Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 29
Filtrar
Más filtros

Banco de datos
País/Región como asunto
Tipo del documento
Intervalo de año de publicación
1.
PLoS Genet ; 20(6): e1011285, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38885195

RESUMEN

The control of transcription is crucial for homeostasis in mammals. A previous selective sweep analysis of horse racing performance revealed a 19.6 kb candidate regulatory region 50 kb downstream of the Endothelin3 (EDN3) gene. Here, the region was narrowed to a 5.5 kb span of 14 SNVs, with elite and sub-elite haplotypes analyzed for association to racing performance, blood pressure and plasma levels of EDN3 in Coldblooded trotters and Standardbreds. Comparative analysis of human HiCap data identified the span as an enhancer cluster active in endothelial cells, interacting with genes relevant to blood pressure regulation. Coldblooded trotters with the sub-elite haplotype had significantly higher blood pressure compared to horses with the elite performing haplotype during exercise. Alleles within the elite haplotype were part of the standing variation in pre-domestication horses, and have risen in frequency during the era of breed development and selection. These results advance our understanding of the molecular genetics of athletic performance and vascular traits in both horses and humans.


Asunto(s)
Rendimiento Atlético , Presión Sanguínea , Haplotipos , Caballos/genética , Animales , Humanos , Presión Sanguínea/genética , Rendimiento Atlético/fisiología , Haplotipos/genética , Endotelina-3/genética , Polimorfismo de Nucleótido Simple , Alelos , Masculino , Células Endoteliales/metabolismo
2.
Hepatology ; 2024 Aug 27.
Artículo en Inglés | MEDLINE | ID: mdl-39190705

RESUMEN

BACKGROUND AIMS: Metabolic dysfunction-associated fatty liver disease (MASLD) is the most prevalent chronic liver pathology in western countries, with serious public health consequences. Efforts to identify causal genes for MASLD have been hampered by the relative paucity of human data from gold-standard magnetic resonance quantification of hepatic fat. To overcome insufficient sample size, genome-wide association studies using MASLD surrogate phenotypes have been used, but only a small number of loci have been identified to date. In this study, we combined GWAS of MASLD composite surrogate phenotypes with genetic colocalization studies followed by functional in vitro screens to identify bona fide causal genes for MASLD. APPROACH RESULTS: We used the UK Biobank to explore the associations of our novel MASLD score, and genetic colocalization to prioritize putative causal genes for in vitro validation. We created a functional genomic framework to study MASLD genes in vitro using CRISPRi. Our data identify VKORC1, TNKS, LYPLAL1 and GPAM as regulators of lipid accumulation in hepatocytes and suggest the involvement of VKORC1 in the lipid storage related to the development of MASLD. CONCLUSIONS: Complementary genetic and genomic approaches are useful for the identification of MASLD genes. Our data supports VKORC1 as a bona fide MASLD gene. We have established a functional genomic framework to study at scale putative novel MASLD genes from human genetic association studies.

3.
Clin Proteomics ; 20(1): 31, 2023 Aug 07.
Artículo en Inglés | MEDLINE | ID: mdl-37550624

RESUMEN

BACKGROUND: Human plasma contains a wide variety of circulating proteins. These proteins can be important clinical biomarkers in disease and also possible drug targets. Large scale genomics studies of circulating proteins can identify genetic variants that lead to relative protein abundance. METHODS: We conducted a meta-analysis on genome-wide association studies of autosomal chromosomes in 22,997 individuals of primarily European ancestry across 12 cohorts to identify protein quantitative trait loci (pQTL) for 92 cardiometabolic associated plasma proteins. RESULTS: We identified 503 (337 cis and 166 trans) conditionally independent pQTLs, including several novel variants not reported in the literature. We conducted a sex-stratified analysis and found that 118 (23.5%) of pQTLs demonstrated heterogeneity between sexes. The direction of effect was preserved but there were differences in effect size and significance. Additionally, we annotate trans-pQTLs with nearest genes and report plausible biological relationships. Using Mendelian randomization, we identified causal associations for 18 proteins across 19 phenotypes, of which 10 have additional genetic colocalization evidence. We highlight proteins associated with a constellation of cardiometabolic traits including angiopoietin-related protein 7 (ANGPTL7) and Semaphorin 3F (SEMA3F). CONCLUSION: Through large-scale analysis of protein quantitative trait loci, we provide a comprehensive overview of common variants associated with plasma proteins. We highlight possible biological relationships which may serve as a basis for further investigation into possible causal roles in cardiometabolic diseases.

4.
Cytokine ; 81: 1-9, 2016 May.
Artículo en Inglés | MEDLINE | ID: mdl-26821299

RESUMEN

IL-5 is a Th2 cytokine which activates eosinophils and is suggested to have an atheroprotective role. Genetic variants in the IL5 locus have been associated with increased risk of CAD and ischemic stroke. In this study we aimed to identify genetic variants associated with IL-5 concentrations and apply a Mendelian randomisation approach to assess IL-5 levels for causal effect on intima-media thickness in a European population at high risk of coronary artery disease. We analysed SNPs within robustly associated candidate loci for immune, inflammatory, metabolic and cardiovascular traits. We identified 2 genetic loci for IL-5 levels (chromosome 5, rs56183820, BETA=0.11, P=6.73E(-5) and chromosome 14, rs4902762, BETA=0.12, P=5.76E(-6)) and one for eosinophil count (rs72797327, BETA=-0.10, P=1.41E(-6)). Both chromosome 5 loci were in the vicinity of the IL5 gene, however the association with IL-5 levels failed to replicate in a meta-analysis of 2 independent cohorts (rs56183820, BETA=0.04, P=0.2763, I(2)=24, I(2)-P=0.2516). No significant associations were observed between SNPs associated with IL-5 levels or eosinophil count and IMT measures. Expression quantitative trait analyses indicate effects of the IL-5 and eosinophil-associated SNPs on RAD50 mRNA expression levels (rs12652920 (r2=0.93 with rs56183820) BETA=-0.10, P=8.64E(-6) and rs11739623 (r2=0.96 with rs72797327) BETA=-0.23, P=1.74E(-29), respectively). Our data do not support a role for IL-5 levels and eosinophil count in intima-media thickness, however SNPs associated with IL-5 and eosinophils might influence stability of the atherosclerotic plaque via modulation of RAD50 levels.


Asunto(s)
Cromosomas Humanos Par 5/genética , Enfermedad de la Arteria Coronaria/genética , Eosinófilos/metabolismo , Sitios Genéticos/genética , Interleucina-5/genética , Ácido Anhídrido Hidrolasas , Anciano , Grosor Intima-Media Carotídeo , Cromosomas Humanos Par 14/genética , Enfermedad de la Arteria Coronaria/sangre , Enzimas Reparadoras del ADN/genética , Proteínas de Unión al ADN/genética , Europa (Continente) , Femenino , Expresión Génica , Predisposición Genética a la Enfermedad/genética , Genética de Población , Estudio de Asociación del Genoma Completo/métodos , Humanos , Interleucina-5/sangre , Recuento de Leucocitos , Modelos Lineales , Masculino , Persona de Mediana Edad , Placa Aterosclerótica/sangre , Placa Aterosclerótica/genética , Polimorfismo de Nucleótido Simple , Factores de Riesgo
5.
Arterioscler Thromb Vasc Biol ; 35(4): 973-80, 2015 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-25745062

RESUMEN

OBJECTIVE: Patients with bicuspid aortic valve (BAV) have an increased risk of developing ascending aortic aneurysms. Transforming growth factor-ß (TGFß) is a crucial factor of vascular remodeling, the impaired signaling of which can alter the structure and composition of the extracellular matrix. In this study, we analyzed the activity of TGFß in aneurysmal and nonaneurysmal ascending aorta from BAV patients, using tricuspid aortic valve (TAV) patients as a reference group. APPROACH AND RESULTS: The response to exogenous TGFß was analyzed with regard to gene expression in primary aortic smooth muscle cells that were isolated from 7 BAV and 5 TAV patients and in valve fibroblasts from 7 BAV and 8 TAV patients. The set of genes that were significantly changed by TGFß (217 genes) was compared with gene expression profiles of the ascending aorta from BAV and TAV patients (139 arrays). By principle component analysis, based on the 217 genes, gene expression differed significantly in the intima/media region between aneurysmal BAV and TAV aortas, driven by the response in TAV patients. During aneurysm development the levels of phosphorylated SMADs and the availability of free TGFß were lower in BAV patients compared with TAV. Confocal microscopy analysis showed a higher colocalization of latency associated peptide and latent TGFß binding protein 3 in BAV aortas. CONCLUSIONS: Our findings suggest that TGFß activation during aneurysm formation is muted in patients with BAV, possibly as a result of an increased TGFß sequestration in the extracellular space.


Asunto(s)
Aneurisma de la Aorta/etiología , Válvula Aórtica/anomalías , Válvula Aórtica/metabolismo , Enfermedades de las Válvulas Cardíacas/complicaciones , Factor de Crecimiento Transformador beta/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Aneurisma de la Aorta/genética , Aneurisma de la Aorta/metabolismo , Aneurisma de la Aorta/patología , Válvula Aórtica/patología , Enfermedad de la Válvula Aórtica Bicúspide , Células Cultivadas , Matriz Extracelular/metabolismo , Femenino , Perfilación de la Expresión Génica/métodos , Regulación de la Expresión Génica , Enfermedades de las Válvulas Cardíacas/genética , Enfermedades de las Válvulas Cardíacas/metabolismo , Enfermedades de las Válvulas Cardíacas/patología , Humanos , Proteínas de Unión a TGF-beta Latente/genética , Proteínas de Unión a TGF-beta Latente/metabolismo , Masculino , Persona de Mediana Edad , Fosforilación , Análisis de Componente Principal , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Receptor Tipo I de Factor de Crecimiento Transformador beta , Receptores de Factores de Crecimiento Transformadores beta/genética , Receptores de Factores de Crecimiento Transformadores beta/metabolismo , Transducción de Señal , Proteínas Smad/genética , Proteínas Smad/metabolismo
6.
BMJ Open ; 14(3): e067977, 2024 Mar 20.
Artículo en Inglés | MEDLINE | ID: mdl-38508639

RESUMEN

OBJECTIVES: The objective of this study was to develop clinical classifiers aiming to identify prevalent ascending aortic dilatation in patients with bicuspid aortic valve (BAV) and tricuspid aortic valve (TAV). DESIGN AND SETTING: A prospective, single-centre and observational cohort. PARTICIPANTS: The study involved 543 BAV and 491 TAV patients with aortic valve disease and/or ascending aortic dilatation, excluding those with coronary artery disease, undergoing cardiothoracic surgery at the Karolinska University Hospital (Sweden). MAIN OUTCOME MEASURES: Predictors of high risk of ascending aortic dilatation (defined as ascending aorta with a diameter above 40 mm) were identified through the application of machine learning algorithms and classic logistic regression models. EXPOSURES: Comprehensive multidimensional data, including valve morphology, clinical information, family history of cardiovascular diseases, prevalent diseases, demographic details, lifestyle factors, and medication. RESULTS: BAV patients, with an average age of 60.4±12.4 years, showed a higher frequency of aortic dilatation (45.3%) compared with TAV patients, who had an average age of 70.4±9.1 years (28.9% dilatation, p <0.001). Aneurysm prediction models for TAV patients exhibited mean area under the receiver-operating-characteristic curve (AUC) values above 0.8, with the absence of aortic stenosis being the primary predictor, followed by diabetes and high-sensitivity C reactive protein. Conversely, prediction models for BAV patients resulted in AUC values between 0.5 and 0.55, indicating low usefulness for predicting aortic dilatation. Classification results remained consistent across all machine learning algorithms and classic logistic regression models. CONCLUSION AND RECOMMENDATION: Cardiovascular risk profiles appear to be more predictive of aortopathy in TAV patients than in patients with BAV. This adds evidence to the fact that BAV-associated and TAV-associated aortopathy involves different pathways to aneurysm formation and highlights the need for specific aneurysm preventions in these patients. Further, our results highlight that machine learning approaches do not outperform classical prediction methods in addressing complex interactions and non-linear relations between variables.


Asunto(s)
Aneurisma , Enfermedades de la Aorta , Enfermedad de la Válvula Aórtica Bicúspide , Enfermedades de las Válvulas Cardíacas , Humanos , Persona de Mediana Edad , Anciano , Válvula Aórtica/cirugía , Enfermedades de las Válvulas Cardíacas/complicaciones , Enfermedades de las Válvulas Cardíacas/cirugía , Estudios Prospectivos , Dilatación , Enfermedades de la Aorta/complicaciones
7.
Artículo en Inglés | MEDLINE | ID: mdl-38748858

RESUMEN

AIMS: Understanding the mechanisms underlying ascending aortic dilation is imperative for refined risk stratification of these patients, particularly among incidentally identified patients, most commonly presenting with tricuspid valves. The aim of this study was to explore associations between ascending aortic hemodynamics, assessed using four-dimensional flow cardiovascular magnetic resonance imaging (4D Flow CMR), and circulating biomarkers in aortic dilation. METHODS AND RESULTS: Forty-seven cases with aortic dilation (diameter ≥40 mm) and 50 sex-and age-matched controls (diameter <40 mm), all with tricuspid aortic valves, underwent 4D flow CMR and venous blood sampling. Associations between flow displacement, wall shear stress (WSS), and oscillatory shear index in the ascending aorta derived from 4D Flow CMR, and biomarkers including interleukin-6, collagen type I α1 chain, metalloproteinases (MMPs), and inhibitors of MMPs derived from blood plasma, were investigated. Cases with dilation exhibited lower peak systolic WSS, higher flow displacement, and higher mean oscillatory shear index compared to controls without dilation. No significant differences in biomarkers were observed between the groups. Correlations between hemodynamics and biomarkers were observed, particularly between maximum time-averaged WSS and interleukin-6 (r = 0.539, p < 0.001), and maximum oscillatory shear index and collagen type I α1 chain (r = -0.575, p < 0.001 in cases). CONCLUSION: Significant associations were discovered between 4D flow CMR derived whole-cardiac cycle WSS and circulating biomarkers representing inflammation and collagen synthesis, suggesting an intricate interplay between hemodynamics and the processes of inflammation and collagen synthesis in patients with early aortic dilation and tricuspid aortic valves.

8.
Nat Cardiovasc Res ; 3(3): 356-371, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-39196121

RESUMEN

Apolipoprotein-B (APOB)-containing lipoproteins cause atherosclerosis. Whether the vasculature is the initially responding site or if atherogenic dyslipidemia affects other organs simultaneously is unknown. Here we show that the liver responds to a dyslipidemic insult based on inducible models of familial hypercholesterolemia and APOB tracing. An acute transition to atherogenic APOB lipoprotein levels resulted in uptake by Kupffer cells and rapid accumulation of triglycerides and cholesterol in the liver. Bulk and single-cell RNA sequencing revealed a Kupffer-cell-specific transcriptional program that was not activated by a high-fat diet alone or detected in standard liver function or pathological assays, even in the presence of fulminant atherosclerosis. Depletion of Kupffer cells altered the dynamic of plasma and liver lipid concentrations, indicating that these liver macrophages help restrain and buffer atherogenic lipoproteins while simultaneously secreting atherosclerosis-modulating factors into plasma. Our results place Kupffer cells as key sentinels in organizing systemic responses to lipoproteins at the initiation of atherosclerosis.


Asunto(s)
Aterosclerosis , Modelos Animales de Enfermedad , Macrófagos del Hígado , Hígado , Macrófagos del Hígado/metabolismo , Animales , Hígado/metabolismo , Hígado/patología , Aterosclerosis/metabolismo , Aterosclerosis/patología , Masculino , Hiperlipoproteinemia Tipo II/metabolismo , Hiperlipoproteinemia Tipo II/complicaciones , Hiperlipoproteinemia Tipo II/sangre , Hiperlipoproteinemia Tipo II/patología , Dislipidemias/metabolismo , Ratones Endogámicos C57BL , Triglicéridos/sangre , Triglicéridos/metabolismo , Apolipoproteínas B/metabolismo , Apolipoproteínas B/sangre , Colesterol/metabolismo , Colesterol/sangre , Dieta Alta en Grasa/efectos adversos , Apolipoproteína B-100/metabolismo , Femenino
9.
medRxiv ; 2024 Feb 04.
Artículo en Inglés | MEDLINE | ID: mdl-38352379

RESUMEN

Background & Aims: Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver pathology in western countries, with serious public health consequences. Efforts to identify causal genes for NAFLD have been hampered by the relative paucity of human data from gold-standard magnetic resonance quantification of hepatic fat. To overcome insufficient sample size, genome-wide association studies using NAFLD surrogate phenotypes have been used, but only a small number of loci have been identified to date. In this study, we combined GWAS of NAFLD composite surrogate phenotypes with genetic colocalization studies followed by functional in vitro screens to identify bona fide causal genes for NAFLD. Approach & Results: We used the UK Biobank to explore the associations of our novel NAFLD score, and genetic colocalization to prioritize putative causal genes for in vitro validation. We created a functional genomic framework to study NAFLD genes in vitro using CRISPRi. Our data identify VKORC1, TNKS, LYPLAL1 and GPAM as regulators of lipid accumulation in hepatocytes and suggest the involvement of VKORC1 in the lipid storage related to the development of NAFLD. Conclusions: Complementary genetic and genomic approaches are useful for the identification of NAFLD genes. Our data supports VKORC1 as a bona fide NAFLD gene. We have established a functional genomic framework to study at scale putative novel NAFLD genes from human genetic association studies.

10.
J Mol Med (Berl) ; 101(10): 1323-1333, 2023 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-37698712

RESUMEN

Degenerative ascending aortic aneurysm (AscAA) is a silent and potentially fatal disease characterized by excessive vascular inflammation and fibrosis. We aimed to characterize the cellular and molecular signature for the fibrotic type of endothelial mesenchymal transition (EndMT) that has previously been described in degenerative AscAA. Patients undergoing elective open-heart surgery for AscAA and/or aortic valve repair were recruited. Gene expression in the intima-media of the ascending aorta was measured in 22 patients with non-dilated and 24 with dilated aortas, and candidate genes were identified. Protein expression was assessed using immunohistochemistry. Interacting distal gene enhancer regions were identified using targeted chromosome conformation capture (HiCap) in untreated and LPS-treated THP1 cells, and the associated transcription factors were analyzed. Differential expression analysis identified SPP1 (osteopontin) as a key gene in the signature of fibrotic EndMT in patients with degenerative AscAA. The aortic intima-media expression of SPP1 correlated with the expression of inflammatory markers, the level of macrophage infiltration, and the aortic diameter. HiCap analysis, followed by transcription factor binding analysis, identified ETS1 as a potential regulator of SPP1 expression under inflammatory conditions. In conclusion, the present findings suggest that SPP1 may be involved in the development of the degenerative type of AscAA. KEY MESSAGES: In the original manuscript titled "SPP1/osteopontin, a driver of fibrosis and inflammation in degenerative ascending aortic aneurysm?" by David Freiholtz, Otto Bergman, Saliendra Pradhananga, Karin Lång, Flore-Anne Poujade, Carl Granath, Christian Olsson, Anders Franco-Cereceda, Pelin Sahlén, Per Eriksson, and Hanna M Björck, we present novel findings on regulatory factors on osteopontin (SPP1) expression in immune cells involved in degenerative ascending aortic aneurysms (AscAA). The central findings convey: SPP1 is a potential driver of the fibrotic endothelial-to-mesenchymal transition in AscAA. SPP1/osteopontin expression in AscAA is predominately by immune cells. ETS1 is a regulatory transcription factor of SPP1 expression in AscAA immune cells.

11.
J Mol Med (Berl) ; 101(7): 801-811, 2023 07.
Artículo en Inglés | MEDLINE | ID: mdl-37162557

RESUMEN

Bicuspid aortic valve (BAV) is the most common congenital heart malformation frequently associated with ascending aortic aneurysm (AscAA). Epithelial to mesenchymal transition (EMT) may play a role in BAV-associated AscAA. The aim of the study was to investigate the type of EMT associated with BAV aortopathy using patients with a tricuspid aortic valve (TAV) as a reference. The state of the endothelium was further evaluated. Aortic biopsies were taken from patients undergoing open-heart surgery. Aortic intima/media miRNA and gene expression was analyzed using Affymetrix human transcriptomic array. Histological staining assessed structure, localization, and protein expression. Migration/proliferation was assessed using ORIS migration assay. We show different EMT types associated with BAV and TAV AscAA. Specifically, in BAV-associated aortopathy, EMT genes related to endocardial cushion formation were enriched. Further, BAV vascular smooth muscle cells were less proliferative and migratory. In contrast, TAV aneurysmal aortas displayed a fibrotic EMT phenotype with medial degenerative insults. Further, non-dilated BAV aortas showed a lower miRNA-200c-associated endothelial basement membrane LAMC1 expression and lower CD31 expression, accompanied by increased endothelial permeability indicated by increased albumin infiltration. Embryonic EMT is a characteristic of BAV aortopathy, associated with endothelial instability and vascular permeability of the non-dilated aortic wall. KEY MESSAGES: Embryonic EMT is a feature of BAV-associated aortopathy. Endothelial integrity is compromised in BAV aortas prior to dilatation. Non-dilated BAV ascending aortas are more permeable than aortas of tricuspid aortic valve patients.


Asunto(s)
Enfermedad de la Válvula Aórtica Bicúspide , Enfermedades de las Válvulas Cardíacas , MicroARNs , Humanos , Enfermedad de la Válvula Aórtica Bicúspide/complicaciones , Enfermedad de la Válvula Aórtica Bicúspide/metabolismo , Enfermedad de la Válvula Aórtica Bicúspide/patología , Enfermedades de las Válvulas Cardíacas/genética , Enfermedades de las Válvulas Cardíacas/complicaciones , Enfermedades de las Válvulas Cardíacas/metabolismo , Transición Epitelial-Mesenquimal/genética , Válvula Aórtica/metabolismo , MicroARNs/metabolismo , Endotelio/metabolismo , Endotelio/patología
12.
J Am Heart Assoc ; 11(9): e024346, 2022 05 03.
Artículo en Inglés | MEDLINE | ID: mdl-35470674

RESUMEN

Background Acetylsalicylic acid (ASA) therapy has been associated with a reduced prevalence and growth rate of abdominal as well as intracranial aneurysms, but the relationship between ASA and ascending aortic aneurysm formation remains largely unknown. The aim of the present study was to investigate whether ASA therapy is associated with a lower prevalence of ascending aortic aneurysm in a surgical cohort. Methods and Results One thousand seven hundred patients undergoing open-heart surgery for ascending aortic aneurysm and/or aortic valve disease were studied in this retrospective cross-sectional study. Aortic dilatation was defined as an aortic root or ascending aortic diameter ≥45 mm. Medications were self-reported by the patients in a systematic questionnaire. Cyclooxygenase gene expression was measured in the intima-media portion of the ascending aorta (n=117). In a multivariable analysis, ASA was associated with a reduced prevalence of ascending aortic aneurysm (relative risk, 0.68 [95% CI, 0.48-0.95], P=0.026) in patients with tricuspid aortic valves, but not in patients with bicuspid aortic valves (relative risk, 0.93 [95% CI, 0.64-1.34], P=0.687). Intima-media cyclooxygenase expression was positively correlated with ascending aortic dimensions (P<0.001 for cyclooxygenase-1 and P=0.05 for cyclooxygenase-2). In dilated, but not nondilated tricuspid aortic valve aortic specimens, ASA was associated with significantly lower cyclooxygenase-2 levels (P=0.034). Conclusions Our findings are consistent with the hypothesis that ASA treatment may attenuate ascending aortic aneurysmal growth, possibly via cyclooxygenase-2 inhibition in the ascending aortic wall and subsequent anti-inflammatory actions.


Asunto(s)
Aneurisma de la Aorta , Enfermedades de las Válvulas Cardíacas , Aorta/cirugía , Aneurisma de la Aorta/cirugía , Aspirina/uso terapéutico , Estudios Transversales , Ciclooxigenasa 2/genética , Enfermedades de las Válvulas Cardíacas/cirugía , Humanos , Prevalencia , Estudios Retrospectivos
13.
Eur J Cardiothorac Surg ; 61(2): 388-392, 2022 Jan 24.
Artículo en Inglés | MEDLINE | ID: mdl-34676406

RESUMEN

OBJECTIVES: Metformin therapy has previously been associated with reduced abdominal aortic aneurysm growth rate in diabetic patients and shown to suppress the formation and progression of abdominal aortic aneurysm in normoglycemic mice. Here, we investigated the association between Metformin treatment and prevalence of aneurysm in the ascending aorta (AscAA). METHODS: A total of 734 patients undergoing open-heart surgery for AscAA and/or aortic valve disease were studied. Diabetes status and medication use were self-reported by the patients in a systematic questionnaire. Aortic dilatation was defined as an aortic root or ascending aortic diameter ≥4.0 cm. High-sensitivity C-reactive protein levels were assessed as a measure of systemic inflammation. RESULTS: We could confirm the inverse association between diabetes and AscAA prevalence (16% vs 43.9%, for diabetic and non-diabetic patients, respectively; Odds ratio 0.243; 95% CI, 0.129-0.460, P < 0.001). Furthermore, in diabetic patients, Metformin treatment was associated with lower high-sensitivity C-reactive protein levels. There was, however, no difference in the prevalence of AscAA among diabetic patients with and without Metformin treatment (16% vs 16% for treated and non-treated patients, respectively; OR 1.039; 95% CI 0.26-4.19, P = 0.957). CONCLUSIONS: Our data do not support a protective effect of Metformin therapy in AscAA formation. SUBJ COLLECTION: 161, 173.


Asunto(s)
Aneurisma de la Aorta Abdominal , Aneurisma de la Aorta , Diabetes Mellitus , Metformina , Animales , Aneurisma de la Aorta/epidemiología , Aneurisma de la Aorta/cirugía , Aneurisma de la Aorta Abdominal/epidemiología , Válvula Aórtica/cirugía , Humanos , Metformina/uso terapéutico , Ratones , Prevalencia , Estudios Retrospectivos
14.
Ann Thorac Surg ; 114(5): 1665-1670, 2022 11.
Artículo en Inglés | MEDLINE | ID: mdl-35271843

RESUMEN

BACKGROUND: We aimed to study sex differences in aortopathy and valve disease among patients undergoing aortic valve replacement and/or surgical procedure for ascending aortic aneurysm and assess whether differences are specific for patients with bicuspid aortic valve (BAV) compared with patients with tricuspid aortic valve. METHODS: We used a single-center and observational cohort including 1045 patients undergoing elective open heart surgical procedure for aortic valve disease and/or ascending aortic aneurysm at the Karolinska Hospital (Stockholm, Sweden). RESULTS: Women (33.0%) were older than men (mean [SD]; 67.9 [11] years vs 62.5 [13] years for men; P < .001). No significant sex difference in prevalence of ascending aortic aneurysm was found according to absolute measures (P = .19); however, women had a greater dilation of the ascending aorta when normalized for body surface area (mean, 21.8 [SD, 6.3] mm/m2 vs 19.3 [SD, 4.4] mm/m2 for men; P < .001). Among the 560 patients with BAV, women had significantly more aortic stenosis (adjusted odds ratio, 2.23; 95% CI, 1.19-4.20; P = .013) and less aortic insufficiency (adjusted odds ratio, 0.42; 95% CI, 0.23-0.78; P < .01); whereas no sex difference was found among patients with tricuspid aortic valve. CONCLUSIONS: In this large study of patients undergoing cardiac surgical procedure, we found a greater degree of aortic dilation in women compared with men, suggesting a need for earlier monitoring of women. Moreover, women with BAV had a significantly higher prevalence of aortic stenosis compared with men. These results describe the aorta and valvular characteristics of patients by sex and provide guidance regarding which patients might benefit from closer surveillance.


Asunto(s)
Aneurisma de la Aorta , Estenosis de la Válvula Aórtica , Enfermedad de la Válvula Aórtica Bicúspide , Procedimientos Quirúrgicos Cardíacos , Endocarditis , Enfermedades de las Válvulas Cardíacas , Humanos , Femenino , Masculino , Enfermedades de las Válvulas Cardíacas/complicaciones , Enfermedades de las Válvulas Cardíacas/epidemiología , Enfermedades de las Válvulas Cardíacas/cirugía , Estudios Retrospectivos , Válvula Aórtica/cirugía , Aneurisma de la Aorta/epidemiología , Aneurisma de la Aorta/cirugía , Estenosis de la Válvula Aórtica/epidemiología , Estenosis de la Válvula Aórtica/cirugía
15.
Biomedicines ; 9(6)2021 Jun 20.
Artículo en Inglés | MEDLINE | ID: mdl-34203009

RESUMEN

A reduced prevalence of a thoracic aortic aneurysm (thoracic AA) is observed in type 2 diabetes (T2D). Glucagon-like peptide-1 (GLP-1)/GLP-1-based anti-diabetic therapy has indicated protective effects in thoracic AA and regulates the processes controlling the vascular tissue expression of Syndecan-1 (Sdc-1). Sdc-1 expression on macrophages infiltrating the aortic tissue contributes to a counter-regulatory response to thoracic AA formation in animal models through the interplay with inflammation/proteolytic activity. We hypothesized that elevated fasting plasma GLP-1 (fpGLP-1) increases the aortic Sdc-1 expression in T2D, which may contribute to a reduced prevalence of thoracic AA. Consequently, we determined whether T2D/thoracic AA associates with an altered Sdc-1 expression in the aortic tissue and the possible associations with fpGLP-1 and inflammation/proteolytic activity. From a cohort of surgical patients with an aortic valve pathology, we compared different disease groups (T2D/thoracic AA) with the same sub-cohort group of controls (patients without T2D and thoracic AA). The MMP-2 activity and Sdc-1, GLP-1R and CD68 expression were analyzed in the aortic tissue. GLP-1, Sdc-1 and cytokines were analyzed in the plasma. The aortic Sdc-1 expression was increased in T2D patients but did not correlate with fpGLP-1. Thoracic AA was associated with an increased aortic expression of Sdc-1 and the macrophage marker CD68. CD68 was not detected in T2D. In conclusion, an increased aortic Sdc-1 expression may contribute to a reduced prevalence of thoracic AA in T2D.

16.
Open Heart ; 8(2)2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-34670833

RESUMEN

OBJECTIVE: Determine whether associations between bicuspid aortic valve (BAV) phenotypes, valve disease and aortopathy differ between sexes. METHODS: 1045 patients with BAV (76.0% men, n=794) from two surgical centres were included in this cross-sectional study. Valve phenotype was classified intraoperatively as right-left (RL), right-non-coronary (RN), left-non-coronary (LN) or 2-sinus BAV. Echocardiography was used to determine type and degree of valve disease, and aortic dimensions. Aortic dilatation was defined as diameter ≥4.5 cm. RESULTS: RL was the most common phenotype (73.6%), followed by RN (16.2%), 2-sinus BAV (9.2%) and LN (1.1%), with no difference in phenotype distribution between men and women (p=0.634). Aortic valve insufficiency (AI) prevalence differed significantly with valve phenotype in men (p=0.047), with RL and LN having the highest prevalence (34.1% and 44.0%, respectively). In women, RN had a higher proportion of AI than RL (21.3% vs 7.3%, p=0.017). Men with RL had larger root dimensions, in particular at the sinus (mean difference 0.24 cm compared with RN, p=0.002). Men with 2-sinus BAV had the highest prevalence of root phenotype dilatation (7.0%, other phenotypes ≤2.3%, p=0.031), whereas women with 2-sinus BAV did not have root dilatation and smaller sinus dimensions (mean difference: 0.35 cm compared with RL, p=0.021). Aortic root segments were larger in men with AI compared with aortic stenosis (sinus mean difference: 0.40 cm, p<0.001). The difference was even larger in women (mean difference: 0.78 cm, p<0.001), and women with AI also had larger tubular segments (mean difference: 0.61 cm, p=0.001). CONCLUSIONS: There are significant sex differences in clinical associations of BAV phenotypes, which should be considered in further studies on the role of phenotypes in individualised patient management.


Asunto(s)
Aorta Torácica/diagnóstico por imagen , Enfermedades de la Aorta/etiología , Enfermedad de la Válvula Aórtica Bicúspide/etiología , Medición de Riesgo/métodos , Enfermedades de la Aorta/epidemiología , Enfermedad de la Válvula Aórtica Bicúspide/epidemiología , Enfermedad de la Válvula Aórtica Bicúspide/cirugía , Estudios Transversales , Ecocardiografía , Femenino , Estudios de Seguimiento , Salud Global , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Distribución por Sexo , Factores Sexuales
17.
J Cardiovasc Dev Dis ; 8(11)2021 Oct 28.
Artículo en Inglés | MEDLINE | ID: mdl-34821696

RESUMEN

Glucagon-like peptide-1 (GLP-1) regulates processes involved in the pathophysiology of thoracic aortic aneurysms (TAAs), including inflammation, while protecting against aortic aneurysms in animal models. Type 2 diabetes (T2D) involves altered GLP-1 signaling due to pathology and/or therapy and is associated with reduced prevalence of TAAs. We aimed to assess whether T2D alters the inflammatory profile/proteolytic activity, possible correlations to elevated fasting GLP-1 (F-GLP-1), and its relevance for TAA. F-GLP-1, pro-inflammatory T helper 1 (Th1) cytokines, Th2 cytokines, C-reactive protein, and matrix metalloproteinase-2 activity (MMP-2) were analyzed in surgical patients with aortic valve pathology with/without T2D and without T2D but with TAA. Patients with T2D displayed an increase in the relative systemic expression of interleukin 6 and tumor necrosis factor α and a clear trend towards reduced levels of interferon γ (IFNγ). In addition, a positive association between GLP-1 and the plasma interleukin 4 (IL-4)/IFNγ ratio was detected. TAA was associated with significantly lower plasma levels of the Th2 cytokines IL-4 and interleukin 5. Plasma MMP-2 activity did not differ between groups. We conclude that T2D involved a Th2 shift, which associates with elevated F-GLP-1 and may-considering Th1 bias in TAA-contribute to reduced prevalence of TAA in T2D.

18.
Front Cardiovasc Med ; 6: 182, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31921896

RESUMEN

Thoracic aortic aneurysm (TAA) is the progressive enlargement of the aorta due to destructive changes in the connective tissue of the aortic wall. Aneurysm development is silent and often first manifested by the drastic events of aortic dissection or rupture. As yet, therapeutic agents that halt or reverse the process of aortic wall deterioration are absent, and the only available therapeutic recommendation is elective prophylactic surgical intervention. Being born with a bicuspid instead of the normal tricuspid aortic valve (TAV) is a major risk factor for developing aneurysm in the ascending aorta later in life. Although the pathophysiology of the increased aneurysm susceptibility is not known, recent studies are suggestive of a transformation of aortic endothelium into a more mesenchymal state i.e., an endothelial-to-mesenchymal transition in these individuals. This process involves the loss of endothelial cell features, resulting in junction instability and enhanced vascular permeability of the ascending aorta that may lay the ground for increased aneurysm susceptibility. This finding differentiates and further emphasizes the specific characteristics of aneurysm development in individuals with a bicuspid aortic valve (BAV). This review discusses the possibility of a developmental fate shared between the aortic endothelium and aortic valves. It further speculates about the impact of aortic endothelium phenotypic shift on aneurysm development in individuals with a BAV and revisits previous studies in the light of the new findings.

19.
Sci Rep ; 8(1): 2777, 2018 02 09.
Artículo en Inglés | MEDLINE | ID: mdl-29426841

RESUMEN

Disturbed flow has been suggested to contribute to aneurysm susceptibility in bicuspid aortic valve (BAV) patients. Lately, flow has emerged as an important modulator of DNA methylation. Hear we combined global methylation analysis with in vitro studies of flow-sensitive methylation to identify biological processes associated with BAV-aortopathy and the potential contribution of flow. Biopsies from non-dilated and dilated ascending aortas were collected from BAV (n = 21) and tricuspid aortic valve (TAV) patients (n = 23). DNA methylation and gene expression was measured in aortic intima-media tissue samples, and in EA.hy926 and primary aortic endothelial cells (ECs) isolated from BAV and TAV exposed to oscillatory (±12 dynes/cm2) or laminar (12 dynes/cm2) flow. We show methylation changes related to epithelial-mesenchymal-transition (EMT) in the non-dilated BAV aorta, associated with oscillatory flow related to endocytosis. The results indicate that the flow-response in BAV ECs involves hypomethylation and increased expression of WNT/ß-catenin genes, as opposed to an angiogenic profile in TAV ECs. The EMT-signature was exasperated in dilated BAV aortas. Aberrant EMT in BAV aortic walls could contribute to increased aneurysm susceptibility, and may be due to disturbed flow-exposure. Perturbations during the spatiotemporally related embryonic development of ascending aorta and semilunar valves can however not be excluded.


Asunto(s)
Aorta , Válvula Aórtica/anomalías , Circulación Sanguínea , Metilación de ADN , Células Endoteliales/metabolismo , Transición Epitelial-Mesenquimal , Enfermedades de las Válvulas Cardíacas/metabolismo , Válvula Tricúspide/metabolismo , Aorta/citología , Aorta/metabolismo , Válvula Aórtica/metabolismo , Enfermedad de la Válvula Aórtica Bicúspide , Dilatación Patológica , Células Endoteliales/citología , Humanos , Transcriptoma
20.
Front Physiol ; 8: 400, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28659821

RESUMEN

Bicuspid aortic valve (BAV) is the most common congenital heart defect. Although many BAV patients remain asymptomatic, at least 20% develop thoracic aortic aneurysm (TAA). Historically, BAV-related TAA was considered as a hemodynamic consequence of the valve defect. Multiple lines of evidence currently suggest that genetic determinants contribute to the pathogenesis of both BAV and TAA in affected individuals. Despite high heritability, only very few genes have been linked to BAV or BAV/TAA, such as NOTCH1, SMAD6, and MAT2A. Moreover, they only explain a minority of patients. Other candidate genes have been suggested based on the presence of BAV in knockout mouse models (e.g., GATA5, NOS3) or in syndromic (e.g., TGFBR1/2, TGFB2/3) or non-syndromic (e.g., ACTA2) TAA forms. We hypothesized that rare genetic variants in these genes may be enriched in patients presenting with both BAV and TAA. We performed targeted resequencing of 22 candidate genes using Haloplex target enrichment in a strictly defined BAV/TAA cohort (n = 441; BAV in addition to an aortic root or ascendens diameter ≥ 4.0 cm in adults, or a Z-score ≥ 3 in children) and in a collection of healthy controls with normal echocardiographic evaluation (n = 183). After additional burden analysis against the Exome Aggregation Consortium database, the strongest candidate susceptibility gene was SMAD6 (p = 0.002), with 2.5% (n = 11) of BAV/TAA patients harboring causal variants, including two nonsense, one in-frame deletion and two frameshift mutations. All six missense mutations were located in the functionally important MH1 and MH2 domains. In conclusion, we report a significant contribution of SMAD6 mutations to the etiology of the BAV/TAA phenotype.

SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA