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2.
PLoS One ; 12(9): e0184354, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28880943

RESUMO

BACKGROUND: Atrial fibrillation (AF) is a mechanistically heterogeneous disorder, and the ability to identify sub-phenotypes ("endophenotypes") of AF would assist in the delivery of personalized medicine. We used the clinical response to pulmonary vein isolation (PVI) to identify a sub-group of patients with non-PV mediated AF and sought to define the clinical associations. METHODS: Subjects enrolled in the Vanderbilt AF Ablation Registry who underwent a repeat AF ablation due to arrhythmia recurrence were analyzed on the basis of PV reconnection. Subjects who had no PV reconnection were defined as "non-PV mediated AF". A comparison group of subjects were identified who had AF that was treated with PVI-only and experienced no arrhythmia recurrence >12 months. They were considered a group enriched for "PV-mediated AF". Univariate and multivariable binary logistic regression analysis was performed to investigate clinical associations between the PV and non-PV mediated AF groups. RESULTS: Two hundred and twenty nine subjects underwent repeat AF ablation and thirty three (14%) had no PV reconnection. They were compared with 91 subjects identified as having PV-mediated AF. Subjects with non-PV mediated AF were older (64 years [IQR 60,71] vs. 60 [52,67], P = 0.01), more likely to have non-paroxysmal AF (82% [N = 27] vs. 35% [N = 32], P<0.001), and had a larger left atrium (LA) (4.2cm [3.6,4.8] vs. 4.0 [3.3,4.4], P = 0.04). In univariate analysis, age (per decade: OR 1.56 [95% CI: 1.04 to 2.33], P = 0.03), LA size (per cm: OR 1.8 [1.06 to 3.21], P = 0.03) and non-paroxysmal AF (OR 8.3 [3.10 to 22.19], P<0.001) were all significantly associated with non-PV mediated AF. However, in multivariable analysis only non-paroxysmal AF was independently associated with non-PV mediated AF (OR 7.47 [95% CI 2.62 to 21.29], P<0.001), when adjusted for age (per decade: OR 1.25 [0.81 to 1.94], P = 0.31), male gender (OR 0.48 [0.18 to 1.28], P = 0.14), and LA size (per 1cm: 1.24 [0.65 to 2.33], P = 0.52). CONCLUSIONS: Non-paroxysmal AF was the only clinical variable found to be independently associated with non-PV mediated AF. We demonstrated that analysis of AF ablation outcomes data can serve as a tool to successfully identify a sub-phenotype of subjects who have non-PV mediated AF. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov ID # NCT02404415.


Assuntos
Fibrilação Atrial/cirurgia , Veias Pulmonares/cirurgia , Idoso , Fibrilação Atrial/fisiopatologia , Ablação por Cateter , Humanos , Pessoa de Meia-Idade , Análise Multivariada , Veias Pulmonares/fisiopatologia , Análise de Regressão
3.
JAMA Cardiol ; 1(9): 1007-1013, 2016 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-27732699

RESUMO

Importance: Atrial fibrillation (AF) contributes to substantial morbidity, mortality, and health care expenditures. Accurate prediction of incident AF would enhance AF management and potentially improve patient outcomes. Objective: To validate the AF risk prediction model originally developed by the Cohorts for Heart and Aging Research in Genomic Epidemiology-Atrial Fibrillation (CHARGE-AF) investigators using a large repository of electronic medical records (EMRs). Design, Setting, and Participants: In this prediction model study, deidentified EMRs of 33 494 individuals 40 years or older who were white or African American and had no history of AF were reviewed and analyzed. The participants were followed up in the internal medicine outpatient clinics at Vanderbilt University Medical Center for incident AF from December 31, 2005, until December 31, 2010. Adjusting for differences in baseline hazard, the CHARGE-AF Cox proportional hazards model regression coefficients were applied to the EMR cohort. A simple version of the model with no echocardiographic variables was also evaluated. Data were analyzed from October 31, 2013, to January 31, 2014. Main Outcomes and Measures: Incident AF. Predictors in the model included age, race, height, weight, systolic and diastolic blood pressure, treatment for hypertension, smoking status, type 2 diabetes, heart failure, history of myocardial infarction, left ventricular hypertrophy, and PR interval. Results: Among the 33 494 participants, the median age was 57 (interquartile range, 49-67) years; 57% of patients were women, 43% were men, 85.7% were white, and 14.3% were African American. During the mean (SD) follow-up of 4.8 (0.9) years, 2455 individuals (7.3%) developed AF. Both models had poor calibration in the EMR cohort, with underprediction of AF among low-risk individuals and overprediction of AF among high-risk individuals (10th and 90th percentiles for predicted probability of incident AF, 0.005 and 0.179, respectively). The full CHARGE-AF model had a C index of 0.708 (95% CI, 0.699-0.718) in our cohort. The simple model had similar discrimination (C index, 0.709; 95% CI, 0.699-0.718; P = .70 for difference between models). Conclusions and Relevance: Despite reasonable discrimination, the CHARGE-AF models showed poor calibration in this EMR cohort. This study highlights the difficulties of applying a risk model derived from prospective cohort studies to an EMR cohort and suggests that these AF risk prediction models be used with caution in the EMR setting. Future risk models may need to be developed and validated within EMR cohorts.

4.
J Cardiovasc Electrophysiol ; 26(10): 1111-6, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26222980

RESUMO

INTRODUCTION: Cardiac implantable electronic device (CIED) infections are potentially preventable complications associated with high morbidity, mortality, and cost. A recently developed bio-absorbable antibacterial envelope (TYRX™-A) might prevent CIED infections in high-risk subjects. However, data regarding safety and efficacy have not been published. METHODS AND RESULTS: In a single-center retrospective cohort study, we compared the prevalence of CIED infections among subjects with ≥2 risk factors treated with the TYRX™-A envelope (N = 135), the nonabsorbable TYRX™ envelope (N = 353), and controls who did not receive an envelope (N = 636). Infection was ascertained by individual chart review. The mean (95% confidence interval) number of risk factors was 3.08 (2.84-3.32) for TYRX™-A, 3.20 (3.07-3.34) for TYRX™, and 3.09 (2.99-3.20) for controls, P = 0.3. After a minimum 300 days follow-up, the prevalence of CIED infection was 0 (0%) for TYRX™-A, 1 (0.3%) for TYRX™, and 20 (3.1%) for controls (P = 1 for TYRX™-A vs. TYRX™, P = 0.03 for TYRX™-A vs. controls, and P = 0.002 for TYRX™ vs. controls). In a propensity score-matched cohort of 316 recipients of either envelope and 316 controls, the prevalence of infection was 0 (0%) and 9 (2.8%), respectively, P = 0.004. When limited to 122 TYRX™-A recipients and 122 propensity-matched controls, the prevalence of CIED infections was 0 (0%) and 5 (4.1%), respectively, P = 0.024. CONCLUSIONS: Among high-risk subjects, the TYRX™-A bio-absorbable envelope was associated with a very low prevalence of CIED related infections that was comparable to that seen with the nonabsorbable envelope.


Assuntos
Antibacterianos/administração & dosagem , Desfibriladores Implantáveis/estatística & dados numéricos , Implantes de Medicamento/administração & dosagem , Marca-Passo Artificial/estatística & dados numéricos , Infecções Relacionadas à Prótese/epidemiologia , Infecções Relacionadas à Prótese/prevenção & controle , Implantes Absorvíveis/estatística & dados numéricos , Idoso , Causalidade , Estudos de Coortes , Preparações de Ação Retardada/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Infecções Relacionadas à Prótese/diagnóstico , Estudos Retrospectivos , Fatores de Risco , Distribuição por Sexo , Taxa de Sobrevida , Tennessee/epidemiologia , Resultado do Tratamento
5.
Circ Arrhythm Electrophysiol ; 8(1): 25-31, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25567478

RESUMO

BACKGROUND: Postoperative atrial fibrillation (PoAF) is common after coronary artery bypass grafting. We previously showed that atrial fibrillation susceptibility single nucleotide polymorphisms (SNPs) at the chromosome 4q25 locus are associated with PoAF. Here, we tested the hypothesis that a combined clinical and genetic model incorporating atrial fibrillation risk SNPs would be superior to a clinical-only model. METHODS AND RESULTS: We developed and externally validated clinical and clinical/genetic risk models for PoAF. The discovery and validation cohorts included 556 and 1164 patients, respectively. Clinical variables previously associated with PoAF and 13 SNPs at loci associated with atrial fibrillation in genome-wide association studies were considered. PoAF occurred in 30% and 29% of patients in the discovery and validation cohorts, respectively. In the discovery cohort, a logistic regression model with clinical factors had good discrimination, with an area under the receiver operator characteristic curve of 0.76. The addition of 10 SNPs to the clinical model did not improve discrimination (area under receiver operator characteristic curve, 0.78; P=0.14 for difference between the 2 models). In the validation cohort, the clinical model had good discrimination (area under the receiver operator characteristic curve, 0.69) and addition of genetic variables resulted in a marginal improvement in discrimination (area under receiver operator characteristic curve, 0.72; P<0.0001). CONCLUSIONS: We developed and validated a model for the prediction of PoAF containing common clinical variables. Addition of atrial fibrillation susceptibility SNPs did not improve model performance. Tools to accurately predict PoAF are needed to risk stratify patients undergoing coronary artery bypass grafting and identify candidates for prophylactic therapies.


Assuntos
Fibrilação Atrial/genética , Ponte de Artéria Coronária/efeitos adversos , Polimorfismo de Nucleotídeo Único , Idoso , Área Sob a Curva , Fibrilação Atrial/diagnóstico , Análise Discriminante , Feminino , Frequência do Gene , Predisposição Genética para Doença , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Fenótipo , Valor Preditivo dos Testes , Curva ROC , Sistema de Registros , Reprodutibilidade dos Testes , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Resultado do Tratamento , Estados Unidos
6.
Am J Cardiol ; 114(4): 593-600, 2014 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-25015694

RESUMO

For many patients with atrial fibrillation, ventricular rate control with atrioventricular (AV) nodal blockers is considered first-line therapy, although response to treatment is highly variable. Using an extreme phenotype of failure of rate control necessitating AV nodal ablation and pacemaker implantation, we conducted a genome-wide association study (GWAS) to identify genomic modulators of rate control therapy. Cases included 95 patients who failed rate control therapy. Controls (n = 190) achieved adequate rate control therapy with ≤2 AV nodal blockers using a conventional clinical definition. Genotyping was performed on the Illumina 610-Quad platform, and results were imputed to the 1000 Genomes reference haplotypes. A total of 554,041 single-nucleotide polymorphisms (SNPs) met criteria for minor allele frequency (>0.01), call rate (>95%), and quality control, and 6,055,224 SNPs were available after imputation. No SNP reached the canonical threshold for significance for GWAS of p <5 × 10(-8). Sixty-three SNPs with p <10(-5) at 6 genomic loci were genotyped in a validation cohort of 130 cases and 157 controls. These included 6q24.3 (near SAMD5/SASH1, p = 9.36 × 10(-8)), 4q12 (IGFBP7, p = 1.75 × 10(-7)), 6q22.33 (C6orf174, p = 4.86 × 10(-7)), 3p21.31 (CDCP1, p = 1.18 × 10(-6)), 12p12.1 (SOX5, p = 1.62 × 10(-6)), and 7p11 (LANCL2, p = 6.51 × 10(-6)). However, none of these were significant in the replication cohort or in a meta-analysis of both cohorts. In conclusion, we identified several potentially important genomic modulators of rate control therapy in atrial fibrillation, particularly SOX5, which was previously associated with heart rate at rest and PR interval. However, these failed to reach genome-wide significance.


Assuntos
Antiarrítmicos/uso terapêutico , Fibrilação Atrial/genética , DNA/genética , Estudo de Associação Genômica Ampla/métodos , Frequência Cardíaca/fisiologia , Polimorfismo de Nucleotídeo Único , Fatores de Transcrição SOXD/genética , Idoso , Fibrilação Atrial/tratamento farmacológico , Fibrilação Atrial/fisiopatologia , Nó Atrioventricular/efeitos dos fármacos , Nó Atrioventricular/fisiopatologia , Feminino , Seguimentos , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Estudos Retrospectivos , Fatores de Transcrição SOXD/metabolismo , Fatores de Tempo
7.
Glob Cardiol Sci Pract ; 2014(1): 24-36, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25054116

RESUMO

Atrial fibrillation (AF) is a common disorder with a complex and incompletely understood pathophysiology. Genetic approaches to understanding the pathophysiology of AF have led to the identification of several biological pathways important in the pathogenesis of the arrhythmia. These include pathways important for cardiac development, generation and propagation of atrial electrical impulses, and atrial remodeling and fibrosis. While common and rare genetic variants in these pathways are associated with increased susceptibility to AF, they differ substantially among patients with lone versus typical AF. Furthermore, how these pathways converge to a final common clinical phenotype of AF is unclear and might also vary among different patient populations. Here, we review the contemporary knowledge of AF pathogenesis and discuss how derangement in cardiac development, ion channel dysfunction, and promotion of atrial fibrosis may contribute to this common and important clinical disorder.

8.
Am J Cardiol ; 113(2): 309-13, 2014 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-24161141

RESUMO

Single nucleotide polymorphisms (SNPs) at chromosome 4q25 (near PITX2) are strongly associated with atrial fibrillation (AF). We assessed whether a 4q25-tagging SNP (rs2200733) is associated with PR interval duration in patients with lone and typical AF and controls. Patients with lone (n = 169) and typical (n = 269) AF enrolled in the Vanderbilt AF registry and controls (n = 1,403) derived from the Vanderbilt DNA Biobank were studied. Carriage of the rs2200733T allele (CT or TT genotype) was more common in patients with lone (39%) than typical (25%) AF or controls (21%, p <0.01 for both comparisons). In both AF cohorts, we observed an association between genotype and PR interval duration (median PR interval for CC, CT, and TT: 162, 178, and 176 ms, respectively, for lone, p = 0.038 and 166, 180, and 196 ms, respectively, for typical, p = 0.001). After adjustment for covariates, the association between T allele and PR prolongation persisted, with mean effect size of 10.9, 12.8, and 4.4 ms for patients with lone and typical AF and controls, respectively (p <0.05 for each comparison). We found that a common 4q25 AF susceptibility allele (rs2200733) is associated with PR interval prolongation in patients with lone and typical AF and controls with no AF. Given that prolonged PR interval is an established risk factor for AF, this observation, in the context of previously described functional effects of PITX2 deficiency, provides further knowledge about the pathophysiological link of 4q25 variants with AF.


Assuntos
Fibrilação Atrial/genética , Cromossomos Humanos Par 4 , DNA/genética , Eletrocardiografia , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Idoso , Alelos , Fibrilação Atrial/epidemiologia , Fibrilação Atrial/fisiopatologia , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Estudos Prospectivos , Fatores de Risco , Estados Unidos/epidemiologia
9.
J Cardiovasc Electrophysiol ; 25(1): 36-42, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24028661

RESUMO

INTRODUCTION: The FDA has issued class I advisories for Medtronic Sprint Fidelis(®) and St. Jude Medical Riata(TM) ICD lead families. Transvenous Riata(TM) ICD lead extraction is typically considered higher risk than Fidelis(®) extraction, based on longer duration from implant, presence of externalized conductors and lack of silicone backfill in the SVC and RV coils. However, published data comparing procedural outcomes between these leads are limited. METHODS: Records were reviewed for all patients undergoing transvenous extraction of Sprint Fidelis(®) or Riata(TM) ICD leads at the Vanderbilt Heart and Vascular Institute from July 2006 to April 2013 to ascertain indication for extraction, procedural details, complications, and 30-day mortality. RESULTS: There were significant differences between those undergoing extraction of a Sprint Fidelis(®) (n = 145) or Riata(TM) lead (n = 47). In the Riata(TM) group, device-related endocarditis was a more common indication for extraction, the mean duration of implant was longer, and larger excimer laser sheaths were required. Lead malfunction was a more common indication in the Fidelis(®) group. There were no statistically significant differences in median procedure duration, procedural success (97.9% vs 95.7%, P = 0.41), median length of hospital stay (1 day vs 1 day, P = 0.23), procedural complication rate (5.5% vs 10.6%, P = 0.23) or 30-day mortality (2.1% vs 2.1%, P = 0.98). Analyses excluding patients with device infection revealed similar results. CONCLUSION: Despite differences in baseline characteristics, this study indicates that Medtronic Sprint Fidelis(®) and St. Jude Riata(TM) ICD leads have similar procedural outcomes with transvenous lead extraction.


Assuntos
Desfibriladores Implantáveis/efeitos adversos , Remoção de Dispositivo/mortalidade , Remoção de Dispositivo/métodos , Eletrodos Implantados/efeitos adversos , Desfibriladores Implantáveis/microbiologia , Eletrodos Implantados/microbiologia , Endocardite/diagnóstico , Endocardite/mortalidade , Endocardite/cirurgia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mortalidade/tendências , Estudos Retrospectivos , Resultado do Tratamento
10.
Pacing Clin Electrophysiol ; 36(3): 354-61, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23252988

RESUMO

INTRODUCTION: The incidence of cardiac implantable electronic device (CIED) infections has risen rapidly since 2004. A commercially available minocycline and rifampin impregnated antibacterial envelope has been associated with a low CIED infection rate. We performed a retrospective cohort study analyzing CIED infection rates in patients receiving an antibacterial envelope. METHODS: Prospectively applied criteria for use of the antibacterial envelope included ≥2 of the following: diabetes, renal insufficiency, anticoagulation, chronic corticosteroid use, fever or leukocytosis at the time of implantation, prior CIED infection, ≥3 leads (cardiac resynchronization therapy or abandoned leads), pacemaker dependence, or early pocket reentry. CIED infection rate was compared to a cohort of patients with matched risk factors and a CIED implanted prior to use of the antibacterial envelope. RESULTS: A total of 260 antibacterial envelopes were implanted from November 1, 2009 to April 30, 2012. The mean number of CIED infection risk factors was 2.8 ± 1.2. The control cohort (N = 639) was matched for mean number of CIED infection risk factors (2.8 ± 1.2), though individual risk factors differed. After a minimum of 90 days of follow-up, there was one CIED infection among patients who received an antibacterial envelope (0.4%), compared to 19 (3%) in controls (odds ratio [95% confidence interval] 0.13 [0.02-0.95], P = 0.04). This difference persisted after adjustment for covariates (0.09 [0.01-0.73], P = 0.02) and propensity score matching (0.11 [0.01-0.85], P = 0.04). CONCLUSIONS: In patients prospectively identified at high risk for CIED infection, use of a commercially available antibacterial envelope was associated with a marked reduction in CIED infections when compared to a matched control cohort.


Assuntos
Antibacterianos/administração & dosagem , Marca-Passo Artificial/efeitos adversos , Infecções Relacionadas à Prótese/etiologia , Infecções Relacionadas à Prótese/prevenção & controle , Idoso , Feminino , Humanos , Masculino , Análise Multivariada , Estudos Prospectivos , Fatores de Risco
11.
Am Heart J ; 156(6): 1155-1162.e2, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19033013

RESUMO

BACKGROUND: Variants at the 9p21 locus have been associated with coronary heart disease, but their precise disease phenotype and utility for clinical risk assessment are uncertain. METHODS: Consenting patients with early-onset angiographic coronary artery disease (CAD) (n = 1,011) were compared with matched subjects (n = 545) free of angiographic disease and with a random population sample (n = 565). Cases and controls were genotyped for 4 variants, and ORs for angio-CAD were determined. Findings were validated in a separate set of cases and controls (n = 1,452). RESULTS: Alleles were highly correlated (r(2) > or = 0.9), and all predicted angio-CAD compared with both control groups. Genotype at rs2383206 (minor allele frequency 45.9%), the most predictive (P < .0001), was associated with an adjusted odds ratio for angio-CAD of 1.39 (95% CI, 1.05-1.85) for heterozygote and 1.73 (1.26-2.37) for homozygote risk-allele carriers and explained 21% of population attributable risk and was independent of traditional risk factors and myocardial infarction. For the comparison of combined cases versus combined control samples (N = 3,573), CAD was predicted by high-risk allele homozygosity at P = 9 x 10(-8). Despite this, extent of disease was not increased. Applied to patients with intermediate Framingham risk scores, 9p21 genotyping modified risk classification in 24%. CONCLUSIONS: Variants at the 9p21 locus robustly predict angiographic CAD prevalence, independent of standard risk factors, but not CAD extent or myocardial infarction; provide pathophysiological insights; and may be clinically useful in refining coronary heart disease risk classification.


Assuntos
Mapeamento Cromossômico , Cromossomos Humanos Par 9/genética , Angiografia Coronária , Doença da Artéria Coronariana/genética , Variação Genética/genética , Alelos , Comorbidade , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/epidemiologia , Estudos Transversais , Feminino , Frequência do Gene/genética , Triagem de Portadores Genéticos , Genótipo , Haplótipos , Homozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/diagnóstico por imagem , Infarto do Miocárdio/epidemiologia , Infarto do Miocárdio/genética , Razão de Chances , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Medição de Risco
12.
Cardiology ; 109(3): 196-201, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-17726321

RESUMO

BACKGROUND: In patients with acute coronary syndrome (ACS), elevated levels of soluble CD40 ligand (sCD40L) are associated with increased risk of cardiovascular events. We evaluated sCD40L levels and future cardiovascular events in patients not experiencing ACS. METHODS: Serum sCD40L levels were measured in 909 patients undergoing angiography. A three-way matching scheme (age, gender and catheterization time period) identified 303 patients with coronary artery disease (CAD) who experienced a cardiac event within 1 year (CAD/event), 303 patients with CAD free of events (CAD/no event) and 303 patients without CAD and free of events (no CAD). RESULTS: Average age was 64 +/- 11 years; 74% were males. Median (+/- SE) sCD40L levels were higher for no CAD patients (335 +/- 60 pg/ml) compared to CAD (248 +/- 65 pg/ml, p = 0.01) and to CAD/event (233 +/- 63 pg/ml, p < 0.001). There was no significant difference in median sCD40L levels between CAD/no event and CAD/event patients. Higher sCD40L quartiles were associated with a significant decrease in the risk of CAD/event versus no CAD (quartile 4 versus quartile 1: odds ratio = 0.59, p = 0.03). There was a nonsignificant trend towards a decreased risk of CAD as compared to no CAD, and for CAD/event versus CAD. CONCLUSIONS: In non-ACS patients, higher sCD40L levels were associated with a decreased risk of CAD. This novel interaction of sCD40L raises interesting questions for CAD pathogenesis.


Assuntos
Ligante de CD40/sangue , Angiografia Coronária , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/diagnóstico por imagem , Idoso , Análise de Variância , Biomarcadores/sangue , Proteína C-Reativa/metabolismo , Distribuição de Qui-Quadrado , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Fatores de Risco
13.
Am Heart J ; 154(4): 751-8, 2007 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17893005

RESUMO

BACKGROUND: Single nucleotide polymorphisms (SNPs) in matrix metalloproteinase (MMP) genes may be associated with myocardial infarction (MI) and coronary artery disease (CAD), but studies of multiple MMP genes and their tissue inhibitors (TIMPs) are scarce. Furthermore, differentiation of predictive ability by end point (MI vs CAD) has not been addressed. This study evaluated the association with MI of SNPs in genes encoding MMPs 1, 2, 3, and 9 and TIMPs 1, 2, and 3. METHODS: Genotypes of patients (N = 5148) with MI (n = 1693) and angiographically defined CAD (> or = 1 lesion of > or = 70% stenosis, n = 1967) were compared with MI-free (n = 3455) and non-CAD patients (n = 1122), respectively. Because of linkage disequilibrium, MMP-1 and MMP-3 SNPs (chromosome 11) were combined, as were the 2 MMP-9 SNPs. RESULTS: For MI, only MMP-9 group CT/RQ (odds ratio [OR] 1.25, P = .007 vs wild-type CC/RR) had greater MI risk, with TT/QQ having a weak trend (OR 1.43, P = .10). These findings remained (CT/RQ) or were strengthened (TT/QQ) after full adjustment. For CAD, association was found for MMP-1/MMP-3 groups 2G1G/6A6A (OR 1.45, P = .022), 2G1G/6A5A (OR = 1.49, P = .001), 2G1G/5A5A (OR 1.64, P = .003), and 1G1G/5A5A (OR 1.35, P = .035) compared to wild type. CONCLUSIONS: Composite MMP-9 genotypes but not other SNPs were associated with MI, whereas MMP-1/MMP-3 genotypes were CAD-associated. The largest MMP/TIMP gene study to date, this study suggests care in selection and definition of clinical phenotypes. Furthermore, this suggests that the evaluated SNPs only approximately account for intragenic variation in these genes and that comprehensive evaluation of all variations in these genes should better elucidate associations with MI and CAD phenotypes.


Assuntos
Doença das Coronárias/genética , Metaloproteinases da Matriz/genética , Infarto do Miocárdio/genética , Inibidores Teciduais de Metaloproteinases/genética , Idoso , Angiografia Coronária , Doença das Coronárias/diagnóstico por imagem , Doença das Coronárias/fisiopatologia , Angiopatias Diabéticas/genética , Genótipo , Humanos , Masculino , Metaloproteinase 1 da Matriz/genética , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 3 da Matriz/genética , Metaloproteinase 9 da Matriz/genética , Pessoa de Meia-Idade , Infarto do Miocárdio/fisiopatologia , Polimorfismo de Nucleotídeo Único , Inibidor Tecidual de Metaloproteinase-1/genética , Inibidor Tecidual de Metaloproteinase-2/genética , Inibidor Tecidual de Metaloproteinase-3/genética
14.
J Am Coll Cardiol ; 49(20): 2053-60, 2007 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-17512363

RESUMO

OBJECTIVES: The objective of this study was to identify associations of the cholesteryl ester transfer protein (CETP) gene with coronary artery disease (CAD) with tagging (t) single nucleotide polymorphisms (SNPs) chosen to optimally account for intra-genic variation. BACKGROUND: The CETP gene plays a critical role in lipoprotein metabolism, but the common and well-studied TaqIB variant is inconsistently predictive of CAD. METHODS: From a deoxyribonucleic acid bank of 10,020 individuals, nondiabetic nonsmoking patients (n = 4,811) with angiographically defined, clinically significant CAD (> or =70% stenosis) or normal coronaries were genotyped for 11 CETP tSNPs. Myocardial infarction (MI) and lipid levels were evaluated as secondary end points. RESULTS: Analysis of single tSNPs, corrected for multiple comparisons (p < 0.00485), identified allele +1086A to be associated with CAD (p = 0.0034). Suggestive allelic and significant genotypic associations were found for -631AA (odds ratio [OR] = 3.95, p = 0.004 vs. CC) and +2389GA (OR = 1.21, p = 0.003 vs. GG). Haplotype analysis by linkage disequilibrium (LD) group revealed a CAD association for LD group B (p = 0.0025 across T+1086A, C+878T, C+408T) and near significance for LD group A (p = 0.013 across C-631A, MspI, G+2389A). A weak protective trend for TaqIB was eliminated by adjustment for other tSNPs, and haplotype analyses suggested that TaqIB was simply a marker for other tSNPs or haplotypes. No tSNP or haplotype associations with MI were found. CONCLUSIONS: Multiple, less common SNPs and haplotype variants underlie CETP-related CAD risk, for which the common TaqIB variant is simply a poor marker. The occurrence of risk-related variants on separate haplotypes suggests genetic-risk complexity and allelic heterogeneity. (Database Registry of the Intermountain Heart Collaborative Study; http://clinicaltrials.gov/ct/show/NCT00406185?order=1; NCT00406185).


Assuntos
Proteínas de Transferência de Ésteres de Colesterol/genética , Doença da Artéria Coronariana/genética , Polimorfismo de Nucleotídeo Único , Estudos de Casos e Controles , Estudos de Coortes , Angiografia Coronária , Feminino , Genótipo , Haplótipos , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Sistema de Registros
15.
J Thromb Thrombolysis ; 22(3): 191-7, 2006 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17111199

RESUMO

BACKGROUND: Warfarin has a narrow therapeutic range and wide inter-individual dosing requirements that may be related to functional variants of genes affecting warfarin metabolism (i.e., CYP2C9) and activity (i.e., vitamin K epoxide reductase complex subunit 1-VKORC1). We hypothesized that variants in these two genes explain a substantial proportion of variability in stable warfarin dose and could be used as a basis for improved dosing algorithms. METHODS: Consecutive consenting outpatients (n = 213) with stable INR (2-3) for >1 month were enrolled. Buccal DNA was extracted using a Qiagen mini-column and CYP2C9*2 and VKORC1 genotyping performed by the Taqman 3' nuclease assay. Sequencing for CYP2C9*3, genotyping was done using Big Dye v3.1 terminator chemistry Dose by genotype was assessed by linear regression. RESULTS: Weekly warfarin dose averaged 30.8 +/- 13.9 mg/week; average INR was 2.42 +/- 0.72. CYP2C9*2/*3 genotype distribution was: CC/AA (wild-type [WT]) = 71.4%, CT/AA = 18.3%, CC/AC = 9.4%, and CT/AC = 1%; VKORC1 genotypes were CC (WT) = 36.6%, CT = 50.7%, and TT = 12.7%. Warfarin doses (mg/week) varied by genotype: for CYP2C9, 33.3 mg/week for WT (CC/AA), 27.2 mg/week for CT/AA (P = 0.04 vs. WT), 23.0 mg/week for CC/AC (P = 0.003), and 6.0 mg/week for CT/AC (P < 0.001), representing dose reductions of 18-31% for single and 82% for double variant carriers; for VKORC1: 38.4 mg/week for WT (CC), 28.6 mg/week for CT (P < 0.001 vs. WT), 20.95 mg/week for TT (P < 0.001). In multiple linear regression, genotype was the dominant predictor of warfarin dose (P = 2.4 x 10(-15)); weak predictors were age, weight, and sex. Genotype-based modeling explained 33% of dose-variance, compared with 12% for clinical variables alone. CONCLUSION: In this large prospective study of warfarin genetic dose-determinants, carriage of a single or double CYP2C9 variant, reduced warfarin dose 18-72%, and of a VKORC1 variant by 65%. Genotype-based modeling explained almost one-half of dose-variance. A quantitative dosing algorithm incorporating genotypes for 2C9 and VKORC1 could substantially improve initial warfarin dose-selection and reduce related complications.


Assuntos
Anticoagulantes/farmacocinética , Hidrocarboneto de Aril Hidroxilases/genética , Sistema Enzimático do Citocromo P-450/genética , Oxigenases de Função Mista/genética , Farmacogenética , Varfarina/farmacocinética , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticoagulantes/administração & dosagem , Citocromo P-450 CYP2C9 , Relação Dose-Resposta a Droga , Feminino , Humanos , Coeficiente Internacional Normatizado , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Vitamina K Epóxido Redutases , Varfarina/administração & dosagem
16.
Am Heart J ; 152(5): 997-1003, 2006 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17070179

RESUMO

BACKGROUND: Whereas C-reactive protein (CRP) is a nonspecific marker of coronary artery disease (CAD) and cardiovascular (CV) events, Lp-PLA2 may be a nonvariable inflammatory biomarker. We evaluated the independent association of lipoprotein-associated phospholipase A2 (Lp-PLA2) to angiographic CAD and CV events adjusting for standard factors, lipids, and CRP. METHODS: Lipoprotein-associated phospholipase A2 (PLAC test, diaDexus, Inc, San Francisco, CA) and CRP were measured from samples donated by consecutive consenting patients (N = 1493) enrolled in the registry of the Intermountain Heart Collaborative Study. All patients underwent coronary angiography (1996-1998) for CAD determination and were followed for 6.7 +/- 0.5 years (range 5.7-7.9 years) for CV events (death [including all-cause, CAD, and non-CAD CV death], myocardial infarction, and cerebrovascular accident). RESULTS: Lipoprotein-associated phospholipase A2 weakly correlated with lipids (low-density lipoprotein: r = 0.22, P < .001; high-density lipoprotein: r = -0.13, P < .001), but not CRP (r = 0.03, P = .26). Increasing quartile (Q) of Lp-PLA2 predicted greater the presence of CAD (vs Q1) for Q2 (adjusted odds ratio [OR] 1.15, 95% CI 0.78-1.71, P = .48), for Q3 (OR 1.53, 95% CI 1.02-2.31, P = .042), and for Q4 (OR 2.44, 95% CI 1.58-3.79, P < .001), although CRP was also predictive (vs Q1, Q2: OR 1.47, P = .057; Q3: OR 1.93, P = .002; Q4: OR 3.43, P < .001). In Cox regression, Lp-PLA2 predicted CAD death (vs Q1; Q2: adjusted hazard ratio [HR] 1.27, 95% CI 0.58-2.78, P = .55; Q3: HR 2.18, 95% CI 1.04-4.57, P = .04; Q4: HR 1.73, 95% CI 0.84-3.61, P = .14). CONCLUSION: Lipoprotein-associated phospholipase A2 was confirmed to predict the presence of CAD, even among patients undergoing coronary angiography. Uniquely, Lp-PLA2 predicted the risk of CAD death, but not all-cause death, myocardial infarction, or cerebrovascular accident.


Assuntos
Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/mortalidade , Fosfolipases A/sangue , 1-Alquil-2-acetilglicerofosfocolina Esterase , Angiografia Coronária , Doença da Artéria Coronariana/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fosfolipases A2 , Valor Preditivo dos Testes
17.
Ann Hum Genet ; 70(Pt 4): 524-34, 2006 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-16759183

RESUMO

Full characterization of intragenic variation may improve candidate gene associations. This study selected tagging (t) single nucleotide polymorphisms (SNPs) to comprehensively represent genetic variability in the cholesteryl ester transfer protein (CETP) gene. Nineteen SNPs were identified in 50 unrelated individuals in the SNP discovery phase, and 13 intronic SNPs were added from the literature. These 32 SNPs were genotyped in 339 apparently healthy individuals and 190 coronary artery disease (CAD) patients. Using phased haplotypes, linkage disequilibrium (LD) structure was characterized and tSNPs selected using a principal component analysis (PCA) method. In healthy individuals, seven LD groups were identified that accounted for 93.4% of the observed genetic variation. These LD groups highlighted a complex LD structure for CETP, including both recombination and mutation, and eleven tSNPs were selected. Among CAD patients the results were essentially the same. Results from PCA using diploid genotype data were reasonably comparable. Finally, the selected tSNPs successfully represented the association evidence discovered for all of the other SNPs studied. This study provides an optimal set of tSNPs for association analyses of CETP. The observed complexity of LD structure highlights the importance of using methods, such as PCA, that allow for multiple dynamics in intragenic LD structure.


Assuntos
Proteínas de Transporte/genética , Glicoproteínas/genética , Desequilíbrio de Ligação , Polimorfismo de Nucleotídeo Único/genética , Idoso , Proteínas de Transferência de Ésteres de Colesterol , Doença da Artéria Coronariana/genética , Feminino , Variação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Análise Numérica Assistida por Computador , Sitios de Sequências Rotuladas
18.
J Card Fail ; 11(9): 677-83, 2005 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-16360962

RESUMO

BACKGROUND: A common variant of the adenosine monophosphate deaminase (AMPD)-1 gene (C34T) results in enzymatic inactivity and may increase adenosine in cardiac muscle and confer cardioprotection through ischemic preconditioning. METHODS AND RESULTS: We hypothesized that AMPD1 carriers with ischemic heart failure (HF) in the Beta-Blocker Evaluation of Survival Trial (BEST) might have a relative survival advantage. Patients (n = 1038, 20% black) with ischemic (58%) and nonischemic (42%) HF were followed for an average of 2.0 years for cardiovascular mortality. DNA was purified from blood using phenol/chloroform. Genotyping was performed by polymerase chain reaction with 5' exonuclease chemistry. Differences in survival were assessed by comparing Kaplan-Meier curves with the log-rank test. Genotype frequencies differed by ethnicity (P < .001) but not by disease etiology. AMPD1 genotype did not significantly modify survival in the entire study population (hazard ratio [HR] = 0.91, 95% CI = 0.61-1.37), among ischemics (HR = 0.73, CI = 0.44-1.22, P = .23), or ischemic non-blacks (HR = 0.74, CI = 0.44-1.24, P = .25). Genotype did not modify the effect of bucindolol on mortality. CONCLUSIONS: Results of this study failed to confirm a reported survival benefit among HF patients carrying the AMPD1 T-allele. However, further studies in larger, more homogeneous populations should explore the possibility of a modest survival advantage for patients with ischemic HF.


Assuntos
AMP Desaminase/genética , Insuficiência Cardíaca/genética , Isquemia Miocárdica/genética , Polimorfismo Genético/genética , AMP Desaminase/metabolismo , Estudos de Casos e Controles , Estudos de Coortes , DNA/análise , Feminino , Seguimentos , Genótipo , Insuficiência Cardíaca/enzimologia , Insuficiência Cardíaca/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Isquemia Miocárdica/enzimologia , Isquemia Miocárdica/mortalidade , Taxa de Sobrevida
19.
Am J Cardiol ; 95(1): 155-8, 2005 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-15619419

RESUMO

A medium-sensitivity assay for C-reactive protein (CRP) was compared with a high-sensitivity, enhanced immunoturbidimetric assay in 803 angiographically studied patients. Different absolute CRP values were found by the assays, but there was a high correlation by quartile rank and similar predictive values for death and myocardial infarction. This suggests that the conclusions of previous studies performed using the medium-sensitivity assay are still valid but that cross-study comparisons should use percentile rank.


Assuntos
Proteína C-Reativa/análise , Doença da Artéria Coronariana/sangue , Análise Química do Sangue/métodos , Doença da Artéria Coronariana/diagnóstico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/sangue , Infarto do Miocárdio/diagnóstico , Valor Preditivo dos Testes , Medição de Risco , Sensibilidade e Especificidade
20.
Am Heart J ; 148(6): 1034-40, 2004 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-15632890

RESUMO

BACKGROUND: Coronary artery disease (CAD) and, increasingly, diabetes are recognized as having an inflammatory basis. Membrane toll-like receptors (TLRs) activate signaling pathways that up-regulate inflammation. We evaluated whether the Asp299Gly polymorphism in the TLR4 gene, which impairs inflammatory responses, is associated with reduced vascular inflammation (assessed by C-reactive protein [CRP]) and a decreased risk for CAD and diabetes. METHODS: 1894 patients without acute myocardial infarction undergoing coronary angiography were studied. Genotyping was performed by real-time polymerase chain reaction. CAD was defined as >or=70% stenosis. Diabetes was diagnosed by patients' referring physicians. CRP was measured by fluorescence polarization immunoassay. Regression analyses adjusted for traditional cardiac risk factors. RESULTS: Patients averaged 64 +/- 11 years of age, and 69% were male. Asp299Gly genotype frequencies were: AA = 0.911 (n = 1725), AG = 0.086 (n = 164), and GG = 0.003 (n = 5), in keeping with Hardy-Weinberg equilibrium. CRP was lower among G-allele carriers (median = 1.11 mg/dL) than wild-type (AA) subjects (1.23 mg/dL, adjusted P = .044). G-allele carriers also had a lower prevalence of CAD (65% vs. 73%, OR = 0.67, CI = 0.46-0.99, adjusted P = .048) and diabetes (11% vs. 18%, OR = 0.63, CI = 0.42-0.95, adjusted P = .029), which persisted in multivariate logistic regression analyses. 299Gly carriage did not affect clinical outcomes nor interact with statin therapy. CONCLUSIONS: The TLR4 299Gly allele was associated with reduced CRP levels and, in parallel, a decreased risk of angiographic CAD and clinical diabetes. These findings suggest that down-regulation of innate immune responsiveness could beneficially modify CAD and diabetes risk and might provide a novel basis for genetic risk stratification and therapeutic targeting.


Assuntos
Proteína C-Reativa/análise , Doença das Coronárias/genética , Diabetes Mellitus/genética , Inflamação/genética , Glicoproteínas de Membrana/genética , Receptores de Superfície Celular/genética , Idoso , Angiografia Coronária , Doença das Coronárias/sangue , Diabetes Mellitus/sangue , Feminino , Marcadores Genéticos , Genótipo , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/genética , Infarto do Miocárdio/mortalidade , Infarto do Miocárdio/prevenção & controle , Polimorfismo Genético , Fatores de Risco , Receptor 4 Toll-Like , Receptores Toll-Like
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