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BACKGROUND: Experimental evidence suggests a key role of SIRT1 (silent information regulator 1) in age- and metabolic-related vascular dysfunction. Whether these effects hold true in the human microvasculature is unknown. We aimed to investigate the SIRT1 role in very early stages of age- and obesity-related microvascular dysfunction in humans. METHODS: Ninety-five subjects undergoing elective laparoscopic surgery were recruited and stratified based on their body mass index status (above or below 30 kg/m2) and age (above or below 40 years) in 4 groups: Young Nonobese, Young Obese, Old Nonobese, and Old Obese. We measured small resistance arteries' endothelial function by pressurized micromyography before and after incubation with a SIRT1 agonist (SRT1720) and a mitochondria reactive oxygen species (mtROS) scavenger (MitoTEMPO). We assessed vascular levels of mtROS and nitric oxide availability by confocal microscopy and vascular gene expression of SIRT1 and mitochondrial proteins by qPCR. Chromatin immunoprecipitation assay was employed to investigate SIRT1-dependent epigenetic regulation of mitochondrial proteins. RESULTS: Compared with Young Nonobese, obese and older patients showed lower vascular expression of SIRT1 and antioxidant proteins (FOXO3 [forkhead box protein O3] and SOD2) and higher expression of pro-oxidant and aging mitochondria proteins p66Shc and Arginase II. Old Obese, Young Obese and Old Nonobese groups endothelial dysfunction was rescued by SRT1720. The restoration was comparable to the one obtained with mitoTEMPO. These effects were explained by SIRT1-dependent chromatin changes leading to reduced p66Shc expression and upregulation of proteins involved in mitochondria respiratory chain. CONCLUSIONS: SIRT1 is a novel central modulator of the earliest microvascular damage induced by age and obesity. Through a complex epigenetic control mainly involving p66Shc and Arginase II, it influences mtROS levels, NO availability, and the expression of proteins of the mitochondria respiratory chain. Therapeutic modulation of SIRT1 restores obesity- and age-related endothelial dysfunction. Early targeting of SIRT1 might represent a crucial strategy to prevent age- and obesity-related microvascular dysfunction.
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Arginasa , Obesidad , Sirtuina 1 , Enfermedades Vasculares , Adulto , Arginasa/metabolismo , Epigénesis Genética , Humanos , Proteínas Mitocondriales/metabolismo , Óxido Nítrico/metabolismo , Obesidad/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Sirtuina 1/genética , Sirtuina 1/metabolismo , Enfermedades Vasculares/etiologíaRESUMEN
BACKGROUND: Metabolic cardiomyopathy (MCM), characterized by intramyocardial lipid accumulation, drives the progression to heart failure with preserved ejection fraction (HFpEF). Although evidence suggests that the mammalian silent information regulator 1 (Sirt1) orchestrates myocardial lipid metabolism, it is unknown whether its exogenous administration could avoid MCM onset. We investigated whether chronic treatment with recombinant Sirt1 (rSirt1) could halt MCM progression. METHODS: db/db mice, an established model of MCM, were supplemented with intraperitoneal rSirt1 or vehicle for 4 weeks and compared with their db/ + heterozygous littermates. At the end of treatment, cardiac function was assessed by cardiac ultrasound and left ventricular samples were collected and processed for molecular analysis. Transcriptional changes were evaluated using a custom PCR array. Lipidomic analysis was performed by mass spectrometry. H9c2 cardiomyocytes exposed to hyperglycaemia and treated with rSirt1 were used as in vitro model of MCM to investigate the ability of rSirt1 to directly target cardiomyocytes and modulate malondialdehyde levels and caspase 3 activity. Myocardial samples from diabetic and nondiabetic patients were analysed to explore Sirt1 expression levels and signaling pathways. RESULTS: rSirt1 treatment restored cardiac Sirt1 levels and preserved cardiac performance by improving left ventricular ejection fraction, fractional shortening and diastolic function (E/A ratio). In left ventricular samples from rSirt1-treated db/db mice, rSirt1 modulated the cardiac lipidome: medium and long-chain triacylglycerols, long-chain triacylglycerols, and triacylglycerols containing only saturated fatty acids were reduced, while those containing docosahexaenoic acid were increased. Mechanistically, several genes involved in lipid trafficking, metabolism and inflammation, such as Cd36, Acox3, Pparg, Ncoa3, and Ppara were downregulated by rSirt1 both in vitro and in vivo. In humans, reduced cardiac expression levels of Sirt1 were associated with higher intramyocardial triacylglycerols and PPARG-related genes. CONCLUSIONS: In the db/db mouse model of MCM, chronic exogenous rSirt1 supplementation rescued cardiac function. This was associated with a modulation of the myocardial lipidome and a downregulation of genes involved in lipid metabolism, trafficking, inflammation, and PPARG signaling. These findings were confirmed in the human diabetic myocardium. Treatments that increase Sirt1 levels may represent a promising strategy to prevent myocardial lipid abnormalities and MCM development.
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Diabetes Mellitus , Cardiomiopatías Diabéticas , Insuficiencia Cardíaca , Animales , Humanos , Ratones , Diabetes Mellitus/metabolismo , Cardiomiopatías Diabéticas/genética , Cardiomiopatías Diabéticas/prevención & control , Insuficiencia Cardíaca/metabolismo , Inflamación/metabolismo , Lipidómica , Lípidos , Miocitos Cardíacos/metabolismo , PPAR gamma/metabolismo , Sirtuina 1/genética , Sirtuina 1/metabolismo , Volumen Sistólico , Triglicéridos/metabolismo , Función Ventricular IzquierdaRESUMEN
BACKGROUND AND AIMS: Whether the association between very high HDL-cholesterol levels and cardiovascular mortality (CVM) is modulated by some facilitating factors is unclear. Aim of the study was to investigate whether the risk of CVM associated with very high HDL-cholesterol is increased in subjects with hyperuricemia. METHODS AND RESULTS: Multivariable Cox analyses were made in 18,072 participants from the multicentre URRAH study stratified by sex and HDL-cholesterol category. During a median follow-up of 11.4 years there were 1307 cases of CVM. In multivariable Cox models a J-shaped association was found in the whole population, with the highest risk being present in the high HDL-cholesterol group [>80 mg/dL, adjusted hazard ratio (HR), 1.28; 95%CI, 1.02-1.61; p = 0.031)]. However, a sex-specific analysis revealed that this association was present only in women (HR, 1.34; 95%CI, 1.02-1.77; p = 0.034) but not in men. The risk of CVM related to high HDL-cholesterol was much greater in the women with high uric acid (>0.30 mmol/L, HR 1.61; 95%CI, 1.08-2.39) than in those with low uric acid (HR, 1.17; 95%CI, 0.80-1.72, p for interaction = 0.016). In women older than 70 years with hyperuricemia the risk related to high HDL-cholesterol was 1.83 (95%CI, 1.19-2.80, p < 0.005). Inclusion of BMI in the models weakened the strength of the associations. CONCLUSION: Our data indicate that very high HDL-cholesterol levels in women are associated with CVM in a J-shaped fashion. The risk of CVM is increased by concomitant hyperuricemia suggesting that a proinflammatory/oxidative state can enhance the detrimental cardiovascular effects associated with high HDL-cholesterol.
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Enfermedades Cardiovasculares , Hipercolesterolemia , Hiperlipidemias , Hiperuricemia , Masculino , Humanos , Femenino , HDL-Colesterol , Enfermedades Cardiovasculares/diagnóstico , Enfermedades Cardiovasculares/epidemiología , Factores de Riesgo , Hiperuricemia/epidemiología , Ácido ÚricoRESUMEN
BACKGROUND: Machine-learning techniques have been recently utilized to predict the probability of unfavorable outcomes among elderly patients suffering from heart failure (HF); yet none has integrated an assessment for frailty and comorbidity. This research seeks to determine which machine-learning-based phenogroups that incorporate frailty and comorbidity are most strongly correlated with death or readmission at hospital for HF within six months following discharge from hospital. METHODS: In this single-center, prospective study of a tertiary care center, we included all patients aged 65 and older discharged for acute decompensated heart failure. Random forest analysis and a Cox multivariable regression were performed to determine the predictors of the composite endpoint. By k-means and hierarchical clustering, those predictors were utilized to phenomapping the cohort in four different clusters. RESULTS: A total of 571 patients were included in the study. Cluster analysis identified four different clusters according to frailty, burden of comorbidities and BNP. As compared with Cluster 4, we found an increased 6-month risk of poor outcomes patients in Cluster 1 (very frail and comorbid; HR 3.53 [95% CI 2.30-5.39]), Cluster 2 (pre-frail with low levels of BNP; HR 2.59 [95% CI 1.66-4.07], and in Cluster 3 (pre-frail and comorbid with high levels of BNP; HR 3.75 [95% CI 2.25-6.27])). CONCLUSIONS: In older patients discharged for ADHF, the cluster analysis identified four distinct phenotypes according to frailty degree, comorbidity, and BNP levels. Further studies are warranted to validate these phenogroups and to guide an appropriate selection of personalized, model of care.
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Fragilidad , Insuficiencia Cardíaca , Anciano , Humanos , Fragilidad/epidemiología , Estudios Prospectivos , Hospitalización , Insuficiencia Cardíaca/epidemiología , Comorbilidad , Análisis por Conglomerados , Anciano FrágilRESUMEN
This paper reports the proceedings of a meeting convened by the Research Group on Thoracic Ultrasound in Older People of the Italian Society of Gerontology and Geriatrics, to discuss the current state-of-the-art of clinical research in the field of geriatric thoracic ultrasound and identify unmet research needs and potential areas of development. In the last decade, point-of-care thoracic ultrasound has entered clinical practice for diagnosis and management of several respiratory illnesses, such as bacterial and viral pneumonia, pleural effusion, acute heart failure, and pneumothorax, especially in the emergency-urgency setting. Very few studies, however, have been specifically focused on older patients with frailty and multi-morbidity, who frequently exhibit complex clinical pictures needing multidimensional evaluation. At the present state of knowledge, there is still uncertainty on the best requirements of ultrasound equipment, methodology of examination, and reporting needed to optimize the advantages of thoracic ultrasound implementation in the care of geriatric patients. Other issues regard differential diagnosis between bacterial and aspiration pneumonia, objective grading of interstitial syndrome severity, quantification and monitoring of pleural effusions and solid pleural lesions, significance of ultrasonographic assessment of post-COVID-19 sequelae, and prognostic value of assessment of diaphragmatic thickness and motility. Finally, application of remote ultrasound diagnostics in the community and nursing home setting is still poorly investigated by the current literature. Overall, the presence of several open questions on geriatric applications of thoracic ultrasound represents a strong call to implement clinical research in this field.
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COVID-19 , Derrame Pleural , Neumonía Viral , Humanos , Anciano , Ultrasonografía/métodos , Atención a la Salud , Derrame Pleural/diagnóstico por imagenRESUMEN
BACKGROUND: during the dementia time course Behavioral and Psychological Symptoms of Dementia (BPSD) may arise. Despite their use is still off-label and they are associated with several side effects, antipsychotics represent the main pharmacological strategy to alleviate BPDS METHOD: aim of this retrospective study was to evaluate the correlation between antipsychotics use and all-cause mortality. BPSD were classified in three clusters: "mood/apathy", "psychosis" and "hyperactivity". ANOVA for repeated measures was used to evaluate the functional/cognitive changes over three time points (baseline, 6 months and 12 months follow-up). Chi-Square test was carried out to verify the correlation between antipsychotic drug use and mortality. Logistic regression and stepwise regression method were used to analyze the relationship between mortality and other potential influencing factors, including ADL, IADL, CFS, in addiction of antipsychotics drugs use. RESULT: a total of 209 patients with a clinical diagnosis of dementia were enrolled (71.3% women; mean age = 83.24±4.98 years). The results of the ANOVA indicated a significant worsening of ADL and IADL over time [ADL Wilks' Lambda = 0.744, F(2,80) = 13.75, p<0.001, η2 = 0.256, IADL Wilks' Lambda = 0.71, F(2,80) = 16.3, p<0.001, η2 = 0.29, respectively], a significant progression of cognitive impairment as measured with MMSE and a significant worsening in frailty at CFS at 6 and 12 months follow up [MMSE Wilks' Lambda = 0.751, F(2,73) = 12.11, p<0.001, η2 = 0.249, CFS Wilks' Lambda = 0.749, F(2,79) = 13.224, p<0.001, η2 = 0.241]. Patients on antipsychotic therapy reported a higher mortality rate, although there is no statistically significant association between antipsychotic use and mortality. We found no significant correlation between mortality and antipsychotic drug use within the different BPSD cluster ("mood/apathy" p = 0.464, "psychosis" p = 0.569, "hyperactivity" 0.528), and no statistically significant association between mortality and other potential influencing factors. Using a stepwise regression, the loss of independence in IADL survived as factor associated to mortality (p = 0.002). CONCLUSION: patients on antipsychotic therapy reported a higher mortality rate, although there is no statistically significant association between antipsychotic use and mortality. Further work is needed to establish the relationship between antipsychotics and mortality in elderly patients with dementia.
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Antipsicóticos , Demencia , Humanos , Femenino , Masculino , Antipsicóticos/uso terapéutico , Antipsicóticos/efectos adversos , Estudios Retrospectivos , Anciano de 80 o más Años , Demencia/tratamiento farmacológico , Anciano , Actividades CotidianasRESUMEN
Systemic arterial hypertension (AH) is a multifaceted disease characterized by accelerated vascular aging and high cardiometabolic morbidity and mortality. Despite extensive work in the field, the pathogenesis of AH is still incompletely understood, and its treatment remains challenging. Recent evidence has shown a deep involvement of epigenetic signals in the regulation of transcriptional programs underpinning maladaptive vascular remodeling, sympathetic activation and cardiometabolic alterations, all factors predisposing to AH. After occurring, these epigenetic changes have a long-lasting effect on gene dysregulation and do not seem to be reversible upon intensive treatment or the control of cardiovascular risk factors. Among the factors involved in arterial hypertension, microvascular dysfunction plays a central role. This review will focus on the emerging role of epigenetic changes in hypertensive-related microvascular disease, including the different cell types and tissues (endothelial cells, vascular smooth muscle cells and perivascular adipose tissue) as well as the involvement of mechanical/hemodynamic factors, namely, shear stress.
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Células Endoteliales , Hipertensión , Humanos , Células Endoteliales/patología , Microvasos/patología , Tejido Adiposo/patología , Epigénesis GenéticaRESUMEN
BACKGROUND AND AIM: The URRAH (URic acid Right for heArt Health) Study has identified cut-off values of serum uric acid (SUA) predictive of total mortality at 4.7 mg/dl, and cardiovascular (CV) mortality at 5.6 mg/dl. Our aim was to validate these SUA thresholds in people with diabetes. METHODS AND RESULTS: The URRAH subpopulation of people with diabetes was studied. All-cause and CV deaths were evaluated at the end of follow-up. A total of 2570 diabetic subjects were studied. During a median follow-up of 107 months, 744 deaths occurred. In the multivariate Cox regression analyses adjusted for several confounders, subjects with SUA ≥5.6 mg/dl had higher risk of total (HR: 1.23, 95%CI: 1.04-1.47) and CV mortality (HR:1.31, 95%CI:1.03-1.66), than those with SUA <5.6 mg/dl. Increased all-cause mortality risk was shown in participants with SUA ≥4.7 mg/dl vs SUA below 4.7 mg/dl, but not statistically significant after adjustment for all confounders. CONCLUSIONS: SUA thresholds previously proposed by the URRAH study group are predictive of total and CV mortality also in people with diabetes. The threshold of 5.6 mg/dl can predict both total and CV mortality, and so is candidate to be a clinical cut-off for the definition of hyperuricemia in patients with diabetes.
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Diabetes Mellitus , Hiperuricemia , Diabetes Mellitus/diagnóstico , Humanos , Hiperuricemia/diagnóstico , Factores de Riesgo , Ácido ÚricoRESUMEN
The development of novel, non-invasive techniques and standardization of protocols to assess microvascular dysfunction have elucidated the key role of microvascular changes in the evolution of cardiovascular (CV) damage, and their capacity to predict an increased risk of adverse events. These technical advances parallel with the development of novel biological assays that enabled the ex vivo identification of pathways promoting microvascular dysfunction, providing novel potential treatment targets for preventing cerebral-CV disease. In this article, we provide an update of diagnostic testing strategies to detect and characterize microvascular dysfunction and suggestions on how to standardize and maximize the information obtained from each microvascular assay. We examine emerging data highlighting the significance of microvascular dysfunction in the development CV disease manifestations. Finally, we summarize the pathophysiology of microvascular dysfunction emphasizing the role of oxidative stress and its regulation by epigenetic mechanisms, which might represent potential targets for novel interventions beyond conventional approaches, representing a new frontier in CV disease reduction.
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Enfermedades Cardiovasculares , Enfermedades Cardiovasculares/prevención & control , Humanos , Estrés OxidativoRESUMEN
ABSTRACT: Longer life span and increased prevalence of chronic, noncommunicable, inflammatory diseases fuel cardiovascular mortality. The microcirculation is central in the cross talk between ageing, inflammation, cardiovascular, and metabolic diseases. Microvascular dysfunction, characterized by alteration in the microvascular endothelial function and wall structure, is described in an increasing number of chronic age-associated diseases, suggesting that it might be a marker of ageing superior to chronological age. The aim of this review is to thoroughly explore the connections between microvascular dysfunction, ageing, and metabolic disorders by detailing the major role played by inflammation and oxidative stress in their evolution. Older age, hypertension, nutrient abundance, and hyperglycemia concur in the induction of a persistent low-grade inflammatory response, defined as meta-inflammation or inflammageing. This increases the local generation of reactive oxygen species that further impairs endothelial function and amplifies the local inflammatory response. Mitochondrial dysfunction is a hallmark of many age-related diseases. The alterations of mitochondrial function promote irreversible modification in microvascular structure. The interest in the hypothesis of chronic inflammation at the center of the ageing process lies in its therapeutic implications. Inhibition of specific inflammatory pathways has been shown to lower the risk of many age-related diseases, including cardiovascular disease. However, the whole architecture of the inflammatory response underpinning the ageing process and its impact on the burden of age-related diseases remain to be fully elucidated. Additional studies are needed to unravel the connection between these biological pathways and to address their therapeutic power in terms of cardiovascular prevention.
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Envejecimiento/metabolismo , Enfermedades Cardiovasculares/metabolismo , Mediadores de Inflamación , Enfermedades Metabólicas/metabolismo , Microvasos/metabolismo , Estrés Oxidativo , Factores de Edad , Envejecimiento/efectos de los fármacos , Envejecimiento/patología , Animales , Antiinflamatorios/uso terapéutico , Antioxidantes/uso terapéutico , Enfermedades Cardiovasculares/patología , Enfermedades Cardiovasculares/fisiopatología , Enfermedades Cardiovasculares/prevención & control , Humanos , Longevidad , Enfermedades Metabólicas/tratamiento farmacológico , Enfermedades Metabólicas/patología , Enfermedades Metabólicas/fisiopatología , Microvasos/efectos de los fármacos , Microvasos/patología , Microvasos/fisiopatología , Estrés Oxidativo/efectos de los fármacos , Transducción de SeñalRESUMEN
Aims: Accumulation of reactive oxygen species (ROS) promotes vascular disease in obesity, but the underlying molecular mechanisms remain poorly understood. The adaptor p66Shc is emerging as a key molecule responsible for ROS generation and vascular damage. This study investigates whether epigenetic regulation of p66Shc contributes to obesity-related vascular disease. Methods and results: ROS-driven endothelial dysfunction was observed in visceral fat arteries (VFAs) isolated from obese subjects when compared with normal weight controls. Gene profiling of chromatin-modifying enzymes in VFA revealed a significant dysregulation of methyltransferase SUV39H1 (fold change, -6.9, P < 0.01), demethylase JMJD2C (fold change, 3.2, P < 0.01), and acetyltransferase SRC-1 (fold change, 5.8, P < 0.01) in obese vs. control VFA. These changes were associated with reduced di-(H3K9me2) and trimethylation (H3K9me3) as well as acetylation (H3K9ac) of histone 3 lysine 9 (H3K9) on p66Shc promoter. Reprogramming SUV39H1, JMJD2C, and SRC-1 in isolated endothelial cells as well as in aortas from obese mice (LepOb/Ob) suppressed p66Shc-derived ROS, restored nitric oxide levels, and rescued endothelial dysfunction. Consistently, in vivo editing of chromatin remodellers blunted obesity-related vascular p66Shc expression. We show that SUV39H1 is the upstream effector orchestrating JMJD2C/SRC-1 recruitment to p66Shc promoter. Indeed, SUV39H1 overexpression in obese mice erased H3K9-related changes on p66Shc promoter, while SUV39H1 genetic deletion in lean mice recapitulated obesity-induced H3K9 remodelling and p66Shc transcription. Conclusion: These results uncover a novel epigenetic mechanism underlying endothelial dysfunction in obesity. Targeting SUV39H1 may attenuate oxidative transcriptional programmes and thus prevent vascular disease in obese individuals.
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Regulación de la Expresión Génica , Histona Demetilasas con Dominio de Jumonji/genética , Metiltransferasas/genética , Coactivador 1 de Receptor Nuclear/genética , Obesidad/genética , Estrés Oxidativo/fisiología , Proteínas Represoras/genética , Proteína Transformadora 1 que Contiene Dominios de Homología 2 de Src/genética , Animales , Western Blotting , Células Cultivadas , Modelos Animales de Enfermedad , Endotelio Vascular/metabolismo , Endotelio Vascular/patología , Endotelio Vascular/fisiopatología , Femenino , N-Metiltransferasa de Histona-Lisina , Humanos , Histona Demetilasas con Dominio de Jumonji/biosíntesis , Masculino , Metiltransferasas/biosíntesis , Ratones Endogámicos C57BL , Ratones Mutantes , Persona de Mediana Edad , Coactivador 1 de Receptor Nuclear/biosíntesis , Obesidad/metabolismo , Obesidad/patología , ARN/genética , Especies Reactivas de Oxígeno/metabolismo , Proteínas Represoras/biosíntesis , Proteína Transformadora 1 que Contiene Dominios de Homología 2 de Src/biosíntesis , Transcripción Genética , VasodilataciónRESUMEN
AIM: To investigate the associations of blood pressure variability (BPV), expressed as long-term (visit-to-visit) and short-term (ambulatory blood pressure monitoring [ABPM] and home blood pressure monitoring [HBPM]) and all-cause mortality, major adverse cardiovascular events (MACEs), extended MACEs, microvascular complications (MiCs) and hypertension-mediated organ damage (HMOD) in adult patients with type 2 diabetes. MATERIALS AND METHODS: PubMed, Medline, Embase, Cinahl, Web of Science, ClinicalTrials.gov and grey literature databases were searched for studies including patients with type 2 diabetes, at least one variable of BPV (visit-to-visit, HBPM, ABPM) and evaluation of the incidence of at least one of the following outcomes: all-cause mortality, MACEs, extended MACEs and/or MiCs and/or HMOD. The extracted information was analyzed using random effects meta-analysis and meta-regression. RESULTS: Data from a total of 377 305 patients were analyzed. Systolic blood pressure (SBP) variability was associated with a significantly increased risk of all-cause mortality (HR 1.12, 95% CI 1.04-1.21), MACEs (HR 1.01, 95% CI 1.04-1.17), extended MACEs (HR 1.07, 95% CI 1.03-1.11) and MiCs (HR 1. 12, 95% CI 1.01-1.24), while diastolic blood pressure was not. Associations were mainly driven from studies on long-term SBP variability. Qualitative analysis showed that BPV was associated with the presence of HMOD expressed as carotid intima-media thickness, pulse wave velocity and left ventricular hypertrophy. Results were independent of mean blood pressure, glycaemic control and serum creatinine levels. CONCLUSIONS: Our results suggest that BPV might provide additional information rather than mean blood pressure on the risk of cardiovascular disease in patients with type 2 diabetes.
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Presión Sanguínea/fisiología , Enfermedades Cardiovasculares , Diabetes Mellitus Tipo 2 , Adulto , Enfermedades Cardiovasculares/complicaciones , Enfermedades Cardiovasculares/mortalidad , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/epidemiología , Diabetes Mellitus Tipo 2/fisiopatología , Femenino , Humanos , MasculinoRESUMEN
PURPOSE OF REVIEW: To review medical literature for evidence of association between hypertension and mitral regurgitation (MR) and summarize potential favorable effects of antihypertensive drugs on MR natural history and treatment. RECENT FINDINGS: Hypertension and MR are common diseases affecting a large proportion of the general population. Contemporary evidence suggests that hypertension may worsen the progression and prognosis of MR through augmented mechanical stress and increased regurgitation volume. Renin-angiotensin axis inhibitors, beta-blockers, and vasodilators have been tested in order to prevent or decrease primary or secondary MR. Although antihypertensive agents may improve hemodynamic parameters and left ventricular remodeling in primary MR, there is no strong evidence of benefit on clinical outcomes. On the other hand, a beneficial effect of these drugs on secondary MR is better established. Moreover, there are no studies evaluating a possible benefit of lower blood pressure targets in MR. Randomized controlled trials are warranted to elucidate the precise role of antihypertensive therapy on treatment of MR.
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Hipertensión , Insuficiencia de la Válvula Mitral , Antagonistas Adrenérgicos beta/uso terapéutico , Antihipertensivos/uso terapéutico , Humanos , Hipertensión/complicaciones , Hipertensión/tratamiento farmacológico , Insuficiencia de la Válvula Mitral/complicaciones , Remodelación VentricularRESUMEN
PURPOSE OF REVIEW: To examine the state of the art on the pathogenesis of endothelial dysfunction in the microcirculation of patients with obesity, focusing on the complex relationship between the consolidated and the novel mechanisms involved in this alteration. RECENT FINDINGS: Human obesity is associated with vascular endothelial dysfunction, caused by a reduced nitric oxide availability secondary to an enhanced oxidative stress production. Pro-inflammatory cytokine generation, secreted by perivascular adipose tissue, is a major mechanism whereby obesity is associated with a reduced vascular NO availability. Vasculature also represents a source of low-grade inflammation and oxidative stress which contribute to endothelial dysfunction in obese patients. Recently, a direct influence of arginase on endothelial function by reducing nitric oxide availability was demonstrated in small vessels from patients with severe obesity. This effect is modulated by ageing and related to the high levels of vascular oxidative stress. Oxidative stress, inflammation, and enzymatic pathways are important players in the pathophysiology of obesity-related vascular disease. The identification of new therapeutic approaches able to interfere with these mechanisms will result in more effective prevention of the cardiovascular complications associated with obesity.
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Endotelio Vascular/fisiopatología , Obesidad/fisiopatología , Humanos , Inflamación , Óxido Nítrico/metabolismo , Estrés OxidativoRESUMEN
Objective- Arginase can reduce NO availability. In this study, we explored arginase as a determinant of endothelial dysfunction in small arteries from obese patients and its relationship with aging and microvascular remodeling. Approach and Results- Small arteries were dissected after subcutaneous fat biopsies and evaluated on a pressurized micromyograph. Endothelium-dependent vasodilation was assessed by acetylcholine, repeated under L-NAME ( N G-nitro-L-arginine-methyl ester), N(ω)-hydroxy-nor-l-arginine (arginase inhibitor) and gp91ds-tat (NADPH [nicotinamide adenine dinucleotide phosphate oxidase] oxidase inhibitor) in vessels from young (age <30 years) control and obese and old (>30 years) control and obese subjects. Media-lumen ratio and amount of vascular wall fibrosis were used as markers of vascular remodeling. Amount of vascular superoxide anions and NO production were determined with immunofluorescence, whereas arginase expression was quantified using Western blot and quantitative polymerase chain reaction. Obese and older age groups had lower vascular NO, as well as higher media-lumen ratio, wall fibrosis, intravascular superoxide, and blunted inhibitory effect of L-NAME on acetylcholine versus controls and younger age groups. N(ω)-hydroxy-nor-l-arginine restored the acetylcholine-induced vasodilation in young and, to a lesser extent, in old obese subjects. This effect was abolished by addition of L-NAME. Gp91ds-tat increased the vasodilatory response to N(ω)-hydroxy-nor-l-arginine in old obese. Superoxide anions and arginase I/II levels were higher in the vascular wall of obese versus controls. Conclusions- Arginase contributes to microvascular endothelial dysfunction in obesity. Its impact is reduced by aging because of higher levels of vascular oxidative stress. Obesity is accompanied by accelerated microvascular remodeling, the extent of which is related to the amount of arginase in the vascular wall.
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Envejecimiento/metabolismo , Arginasa/metabolismo , Arterias/enzimología , Óxido Nítrico/metabolismo , Obesidad/enzimología , Grasa Subcutánea/irrigación sanguínea , Vasodilatación , Adulto , Factores de Edad , Arginasa/antagonistas & inhibidores , Arterias/efectos de los fármacos , Arterias/fisiopatología , Estudios de Casos y Controles , Inhibidores Enzimáticos/farmacología , Femenino , Humanos , Masculino , Persona de Mediana Edad , NADPH Oxidasas/metabolismo , Obesidad/diagnóstico , Obesidad/fisiopatología , Estrés Oxidativo , Transducción de Señal , Superóxidos/metabolismo , Remodelación Vascular , Vasodilatación/efectos de los fármacos , Vasodilatadores/farmacología , Adulto JovenAsunto(s)
Enfermedades Cardiovasculares , Sistema Cardiovascular , Hiperuricemia , Insuficiencia Renal Crónica , Humanos , HDL-Colesterol , Hiperuricemia/diagnóstico , Hiperuricemia/complicaciones , Insuficiencia Renal Crónica/diagnóstico , Insuficiencia Renal Crónica/complicaciones , Factores de RiesgoRESUMEN
A large body of homogeneous reports documented that endothelial dysfunction, which characterizes human essential hypertension is largely dependent on an impaired endothelial nitric oxide availability and an increased production of endothelium-derived contracting factors. These factors include endothelin, prostanoids, and reactive oxygen species (ROS). In particular, it was evidenced that acute intraarterial administration of indomethacin, a nonselective cyclooxygenase (COX)-inhibitor, and ascorbic acid, an antioxidant, normalized the blunted endothelial dysfunction by restoring nitric oxide availability at the level of peripheral microcirculation, thus demonstrating that COX-derived endothelium-derived contracting factors are one of the major sources of ROS. Recent studies put in evidence new lights on the mechanisms involved in endothelial dysfunction in human hypertension, identified as "new conspirators." In particular, functional and immunohistochemical experiments with selective COX inhibitors identified the isoform COX-2 as the main source of intravascular ROS generation in isolated small vessels from essential hypertensive patients. In addition, important vascular protective properties by human ghrelin have been demonstrated in human hypertension, in terms that its systemic reduction is involved in the pathophysiology of endothelial dysfunction, while a normalization of its levels may restore vascular homeostasis.
Asunto(s)
Ciclooxigenasa 2/metabolismo , Endotelinas/metabolismo , Endotelio Vascular/fisiopatología , Hipertensión/fisiopatología , Factores de Edad , Hipertensión Esencial , Ghrelina/metabolismo , Humanos , Microcirculación/fisiología , Óxido Nítrico/metabolismo , Prostaglandinas/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Vasoconstricción/fisiología , Vasodilatación/fisiologíaRESUMEN
AIMS: We assessed whether acute intra-arterial infusion of exogenous ghrelin can improve endothelial dysfunction by restoring nitric oxide (NO) availability in the forearm microcirculation of essential hypertensive patients. The effect of ghrelin on endothelial dysfunction (pressurized myograph), vascular oxidative stress generation (fluorescent dihydroethidium), and phosphorylation of p47phox (western blot), an index of NAD(P)H oxidase activation, in isolated small arteries taken from essential hypertensive patients (subcutaneous biopsy) were also investigated. METHODS AND RESULTS: In 18 normotensive control subjects and 18 essential hypertensive patients, we studied the forearm blood flow (strain-gauge plethysmography) response to intra-arterial acetylcholine, repeated under NO synthase inhibitor N(G)-monomethyl-l-arginine (l-NMMA) or the antioxidant ascorbic acid. The protocol was repeated at the end of exogenous ghrelin intra-arterial infusion. In hypertensive patients, ghrelin normalized the blunted response to acetylcholine, restored the inhibiting effect of l-NMMA and abrogated the potentiating effect of ascorbic acid on acetylcholine. In controls, ghrelin failed to modify these vascular responses. In hypertensive patients, ghrelin decreased venous levels of malondialdehyde, lipoperoxide, and interleukin-6, and concomitantly increased endogenous antioxidant capacity. Small vessels from hypertensive patients showed an enhanced intravascular oxidative stress, which was strongly and similarly decreased by incubation with ghrelin, the NAD(P)H oxidase inhibitor gp91 ds-tat, or both. Ghrelin also normalized the overexpression of p47 phosphorylation and restored the NO availability in small vessels from hypertensive patients. CONCLUSIONS: Exogenous ghrelin increases endothelial dysfunction by restoring NO availability in the forearm microcirculation of essential hypertensive patients, an effect ascribable to an antioxidant effect via inhibition of NAD(P)H oxidase activation.
Asunto(s)
Ghrelina/farmacología , Hipertensión/fisiopatología , NADPH Oxidasas/fisiología , Óxido Nítrico/biosíntesis , Vasodilatadores/farmacología , Análisis de Varianza , Antioxidantes/farmacología , Ácido Ascórbico/farmacología , Estudios de Casos y Controles , Endotelio Vascular , Inhibidores Enzimáticos/farmacología , Femenino , Antebrazo/irrigación sanguínea , Ghrelina/administración & dosificación , Humanos , Hipertensión/enzimología , Infusiones Intraarteriales , Masculino , Persona de Mediana Edad , NADPH Oxidasas/metabolismo , Estrés Oxidativo/fisiología , Especies Reactivas de Oxígeno/metabolismo , Superóxidos/metabolismo , Vasodilatadores/administración & dosificación , omega-N-Metilarginina/farmacologíaRESUMEN
AIMS: We assessed the impact of vascular and perivascular tumour necrosis factor-alpha (TNF-α) on the endothelin (ET)-1/nitric oxide (NO) system and the molecular pathways involved in small arteries from visceral fat of obese patients (Obese) and Controls. METHODS AND RESULTS: Isolated small arteries from 16 Obese and 14 Controls were evaluated on a pressurized micromyograph. Endogenous ET-1 activity was assessed by the ETA blocker BQ-123. TNF-α and NO were tested by anti-TNF-α infliximab (IFX) and N(ω)-nitro-l-arginine methylester (L-NAME). Gene and protein expression of TNF-α, ET-1, ETA, and ETB receptors were determined by RT-PCR and IHC on arterial wall and in isolated adipocytes. Obese showed a blunted L-NAME-induced vasoconstriction, which was potentiated by IFX, and an increased relaxation to BQ-123, unaffected by L-NAME but attenuated by IFX. Perivascular adipose tissue (PVAT) removal reversed these effects. Obese showed intravascular superoxide excess, which was decreased by apocynin (NAD(P)H oxidase inhibitor), L-NAME, and BQ-123 incubations, and abolished by IFX. An increased vascular expression of ET-1, ETA, and ETB receptors, and higher vascular/perivascular TNF-α and TNF-α receptor expression were also detected. The arterial expression and phosphorylation of c-Jun N-terminal kinase (JNK) were higher in Obese vs. Controls, and downregulated by IFX. CONCLUSIONS: In small arteries of Obese, PVAT-derived TNF-α excess, and an increased vascular expression of ET-1 and ETA receptor, contribute to the ET-1/NO system imbalance, by impairing tonic NO release. Reactive oxygen species excess, via NAD(P)H oxidase activation, induces the endothelial nitric oxide synthase uncoupling, which in turn generates superoxide and impairs NO production. The up-regulated JNK pathway represents a crucial molecular signalling involved in this process.