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Spatio-temporal variation in activation rates during ventricular fibrillation (VF)provides insight into mechanisms of sustained re-entry during VF. This study had three objectives related to spatio-temporal dynamics in activation rates during VF. The first objective was to quantify spatio-temporal variability in activation rates,that is, in dominant frequencies, computed from epicardial electrograms recorded during VF in swine. Results showed that temporally and spatially, dominant frequencies variedas much as 20% of the mean dominant frequency, and the mean dominant frequencies increased during first 30 sec of VF. These results suggest that activation rates are nonstationary during VF. The second objective of the study was to develop a new stimulation protocol for quantifying restitution of action potential duration (APD) by independently controlling diastolic intervals (DI). A property of cardiac cells that determines spatio-temporal variability in dominant frequencies is restitution of APD, which relates APD to the previous DI. Independent control of DI permits explicit determination of the role of memory in restitution. Restitution functions quantified using mathematical models of activation and our stimulation protocol, showed significant hysteresis. That is, for adiastolic interval, the action potential durations were as much as 15% longer during periods when the DI were decreasing than when the DI were increasing. We verified the feasibility of implementing our protocol experimentally in isolated and perfused rat hearts with action potentials recorded using floating glass microelectrodes. The third objective of our study was to verify that spatio-temporal variability in dominant frequencies during VF could be modified using spatially distributed pacing strength stimuli. Simulated VF was induced in 400x400 and 400x800 matrices of cells. Electrical function of cells was simulated using the Luo-Rudy model. Stimulators were arranged in the matrices such that there were 5 rows of line stimulators. Results showed that it was possible to modify activations in almost 54% of the area and to modify spatio-temporal variability in activation during VF into a desired pattern by the use of synchronized pacing from multiple sites. These results support further exploration of distributed stimulation approach for potential improvements in defibrillation therapy.

INTRODUÇÃO: O aumento da proporção de idosos implica estudar os determinantes dos principais agravos associados ao envelhecimento como a demência, principalmente a associada à doença cerebrovascular. Um fator de risco relevante para doença cerebrovascular é a freqüência de fibrilação atrial crônica. O São Paulo Health and Ageing Study com base populacional para estudo de distúrbio cognitivo e demência é uma oportunidade única para verificar a prevalência de fibrilação atrial e de sua associação com demência. MÉTODOS: Estudo transversal, por arrolamento de 1524 idosos com 65 anos ou mais estudo acima, no distrito do Butantã, cidade de São Paulo. O diagnóstico de fibrilação atrial foi feito com o eletrocardiograma de repouso de doze derivações e o de demência foi feito utilizando-se o protocolo do Research Group of Dementia 10/66. Estudaram-se variáveis sócio-econômicas e fatores de risco cardiovascular como hipertensão, diabetes, dislipidemia e obesidade. RESULTADOS: A amostra estudada tinha idade média de 72,2 anos, era predominantemente feminina, branca, casada, de baixa escolaridade e renda. A prevalência de fibrilação atrial associou-se ao aumento da idade e foi de 1,9% para o sexo feminino e 3,1% para o sexo masculino, com prevalência para ambos os sexos ajustada para idade de 2,7%. A prevalência de demência também se associou ao aumento da idade e sua prevalência idade ajustada foi de 4,9%, maior em mulheres (4,8%) do que em homens (3,6%). A razão de chances ajustada para idade para a associação de fibrilação atrial e demência foi de 2,88 (Intervalo de Confiança, IC 95% - 0,98 8,40) para ambos os sexos sendo e, de 1,50 (IC95% - 0,19 11,83) para homens e 4,48 (IC95% - 1,23 16,29) para mulheres. Encontrou-se maior risco de demência entre mulheres com fibrilação atrial (17,7%) do que entre os participantes do mesmo sexo sem demência (4,6%) Outras alterações no eletrocardiograma de repouso com interesse foram determinadas como com área inativa (código de Minnesotta q1- q2) de: 9,1% nas mulheres e 16,6% nos homens; e também bloqueio de ramo esquerdo de 3,3%, nas mulheres 3,0% e nos homens 3,6%. CONCLUSÃO: Mulheres idosas com fibrilação atrial têm diagnóstico de demência quase quatro vezes mais do que aquelas em ritmo sinusal / INTRODUCTION: The growing aging population proportion makes us study the most important illness related with aging of the population as dementia, specially the dementia associated to stroke. Atrial fibrillation is a main risk factor with cerebrovascular disease. The São Paulo Heath and Ageing Study a population based study for cognitive disturb and dementia is an unique opportunity to verify the atrial fibrillation prevalence and its association with dementia. Methods: This is a cross-sectional study. The population of this study was composed by 1,524 elderly people, over 65 years of age, covered by the Health Program Family in the Butantã district, São Paulo, who were recruited door by door. The diagnosis of atrial fibrillation was made using a twelve lead resting electrocardiogram and the diagnosis of dementia was made by the protocol of Research Group of Dementia 10/66. We studied socio economic variables and cardiovascular risk factors as hypertension, diabetes, dislipidemia and obesity. RESULTS: The studied population had a mean age of 72.2 years old and was predominantly female, white, married and of low educational and financial status. We found that atrial fibrillation prevalence increased throughout age-strata and was of 1.9% among the females and 3.1% among the males, and age-adjusted prevalence of 2.7%. The prevalence of dementia also increases with age and its ageadjusted prevalence was of 4.9%, greater among the females (4.8%) than among the males (3.6%). The odds ratio age-adjusted for the association of atrial fibrillations and dementia was of 2.88 (Confidence interval, 95% CI 0.98 8.40) for both sex: 1.50 among men (95% CI 0.19 11.83), and 4.48 among women (95% CI 1.23 16.29). We found a higher risk of dementia among the female with atrial fibrillation (17.7%) than among female participants without atrial fibrillation (4.6%). Other resting electrocardiogram alterations were determined as previous inactive areas (Minnesotta Code q1-q2) of 12.4%: among the females of 9.1% and among the males of 16.6%. The frequency of left bundle-branch block was of 3.3%: among the females of 3.0% and among the males of 3.6% .CONCLUSION: Elderly women with atrial fibrillation had the diagnosis of dementia almost four times greater than that of women with sinus rhythm

A fibrilação atrial (FA) é um dos tipos mais freqüentes de arritmia cardíaca e é caracterizada principalmente pela aleatoriedade na ocorrência dos batimentos do coração. Sob este aspecto, a fibrilação atrial pode ser considerada um processo estocástico e por isso tem sido freqüentemente modelada através de cadeias de Markov. Seguindo trabalhos anteriores sobre este tópico, este trabalho modela seqüências temporais de batimentos cardíacos como um processo markoviano de três estados para detecção automática de FA. O modelo foi treinado e desenvolvido através dos sinais da base de dados MIT-BIH. Outro método mais consolidado na detecção de FA, denominado \"Razão RR\", também foi implementado, com o objetivo de comparar os resultados do Modelo Markoviano. A avaliação de desempenho para ambos os métodos implementados fo i realizada medindo-se a sensibilidade (Se) e o valor preditivo positivo (+P) para a detecção de FA. Estes dois métodos - Modelos Markovianos e \"Razão RR\" - tiveram seus coeficientes e limiares otimizados com o objetivo de maximizar, ao mesmo tempo, os valores de Se e +P. Após a otimização, ambos os métodos foram testados com uma nova base de dados, independente da base de dados de desenvolvimento. Os resultados obtidos com a base de dados de teste foram Se=84,940% e +P=81,579%, consolidando os Modelos Markoviano s para detecção de batimentos aleatórios. / Atrial fibrillation (AF) is one of the most common cardiac arrhythmia and it is mainly characterized by the presence of random RR intervals. In this way, atrial fibrillation has been studied as a stochastic process and it has been often modeled through Markov chains. Following previous studies on this subject, this work models time sequences of heartbeats as a three states Markov process for AF automatic detection. The model was trained and developed using signals from MIT-BIH database. Another consolidated method for AF detection, called \"RR Ratios\", was also applied to compare Markov Model\'s results. The performance evaluation of both methods was measured through sensitivity (Se) and positive predictive (+P) for AF detection. These two methods - Markov Model and \"RR Ratio\" - had their coefficients and thresholds optimized in order to maximize the values of Se and +P at the same time. After optimization, both methods were tested with another database, independent of development database. The obtained results were Se = 84,940% and +P = 81,579%, consolidating Markov Models for detecting random heartbeats.

BACKGROUND: Atrial fibrillation (AF) is the most common cardiac arrhythmia, and previous studies have focused on the epidemiology, mechanisms and risk factors for this global disease (Ryder and Benjamin 1999). Various studies have examined the mechanism, epidemiology, and risk factors for AF. One of the most common triggers for AF is believed to be premature atrial contractions (PACs) usually arising from the pulmonary veins of the left atrium, but the relationship between AF and premature ventricular complexes (PVCs) is not well understood. Studies investigating the triggers of premature beats in both the atria and ventricles are similar, so it is possible that treatment for one arrhythmia may affect the incidence of another. It is hypothesized that due to commonly shared mechanisms of triggered activity or automaticity between PACs and PVCs, and shared risk factors, that patients with AF undergoing treatment with catheter ablation may be prone to develop PVCs. OBJECTIVE: To investigate the incidence of clinically detected PVCs among patients undergoing catheter ablation for AF, and clinical predictors of PVC development in this cohort of patients. We also aim to evaluate if incident PVC detection is associated with recurrent AF following AF ablation in a cohort of 317 patients receiving treatment at a single academic medical center. METHODS: A total of 375 patients undergoing AF ablation from 2009-2012 were reviewed, and patients that underwent repeat ablations were excluded, yielding 317 patients for analysis. T-tests and Chi-squared analyses were used in univariate analyses to test for significance between characteristics of AF patients who did and did not develop PVCs. Kaplan-Meier analyses and Cox proportional hazards models were used for univariate and multivariate survival analyses, respectively, to assess the risks of incident PVC development. RESULTS: Of 317 patients with AF undergoing pulmonary vein isolation (PVI) ablation, 36.3% developed clinically detectable PVCs following ablation. A history of clinically evident PVC prior to catheter ablation for AF was associated with an 80% increase in risk of incident PVC development (HR=1.83, 95% CI 1.02-3.26, p=0.041). Additionally, a history of prior angioplasty, stent, or percutaneous coronary intervention (PCI) was associated with a 73% decreased risk of incident PVCs (HR=0.27, 95% CI 0.08-0.88, p=0.03). In patients with a history of PVC prior to ablation, or who developed PVCs after ablation, there was no significant difference in the risk of AF recurrence (HR=1.01, 95% CI 0.70-1.46, p=0.96; and HR=1.09, 95% CI 0.78-1.53, p=0.60, respectively). CONCLUSIONS: Over 1 in 3 patients develop clinically detected PVCs following catheter ablation. Predictors of incident PVC development include a history of PVC, whereas a history of angioplasty, stent, or PCI was associated with less incident PVC development. Furthermore, there was no significant association between both a history of PVC or incident PVC and risk of recurrent AF following ablation.

In a systematic review and random effects meta-analysis, we evaluated whether obesity is associated with postoperative atrial fibrillation (POAF) in patients undergoing cardiac surgery. Eighteen observational studies that excluded patients with preoperative AF were selected until December 2011 (n=36,147). Obese patients had a modest higher risk of POAF in comparison to non-obese (OR 1.12, 95%CI 1.04-1.21, p=0.002). The association between obesity and POAF did not vary substantially by type of cardiac surgery, study design or year of publication. POAF was significantly associated with higher risk of stroke, respiratory failure, and operative mortality. / Revisión por pares

Atrial Fibrillation (AF) is rare amongst young people whilst epidemic in the elderly. Whilst much is known about the pathophysiology of AF, the mechanisms underlying the vulnerability to AF amongst older people in incompletely understood. Young (< 18 months, first quintile of life) and old (> 8 years, last quintile of life) Welsh mountain sheep were used to investigate changes in atrial electrophysiology with age. Old sheep were more vulnerable to induced AF than young sheep. On the surface ECG, p-wave duration increased with age suggesting increasing atrial size. The corrected sinus node recovery time increased with age, suggesting deteriorating sinus node function. These findings confirmed the validity of sheep as a model for human ageing. In isolated atrial myocytes, action potentials (APs) were recorded using the perforated patch clamp technique. AP duration increased with age, and an increase in AP amplitude was also seen at the lowest stimulation rates. Right atrial AP durations were prolonged compared to those from left atrial myocytes, and the inter-atrial difference was similar between old and young. However, when right atrial monophasic APs were recorded from anaesthetised sheep in vivo, no difference in AP duration was seen between age groups. Alternans occurred at lower stimulation rates in old compared to young myocytes and was of greater magnitude. These age-related differences were present in isolated myocytes and in vivo. Alternans mechanisms were explored by simultaneously recording APs and intracellular calcium concentration. Atrial alternans was driven by alternans of Ca2+ cycling at low stimulation rates. However, despite disabling Ca2+ cycling using thapsigargin, alternans could still be elicited from myocytes during rapid stimulation. Right atrial conduction velocity (CV) was assessed in vivo and found to increase with age. A key determinant of CV, the Na+ current INa was investigated using the whole cell patch clamp technique. INa increased with age in left atrial myocytes and recovered faster from inactivation. Protein expression was investigated using Western blotting. Expression of the Na+ channel α-subunit did not change with age. The gap junction protein Cx43 was expressed less in older subjects, but Cx40 expression was similar. This work has cast light on several aspects of atrial electrophysiology in which the effects of age have not been thoroughly investigated. The longer cellular APs seen with age decrease the wavelength of potential re-entrant circuits which could be seen as protective against AF. However, AP prolongation is also associated with afterdepolarisations which could serve to trigger AF. The increase in alternans behaviour may set the stage for wavebreak, leading to re-entrant circuit formation. The increase in CV was surprising and might be seen as protective against AF as it increases arrhythmia wavelength, and is likely to be caused by the increased INa.

Sickle cell trait (SCT), sickle cell disease’s carrier status, is a common genetic variant found in many people of African, South Asian, Middle Eastern and Mediterranean descent. While overall considered a benign carrier status, it has been associated with an increased risk of several diseases, including exertional rhabdomyolysis (ER), and chronic kidney disease. While epidemiological evidence links SCT with ER, the actual pathophysiological mechanism less understood. Additionally, while there is an increased prevalence of atrial fibrillation (AF) documented in people with sickle cell disease, studies in individuals with SCT are lacking. The objectives of this thesis are twofold: The first chapter is a literature review of studies to examine the physiological mechanisms linking SCT and exertional rhabdomyolysis. The second chapter is original research into the associations of SCT with AF. The first chapter reviews studies that identify aggravating factors that may promote ER. It then reviews observed pathophysiological changes in people with SCT that may increase the risk of ER. It summarizes studies that assess mitigating factors that decrease the risk of ER. It then presents a postulated pathway of mechanisms that associate SCT with ER. The second chapter uses data from African-American participants in the REasons for Geographic and Racial Differences in Stroke (REGARDS) study to assess the association of SCT with prevalent AF (by electrocardiogram or medical history) using logistic regression models adjusting for age, sex, income, education, history of stroke, myocardial infarction, diabetes, hypertension, and chronic kidney disease. In 10,409 participants with baseline ECG data and genotyping, 778 (7.5%) had SCT and 811 (7.8%) had prevalent AF. After adjusting for age, sex, education and income, SCT was associated with AF, OR 1.32 (95% CI 1.03-1.70). SCT remained associated with prevalent AF after adjusting for potential factors on the causal pathway such as hypertension and chronic kidney disease suggesting alternate mechanisms for the increased risk. SCT was associated with a higher prevalence of AF and a non-significantly higher incident AF over a 9.2 year period independent of AF risk factors.

Accumulation or aggregation of amyloidogenic proteins in the brain plays a central role in neurodegenerative diseases. The most common and highly growing form of dementia in the elderly population is Alzheimer's disease (AD) followed by Parkinson's disease (PD). The major proteins associated are amyloid beta (Abeta) and alpha-synuclein (alpha-syn) in AD and PD, respectively. These proteins are released or found near the neuronal membranes in the brain. Consequently to understand the behavior of the proteins using a model membrane system becomes an important facet of understanding these diseases. Langmuir monolayer approach was used to study the surface chemistry and spectroscopy of Abeta (1-40), Abeta(1-42) and alpha-synuclein. Moreover, surface chemistry of a model protein namely, lysozyme was investigated. In recent times, quantum dots (QDs) are considered as potential probes for bio-imaging. These particles can be beneficial when it comes to the investigation of neurodegenerative diseases. The effect of nanoparticles, i.e., CdSe/ZnS QDs on Abeta (1-42) morphology was investigated. Nevertheless, it was observed that the capping ligand plays a significant role in the surface chemistry of QDs when mixed with or conjugated to Abeta (1-42). Surface pressure- and surface potential-area isotherms were used to characterize the lysozyme Langmuir monolayer. The compression-decompression cycles and stability measurements showed a homogeneous and stable monolayer at the air-water interface. Salt concentration in the subphase and pH of the subphase were parameters controlling homogeneity and stability of the Langmuir monolayer. In situ UV-vis and fluorescence spectroscopies were used to verify the homogeneity of the lysozyme monolayer, and to identify the chromophore residues in the lysozyme. Optimal experimental conditions were determined to prepare a homogeneous and stable lysozyme Langmuir monolayer. The surface chemistry and spectroscopy of the reduced lysozyme Langmuir monolayer were investigated at different pH values and were compared to a native lysozyme. It was established that the limiting molecular area of the reduced lysozyme was not subphase pH dependent as was found for the native one. To explain this result in terms of the conformation and orientation of the lysozyme Langmuir monolayer at various subphase pH values, we have used Infrared Reflection Absorption Spectroscopy (IRRAS). The interpretation of the results suggests a change in the conformation and orientation of the native lysozyme Langmuir monolayer with the subphase pH 3, 6 and 11. The surface chemistry of Abeta (1-40) and its interaction with the lipid raft Langmuir monolayer were examined where the stability of the lipid raft Langmuir monolayer came out as an essential parameter. Lipid raft Langmuir monolayer in the presence or absence of ganglioside GM1 having POPC as one of the phospholipids was found to be very unstable and collapsed within 26 min. Whereas, the phospholipid DPPG improved the stability of the monolayer significantly when cholesterol was used in excess. We have examined the surface and spectroscopic properties of Abeta (1-42) mixed with or conjugated to dihydrolipoic acid (DHLA)- and polyethylene glycol (PEG)- capped CdSe/ZnS QDs. Surface pressure-area isotherms, in situ UV-vis absorption, and fluorescence spectroscopy were used to characterize the Abeta (1-42) mixed with or conjugated to QDs at the air-water interface. The capping of QDs played a role in surface chemistry as was determined by surface pressure-area isotherms and spectroscopic properties of the Langmuir monolayer. Furthermore Abeta(1-42) was bioconjugated to DHLA-capped CdSe/ZnS QDs. Upon conjugation of Abeta (1-42) to DHLA-capped QDs, the sample was incubated at 37oC, the process of fibrillation was inhibited as compared with a sample where Abeta (1-42) was simply mixed with the QDs. Transmission electron microscopy (TEM) and atomic force microscopy (AFM) were employed for the analysis of the samples. The morphology of fibrils and reduction in number of fibrils was substantial in the case of Abeta(1-42) conjugated to QDs. Reduction in fibrillation was also confirmed using a Thioflavin T assay. Moreover, quenching of tyrosine signal was observed in presence of the QDs, which indicates an interaction of QDs to the tyrosine residue in Abeta (1-42). The Surface chemistry and spectroscopy of alpha-syn, which is a natively unstructured protein important in the neuropathology of PD was investigated. IRRAS was utilized to investigate its conformation, alpha-syn was found to form a Langmuir monolayer in alpha-helical conformation with its helical axis parallel to the air-water interface.

Thesis (M.S.)--University of Florida, 2003. / Title from title page of source document. Includes vita. Includes bibliographical references.