Thesis (Ph. D.)--University of Oklahoma. / Includes bibliographical references (leaves 148-162).

La dysfonction endothéliale vasculaire, processus majeur initiant l’athérosclérose, est étroitement liée à l’altération de la synthèse et/ou biodisponibilité du monoxyde d’azote (NO), dont l’arginine est le précurseur. Elle apparait aussi dès la phase postprandiale après un repas gras et sucré. Chez des sujets avec des facteurs de risque cardiométabolique, une supplémentation orale en arginine a un effet bénéfique sur des fonctions associées au NO. Aucune donnée ne permet cependant de lier la mise à disposition de l’arginine et la synthèse de NO, en situation normale ou de risque cardiométabolique. De plus, peu d’études ont étudié l’effet d’une supplémentation en arginine, dans un contexte nutritionnel (faible dose et libération lente) chez des sujets avec des facteurs de risque cardiométabolique. Ce travail vise donc à évaluer l’effet d’une supplémentation nutritionnelle en arginine, sur le métabolisme de l’arginine et la fonction endothéliale (FE), chez des sujets sains présentant des facteurs de risque cardiométabolique. Dans une première étude clinique, nous avons ainsi comparé la biodisponibilité de l’arginine ingérée et son utilisation pour la synthèse de NO, selon la présence de facteurs de risque cardiométabolique, et selon qu’elle était consommée sous une forme à libération immédiate (LI) ou sous une forme à libération prolongée (LP), mimant la mise à disposition naturelle de l’arginine alimentaire. Puis, dans une deuxième étude clinique, nous avons étudié l’effet de la supplémentation en arginine LP sur la FE à jeun et sur son altération postprandiale, chez des sujets sains présentant des facteurs de risque cardiométabolique; et si cet effet pourrait varier selon leur argininémie basale. Ce travail de thèse a ainsi mis en évidence une utilisation de l’arginine ingérée plus élevée pour la synthèse de NO chez les sujets avec des facteurs de risque cardiométabolique, et plus élevée avec la forme LP qu’avec la forme LI, en particulier chez ces sujets à risque. La deuxième étude, quant à elle, a révélé que les effets de la supplémentation en arginine-LP variaient selon l’argininémie basale des sujets présentant des facteurs de risque cardiométabolique. Chez les sujets avec une argininémie basale relativement plus faible, l’arginine-LP a atténué la diminution postprandiale de la FE et a conduit à une FE significativement meilleure à la fin de la période postprandiale. / Vascular endothelial dysfunction, the hallmark of early atherosclerosis, results from an impairment of the synthesis and/or bioavailability of nitric oxide (NO), the precursor of which is arginine. Endothelial dysfunction is also known to be induced transiently by a high-fat meal. In subject with cardiometabolic risk factors, oral arginine supplementation has a beneficial effect on NO-related physiological functions. However, no data relates the availability of arginine to the synthesis of NO in normal or cardiometabolic risk condition. In addition, few studies only have investigated the effect of arginine supplementation in a nutritional context (low dose and slow release) in subjects with cardiometabolic risk factors. This work aims to evaluate the effect of a nutritional arginine supplementation, on the arginine metabolism and endothelial function in healthy subjects with cardiometabolic risk factors. In a first clinical study, we have compared the bioavailability of oral arginine and its utilization for NO synthesis, as a function of the presence of cardiometabolic risk factors, and as a function of the form of release (immediate release, IR, as free arginine, or sustained release, SR, which mimics the slow release of dietary arginine). Then, in a second clinical study, we studied the effect of SR-arginine supplementation on fasting endothelial function and its postprandial alteration in healthy subjects with cardiometabolic factors. A further aim was to investigate whether this effect may vary according to the baseline arginine status of subjects. This thesis work has demonstrated a higher utilization of oral arginine for NO synthesis in subjects with cardiometabolic risk factors, and a higher utilization with the SR form, particularly in these subjects at risk. As to the second study, it showed that the SRarginine supplementation effects largely varied with baseline fasting arginine concentration of subjects with cardiometabolic risk factors. In subjects with a relatively lower baseline arginine concentration, SR-arginine attenuated the decrease in postprandial endothelial function and led to a significantly higher endothelial function at the end of the postprandial period.

Introdução: Estudos têm demonstrado a associação de doença arterial coronária (DAC) grave com triglicérides (TG) pós prandial. No entanto, a relação entre a aterosclerose leve a moderada e TG pós prandial não está bem estabelecida. No presente estudo avaliamos a relação entre TG pós prandial e DAC detectada por angiografia coronária por tomografia computadorizada (TC cor). Material e Métodos: Foram incluídos 130 pacientes (85 com DAC detectado pelo TC cor coronária e 45 sem DAC), submetidos a um teste de tolerância oral de gordura. Estudamos a lipemia pós prandial medindo TG de T0h para T6H com intervalos de duas horas, e analisamos a mudança TG ao longo do tempo através de um modelo linear misto multivariável longitudinal, utilizando como desfecho primário o log normal do TG. Resultados: Os pacientes com DAC eram mais velhos (56,5 ± 6,8 vs. 50,4 ± 7,1 anos, p < 0,001), predominantemente do sexo masculino (68,2% vs. 37,8%, p < 0,001) e com HDL-colesterol (HDL-C) menor (49 ± 14 vs. 54 ± 12 mg / dl, p = 0,015). A maioria dos indivíduos com DAC tinha aterosclerose leve com doença não obstrutiva (63,5%). Pacientes com DAC tiveram uma depuração mais lenta TG pós prandial de 4h a 6h (p < 0,05) em comparação com pacientes sem DAC. Estes resultados permanecerem significativos mesmo após ajuste para o TG de jejum, idade, sexo, índice de massa corporal e glicemia de jejum. No entanto, essas diferenças não foram significativas após o ajuste para o HDL-C de jejum. Conclusão: Os pacientes com DAC leve e moderada detectados pelo TC cor demonstraram alteração do metabolismo de TG pós prandial, com remoção mais lenta de TG, especialmente entre 4h e 6h quando comparados a indivíduos sem DAC. Esta diferença foi explicada em parte pelo menor HDL-C de jejum no grupo com DAC. Assim, embora TG pós prandial possa contribuir para o desenvolvimento de DAC, esta associação é parcialmente relacionada com a menor concentração de HDL-C em indivíduos com DAC / Background: Studies have demonstrated the association of severe coronary artery disease (CAD) with postprandial triglycerides (TG). Nevertheless the relationship between less severe atherosclerosis and postprandial triglycerides is less established. Objective: to study the relationship between postprandial TG and CAD detected by coronary computed tomographic angiography (CTA). Material and Methods: We enrolled 130 patients, (85 with CAD detected by coronary CTA and 45 without); who underwent an oral fat tolerance test. We studied the postprandial lipemia measuring TG from T0h to T6h with 2 hour intervals, and analyzed the TG change over time using a longitudinal multivariable linear mixed effects model with the log normal of the TG as the primary outcome.Results: Patients with CAD were older (56.5 ± 6.8 vs. 50.4 ± 7.1 years, p < 0.001), predominantly male (68.2% vs. 37.8%, p < 0.001) and had lower HDL-cholesterol (HDL-C) (49 ± 14 vs. 54 ± 12 mg/dL, p=0.015). The majority of individuals with CAD had mild atherosclerosis with non-obstructive disease (63.6%). Patients with CAD had a slower clearance of postprandial TG change from 4h to 6h (p < 0.05) compared to patients without CAD. These results remained significant after adjustment for fasting TG, age, gender, body mass index and glucose. However, those differences did not reach statistical significance after adjustment for fasting HDL-C. Conclusion: Patients with mild and moderate CAD detected by coronary CTA had an impaired postprandial metabolism, with a delayed TG clearance, when compared to individuals with no CAD. This difference was partially explained by the lower HDL-C. Thus, though postprandial TG may contribute to the development of CAD, this association is partially related to the low HDL-C in individuals with CAD

Introdução: Estudos têm demonstrado a associação de doença arterial coronária (DAC) grave com triglicérides (TG) pós prandial. No entanto, a relação entre a aterosclerose leve a moderada e TG pós prandial não está bem estabelecida. No presente estudo avaliamos a relação entre TG pós prandial e DAC detectada por angiografia coronária por tomografia computadorizada (TC cor). Material e Métodos: Foram incluídos 130 pacientes (85 com DAC detectado pelo TC cor coronária e 45 sem DAC), submetidos a um teste de tolerância oral de gordura. Estudamos a lipemia pós prandial medindo TG de T0h para T6H com intervalos de duas horas, e analisamos a mudança TG ao longo do tempo através de um modelo linear misto multivariável longitudinal, utilizando como desfecho primário o log normal do TG. Resultados: Os pacientes com DAC eram mais velhos (56,5 ± 6,8 vs. 50,4 ± 7,1 anos, p < 0,001), predominantemente do sexo masculino (68,2% vs. 37,8%, p < 0,001) e com HDL-colesterol (HDL-C) menor (49 ± 14 vs. 54 ± 12 mg / dl, p = 0,015). A maioria dos indivíduos com DAC tinha aterosclerose leve com doença não obstrutiva (63,5%). Pacientes com DAC tiveram uma depuração mais lenta TG pós prandial de 4h a 6h (p < 0,05) em comparação com pacientes sem DAC. Estes resultados permanecerem significativos mesmo após ajuste para o TG de jejum, idade, sexo, índice de massa corporal e glicemia de jejum. No entanto, essas diferenças não foram significativas após o ajuste para o HDL-C de jejum. Conclusão: Os pacientes com DAC leve e moderada detectados pelo TC cor demonstraram alteração do metabolismo de TG pós prandial, com remoção mais lenta de TG, especialmente entre 4h e 6h quando comparados a indivíduos sem DAC. Esta diferença foi explicada em parte pelo menor HDL-C de jejum no grupo com DAC. Assim, embora TG pós prandial possa contribuir para o desenvolvimento de DAC, esta associação é parcialmente relacionada com a menor concentração de HDL-C em indivíduos com DAC / Background: Studies have demonstrated the association of severe coronary artery disease (CAD) with postprandial triglycerides (TG). Nevertheless the relationship between less severe atherosclerosis and postprandial triglycerides is less established. Objective: to study the relationship between postprandial TG and CAD detected by coronary computed tomographic angiography (CTA). Material and Methods: We enrolled 130 patients, (85 with CAD detected by coronary CTA and 45 without); who underwent an oral fat tolerance test. We studied the postprandial lipemia measuring TG from T0h to T6h with 2 hour intervals, and analyzed the TG change over time using a longitudinal multivariable linear mixed effects model with the log normal of the TG as the primary outcome.Results: Patients with CAD were older (56.5 ± 6.8 vs. 50.4 ± 7.1 years, p < 0.001), predominantly male (68.2% vs. 37.8%, p < 0.001) and had lower HDL-cholesterol (HDL-C) (49 ± 14 vs. 54 ± 12 mg/dL, p=0.015). The majority of individuals with CAD had mild atherosclerosis with non-obstructive disease (63.6%). Patients with CAD had a slower clearance of postprandial TG change from 4h to 6h (p < 0.05) compared to patients without CAD. These results remained significant after adjustment for fasting TG, age, gender, body mass index and glucose. However, those differences did not reach statistical significance after adjustment for fasting HDL-C. Conclusion: Patients with mild and moderate CAD detected by coronary CTA had an impaired postprandial metabolism, with a delayed TG clearance, when compared to individuals with no CAD. This difference was partially explained by the lower HDL-C. Thus, though postprandial TG may contribute to the development of CAD, this association is partially related to the low HDL-C in individuals with CAD