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BACKGROUND AND AIMS: Familial hypercholesterolemia (FH) variants are associated with higher atherosclerotic cardiovascular disease risk (ASCVD) even when compared with other forms of severe hypercholesterolemia, especially in young people. Lipid lowering therapies (LLT) may change hypercholesterolemia natural history. This study aimed at evaluating factors associated with occurrence of ASCVD in old severe hypercholesterolemics diagnosed or not with FH and undergoing LLT. METHODS: Hypercholesterolemic individuals ≥60 years participating on a genetic cascade screening for FH were divided in 4 groups (2 × 2) according to the presence (variant+) or not (variant-) of FH genetic variants and previous ASCVD (ASCVD+ and ASCVD-). Biomarkers associated with new incident ASCVD events were tested using Cox models. Continuous data shown as medians (%25; %75). RESULTS: From 4,111 genotyped individuals, 377 (9.1%) were elderly [age 66 (63; 71) years], 28.9% males, 42.7% variant+, 32.1% with previous ASCVD, LLT duration 9 (5; 16) years, and on treatment LDL-cholesterol 144 (109; 200) mg/dL. After 4.8 (7; 3) years of follow up there were 47 incident events (12.4%, 2.7% patient/year). The annualized event rates were 0.8% (95% CI 0.36%; 1.70%), 2.3% (95% CI 1.3%; 4.1%), 5.2% (95% CI 2.8%; 9.7%) and 6.3% (95% CI 4.0%; 10.0%) respectively for groups variant-/ASCVD-, variant+/ASCVD-, variant-/ASCVD+ and, variant+/ASCVD+ (p log rank p < 0.001). Only presence of previous ASCVD was independently associated with incident ASCVD [hazard ratio 3.236 (95%CI 1.497-6.993, p = 0.003)]. No interaction was found for previous ASCVD and variants. CONCLUSIONS: In old severe hypercholesterolemic individuals undergoing long-term LLT previous ASCVD was associated with incident events while FH causing variants were not.
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Aterosclerose , Doenças Cardiovasculares , Hipercolesterolemia , Hiperlipoproteinemia Tipo II , Masculino , Humanos , Adolescente , Idoso , Feminino , Doenças Cardiovasculares/epidemiologia , Hipercolesterolemia/complicações , Hiperlipoproteinemia Tipo II/genética , LDL-Colesterol , Aterosclerose/genética , Fatores de RiscoRESUMO
Resumo A produção de ceramida ocorre em todo o corpo e desempenha um papel importante na manutenção da fisiologia normal. No entanto, os níveis de ceramidas são alterados em estados de doença, principalmente durante o desenvolvimento de diabetes e dislipidemia. A produção de ceramidas também está associada à instabilidade das placas ateroscleróticas. Estudos recentes revelam que pacientes com doença arterial coronariana instável apresentam níveis plasmáticos aumentados de ceramidas (principalmente C16, C18 e C24:1). Atualmente, são consideradas biomarcadores emergentes nas doenças cardiovasculares, sendo utilizadas na predição de instabilidade da placa aterosclerótica e eventos cardiovasculares adversos de forma independente aos fatores de risco tradicionais. Com o objetivo de descrever e discutir o papel das ceramidas na estratificação das doenças cardiovasculares, o desenvolvimento desta revisão narrativa contextualiza a importância desse biomarcador no cenário atual da cardiologia.
Abstract Ceramide production takes place throughout the body and plays a key role in the maintenance of normal physiology. However, ceramide levels are altered during disease states, particularly considering the development of diabetes and dyslipidemia. Ceramide production is also associated with atherosclerotic plaque instability. Recent studies revealed that patients with unstable coronary artery disease (CAD) presented increased plasma ceramide levels (especially C16, C18, and C24:1). These molecules are currently considered emerging biomarkers of cardiovascular diseases (CVD), being used for predicting atherosclerotic plaque instability and adverse cardiovascular events independently from traditional risk factors. With the aim of describing and discussing the role of ceramides in the stratification of cardiovascular diseases, this narrative review contextualizes the importance of this biomarker in the present cardiology scenario.
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BACKGROUND: Familial hypercholesterolemia (FH) is an autosomal dominant disease characterized by the presence of high levels of total and low-density lipoprotein cholesterol (LDL-C). Statin treatment is recommended for all adults with FH. OBJECTIVE: Here we have studied the main predictors of the use of lipid-lowering agents at one-year follow-up in a large cohort of FH patients. METHODS: Open prospective cohort of individuals resident in São Paulo, Brazil who were enrolled in a FH cascade screening program. We used a multivariate logistic regression analysis to determine predictive variables for the non-adherence of lipid-lowering drugs. RESULTS: A total of 1,360 HF participants were included. At the one-year follow-up (T1), the rates of lipid-lowering treatment were 92%, 76%, and 78% from the genetic positive proband (index cases, IC), genetic negative IC and genetic positive first-degree relatives, respectively. Receiving a positive genetic test for FH (OR: 4.85; CI 95%: 2.97 - 7.93, p value < 0.05), use of lipid-lowering treatment at T0 (OR: 5.01; CI 95%: 3.18 - 7.90, p value < 0.05) and age (OR: 1.04; CI 95%: 1.02 - 1.06) were independently associated with the use of a lipid-lowering drug at T1. CONCLUSION: Index cases with a positive genetic result increase their prevalence of lipid-lowering medication use. Positive relatives did not have the expected adherence; we could notice a significant increase in the prevalence of treatment starting after a positive genetic test. The independent predictors for lipid-lowering treatment were age, a positive genetic test and previous institution of treatment before the genetic test result.
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Hiperlipoproteinemia Tipo II , Adulto , Brasil/epidemiologia , LDL-Colesterol , Humanos , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Hiperlipoproteinemia Tipo II/genética , Estudos Prospectivos , Fatores de RiscoRESUMO
The angiotensin-converting enzyme (ACE)/Angiotensin II (Ang II) and angiotensin-converting enzyme 2 (ACE2)/angiotensin-(1-7) (Ang-(1-7)) pathways are coexpressed in most tissues. The balance between these pathways determines, at least in part, whether tissue damage will occur in response to pathological stimuli. The present study tested the hypothesis that male sex and high blood pressure are associated with ACE/ACE2 imbalance in the lungs. Experiments were conducted in male and female Wistar rats and spontaneously hypertensive rats (SHRs). Lung ACE and ACE2 gene expression was also evaluated in normotensive and hypertensive humans using the Genotype-Tissue Expression (GTEx) project. Compared with Wistar rats and female SHRs, male SHRs displayed reduced lung ACE2 mRNA, ACE2 protein abundance and ACE2 activity, and increased Ang II concentration. Lung ACE mRNA levels were higher in male SHRs than in Wistar rats, whereas lung ACE protein abundance and activity were similar among the four groups of rats. Lung Ang-(1-7) concentration was higher in female than in male SHRs (89 ± 17 vs. 43 ± 2 pg/g, P<0.05). Lung ACE to ACE2 mRNA expression in hypertensive patients was significantly higher than that in normotensive subjects. Taken together, these results demonstrate that male hypertensive rats display imbalance between the ACE/Ang II and ACE2/Ang-(1-7) pathways in the lungs mainly attributable to ACE2 down-regulation. Further studies should be conducted to investigate whether this imbalance between ACE/ACE2 may promote and accelerate lung injury in respiratory infections, including coronavirus disease 2019 (COVID-19).
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Enzima de Conversão de Angiotensina 2/metabolismo , Pulmão/metabolismo , Peptidil Dipeptidase A/metabolismo , Proteína ADAM17/metabolismo , Angiotensina I/metabolismo , Angiotensina II/metabolismo , Enzima de Conversão de Angiotensina 2/genética , Animais , Regulação para Baixo , Feminino , Masculino , Fragmentos de Peptídeos/metabolismo , Peptidil Dipeptidase A/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Endogâmicos SHR , Ratos Wistar , Caracteres SexuaisRESUMO
BACKGROUND AND AIMS: Familial Hypercholesterolemia (FH) is characterized by elevated LDL-cholesterol (LDL-C) and high atherosclerosis risk. The impact of different dietary patterns on atherosclerosis biomarkers has been poorly studied in FH. This study verified the association of adherence to a Mediterranean diet with biomarkers of dyslipidemia and low-grade inflammation in molecularly proven FH adults from Brazil (BR) and Spain (SP). METHODS AND RESULTS: In this cross-sectional study adherence to the Mediterranean diet was assessed by a validated score and generalized estimating equations were used to evaluate its association with plasma LDL-C, apolipoprotein-B (ApoB) and high sensitivity C-reactive protein (hs-CRP) concentrations. We included 92 (mean age 45 years, 58.7% females) and 98 FH individuals (mean age 46.8 years, 60.2% females) respectively from BR and SP. FH causing variants did not differ between countries. LDL-C, ApoB and hs-CRP concentrations were higher in BR than in SP: 179 (135-250) and 161 (133-193) mg/dL; 141 (109-181) and 103 (88-134) mg/dL; and 1.6 (0.8-4.0) and 0.8 (0.4-1.5) mg/L respectively (all p < 0.001). Most of BR had low adherence (n = 77, 83.7%), while the majority of SP were divided into moderate (n = 35, 35.7%) and strong adherence to the Mediterranean diet (n = 37, 37.8%), p < 0.001. There was a significant inverse association of adherence to the Mediterranean diet score with higher LDL-C, ApoB, and hs-CRP after adjusting for socio economic parameters, caloric and fatty acid intakes as well as pharmacological lipid lowering therapies. CONCLUSIONS: Higher adherence to a Mediterranean diet was associated with better dyslipidemia and low-grade inflammation profiles in FH.
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Doenças Cardiovasculares/prevenção & controle , Dieta Saudável , Dieta Mediterrânea , Hiperlipoproteinemia Tipo II/dietoterapia , Mediadores da Inflamação/sangue , Inflamação/prevenção & controle , Lipídeos/sangue , Cooperação do Paciente , Comportamento de Redução do Risco , Adulto , Biomarcadores/sangue , Brasil/epidemiologia , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , Estudos Transversais , Comportamento Alimentar , Feminino , Fatores de Risco de Doenças Cardíacas , Humanos , Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/epidemiologia , Inflamação/sangue , Inflamação/diagnóstico , Inflamação/epidemiologia , Masculino , Pessoa de Meia-Idade , Valor Nutritivo , Fatores de Proteção , Medição de Risco , Espanha/epidemiologia , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND AND AIMS: Familial hypercholesterolemia (FH) is characterized by high LDL-cholesterol (LDL-C) and early atherosclerotic cardiovascular disease (ASCVD). With a lipid lowering therapy (LLT), most individuals with FH may have a longer ASCVD-free survival. However, there is scant data about older individuals with FH. METHODS: We compared characteristics of genetically defined FH older individuals with age-matched non-FH counterparts. RESULTS: From 4111 genotyped individuals, 462 older than 60 years were included (198 positive and 264 negative for FH variants). There were no differences regarding median age [%25; 75%] 66.0 (62.0; 71.0) and 66.0 (62.2; 71.0) years, p = 0.68 for FH and non-FH, respectively. In both groups, there was a higher frequency of females, however, there were more males in the FH group 37.4% vs. 24.2%, p = 0.002. No differences were seen between FH and non-FH in LLT use: 88.5% vs. 91.5%, p = 0.29. Despite a longer LLT duration in FH patients (with 11.0 (7.0; 20.0) vs. 7.0 (3.0; 13.0) years, p < 0.001), treatment was started late in both groups: at 54.0 (47.0; 61.0) and 59.0 (52.0; 64.0) years, p < 0.001, in FH and non-FH, respectively. FH had greater frequencies of previous and early ASCVD (40.9% vs. 27.3%, p = 0.002, and 22.2% vs. 9.0%, p < 0.001). In FH, male sex [HR (95%CI)] 2.67 (1.50-4.73), p = 0.001, and LLT onset age 0.96 (0.93-0.99), p = 0.009, were independently associated with ASCVD. CONCLUSIONS: Among hypercholesterolemic older individuals participating in a cascade screening program, the genetic diagnosis of FH was associated with higher ASCVD rates, emphasizing the relevance of a monogenic defect as the cause of long-lasting hypercholesterolemia and ASCVD risk, particularly in men.
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Doenças Cardiovasculares , Hipercolesterolemia , Hiperlipoproteinemia Tipo II , Idoso , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/genética , LDL-Colesterol , Feminino , Humanos , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/epidemiologia , Hiperlipoproteinemia Tipo II/genética , Lactente , Masculino , Fatores de RiscoRESUMO
Cardiac fibroblasts are present throughout the myocardium and are enriched in the microenvironment surrounding the ventricular conduction system (VCS). Several forms of arrhythmias are linked to VCS abnormalities, but it is still unclear whether VCS malformations are cardiomyocyte autonomous or could be linked to crosstalk between different cell types. We reasoned that fibroblasts influence cardiomyocyte specialization in VCS cells. We developed 2D and 3D culture models of neonatal rat cardiac cells to assess the influence of cardiac fibroblasts on cardiomyocytes. Cardiomyocytes adjacent to cardiac fibroblasts showed a two-fold increase in expression of VCS markers (NAV1.5 and CONTACTIN 2) and calcium transient duration, displaying a Purkinje-like profile. Fibroblast-conditioned media (fCM) was sufficient to activate VCS-related genes (Irx3, Scn5a, Connexin 40) and to induce action potential prolongation, a hallmark of Purkinge phenotype. fCM-mediated response seemed to be spatially-dependent as cardiomyocyte organoids treated with fCM had increased expression of connexin 40 and NAV1.5 primarily on its outer surface. Finally, NOTCH1 activation in both cardiomyocytes and fibroblasts was required for connexin 40 up-regulation (a proxy of VCS phenotype). Altogether, we provide evidence that cardiac fibroblasts influence cardiomyocyte specialization into VCS-like cells via NOTCH1 signaling in vitro.
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Diferenciação Celular/fisiologia , Fibroblastos/metabolismo , Sistema de Condução Cardíaco/metabolismo , Miócitos Cardíacos/metabolismo , Receptor Notch1/metabolismo , Animais , Técnicas de Cultura de Células , Conexinas/metabolismo , Meios de Cultivo Condicionados , Fibroblastos/citologia , Técnicas In Vitro , Células-Tronco Mesenquimais/metabolismo , Miócitos Cardíacos/citologia , Ratos , Ratos Wistar , Proteína alfa-5 de Junções ComunicantesRESUMO
OBJECTIVE: Characterize homozygous familial hypercholesterolemia (HoFH) individuals from Iberoamerica. Approach and Results: In a cross-sectional retrospective evaluation 134 individuals with a HoFH phenotype, 71 adults (age 39.3±15.8 years, 38.0% males), and 63 children (age 8.8±4.0 years, 50.8% males) were studied. Genetic characterization was available in 129 (96%). The majority (91%) were true homozygotes (true HoFH, n=79, 43.0% children, 46.8% males) or compound heterozygotes (compound heterozygous familial hypercholesterolemia, n=39, 51.3% children, 46.2% males) with putative pathogenic variants in the LDLR. True HoFH due to LDLR variants had higher total (P=0.015) and LDL (low-density lipoprotein)-cholesterol (P=0.008) compared with compound heterozygous familial hypercholesterolemia. Children with true HoFH (n=34) tended to be diagnosed earlier (P=0.051) and had a greater frequency of xanthomas (P=0.016) than those with compound heterozygous familial hypercholesterolemia (n=20). Previous major cardiovascular events were present in 25 (48%) of 52 children (missing information in 2 cases), and in 43 (67%) of 64 adults with LDLR variants. Children who are true HoFH had higher frequency of major cardiovascular events (P=0.02), coronary heart (P=0.013), and aortic/supra-aortic valve diseases (P=0.022) than compound heterozygous familial hypercholesterolemia. In adults, no differences were observed in major cardiovascular events according to type of LDLR variant. From 118 subjects with LDLR variants, 76 (64%) had 2 likely pathogenic or pathogenic variants. In 89 subjects with 2 LDLR variants, those with at least one null allele were younger (P=0.003) and had a greater frequency of major cardiovascular events (P=0.038) occurring at an earlier age (P=0.001). CONCLUSIONS: There was a high frequency of cardiovascular disease even in children. Phenotype and cardiovascular complications were heterogeneous and associated with the type of molecular defect.
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Doenças Cardiovasculares/epidemiologia , LDL-Colesterol/sangue , Homozigoto , Hiperlipoproteinemia Tipo II/genética , Mutação , Proteínas Adaptadoras de Transdução de Sinal/genética , Adolescente , Adulto , Fatores Etários , Apolipoproteína B-100/genética , Biomarcadores/sangue , Doenças Cardiovasculares/diagnóstico , Criança , Pré-Escolar , Estudos Transversais , Europa (Continente)/epidemiologia , Feminino , Predisposição Genética para Doença , Humanos , Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/epidemiologia , Masculino , México/epidemiologia , Pessoa de Meia-Idade , Fenótipo , Pró-Proteína Convertase 9/genética , Receptores de LDL/genética , Estudos Retrospectivos , Fatores de Risco , América do Sul/epidemiologia , Adulto JovemRESUMO
The nature of the early post-natal immune response in rodents appears to influence cardiac regeneration even though the underlying molecules remain poorly understood. Consistent with this idea, we show now significant changes in the expression of immune and cell movement gene pathways in heart samples from 1- and 7-day-old rats with ventricle resection. We then tested whether conditioned media from adult M2 anti-inflammatory macrophages target neonatal cardiac cells to a pro-regenerative like phenotype compared to the M1 pro-inflammatory macrophages. We found that M2 compared to M1 macrophage-conditioned media upregulates neonatal cardiomyocyte proliferation, suppresses myofibroblast-induced differentiation and stimulates endothelial cell tube formation. Using a cytokine array, we selected four candidate cytokine molecules uniquely expressed in M2 macrophage-conditioned media and showed that two of them (IL-4 and IL-6) induce endothelial cell proliferation whilst IL-4 promotes proliferation in neonatal cardiomyocytes and prevents myofibroblast-induced collagen type I secretion. Altogether, we provided evidence that adult M2 macrophage-conditioned media displays a paracrine beneficial pro-regenerative response in target cardiac cells and that IL-4 and IL-6 recapitulate, at least in part, these pleiotropic effects. Further characterization of macrophage immune phenotypes and their secreted molecules may give rise to novel therapeutic approaches for post-natal cardiac repair.
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Células Endoteliais/metabolismo , Interleucina-4/metabolismo , Interleucina-6/metabolismo , Macrófagos/metabolismo , Miocárdio/metabolismo , Comunicação Parácrina , Animais , Animais Recém-Nascidos , Meios de Cultivo Condicionados , Células Endoteliais/citologia , Macrófagos/citologia , Miocárdio/citologia , Miócitos Cardíacos , RatosRESUMO
Among the mechanisms of action of hyperbaric oxygenation (HBO), the chance of reducing injury by interfering with the mechanisms of redox homeostasis in the heart leads to the possibility of extending the period of viability of the myocardium at risk. This would benefit late interventions for reperfusion to the ischemic area. The objective of the present study was to investigate the changes in the redox system associated with HBO therapy maintained during the first hour after coronary occlusion in an acute myocardial infarction (MI) rat model. Surviving male rats (n=105) were randomly assigned to one of three groups: Sham (SH=26), myocardial infarction (MI=45) and infarction+hyperbaric therapy (HBO=34, 1 h at 2.5 atm). After 90 min of coronary occlusion, a sample of the heart was collected for western blot analysis of total protein levels of superoxide dismutase, catalase, peroxiredoxin and 3nitrotyrosine. Glutathione was measured by enzymelinked immunosorbent assay (ELISA). The detection of the superoxide radical anion was carried out by oxidation of dihydroethidium analyzed with confocal microscopy. The mortality rate of the MI group was significantly higher than that of the HBO group. No difference was noted in the myocardial infarction size. The oxidized/reduced glutathione ratio and peroxiredoxin were significantly higher in the SH and MI when compared to the HBO group. Superoxide dismutase enzymes and catalase were significantly higher in the HBO group compared to the MI and SH groups. 3Nitrotyrosine and the superoxide radical were significantly lower in the HBO group compared to these in the MI and SH groups. These data demonstrated that hyperbaric oxygenation therapy decreased mortality by improving redox control in the hearts of rats in the acute phase of myocardial infarction.
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Oclusão Coronária/terapia , Oxigenoterapia Hiperbárica , Infarto do Miocárdio/terapia , Animais , Catalase/metabolismo , Modelos Animais de Doenças , Glutationa/metabolismo , Masculino , Infarto do Miocárdio/mortalidade , Miocárdio/metabolismo , Oxirredução , Distribuição Aleatória , Ratos , Ratos Wistar , Superóxido Dismutase/metabolismoRESUMO
AIMS: The objective of this study was to evaluate if vascular age derived from coronary artery calcium (CAC) score improves atherosclerosis cardiovascular disease (ASCVD) risk discrimination in primary prevention asymptomatic heterozygous familial hypercholesterolaemia (FH) patients undergoing standard lipid-lowering therapy. METHODS AND RESULTS: Two hundred and six molecularly confirmed FH individuals (age 45 ± 14 years, 36% males, baseline LDL-cholesterol 6.2 ± 2.2 mmol/L; 239 ± 85mg/dL) were followed by 4.4 ± 2.9 years (median: 3.7 years, interquartile ranges 2.7-6.8). CAC measurement was performed, and lipid-lowering therapy was optimized according to FH guidelines. Vascular age was derived from CAC and calculated according to the Multi Ethnic Study of Atherosclerosis algorithm. Risk estimation based on the Framingham equations was calculated for both biological (bFRS) and vascular (vaFRS) age. During follow-up, 15 ASCVD events (7.2%) were documented. The annualized rate of events for bFRS <10%, 10-20%, and >20% was respectively: 8.45 [95% confidence interval (CI) 3.17-22.52], 23.28 (95% CI 9.69-55.94), and 28.13 (95% CI 12.63-62.61) per 1000 patients. The annualized rate of events for vaFRS <10%, 10-20%, and >20% was respectively: 0, 0, and 50.37 (95% CI 30.37-83.56) per 1000 patients. vaFRS presented a better discrimination for ASCVD events compared to bFRS 0.7058 (95% CI 0.5866-0.8250) vs. vaFRS 0.8820 (95% CI 0.8286-0.9355), P = 0.0005. CONCLUSION: CAC derived vascular age can improve ASCVD risk discrimination in primary prevention FH subjects. This tool may help further stratify risk in FH patients already receiving lipid-lowering medication who might be candidates for further treatment with newer therapies.
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Doença da Artéria Coronariana , Hiperlipoproteinemia Tipo II , Calcificação Vascular , Adulto , Cálcio , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/epidemiologia , Feminino , Humanos , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Hiperlipoproteinemia Tipo II/genética , Masculino , Pessoa de Meia-Idade , Medição de Risco , Fatores de Risco , Calcificação Vascular/diagnóstico por imagem , Calcificação Vascular/epidemiologiaRESUMO
The association of components of a low saturated fat (SFA) and of a Mediterranean diet was tested with atherosclerosis biomarkers in 190 familial hypercholesterolemia adults (FH) from Brazil (BR) and Spain (SP). Median blood LDL-C, Apolipoprotein B (apoB), and C reactive protein (hs-CRP) concentrations were higher in BR than in SP: 179.0 vs.161 mg/dL; 141 vs. 103 mg/dL; and 1.6 vs. 0.8 mg/L respectively (all p < 0.001). In BR there was lower median total fat (22.3 vs. 38.3%) and SFA (8.1 vs. 12.5%) but higher cholesterol (283.3 mg vs.188.9 mg) and carbohydrate (57.1 vs. 42.5%) consumption (all p < 0.001). Inverse associations were encountered between fibers, mono, and polyunsaturated fats and their ratios to SFA with LDL-C and ApoB (all p < 0.001). There was a direct association respectively of cholesterol with lipid biomarkers and of carbohydrates and trans-fatty acids with hs-CRP while other fats showed inverse relations with the latter (p < 0.001).
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Gorduras na Dieta/análise , Dislipidemias , Hiperlipoproteinemia Tipo II , Inflamação , Lipídeos/sangue , Adulto , Proteína C-Reativa/análise , Colesterol/sangue , Dieta/estatística & dados numéricos , Humanos , Inquéritos e QuestionáriosRESUMO
Sepsis is a dynamic disease, displaying an inflammatory profile that varies over time and for each organ. Controlling the inflammatory response based in targeting a single molecule has been proved useless. We hypothesized that treatment with bone marrow-derived mononuclear cells (BMDMCs) may be more efficient to modulate the systemic inflammatory response to infection. Adult male Balb/c mice were subjected to cecal ligation and puncture (CLP) or endotoxemia model of experimental sepsis. BMDMCs were separated under Ficoll gradient and injected intravenously 1 h after the procedures. Cytokines concentration was quantified in plasma, lungs, heart, and gut. Spleens, lymph nodes, and thymus were used for lymphocytes isolation and cell death assessment. All measurements were performed 2âh after BMDMCs injection. RAW264.7 macrophages and BMDMCs were cocultivated in vitro to investigate the mechanisms involved. Our data showed that an early single intravenous injection of BMDMCs in animals submitted to the murine model of endotoxemia led to the improvement of survival rate; BMDMCs persistency in lung, liver, and spleen after 24âh; decreased necrosis and apoptosis of mononuclear cells; lower TNF-α, but increased IL-10 concentration in plasma; and tissue-specific cytokine profile. In vitro experiments demonstrated that IL-6, IL-10, and nitric oxide production depends on direct contact of BMDMCs to macrophages and that TNF-α production is negatively regulated by PGE2. BMDMCs are efficient in protecting animals from endotoxemia and sepsis, reducing systemic inflammation as well as specifically modulating tissue inflammation, producing the necessary immune regulation to re-equilibrate the inflammatory response.
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Células da Medula Óssea/imunologia , Transplante de Medula Óssea , Comunicação Celular/imunologia , Citocinas/imunologia , Endotoxemia/imunologia , Endotoxemia/terapia , Animais , Células da Medula Óssea/patologia , Endotoxemia/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Células RAW 264.7RESUMO
OBJECTIVES: The aim of this study was to evaluate the role of coronary artery calcium (CAC) as a predictor of atherosclerotic cardiovascular disease (ASCVD) (fatal or not myocardial infarction, stroke, unstable angina requiring revascularization, and elective myocardial revascularization) events in asymptomatic primary prevention molecularly proven heterozygous familial hypercholesterolemia (FH) subjects receiving standard lipid-lowering therapy. BACKGROUND: FH is associated with premature ASCVD. However, the clinical course of ASCVD in subjects with FH is heterogeneous. CAC score, a marker of subclinical atherosclerosis burden, may optimize ASCVD risk stratification in FH. METHODS: Subjects with FH underwent CAC measurement and were followed prospectively. The association of CAC with ASCVD was evaluated using multivariate analysis. RESULTS: A total of 206 subjects (mean age 45 ± 14 years, 36.4% men, baseline and on-treatment low-density lipoprotein cholesterol 269 ± 70 mg/dl and 150 ± 56 mg/dl, respectively) were followed for a median of 3.7 years (interquartile range: 2.7 to 6.8 years). CAC was present in 105 (51%), and 15 ASCVD events (7.2%) were documented. Almost one-half of events were hard outcomes, and the others were elective myocardial revascularizations. The annualized rates of events per 1,000 patients for CAC scores of 0 (n = 101 [49%]), 1 to 100 (n = 62 [30%]) and >100 (n = 43 [21%]) were, respectively, 0, 26.4 (95% confidence interval: 12.9 to 51.8), and 44.1 (95% confidence interval, 26.0 to 104.1). In multivariate Cox regression analysis, log(CAC score + 1) was independently associated with incident ASCVD events (hazard ratio: 3.33; 95% CI: 1.635 to 6.790; p = 0.001). CONCLUSIONS: CAC was independently associated with ASCVD events in patients with FH receiving standard lipid-lowering therapy. This may help further stratify near-term risk in patients who might be candidates for further treatment with newer therapies.
Assuntos
Anticolesterolemiantes/uso terapêutico , Colesterol/sangue , Doença da Artéria Coronariana/prevenção & controle , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Prevenção Primária , Calcificação Vascular/prevenção & controle , Adulto , Anticolesterolemiantes/efeitos adversos , Biomarcadores/sangue , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/mortalidade , Regulação para Baixo , Feminino , Humanos , Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/genética , Hiperlipoproteinemia Tipo II/mortalidade , Incidência , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Estudos Prospectivos , Medição de Risco , Fatores de Risco , Fatores de Tempo , Calcificação Vascular/sangue , Calcificação Vascular/mortalidadeRESUMO
BACKGROUND AND AIMS: Familial hypercholesterolemia (FH) is a genetic disorder associated with high risk of early major cardiovascular events (MACE) that can impact the health related quality of life (HRQoL), however, this association is unclear. This study evaluated HRQoL in index cases (IC) and first-degree relatives (FDR) of individuals at high risk of FH undergoing genetic cascade screening. METHODS: Data collection was performed before awareness of molecular diagnosis results. Individuals were divided into four groups according to the molecular diagnosis: IC with (IC+) and without (IC-) identified mutations (n = 93 and n = 175, respectively), and affected (FDR+, n = 231) and non-affected (FDR-, n = 159) FDR of IC+. HRQoL measurements, mental (MCS) and physical component (PCS) scores were carried out with SF-12 questionnaire. Associations were tested by generalized linear models. RESULTS: The mean age was 49⯱â¯15 years, 42.2% were men, MACE had occurred in 30.7%. Overall, both PCS and MCS did not differ between FH and non-FH individuals, however, IC trended to have lower PCS independent of FH presence (p=0.003). Lower PCS were associated with female sex (p=0.018), lower education (p<0.001), professional inactivity (p=0.028), previous MACE occurrence (p<0.001), hypertension (p=0.016), depression (p<0.001) and obesity (p<0.001). Lower MCS were associated with female sex (p=0.009), previous MACE occurrence (p=0.034), depression (p<0.001) and smoking (p=0.009). Neither the presence of FH causing mutations nor pharmacological lipid lowering treatment was associated with HRQoL. CONCLUSIONS: HRQoL is not reduced in both IC and FDR FH individuals in comparison with their non-affected counterparts. Previous MACE and co-morbidities are associated with reduced HRQoL.
Assuntos
LDL-Colesterol/sangue , Testes Genéticos/métodos , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/genética , Mutação , Qualidade de Vida , Adulto , Anticolesterolemiantes/uso terapêutico , Biomarcadores/sangue , Brasil , Comorbidade , Estudos Transversais , Feminino , Marcadores Genéticos , Predisposição Genética para Doença , Hereditariedade , Humanos , Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Valor Preditivo dos Testes , Medição de Risco , Fatores de Risco , Inquéritos e Questionários , Resultado do TratamentoRESUMO
Abstract Background: Genetic cascade screening is the most cost-effective method for the identification of individuals with familial hypercholesterolemia (FH), but the best strategies for the enrollment of at-risk individuals in a FH screening program are not fully known. Objective: The aim of this study is to identify the best predictors of familial enrollment into genetic screening, using features derived from tested probands. Methods: One hundred and eighty-three index-cases (ICs) with a positive genetic result that had relatives screened from 01/2011 to 07/2015 were included. The response variable was the number of relatives for each enrolled IC. All variables in the study were based on ICs' derived clinical and socioeconomical features. The effect size of predictor variables were obtained through a general linear model using a negative binomial regression link function. Significance was considered with a p < 0.05. Results: Mean IC age when enrolling into the program was 50 years old; 78.1% of individuals reported knowledge of relatives with dyslipidemia. Mean baseline LDL-cholesterol level was 316 ± 90 mg/dL. Referral origin through the cascade program website vs. tertiary care, IC LDL-cholesterol and familial history of high LDL-cholesterol levels were independent predictors associated with a higher number of enrolled relatives. Conclusions: Our data suggest that FH cascade screening programs can predict family enrollment based on IC features. This information may be useful for devising better and more effective screening approaches for at-risk individuals.
Resumo Fundamento: O rastreamento genético em cascata é o método mais economicamente viável para a identificação de indivíduos com hipercolesterolemia familiar, mas as melhores estratégias para o recrutamento de indivíduos em risco em um programa de rastreamento deste tipo não são inteiramente conhecidas. Objetivo: Identificar os melhores preditores de recrutamento familiar em rastreamento genético, usando características derivadas de probandos testados. Métodos: Foram inscritos 183 casos índices com resultado genético positivo, que tiveram familiares rastreados de janeiro de 2011 a julho de 2015. A variável de resposta foi o número de familiares para cada caso índice inscrito. Todas as variáveis do estudo foram baseadas em características clínicas e socioeconômicas derivadas dos casos índices. O tamanho do efeito das variáveis preditoras foi obtido de modelo linear geral utilizando função de associação de regressão binomial negativa. A significância foi considerada com p < 0,05. Resultados: A média de idade dos casos índices ao ingressar no programa foi de 50 anos; 78,1% dos indivíduos relataram conhecimento de familiares com dislipidemia. O nível médio de LDL-colesterol inicial foi de 316 ± 90 mg/dL. Origem de referência por meio do site do programa em cascata vs. cuidados terciários, LDL-colesterol do caso índice e história familiar de níveis elevados de LDL-colesterol foram preditores independentes associados a um maior número de familiares inscritos. Conclusões: Programas de rastreamento genético em cascata da hipercolesterolemia familiar podem prever o recrutamento da família com base nas características do caso índice. Esta informação pode ser útil para criar abordagens de rastreamento melhores e mais eficazes para indivíduos em risco.
Assuntos
Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Idoso , Família , Testes Genéticos/métodos , Seleção de Pacientes , Hiperlipoproteinemia Tipo II/genética , Valores de Referência , Brasil , Modelos Lineares , Programas de Rastreamento/métodos , Análise de Regressão , Fatores de Risco , Diagnóstico Precoce , Hiperlipoproteinemia Tipo II/diagnósticoRESUMO
BACKGROUND: Genetic cascade screening is the most cost-effective method for the identification of individuals with familial hypercholesterolemia (FH), but the best strategies for the enrollment of at-risk individuals in a FH screening program are not fully known. OBJECTIVE: The aim of this study is to identify the best predictors of familial enrollment into genetic screening, using features derived from tested probands. METHODS: One hundred and eighty-three index-cases (ICs) with a positive genetic result that had relatives screened from 01/2011 to 07/2015 were included. The response variable was the number of relatives for each enrolled IC. All variables in the study were based on ICs' derived clinical and socioeconomical features. The effect size of predictor variables were obtained through a general linear model using a negative binomial regression link function. Significance was considered with a p < 0.05. RESULTS: Mean IC age when enrolling into the program was 50 years old; 78.1% of individuals reported knowledge of relatives with dyslipidemia. Mean baseline LDL-cholesterol level was 316 ± 90 mg/dL. Referral origin through the cascade program website vs. tertiary care, IC LDL-cholesterol and familial history of high LDL-cholesterol levels were independent predictors associated with a higher number of enrolled relatives. CONCLUSIONS: Our data suggest that FH cascade screening programs can predict family enrollment based on IC features. This information may be useful for devising better and more effective screening approaches for at-risk individuals.
Assuntos
Família , Testes Genéticos/métodos , Hiperlipoproteinemia Tipo II/genética , Seleção de Pacientes , Adulto , Idoso , Brasil , Diagnóstico Precoce , Feminino , Humanos , Hiperlipoproteinemia Tipo II/diagnóstico , Modelos Lineares , Masculino , Programas de Rastreamento/métodos , Pessoa de Meia-Idade , Valores de Referência , Análise de Regressão , Fatores de RiscoRESUMO
BACKGROUND AND AIMS: There is controversy on the accuracy of different diagnostic criteria for familial hypercholesterolemia (FH). The aim of this study is to assess the performance of different clinical criteria used to identify individuals for FH genetic cascade screening in Brazil. METHODS: All index cases (IC) registered in the Hipercol Brasil program between 2011 and 2016 were analyzed. Inclusion criteria were age ≥18 years and elevated LDL-cholesterol (LDL-C) levels, with a conclusive result in the genetic test, whether positive or negative. Initially, we tested the multivariable association between clinical and laboratory markers and the presence of an FH causing mutation. Then, we analyzed sensitivity, specificity, positive and negative predictive values for the LDL-C quartile distribution, LDL-C as a continuous variable, as well as the performance measures for the Dutch Lipid Clinic Network (DLCN) score to identify a mutation. RESULTS: Overall, 753 ICs were included and an FH causing mutation was found in 34% (n = 257) of the subjects. After multivariable analysis, LDL-C as a continuous variable, tendon xanthomas and corneal arcus were independently associated with the presence of FH mutations. LDL-C values ≥ 230 mg/dL (5.9 mmol/L) had the best tradeoff between sensitivity and specificity to diagnose a mutation. The DLCN score presented a better performance than LDL-C to identify a mutation, area under the ROC curve were 0.744 (95% CI: 0.704-0.784) and 0.730 (95% CI: 0.687-0.774), respectively, p=0.014. CONCLUSIONS: In our population, LDL ≥230 mg/dL is a feasible criterion to indicate ICs to genetic testing.
Assuntos
LDL-Colesterol/sangue , Análise Mutacional de DNA , Testes Genéticos/métodos , Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/genética , Mutação , Adulto , Idoso , Arco Senil/sangue , Arco Senil/genética , Área Sob a Curva , Biomarcadores/sangue , Brasil , Distribuição de Qui-Quadrado , Tomada de Decisão Clínica , Estudos de Viabilidade , Feminino , Predisposição Genética para Doença , Humanos , Hiperlipoproteinemia Tipo II/diagnóstico , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Seleção de Pacientes , Fenótipo , Valor Preditivo dos Testes , Curva ROC , Reprodutibilidade dos Testes , Fatores de Risco , Regulação para Cima , Xantomatose/sangue , Xantomatose/genéticaRESUMO
Cell therapy repair strategies using adult mesenchymal stromal cells have shown promising evidence to prevent cardiac deterioration in rodents even in the absence of robust differentiation of the cells into cardiomyocytes. We tested whether increasing doses of porcine adipose-tissue derived mesenchymal stem cells (pASCs) increase cardiac tissue perfusion in pigs post-myocardial infarction (MI) receiving angiotensin-converting-enzyme inhibitor (ACE inhibitors) and Beta-blockers similarly to patients. Female pigs were subjected to MI induction by sponge permanent occlusion of left circumflex coronary artery (LCx) generating approximately 10% of injured LV area with minimum hemodynamic impact. We assessed tissue perfusion by real time myocardial perfusion echocardiography (RTMPE) using commercial microbubbles before and following pASCs treatment. Four weeks after the occlusion of the left circumflex artery, we transplanted placebo or pASCs (1, 2 and 4x106 cells/Kg BW) into the myocardium. The highest dose of pASCs increased myocardial vessel number and blood flow in the border (56% and 3.7-fold, respectively) and in the remote area (54% and 3.9-fold, respectively) while the non-perfused scar area decreased (up to 38%). We also found an increase of immature collagen fibers, although the increase in total tissue collagen and types I and III was similar in all groups. Our results provide evidence that pASCs-induced stimulation of tissue perfusion and accumulation of immature collagen fibers attenuates adverse remodeling post-MI beyond the normal beneficial effects associated with ACE inhibition and beta-blockade.
Assuntos
Tecido Adiposo/citologia , Transplante de Células-Tronco Mesenquimais , Infarto do Miocárdio/patologia , Infarto do Miocárdio/terapia , Remodelação Ventricular , Animais , Circulação Coronária/efeitos dos fármacos , Enalaprilato/farmacologia , Feminino , Hemodinâmica/efeitos dos fármacos , Metoprolol/farmacologia , Infarto do Miocárdio/fisiopatologia , Suínos , Transplante Homólogo , Remodelação Ventricular/efeitos dos fármacosRESUMO
BACKGROUND: There is little information about familial hypercholesterolemia (FH) epidemiology and care in Ibero-American countries. The Ibero-American FH network aims at reducing the gap on diagnosis and treatment of this disease in the region. OBJECTIVE: To describe clinical, molecular, and organizational characteristics of FH diagnosis in Argentina, Brazil, Chile, Colombia, Mexico, Portugal, Spain, and Uruguay. METHODS: Descriptive analysis of country data related to FH cascade screening, molecular diagnosis, clinical practice guidelines, and patient organization presence in Ibero-America. RESULTS: From a conservative estimation of an FH prevalence of 1 of 500 individuals, there should be 1.2 million heterozygous FH individuals in Ibero-America and roughly 27,400 were diagnosed so far. Only Spain, Brazil, Portugal, and Uruguay have active cascade screening programs. The prevalence of cardiovascular disease ranged from 10% to 42% in member countries, and the highest molecular identification rates are seen in Spain, 8.3%, followed by Portugal, 3.8%, and Uruguay with 2.5%. In the 3 countries with more FH patients identified (Spain, Portugal, and Brazil) between 10 and 15 mutations are responsible for 30% to 47% of all FH cases. Spain and Portugal share 5 of the 10 most common mutations (4 in low density lipoprotein receptor [LDLR] and the APOB3527). Spain and Spanish-speaking Latin American countries share 6 of the most common LDLR mutations and the APOB3527. LDL apheresis is available only in Spain and Portugal and not all countries have specific FH diagnostic and treatment guidelines as well as patient organizations. CONCLUSIONS: Ibero-American countries share similar mutations and gaps in FH care.