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BACKGROUND AND AIMS: Cardiopulmonary fitness in congenital heart disease (CHD) decreases faster than in the general population resulting in impaired health-related quality of life (HRQoL). As the standard of care seems insufficient to encourage and maintain fitness, an early hybrid cardiac rehabilitation programme could improve HRQoL in CHD. METHODS: The QUALIREHAB multicentre, randomized, controlled trial evaluated and implemented a 12-week centre- and home-based hybrid cardiac rehabilitation programme, including multidisciplinary care and physical activity sessions. Adolescent and young adult CHD patients with impaired cardiopulmonary fitness were randomly assigned to either the intervention (i.e. cardiac rehabilitation) or the standard of care. The primary outcome was the change in HRQoL from baseline to 12-month follow-up in an intention-to-treat analysis. The secondary outcomes were the change in cardiovascular parameters, cardiopulmonary fitness, and mental health. RESULTS: The expected number of 142 patients was enroled in the study (mean age 17.4 ± 3.4 years, 52% female). Patients assigned to the intervention had a significant positive change in HRQoL total score [mean difference 3.8; 95% confidence interval (CI) 0.2; 7.3; P = .038; effect size 0.34], body mass index [mean difference -0.7â kg/m2 (95% CI -1.3; -0.1); P = .022; effect size 0.41], level of physical activity [mean difference 2.5 (95% CI 0.1; 5); P = .044; effect size 0.39], and disease knowledge [mean difference 2.7 (95% CI 0.8; 4.6); P = .007; effect size 0.51]. The per-protocol analysis confirmed these results with a higher magnitude of differences. Acceptability, safety, and short-time effect of the intervention were good to excellent. CONCLUSIONS: This early hybrid cardiac rehabilitation programme improved HRQoL, body mass index, physical activity, and disease knowledge, in youth with CHD, opening up the possibility for the QUALIREHAB programme to be rolled out to the adult population of CHD and non-congenital cardiac disease.
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Reabilitação Cardíaca , Cardiopatias Congênitas , Adolescente , Feminino , Humanos , Masculino , Adulto Jovem , Reabilitação Cardíaca/métodos , Exercício Físico , Terapia por Exercício , Qualidade de VidaRESUMO
BACKGROUND: Obesity is associated with incident heart failure (HF), but the underlying mechanisms are unclear. METHODS: We performed a nested case-control study within the Swedish-Obese-Subjects study, by identifying 411 cases who developed HF and matched them with respect to age, sex, weight-loss-surgery and length of follow-up with 410 controls who did not develop HF. In analyses corrected for multiple testing, we studied 182 plasma proteins known to be related to cardiovascular disease to investigate whether they could add to the understanding of the processes underlying obesity-related HF. RESULTS: A total of 821 subjects were followed for 16 ± 6 years. Multivariable analysis adjusted for matching variables revealed that 32 proteins were significantly associated with HF. Twelve proteins were related to HF ≥ 80% of the time using a bootstrap resampling approach (false-discovery-rate [FDR] < 0.05): 11 were associated with increased HF-risk: TNFRSF10A*, ST6GAL1, PRCP, MMP12, TIMP1, CCL3, QPCT, ANG, C1QTNF1, SERPINA5 and GAL-9; and one was related to reduced HF-risk: LPL. An further 20 proteins were associated with onset of HF 50-80% of the time using bootstrap resampling (FDR < 0.05). A pathway analysis including all significant 32 proteins suggested that these biomarkers were related to inflammation, matrix remodeling, cardiometabolic hormones and hemostasis. Three proteins, C1QTNF1, FGF-21 and CST3, reflecting dyslipidemia and kidney disease, displayed a higher association with HF in patients who did not undergo weight-loss-surgery and maintained with obesity. CONCLUSION: Pathways associated with HF in obesity include inflammation, matrix remodeling, cardiometabolic hormones and hemostasis; three protein biomarkers predicting HF appeared to be obesity-specific.
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Insuficiência Cardíaca , Proteômica , Humanos , Estudos de Casos e Controles , Obesidade/complicações , Obesidade/cirurgia , Biomarcadores , Inflamação/complicações , HormôniosRESUMO
Cardiopulmonary complications are the leading cause of mortality in sickle cell anemia (SCA). Elevated tricuspid regurgitant jet velocity, pulmonary hypertension, diastolic, and autonomic dysfunction have all been described, but a unifying pathophysiology and mechanism explaining the poor prognosis and propensity to sudden death has been elusive. Herein, SCA mice underwent a longitudinal comprehensive cardiac analysis, combining state-of-the-art cardiac imaging with electrocardiography, histopathology, and molecular analysis to determine the basis of cardiac dysfunction. We show that in SCA mice, anemia-induced hyperdynamic physiology was gradually superimposed with restrictive physiology, characterized by progressive left atrial enlargement and diastolic dysfunction with preserved systolic function. This phenomenon was absent in WT mice with experimentally induced chronic anemia of similar degree and duration. Restrictive physiology was associated with microscopic cardiomyocyte loss and secondary fibrosis detectable as increased extracellular volume by cardiac-MRI. Ultrastructural mitochondrial changes were consistent with severe chronic hypoxia/ischemia and sarcomere diastolic-length was shortened. Transcriptome analysis revealed up-regulation of genes involving angiogenesis, extracellular-matrix, circadian-rhythm, oxidative stress, and hypoxia, whereas ion-channel transport and cardiac conduction were down-regulated. Indeed, progressive corrected QT prolongation, arrhythmias, and ischemic changes were noted in SCA mice before sudden death. Sudden cardiac death is common in humans with restrictive cardiomyopathies and long QT syndromes. Our findings may thus provide a unifying cardiac pathophysiology that explains the reported cardiac abnormalities and sudden death seen in humans with SCA.
Assuntos
Anemia Falciforme/fisiopatologia , Cardiomiopatias/fisiopatologia , Insuficiência Cardíaca Diastólica/fisiopatologia , Hipertensão Pulmonar/fisiopatologia , Anemia Falciforme/complicações , Animais , Arritmias Cardíacas/etiologia , Arritmias Cardíacas/genética , Arritmias Cardíacas/fisiopatologia , Cardiomiopatias/etiologia , Cardiomiopatias/genética , Morte Súbita Cardíaca/etiologia , Modelos Animais de Doenças , Eletrocardiografia/métodos , Perfilação da Expressão Gênica , Insuficiência Cardíaca Diastólica/etiologia , Insuficiência Cardíaca Diastólica/genética , Humanos , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/genética , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Miocárdio/metabolismo , Miocárdio/patologiaRESUMO
BACKGROUND: In obesity, the excessive synthesis of aldosterone contributes to the development and progression of metabolic and cardiovascular dysfunctions. Obesity-induced hyperaldosteronism is independent of the known regulators of aldosterone secretion, but reliant on unidentified adipocyte-derived factors. We hypothesized that the adipokine leptin is a direct regulator of aldosterone synthase (CYP11B2) expression and aldosterone release and promotes cardiovascular dysfunction via aldosterone-dependent mechanisms. METHODS AND RESULTS: Immunostaining of human adrenal cross-sections and adrenocortical cells revealed that adrenocortical cells coexpress CYP11B2 and leptin receptors. Measurements of adrenal CYP11B2 expression and plasma aldosterone levels showed that increases in endogenous (obesity) or exogenous (infusion) leptin dose-dependently raised CYP11B2 expression and aldosterone without elevating plasma angiotensin II, potassium or corticosterone. Neither angiotensin II receptors blockade nor α and ß adrenergic receptors inhibition blunted leptin-induced aldosterone secretion. Identical results were obtained in cultured adrenocortical cells. Enhanced leptin signaling elevated CYP11B2 expression and plasma aldosterone, whereas deficiency in leptin or leptin receptors blunted obesity-induced increases in CYP11B2 and aldosterone, ruling out a role for obesity per se. Leptin increased intracellular calcium, elevated calmodulin and calmodulin-kinase II expression, whereas calcium chelation blunted leptin-mediated increases in CYP11B2, in adrenocortical cells. Mineralocorticoid receptor blockade blunted leptin-induced endothelial dysfunction and increases in cardiac fibrotic markers. CONCLUSIONS: Leptin is a newly described regulator of aldosterone synthesis that acts directly on adrenal glomerulosa cells to increase CYP11B2 expression and enhance aldosterone production via calcium-dependent mechanisms. Furthermore, leptin-mediated aldosterone secretion contributes to cardiovascular disease by promoting endothelial dysfunction and the expression of profibrotic markers in the heart.
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Adipócitos/metabolismo , Aldosterona/metabolismo , Endotélio Vascular/metabolismo , Cardiopatias/metabolismo , Cardiopatias/patologia , Leptina/fisiologia , Córtex Suprarrenal/citologia , Córtex Suprarrenal/metabolismo , Animais , Linhagem Celular Tumoral , Células Cultivadas , Feminino , Fibrose/patologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Obesos , Ratos , Ratos Endogâmicos WKY , Ratos ZuckerRESUMO
Increase in the apoptotic molecule Fas ligand (FasL) in serum and cardiomyocytes has been shown to be associated with progressive dilated cardiomyopathy (DCM) and congestive heart failure (CHF) in humans. However, the underlying mechanism(s) of FasL-related deterioration of heart function remain obscure. The aim of the present study is to determine roles of myocardial FasL in the activation of alternative pathways such as extracellular-signal-regulated kinase 1/2 (ERK1/2), inflammation or fibrosis and to identify effective treatments of progressive DCM and advanced CHF. Transgenic mice with cardiomyocyte-specific overexpression of FasL were investigated and treated with an ERK1/2 inhibitor (U-0126), losartan (los), prednisolone (pred) or placebo. Morpho-histological and molecular studies were subsequently performed. FasL mice showed significantly higher mortality compared with wild-type (WT) littermates due to DCM and advanced CHF. Prominent perivascular and interstitial fibrosis, increased interleukin secretion and diffuse CD3-positive cell infiltration were evident in FasL hearts. Up-regulation of the short form of Fas-associated death domain (FADD)-like interleukin 1ß-converting enzyme (FLICE) inhibitory protein (s-FLIP), RIP (receptor-interacting protein) and ERK1/2 and down-regulation of transforming growth factor beta 1 (TGFß1) and nuclear factor-κB (NF-κB) was determined in the myocardium, whereas expression of ERK1/2, periostin (Postn) and osteopontin increased in cardiac fibroblasts. U-0126 and los increased CHF survival by 75% compared with pred and placebo groups. U-0126 had both anti-fibrotic and anti-apoptotic effects, whereas los reduced fibrosis only. Myocardial FasL expression in mice activates differential robust fibrotic, apoptotic and inflammatory responses via ERK1/2 in cardiomyocytes and cardiac fibroblasts inducing DCM and CHF. Blocking the ERK1/2 pathway prevented progression of FasL-induced DCM and CHF by reducing fibrosis, inflammation and apoptosis in the myocardium.
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Cardiomiopatia Dilatada/enzimologia , Proteína Ligante Fas/metabolismo , Insuficiência Cardíaca/enzimologia , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Miócitos Cardíacos/enzimologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Apoptose , Proteínas Reguladoras de Apoptose/metabolismo , Cardiomiopatia Dilatada/genética , Cardiomiopatia Dilatada/patologia , Cardiomiopatia Dilatada/fisiopatologia , Cardiomiopatia Dilatada/prevenção & controle , Células Cultivadas , Progressão da Doença , Ativação Enzimática , Proteína Ligante Fas/genética , Fibroblastos/metabolismo , Fibroblastos/patologia , Fibrose , Predisposição Genética para Doença , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/fisiopatologia , Insuficiência Cardíaca/prevenção & controle , Mediadores da Inflamação/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , Fenótipo , Inibidores de Proteínas Quinases/farmacologia , Transdução de Sinais , Fatores de TempoRESUMO
Obesity is a multifactorial disease associated with hypertension. In the obese population, the incidence of hypertension is high and resistant hypertension is commonly observed. Mechanisms to explain the resistance to current antihypertensive treatments are still poorly understood. Emerging knowledge of the role of aldosterone in controlling blood pressure in obesity may have therapeutic benefit. Mineralocorticoid receptor (MR) inhibitors are currently used as the fourth line of treatment. Clinical studies summarized in this short review suggest that MR antagonists have a strong efficacy in decreasing blood pressure in the hypertensive obese population and could be used as a primary antihypertensive in obesity.
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Aldosterona/metabolismo , Hipertensão/tratamento farmacológico , Hipertensão/metabolismo , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Obesidade/metabolismo , Receptores de Mineralocorticoides/metabolismo , Animais , Medicina Baseada em Evidências , Humanos , Hipertensão/etiologia , Modelos Biológicos , Terapia de Alvo Molecular/métodos , Obesidade/complicações , Obesidade/tratamento farmacológico , Resultado do TratamentoRESUMO
Abnormalities in Z-disc proteins cause hypertrophic (HCM), dilated (DCM) and/or restrictive cardiomyopathy (RCM), but disease-causing mechanisms are not fully understood. Myopalladin (MYPN) is a Z-disc protein expressed in striated muscle and functions as a structural, signaling and gene expression regulating molecule in response to muscle stress. MYPN was genetically screened in 900 patients with HCM, DCM and RCM, and disease-causing mechanisms were investigated using comparative immunohistochemical analysis of the patient myocardium and neonatal rat cardiomyocytes expressing mutant MYPN. Cardiac-restricted transgenic (Tg) mice were generated and protein-protein interactions were evaluated. Two nonsense and 13 missense MYPN variants were identified in subjects with DCM, HCM and RCM with the average cardiomyopathy prevalence of 1.66%. Functional studies were performed on two variants (Q529X and Y20C) associated with variable clinical phenotypes. Humans carrying the Y20C-MYPN variant developed HCM or DCM, whereas Q529X-MYPN was found in familial RCM. Disturbed myofibrillogenesis with disruption of α-actinin2, desmin and cardiac ankyrin repeat protein (CARP) was evident in rat cardiomyocytes expressing MYPN(Q529X). Cardiac-restricted MYPN(Y20C) Tg mice developed HCM and disrupted intercalated discs, with disturbed expression of desmin, desmoplakin, connexin43 and vinculin being evident. Failed nuclear translocation and reduced binding of Y20C-MYPN to CARP were demonstrated using in vitro and in vivo systems. MYPN mutations cause various forms of cardiomyopathy via different protein-protein interactions. Q529X-MYPN causes RCM via disturbed myofibrillogenesis, whereas Y20C-MYPN perturbs MYPN nuclear shuttling and leads to abnormal assembly of terminal Z-disc within the cardiac transitional junction and intercalated disc.
Assuntos
Cardiomiopatia Dilatada/genética , Cardiomiopatia Hipertrófica Familiar/genética , Proteínas Musculares/genética , Mutação , Animais , Animais Recém-Nascidos , Cardiomiopatia Dilatada/patologia , Cardiomiopatia Dilatada/fisiopatologia , Cardiomiopatia Hipertrófica Familiar/patologia , Cardiomiopatia Hipertrófica Familiar/fisiopatologia , Estudos de Casos e Controles , Códon sem Sentido , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microscopia Eletrônica de Transmissão , Proteínas Musculares/química , Proteínas Musculares/metabolismo , Proteínas Musculares/fisiologia , Proteínas Mutantes/química , Proteínas Mutantes/genética , Proteínas Mutantes/fisiologia , Mutação de Sentido Incorreto , Miocárdio/patologia , Miócitos Cardíacos/ultraestrutura , Proteínas Nucleares/metabolismo , Linhagem , Fenótipo , Ligação Proteica , Ratos , Ratos Mutantes , Ratos Sprague-Dawley , Proteínas Repressoras/metabolismoRESUMO
OBJECTIVES: This study aims to describe the various presentations of the prenatally diagnosed isolated right aortic arch (RAA), that is, without associated congenital heart defect and to evaluate the impact of prenatal diagnosis of isolated RAA in terms of postnatal outcome. METHOD: In this multicentric retrospective study, from 2010 to 2019, all live births with a prenatal ultrasound diagnosis of isolated RAA were included, with a 1-year postnatal follow-up. The concordance between the different diagnostic steps (prenatal ultrasound, postnatal ultrasound and postnatal CT scan) was evaluated using Gwet's AC1 coefficient. RESULTS: A total of 309 cases of prenatally diagnosed RAA were analysed, most of which had a left ductus arteriosus (83%). The concordance between prenatal and postnatal ultrasound diagnosis was excellent regarding the RAA type (AC1=0.97, 95% CI=(0.94 to 0.99)). The rare discrepancies mainly involved non-diagnosed or misdiagnosed double aortic arch (2%). CT scan was performed in 108 neonates (35%) and the concordance between prenatal ultrasound and postnatal CT scan was good regarding the RAA diagnosis (AC1=0.80, 95% CI=(0.69 to 0.90)) but poor regarding the distribution of brachiocephalic vessels (AC1=0.21, 95% CI=(0.06 to 0.36)). An associated genetic anomaly was sought for in half of the cases and identified in 4% of the cohort. During the first year of life, 50 (18%) infants presented with vascular ring symptoms and 24 (8%) underwent aortic arch surgery. CONCLUSION: This multicentric nationwide cohort of 309 prenatally diagnosed isolated RAA demonstrated the reliability of prenatal screening, highlighted the rare cases of discrepancies between prenatal and postnatal diagnosis and underlined the value of CT scan to improve the postnatal follow-up. TRIAL REGISTRATION NUMBER: NCT04029064.
RESUMO
PURPOSE: Currently, nearly 90% of patients with congenital heart disease (CHD) reach adulthood in relatively good health. Structured transition programs have emerged to support adolescents and young adults in transitioning to adult care structures, improve their autonomy, and limit healthcare ruptures. The TRANSITION-CHD randomized controlled trial aimed to assess the impact of a transition program on health-related quality of life (HRQoL) in adolescents and young adults with CHD. METHODS: From January 2017 to February 2020, 200 subjects with a CHD, aged 13-25 years, were enrolled in a prospective, controlled, multicenter study and randomized in two balanced groups (transition program vs. standard of care). The primary outcome was the change in PedsQL self-reported HRQoL score between baseline and 12-month follow-up, using an intention-to-treat analysis. The secondary outcomes were the change in disease knowledge, physical health (cardiopulmonary fitness, physical activity), and mental health (anxiety, depression). RESULTS: The change in HRQoL differed significantly between the transition group and the control group (mean difference = 3.03, 95% confidence interval (CI) = [0.08; 5.98]; p = .044; effect size = 0.30), in favor of the intervention group. A significant increase was also observed in the self-reported psychosocial HRQoL (mean difference = 3.33, 95% CI = [0.01; 6.64]; p = .049; effect size = 0.29), in the proxy-reported physical HRQoL (mean difference = 9.18, 95% CI = [1.86; 16.51]; p = .015; effect size = 0.53), and in disease knowledge (mean difference = 3.13, 95% CI = [1.54; 4.72]; p < .001; effect size = 0.64). DISCUSSION: The TRANSITION-CHD program improved HRQoL and disease knowledge in adolescents and young adults with CHD, supporting the generalization and systematization of similar preventive interventions in pediatric and congenital cardiology.
Assuntos
Cardiopatias Congênitas , Qualidade de Vida , Transição para Assistência do Adulto , Humanos , Cardiopatias Congênitas/psicologia , Cardiopatias Congênitas/terapia , Adolescente , Feminino , Masculino , Adulto Jovem , Estudos Prospectivos , AdultoRESUMO
OBJECTIVE: In the context of vaccine scepticism, our study aimed to analyse the association between immunization status and the occurrence of sudden unexpected death in infancy (SUDI). STUDY DESIGN: A multi-centre case-control study was conducted between May 2015 and June 2017 with data from the French national SUDI registry (OMIN) for 35 French regional SUDI centres. Cases were infants under age 1 year who died from SUDI and who were registered in OMIN. Controls, matched to cases by age and sex at a 2:1 ratio, were infants admitted to Nantes University Hospital. All immunization data for diphtheria (D), tetanus (T), acellular pertussis (aP), inactivated poliovirus (IPV), Haemophilus influenzae b (Hib), hepatitis B (HB) and 13-valent pneumococcal conjugate vaccine (PCV13) were collected by a physician. Cases and controls were considered immunized if at least one dose of vaccine was administered. RESULTS: A total of 91 cases and 182 controls were included. The median age was 131 days (interquartile range 98-200.0) and the sex ratio (M/F) was about 1.1. For all vaccines combined (D-T-aP-IPV-Hib and PCV13), 22 % of SUDI cases versus 12 % of controls were non-immunized, which was significantly associated with SUDI after adjustment for potential adjustment factors (adjusted odds ratio 2.01 [95 % confidence interval 1.01-3.98, p = 0,047]). CONCLUSIONS: Non-immunization for D-T-aP-IPV-Hib-HB and PCV13 was associated with increased risk of SUDI. This result can be used to inform the general public and health professionals about this risk of SUDI in case of vaccine hesitancy.
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Vacinas Anti-Haemophilus , Hepatite B , Humanos , Lactente , Vacinas Combinadas , Estudos de Casos e Controles , Vacina Antipólio de Vírus Inativado , Toxoide Tetânico , Hepatite B/prevenção & controle , Vacinas Conjugadas , Haemophilus influenzae , Vacina contra Difteria, Tétano e Coqueluche , Vacinas contra Hepatite B , Esquemas de ImunizaçãoRESUMO
BACKGROUND: We sought to identify protein biomarkers of new-onset heart failure (HF) in 3 independent cohorts (HOMAGE cohort [Heart Omics and Ageing], ARIC study [Atherosclerosis Risk in Communities], and FHS [Framingham Heart Study]) and assess if and to what extent they improve HF risk prediction compared to clinical risk factors alone. METHODS: A nested case-control design was used with cases (incident HF) and controls (without HF) matched on age and sex within each cohort. Plasma concentrations of 276 proteins were measured at baseline in ARIC (250 cases/250 controls), FHS (191/191), and HOMAGE cohort (562/871). RESULTS: In single protein analysis, after adjusting for matching variables and clinical risk factors (and correcting for multiple testing), 62 proteins were associated with incident HF in ARIC, 16 in FHS, and 116 in HOMAGE cohort. Proteins associated with incident HF in all cohorts were BNP (brain natriuretic peptide), NT-proBNP (N-terminal pro-B-type natriuretic peptide), eukaryotic translation initiation factor 4E-BP1 (4E-binding protein 1), hepatocyte growth factor (HGF), Gal-9 (galectin-9), TGF-alpha (transforming growth factor alpha), THBS2 (thrombospondin-2), and U-PAR (urokinase plasminogen activator surface receptor). The increment in C-index for incident HF based on a multiprotein biomarker approach, in addition to clinical risk factors and NT-proBNP, was 11.1% (7.5%-14.7%) in ARIC, 5.9% (2.6%-9.2%) in FHS, and 7.5% (5.4%-9.5%) in HOMAGE cohort, all P<0.001), each of which was a larger increase than that for NT-proBNP on top of clinical risk factors. Complex network analysis revealed a number of overrepresented pathways related to inflammation (eg, tumor necrosis factor and interleukin) and remodeling (eg, extracellular matrix and apoptosis). CONCLUSIONS: A multiprotein biomarker approach improves prediction of incident HF when added to natriuretic peptides and clinical risk factors.
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Aterosclerose , Insuficiência Cardíaca , Humanos , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/epidemiologia , Biomarcadores , Estudos Longitudinais , Fatores de Risco , Envelhecimento , Aterosclerose/diagnóstico , Aterosclerose/epidemiologia , Peptídeo Natriurético Encefálico , Fragmentos de PeptídeosRESUMO
OBJECTIVES: This study sought to identify homogenous echocardiographic phenotypes in community-based cohorts and assess their association with outcomes. BACKGROUND: Asymptomatic cardiac dysfunction leads to a high risk of long-term cardiovascular morbidity and mortality; however, better echocardiographic classification of asymptomatic individuals remains a challenge. METHODS: Echocardiographic phenotypes were identified using K-means clustering in the first generation of the STANISLAS (Yearly non-invasive follow-up of Health status of Lorraine insured inhabitants) cohort (N = 827; mean age: 60 ± 5 years; men: 48%), and their associations with vascular function and circulating biomarkers were also assessed. These phenotypes were externally validated in the Malmö Preventive Project cohort (N = 1,394; mean age: 67 ± 6 years; men: 70%), and their associations with the composite of cardiovascular mortality (CVM) or heart failure hospitalization (HFH) were assessed as well. RESULTS: Three echocardiographic phenotypes were identified as "mostly normal (MN)" (n = 334), "diastolic changes (D)" (n = 323), and "diastolic changes with structural remodeling (D/S)" (n = 170). The D and D/S phenotypes had similar ages, body mass indices, cardiovascular risk factors, vascular impairments, and diastolic function changes. The D phenotype consisted mainly of women and featured increased levels of inflammatory biomarkers, whereas the D/S phenotype, consisted predominantly of men, displayed the highest values of left ventricular mass, volume, and remodeling biomarkers. The phenotypes were predicted based on a simple algorithm including e', left ventricular mass and volume (e'VM algorithm). In the Malmö cohort, subgroups derived from e'VM algorithm were significantly associated with a higher risk of CVM and HFH (adjusted HR in the D phenotype = 1.87; 95% CI: 1.04 to 3.37; adjusted HR in the D/S phenotype = 3.02; 95% CI: 1.71 to 5.34). CONCLUSIONS: Among asymptomatic, middle-aged individuals, echocardiographic data-driven classification based on the simple e'VM algorithm identified profiles with different long-term HF risk. (4th Visit at 17 Years of Cohort STANISLAS-Stanislas Ancillary Study ESCIF [STANISLASV4]; NCT01391442).
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Ecocardiografia , Insuficiência Cardíaca , Idoso , Feminino , Insuficiência Cardíaca/diagnóstico por imagem , Insuficiência Cardíaca/epidemiologia , Humanos , Incidência , Aprendizado de Máquina , Masculino , Pessoa de Meia-Idade , Fenótipo , Valor Preditivo dos Testes , Prognóstico , Volume Sistólico , Função Ventricular EsquerdaRESUMO
Chronic kidney disease is promoted by a variety of factors that induce chronic inflammation and fibrosis. Inflammation and excessive scaring have been recently associated with disruptions of the gap junction-mediated intercellular communication. Nevertheless, little is known about alterations of the expression of gap junction proteins such as connexin (Cx) 43 and 37 in chronic renal disease. In this study, we investigated the expression of these two Cxs in the hypertensive RenTg mice, the anti-glomerular basement membrane glomerulonephritis, and the unilateral ureteral obstruction models, all leading to the development of chronic kidney disease in mice. Expression of Cx43 was almost negligible in the renal cortex of control mice. In contrast, Cx43 was markedly increased in the endothelium of peritubular and glomerular capillaries of the 3-mo-old RenTg mice, in the glomeruli of mice suffering from glomerulonephritis, and in the tubules after obstructive nephropathy. The Cx43 expression pattern was paralleled closely by that of the adhesion markers such as vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 as well as the inflammatory biomarker monocyte chemoattractant protein-1. In contrast, Cx37 that was abundantly expressed in the renal cortex of healthy mice was markedly decreased in the three experimental models. Interestingly, Cx43+/- mice showed restricted expression of VCAM-1 after 2 wk of obstructive nephropathy. These findings suggest the importance of Cxs as markers of chronic renal disease and indicate that these proteins may participate in the inflammatory process during the development of this pathology.
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Conexinas/biossíntese , Nefropatias/metabolismo , Animais , Doença Antimembrana Basal Glomerular/genética , Doença Antimembrana Basal Glomerular/metabolismo , Biomarcadores , Pressão Sanguínea/fisiologia , Nitrogênio da Ureia Sanguínea , Moléculas de Adesão Celular/biossíntese , Quimiocina CCL2/biossíntese , Doença Crônica , Conexina 43/metabolismo , Imunofluorescência , Imuno-Histoquímica , Inflamação/patologia , Fígado/metabolismo , Camundongos , Camundongos Knockout , Proteinúria/genética , Proteinúria/metabolismo , RNA/biossíntese , RNA/isolamento & purificação , Renina/biossíntese , Renina/genética , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
The need for novel insights into the mechanisms of progression of renal disease has become urgent during the last several years because of the increasing incidence of chronic renal disease worldwide. Independent of the underlying disease, the subsequent progression of renal fibrosis is characterized mainly by both an exaggerated synthesis and abnormal accumulation of extracellular matrix proteins produced by mesenchymal cells within the kidney. These cells are mainly myofibroblasts deriving from a variety of renal cells such as vascular smooth muscle, mesangial, resident stem, tubular epithelial, vascular endothelial cells or pericytes. The appearance of myofibroblasts is a reversible process, as suggested by studies in experimental models showing regression of renal fibrosis during therapy with antagonists and/or blockers of the renin-angiotensin system. An additional factor that can also affect the mechanisms of progression/regression of fibrosis is the plasticity of podocytes controlling glomerular filtration.
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Glomérulos Renais/patologia , Túbulos Renais/patologia , Rim/patologia , Músculo Liso Vascular/patologia , Animais , Modelos Animais de Doenças , Progressão da Doença , Fibrose , Humanos , Rim/fisiopatologia , Glomérulos Renais/fisiopatologia , Túbulos Renais/fisiopatologia , Mesoderma/patologia , Mesoderma/fisiopatologia , Camundongos , Músculo Liso Vascular/fisiopatologiaRESUMO
With the increasing incidence of chronic renal diseases worldwide, there is an urgent need to understand the mechanisms involved in progression of renalfibrosis. Independently of the underlying cause or trigger, progression of renalfibrosis is mainly characterized by excessive synthesis and abnormal accumulation of extracellular matrix proteins in renal mesenchymal cells. These cells are mainly myofibroblasts deriving from phenotypic transformation of a variety of renal cells, including vascular smooth muscle cells, mesangial cells, tubular epithelial cells, endothelial cells, and pericytes. Recent animal studies showing the regression of renal fibrosis during curative therapy suggest that this phenotypic "transition" is reversible. The plasticity of podocytes controlling glomerular filtration may also play a role in the progression/regression of fibrosis in this setting
Assuntos
Rim/patologia , Diferenciação Celular , Progressão da Doença , Fibroblastos/patologia , Fibrose , HumanosRESUMO
Compelling clinical evidence indicates that obesity and its associated metabolic abnormalities supersede the protective effects of female sex-hormones and predisposes premenopausal women to cardiovascular disease. The underlying mechanisms remain poorly defined; however, recent studies have implicated overactivation of the aldosterone-MR (mineralocorticoid receptor) axis as a cause of sex-specific cardiovascular risk in obese females. Experimental evidence indicates that the MR on endothelial cells contributes to obesity-associated, leptin-induced endothelial dysfunction in female experimental models, however, the vascular-specific mechanisms via which females are predisposed to heightened endothelial MR activation remain unknown. Therefore, we hypothesized that endogenous expression of endothelial MR is higher in females than males, which predisposes them to obesity-associated, leptin-mediated endothelial dysfunction. We found that endothelial MR expression is higher in blood vessels from female mice and humans compared with those of males, and further, that PrR (progesterone receptor) activation in endothelial cells is the driving mechanism for sex-dependent increases in endothelial MR expression in females. In addition, we show that genetic deletion of either the endothelial MR or PrR in female mice prevents leptin-induced endothelial dysfunction, providing direct evidence that interaction between the PrR and MR mediates obesity-associated endothelial impairment in females. Collectively, these novel findings suggest that progesterone drives sex-differences in endothelial MR expression and predisposes female mice to leptin-induced endothelial dysfunction, which indicates that MR antagonists may be a promising sex-specific therapy to reduce the risk of cardiovascular diseases in obese premenopausal women.
Assuntos
Endotélio Vascular/patologia , Regulação da Expressão Gênica , Obesidade/fisiopatologia , Progesterona/metabolismo , Receptores de Mineralocorticoides/genética , Animais , Modelos Animais de Doenças , Endotélio Vascular/metabolismo , Feminino , Leptina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Obesidade/genética , Distribuição Aleatória , Medição de Risco , Sensibilidade e Especificidade , Fatores Sexuais , Regulação para CimaRESUMO
BACKGROUND: An increase in myocardial collagen content may contribute to the development of heart failure; this might be inhibited or reversed by mineralocorticoid receptor antagonists (MRAs). We investigated changes in serum concentrations of the collagen synthesis biomarkers N-terminal propeptide of procollagen type III (PIIINP) (primary outcome) and C-terminal propeptide of procollagen type I (PICP) (secondary outcome) after non-randomised initiation of spironolactone as add-on therapy among patients with resistant hypertension enrolled in the 'Anglo-Scandinavian Cardiac Outcomes' trial (ASCOT). METHODS: An age/sex matching plus propensity-scored logistic regression model incorporating variables related to the outcome and spironolactone treatment was created to compare patients treated with spironolactone for a 9-month period versus matched controls. A within-person analysis comparing changes in serum biomarker concentrations in the 9 months before versus after spironolactone treatment was also performed. RESULTS: Patients included in the between-person analysis (n=146) were well matched: the mean age was 63±7 years and 11% were woman. Serum concentrations of PIIINP and PICP rose in 'controls' and fell during spironolactone treatment (adjusted means +0.52 (-0.05 to 1.09) vs -0.41 (-0.97 to 0.16) ng/mL, p=0.031 for PIIINP and +4.54(-1.77 to 10.9) vs -6.36 (-12.5 to -0.21) ng/mL, p=0.023 for PICP). For the within-person analysis (n=173), spironolactone treatment was also associated with a reduction in PICP (beta estimate=-11.82(-17.53 to -6.10) ng/mL, p<0.001) but not in PIIINP levels. CONCLUSIONS: Treatment with spironolactone was associated with a reduction in serum biomarkers of collagen synthesis independently of blood pressure in patients with hypertension, suggesting that spironolactone might exert favourable effects on myocardial collagen synthesis and fibrosis. Whether this effect might contribute to slowing the progression to heart failure is worth investigating.
Assuntos
Colágeno , Insuficiência Cardíaca , Hipertensão , Fragmentos de Peptídeos/sangue , Pró-Colágeno/sangue , Espironolactona , Idoso , Disponibilidade Biológica , Biomarcadores/sangue , Pressão Sanguínea/efeitos dos fármacos , Colágeno/biossíntese , Colágeno/metabolismo , Monitoramento de Medicamentos/métodos , Resistência a Medicamentos , Feminino , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/prevenção & controle , Humanos , Hipertensão/complicações , Hipertensão/diagnóstico , Hipertensão/tratamento farmacológico , Hipertensão/metabolismo , Masculino , Pessoa de Meia-Idade , Antagonistas de Receptores de Mineralocorticoides/administração & dosagem , Antagonistas de Receptores de Mineralocorticoides/farmacocinética , Avaliação de Resultados em Cuidados de Saúde , Espironolactona/administração & dosagem , Espironolactona/farmacocinéticaRESUMO
Background Identifying the mechanistic pathways potentially associated with incident heart failure (HF) may provide a basis for novel preventive strategies. Methods and Results To identify proteomic biomarkers and the potential underlying mechanistic pathways that may be associated with incident HF defined as the first hospitalization for HF, a nested-matched case-control design was used with cases (incident HF) and controls (without HF) selected from 3 cohorts (>20 000 individuals). Controls were matched on cohort, follow-up time, age, and sex. Two independent sample sets (a discovery set with 286 cases and 591 controls and a replication set with 276 cases and 280 controls) were used to discover and replicate the findings. Two hundred fifty-two circulating proteins in the plasma were studied. Adjusting for the matching variables age, sex, and follow-up time (and correcting for multiplicity of tests), 89 proteins were found to be associated with incident HF in the discovery phase, of which 38 were also associated with incident HF in the replication phase. These 38 proteins pointed to 4 main network clusters underlying incident HF: (1) inflammation and apoptosis, indicated by the expression of the TNF (tumor necrosis factor)-family members; (2) extracellular matrix remodeling, angiogenesis and growth, indicated by the expression of proteins associated with collagen metabolism, endothelial function, and vascular homeostasis; (3) blood pressure regulation, indicated by the expression of natriuretic peptides and proteins related to the renin-angiotensin-aldosterone system; and (4) metabolism, associated with cholesterol and atherosclerosis. Conclusions Clusters of biomarkers associated with mechanistic pathways leading to HF were identified linking inflammation, apoptosis, vascular function, matrix remodeling, blood pressure control, and metabolism. These findings provide important insight on the pathophysiological mechanisms leading to HF. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02556450.
Assuntos
Biomarcadores/sangue , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/fisiopatologia , Proteoma/análise , Idoso , Estudos de Casos e Controles , Progressão da Doença , Feminino , Humanos , Masculino , ProteômicaRESUMO
Obesity is a major risk factor for cardiovascular disease in males and females. Whether obesity triggers cardiovascular disease via similar mechanisms in both the sexes is, however, unknown. In males, the adipokine leptin highly contributes to obesity-related cardiovascular disease by increasing sympathetic activity. Females secrete 3× to 4× more leptin than males, but do not exhibit high sympathetic tone with obesity. Nevertheless, females show inappropriately high aldosterone levels that positively correlate with adiposity and blood pressure (BP). We hypothesized that leptin induces hypertension and endothelial dysfunction via aldosterone-dependent mechanisms in females. Leptin control of the cardiovascular function was analyzed in female mice sensitized to leptin via the deletion of protein tyrosine phosphatase 1b (knockout) and in agouti yellow obese hyperleptinemic mice (Ay). Hypersensitivity to leptin (wild-type, 115 ± 2; protein tyrosine phosphatase 1b knockout, 124 ± 2 mm Hg; P<0.05) and obesity elevated BP (a/a, 113 ± 1; Ay, 128 ± 7 mm Hg; P<0.05) and impaired endothelial function. Chronic leptin receptor antagonism restored BP and endothelial function in protein tyrosine phosphatase 1b knockout and Ay mice. Hypersensitivity to leptin and obesity reduced BP response to ganglionic blockade in both strains and plasma catecholamine levels in protein tyrosine phosphatase 1b knockout mice. Hypersensitivity to leptin and obesity significantly increased plasma aldosterone levels and adrenal CYP11B2 expression. Chronic leptin receptor antagonism reduced aldosterone levels. Furthermore, chronic leptin and mineralocorticoid receptor blockade reduced BP and improved endothelial function in both leptin-sensitized and obese hyperleptinemic female mice. Together, these data demonstrate that leptin induces hypertension and endothelial dysfunction via aldosterone-dependent mechanisms in female mice and suggest that obesity leads to cardiovascular disease via sex-specific mechanisms.
Assuntos
Aldosterona/metabolismo , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiopatologia , Hipertensão/fisiopatologia , Leptina/sangue , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , Análise de Variância , Animais , Doenças Cardiovasculares/fisiopatologia , Modelos Animais de Doenças , Feminino , Hipertensão/etiologia , Masculino , Camundongos , Camundongos Knockout , Camundongos Obesos , Proteína Tirosina Fosfatase não Receptora Tipo 1/genética , Distribuição Aleatória , Sistema Renina-Angiotensina/fisiologia , Sensibilidade e Especificidade , Fatores Sexuais , Estatísticas não ParamétricasRESUMO
Protein tyrosine phosphatase 1B (PTP1B) dephosphorylates receptors tyrosine kinase and acts as a molecular brake on insulin signaling pathway. Conditions of metabolic dysfunction increase PTP1B, when deletion of PTP1B protects against metabolic disorders by increasing insulin signaling. Although vascular insulin signaling contributes to the control of glucose disposal, little is known regarding the direct role of PTP1B in the control of endothelial function. We hypothesized that metabolic dysfunctions increase PTP1B expression in endothelial cells and that PTP1B deletion prevents endothelial dysfunction in situation of diminished insulin secretion. Type I diabetes (T1DM) was induced in wild-type (WT) and PTP1B-deficient mice (KO) with streptozotocin (STZ) injection. After 28 days of T1DM, KO mice exhibited a similar reduction in body weight and plasma insulin levels and a comparable increase in glycemia (WT: 384 ± 20 vs. Ko: 432 ± 29 mg/dL), cholesterol and triglycerides, as WT mice. T1DM increased PTP1B expression and impaired endothelial NO-dependent relaxation, in mouse aorta. PTP1B deletion did not affect baseline endothelial function, but preserved endothelium-dependent relaxation, in T1DM mice. NO synthase inhibition with L-NAME abolished endothelial relaxation in control and T1DM WT mice, whereas L-NAME and the cyclooxygenases inhibitor indomethacin were required to abolish endothelium relaxation in T1DM KO mice. PTP1B deletion increased COX-2 expression and PGI2 levels, in mouse aorta and plasma respectively, in T1DM mice. In parallel, simulation of diabetic conditions increased PTP1B expression and knockdown of PTP1B increased COX-2 but not COX-1 expression, in primary human aortic endothelial cells. Taken together these data indicate that deletion of PTP1B protected endothelial function by compensating the reduction in NO bioavailability by increasing COX-2-mediated release of the vasodilator prostanoid PGI2, in T1DM mice.