La fibrillation atriale est l'arythmie cardiaquela plus fréquente. Les études sur les modèles animaux ont fourni beaucoup de renseignements sur les mécanismes de cette arythmie, mais, à ce jour, nous ne disposons pas de modèle animal d'arythmie atriale spontanée.Nous avons cherché à développer un modèle d'arythmie atriale spontanée chez le rat et àidentifier les mécanismes physiopathologiques de ces arythmies. Nous avons également cherché àévaluer la présence et la sévérité de l'inflammation et de la dysfonction endothéliale, impliquées dansla survenue des complications de la fibrillation atriale comme les accidents vasculaires cérébraux, chezles patients avec fibrillation atriale. Nous avons également constaté des niveauxélevés de facteur de croissance endothélial vasculaire et de facteur von Willebrand chez les patientsavec fibrillation atriale par rapport aux contrôles. Ces résultats suggèrent un profil spécifique du risquethromboembolique en fonction de la forme clinique de l'arythmie et mettent en évidence une évolutionparallèle de la fibrillation atriale et de la dysfonction endothéliale.Ce nouveau modèle animal permettra d'étudier les mécanismes physiopathologiques desarythmies atriales et d'évaluer de nouveaux agents thérapeutiques dans un cadre qui reproduitfidèlement la présentation clinique de l'arythmie / Atrial fibrillation is the most prevalent form of cardiac arrhythmia. Studies in animal modelshave provided important insights into arrhythmia mechanisms. However, to date, we do not dispose ofanimal models of spontaneous atrial arrhythmia.Thus, we aimed to develop a model of spontaneous atrial arrhythmia in rats and to assesspathophysiological mechanisms of these arrhythmias by using a multidisciplinary approach. We alsoaimed to assess the presence and the extent of inflammation and endothelial dysfunction, incriminatedin atrial fibrillation-related complications such as stroke, in atrial fibrillation patients.The animal study describes the first animal model of spontaneous atrial arrhythmias. We alsoprovide evidence that multiple mechanisms participate in arrhythmia occurrence in this model,particularly autonomic imbalance with relative vagal hyperactivity, left atrial endocardial fibrosis, anddecreased left atrial expression of the Pitx2 gene. In our clinical study, we found high levels ofvascular endothelial growth factor and von Willebrand factor in atrial fibrillation patients compared tosinus rhythm controls. These results suggest specific thromboembolic risk patterns according to theclinical form of arrhythmia and highlight a parallel evolution of atrial fibrillation and endothelialdysfunction. These results add new insights into the understanding of atrial arrhythmias. This new animalmodel could facilitate studies of pathophysiological mechanisms involved in atrial arrhythmias andallow assessment of efficacy and toxicity of therapeutic agents in a setting that faithfully reproducesthe clinical presentation of the arrhythmia

Introdução: A Insuficiência Cardíaca (IC) e a Fibrilação Atrial (FA) são patologias frequentes na população idosa e estão associadas a alterações da esfera cognitiva. No entanto, suas consequências sobre as funções executivas, responsáveis pela resolução de problemas, ainda não estão totalmente esclarecidas. Objetivo: investigar as características do funcionamento executivo em pacientes com FA e/ou IC e identificar se tal funcionamento é equiparável ao de um grupo controle. Método: Estudo observacional, de coorte transversal, realizado em hospital de atenção terciária em cardiologia que avaliou 191 sujeitos, com uma média de 69,1 anos de idade (mín.: 60; Max.: 82) distribuídos em cinco grupos distintos: com FA, com IC associada à FA, com IC e controles (com e sem marca-passo artificial MP). Os grupos foram pareados por faixa etária e variáveis sócio-demográficas, submetidos à avaliação neuropsicológica e a análise estatística envolveu testes não paramétricos (Kruskall-Wallys e Mann-Whitney), qui-quadrado de Pearson e teste exato de Fisher. Resultados: Nos indivíduos com FA comparados aos controles sem MP, observamos diferenças estatisticamente significativas relacionadas a memória operacional (p = 0,034), a memória tardia (p = 0,015), a memória semântica e fluência verbal (p < 0,001), a compreensão (p < 0,001), ao planejamento e a habilidade visuoespacial (p < 0,001), a percepção visual e a linguagem (p< 0,001) e ao controle inibitório e a velocidade de processamento, nas três fases do instrumento (p < 0,008; p < 0,004; p < 0,002). Já nos indivíduos com FA associada à IC, as diferenças observadas envolveram: a memória semântica e a fluência verbal (p = 0,05), o planejamento e a habilidade visuoespacial (p < 0,001), a percepção visual e a linguagem (p < 0,001) e o controle inibitório e a velocidade de processamento (p = 0,002; p < 0,001; p = 0,145, respectivamente). Os sujeitos com IC demonstraram o mesmo desempenho do grupo de indivíduos com FA e IC, com diferenças relacionadas às mesmas funções, exceto na primeira fase do instrumento que avaliou controle inibitório e a velocidade de processamento (p < 0,001). Quanto à funcionalidade, não observamos diferença estatisticamente significativa entre os grupos. Conclusões: O funcionamento executivo de indivíduos com FA ou IC não é equiparável ao de indivíduos sem essas doenças. A FA, de uma perspectiva neuropsicológica, intensifica o prejuízo das FE e também da memória / Introduction: Heart Failure (HF) and Atrial Fibrillation (AF) are frequent pathologies in the elderly population and are associated with cognitive disorders. However, its consequences on executive functions, which are responsible for solving problems, have not yet been fully clarified. Objective: to investigate the characteristics of executive functioning in patients with AF and/or HF and to identify if such functioning is comparable to that of a control group. Methods: A cross-sectional observational study performed in a tertiary care hospital in cardiology, which evaluated 191 subjects with a mean age of 69.1 years (min.: 60, Max.: 82) distributed in five different groups: AF, with HF associated with AF, with HF and controls (with and without pacemaker). The groups were matched by age group and socio-demographic variables, submitted to neuropsychological evaluation and statistical analysis involved non-parametric tests (Kruskall-Wallys and Mann-Whitney), Pearson\'s chi-square and Fisher\'s exact test. Results: In subjects with AF compared to non-pacemaker controls, we observed statistically significant differences related to operational memory (p = 0.034), late memory (p = 0.015), semantic memory and verbal fluency (p < 0.001), comprehension P < 0.001), visuospatial planning and ability (p < 0.001), visual perception and language (p < 0.001) and inhibitory control and processing speed in the three phases of the instrument (p < 0.008; p < 0.004, p < 0.002). In subjects with HF associated with HF, the observed differences involved: semantic memory and verbal fluency (p = 0.05), planning and visuospatial ability (p < 0.001), visual perception and language (p < 0.001) and inhibitory control and processing speed (p = 0.002, p < 0.001, p = 0.145, respectively). Subjects with HF demonstrated the same performance of the group of individuals with AF and HF, with differences related to the same functions, except in the first phase of the instrument that evaluated inhibitory control and processing speed (p < 0.001). Regarding functionality, we did not observe a statistically significant difference between groups. Conclusions: The executive functioning of individuals with AF or IC is not comparable to that of individuals without these diseases. AF, from a neuropsychological perspective, intensifies the damage of FE and memory

De nombreuses études soulignent une relation directe entre la prévalence de la fibrillation auriculaire (FA) et le vieillissement. La senescence cellulaire et le phénotype sécrétoire associé semblent jouer un rôle central dans le développement de l'inflammation auriculaire. Cette inflammation est à l’origine d’un remodelage auriculaire délétère (stress oxydant, fibrose) favorable à la perpétuation et au maintien de la FA. Par ailleurs, il est connu que la FA favorise la coagulation locale et systémique. Cependant, l'impact des facteurs de la coagulation, notamment la thrombine, sur la FA est peu connu. L’objectif de cette étude était de déterminer le lien entre la sénescence des cellules endothéliales atriales et le phénotype pro-inflammatoire et pro-adhésif, la fibrose et le remodelage auriculaire tout en évaluant l’impact de la coagulation, et en particulier le rôle de la thrombine. / Many studies documented strong relationship between ageing and development of atrial fibrillation (AF). Moreover, it has been found that senescence and senescence-associated- secretory-phenotype play an important role in development of overall atrial inflammation which can ultimately ends up in atrial structural remodeling paving the way to AF perpetuation and maintenance. Moreover, it has been known for decades that AF has been associated with the activation of local and circulating coagulation factors. However, little is known about the impact of coagulation-derived factors, in particular thrombin, on the onset of AF. The aim of the present study was to determine the link between atrial endothelial cells (AECs) senescence and the induction of pro-inflammatory, pro-adhesive, pro-fibrotic and pro-remodelling AECs patterns and also to evaluate the contribution of coagulation derived-factors such as thrombin.

<p>The aim was to study pathophysiological mechanisms and risk factors for developing atrial fibrillation (AF) after coronary artery bypass grafting (CABG), and the effect of thoracic epidural anaesthesia (TEA).</p><p>The study comprised 141 patients undergoing CABG, including 45 patients randomised for TEA intra- and postoperatively. All patients underwent 24-hour Holter monitoring pre- and postoperatively for the analysis of arrhythmias and heart rate variability (HRV). Catecholamines and neuropeptides (reflecting sympathetic and parasympathetic activity), atrial peptides and echocardiographically assessed atrial arias were obtained pre- and postoperatively.</p><p>Logistic regression analysis identified body mass index (BMI), maximum supraventricular beats (SPB) per minute, and total amount of cardioplegia as independent predictors of postoperative AF. Patients developing AF showed limited diurnal variation of HRV preoperatively. All HRV parameters decreased significantly in all patients postoperatively. The significant postoperative increase in atrial areas and atrial peptides did not differ between patients developing AF and those who did not. TEA had no effect on the incidence of postoperative AF, but resulted in lower heart rate, less increase in adrenaline levels, and decreased neuropeptide levels (reflecting sympathetic and parasympathetic activity). AF was initiated by an SPB in 72.4% of non-TEA and 100% of TEA treated patients, whereas changes in heart rate only, before onset, were seen in 17.2% non-TEA patients.</p><p>The observed risk factors, SPB and cardioplegia, may both induce electrophysiological changes known to increase the susceptibility to AF. The observed postoperative atrial dilatation and autonomic imbalance, indicated by HRV and neuropeptide levels, may further favour the development of AF. The observation that a majority of postoperative AF was initiated by a premature atrial contraction supports our hypothesis that latent atrial foci may be a major trigger mechanism of postoperative AF.</p>

The aim was to study pathophysiological mechanisms and risk factors for developing atrial fibrillation (AF) after coronary artery bypass grafting (CABG), and the effect of thoracic epidural anaesthesia (TEA). The study comprised 141 patients undergoing CABG, including 45 patients randomised for TEA intra- and postoperatively. All patients underwent 24-hour Holter monitoring pre- and postoperatively for the analysis of arrhythmias and heart rate variability (HRV). Catecholamines and neuropeptides (reflecting sympathetic and parasympathetic activity), atrial peptides and echocardiographically assessed atrial arias were obtained pre- and postoperatively. Logistic regression analysis identified body mass index (BMI), maximum supraventricular beats (SPB) per minute, and total amount of cardioplegia as independent predictors of postoperative AF. Patients developing AF showed limited diurnal variation of HRV preoperatively. All HRV parameters decreased significantly in all patients postoperatively. The significant postoperative increase in atrial areas and atrial peptides did not differ between patients developing AF and those who did not. TEA had no effect on the incidence of postoperative AF, but resulted in lower heart rate, less increase in adrenaline levels, and decreased neuropeptide levels (reflecting sympathetic and parasympathetic activity). AF was initiated by an SPB in 72.4% of non-TEA and 100% of TEA treated patients, whereas changes in heart rate only, before onset, were seen in 17.2% non-TEA patients. The observed risk factors, SPB and cardioplegia, may both induce electrophysiological changes known to increase the susceptibility to AF. The observed postoperative atrial dilatation and autonomic imbalance, indicated by HRV and neuropeptide levels, may further favour the development of AF. The observation that a majority of postoperative AF was initiated by a premature atrial contraction supports our hypothesis that latent atrial foci may be a major trigger mechanism of postoperative AF.

In Part I we found that the CYP2C9 genotype appears to influence the diastolic blood pressure response to the angiotensin II-receptor antagonist irbesartan in patients with hypertension and left ventricular hypertrophy. Those with the *1/*2 genotype (slower metabolism) responded better than those with the *1/*1 genotype (normal metabolism), likely due to a slower elimination of the drug. We further found that a +9/-9 exon 1 polymorphism of the B2 bradykinin receptor gene – shown to affect mRNA expression - appears to influence the regression of left ventricular mass during therapy with irbesartan or the beta-blocker atenolol in the same patients. Subjects with the -9/-9 genotype (higher mRNA expression) had a greater regression than carriers of the +9 allele. In Part II we found that women on digoxin therapeutic drug monitoring have higher serum digoxin concentrations (SDCs) as compared to men (1.54±0.04 [nmol/L±SE] vs 1.20±0.05 [nmol/L±SE], p&lt;0.001), which could be of importance since an SDC &gt;1.4 nmol/L has been associated with increased mortality. We further found that coadministration of P-glycoprotein inhibitors with digoxin was common (47%) among the same patients, and that the SDC increased in a stepwise fashion with the number of P-glycoprotein inhibitors (20-60%). Lastly, we found that patients admitted to Swedish coronary care units with atrial fibrillation without heart failure and who had been given digoxin had a higher 1-year mortality than those not given digoxin (RR 1.44 [95% CI 1.29-1.60], adjustment made for potential confounders). In conclusion, Part I represents a further step in the pharmacogenomic prospect of tailoring antihypertensive therapy. Part II indicates that heightened attention to the digoxin-dose is warranted in women, that there is a need for awareness about P-glycoprotein interactions with digoxin, and that long-term therapy with digoxin is an independent risk factor for death among patients with atrial fibrillation without heart failure.

The overall aim of this thesis was to study the influence of physical activity on health. Risks and benefits of physical activity is of particular interest since there is a global trend of less physical activity among youths and adults. In order to investigate this aim we used a database from a large cross country ski race, Vasaloppet, with participants with a wide age range, and with both elite athletes and ordinary people who exercise and promote their health. The most serious risk of strenuous exercise is sudden death and it is challenging to identify preventive effects of major endemic diseases. Using epidemiological methodology we studied 200 000 Vasaloppet skiers and compared them with the general population. Based on personal identification numbers we added data from Swedish national personal and health registers, clinical registers as the cancer register, Swedeheart, or Swedish stroke register, and socioeconomic information from Statistics Sweden. In the Vasaloppet database we collected data on age, gender, finish time and number of races during the period 1989 to 2010. We evaluated risk of death during the race in two papers (I,II). During 90 years of annual races, cardiac arrest occurred in 20 skiers, of which five survived. The death rate is in average two per 100 000 skiers. We also studied the association with cancer incidence (paper III). The overall reduction of cancer was modest among skiers compared with the general population, but for cancers related to lifestyle the risks were markedly lower. We investigated the risk for recurrent myocardial infarction and found a 30% reduction among skiers (paper IV). In paper V we showed that skiers with a first stroke have a lower incidence of all-cause death. The skiers had a higher frequency of atrial fibrillation but had less severe stroke and no increased risk of recurrent stroke. Thus our data suggest that a lifestyle with a high level of physical activity may work as a protection after a cardiovascular event. Summary: The short excess mortality in endurance physical activity is by far outweighed by the long term protective effect of exercise in cardiovascular diseases and cancer.

Postoperative atrial fibrillation (AF) after cardiac surgery with cardiopulmonary bypass (CPB) remains unresolved problem. Some authors noticed that there were changes in electrolyte balance after coronary artery bypass grafting (CABG) surgery with CPB. The changes in serum magnesium level and their relation with the rate of postoperative AF are usually analyzed in scientific publications. The aim of the study has been to estimate the relationship between the rate of postoperative AF and the changes in serum electrolyte concentration and their urinary excretion after CABG surgery with CPB. The goals: 1) To estimate the rate and the character of postoperative AF and its influence on haemodynamics after CABG surgery. 2) To estimate changes in serum K+, Na+, Mg++, Ca++, Cl–, P– concentration and compare them between the patients who received, and who did not receive magnesium sulphate supplementation during the surgery. 3)To estimate changes of urinary excretion of K+, Na+, Mg++, Ca++, Cl–, P– and compare them between the patients who received, and who did not receive magnesium sulphate supplementation during the surgery. 3) To evaluate the effects of intraoperatively infused magnesium sulphate on the rate of postoperative AF in the early postoperative period. In our study the rate of postoperative AF was 27.4 %. AF in 91.3 % of cases was tachyarrhythmic, but haemodynamic remained stabile. Serum Mg++ level was > 1.05 mmol/l during the suregry in all patients. The infusion of... [to full text]

The aim of present study was to investigate the prognostic value of plasma and atrial tissue expression of prothrombotic, proinflammatory and extracellular matrix turnover indices for the development of atrial fibrillation (AF) after on-pump coronary artery bypass grafting (CABG) surgery and to describe atrial ultrastructural changes in patients suffering from severe coronary artery disease. Methods: Blood samples were obtained from peripheral vein (PV) and from intracardiac chambers (right atrium (RA), right atrial appendage (RAA), left atrium (LA) and left atrial appendage (LAA)) amongst 100 consecutive patients undergoing elective on-pump CABG. Biomarker (high sensitivity C reactive protein (hs-CRP), interleukin 6 (IL-6), von Willebrand factor (vWF), tissue factor (TF), matrix metalloproteinase 9 (MMP-9) and tissue inhibitor of matrix metalloproteinase 1 (TIMP-1)) concentrations were related to incident AF (in 30 days after CABG). The RAA and LAA tissues were tested for expression of vWF, TF, IL-6, MMP-9 and TIMP-1 using immunohistochemistry. The ultrastructure of the RAA and LAA in 20 patients was examined by electron microscopy. Results: Levels of plasma vWF, TF, hs-CRP, MMP-9 and TIMP-1 differ in-between various intracardiac sampling sites. Higher plasma hs-CRP levels in the PV, RAA and LA, higher plasma IL-6 levels in the RAA, LA and LAA and higher plasma MMP-9 levels in the LAA are associated with postoperative AF. An increased expression of vWF by the LAA is a risk... [to full text] / Tyrimo tikslas – išaiškinti prognostinę kraujo plazmoje ir prieširdžių audinyje nustatomų prokoaguliacinių, prouždegiminių citokinų ir ekstraląstelinio matrikso degradacijos žymenų vertę pooperacinio prieširdžių virpėjimo (PV) išsivystymui pacientams, kuriems atliekama izoliuota AVJO su dirbtine kraujo apytaka (DKA) bei aprašyti šių pacientų prieširdžių audinio ultrastruktūros pakitimus. Metodai: Kraujo mėginiai paimti iš 5 skirtingų 100 pacientų, kuriems buvo atliekama izoliuota AVJO su DKA, vietų: periferinio kraujo (PK), dešiniojo prieširdžio (DP), dešiniojo prieširdžio ausytės (DPA), kairiojo prieširdžio (KP), kairiojo prieširdžio ausytės (KPA). Kraujo plazmos citokinai (von Willebrand faktorius (vWF), audinių faktorius (AF), didelio jautrumo C reaktyvus baltymas (dj-CRB), interleukinas 6 (IL-6), matrikso metaloproteinazė 9 (MMP-9) bei matrikso metaloproteinazių audinių inhibitorius 1 (TIMP-1)) tirti imunofermentiniais metodais. DPA ir KPA biopsijos tirtos imunohistocheminiais metodais dėl vWF, AF, IL-6, MMP-9 bei TIMP-1 ekspresijos. DPA ir KPA ultrastruktūros pakitimai ištirti 20-iai pacientų elektroninės mikroskopijos būdu. Rezultatai: Nustatėme, kad plazmos vWF, AF, MMP-9, TIMP-1 ir dj-CRB koncentracijos skiriasi įvairiose prieširdžių vietose. Didesnės plazmos dj-CRB koncentracijos PK, DPA ir KP, taip pat plazmos IL-6 koncentracijos DPA, KP ir KPA bei plazmos MMP-9 koncentracija KPA buvo susiję su pooperacinio PV kilimu. vWF žymesnė ekspresija KPA buvo susijusi su PV... [toliau žr. visą tekstą]

Tyrimo tikslas – išaiškinti prognostinę kraujo plazmoje ir prieširdžių audinyje nustatomų prokoaguliacinių, prouždegiminių citokinų ir ekstraląstelinio matrikso degradacijos žymenų vertę pooperacinio prieširdžių virpėjimo (PV) išsivystymui pacientams, kuriems atliekama izoliuota AVJO su dirbtine kraujo apytaka (DKA) bei aprašyti šių pacientų prieširdžių audinio ultrastruktūros pakitimus. Metodai: Kraujo mėginiai paimti iš 5 skirtingų 100 pacientų, kuriems buvo atliekama izoliuota AVJO su DKA, vietų: periferinio kraujo (PK), dešiniojo prieširdžio (DP), dešiniojo prieširdžio ausytės (DPA), kairiojo prieširdžio (KP), kairiojo prieširdžio ausytės (KPA). Kraujo plazmos citokinai (von Willebrand faktorius (vWF), audinių faktorius (AF), didelio jautrumo C reaktyvus baltymas (dj-CRB), interleukinas 6 (IL-6), matrikso metaloproteinazė 9 (MMP-9) bei matrikso metaloproteinazių audinių inhibitorius 1 (TIMP-1)) tirti imunofermentiniais metodais. DPA ir KPA biopsijos tirtos imunohistocheminiais metodais dėl vWF, AF, IL-6, MMP-9 bei TIMP-1 ekspresijos. DPA ir KPA ultrastruktūros pakitimai ištirti 20-iai pacientų elektroninės mikroskopijos būdu. Rezultatai: Nustatėme, kad plazmos vWF, AF, MMP-9, TIMP-1 ir dj-CRB koncentracijos skiriasi įvairiose prieširdžių vietose. Didesnės plazmos dj-CRB koncentracijos PK, DPA ir KP, taip pat plazmos IL-6 koncentracijos DPA, KP ir KPA bei plazmos MMP-9 koncentracija KPA buvo susiję su pooperacinio PV kilimu. vWF žymesnė ekspresija KPA buvo susijusi su PV... [toliau žr. visą tekstą] / The aim of present study was to investigate the prognostic value of plasma and atrial tissue expression of prothrombotic, proinflammatory and extracellular matrix turnover indices for the development of atrial fibrillation (AF) after on-pump coronary artery bypass grafting (CABG) surgery and to describe atrial ultrastructural changes in patients suffering from severe coronary artery disease. Methods: Blood samples were obtained from peripheral vein (PV) and from intracardiac chambers (right atrium (RA), right atrial appendage (RAA), left atrium (LA) and left atrial appendage (LAA)) amongst 100 consecutive patients undergoing elective on-pump CABG. Biomarker (high sensitivity C reactive protein (hs-CRP), interleukin 6 (IL-6), von Willebrand factor (vWF), tissue factor (TF), matrix metalloproteinase 9 (MMP-9) and tissue inhibitor of matrix metalloproteinase 1 (TIMP-1)) concentrations were related to incident AF (in 30 days after CABG). The RAA and LAA tissues were tested for expression of vWF, TF, IL-6, MMP-9 and TIMP-1 using immunohistochemistry. The ultrastructure of the RAA and LAA in 20 patients was examined by electron microscopy. Results: Levels of plasma vWF, TF, hs-CRP, MMP-9 and TIMP-1 differ in-between various intracardiac sampling sites. Higher plasma hs-CRP levels in the PV, RAA and LA, higher plasma IL-6 levels in the RAA, LA and LAA and higher plasma MMP-9 levels in the LAA are associated with postoperative AF. An increased expression of vWF by the LAA is a risk... [to full text]