CARLOS VICENTE SERRANO JUNIOR
Projetos de Pesquisa
Unidades Organizacionais
Departamento de Cardio-Pneumologia, Faculdade de Medicina - Docente
Instituto do Coração, Hospital das Clínicas, Faculdade de Medicina
LIM/11 - Laboratório de Cirurgia Cardiovascular e Fisiopatologia da Circulação, Hospital das Clínicas, Faculdade de Medicina
Instituto do Coração, Hospital das Clínicas, Faculdade de Medicina
LIM/11 - Laboratório de Cirurgia Cardiovascular e Fisiopatologia da Circulação, Hospital das Clínicas, Faculdade de Medicina
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conferenceObject Defective function of hdl particles in familial apolipoprotein A-I deficiency: relevance of alterations in the lipidome(2014) RACHED, F.; SANTOS, R. Dos; MINAME, M.; LHOMME, M.; DAUTEILLE, C.; SERRANO JR., C. V.; CHAPMAN, J.; KONTUSH, A.- Phospholipid transfer to high-density lipoprotein (HDL) upon triglyceride lipolysis is directly correlated with HDL-cholesterol levels and is not associated with cardiovascular risk (vol 324, pg 1, 2021)(2023) MA, Feng; DARABI, Maryam; LHOMME, Marie; TUBEUF, Emilie; CANICIO, Aurelie; BRERAULT, Jean; MEDADJE, Narcisse; RACHED, Fabiana; LEBRETON, Sandrine; FRISDAL, Eric; BRITES, Fernando; SERRANO, Carlos; SANTOS, Raul; GAUTIER, Emmanuel; HUBY, Thierry; KHOURY, Petra El; CARRIE, Alain; ABIFADEL, Marianne; BRUCKERT, Eric; GUERIN, Maryse; COUVERT, Philippe; GIRAL, Philippe; LESNIK, Philippe; GOFF, Wilfried Le; GUILLAS, Isabelle; KONTUSH, Anatol
- UNSATURATED, LOW-ABUNDANT SPECIES OF HDL (LYSO) PHOSPHOLIPIDS ARE MOST AFFECTED BY ST SEGMENT ELEVATION MYOCARDIAL INFARCTION(2018) ZAKIEV, E.; MA, F.; RACHED, F.; LHOMME, M.; SUKHORUKOV, V.; SERRANO, C. V.; SANTOS, R. D.; CHAPMAN, M. J.; OREKHOV, A.; KONTUSH, A.
- Defective functionality of small, dense HDL3 subpopulations in ST segment elevation myocardial infarction: Relevance of enrichment in lysophosphatidylcholine, phosphatidic acid and serum amyloid A(2015) RACHED, Fabiana; LHOMME, Marie; CAMONT, Laurent; GOMES, Fernando; DAUTEUILLE, Carolane; ROBILLARD, Paul; SANTOS, Raul D.; LESNIK, Philippe; SERRANO JR., Carlos V.; CHAPMAN, M. John; KONTUSH, AnatolBackground: Low plasma levels of high-density lipoprotein-cholesterol (HDL-C) are typical of acute myocardial infarction (MI) and predict risk of recurrent cardiovascular events. The potential relationships between modifications in the molecular composition and the functionality of HDL subpopulations in acute MI however remain indeterminate. Methods and results: ST segment elevation MI (STEMI) patients were recruited within 24 h after diagnosis (n = 16) and featured low HDL-C (-31%, p < 0.05) and acute-phase inflammation (determined as marked elevations in C-reactive protein, serum amyloid A (SAA) and interleukin-6) as compared to age- and sex-matched controls (n = 10). STEM! plasma HDL and its subpopulations (HDL2b, 2a, 3a, 3b, 3c) displayed attenuated cholesterol efflux capacity from THP-1 cells (up to -32%, p < 0.01, on a unit phospholipid mass basis) vs. controls. Plasma HDL and small, dense HDL3b and 3c subpopulations from STEMI patients exhibited reduced anti-oxidative activity (up to 68%, p < 0.05, on a unit HDL mass basis). HDL subpopulations in STEMI were enriched in two proinflammatory bioactive lipids, lysophosphatidylcholine (up to 3.0-fold, p < 0.05) and phosphatidic acid (up to 8.4-fold, p < 0.05), depleted in apolipoprotein A-I (up to 23%, p < 0.05) and enriched in SAA (up to + 10.2-fold, p < 0.05); such changes were most marked in the HDL3b subfraction. In vitro HDL enrichment in both lysophosphatidylcholine and phosphatidic acid exerted deleterious effects on HDL functionality. Conclusions: In the early phase of STEM!, HDL particle subpopulations display marked, concomitant alterations in both lipidome and proteome which are implicated in impaired HDL functionality. Such modifications may act synergistically to confer novel deleterious biological activities to STEM! HDL Significance: Our present data highlight complex changes in the molecular composition and functionality of HDL particle subpopulations in the acute phase of STEMI, and for the first time, reveal that concomitant modifications in both the lipidome and proteome contribute to functional deficiencies in cholesterol efflux and antioxidative activities of HDL particles. These findings may provide new biomarkers and new insights in therapeutic strategy-to reduce cardiovascular risk in this clinical setting where such net deficiency in HDL function, multiplied by low circulating HDL concentrations, can be expected to contribute to accelerated atherogenesis.
- Free cholesterol transfer to high-density lipoprotein (HDL) upon triglyceride lipolysis underlies the U-shape relationship between HDL-cholesterol and cardiovascular disease(2020) FENG, Ma; DARABI, Maryam; TUBEUF, Emilie; CANICIO, Aurelie; LHOMME, Marie; FRISDAL, Eric; LANFRANCHI-LEBRETON, Sandrine; MATHERON, Lucrece; RACHED, Fabiana; PONNAIAH, Maharajah; V, Carlos Serrano Jr; SANTOS, Raul D.; BRITES, Fernando; BOLBACH, Gerard; GAUTIER, Emmanuel; HUBY, Thierry; CARRIE, Alain; BRUCKERT, Eric; GUERIN, Maryse; COUVERT, Philippe; GIRAL, Philippe; LESNIK, Philippe; GOFF, Wilfried Le; GUILLAS, Isabelle; KONTUSH, AnatolBackground Low concentrations of high-density lipoprotein cholesterol (HDL-C) represent a well-established cardiovascular risk factor. Paradoxically, extremely high HDL-C levels are equally associated with elevated cardiovascular risk, resulting in the U-shape relationship of HDL-C with cardiovascular disease. Mechanisms underlying this association are presently unknown. We hypothesised that the capacity of high-density lipoprotein (HDL) to acquire free cholesterol upon triglyceride-rich lipoprotein (TGRL) lipolysis by lipoprotein lipase underlies the non-linear relationship between HDL-C and cardiovascular risk. Methods To assess our hypothesis, we developed a novel assay to evaluate the capacity of HDL to acquire free cholesterol (as fluorescent TopFluor (R) cholesterol) from TGRL upon in vitro lipolysis by lipoprotein lipase. Results When the assay was applied to several populations markedly differing in plasma HDL-C levels, transfer of free cholesterol was significantly decreased in low HDL-C patients with acute myocardial infarction (-45%) and type 2 diabetes (-25%), and in subjects with extremely high HDL-C of >2.59 mmol/L (>100 mg/dL) (-20%) versus healthy normolipidaemic controls. When these data were combined and plotted against HDL-C concentrations, an inverse U-shape relationship was observed. Consistent with these findings, animal studies revealed that the capacity of HDL to acquire cholesterol upon lipolysis was reduced in low HDL-C apolipoprotein A-I knock-out mice and was negatively correlated with aortic accumulation of [H-3]-cholesterol after oral gavage, attesting this functional characteristic as a negative metric of postprandial atherosclerosis. Conclusions Free cholesterol transfer to HDL upon TGRL lipolysis may underlie the U-shape relationship between HDL-C and cardiovascular disease, linking HDL-C to triglyceride metabolism and atherosclerosis.
- The association of myocardial strain with cardiac magnetic resonance and clinical outcomes in patients with acute myocarditis(2023) SOEIRO, Alexandre M.; BOSSA, Aline S.; CESAR, Maria C.; LEAL, Tatiana C. A. T.; GARCIA, Guilherme; FONSECA, Rafael A.; NAKAMURA, Debora; GUIMARAES, Patricia O.; SOEIRO, Maria C. F. A.; JR, Carlos V. Serrano; SOARES, Paulo R.; MUELLER, Christian; MEBAZAA, Alexandre; FERNANDES, Fabio; NOMURA, Cesar H.; ROCHITTE, Carlos E.; JR, Mucio T. de OliveiraIntroductionThe role of myocardial strain in risk prediction for acute myocarditis (AMC) patients, measured by cardiac magnetic resonance (CMR), deserves further investigation. Our objective was to evaluate the association between myocardial strain measured by CMR and clinical events in AMC patients. Material and methodsThis was a prospective single-center study of patients with AMC. We included 100 patients with AMC with CMR confirmation. The primary outcome was the composite of all-cause mortality, heart failure and AMC recurrence in 24 months. A subgroup analysis was performed on a sample of 36 patients who underwent a second CMR between 6 and 18 months. The association between strain measures and clinical events or an increase in left ventricular ejection fraction (LVEF) was explored using Cox regression analysis. Global peak radial, circumferential and longitudinal strain in the left and right ventricles was assessed. ROC curve analysis was performed to identify cutoff points for clinical event prediction. ResultsThe mean follow-up was 18.7 & PLUSMN; 2.3 months, and the composite primary outcome occurred in 26 patients. The median LVEF at CMR at baseline was 57.5% (14.6%). LV radial strain (HR = 0.918, 95% CI: 0.858-0.982, p = 0.012), LV circumferential strain (HR = 1.177, 95% CI: 1.046-1.325, p = 0.007) and LV longitudinal strain (HR = 1.173, 95% CI: 1.031-1.334, p = 0.015) were independently associated with clinical event occurrence. The areas under the ROC curve for clinical event prediction were 0.80, 0.79 and 0.80 for LV radial, circumferential, and longitudinal strain, respectively. LV longitudinal strain was independently correlated with prognosis (HR = 1.282, CI 95%: 1.022-1.524, p = 0.007), even when analyzed together with ejection fraction and delayed enhancement. LV and right ventricle (RV) strain were not associated with an increase in LVEF. Finally, when the initial CMR findings were compared with the follow-up CMR findings, improvements in the measures of LV and RV myocardial strain were observed. ConclusionMeasurement of myocardial strain by CMR can provide prognostic information on AMC patients. LV radial, circumferential and longitudinal strain were associated with long-term clinical events in these patients.
- Distinct phospholipid and sphingolipid species are linked to altered HDL function in apolipoprotein A-I deficiency(2019) ZAKIEV, Emile; RACHED, Fabiana; LHOMME, Marie; DARABI-AMIN, Maryam; PONNAIAH, Maharajah; BECKER, Pierre Hadrien; THEROND, Patrice; SERRANO JR., Carlos V.; SANTOS, Raul D.; CHAPMAN, M. John; OREKHOV, Alexander; KONTUSH, AnatolBACKGROUND: Familial apolipoprotein A-I (apoA-I) deficiency (FAID) involving low levels of both apoA-I and high-density lipoprotein (HDL) cholesterol is associated with accelerated atherosclerosis. OBJECTIVE: The objective of this study was to define distinctive patterns in the lipidome of HDL subpopulations in FAID in relationship to antiatherogenic activities. METHODS: Five HDL subfractions were isolated by ultracentrifugation from plasma of FAID Caucasian patients (n = 5) and age-matched healthy normolipidemic Caucasian controls (n = 8), and the HDL lipidome (160 molecular species of 9 classes of phospholipids and sphingolipids) was quantitatively evaluated. RESULTS: Increased concentrations of numerous molecular species of lysophosphatidylcholine (up to 12-fold), ceramides (up to 3-fold), phosphatidylserine (up to 34-fold), phosphatidic acid (up to 71 fold), and phosphatidylglycerol (up to 20-fold) were detected throughout all five HDL subpopulations as compared with their counterparts from controls, whereas concentrations of phosphatidylethanolamine species were decreased (up to 5-fold). Moderately to highly abundant, within their lipid class, species of phosphatidylcholine, sphingomyelin, phosphatidylinositol, phosphatidylethanolamine, phosphatidylserine, and ceramide featuring multiple unsaturations were primarily affected by apoA-I deficiency; their HDL content, particularly that of phosphatidylcholine (34:2), was strongly correlated with HDL function, impaired in FAID. Metabolic pathway analysis revealed that sphingolipid, glycerophospholipid, and linoleic acid metabolism was significantly affected by FAID. CONCLUSION: These data reveal that altered content of specific phospholipid and sphingolipid species is linked to deficient antiatherogenic properties of HDL in FAID.
- Defective functionality of HDL particles in familial apoA-I deficiency: relevance of alterations in HDL lipidome and proteome(2014) RACHED, Fabiana; SANTOS, Raul D.; CAMONT, Laurent; MINAME, Marcio H.; LHOMME, Marie; DAUTEUILLE, Carolane; LECOCQ, Sora; SERRANO JR., Carlos V.; CHAPMAN, M. John; KONTUSH, AnatolTo evaluate functional and compositional properties of HDL in subjects from a kindred of genetic apoA-I deficiency, two homozygotes and six heterozygotes, with a nonsense mutation at APOA1 codon -2, Q[-2]X, were recruited together with age- and sex-matched healthy controls (n = 11). Homozygotes displayed undetectable plasma levels of apoA-I and reduced levels of HDL-cholesterol (HDL-C) and apoC-III (5.4% and 42.6% of controls, respectively). Heterozygotes displayed low HDL-C (21 +/- 9 mg/dl), low apoA-I (79 +/- 24 mg/dl), normal LDL-cholesterol (132 +/- 25 mg/dl), and elevated TG (130 +/- 45 mg/dl) levels. Cholesterol efflux capacity of ultracentrifugally isolated HDL subpopulations was reduced (up to -25%, P < 0.01, on a glycerophospholipid [GP] basis) in heterozygotes versus controls. Small, dense HDL3 and total HDL from heterozygotes exhibited diminished antioxidative activity (up to -48%, P < 0.001 on a total mass basis) versus controls. HDL subpopulations from both homozygotes and heterozygotes displayed altered chemical composition, with depletion in apoA-I, GP, and cholesteryl ester; enrichment in apoA-II, free cholesterol, and TG; and altered phosphosphingolipidome. The defective atheroprotective activities of HDL were correlated with altered lipid and apo composition. These data reveal that atheroprotective activities of HDL particles are impaired in homozygous and heterozygous apoA-I deficiency and are intimately related to marked alterations in protein and lipid composition.
conferenceObject DEFECTIVE FUNCTION OF HDL PARTICLES IN FAMILIAL APOLIPOPROTEIN A-I DEFICIENCY: RELEVANCE OF ALTERATIONS IN THE LIPIDOME(2014) RACHED, F.; SANTOS, R. D.; MINAME, M.; LHOMME, M.; DAUTEILLE, C.; SERRANO, C. V.; CHAPMAN, M. J.; KONTUSH, A.- Acute myocardial infarction preferentially alters low-abundant, long-chain unsaturated phospholipid and sphingolipid species in plasma high-density lipoprotein subpopulations(2024) PONNAIAH, Maharajah; ZAKIEV, Emile; LHOMME, Marie; RACHED, Fabiana; CAMONT, Laurent; JR, Carlos V. Serrano; SANTOS, Raul D.; CHAPMAN, M. John; OREKHOV, Alexander; KONTUSH, AnatolAim: High-density lipoprotein (HDL) particles in ST-segment elevation myocardial infarction (STEMI) are deficient in their anti-atherogenic function. Molecular determinants of such deficiency remain obscure. Methods: Five major HDL subpopulations were isolated using density-gradient ultracentrifugation from STEMI patients (n = 12) and healthy age- and sex-matched controls (n = 12), and 160 species of phosphatidylcholine, lysophosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, phosphatidylglycerol, phosphatidylserine, phosphatidic acid, sphingomyelin and ceramide were quantified by LC-MS/MS. Results: Multiple minor species of proinflammatory phosphatidic acid and lysophosphatidylcholine were enriched by 1.7-27.2-fold throughout the majority of HDL subpopulations in STEMI. In contrast, minor phosphatidylcholine, phosphatidylglycerol, phosphatidylinositol, phosphatidylethanolamine, sphingomyelin and ceramide species were typically depleted up to 3-fold in STEMI vs. control HDLs, while abundances of their major species did not differ between the groups. Intermediate-to-long-chain phosphatidylcholine, phosphatidylinositol and phosphatidylglycerol species were more affected by STEMI than their short-chain counterparts, resulting in positive correlations between their fold decrease and the carbon chain length. Additionally, fold decreases in the abundances of multiple lipid species were positively correlated with the double bond number in their carbon chains. Finally, abundances of several phospholipid and ceramide species were positively correlated with cholesterol efflux capacity and antioxidative activity of HDL subpopulations, both reduced in STEMI vs controls. KEGG pathway analysis tied these species to altered glycerophospholipid and linoleic acid metabolism. Conclusions: Minor unsaturated intermediate-to-long-chain phospholipid and sphingolipid species in HDL subpopulations are most affected by STEMI, reflecting alterations in glycerophospholipid and linoleic acid metabolism with the accumulation of proinflammatory lysolipids and maintenance of homeostasis of major phospholipid species.