULTS: In HGMD, 382 BrS-associated genetic variants were identified. Of these, 28 variants were identified in the study cohort. None of the carriers presented with type 1 BrS ECG pattern. Mean J-point elevation in V1 and V2 were within normal guideline limits for carriers and noncarriers. There was no difference in syncope susceptibility (carriers 8/624; noncarriers 98/5,562; P = 0.51), ventricular arrhythmia (carriers 4/620; noncarriers 9/5,524; P = 0.24), or overall mortality (hazard ratio 0.93, 95% CI 0.63-1.4). CONCLUSIONS: Our data indicate that a significant number of BrS-associated variants are not the monogenic cause of BrS.Genet Med advance online publication 06 October 2016.
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Arritmias Cardíacas/epidemiologia , Síndrome de Brugada/genética , Síndrome de Brugada/mortalidade , Variação Genética , Coração/fisiopatologia , Síncope/epidemiologia , Adulto , Arritmias Cardíacas/etiologia , Síndrome de Brugada/complicações , Síndrome de Brugada/fisiopatologia , Dinamarca/epidemiologia , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Distribuição Aleatória , Sistema de Registros , Síncope/etiologia , Sequenciamento do Exoma/métodosAssuntos
Fibrilação Atrial , Encéfalo , Fibrilação Atrial/epidemiologia , Fibrilação Atrial/genética , Atrofia , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Causalidade , Estudo de Associação Genômica Ampla , Humanos , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo ÚnicoRESUMO
We showed an association between atrial fibrillation and rare loss-of-function (LOF) variants in the cardiac splicing regulator RBM20 in 2 independent cohorts. In a rat model with loss of RBM20, we demonstrated altered splicing of sarcomere genes (NEXN, TTN, TPM1, MYOM1, and LDB3), and differential expression in key cardiac genes. We identified altered sarcomere and mitochondrial structure on electron microscopy imaging and found compromised mitochondrial function. Finally, we demonstrated that 3 novel LOF variants in RBM20, identified in patients with atrial fibrillation, lead to significantly reduced splicing activity. Our results implicate alternative splicing as a novel proarrhythmic mechanism in the atria.
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Importance: Atrial fibrillation (AF) has a substantial genetic component. The importance of polygenic risk is well established, while the contribution of rare variants to disease risk warrants characterization in large cohorts. Objective: To identify rare predicted loss-of-function (pLOF) variants associated with AF and elucidate their role in risk of AF, cardiomyopathy (CM), and heart failure (HF) in combination with a polygenic risk score (PRS). Design, Setting, and Participants: This was a genetic association and nested case-control study. The impact of rare pLOF variants was evaluated on the risk of incident AF. HF and CM were assessed in cause-specific Cox regressions. End of follow-up was July 1, 2022. Data were analyzed from January to October 2023. The UK Biobank enrolled 502â¯480 individuals aged 40 to 69 years at inclusion in the United Kingdom between March 13, 2006, and October 1, 2010. UK residents of European ancestry were included. Individuals with prior diagnosis of AF were excluded from analyses of incident AF. Exposures: Rare pLOF variants and an AF PRS. Main Outcomes and Measures: Risk of AF and incident HF or CM prior to and subsequent to AF diagnosis. Results: A total of 403â¯990 individuals (218â¯489 [54.1%] female) with a median (IQR) age of 58 (51-63) years were included; 24â¯447 were diagnosed with incident AF over a median (IQR) follow-up period of 13.3 (12.4-14.0) years. Rare pLOF variants in 6 genes (TTN, RPL3L, PKP2, CTNNA3, KDM5B, and C10orf71) were associated with AF. Of these, TTN, RPL3L, PKP2, CTNNA3, and KDM5B replicated in an external cohort. Combined with high PRS, rare pLOF variants conferred an odds ratio of 7.08 (95% CI, 6.03-8.28) for AF. Carriers with high PRS also had a substantial 10-year risk of AF (16% in female individuals and 24% in male individuals older than 60 years). Rare pLOF variants were associated with increased risk of CM both prior to AF (hazard ratio [HR], 3.13; 95% CI, 2.24-4.36) and subsequent to AF (HR, 2.98; 95% CI, 1.89-4.69). Conclusions and Relevance: Rare and common genetic variation were associated with an increased risk of AF. The findings provide insights into the genetic underpinnings of AF and may aid in future genetic risk stratification.
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Fibrilação Atrial , Variação Genética , Humanos , Fibrilação Atrial/genética , Fibrilação Atrial/epidemiologia , Feminino , Masculino , Pessoa de Meia-Idade , Estudos de Casos e Controles , Idoso , Adulto , Predisposição Genética para Doença , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/epidemiologia , Reino Unido/epidemiologia , Cardiomiopatias/genética , Cardiomiopatias/epidemiologia , Mutação com Perda de Função , Fatores de Risco , IncidênciaRESUMO
To date only a fraction of the genetic footprint of thyroid function has been clarified. We report a genome-wide association study meta-analysis of thyroid function in up to 271,040 individuals of European ancestry, including reference range thyrotropin (TSH), free thyroxine (FT4), free and total triiodothyronine (T3), proxies for metabolism (T3/FT4 ratio) as well as dichotomized high and low TSH levels. We revealed 259 independent significant associations for TSH (61% novel), 85 for FT4 (67% novel), and 62 novel signals for the T3 related traits. The loci explained 14.1%, 6.0%, 9.5% and 1.1% of the total variation in TSH, FT4, total T3 and free T3 concentrations, respectively. Genetic correlations indicate that TSH associated loci reflect the thyroid function determined by free T3, whereas the FT4 associations represent the thyroid hormone metabolism. Polygenic risk score and Mendelian randomization analyses showed the effects of genetically determined variation in thyroid function on various clinical outcomes, including cardiovascular risk factors and diseases, autoimmune diseases, and cancer. In conclusion, our results improve the understanding of thyroid hormone physiology and highlight the pleiotropic effects of thyroid function on various diseases.
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Glândula Tireoide , Tiroxina , Humanos , Glândula Tireoide/metabolismo , Tiroxina/metabolismo , Estudo de Associação Genômica Ampla , Tri-Iodotironina/metabolismo , Tireotropina/metabolismoRESUMO
BACKGROUND: Substantial data support a heritable basis for supraventricular tachycardias, but the genetic determinants and molecular mechanisms of these arrhythmias are poorly understood. We sought to identify genetic loci associated with atrioventricular nodal reentrant tachycardia (AVNRT) and atrioventricular accessory pathways or atrioventricular reciprocating tachycardia (AVAPs/AVRT). METHODS: We performed multiancestry meta-analyses of genome-wide association studies to identify genetic loci for AVNRT (4 studies) and AVAP/AVRT (7 studies). We assessed evidence supporting the potential causal effects of candidate genes by analyzing relations between associated variants and cardiac gene expression, performing transcriptome-wide analyses, and examining prior genome-wide association studies. RESULTS: Analyses comprised 2384 AVNRT cases and 106â 489 referents, and 2811 AVAP/AVRT cases and 1,483â 093 referents. We identified 2 significant loci for AVNRT, which implicate NKX2-5 and TTN as disease susceptibility genes. A transcriptome-wide association analysis supported an association between reduced predicted cardiac expression of NKX2-5 and AVNRT. We identified 3 significant loci for AVAP/AVRT, which implicate SCN5A, SCN10A, and TTN/CCDC141. Variant associations at several loci have been previously reported for cardiac phenotypes, including atrial fibrillation, stroke, Brugada syndrome, and electrocardiographic intervals. CONCLUSIONS: Our findings highlight gene regions associated with ion channel function (AVAP/AVRT), as well as cardiac development and the sarcomere (AVAP/AVRT and AVNRT) as important potential effectors of supraventricular tachycardia susceptibility.
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Estudo de Associação Genômica Ampla , Taquicardia Supraventricular , Humanos , Taquicardia Supraventricular/genética , Predisposição Genética para Doença , Taquicardia por Reentrada no Nó Atrioventricular/genética , Polimorfismo de Nucleotídeo Único , Conectina/genética , TranscriptomaRESUMO
The QT interval is an electrocardiographic measure representing the sum of ventricular depolarization and repolarization, estimated by QRS duration and JT interval, respectively. QT interval abnormalities are associated with potentially fatal ventricular arrhythmia. Using genome-wide multi-ancestry analyses (>250,000 individuals) we identify 177, 156 and 121 independent loci for QT, JT and QRS, respectively, including a male-specific X-chromosome locus. Using gene-based rare-variant methods, we identify associations with Mendelian disease genes. Enrichments are observed in established pathways for QT and JT, and previously unreported genes indicated in insulin-receptor signalling and cardiac energy metabolism. In contrast for QRS, connective tissue components and processes for cell growth and extracellular matrix interactions are significantly enriched. We demonstrate polygenic risk score associations with atrial fibrillation, conduction disease and sudden cardiac death. Prioritization of druggable genes highlight potential therapeutic targets for arrhythmia. Together, these results substantially advance our understanding of the genetic architecture of ventricular depolarization and repolarization.
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Arritmias Cardíacas , Eletrocardiografia , Arritmias Cardíacas/genética , Morte Súbita Cardíaca , Eletrocardiografia/métodos , Testes Genéticos , Humanos , MasculinoRESUMO
Atrial fibrillation (AF) is the most common type of arrhythmia. Epidemiological studies have documented a substantial genetic component. More than 160 genes have been associated with AF during the last decades. Some of these were discovered by classical linkage studies while the majority relies on functional studies or genome-wide association studies. In this review, we will evaluate the genetic basis of AF and the role of both common and rare genetic variants in AF. Rare variants in multiple ion-channel genes as well as gap junction and transcription factor genes have been associated with AF. More recently, a growing body of evidence has implicated structural genes with AF. An increased burden of atrial fibrosis in AF patients compared with non-AF patients has also been reported. These findings challenge our traditional understanding of AF being an electrical disease. We will focus on several quantitative landmark papers, which are transforming our understanding of AF by implicating atrial cardiomyopathies in the pathogenesis. This new AF research field may enable better diagnostics and treatment in the future.
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Fibrilação Atrial/etiologia , Estudos de Associação Genética , Predisposição Genética para Doença , Herança Multifatorial , Alelos , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/epidemiologia , Fibrilação Atrial/terapia , Estudos de Associação Genética/métodos , Variação Genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Fenótipo , Polimorfismo de Nucleotídeo ÚnicoRESUMO
BACKGROUND: Angioedema is a rare but potentially life-threatening adverse reaction associated with angiotensin-converting enzyme (ACE) inhibitors. Identification of potential genetic factors related to this adverse event may help identify at-risk patients. OBJECTIVES: The aim of this study was to identify genetic factors associated with ACE inhibitor-associated angioedema. METHODS: A genomewide association study involving patients of European descent, all taking ACE inhibitors, was conducted in a discovery cohort (Copenhagen Hospital Biobank), and associations were confirmed in a replication cohort (Swedegene). Cases were defined as subjects with angioedema events and filled prescriptions for ACE inhibitors ≤180 days before the events. Control subjects were defined as those with continuous treatment with ACE inhibitors without any history of angioedema. Odds ratios (ORs) and 95% confidence intervals (CIs) were computed for angioedema risk using logistic mixed model regression analysis. Summary statistics from the discovery and replication cohorts were analyzed using a fixed-effects meta-analysis model. RESULTS: The discovery cohort consisted of 462 cases and 53,391 ACE inhibitor-treated control subjects. The replication cohort consisted of 142 cases and 1,345 ACE inhibitor-treated control subjects. In the discovery cohort, 1 locus, residing at chromosome 14q32.2, was identified that associated with angioedema at the genomewide significance level of P <5 × 10-8. The lead variant at this locus, rs34485356, is an intergenic variant located 60 kb upstream of BDKRB2 (OR: 1.62; 95% CI: 1.38 to 1.90; P = 4.3 × 10-9). This variant was validated in our replication cohort with a similar direction and effect size (OR: 1.60; 95% CI: 1.13 to 2.25; P = 7.2 × 10-3). We found that carriers of the risk allele had significantly lower systolic (-0.46 mm Hg per T allele; 95% CI: -0.83 to -0.10; P = 0.013) and diastolic (-0.26 mm Hg per T allele; 95% CI: -0.46 to -0.05; P = 0.013) blood pressure. CONCLUSIONS: In this genomewide association study involving individuals treated with ACE inhibitors, we found that common variants located in close proximity to the bradykinin receptor B2 gene were associated with increased risk for ACE inhibitor-related angioedema.
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Angioedema/induzido quimicamente , Angioedema/genética , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Receptor B2 da Bradicinina/genética , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , MasculinoRESUMO
OBJECTIVE: Cardiac MRI is quickly emerging as the gold standard for assessment of mitral regurgitation, most commonly with the indirect method subtracting forward flow in aorta from volumetric segmentation of the left ventricle. We aimed to investigate how aortic flow measurements with increasing distance from the aortic valve affect calculated mitral regurgitations and whether measurements were influenced by breath-hold regimen. METHODS: Free-breathing and breath-hold phase contrast flows were measured in aorta at valve level, sinotubular (ST) junction, mid-ascending aorta and in the pulmonary trunk. Flow measurements were pairwise compared, and subsequently, after exclusion of patients with visible mitral and tricuspid regurgitations for left-sided and right-sided comparisons, respectively, flow-measured stroke volumes were compared with ventricular volumetric segmentations. RESULTS: Thirty-nine participants without arrhythmias or structural abnormalities of the large vessels were included. Stroke volumes measured with free-breathing and breath-hold flow decreased equally with increasing distance to the aortic valves (breath-hold flow: aortic valve 105.6±20.8 mL, ST junction 101.5±20.7 mL, mid-ascending aorta 98.1±21.5 mL). After exclusion of atrioventricular regurgitations, stroke volumes determined by volumetric measurements were higher compared with values determined by flow measurements, corresponding to 'false' atrioventricular regurgitations of 8.0%±5.8% with flow measured at valve level, 11.6%±5.2% at the ST junction and 15.3%±5.0% at the mid-ascending aorta. CONCLUSIONS: Stroke volumes determined by flow decrease throughout the proximal aorta and are systematically lower than volumetrically measured stroke volumes. The indirect method systematically overestimates mitral regurgitations, especially with increasing distance from the aortic valves.
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Imagem Cinética por Ressonância Magnética , Insuficiência da Valva Mitral/diagnóstico por imagem , Valva Mitral/diagnóstico por imagem , Adulto , Suspensão da Respiração , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valva Mitral/fisiopatologia , Insuficiência da Valva Mitral/fisiopatologia , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Índice de Gravidade de Doença , Volume SistólicoRESUMO
The use of cardiovascular magnetic resonance imaging left atrial late gadolinium enhancement (LA LGE) is increasing for fibrosis evaluation though the use is still limited to specialized centres due to complex image acquisition and lack of consensus on image analyses. Analysis of LA LGE with image intensity ratio (IIR) (pixel intensity of atrial wall normalized by blood pool intensity) provides an objective method to obtain quantitative data on atrial fibrosis. A threshold between healthy myocardium and fibrosis of 1.2 has previously been established in 3T scans. The aim of the study was to reaffirm this threshold in 1.5T scans. LA LGE was performed using a 1.5T magnetic resonance scanner on: 11 lone-AF patients, 11 age-matched healthy volunteers (aged 27-44) and 11 elderly patients without known history of AF but varying degrees of comorbidities. Mean values of IIR for all healthy volunteers +2SD were set as upper limit of normality and was reproduced to 1.21 and the original IIR-threshold of 1.20 was maintained. The degree of fibrosis in lone-AF patients [median 9.0% (IQR 3.9-12.0)] was higher than in healthy volunteers [2.8% (1.3-8.3)] and even higher in elderly non-AF [20.1% (10.2-35.8), p = 0.001]. The previously established IIR-threshold of 1.2 was reaffirmed in 1.5T LA LGE scans. Patients with lone AF presented with increased degrees of atrial fibrosis compared to healthy volunteers in the same age-range. Elderly patients with no history of AF showed significantly higher degrees of fibrosis compared to both groups with younger individuals.
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Fibrilação Atrial/diagnóstico por imagem , Função do Átrio Esquerdo , Remodelamento Atrial , Meios de Contraste/administração & dosagem , Átrios do Coração/diagnóstico por imagem , Imagem Cinética por Ressonância Magnética , Compostos Organometálicos/administração & dosagem , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Fibrilação Atrial/fisiopatologia , Estudos de Casos e Controles , Feminino , Fibrose , Átrios do Coração/fisiopatologia , Humanos , Masculino , Valor Preditivo dos TestesRESUMO
INTRODUCTION: Current clinical guidelines for management of diabetic peripheral neuropathy (DPN) emphasize good glycemic control. However, this has limited effect on prevention of DPN in type 2 diabetic (T2D) patients. This study investigates the effect of insulin treatment on development of DPN in a rat model of T2D to assess the underlying causes leading to DPN. METHODS: Twelve-week-old male Sprague-Dawley rats were allocated to a normal chow diet or a 45% kcal high-fat diet. After eight weeks, the high-fat fed animals received a mild dose of streptozotocin to induce hyperglycemia. Four weeks after diabetes induction, the diabetic animals were allocated into three treatment groups receiving either no insulin or insulin-releasing implants in a high or low dose. During the 12-week treatment period, blood glucose and body weight were monitored weekly, whereas Hargreaves' test was performed four, eight, and 12 weeks after treatment initiation. At study termination, several blood parameters, body composition, and neuropathy endpoints were assessed. RESULTS: Insulin treatment lowered blood glucose in a dose-dependent manner. In addition, both doses of insulin lowered lipids and increased body fat percentage. High-dose insulin treatment attenuated small nerve fiber damage assessed by Hargreaves' test and intraepidermal nerve fiber density compared to untreated diabetes and low-dose insulin; however, neuropathy was not completely prevented by tight glycemic control. Linear regression analysis revealed that glycemic status, circulating lipids, and sciatic nerve sorbitol level were all negatively associated with the small nerve fiber damage observed. CONCLUSION: In summary, our data suggest that high-dose insulin treatment attenuates small nerve fiber damage. Furthermore, data also indicate that both poor glycemic control and dyslipidemia are associated with disease progression. Consequently, this rat model of T2D seems to fit well with progression of DPN in humans and could be a relevant preclinical model to use in relation to research investigating treatment opportunities for DPN.
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Diabetes Mellitus Experimental/tratamento farmacológico , Neuropatias Diabéticas/prevenção & controle , Insulina/uso terapêutico , Neuropatia de Pequenas Fibras/prevenção & controle , Animais , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/patologia , Dieta Hiperlipídica , Progressão da Doença , Humanos , Masculino , Fibras Nervosas/efeitos dos fármacos , Fibras Nervosas/fisiologia , Obesidade/complicações , Obesidade/tratamento farmacológico , Obesidade/patologia , Ratos , Ratos Sprague-Dawley , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/fisiologiaRESUMO
Atrial fibrillation (AF) has traditionally been considered an electrical heart disease. However, genetic studies have revealed that the structural architecture of the heart also play a significant role. We evaluated the functional and structural consequences of harboring a titin-truncating variant (TTNtv) in AF patients, using cardiac magnetic resonance (CMR). Seventeen early-onset AF cases carrying a TTNtv, were matched 1:1 with non-AF controls and a replication cohort of early-onset AF cases without TTNtv, and underwent CMR. Cardiac volumes and left atrial late gadolinium enhancement (LA LGE), as a fibrosis proxy, were measured by a blinded operator. Results: AF cases with TTNtv had significantly reduced left ventricular ejection fraction (LVEF) compared with controls (57 ± 4 vs 64 ± 5%, P < 0.001). We obtained similar findings in early-onset AF patients without TTNtv compared with controls (61 ± 4 vs 64 ± 5%, P = 0.02). We furthermore found a statistically significant increase in LA LGE when comparing early-onset AF TTNtv cases with controls. Using state-of-the-art CMR, we found that early-onset AF patients, irrespective of TTNtv carrier status, had reduced LVEF, indicating that early-onset AF might not be as benign as previously thought.
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Fibrilação Atrial/diagnóstico por imagem , Fibrilação Atrial/fisiopatologia , Conectina/genética , Mutação , Adulto , Idade de Início , Fibrilação Atrial/genética , Fibrilação Atrial/patologia , Estudos de Casos e Controles , Meios de Contraste/administração & dosagem , Feminino , Fibrose , Gadolínio/administração & dosagem , Humanos , Imagem Cinética por Ressonância Magnética , Masculino , Interpretação de Imagem Radiográfica Assistida por Computador , Função Ventricular Esquerda , Adulto JovemRESUMO
Atrial fibrillation (AF) is the most common cardiac arrhythmia, and it is associated with an increased risk of heart failure, stroke, dementia, and death. Recently, titin-truncating variants (TTNtv), which are predominantly associated with dilated cardiomyopathy (DCM), were associated with early-onset AF. Furthermore, genome-wide association studies (GWAS) associated AF with other structural genes. In this study, we investigated whether early-onset AF was associated with loss-of-function variants in DCM-associated genes encoding cytoskeletal proteins. Using targeted sequencing, we examined a cohort of 527 Scandinavian individuals with early-onset AF and a control group of individuals free of AF (n = 383). The patients had onset of AF before 50 years of age, normal echocardiogram, and no other cardiovascular disease at onset of AF. We identified six individuals with rare loss-of-function variants in three different genes (dystrophin (DMD), actin-associated LIM protein (PDLIM3), and fukutin (FKTN)), of which two variants were novel. Loss-of-function variants in cytoskeletal genes were significantly associated with early-onset AF when patients were compared with controls (p = 0.044). Using publicly available GWAS data, we performed genetic correlation analyses between AF and 13 other traits, e.g., showing genetic correlation between AF and non-ischemic cardiomyopathy (p = 0.0003). Our data suggest that rare loss-of-function variants in cytoskeletal genes previously associated with DCM may have a role in early-onset AF, perhaps through the development of an atrial cardiomyopathy.
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AIMS: Syncope is a common condition associated with frequent hospitalization or visits to the emergency department. Family aggregation and twin studies have shown that syncope has a heritable component. We investigated whether common genetic variants predispose to syncope and collapse. METHODS AND RESULTS: We used genome-wide association data on syncope on 408 961 individuals with European ancestry from the UK Biobank study. In a replication study, we used the Integrative Psychiatric Research Consortium (iPSYCH) cohort (n = 86 189), to investigate the risk of incident syncope stratified by genotype carrier status. We report on a genome-wide significant locus located on chromosome 2q32.1 [odds ratio = 1.13, 95% confidence interval (CI) 1.10-1.17, P = 5.8 × 10-15], with lead single nucleotide polymorphism rs12465214 in proximity to the gene zinc finger protein 804a (ZNF804A). This association was also shown in the iPSYCH cohort, where homozygous carriers of the C allele conferred an increased hazard ratio (1.30, 95% CI 1.15-1.46, P = 1.68 × 10-5) of incident syncope. Quantitative polymerase chain reaction analysis showed ZNF804A to be expressed most abundantly in brain tissue. CONCLUSION: We identified a genome-wide significant locus (rs12465214) associated with syncope and collapse. The association was replicated in an independent cohort. This is the first genome-wide association study to associate a locus with syncope and collapse.