京都大学 / 新制・課程博士 / 博士(医科学) / 甲第23815号 / 医科博第136号 / 新制||医科||9(附属図書館) / 京都大学大学院医学研究科医科学専攻 / (主査)教授 山下 潤, 教授 遊佐 宏介, 教授 伊藤 貴浩 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

The human body is a well tuned mechanism where systems work in synergy to provide a healthy quality of life. The human circulatory system transports oxygenated blood from the heart to the rest of the body delivering the proper nutrients for cells to function. When the heart malfunctions, serious complications can arise leading to sudden cardiac arrest. Congestive heart failure (CHF) is one heart disease that affects the synchrony of the heart’s ventricles. Cardiac resynchronization therapy (CRT) has been widely accepted as a treatment for CHF. Similar to traditional dual chamber pacing techniques, CRT adds a pacing lead to stimulate the left ventricle. Left ventricular leads are implanted via the coronary sinus which provides the easiest surgical access to the left ventricle. Another option for LV pacing is by using an epicardial lead. This option has proven to be safe and effective but requires major surgery. An epicardial lead is usually implanted by performing a thoracotomy. Many studies have been done to show the benefits of bi-ventricular pacing, therefore developing new methods to gain LV access safely and reliable are highly desirable. The epicardial satellite pacemaker, or EPI pacemaker, is a component of a larger CRT system. This implantable cardiac system is composed of a master pacing unit with leads and a remote satellite pacing unit. The master unit is a traditional CRT device electrically coupled to the right side of the heart. It controls the right atrium and ventricle via transvenous leads anchored to the endocardium of the heart. The master device generates the pacing pulses to stimulate the right atrium and right ventricle and a communications module to transmit pacing commands to the epicardial satellite device. The epicardial satellite pacemaker is a leadless device mounted directly on the epicardium of the left ventricle. The epicardial pacemaker can be implanted using a thoracoscopic procedure during implant of the master unit. In special events, it can be implanted using prophylactic techniques during heart bypass surgery of other surgical procedures where access to the heart is available. Much work needs to be done to prove the technology. But current RF communication capabilities in today’s devices offer the groundbreaking path to develop a satellite LV pacing design.

Le projet de cette thèse porte sur la graisse ectopique cardiaque et son lien avec les pathologies cardiovasculaires. Dans un premier travail, nous avons mis au point la technique de mesure du volume de graisse épicardique, et du contenu en triglycérides intramyocardique chez le patient obèse morbide en imagerie de résonance magnétique à 3T, et spectroscopie proton. Nous avons montré que les deux dépôts de graisse ectopique augmentent avec l’obésité, mais sans continuum avec la prise de poids. Alors que la graisse épicardique est liée aux paramètres de la tolérance glucidique, la graisse intramyocardique est liée à la fonction cardiaque. Dans un second travail, nous avons montré qu’une perte de poids induite par une chirurgie bariatrique induit une diminution significative de la graisse épicardique, sans modifier la graisse intramyocardique, suggérant une différence de flexibilité de ces graisses avec la perte de poids. Nous avons également exploré le lien entre graisse épicardique et athérosclérose. Sur une cohorte de volontaires sains, nous avons montré que l’accumulation de graisse épicardique était inversement corrélée à la vasoréactivité de la microcirculation coronaire, suggérant que la graisse épicardique pourrait influer de manière précoce la fonction endothéliale. Enfin, en utilisant une approche transcriptomique, nous avons montré une signature spécifique du TAE humain en fonction de sa localisation anatomique. Ces travaux ouvrent de nouvelles pistes dans la compréhension du développement de la graisse ectopique cardiaque. / Cardiac ectopic fat deposition and its link with cardiovascular pathophysiology was the aim of this PhD project. We first developed 3T cardiovascular magnetic resonance imaging assessment of epicardial fat volume, and proton spectroscopy measurement of myocardial triglyceride content in a cohort of morbid obese subjects. We demonstrated that the two cardiac depots increased with obesity, but not continuously with gain weight. While epicardial fat was related to glucose tolerance parameters, myocardial fat was related to cardiac function. We then studied the effect of bariatric surgery induced weight loss on epicardial and myocardial fat, and found a significant decrease in epicardial fat, but no change in myocardial fat, highlighting differences in the dynamics and flexibility of these two fat pads with weight loss. Focusing on epicardial fat and its potential role in atherosclerosis, we evaluated the effect of epicardial fat volume on endothelium dependent vasoreactivity of the coronary microcirculation, in highly selected healthy volunteers. We found that a high epicardial fat amount was associated with a lower coronary microvascular response, suggesting that epicardial fat could early influence endothelial function. Finally, we identified a specific signature of three anatomically distinct human epicardial adipose tissues, using a transcriptomic approach. All together, our data bring new insights in the comprehension of specific partitioning of cardiac ectopic lipid deposition.

Atualmente, temos a disposição modernas técnicas de mapeamento eletroanatômico gerando imagens tridimensionais da propagação do impulso nas câmaras cardíacas através de catéteres endocavitários. Apesar disso, poucos estudos estão disponíveis a respeito do mapeamento eletrofisiológico epicárdico. A avaliação intraoperatória de contratilidade miocárdica imediatamente após a revascularização miocárdica é visual e Ecocardiográfica, porém este é muito pouco utilizado para este fim. Há, portanto, a necessidade de desenvolvimento de novos métodos capazes de avaliar o impacto funcional da revascularização miocárdica. Objetivo: Avaliar a resposta intra-operatória de contratilidade miocárdica regional mediante o mapeamento epicárdico com eletrodo decapolar. Métodos: 20 pacientes serão submetidos a revascularização miocárdica e será realizado o mapeamento epicárdico com eletrodo decapolar após confecção da anastomose distal com perfusão seletiva para área revascularizada com a aorta pinçada e portanto sem perfusão para as demais artérias coronárias. Nesta análise será avaliado a duração do impulso do eletrograma. Concomitante será realizada fluxometria dos enxertos e comparada com o resultado obtido no mapeamento epicárdico. Resultados: A técnica é uma forma eficaz de avaliar a contratilidade miocárdica regional após a revascularização miocárdica seletiva. O fluxo intravascular dos enxertos estudados não interfere na duração do impulso durante a perfusão seletiva das áreas estudadas / At present, we have available modern tecnics of electroanatomic mapping generating tridimensional images of impulse propagation on heart chambers through intracavitary catheters. Despite this, very few scientific studies are available about epicardial electrophysiologic mapping. Intraoperative evaluation of myocardial contractility right after coronary artery bypass is visual and Echocardiographic, even though this is rarely used to this end. Therefore, there is a need for development of new methods capable of evaluate the functional impact of myocardial revascularization. Objective: Evaluate the intra-operative response of regional myocardial contractility with epicardial mapping with a decapolar catheter. Methods: 20 patients will be submitted to coronary artery bypass graft surgery and epicardial mapping with decapolar catheter was performed after distal anastomosis is made with selective perfusion on the revascularized area with cross clamped aorta, therefore without blood perfusion to the other coronary arteries. On this basis it will be evaluated the duration of the electrogram impulse. It was held the grafts flowmetry and compared to the results obtained on epicardial mapping. Results: The presented tecnic is an effective way to evaluate the regional myocardial contractility after the selective myocardial revascularization. The graft flowmetry doesn\'t interfere with the duration of the impulse obtained during the selective perfusion for the studied areas.

The development of the mature cardiovascular system is one of the most captivating stories in embryonic development. The heart is the first organ to form in embryogenesis, and is functional early in development to perfuse the embryo with blood supplying oxygen and the nutrients required for organogenesis. The structural changes in heart development required for formation of the mature four chambered heart are under tight molecular regulation. Severe defects manifest as gross structural malformations of the valves, septa, or vessels that result in physiological consequences that my include hypertension, arrhythmia, or heart failure and may ultimately lead to lethality. According to the American Heart Association, cardiovascular disease is the leading cause of mortality worldwide. A more detailed understanding of the origin of congenital heart defects is necessary for improving prediction, diagnosis, and treatment of cardiovascular disease. Derived from the epicardium, coronary vessel formation relies on growth factor as well as extracellular matrix (ECM) influences on cells of the epicardium that regulate proliferation, motility, invasion and differentiation. The Transforming Growth Factor β (TGFβ) family of receptors have been well described in regulating cardiovascular development. The Type III TGFβ receptor (TGFβR3) has been shown to be required for development of the coronary vessels. Mouse embryos lacking TGFβR3 exhibit inhibited invasion of epicardially derived cells (EPDCs) into the myocardium. This delay of cell invasion of EPDCs and formation of coronary vessels is lethal at E 14.5. Relative to Tgfbr3+/+ cells, epicardial cells lacking TGFβR3 are hypo-proliferative, deficient in cell invasion, and deficient in executing TGFβ ligand and High-Molecular Weight Hyaluronan (HMWHA) stimulated cell invasion. Hyaluronan (HMWHA) is a glycosaminoglycan unmodified sugar extracellular matrix (ECM) molecule synthesized by the Hyaluronan Synthase (Has) family of enzymes. Mouse embryos lacking Hyaluronan Synthase 2 (Has2) are lethal at E 9.5 as a result of severely blocked cardiogenesis due to insufficient endocardial EMT. HA serves structural and bioactive functions in its capacity to stimulate signal transduction pathways required for EMT. Src kinase is a non-receptor tyrosine kinase well characterized to function in growth factor as well as ECM signal transduction, but its role in epicardial cell biology is unclear. Our hypothesis is that Src kinase is a critical regulator of TGFβ and Hyaluronan induced epicardial cell invasion, differentiation and migration during coronary vessel development. Our studies reveal that Src activity is required for TGFβ2-induced synthesis of HA in epicardial cells. We show Src is required for TGFβ2-induced vascular smooth muscle differentiation as well as TGFβ2-induced EMT, cell invasion, and filamentous actin polymerization. Src activity is sufficient to drive epicardial activation of EMT, but not vascular smooth muscle differentiation. These data show that Src is required in the context of TGFβ2-stimulated invasion and differentiation, and sufficient to drive activation of EMT. Next we demonstrate that TGFβR3 and Src are required for HMWHA induced cell invasion and filamentous actin polymerization in epicardial cells. HMWHA induces activation of Src kinase in Tgfbr3+/+ epicardial cells, but not Tgfbr3-/- epicardial cells. siRNA knockdown of TGFβR3 in Tgfbr3+/+ epicardial cells subsequently stimulated with HMWHA phenocopy this deficit in Src activation. Tgfbr3-/- epicardial cells fail to activate Rac1 or RhoA GTPases in the presence of HMWHA. Finally, we demonstrate stimulus independent activation of TGFβR3 is sufficient to activate Src. Taken together, these constitute novel findings establishing TGFβR3 as an HMWHA responsive receptor that is upstream of Src signal transduction. Migration of the epicardium to cover the looped and functioning heart tube is an early step required for development of the coronary vessels. We demonstrate that Tgfbr3-/- epicardial cells are delayed in cell migration relative to Tgfbr3+/+ cells in a wound healing model of cell migration. Tgfbr3-/- cells lack expression of BMP2 mRNA, we found that exogenous BMP2 is sufficient to drive Tgfbr3-/- (but not Tgfbr3+/+) cell migration to levels comparable to unstimulated Tgfbr3+/+ epicardial cells, without enhancing cell proliferation. We demonstrate that Src is required for this BMP2 induced cell migration and filamentous actin polymerization in Tgfbr3-/- cells. These studies demonstrate mechanisms required for TGFβ ligand as well as HMWHA stimulated epicardial cell behavior changes have a common mediator in Src kinase, and provide novel insights into early events in the development of the cardiovascular system. The adult epicardium has been demonstrated to participate in repair of ischemic myocardium in mouse models of myocardial infarction. Expression of molecules required for coronary vessel development are re-expressed in this regeneration (as discussed in chapter 5). Elucidating these pathways will constitute important future targets in aiding in adult cardiovascular regeneration and cardioprotection in adult heart disease.

Made available in DSpace on 2015-07-22T20:50:25Z (GMT). No. of bitstreams: 0 Previous issue date: 2011-01-26. Added 1 bitstream(s) on 2015-08-11T03:25:26Z : No. of bitstreams: 1 Publico-0021a.pdf: 1600053 bytes, checksum: 7857382dabdbe2c1244a470f04a307d0 (MD5). Added 1 bitstream(s) on 2015-08-11T03:25:26Z : No. of bitstreams: 2 Publico-0021a.pdf: 1600053 bytes, checksum: 7857382dabdbe2c1244a470f04a307d0 (MD5) Publico-0021b.pdf: 1840605 bytes, checksum: 6332e90958fa262a4e0df6f8545a5303 (MD5). Added 1 bitstream(s) on 2015-08-11T03:25:26Z : No. of bitstreams: 3 Publico-0021a.pdf: 1600053 bytes, checksum: 7857382dabdbe2c1244a470f04a307d0 (MD5) Publico-0021b.pdf: 1840605 bytes, checksum: 6332e90958fa262a4e0df6f8545a5303 (MD5) Publico-0021c.pdf: 2001738 bytes, checksum: a1284696a0e1de7fec9bd415286e36b2 (MD5) / INTRODUÇÃO: Taquicardias Ventriculares Sustentadas (TVs) epicárdicas são comuns na Cardiopatia Chagásica Crônica (CCC). A ablação por cateter com radiofrequência, pode ser realizada com o auxílio de mapeamento eletroanatômico. O mapeamento eletroanatômico, por sua vez, necessita de definição especial, que pode ser incrementada com a integração de imagens oriundas de Tomografia Computadorizada do coração (TC do coração). A TC do coração pode fornecer a localização das áreas de fibrose, a extensão do comprometimento miocárdico, as características da anatomia coronariana e a função ventricular (esquerda e direita). Enquanto o acoplamento de imagens foi exaustivamente estudado no endocárdio, o acoplamento epicárdico e as informações advindas da aquisição de tomografia pré-procedimento não foram adequadamente avaliados até o momento. OBJETIVOS: Determinar a viabilidade técnica e a acurácia do mapeamento eletroanatômico com a integração de imagens associadas à TC em pacientes com TVS e CCC. Avaliar a precisão da TC em delimitar áreas de miocárdio anormal em comparação com o mapeamento eletroanatômico em portadores de CCC e TVS. MÉTODOS E RESULTADOS: Foi realizado o mapeamento e a ablação endocárdica e epicárdica em 8 pacientes portadores de CCC e TVS utilizando Carto® XP e sistema de integração de imagens Carto® Merge. A integração de imagens foi realizada utilizando TC em 3 fases para a obtenção do escore de cálcio, angiotomografia de coronárias e realce tardio. Para a comparação das imagens tridimensionais do sistema de mapeamento eletroanatômico e bidimensional da fluoroscopia, foi utilizado um editor gráfico vetorial. Este permitiu a comparação da distância entre a posição do cateter observado pela fluoroscopia e a obtida pelo mapa eletroanatômico. A diferença média entre os métodos analisados foi de 6,03mm (DP ±2,09mm). Cicatrizes estavam presentes no endocárdio e epicárdio de ambos ventrículos, sendo encontradas mais frequentemente na região póstero-basal de VE. A análise da contratilidade segmentar demonstrou-se superiora à técnica de realce tardio para a localização de miocárdio anormal conforme delimitado pelo mapeamento eletroanatomico em sensibilidade, valor preditivo positivo, acurácia e concordância. CONCLUSÃO: A combinação de mapeamento eletroanatômico e TC é tecnicamente possível e pode fornecer informações importantes para a ablação de pacientes com TV e CCC. / BACKGROUND: Chronic Chagasic Cardiomiopathy (CCC) is a parasitic disease where epicardial VTs are common. Eletroanatomic mapping merged with CT scan data is a useful tool for mapping the endocardium, and its accuracy in guiding ablation on the epicardium was not adequately evaluated . OBJECTIVE: Compare electronatomic map merged with Heart CT to fluoroscopy for epicardial ablation of CCC. Describe the distribution of the scars on CCC. METHODS AND RESULTS: We performed epicardial and endocardial mapping and ablation using electroanatomic mapping on eight patients and merged the map with coronary arteries CT Scan using at least three landmarks. To compare the 3D image obtained with 3dEA mapping with image integration capabilities and the 2D fluoroscopic image obtained during the ablation procedure we used vectorial computer graphic software in order to prove the images were equivalent and to compare the distance between the catheter tip on fluoroscopy to catheter tip on 3D EA map. EPRFCA was successfully performed in all patients and they did not present recurrence for at least 3 months follow up. The mean difference between the tip of the catheter on fluoroscopy and on the 3D model was 6.03 ± 2.09mm. Scars were present in the epicardium and endocardium and most of patients presented with posterior wall scars and RV scar. CONCLUSION: The combination of electroanatomic map and heart CT scan data is feasible and can be an important tool for EPRFCA in patients with CCC and VT. / TEDE / BV UNIFESP: Teses e dissertações

Atualmente, temos a disposição modernas técnicas de mapeamento eletroanatômico gerando imagens tridimensionais da propagação do impulso nas câmaras cardíacas através de catéteres endocavitários. Apesar disso, poucos estudos estão disponíveis a respeito do mapeamento eletrofisiológico epicárdico. A avaliação intraoperatória de contratilidade miocárdica imediatamente após a revascularização miocárdica é visual e Ecocardiográfica, porém este é muito pouco utilizado para este fim. Há, portanto, a necessidade de desenvolvimento de novos métodos capazes de avaliar o impacto funcional da revascularização miocárdica. Objetivo: Avaliar a resposta intra-operatória de contratilidade miocárdica regional mediante o mapeamento epicárdico com eletrodo decapolar. Métodos: 20 pacientes serão submetidos a revascularização miocárdica e será realizado o mapeamento epicárdico com eletrodo decapolar após confecção da anastomose distal com perfusão seletiva para área revascularizada com a aorta pinçada e portanto sem perfusão para as demais artérias coronárias. Nesta análise será avaliado a duração do impulso do eletrograma. Concomitante será realizada fluxometria dos enxertos e comparada com o resultado obtido no mapeamento epicárdico. Resultados: A técnica é uma forma eficaz de avaliar a contratilidade miocárdica regional após a revascularização miocárdica seletiva. O fluxo intravascular dos enxertos estudados não interfere na duração do impulso durante a perfusão seletiva das áreas estudadas / At present, we have available modern tecnics of electroanatomic mapping generating tridimensional images of impulse propagation on heart chambers through intracavitary catheters. Despite this, very few scientific studies are available about epicardial electrophysiologic mapping. Intraoperative evaluation of myocardial contractility right after coronary artery bypass is visual and Echocardiographic, even though this is rarely used to this end. Therefore, there is a need for development of new methods capable of evaluate the functional impact of myocardial revascularization. Objective: Evaluate the intra-operative response of regional myocardial contractility with epicardial mapping with a decapolar catheter. Methods: 20 patients will be submitted to coronary artery bypass graft surgery and epicardial mapping with decapolar catheter was performed after distal anastomosis is made with selective perfusion on the revascularized area with cross clamped aorta, therefore without blood perfusion to the other coronary arteries. On this basis it will be evaluated the duration of the electrogram impulse. It was held the grafts flowmetry and compared to the results obtained on epicardial mapping. Results: The presented tecnic is an effective way to evaluate the regional myocardial contractility after the selective myocardial revascularization. The graft flowmetry doesn\'t interfere with the duration of the impulse obtained during the selective perfusion for the studied areas.

Although several investigations have shown a relationship between increased epicardial adipose tissue (EAT) and atrial fibrillation (AF), the association between EAT and ventricular tachycardia (VT) has not been evaluated. We investigated the association between EAT and post-ablation VT recurrence. In this study, sixty-one consecutive patients (mean age=62.0±13.9) undergoing VT ablation with pre-procedural cardiac magnetic resonance imaging (MRI) were recruited. EAT thickness was measured using cardiac MRI in the right and left atrioventricular grooves (AVGs), RV free wall, anterior, inferior, and superior interventricular grooves (IVGs). During a mean follow-up period of 392.9±180.2 days, post-ablation VT recurrence occurred in 15 (24.6%) patients. EAT thickness was significantly higher in the VT recurrence group than that in the non-recurrent VT at the right (18.7±5.7 vs. 14.1±4.4 mm; p=0.012) and left (13.3±3.9 vs. 10.4±4.1; p=0.020) AVGs. The best cut-off points for predicting VT recurrence were calculated as 15.5 mm for the right AVG (area under ROC curve=0.74) and 11.5 mm for the left AVG (area under ROC curve=0.72). Multivariate Cox regression analysis showed that pre procedural right AVG-EAT (HR: 1.2; 95% CI: [1.06-1.39], p=0.004) was the only independent predictor of VT recurrence after adjustment for covariates. Kaplan–Meier analysis showed a difference for post-ablation VT recurrence between the two groups with right AVG-EAT thickness cut-off value of <15.5 mm versus ≥15.5 mm (log-rank, p=0.003). Based on the finding of this study, we suggested a new possible imaging marker for risk stratification of post-ablation VT recurrence. A higher EAT may be associated with VT recurrence after catheter ablation of VTs.:Epicardial Adipose Tissue Anatomy Embryology Physiology and Pathophysiology Measurement of EAT EAT and heart disorders Future direction VT Catheter Ablation History of VT ablation Catheter ablation for VT in structural and non-structural heart Outcome of VT catheter ablation Predictors of VT recurrence after catheter ablation Objectives of the thesis Publication Summary References

Na Síndrome Metabólica, ações lipotóxicas e glicotóxicas contribuem para a aceleração do processo aterogênico cuja base é a inflamação. O tecido adiposo epicárdico vem sendo reconhecido como metabolicamente ativo e foi relacionado à elevação da produção de citocinas e adipocinas inflamatórias e aumento de DAC. Pioglitazona e Sinvastatina comprovadamente atuam como drogas pleiotrópicas na redução do processo inflamatório sistêmico. O presente estudo teve como objetivo principal avaliar possíveis correlações entre a presença de citocinas inflamatórias plasmáticas versus teciduais e a resposta de ambas à terapia medicamentosa. Para tanto, foram utilizadas monoterapia com Sinvastatina ou Pioglitazona e terapia combinada Pioglitazona+Sinvastatina e acompanhadas as variáveis lipídicas, glicêmicas e inflamatórias sistêmicas, células e citocinas inflamatórias em TAE, um tipo de tecido adiposo branco visceral instalado nas adjacências de focos ateroscleróticos em artérias coronárias de pacientes portadores de DAC e SMet. O estudo envolveu 73 pacientes com DAC multiarterial, avaliada pela cinecoronariografia e SMet que foram submetidos a revascularização e 20 pacientes submetidos à cirurgia valvar para substituição de valva mitral. Os pacientes com DAC eram incluídos de forma não aleatória a um dos 4 subgrupos: controle (n = 17), Simvastatina (20 mg / dia, n = 20), Pioglitazona (15 mg ou 30 mg / dia, n = 18) e Simvastatina + Pioglitazona (20 mg / dia + 15 mg ou 30 mg / dia, respectivamente, n = 18). Amostras de tecido adiposo epicárdico foram obtidas durante a cirurgia. Infiltração de macrófagos, linfócitos e secreção adipocitocinas foram investigados por coloração imunohistoquímica e comparados aos biomarcadores inflamatórios plasmáticos. Os resultados mostraram que a infiltração de macrófagos e a presença de citocinas pró-inflamatórias tais como TNF-, IL-6, leptina and resistina foram reduzidas em TAE de pacientes DAC/SMet após monoterapia com Pioglitazona. Os pacientes tratados apenas com Sinvastatina apresentaram os menores valores plasmáticos de leptina, resistina and MCP-1. Pioglitazona+Sinvastatina foram associadas aos menores valores plasmáticos de IL-6, TNF-, resistina, ADMA, MMP-9 em comparação ao grupo de pacientes não tratados. Além disso, a terapia combinada revelou a mais alta concentração de adiponectina plasmática concomitante ao menor valor de PCRus. Esses achados refletiram não só a condição plasmática como se correlacionaram positivamente à condição tecidual mostrada pela porcentagem média de área ocupada por macrófagos no TAE e a quantidade de PCRus presente no plasma após os tratamentos. Houve correlação positiva também entre citocinas sistêmicas e teciduais após os tratamentos, exceto para o TNF- após o tratamento com sinvastatina ( r = - 0,025, p = 0,33) e leptina após o tratamento com pioglitazona (r = -0,877, p <0,0001). Nos pacientes tratados com Sinvastatina, os fragmentos de TAE apresentaram agregados de linfócitos T, B e macrófagos concentrados na borda e ao redor de vasos sanguíneos / In the Metabolic Syndrome, the concentration of free fatty acids and the elevation of glycemia result in lipotoxic and glycotoxic actions, respectively, which contribute to accelerate the atherogenic process. (MS). Inapropriate secretion of adipocytokines plays a critical role in chronic inflammatory states associated with obesity-linked diseases, such as type 2 diabetes and atherosclerosis. The pleiotropic anti-inflammatory action of Simvastatin and/or Pioglitazone may counteract such systemic effects but its influence upon human epicardial adipose tissue is unknown. To assess the anti-inflammatory action of Simvastatin, Pioglitazone or both in epicardial adipose tissue in patients with coronary artery disease (CAD) and metabolic syndrome. The study comprised 73 patients with multivessel CAD, evaluated by cinecoronariography, and MS who underwent bypass grafting and 20 valvar patients who underwent surgery for mitral valve replacement. The 73 who underwent elective bypass grafting were non-randomly allocated to one of 4 subgroups: control (n=17), Simvastatin alone (20 mg/day, n=20), Pioglitazone alone (15 mg or 30 mg/day, n=18), or Simvastatin+Pioglitazone (20 mg/day + 15 mg or 30 mg/day, respectively, n=18). Epicardial adipose tissue sample was obtained during surgery. Infiltration of macrophages, lymphocytes and adipocytokines secretion were investigated by immunohistochemical staining and compared to plasma inflammatory biomarkers. Among CAD/MS patients, treatment with Simvastatin alone, Pioglitazone alone and Simvastatin+Pioglitazone significantly reduced plasma CRP and cytokines compared with control group. Monotherapy with Simvastatin significantly reduced plasma IL-6, leptin, resistin, MCP-1 (p<0.001 for all), whereas monotherapy with Pioglitazone reduced IL-6, TNF-, resistin and MMP-9 (p<0.001 for all) compared with control group. Simvastatin+Pioglitazone treatment reduced more plasmatic variables (IL-6, TNF-, resistin, ADMA and MMP-9 vs. control group (p<0.001). All treatments increased adiponectin plasma levels (p<0.001). In the combined treatment group, higher concentration in plasma adiponectin and lower hsCRP, were found simultaneously. There was positive correlation between mean percentage macrophages area in EAT and plasma hsCRP; also between systemic and tecidual citokynes after the treatments, except for TNF- after treatment with simvastatin (r = -0.025, p = 0.33) and leptin after treatment with pioglitazone (r = -0.877, p <0.0001). In fat fragments of patients treated with Simvastatin, T- and B-lymphocytes, and macrophages clusters concentrated near the edge or around blood vessels were observed by first time. In patients with CAD and MS treatment with Pioglitazone, Sinvastatin or combination can substantially reduce both epicardial tissue and plasma inflammatory markers. Such tissue effects may contribute to the control of coronary atherosclerosis progression

No description available.