Introdução: A indicação de endarterectomia carotídea (EAC) profilática em conjunto com revascularização miocárdica (CRM) permanece assunto indefinido. A cirurgia conjunta é amplamente difundida, mas seus resultados vêm sendo questionados. Método: Coorte retrospectiva de 691 pacientes submetidos à CRM, escolhidos aleatoriamente. Avaliação realizada para dados gerais, presença de lesão carotídea, ateromatose aórtica, desfechos neurológicos e óbito. Resultados: Dentre 691 pacientes submetidos à CRM, 16 pacientes apresentaram acidentes vasculares cerebrais (AVC). Dentre esses, 11 pacientes (68.75%) apresentaram AVC localizados em áreas não compatíveis com as lesões carotídeas, sendo três deles com lesões calcificadas na aorta ascendente. Os pacientes com estenose carotídea apresentaram taxa similar de eventos neurológicos totais, AVC e óbito, comparados com pacientes sem estenose carotídea. Um subgrupo de 35 pacientes com estenose carotídea foi submetido à cirurgia coronariana com (14 pacientes) ou sem (21 pacientes) cirurgia de carótida, obtendo-se taxa de eventos neurológicos totais, AVC e óbito estatisticamente semelhantes. Os pacientes com calcificações aórticas apresentaram risco maior de eventos neurológicos (14,58% versus 6.55%, p=0.011), AVC (3,12% versus 2,18%, p=0,47) e óbito (8,33% versus 4,37%, p=0.12). Discussão: Os eventos neurológicos após CRM correlacionam-se com ateromatose aórtica. Os AVC freqüentemente não têm relação linear com a estenose carotídea. Estratégias para minimizar embolia da aorta podem diminuir as taxas de intercorrências neurológicas. / Introduction: The management of patients with simultaneous disease of carotid and coronary arteries is controversial. Studies showed that aortic calcifications might play a role in postoperative stroke at coronary artery bypass graft (CABG), carotid lesions may not be as important as previously considered. Method: A retrospective cohort of a randomly selected group (including elective and emergency operations) of 691 patients submitted to CABG was reviewed for general data, neurological complications and mortality. Results: Among 691 CABGs 16 patients had postoperative stroke. Among these, 11 patients (68.75%) had strokes not matching carotid lesions and anatomic presentation, three of those had detectable aortic calcifications. The patients with critical carotid stenosis had similar rates of neurological events, stroke and death as compared to patients without. The patients with aortic calcifications presented a higher risk of neurological events (14.58% versus 6.55%, p=0.011), stroke (3.12% versus 2.18%, p=0.47) and death (8.33% versus 4.37%, p=0.12). Discussion: The postoperative neurological events after CABG can be related to aortic calcifications. The strokes after coronary bypass may occur independently of the carotid lesions. Strategies to prevent aortic emboli may help preventing many post-operative strokes.

Introdução: A indicação de endarterectomia carotídea (EAC) profilática em conjunto com revascularização miocárdica (CRM) permanece assunto indefinido. A cirurgia conjunta é amplamente difundida, mas seus resultados vêm sendo questionados. Método: Coorte retrospectiva de 691 pacientes submetidos à CRM, escolhidos aleatoriamente. Avaliação realizada para dados gerais, presença de lesão carotídea, ateromatose aórtica, desfechos neurológicos e óbito. Resultados: Dentre 691 pacientes submetidos à CRM, 16 pacientes apresentaram acidentes vasculares cerebrais (AVC). Dentre esses, 11 pacientes (68.75%) apresentaram AVC localizados em áreas não compatíveis com as lesões carotídeas, sendo três deles com lesões calcificadas na aorta ascendente. Os pacientes com estenose carotídea apresentaram taxa similar de eventos neurológicos totais, AVC e óbito, comparados com pacientes sem estenose carotídea. Um subgrupo de 35 pacientes com estenose carotídea foi submetido à cirurgia coronariana com (14 pacientes) ou sem (21 pacientes) cirurgia de carótida, obtendo-se taxa de eventos neurológicos totais, AVC e óbito estatisticamente semelhantes. Os pacientes com calcificações aórticas apresentaram risco maior de eventos neurológicos (14,58% versus 6.55%, p=0.011), AVC (3,12% versus 2,18%, p=0,47) e óbito (8,33% versus 4,37%, p=0.12). Discussão: Os eventos neurológicos após CRM correlacionam-se com ateromatose aórtica. Os AVC freqüentemente não têm relação linear com a estenose carotídea. Estratégias para minimizar embolia da aorta podem diminuir as taxas de intercorrências neurológicas. / Introduction: The management of patients with simultaneous disease of carotid and coronary arteries is controversial. Studies showed that aortic calcifications might play a role in postoperative stroke at coronary artery bypass graft (CABG), carotid lesions may not be as important as previously considered. Method: A retrospective cohort of a randomly selected group (including elective and emergency operations) of 691 patients submitted to CABG was reviewed for general data, neurological complications and mortality. Results: Among 691 CABGs 16 patients had postoperative stroke. Among these, 11 patients (68.75%) had strokes not matching carotid lesions and anatomic presentation, three of those had detectable aortic calcifications. The patients with critical carotid stenosis had similar rates of neurological events, stroke and death as compared to patients without. The patients with aortic calcifications presented a higher risk of neurological events (14.58% versus 6.55%, p=0.011), stroke (3.12% versus 2.18%, p=0.47) and death (8.33% versus 4.37%, p=0.12). Discussion: The postoperative neurological events after CABG can be related to aortic calcifications. The strokes after coronary bypass may occur independently of the carotid lesions. Strategies to prevent aortic emboli may help preventing many post-operative strokes.

Introdução: A indicação de endarterectomia carotídea (EAC) profilática em conjunto com revascularização miocárdica (CRM) permanece assunto indefinido. A cirurgia conjunta é amplamente difundida, mas seus resultados vêm sendo questionados. Método: Coorte retrospectiva de 691 pacientes submetidos à CRM, escolhidos aleatoriamente. Avaliação realizada para dados gerais, presença de lesão carotídea, ateromatose aórtica, desfechos neurológicos e óbito. Resultados: Dentre 691 pacientes submetidos à CRM, 16 pacientes apresentaram acidentes vasculares cerebrais (AVC). Dentre esses, 11 pacientes (68.75%) apresentaram AVC localizados em áreas não compatíveis com as lesões carotídeas, sendo três deles com lesões calcificadas na aorta ascendente. Os pacientes com estenose carotídea apresentaram taxa similar de eventos neurológicos totais, AVC e óbito, comparados com pacientes sem estenose carotídea. Um subgrupo de 35 pacientes com estenose carotídea foi submetido à cirurgia coronariana com (14 pacientes) ou sem (21 pacientes) cirurgia de carótida, obtendo-se taxa de eventos neurológicos totais, AVC e óbito estatisticamente semelhantes. Os pacientes com calcificações aórticas apresentaram risco maior de eventos neurológicos (14,58% versus 6.55%, p=0.011), AVC (3,12% versus 2,18%, p=0,47) e óbito (8,33% versus 4,37%, p=0.12). Discussão: Os eventos neurológicos após CRM correlacionam-se com ateromatose aórtica. Os AVC freqüentemente não têm relação linear com a estenose carotídea. Estratégias para minimizar embolia da aorta podem diminuir as taxas de intercorrências neurológicas. / Introduction: The management of patients with simultaneous disease of carotid and coronary arteries is controversial. Studies showed that aortic calcifications might play a role in postoperative stroke at coronary artery bypass graft (CABG), carotid lesions may not be as important as previously considered. Method: A retrospective cohort of a randomly selected group (including elective and emergency operations) of 691 patients submitted to CABG was reviewed for general data, neurological complications and mortality. Results: Among 691 CABGs 16 patients had postoperative stroke. Among these, 11 patients (68.75%) had strokes not matching carotid lesions and anatomic presentation, three of those had detectable aortic calcifications. The patients with critical carotid stenosis had similar rates of neurological events, stroke and death as compared to patients without. The patients with aortic calcifications presented a higher risk of neurological events (14.58% versus 6.55%, p=0.011), stroke (3.12% versus 2.18%, p=0.47) and death (8.33% versus 4.37%, p=0.12). Discussion: The postoperative neurological events after CABG can be related to aortic calcifications. The strokes after coronary bypass may occur independently of the carotid lesions. Strategies to prevent aortic emboli may help preventing many post-operative strokes.

Les maladies cardiovasculaires (MCV) demeurent au tournant de ce siècle la principale cause de mortalité dans le monde. Parmi les facteurs de risque, l’hypercholestérolémie et l’obésité abdominale sont directement liées au développement précoce de l’athérosclérose. L’hypercholestérolémie familiale, communément associée à une déficience des récepteurs des lipoprotéines de basse densité (LDLR), est connue comme cause de maladie précoce d’athérosclérose et de calcification aortique chez l’humain. La subtilisine convertase proprotéine/kexine du type 9 (PCSK9), membre de la famille des proprotéines convertases, est trouvée indirectement associée aux MCV par son implication dans la dégradation du LDLR. Chez l'humain, des mutations du gène PCSK9 conduisent soit à une hypercholestérolémie familiale, soit à une hypocholestérolémie, selon que la mutation entraîne un gain ou une perte de fonction, respectivement. Il demeure incertain si les individus porteurs de mutations causant un gain de fonction de la PCSK9 développeront une calcification aortique ou si des mutations entraînant une perte de fonction provoqueront une obésité abdominale. Dans cette étude, nous avons examiné : 1) l’effet d’une surexpression de PCSK9 dans le foie de souris sur la calcification aortique ; 2) les conséquences d’une déficience en PCSK9 (Pcsk9 KO), mimant une inhibition pharmacologique, sur le tissu graisseux. Nous avons utilisé un modèle de souris transgénique (Tg) surexprimant le cDNA de PCSK9 de souris dans les hépatocytes de souris et démontrons par tomographie calculée qu’une calcification survient de façon moins étendue chez les souris PCSK9 Tg que chez les souris déficientes en LDLR. Alors que le PCSK9 Tg et la déficience en LDLR causaient tous deux une hypercholestérolémie familiale, les niveaux seuls de cholestérol circulant ne parvenaient pas à prédire le degré de calcification aortique. Dans une seconde étude, nous utilisions des souris génétiquement manipulées dépourvues de PSCK9 et démontrons que l’accumulation de graisses viscérales (adipogenèse) apparaît régulée par la PCSK9 circulante. Ainsi, en l’absence de PCSK9, l’adipogenèse viscérale augmente vraisemblablement par régulation post-traductionnelle des récepteurs à lipoprotéines de très basse densité (VLDLR) dans le tissu adipeux. Ces deux modèles mettent en évidence un équilibre dynamique de la PCSK9 dans des voies métaboliques différentes, réalisant un élément clé dans la santé cardiovasculaire. Par conséquent, les essais d’investigations et d’altérations biologiques de la PCSK9 devraient être pris en compte dans un modèle animal valide utilisant une méthode sensible et en portant une attention prudente aux effets secondaires de toute intervention. / Cardiovascular disease (CVD) is the leading cause of death in the 21st century. Among risk factors, hypercholesterolemia and abdominal obesity are directly linked to premature development of atherosclerosis. Familial hypercholesterolemia, commonly due to low-density lipoprotein receptor (LDLR) deficiency, is known to cause premature atherosclerosis and aortic calcification in humans. Proprotein convertase subtilisin/kexin 9 (PCSK9), a member of the proprotein convertase family, is indirectly associated with CVD through enhanced LDLR degradation. Mutations in the human PCSK9 gene lead to either familial hypercholesterolemia or hypocholesterolemia, depending on whether the mutation causes a gain or a loss of function, respectively. It is uncertain if individuals carrying mutations causing a gain-of-function of PCSK9 will develop aortic calcification or whether loss-of-function mutations will lead to abdominal obesity. In this thesis, we investigated: 1) the effect of PCSK9 overexpression on aortic calcification; 2) the consequences of PSCK9 deficiency, mimicking pharmacological inhibition of PCSK9 on fat tissue. We employed a transgenic (Tg) mouse model overexpressing mouse PCSK9 and illustrated by micro-computerized tomography that calcification occurs to a lesser extent in PCSK9 Tg mice than in LDLR-deficient mice. While both PCSK9 Tg and LDLR deficiency caused familial hypercholesterolemia, circulating cholesterol levels alone could not dictate the degree of aortic calcification. In another study, we used genetically modified mice lacking PCSK9 and demonstrated that visceral fat accumulation (adipogenesis) is regulated by circulating PCSK9. Thus in the absence of PCSK9, visceral adipogenesis increases likely via post-translational regulation of very-low-density lipoproteins receptors (VLDLR) in the adipose tissue. In conclusion, these two studies highlight the dynamic balance of PCSK9 in different metabolic pathways, making it a key element in cardiovascular health. Consequently, attempts to survey and/or alter PCSK9 biology should be performed in a valid animal model using sensitive methods and with careful attention to side effects of any given intervention.

Les maladies cardiovasculaires (MCV) demeurent au tournant de ce siècle la principale cause de mortalité dans le monde. Parmi les facteurs de risque, l’hypercholestérolémie et l’obésité abdominale sont directement liées au développement précoce de l’athérosclérose. L’hypercholestérolémie familiale, communément associée à une déficience des récepteurs des lipoprotéines de basse densité (LDLR), est connue comme cause de maladie précoce d’athérosclérose et de calcification aortique chez l’humain. La subtilisine convertase proprotéine/kexine du type 9 (PCSK9), membre de la famille des proprotéines convertases, est trouvée indirectement associée aux MCV par son implication dans la dégradation du LDLR. Chez l'humain, des mutations du gène PCSK9 conduisent soit à une hypercholestérolémie familiale, soit à une hypocholestérolémie, selon que la mutation entraîne un gain ou une perte de fonction, respectivement. Il demeure incertain si les individus porteurs de mutations causant un gain de fonction de la PCSK9 développeront une calcification aortique ou si des mutations entraînant une perte de fonction provoqueront une obésité abdominale. Dans cette étude, nous avons examiné : 1) l’effet d’une surexpression de PCSK9 dans le foie de souris sur la calcification aortique ; 2) les conséquences d’une déficience en PCSK9 (Pcsk9 KO), mimant une inhibition pharmacologique, sur le tissu graisseux. Nous avons utilisé un modèle de souris transgénique (Tg) surexprimant le cDNA de PCSK9 de souris dans les hépatocytes de souris et démontrons par tomographie calculée qu’une calcification survient de façon moins étendue chez les souris PCSK9 Tg que chez les souris déficientes en LDLR. Alors que le PCSK9 Tg et la déficience en LDLR causaient tous deux une hypercholestérolémie familiale, les niveaux seuls de cholestérol circulant ne parvenaient pas à prédire le degré de calcification aortique. Dans une seconde étude, nous utilisions des souris génétiquement manipulées dépourvues de PSCK9 et démontrons que l’accumulation de graisses viscérales (adipogenèse) apparaît régulée par la PCSK9 circulante. Ainsi, en l’absence de PCSK9, l’adipogenèse viscérale augmente vraisemblablement par régulation post-traductionnelle des récepteurs à lipoprotéines de très basse densité (VLDLR) dans le tissu adipeux. Ces deux modèles mettent en évidence un équilibre dynamique de la PCSK9 dans des voies métaboliques différentes, réalisant un élément clé dans la santé cardiovasculaire. Par conséquent, les essais d’investigations et d’altérations biologiques de la PCSK9 devraient être pris en compte dans un modèle animal valide utilisant une méthode sensible et en portant une attention prudente aux effets secondaires de toute intervention. / Cardiovascular disease (CVD) is the leading cause of death in the 21st century. Among risk factors, hypercholesterolemia and abdominal obesity are directly linked to premature development of atherosclerosis. Familial hypercholesterolemia, commonly due to low-density lipoprotein receptor (LDLR) deficiency, is known to cause premature atherosclerosis and aortic calcification in humans. Proprotein convertase subtilisin/kexin 9 (PCSK9), a member of the proprotein convertase family, is indirectly associated with CVD through enhanced LDLR degradation. Mutations in the human PCSK9 gene lead to either familial hypercholesterolemia or hypocholesterolemia, depending on whether the mutation causes a gain or a loss of function, respectively. It is uncertain if individuals carrying mutations causing a gain-of-function of PCSK9 will develop aortic calcification or whether loss-of-function mutations will lead to abdominal obesity. In this thesis, we investigated: 1) the effect of PCSK9 overexpression on aortic calcification; 2) the consequences of PSCK9 deficiency, mimicking pharmacological inhibition of PCSK9 on fat tissue. We employed a transgenic (Tg) mouse model overexpressing mouse PCSK9 and illustrated by micro-computerized tomography that calcification occurs to a lesser extent in PCSK9 Tg mice than in LDLR-deficient mice. While both PCSK9 Tg and LDLR deficiency caused familial hypercholesterolemia, circulating cholesterol levels alone could not dictate the degree of aortic calcification. In another study, we used genetically modified mice lacking PCSK9 and demonstrated that visceral fat accumulation (adipogenesis) is regulated by circulating PCSK9. Thus in the absence of PCSK9, visceral adipogenesis increases likely via post-translational regulation of very-low-density lipoproteins receptors (VLDLR) in the adipose tissue. In conclusion, these two studies highlight the dynamic balance of PCSK9 in different metabolic pathways, making it a key element in cardiovascular health. Consequently, attempts to survey and/or alter PCSK9 biology should be performed in a valid animal model using sensitive methods and with careful attention to side effects of any given intervention.