RESUMEN
Familial hypercholesterolemia (FH) is characterized by high low-density lipoprotein cholesterol (LDL-C) levels and a high risk of early coronary heart disease. Structural alterations in the LDLR, APOB, and PCSK9 genes were not found in 20-40% of patients diagnosed using the Dutch Lipid Clinic Network (DCLN) criteria. We hypothesized that methylation in canonical genes could explain the origin of the phenotype in these patients. This study included 62 DNA samples from patients with a clinical diagnosis of FH according to the DCLN criteria, who previously tested negative for structural alterations in the canonical genes, and 47 DNA samples from patients with normal blood lipids (control group). All DNA samples were tested for methylation in the CpG islands of the three genes. The prevalence of FH relative to each gene was determined in both groups and the respective prevalence ratios (PRs) were calculated. The methylation analysis of APOB and PCSK9 was negative in both groups, showing no relationship between methylation in these genes and the FH phenotype. As the LDLR gene has two CpG islands, we analyzed each island separately. The analysis of LDLR-island1 showed PR = 0.982 (CI 0.33-2.95; χ2 = 0.001; p = 0.973), also suggesting no relationship between methylation and the FH phenotype. Analysis of LDLR-island2 showed a PR of 4.12 (CI 1.43-11.88; χ2 = 13,921; p = 0.00019), indicating a possible association between methylation on this island and the FH phenotype.
Asunto(s)
Hiperlipoproteinemia Tipo II , Proproteína Convertasa 9 , Humanos , Proproteína Convertasa 9/genética , Hiperlipoproteinemia Tipo II/diagnóstico , Fenotipo , HDL-Colesterol/genética , Apolipoproteínas B/genética , Regiones Promotoras Genéticas , Receptores de LDL/genética , MutaciónRESUMEN
The rate of the remodeling of the arterialized saphenous vein conduit limits the outcomes of coronary artery bypass graft surgery (CABG), which may be influenced by endothelial dysfunction. We tested the hypothesis that high stretch (HS) induces human saphenous vein endothelial cell (hSVEC) dysfunction and examined candidate underlying mechanisms. Our results showed that in vitro HS reduces NO bioavailability, increases inflammatory adhesion molecule expression (E-selectin and VCAM1) and THP-1 cell adhesion. HS decreases F-actin in hSVECs, but not in human arterial endothelial cells, and is accompanied by G-actin and cofilin's nuclear shuttling and increased reactive oxidative species (ROS). Pre-treatment with the broad-acting antioxidant N-acetylcysteine (NAC) supported this observation and diminished stretch-induced actin remodeling and inflammatory adhesive molecule expression. Altogether, we provide evidence that increased oxidative stress and actin cytoskeleton remodeling play a role in HS-induced saphenous vein endothelial cell dysfunction, which may contribute to predisposing saphenous vein graft to failure.
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Actinas/metabolismo , Células Endoteliales/metabolismo , Estrés Oxidativo , Vena Safena/metabolismo , Estrés Mecánico , Humanos , Especies Reactivas de Oxígeno/metabolismo , Células THP-1RESUMEN
AIMS: SCN5A gene encodes the α-subunit of Nav1.5, mainly found in the human heart. SCN5A variants are the most common genetic alterations associated with Brugada syndrome (BrS). In rare cases, compound heterozygosity is observed; however, its functional consequences are poorly understood. We aimed to analyze the functional impact of de novo Nav1.5 mutations in compound heterozygosity in distinct alleles (G400R and T1461S positions) previously found in a patient with BrS. Moreover, we evaluated the potential benefits of quinidine to improve the phenotype of mutant Na+ channels in vitro. MATERIALS AND METHODS: The functional properties of human wild-type and Nav1.5 variants were evaluated using whole-cell patch-clamp and immunofluorescence techniques in transiently expressed human embryonic kidney (HEK293) cells. KEY FINDINGS: Both variants occur in the highly conservative positions of SCN5A. Although all variants were expressed in the cell membrane, a significant reduction in the Na+ current density (except for G400R alone, which was undetected) was observed along with abnormal biophysical properties, once the variants were expressed in homozygosis and heterozygosis. Interestingly, the incubation of transfected cells with quinidine partially rescued the biophysical properties of the mutant Na+ channel. SIGNIFICANCE: De novo compound heterozygosis mutations in SNC5A disrupt the Na+ macroscopic current. Quinidine could partially reverse the in vitro loss-of-function phenotype of Na+ current. Thus, our data provide, for the first time, a detailed biophysical characterization of dysfunctional Na+ channels linked to compound heterozygosity in BrS as well as the benefits of the pharmacological treatment using quinidine on the biophysical properties of Nav1.5.
Asunto(s)
Síndrome de Brugada/genética , Mutación con Pérdida de Función , Canal de Sodio Activado por Voltaje NAV1.5/genética , Secuencia de Aminoácidos , Síndrome de Brugada/tratamiento farmacológico , Síndrome de Brugada/metabolismo , Células HEK293 , Heterocigoto , Humanos , Mutación con Pérdida de Función/efectos de los fármacos , Canal de Sodio Activado por Voltaje NAV1.5/química , Canal de Sodio Activado por Voltaje NAV1.5/metabolismo , Mutación Puntual/efectos de los fármacos , Quinidina/farmacologíaRESUMEN
Chronotype or diurnal preference is a questionnaire-based measure influenced both by circadian period and by the sleep homeostat. In order to further characterize the biological determinants of these measures, we used a hypothesis-free approach to investigate the association between the score of the morningness-eveningness questionnaire (MEQ) and the Munich chronotype questionnaire (MCTQ), as continuous variables, and volumetric measures of brain regions acquired by magnetic resonance imaging (MRI). Data were collected from the Baependi Heart Study cohort, based in a rural town in South-Eastern Brazil. MEQ and anatomical 1.5-T MRI scan data were available from 410 individuals, and MCTQ scores were available from a subset of 198 of them. The average MEQ (62.2 ± 10.6) and MCTQ (average MSFsc 201 ± 85 min) scores were suggestive of a previously reported strong general tendency toward morningness in this community. Setting the significance threshold at P > .002 to account for multiple comparisons, we observed a significant association between lower MEQ score (eveningness) and greater volume of the left anterior occipital sulcus (ß = -0.163, p = .001) of the occipital lobe. No significant associations were observed for MCTQ. This may reflect the smaller dataset for MCTQ, and/or the fact that MEQ, which asks questions about preferred timings, is more trait-like than the MCTQ, which asks questions about actual timings. The association between MEQ and a brain region dedicated to visual information processing is suggestive of the increasingly recognized fluidity in the interaction between visual and nonvisual photoreception and the circadian system, and the possibility that chronotype includes an element of masking.
Asunto(s)
Ritmo Circadiano , Vigilia , Encéfalo/diagnóstico por imagen , Brasil , Humanos , Lóbulo Occipital/diagnóstico por imagen , Sueño , Encuestas y CuestionariosRESUMEN
Individual variability in word generation is a product of genetic and environmental influences. The genetic effects on semantic verbal fluency were estimated in 1,735 participants from the Brazilian Baependi Heart Study. The numbers of exemplars produced in 60 s were broken down into time quartiles because of the involvement of different cognitive processes-predominantly automatic at the beginning, controlled/executive at the end. Heritability in the unadjusted model for the 60-s measure was 0.32. The best-fit model contained age, sex, years of schooling, and time of day as covariates, giving a heritability of 0.21. Schooling had the highest moderating effect. The highest heritability (0.17) was observed in the first quartile, decreasing to 0.09, 0.12, and 0.0003 in the following ones. Heritability for average production starting point (intercept) was 0.18, indicating genetic influences for automatic cognitive processes. Production decay (slope), indicative of controlled processes, was not significant. The genetic influence on different quartiles of the semantic verbal fluency test could potentially be exploited in clinical practice and genome-wide association studies.
Asunto(s)
Cognición , Estudio de Asociación del Genoma Completo , Semántica , Conducta Verbal , Adolescente , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Cardiometabolic risk factors influence white matter hyperintensity (WMH) development: in metabolic syndrome (MetS), higher WMH load is often reported but the relationships between specific cardiometabolic variables, WMH load and cognitive performance are uncertain. We investigated these in a Brazilian sample (aged 50-85) with (N = 61) and without (N = 103) MetS. Stepwise regression models identified effects of cardiometabolic and demographic variables on WMH load (from FLAIR MRI) and verbal recall performance. WMH volume was greater in MetS, but verbal recall performance was not impaired. Age showed the strongest relationship with WMH load. Across all participants, systolic blood pressure (SBP) and fasting blood glucose were also contributors, and WMH volume was negatively associated with verbal recall performance. In non-MetS, higher HbA1c, SBP, and number of MetS components were linked to poorer recall performance while higher triglyceride levels appeared to be protective. In MetS only, these relationships were absent but education exerted a strongly protective effect on recall performance. Thus, results support MetS as a construct: the clustering of cardiometabolic variables in MetS alters their individual relationships with cognition; instead, MetS is characterised by a greater reliance on cognitive reserve mechanisms. In non-MetS, strategies to control HbA1c and SBP should be prioritised as these have the largest impact on cognition.
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Cognición , Síndrome Metabólico/metabolismo , Síndrome Metabólico/patología , Sustancia Blanca/patología , Sustancia Blanca/fisiopatología , Anciano , Anciano de 80 o más Años , Biomarcadores , Enfermedades Cardiovasculares/complicaciones , Metabolismo Energético , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Síndrome Metabólico/complicaciones , Persona de Mediana Edad , Pruebas Neuropsicológicas , Factores de Riesgo , Sustancia Blanca/diagnóstico por imagenRESUMEN
Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) molecule is expressed on T-lymphocyte membrane and negatively influences the antigen-presenting process. Reduced expression of CTLA-4 due to gene polymorphisms is associated with increased risk of autoimmune disorders, whose physiopathology is similar to that of post-transfusion red blood cell (RBC) alloimmunization. Our goal was to evaluate if polymorphisms of CTLA-4 gene that affect protein expression are associated with RBC alloimmunization. This was a case-control study in which 134 sickle cell disease (SCD) patients and 253 non-SCD patients were included. All patients were genotyped for the polymorphisms 49A/G and -318C/T of CTLA-4 gene. The genotype frequency of -318C/T differed significantly between alloimmunized and nonalloimmunized SCD patients, irrespective of clinical confounders (p = .016). SCD patients heterozygous for -318T allele presented higher risk of alloantibody development (OR: 5.4, CI: 1.15-25.6). In conclusion, the polymorphism -318C/T of CTLA-4 gene is associated with RBC alloimmunization among SCD patients. This highlights the role played by CTLA-4 on post-transfusion alloantibody development.
Asunto(s)
Anemia de Células Falciformes/genética , Enfermedades Autoinmunes/genética , Antígeno CTLA-4/genética , Eritrocitos/inmunología , Adulto , Anemia de Células Falciformes/sangre , Anemia de Células Falciformes/inmunología , Anemia de Células Falciformes/prevención & control , Células Presentadoras de Antígenos/inmunología , Células Presentadoras de Antígenos/patología , Enfermedades Autoinmunes/sangre , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/patología , Antígeno CTLA-4/inmunología , Eritrocitos/patología , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Inmunización/efectos adversos , Isoanticuerpos/inmunología , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple/genética , Factores de Riesgo , Linfocitos T/inmunología , Linfocitos T/patologíaRESUMEN
Sleep is modulated by several factors, including sex, age, and chronotype. It has been hypothesised that contemporary urban populations are under pressure towards shorter sleep duration and poorer sleep quality. Baependi is a small town in Brazil that provides a window of opportunity to study the influence of sleep patterns in a highly admixed rural population with a conservative lifestyle. We evaluated sleep characteristics, excessive daytime sleepiness, and chronotype using the Pittsburgh Sleep Quality Index, Epworth Sleepiness Scale and Morningness-Eveningness Questionnaire questionnaires, respectively. The sample consisted of 1,334 subjects from the Baependi Heart study (41.5% male; age: 46.5 ± 16.2 y, range: 18-89 years). Average self-reported sleep duration was 07:07 ± 01:31 (bedtime 22:32 ± 01:27, wake up time: 06:17 ± 01:25 hh:min), sleep quality score was 4.9 + 3.2, chronotype was 63.6 ± 10.8 and daytime sleepiness was 7.4 ± 4.8. Despite a shift towards morningness in the population, chronotype remained associated with reported actual sleep timing. Age and sex modulated the ontogeny of sleep and chronotype, increasing age was associated with earlier sleep time and shorter sleep duration. Women slept longer and later, and reported poorer sleep quality than men (p < 0.0001). This study provides indirect evidence in support of the hypothesis that sleep timing was earlier prior to full urbanisation.
Asunto(s)
Higiene del Sueño , Adolescente , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Brasil , Femenino , Humanos , Masculino , Persona de Mediana Edad , Población Rural , Factores Sexuales , Encuestas y Cuestionarios , Factores de Tiempo , Adulto JovenRESUMEN
AIMS: The CYBA C242T polymorphism has been associated with cardiovascular phenotypes such as hypertension and atherosclerosis, but available data are conflicting. This report investigated the impact of this variant on hypertension and metabolic determinants of cardiovascular risk in a large Brazilian sample. METHODS: We cross-sectionally evaluated 1856 subjects (826 normotensive subjects and 1030 hypertensive patients) by clinical history, anthropometry, laboratory analysis and genotyping of the CYBA C242T polymorphism. RESULTS: Genotype frequencies in the whole population were consistent with the Hardy-Weinberg equilibrium and genotype distributions were not different between hypertensive and normotensive subjects. Hypertensive patients with the CC genotype presented lower fasting plasma glucose levels (5.9 ± 0.1 vs. 6.2 ± 0.1 mmol/l, P = 0.020) and waist circumference (94.5 ± 0.6 vs. 96.3 ± 0.6 cm, P = 0.028) than CT + TT ones. Similarly, the prevalence of diabetes mellitus and obesity was also lower in hypertensive patients carrying the CC genotype (16% vs. 21%, P = 0.041; 36% vs. 43%, P = 0.029, respectively). In addition, multiple and logistic regression analysis demonstrated that the CYBA C242T polymorphism was associated with glucose levels, waist circumference, obesity and diabetes mellitus in hypertensive patients independently of potential confounders. Conversely, in normotensive subjects, no significant difference in studied variables was detected between the genotype groups. CONCLUSIONS: These data suggest that the T allele of the CYBA C242T polymorphism may be used as a marker for adverse metabolic features in Brazilian subjects with systemic hypertension.
Asunto(s)
Enfermedad de la Arteria Coronaria/genética , Diabetes Mellitus/genética , Hipertensión/genética , NADPH Oxidasas/genética , Obesidad/genética , Polimorfismo de Nucleótido Simple , Adulto , Anciano , Brasil/epidemiología , Enfermedad de la Arteria Coronaria/sangre , Enfermedad de la Arteria Coronaria/epidemiología , Enfermedad de la Arteria Coronaria/etiología , Estudios Transversales , Cisteína , Diabetes Mellitus/sangre , Diabetes Mellitus/epidemiología , Femenino , Genotipo , Humanos , Hipertensión/sangre , Hipertensión/epidemiología , Masculino , Persona de Mediana Edad , NADPH Oxidasas/sangre , Obesidad/sangre , Obesidad/epidemiología , Fenotipo , Factores de Riesgo , TreoninaRESUMEN
Thioredoxin interacting protein plays a pivotal role in several important processes of cardiovascular homeostasis by functioning as a biological sensor for biomechanical and oxidative stress. However, the effects of genetic variants in the modulation of arterial stiffness are unknown. In this scenario, the present study evaluated the relationship between the TXNIP rs7212 polymorphism and arterial stiffness. In the overall sample and in the diabetic group, individuals carrying CG+GG genotypes had higher PWV values compared with CC genotype group (10.0 vs 9.8 m s (-1), P=0.03; 12.3 vs 11.2 m s(-1), P=0.01; respectively). Our findings indicated that the G allele may contribute to increased arterial stiffness in the Brazilian general population and suggest a possible interaction with diabetes.
Asunto(s)
Arterias/fisiopatología , Proteínas Portadoras/genética , Polimorfismo Genético , Enfermedades Vasculares/genética , Adulto , Brasil , Estudios Transversales , Diabetes Mellitus/genética , Diabetes Mellitus/fisiopatología , Elasticidad , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Fenotipo , Medición de Riesgo , Factores de Riesgo , Enfermedades Vasculares/diagnóstico , Enfermedades Vasculares/fisiopatologíaRESUMEN
In this study, we analyzed whether transplantation of cardiac fibroblasts (CFs) expressing vascular endothelial growth factor (VEGF) mitigates cardiac dysfunction after myocardial infarction (MI) in rats. First, we observed that the transgene expression lasts longer (45 vs 7 days) when fibroblasts are used as vectors compared with myoblasts. In a preventive protocol, induction of cardiac neovascularization accompanied by reduction in myocardial scar area was observed when cell transplantation was performed 1 week before ischemia/reperfusion and the animals analyzed 3 weeks later. Finally, the therapeutic efficacy of this approach was tested injecting cells in a fibrin biopolymer, to increase cardiac retention, 24 h post-MI. After 4 weeks, an increase in neovascularization and a decrease in myocardial collagen were observed only in rats that received cells expressing VEGF. Basal indirect or direct hemodynamic measurements showed no differences among the groups whereas under pharmacological stress, only the group that received cells expressing VEGF showed a significant reduction in end-diastolic pressure and improvement in stroke volume and cardiac work. These results indicate that transplantation of CFs expressing VEGF using fibrin biopolymer induces neovascularization and attenuates left ventricle fibrosis and cardiac dysfunction in ischemic heart.
Asunto(s)
Fibroblastos/trasplante , Terapia Genética/métodos , Infarto del Miocardio/terapia , Transgenes , Factores de Crecimiento Endotelial Vascular/genética , Animales , Fibrina/administración & dosificación , Fibroblastos/metabolismo , Masculino , Infarto del Miocardio/prevención & control , Daño por Reperfusión Miocárdica/prevención & control , Daño por Reperfusión Miocárdica/terapia , Neovascularización Fisiológica/genética , Ratas , Ratas Endogámicas LewRESUMEN
Angiotensin-converting enzyme (ACE) activity and polymorphism contribute significantly to the prognosis of patients with cardiomyopathy. The aim of this study was to determine the activity and type of ACE polymorphism in patients with familial and nonfamilial hypertrophic cardiomyopathy (HCM) and to correlate these with echocardiographic measurements (echo-Doppler). We studied 136 patients (76 males) with HCM (69 familial and 67 nonfamilial cases). Mean age was 41 ¡À 17 years. DNA was extracted from blood samples for the polymerase chain reaction and the determination of plasma ACE levels. Left ventricular mass, interventricular septum, and wall thickness were measured. Mean left ventricular mass index, interventricular septum and wall thickness in familial and nonfamilial forms were 154 ¡À 63 and 174 ¡À 57 g/m2 (P = 0.008), 19 ¡À 5 and 21 ¡À 5 mm (P = 0.02), and 10 ¡À 2 and 12 ¡À 3 mm (P = 0.0001), respectively. ACE genotype frequencies were DD = 35%, ID = 52%, and II = 13%. A positive association was observed between serum ACE activity and left ventricular mass index (P = 0.04). Logistic regression showed that ACE activity was twice as high in patients with familial HCM and left ventricular mass index ¡Ý190 g/m2 compared with the nonfamilial form (P = 0.02). No other correlation was observed between ACE polymorphisms and the degree of myocardial hypertrophy. In conclusion, ACE activity, but not ACE polymorphisms, was associated with the degree of myocardialhypertrophy in the patients with HCM.
Asunto(s)
Adulto , Femenino , Humanos , Masculino , Cardiomiopatía Hipertrófica/enzimología , Peptidil-Dipeptidasa A/genética , Peptidil-Dipeptidasa A/metabolismo , Polimorfismo Genético/genética , Cardiomiopatía Hipertrófica Familiar/enzimología , Cardiomiopatía Hipertrófica Familiar/genética , Cardiomiopatía Hipertrófica Familiar , Cardiomiopatía Hipertrófica/genética , Cardiomiopatía Hipertrófica , Ecocardiografía Doppler , Genotipo , Hipertrofia Ventricular Izquierda , Fenotipo , Índice de Severidad de la EnfermedadRESUMEN
The contribution of kinins to the beneficial effects in cardiovascular risk reductions remains unclear. In this context, the present study examined whether the +9 bp/-9 bp polymorphism in bradykinin type 2 receptor gene, predicts hypertension risk in a large urban Brazilian population. Our finding indicated that the -9 bp allele may contribute to hypertension because of increased diastolic pressure.
Asunto(s)
Hipertensión/genética , Mutación INDEL , Polimorfismo Genético/genética , Receptor de Bradiquinina B2/genética , Adulto , Presión Sanguínea/genética , Brasil , Estudios Transversales , Diástole/genética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Factores de Riesgo , Población UrbanaRESUMEN
Angiotensin-converting enzyme (ACE) activity and polymorphism contribute significantly to the prognosis of patients with cardiomyopathy. The aim of this study was to determine the activity and type of ACE polymorphism in patients with familial and nonfamilial hypertrophic cardiomyopathy (HCM) and to correlate these with echocardiographic measurements (echo-Doppler). We studied 136 patients (76 males) with HCM (69 familial and 67 nonfamilial cases). Mean age was 41 +/- 17 years. DNA was extracted from blood samples for the polymerase chain reaction and the determination of plasma ACE levels. Left ventricular mass, interventricular septum, and wall thickness were measured. Mean left ventricular mass index, interventricular septum and wall thickness in familial and nonfamilial forms were 154 +/- 63 and 174 +/- 57 g/m(2) (P = 0.008), 19 +/- 5 and 21 +/- 5 mm (P = 0.02), and 10 +/- 2 and 12 +/- 3 mm (P = 0.0001), respectively. ACE genotype frequencies were DD = 35%, ID = 52%, and II = 13%. A positive association was observed between serum ACE activity and left ventricular mass index (P = 0.04). Logistic regression showed that ACE activity was twice as high in patients with familial HCM and left ventricular mass index >or=190 g/m(2) compared with the nonfamilial form (P = 0.02). No other correlation was observed between ACE polymorphisms and the degree of myocardial hypertrophy. In conclusion, ACE activity, but not ACE polymorphisms, was associated with the degree of myocardial hypertrophy in the patients with HCM.
Asunto(s)
Cardiomiopatía Hipertrófica/enzimología , Peptidil-Dipeptidasa A/genética , Peptidil-Dipeptidasa A/metabolismo , Polimorfismo Genético/genética , Adulto , Cardiomiopatía Hipertrófica/diagnóstico por imagen , Cardiomiopatía Hipertrófica/genética , Cardiomiopatía Hipertrófica Familiar/diagnóstico por imagen , Cardiomiopatía Hipertrófica Familiar/enzimología , Cardiomiopatía Hipertrófica Familiar/genética , Ecocardiografía Doppler , Femenino , Genotipo , Humanos , Hipertrofia Ventricular Izquierda/diagnóstico por imagen , Masculino , Fenotipo , Índice de Severidad de la EnfermedadRESUMEN
The autonomic nervous system plays an important role in physiological and pathological conditions, and has been extensively evaluated by parametric and non-parametric spectral analysis. To compare the results obtained with fast Fourier transform (FFT) and the autoregressive (AR) method, we performed a comprehensive comparative study using data from humans and rats during pharmacological blockade (in rats), a postural test (in humans), and in the hypertensive state (in both humans and rats). Although postural hypotension in humans induced an increase in normalized low-frequency (LFnu) of systolic blood pressure, the increase in the ratio was detected only by AR. In rats, AR and FFT analysis did not agree for LFnu and high frequency (HFnu) under basal conditions and after vagal blockade. The increase in the LF/HF ratio of the pulse interval, induced by methylatropine, was detected only by FFT. In hypertensive patients, changes in LF and HF for systolic blood pressure were observed only by AR; FFT was able to detect the reduction in both blood pressure variance and total power. In hypertensive rats, AR presented different values of variance and total power for systolic blood pressure. Moreover, AR and FFT presented discordant results for LF, LFnu, HF, LF/HF ratio, and total power for pulse interval. We provide evidence for disagreement in 23 percent of the indices of blood pressure and heart rate variability in humans and 67 percent discordance in rats when these variables are evaluated by AR and FFT under physiological and pathological conditions. The overall disagreement between AR and FFT in this study was 43 percent.
Asunto(s)
Animales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Ratas , Adulto Joven , Sistema Nervioso Autónomo/fisiopatología , Análisis de Fourier , Bloqueo Cardíaco/fisiopatología , Hipertensión/fisiopatología , Derivados de Atropina/farmacología , Bloqueo Cardíaco/inducido químicamente , Frecuencia Cardíaca/fisiología , Ratas Endogámicas SHR , Ratas Wistar , Índice de Severidad de la Enfermedad , Pruebas de Mesa Inclinada , Adulto JovenRESUMEN
The autonomic nervous system plays an important role in physiological and pathological conditions, and has been extensively evaluated by parametric and non-parametric spectral analysis. To compare the results obtained with fast Fourier transform (FFT) and the autoregressive (AR) method, we performed a comprehensive comparative study using data from humans and rats during pharmacological blockade (in rats), a postural test (in humans), and in the hypertensive state (in both humans and rats). Although postural hypotension in humans induced an increase in normalized low-frequency (LFnu) of systolic blood pressure, the increase in the ratio was detected only by AR. In rats, AR and FFT analysis did not agree for LFnu and high frequency (HFnu) under basal conditions and after vagal blockade. The increase in the LF/HF ratio of the pulse interval, induced by methylatropine, was detected only by FFT. In hypertensive patients, changes in LF and HF for systolic blood pressure were observed only by AR; FFT was able to detect the reduction in both blood pressure variance and total power. In hypertensive rats, AR presented different values of variance and total power for systolic blood pressure. Moreover, AR and FFT presented discordant results for LF, LFnu, HF, LF/HF ratio, and total power for pulse interval. We provide evidence for disagreement in 23% of the indices of blood pressure and heart rate variability in humans and 67% discordance in rats when these variables are evaluated by AR and FFT under physiological and pathological conditions. The overall disagreement between AR and FFT in this study was 43%.
Asunto(s)
Sistema Nervioso Autónomo/fisiopatología , Análisis de Fourier , Bloqueo Cardíaco/fisiopatología , Hipertensión/fisiopatología , Animales , Derivados de Atropina/farmacología , Femenino , Bloqueo Cardíaco/inducido químicamente , Frecuencia Cardíaca/fisiología , Humanos , Masculino , Persona de Mediana Edad , Ratas , Ratas Endogámicas SHR , Ratas Wistar , Índice de Severidad de la Enfermedad , Pruebas de Mesa Inclinada , Adulto JovenRESUMEN
The role of exercise training (ET) on cardiac renin-angiotensin system (RAS) was investigated in 3-5 month-old mice lacking alpha(2A-) and alpha(2C-)adrenoceptors (alpha(2A)/alpha(2C)ARKO) that present heart failure (HF) and wild type control (WT). ET consisted of 8-week running sessions of 60 min, 5 days/week. In addition, exercise tolerance, cardiac structural and function analysis were made. At 3 months, fractional shortening and exercise tolerance were similar between groups. At 5 months, alpha(2A)/alpha(2C)ARKO mice displayed ventricular dysfunction and fibrosis associated with increased cardiac angiotensin (Ang) II levels (2.9-fold) and increased local angiotensin-converting enzyme activity (ACE 18%). ET decreased alpha(2A)/alpha(2C)ARKO cardiac Ang II levels and ACE activity to age-matched untrained WT mice levels while increased ACE2 expression and prevented exercise intolerance and ventricular dysfunction with little impact on cardiac remodeling. Altogether, these data provide evidence that reduced cardiac RAS explains, at least in part, the beneficial effects of ET on cardiac function in a genetic model of HF.
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Angiotensina II/metabolismo , Insuficiencia Cardíaca/genética , Insuficiencia Cardíaca/prevención & control , Miocardio/metabolismo , Condicionamiento Físico Animal/fisiología , Receptores Adrenérgicos alfa 2/genética , Animales , Presión Sanguínea/fisiología , Modelos Animales de Enfermedad , Corazón/fisiopatología , Insuficiencia Cardíaca/fisiopatología , Frecuencia Cardíaca/fisiología , Masculino , Ratones , Ratones Congénicos , Ratones Endogámicos C57BL , Ratones Noqueados , Modelos Genéticos , Receptores Adrenérgicos alfa 2/metabolismo , Sistema Renina-Angiotensina/fisiología , Sistema Nervioso Simpático/fisiopatología , Disfunción Ventricular/fisiopatologíaRESUMEN
BACKGROUND: Genetic polymorphisms of the TCF7L2 gene are strongly associated with large increments in type 2 diabetes risk in different populations worldwide. In this study, we aimed to confirm the effect of the TCF7L2 polymorphism rs7903146 on diabetes risk in a Brazilian population and to assess the use of this genetic marker in improving diabetes risk prediction in the general population. METHODS: We genotyped the single nucleotide polymorphisms (SNP) rs7903146 of the TCF7L2 gene in 560 patients with known coronary disease enrolled in the MASS II (Medicine, Angioplasty, or Surgery Study) Trial and in 1,449 residents of Vitoria, in Southeast Brazil. The associations of this gene variant to diabetes risk and metabolic characteristics in these two different populations were analyzed. To access the potential benefit of using this marker for diabetes risk prediction in the general population we analyzed the impact of this genetic variant on a validated diabetes risk prediction tool based on clinical characteristics developed for the Brazilian general population. RESULTS: SNP rs7903146 of the TCF7L2 gene was significantly associated with type 2 diabetes in the MASS-II population (OR = 1.57 per T allele, p = 0.0032), confirming, in the Brazilian population, previous reports of the literature. Addition of this polymorphism to an established clinical risk prediction score did not increased model accuracy (both area under ROC curve equal to 0.776). CONCLUSION: TCF7L2 rs7903146 T allele is associated with a 1.57 increased risk for type 2 diabetes in a Brazilian cohort of patients with known coronary heart disease. However, the inclusion of this polymorphism in a risk prediction tool developed for the general population resulted in no improvement of performance. This is the first study, to our knowledge, that has confirmed this recent association in a South American population and adds to the great consistency of this finding in studies around the world. Finally, confirming the biological association of a genetic marker does not guarantee improvement on already established screening tools based solely on demographic variables.
Asunto(s)
Diabetes Mellitus Tipo 2/genética , Genotipo , Factores de Transcripción TCF/genética , Anciano , Brasil/epidemiología , Estudios de Cohortes , Enfermedad de la Arteria Coronaria/complicaciones , Enfermedad de la Arteria Coronaria/epidemiología , Enfermedad de la Arteria Coronaria/genética , Estudios Transversales , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/epidemiología , Femenino , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Curva ROC , Medición de Riesgo , Proteína 2 Similar al Factor de Transcripción 7RESUMEN
Cardiac interstitial fibrosis may contribute to ventricular dysfunction and the prognosis of patients with dilated cardiomyopathy. The objective of the present study was to determine if total myocardial collagen content and collagen type III/I (III/I ratio) mRNAs differ in hypertensive, alcoholic, and idiopathic dilated cardiomyopathy subjects. Echocardiography and exercise cardiopulmonary testing were performed in patients with idiopathic (N = 22), hypertensive (N = 12), and alcoholic (N = 11) dilated cardiomyopathy. Morphometric analysis of collagen was performed in fragments obtained by endomyocardial biopsy with picrosirius red staining. The collagen III/I ratio was determined by reverse transcription polymerase chain reaction. Samples of controls (N = 10) were obtained from autopsy. Echocardiographic variables and maximal oxygen uptake were not different among dilated cardiomyopathy groups. Collagen was higher in all dilated cardiomyopathy groups (idiopathic, hypertensive and alcoholic, 7.36 ± 1.09 percent) versus controls (1.12 ± 0.18 percent), P < 0.05. Collagen was lower in idiopathic dilated cardiomyopathy (4.97 ± 0.83 percent) than hypertensive (8.50 ± 1.11 percent) and alcoholic (10.77 ± 2.09 percent) samples (P < 0.005 for both). The collagen III/I ratio in all samples from dilated cardiomyopathy patients was higher compared to that in controls (0.29 ± 0.04, P < 0.05) but was the same in the samples from idiopathic (0.77 ± 0.07), hypertensive (0.75 ± 0.07), and alcoholic (0.81 ± 0.16) dilated cardiomyopathy groups. Because of the different physical properties of the types of collagen, the higher III/I ratio may contribute to progressive ventricular dilation and dysfunction in dilated cardiomyopathy patients.