Genetic Loci Associated With Atrial Fibrillation: Relation to Left Atrial Structure in the Framingham Heart Study

Background: Atrial fibrillation (AF) results in significant morbidity and mortality. Genome‐wide association studies (GWAS) have identified genetic variants associated with AF. Whether genetic variants associated with AF are also associated with atrial structure, an intermediate phenotype for AF, has had limited investigation. We sought to investigate associations between single nucleotide polymorphisms (SNPs) and atrial structure obtained by cardiovascular imaging in the Framingham Heart Study. Methods and Results: We selected 11 SNPs that have been associated with AF in GWAS. We examined the SNPs' relations to cross‐sectional left atrial (LA) dimensions (determined by transthoracic echocardiography) and LA volume (determined by cardiovascular magnetic resonance [CMR]) employing linear regression. The total sample included 1555 participants with CMR LA volume (age 60±9 years, 53% women) and 6861 participants with echocardiographic LA diameter (age 48±13 years, 52% women) measured. We employed a significance threshold of P<0.0023 to account for multiple testing of the 11 SNPs and 2 LA measures. In a primary analysis, no SNPs were significantly related to the LA measures. Likewise, in secondary analyses excluding individuals with prevalent AF (n=77, CMR sample; n=105, echocardiography sample) no SNPs were related to LA volume or diameter. Conclusion: In a community‐based cohort, we did not identify a statistically significant association between selected SNPs associated with AF and measures of LA anatomy. Further investigations with larger longitudinally assessed samples and a broader array of SNPs may be necessary to determine the relation between genetic loci associated with AF and atrial structure

SUPPORT-AF: Piloting a Multi-Faceted, Electronic Medical Record-Based Intervention to Improve Prescription of Anticoagulation

Background: Only 50% of eligible atrial fibrillation ( AF ) patients receive anticoagulation ( AC ). Feasibility and effectiveness of electronic medical record (EMR)-based interventions to profile and raise provider AC percentage is poorly understood. The SUPPORT-AF (Supporting Use of AC Through Provider Profiling of Oral AC Therapy for AF) study aims to improve rates of adherence to AC guidelines by developing and delivering supportive tools based on the EMR to providers treating patients with AF. Methods and Results: We emailed cardiologists and community-based primary care providers affiliated with our institution reports of their AC percentage relative to peers. We also sent an electronic medical record-based message to these providers the day before an appointment with an atrial fibrillation patient who was eligible but not receiving AC . The electronic medical record message asked the provider to discuss AC with the patient if he or she deemed it appropriate. To assess feasibility, we tracked provider review of our correspondence. We also tracked the change in AC for intervention providers relative to alternate primary care providers not receiving our intervention. We identified 3786, 1054, and 566 patients cared for by 49 cardiology providers, 90 community-based primary care providers, and 88 control providers, respectively. At baseline, the percentage of AC was 71.3%, 63.5%, and 58.3% for these 3 respective groups. Intervention providers reviewed our e-mails and electronic medical record messages 45% and 96% of the time, respectively. For providers responding, patient refusal was the most common reason for patients not being on AC (21%) followed by high bleeding risk (19%). At follow-up 10 weeks later, change in AC was no different for either cardiology or community-based primary care providers relative to controls (0.2% lower and 0.01% higher, respectively). Conclusions: Our intervention profiling AC was feasible, but not sufficient to increase AC in our population

Genetic risk prediction of atrial fibrillation

Background—Atrial fibrillation (AF) has a substantial genetic basis. Identification of individuals at greatest AF risk could minimize the incidence of cardioembolic stroke. Methods—To determine whether genetic data can stratify risk for development of AF, we examined associations between AF genetic risk scores and incident AF in five prospective studies comprising 18,919 individuals of European ancestry. We examined associations between AF genetic risk scores and ischemic stroke in a separate study of 509 ischemic stroke cases (202 cardioembolic [40%]) and 3,028 referents. Scores were based on 11 to 719 common variants (≥5%) associated with AF at P-values ranging from &lt;1x10-3 to &lt;1x10-8 in a prior independent genetic association study. Results—Incident AF occurred in 1,032 (5.5%) individuals. AF genetic risk scores were associated with new-onset AF after adjusting for clinical risk factors. The pooled hazard ratio for incident AF for the highest versus lowest quartile of genetic risk scores ranged from 1.28 (719 variants; 95%CI, 1.13-1.46; P=1.5x10-4) to 1.67 (25 variants; 95%CI, 1.47-1.90; P=9.3x10-15). Discrimination of combined clinical and genetic risk scores varied across studies and scores (maximum C statistic, 0.629-0.811; maximum ΔC statistic from clinical score alone, 0.009-0.017). AF genetic risk was associated with stroke in age- and sex-adjusted models. For example, individuals in the highest versus lowest quartile of a 127-variant score had a 2.49-fold increased odds of cardioembolic stroke (95%CI, 1.39-4.58; P=2.7x10-3). The effect persisted after excluding individuals (n=70) with known AF (odds ratio, 2.25; 95%CI, 1.20-4.40; P=0.01). Conclusions—Comprehensive AF genetic risk scores were associated with incident AF beyond associations for clinical AF risk factors, though offered small improvements in discrimination. AF genetic risk was also associated with cardioembolic stroke in age- and sex-adjusted analyses. Efforts are warranted to determine whether AF genetic risk may improve identification of subclinical AF or help distinguish between stroke mechanisms

Lifetime risk of atrial fibrillation according to optimal, borderline, or elevated levels of risk factors: cohort study based on longitudinal data from the Framingham Heart Study

OBJECTIVE: To examine the association between risk factor burdens-categorized as optimal, borderline, or elevated-and the lifetime risk of atrial fibrillation. DESIGN: Community based cohort study. SETTING: Longitudinal data from the Framingham Heart Study. PARTICIPANTS: Individuals free of atrial fibrillation at index ages 55, 65, and 75 years were assessed. Smoking, alcohol consumption, body mass index, blood pressure, diabetes, and history of heart failure or myocardial infarction were assessed as being optimal (that is, all risk factors were optimal), borderline (presence of borderline risk factors and absence of any elevated risk factor), or elevated (presence of at least one elevated risk factor) at index age. MAIN OUTCOME MEASURE: Lifetime risk of atrial fibrillation at index age up to 95 years, accounting for the competing risk of death. RESULTS: At index age 55 years, the study sample comprised 5338 participants (2531 (47.4%) men). In this group, 247 (4.6%) had an optimal risk profile, 1415 (26.5%) had a borderline risk profile, and 3676 (68.9%) an elevated risk profile. The prevalence of elevated risk factors increased gradually when the index ages rose. For index age of 55 years, the lifetime risk of atrial fibrillation was 37.0% (95% confidence interval 34.3% to 39.6%). The lifetime risk of atrial fibrillation was 23.4% (12.8% to 34.5%) with an optimal risk profile, 33.4% (27.9% to 38.9%) with a borderline risk profile, and 38.4% (35.5% to 41.4%) with an elevated risk profile. Overall, participants with at least one elevated risk factor were associated with at least 37.8% lifetime risk of atrial fibrillation. The gradient in lifetime risk across risk factor burden was similar at index ages 65 and 75 years. CONCLUSIONS: Regardless of index ages at 55, 65, or 75 years, an optimal risk factor profile was associated with a lifetime risk of atrial fibrillation of about one in five; this risk rose to more than one in three a third in individuals with at least one elevated risk factor

Whole Blood Gene Expression and Atrial Fibrillation: The Framingham Heart Study

Background: Atrial fibrillation (AF) involves substantial electrophysiological, structural and contractile remodeling. We hypothesize that characterizing gene expression might uncover important pathways related to AF. Methods and Results: We performed genome-wide whole blood transcriptomic profiling (Affymetrix Human Exon 1.0 ST Array) of 2446 participants (mean age 66±9 years, 55% women) from the Offspring cohort of Framingham Heart Study. The study included 177 participants with prevalent AF, 143 with incident AF during up to 7 years follow up, and 2126 participants with no AF. We identified seven genes statistically significantly up-regulated with prevalent AF. The most significant gene, PBX1 (P = 2.8×10−7), plays an important role in cardiovascular development. We integrated differential gene expression with gene-gene interaction information to identify several signaling pathways possibly involved in AF-related transcriptional regulation. We did not detect any statistically significant transcriptomic associations with incident AF. Conclusion: We examined associations of gene expression with AF in a large community-based cohort. Our study revealed several genes and signaling pathways that are potentially involved in AF-related transcriptional regulation

Adenosine A2A receptor modulation of hippocampal CA3-CA1 synapse plasticity during associative learning in behaving mice

© 2009 Nature Publishing Group All rights reservedPrevious in vitro studies have characterized the electrophysiological and molecular signaling pathways of adenosine tonic modulation on long-lasting synaptic plasticity events, particularly for hippocampal long-term potentiation(LTP). However, it remains to be elucidated whether the long-term changes produced by endogenous adenosine in the efficiency of synapses are related to those required for learning and memory formation. Our goal was to understand how endogenous activation of adenosine excitatory A2A receptors modulates the associative learning evolution in conscious behaving mice. We have studied here the effects of the application of a highly selective A2A receptor antagonist, SCH58261, upon a well-known associative learning paradigm - classical eyeblink conditioning. We used a trace paradigm, with a tone as the conditioned stimulus (CS) and an electric shock presented to the supraorbital nerve as the unconditioned stimulus(US). A single electrical pulse was presented to the Schaffer collateral–commissural pathway to evoke field EPSPs (fEPSPs) in the pyramidal CA1 area during the CS–US interval. In vehicle-injected animals, there was a progressive increase in the percentage of conditioning responses (CRs) and in the slope of fEPSPs through conditioning sessions, an effect that was completely prevented (and lost) in SCH58261 (0.5 mg/kg, i.p.)-injected animals. Moreover, experimentally evoked LTP was impaired in SCH58261- injected mice. In conclusion, the endogenous activation of adenosine A2A receptors plays a pivotal effect on the associative learning process and its relevant hippocampal circuits, including activity-dependent changes at the CA3-CA1 synapse.This study was supported by grants from the Spanish Ministry of Education and Research (BFU2005-01024 and BFU2005-02512), Spanish Junta de Andalucía (BIO-122 and CVI-02487), and the Fundación Conocimiento y Cultura of the Pablo de Olavide University (Seville, Spain).B. Fontinha was in receipt of a studentship from a project grant (POCI/SAU-NEU/56332/2004) supported by Fundação para a Ciência e Tecnologia (FCT, Portugal), and of an STSM from Cost B30 concerted action of the EU

A [4Fe-4S]-Fe(CO)(CN)-L-cysteine intermediate is the first organometallic precursor in [FeFe] hydrogenase H-cluster bioassembly.

Biosynthesis of the [FeFe] hydrogenase active site (the 'H-cluster') requires the interplay of multiple proteins and small molecules. Among them, the radical S-adenosylmethionine enzyme HydG, a tyrosine lyase, has been proposed to generate a complex that contains an Fe(CO)2(CN) moiety that is eventually incorporated into the H-cluster. Here we describe the characterization of an intermediate in the HydG reaction: a [4Fe-4S][(Cys)Fe(CO)(CN)] species, 'Complex A', in which a CO, a CN- and a cysteine (Cys) molecule bind to the unique 'dangler' Fe site of the auxiliary [5Fe-4S] cluster of HydG. The identification of this intermediate-the first organometallic precursor to the H-cluster-validates the previously hypothesized HydG reaction cycle and provides a basis for elucidating the biosynthetic origin of other moieties of the H-cluster

Efeitos da melatonina sobre as alterações comportamentais e bioquímicas induzidas pela administração intranasal de dimetilditiocarbamato de sódio em camundongos

Tese (doutorado) - Universidade Federal de Santa Catarina, Centro de Ciências Biológicas, Programa de Pós-Graduação em Farmacologia, Florianópolis, 2017.A doença de Parkinson (DP) é a segunda doença neurodegenerativa mais comum em humanos, sendo classicamente caracterizada por sintomas motores que estão relacionados à degeneração de neurônios dopaminérgicos da via nigroestriatal. A etiologia da DP ainda não é completamente compreendida, mas acredita-se que se trata de uma doença multifatorial, onde fatores genéticos e ambientais influenciam no seu desenvolvimento. Entre os fatores ambientais, a exposição a pesticidas, como o ziram (dimetilditiocarbamato de zinco), vem ganhando destaque. A exposição ocupacional e residencial ao ziram foi recentemente relacionada ao aumento do risco do desenvolvimento da DP. Diferentes sais de dimetilditiocarbamato são amplamente utilizados na agricultura e indústria, expondo a população em geral aos seus efeitos tóxicos. Estes contaminantes ambientais podem atingir estruturas encefálicas através do sistema olfatório, via nervos olfatório e trigêmeo, ou mesmo pela passagem transcelular a partir da mucosa nasal. Neste sentido, este estudo teve como objetivo avaliar os efeitos da administração intranasal (i.n.) de dimetilditiocarbamato de sódio (NaDMDC), um sal mais solúvel de dimetilditiocarbamato, sobre os comportamentos motores e as alterações bioquímicas relacionadas ao estresse oxidativo/nitrosativo, inflamação e sistema dopaminérgico de camundongos. Além disso, avaliou-se possíveis alterações no sistema melatoninérgico (níveis de melatonina e seus receptores MT1 e MT2) no sistema nervoso central (SNC) de camundongos após a administração i.n. de NaDMDC e o efeito do tratamento com a melatonina sobre as alterações comportamentais e bioquímicas induzidas pelo NaDMDC. A administração de NaDMDC (1 mg/narina/dia) por quatro dias consecutivos induziu déficits motores avaliados no teste do campo aberto, escore neurológico de severidade (ENS) e rotarod até o dia 7 após a última administração da toxina. Os déficits comportamentais no teste do rotarod assim como a redução da massa corporal induzida pelo NaDMDC foram observados até o 35o dia após o término da administração. O tratamento com os fármacos usados no tratamento da DP L-DOPA e apomorfina atenuaram os déficits locomotores induzidos pelo NaDMDC. As alterações comportamentais foram relacionadas ao aumento inicial dos níveis de espécies reativas de oxigênio (EROs) no bulbo olfatório (BO) e estriado, 2 horas e 24 horas após a última administração, além de dano a membrana celular no estriado, a qual demonstrou ser mais susceptível a toxicidade exercida pelo NaDMDC. A administração de NaDMDC também provocou o aumento de metabólitos do estresse oxidativo/nitrosativo no BO, estriado, córtex pré-frontal e hipocampo, assim como o aumento nos níveis do fator de necrose tumoral-a (TNF-a) no BO e estriado, 24 horas após a última administração de NaDMDC. Com relação ao sistema dopaminérgico, a administração de NaDMDC provocou um aumento no imunoconteúdo de tirosina hidroxilase (TH) no estriado, no 1o e 7o dia após a última administração de NaDMDC, e a sua redução no 35o dia. No dia 1 após o tratamento com NaDMDC observou-se uma redução nos níveis de dopamina e o aumento no seu turnover no estriado. Com relação ao sistema melatoninérgico, a administração de NaDMDC aumentou os níveis de melatonina no BO, nos dias 1 e 7, e no hipocampo no dia 1. Além disso, observou-se um aumento no dia 1 após o término do tratamento com NaDMDC no imunoconteúdo do receptor melatoninérgico MT2 no BO. O tratamento com melatonina (30 mg/kg, via intraperitoneal), 1 h antes de cada administração de NaDMDC, preveniu o aparecimento de déficits motores, perda de massa corporal, alterações do sistema dopaminérgico, assim como, inibiu o aumento de metabólitos do estresse oxidativo/nitrosativo no BO, estriado e córtex pré-frontal dos animais. Em conjunto, estes resultados demonstram que a administração i.n. de NaDMDC provoca alterações comportamentais e bioquímicas em camundongos relacionadas à DP. O presente estudo demonstra de maneira pioneira que o tratamento com a melatonina possui efeitos neuroprotetores frente à toxicidade exercida pelo NaDMDC, o que destaca o potencial terapêutico deste neuro-hormônio em condições de dano neuronal.Abstract : Parkinson's disease (PD) is the second most common neurodegenerative disease in humans, being classically characterized by motor symptoms, which are related to the dopaminergic neuronal loss in the nigrostriatal pathway. The primary PD etiology remais unclear, but it is believed to be a multifactorial disease, where the combination of genetic and environmental factors influence its development. Among environmental factors, exposure to pesticides, such as ziram (zinc dimethyldithiocarbamate), has been highlighted. Occupational and residential exposure to ziram has recently been linked to increased risk of PD developing. Different dimethyldithiocarbamate salts are widely used in agriculture and industry, exposing the general population to their toxic effects. These environmental contaminants can target encephalic structures to exert their toxic effects via the olfactory pathway, through olfactory and trigeminal nerves, or even through transcellular passage from nasal mucosa. Therefore, this study aimed to evaluate the effects of intranasal (i.n.) administration of sodium dimethyldithiocarbamate (NaDMDC), a more soluble salt of dimethyldithiocarbamate, on motor function and biochemical changes related to oxidative/nitrosative stress, inflammation and dopaminergic system of mice. In addition, putative NaDMDC-induced alterations on the melatoninergic system in the central nervous system (CNS) and the effects of melatonin treatment on changes caused by NaDMDC were also evaluated. I.n. administration of NaDMDC (1 mg/nostril/day) for four consecutive days induced motor deficits addressed in the open field, neurological severity score (NSS) and rotarod tests up to day 7 after the last administration. Behavioral deficits in the rotarod test as well as the reduction of body mass induced by NaDMDC were found to remain significant up to 35th day after the end of its administration. Pharmacological treatment with the anti-parkinsonian drugs L-DOPA and apomorphine improved the locomotor deficits induced by NaDMDC. Behavioral changes were related to the initial increase of reactive oxygen species (ROS) levels in the olfactory bulb (OB) and striatum, 2 hours and 24 hours after the last administration, besides cell membrane damage in the striatum, which proved to be more susceptible to NaDMDC toxicity. The administration of NaDMDC also increased oxidative/nitrosative stress metabolites in OB, striatum, prefrontal cortex and hippocampus, as well as increased tumor necrosis factor-a (TNF-a) levels in the BO and striatum, 24 hours after the last NaDMDC administration. Regarding the dopaminergic system, administration of NaDMDC increased striatal tyrosine hydroxylase (TH) immunocontent on the 1st and 7th day after the last administration of NaDMDC, and decreased TH levels in the 35th day. On day 1, there was a reduction in dopamine levels and an increase in dopamine turnover in the striatum. Regarding the melatoninerg system, the administration of NaDMDC increased the OB melatonin levels on days 1 and 7, whereas in the hippocampus only on day 1. In addition, on day 1 after the end of NaDMDC treatment, the immunocontent of melatonin MT2 receptor was increased in the OB. Treatment with melatonin (30 mg/kg intraperitoneally), 1 h before each administration of NaDMDC, prevented the onset of motor deficits, loss of body mass, changes in the dopaminergic system, as well as inhibited the increase of stress oxidative/nitrosative metabolites in OB, striatum and prefrontal cortex in animals. Taken together, these results demonstrate that i.n. NaDMDC administration promotes behavioral and biochemical changes in mice, related to PD in humans. These findings reinforce the relationship of dimethyldithiocarbamate exposure with increased PD development risk, as well as highlight the importance of olfactory vectoring of environmental toxins as a possible access route to the CNS. Finally, we demonstrated for the first time that treatment with melatonin exerts neuroprotective effects against the NaDMDC toxicity, reinforcing the therapeutic potential of this neurohormone in neuronal damage conditions including PD

Evaluating the quality of interaction between medical students and nurses in a large teaching hospital

BACKGROUND: Effective health care depends on multidisciplinary collaboration and teamwork, yet little is known about how well medical students and nurses interact in the hospital environment, where physicians-in-training acquire their first experiences as members of the health care team. The objective of this study was to evaluate the quality of interaction between third-year medical students and nurses during clinical rotations. METHODS: We surveyed 268 Indiana University medical students and 175 nurses who worked at Indiana University Hospital, the School's chief clinical training site. The students had just completed their third year of training. The survey instrument consisted of 7 items that measured "relational coordination" among members of the health care team, and 9 items that measured psychological distress. RESULTS: Sixty-eight medical students (25.4%) and 99 nurses (56.6%) completed the survey. The relational coordination score (ranked 1 to 5, low to high), which provides an overall measure of interaction quality, showed that medical students interacted with residents the best (4.16) and with nurses the worst (2.98; p < 0.01). Conversely, nurses interacted with other nurses the best (4.36) and with medical students the worst (2.68; p < 0.01). Regarding measures of psychological distress (ranked 0 to 4, low to high), the interpersonal sensitivity score of medical students (1.56) was significantly greater than that of nurses (1.03; p < 0.01), whereas the hostility score of nurses (0.59) was significantly greater than that of medical students (0.39; p < 0.01). CONCLUSION: The quality of interaction between medical students and nurses during third-year clinical rotations is poor, which suggests that medical students are not receiving the sorts of educational experiences that promote optimal physician-nurse collaboration. Medical students and nurses experience different levels of psychological distress, which may adversely impact the quality of their interaction

Atrial fibrillation genetic risk differentiates cardioembolic stroke from other stroke subtypes

Objective: We sought to assess whether genetic risk factors for atrial fibrillation (AF) can explain cardioembolic stroke risk. Methods: We evaluated genetic correlations between a previous genetic study of AF and AF in the presence of cardioembolic stroke using genome-wide genotypes from the Stroke Genetics Network (N = 3,190 AF cases, 3,000 cardioembolic stroke cases, and 28,026 referents). We tested whether a previously validated AF polygenic risk score (PRS) associated with cardioembolic and other stroke subtypes after accounting for AF clinical risk factors. Results: We observed a strong correlation between previously reported genetic risk for AF, AF in the presence of stroke, and cardioembolic stroke (Pearson r = 0.77 and 0.76, respectively, across SNPs with p &lt; 4.4 × 10−4 in the previous AF meta-analysis). An AF PRS, adjusted for clinical AF risk factors, was associated with cardioembolic stroke (odds ratio [OR] per SD = 1.40, p = 1.45 × 10−48), explaining ∼20% of the heritable component of cardioembolic stroke risk. The AF PRS was also associated with stroke of undetermined cause (OR per SD = 1.07, p = 0.004), but no other primary stroke subtypes (all p &gt; 0.1). Conclusions: Genetic risk of AF is associated with cardioembolic stroke, independent of clinical risk factors. Studies are warranted to determine whether AF genetic risk can serve as a biomarker for strokes caused by AF