RESUMO
BACKGROUND: Aortic stenosis (AS) is driven by progressive inflammatory and fibrocalcific processes regulated by circulating inflammatory and valve resident endothelial and interstitial cells. The impact of platelets, platelet-derived mediators, and platelet-monocyte interactions on the acceleration of local valvular inflammation and mineralization is presently unknown. METHODS: We prospectively enrolled 475 consecutive patients with severe symptomatic AS undergoing aortic valve replacement. Clinical workup included repetitive echocardiography, analysis of platelets, monocytes, chemokine profiling, aortic valve tissue samples for immunohistochemistry, and gene expression analysis. RESULTS: The patients were classified as fast-progressive AS by the median ∆Vmax of 0.45 m/s per year determined by echocardiography. Immunohistological aortic valve analysis revealed enhanced cellularity in fast-progressive AS (slow- versus fast-progressive AS; median [interquartile range], 247 [142.3-504] versus 717.5 [360.5-1234]; P<0.001) with less calcification (calcification area, mm2: 33.74 [27.82-41.86] versus 20.54 [13.52-33.41]; P<0.001). MIF (macrophage migration inhibitory factor)-associated gene expression was significantly enhanced in fast-progressive AS accompanied by significantly elevated MIF plasma levels (mean±SEM; 6877±379.1 versus 9959±749.1; P<0.001), increased platelet activation, and decreased intracellular MIF expression indicating enhanced MIF release upon platelet activation (CD62P, %: median [interquartile range], 16.8 [11.58-23.8] versus 20.55 [12.48-32.28], P=0.005; MIF, %: 4.85 [1.48-9.75] versus 2.3 [0.78-5.9], P<0.001). Regression analysis confirmed that MIF-associated biomarkers are strongly associated with an accelerated course of AS. CONCLUSIONS: Our findings suggest a key role for platelet-derived MIF and its interplay with circulating and valve resident monocytes/macrophages in local and systemic thromboinflammation during accelerated AS. MIF-based biomarkers predict an accelerated course of AS and represent a novel pharmacological target to attenuate progression of AS.
Assuntos
Estenose da Valva Aórtica , Valva Aórtica , Biomarcadores , Progressão da Doença , Oxirredutases Intramoleculares , Fatores Inibidores da Migração de Macrófagos , Tromboinflamação , Humanos , Estenose da Valva Aórtica/genética , Estenose da Valva Aórtica/patologia , Estenose da Valva Aórtica/metabolismo , Estenose da Valva Aórtica/sangue , Fatores Inibidores da Migração de Macrófagos/sangue , Fatores Inibidores da Migração de Macrófagos/genética , Fatores Inibidores da Migração de Macrófagos/metabolismo , Masculino , Feminino , Idoso , Estudos Prospectivos , Valva Aórtica/patologia , Valva Aórtica/metabolismo , Valva Aórtica/diagnóstico por imagem , Oxirredutases Intramoleculares/genética , Oxirredutases Intramoleculares/metabolismo , Oxirredutases Intramoleculares/sangue , Biomarcadores/sangue , Tromboinflamação/genética , Tromboinflamação/patologia , Tromboinflamação/metabolismo , Plaquetas/metabolismo , Plaquetas/patologia , Idoso de 80 Anos ou mais , Monócitos/metabolismo , Pessoa de Meia-Idade , Implante de Prótese de Valva Cardíaca , Fatores de Tempo , Índice de Gravidade de Doença , Calcinose/patologia , Calcinose/genética , Calcinose/sangue , Calcinose/metabolismoRESUMO
BACKGROUND: Type 2 diabetes (T2D) is a frequent comorbidity encountered in patients with severe aortic stenosis (AS), leading to an adverse left ventricular (LV) remodeling and dysfunction. Metabolic alterations have been suggested as contributors of the deleterious effect of T2D on LV remodeling and function in patients with severe AS, but so far, the underlying mechanisms remain unclear. Mitochondria play a central role in the regulation of cardiac energy metabolism. OBJECTIVES: We aimed to explore the mitochondrial alterations associated with the deleterious effect of T2D on LV remodeling and function in patients with AS, preserved ejection fraction, and no additional heart disease. METHODS: We combined an in-depth clinical, biological and echocardiography phenotype of patients with severe AS, with (n = 34) or without (n = 50) T2D, referred for a valve replacement, with transcriptomic and histological analyses of an intra-operative myocardial LV biopsy. RESULTS: T2D patients had similar AS severity but displayed worse cardiac remodeling, systolic and diastolic function than non-diabetics. RNAseq analysis identified 1029 significantly differentially expressed genes. Functional enrichment analysis revealed several T2D-specific upregulated pathways despite comorbidity adjustment, gathering regulation of inflammation, extracellular matrix organization, endothelial function/angiogenesis, and adaptation to cardiac hypertrophy. Downregulated gene sets independently associated with T2D were related to mitochondrial respiratory chain organization/function and mitochondrial organization. Generation of causal networks suggested a reduced Ca2+ signaling up to the mitochondria, with the measured gene remodeling of the mitochondrial Ca2+ uniporter in favor of enhanced uptake. Histological analyses supported a greater cardiomyocyte hypertrophy and a decreased proximity between the mitochondrial VDAC porin and the reticular IP3-receptor in T2D. CONCLUSIONS: Our data support a crucial role for mitochondrial Ca2+ signaling in T2D-induced cardiac dysfunction in severe AS patients, from a structural reticulum-mitochondria Ca2+ uncoupling to a mitochondrial gene remodeling. Thus, our findings open a new therapeutic avenue to be tested in animal models and further human cardiac biopsies in order to propose new treatments for T2D patients suffering from AS. TRIAL REGISTRATION: URL: https://www. CLINICALTRIALS: gov ; Unique Identifier: NCT01862237.
Assuntos
Estenose da Valva Aórtica , Sinalização do Cálcio , Diabetes Mellitus Tipo 2 , Perfilação da Expressão Gênica , Mitocôndrias Cardíacas , Índice de Gravidade de Doença , Transcriptoma , Função Ventricular Esquerda , Remodelação Ventricular , Humanos , Estenose da Valva Aórtica/metabolismo , Estenose da Valva Aórtica/genética , Estenose da Valva Aórtica/fisiopatologia , Estenose da Valva Aórtica/diagnóstico por imagem , Estenose da Valva Aórtica/cirurgia , Estenose da Valva Aórtica/patologia , Masculino , Mitocôndrias Cardíacas/metabolismo , Mitocôndrias Cardíacas/patologia , Feminino , Idoso , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/complicações , Pessoa de Meia-Idade , Idoso de 80 Anos ou mais , Disfunção Ventricular Esquerda/fisiopatologia , Disfunção Ventricular Esquerda/genética , Disfunção Ventricular Esquerda/metabolismo , Disfunção Ventricular Esquerda/diagnóstico por imagemRESUMO
Background: Non-alcoholic fatty liver disease (NAFLD) has emerged as a predominant driver of chronic liver disease globally and is associated with increased cardiovascular disease morbidity and mortality. However, the association between NAFLD and calcific aortic valve disease remains unclear. We aimed to prospectively investigate the association between NAFLD and incident aortic valve calcification (AVC), as well as its genetic relationship with incident calcific aortic valve stenosis (CAVS). Methods: A post hoc analysis was conducted on 4226 participants from the Multi-Ethnic Study of Atherosclerosis (MESA) database. We employed the adjusted Cox models to assess the observational association between NAFLD and incident AVC. Additionally, we conducted two-sample Mendelian randomization (MR) analyses to investigate the genetic association between genetically predicted NAFLD and calcific aortic valve stenosis (CAVS), a severe form of CAVD. We repeated the MR analyses by excluding NAFLD susceptibility genes linked to impaired very low-density lipoprotein (VLDL) secretion. Results: After adjustment for potential risk factors, participants with NAFLD had a hazard ratio of 1.58 (95% CI: 1.03-2.43) for incident AVC compared to those without NAFLD. After excluding genes associated with impaired VLDL secretion, the MR analyses consistently showed the significant associations between genetically predicted NAFLD and CAVS for 3 traits: chronic elevation of alanine aminotransferase (odds ratio = 1.13 [95% CI: 1.01-1.25]), imaging-based NAFLD (odds ratio = 2.81 [95% CI: 1.66-4.76]), and biopsy-confirmed NAFLD (odds ratio = 1.12 [95% CI: 1.01-1.24]). However, the association became non-significant when considering all NAFLD susceptibility genes. Conclusions: NAFLD was independently associated with an elevated risk of incident AVC. Genetically predicted NAFLD was also associated with CAVS after excluding genetic variants related to impaired VLDL secretion.
Assuntos
Estenose da Valva Aórtica , Valva Aórtica , Calcinose , Análise da Randomização Mendeliana , Hepatopatia Gordurosa não Alcoólica , Humanos , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Hepatopatia Gordurosa não Alcoólica/patologia , Hepatopatia Gordurosa não Alcoólica/complicações , Calcinose/genética , Feminino , Masculino , Valva Aórtica/patologia , Pessoa de Meia-Idade , Estenose da Valva Aórtica/genética , Estenose da Valva Aórtica/epidemiologia , Estenose da Valva Aórtica/patologia , Idoso , Fatores de Risco , Predisposição Genética para Doença , Idoso de 80 Anos ou mais , Estudos ProspectivosRESUMO
Calcific aortic valve disease (CAVD) is becoming an increasingly important global medical problem, but effective pharmacological treatments are lacking. Noncoding RNAs play a pivotal role in the progression of cardiovascular diseases, but their relationship with CAVD remains unclear. Sequencing data revealed differential expression of many noncoding RNAs in normal and calcified aortic valves, with significant differences in circHIPK3 and miR-182-5p expression. Overexpression of circHIPK3 ameliorated aortic valve lesions in a CAVD mouse model. In vitro experiments demonstrated that circHIPK3 inhibits the osteogenic response of aortic valve interstitial cells. Mechanistically, DEAD-box helicase 5 (DDX5) recruits methyltransferase 3 (METTL3) to promote the N6-methyladenosine (m6A) modification of circHIPK3. Furthermore, m6A-modified circHIPK3 increases the stability of Kremen1 (Krm1) mRNA, and Krm1 is a negative regulator of the Wnt/ß-catenin pathway. Additionally, miR-182-5p suppresses the expression of Dickkopf2 (Dkk2), the ligand of Krm1, and attenuates the Krm1-mediated inhibition of Wnt signaling. Activation of the Wnt signaling pathway significantly contributes to the promotion of aortic valve calcification. Our study describes the role of the Krm1-Dkk2 axis in inhibiting Wnt signaling in aortic valves and suggests that noncoding RNAs are upstream regulators of this process.
Assuntos
Estenose da Valva Aórtica , Valva Aórtica , Calcinose , Regulação da Expressão Gênica , Peptídeos e Proteínas de Sinalização Intercelular , MicroRNAs , Animais , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/genética , Valva Aórtica/patologia , Valva Aórtica/metabolismo , Camundongos , Calcinose/genética , Calcinose/metabolismo , Calcinose/patologia , Estenose da Valva Aórtica/genética , Estenose da Valva Aórtica/metabolismo , Estenose da Valva Aórtica/patologia , MicroRNAs/genética , MicroRNAs/metabolismo , Via de Sinalização Wnt , Modelos Animais de Doenças , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Humanos , Metiltransferases/metabolismo , Metiltransferases/genética , RNA Circular/genética , RNA Circular/metabolismo , MasculinoRESUMO
OBJECTIVE: Calcific aortic valve disease (CAVD) predominantly affects the elderly and currently lacks effective medical treatments. Nesfatin-1, a peptide derived from the cleavage of Nucleobindin 2, has been implicated in various calcification processes, both physiological and pathological. This study explores the impact of Nesfatin-1 on the transformation of aortic valve interstitial cells (AVICs) in CAVD. METHODS AND RESULTS: In vitro experiments showed that Nesfatin-1 treatment mitigated the osteogenic differentiation of AVICs. Corresponding in vivo studies demonstrated a deceleration in the progression of CAVD. RNA-sequencing of AVICs treated with and without Nesfatin-1 highlighted an enrichment of the Ferroptosis pathway among the top pathways identified by the Kyoto Encyclopedia of Genes and Genomes analysis. Further examination confirmed increased ferroptosis in both calcified valves and osteoblast-like AVICs, with a reduction in ferroptosis following Nesfatin-1 treatment. Within the Ferroptosis pathway, ZIP8 showed the most notable modulation by Nesfatin-1. Silencing ZIP8 in AVICs increased ferroptosis and osteogenic differentiation, decreased intracellular Mn2+ concentration, and reduced the expression and activity of superoxide dismutase (SOD2). Furthermore, the silencing of SOD2 exacerbated ferroptosis and osteogenic differentiation. Nesfatin-1 treatment was found to elevate the expression of glutathione peroxidase 4 (GPX4) and levels of glutathione (GSH), as confirmed by Western blotting and GSH concentration assays. CONCLUSION: In summary, Nesfatin-1 effectively inhibits the osteogenic differentiation of AVICs by attenuating ferroptosis, primarily through the GSH/GPX4 and ZIP8/SOD2 pathways.
Assuntos
Estenose da Valva Aórtica , Valva Aórtica , Calcinose , Ferroptose , Nucleobindinas , Fosfolipídeo Hidroperóxido Glutationa Peroxidase , Superóxido Dismutase , Ferroptose/genética , Nucleobindinas/metabolismo , Nucleobindinas/genética , Animais , Valva Aórtica/patologia , Valva Aórtica/metabolismo , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/genética , Calcinose/metabolismo , Calcinose/patologia , Calcinose/genética , Estenose da Valva Aórtica/metabolismo , Estenose da Valva Aórtica/patologia , Estenose da Valva Aórtica/genética , Superóxido Dismutase/metabolismo , Superóxido Dismutase/genética , Humanos , Proteínas de Transporte de Cátions/metabolismo , Proteínas de Transporte de Cátions/genética , Glutationa/metabolismo , Masculino , Osteogênese/efeitos dos fármacos , Osteogênese/genética , Camundongos , Ratos , Proteínas de Ligação a DNA/metabolismo , Proteínas de Ligação a DNA/genética , Osteoblastos/metabolismo , Osteoblastos/patologia , Osteoblastos/efeitos dos fármacos , Modelos Animais de Doenças , Diferenciação Celular , Proteínas de Ligação ao Cálcio/metabolismo , Proteínas de Ligação ao Cálcio/genéticaRESUMO
The prevalence of calcific aortic valve disease (CAVD) remains substantial while there is currently no medical therapy available. Forkhead box O1 (FOXO1) is known to be involved in the pathogenesis of cardiovascular diseases, including vascular calcification and atherosclerosis; however, its specific role in calcific aortic valve disease remains to be elucidated. In this study, we identified FOXO1 significantly down-regulated in the aortic valve interstitial cells (VICs) of calcified aortic valves by investigating clinical specimens and GEO database analysis. FOXO1 silencing or inhibition promoted VICs osteogenic differentiation in vitro and aortic valve calcification in Apoe-/- mice, respectively. We identified that FOXO1 facilitated the ubiquitination and degradation of RUNX2, which process was mainly mediated by SMAD-specific E3 ubiquitin ligase 2 (SMURF2). Our discoveries unveil a heretofore unacknowledged mechanism involving the FOXO1/SMURF2/RUNX2 axis in CAVD, thereby proposing the potential therapeutic utility of FOXO1 or SMURF2 as viable strategies to impede the progression of CAVD.
Assuntos
Estenose da Valva Aórtica , Valva Aórtica , Calcinose , Subunidade alfa 1 de Fator de Ligação ao Core , Proteína Forkhead Box O1 , Ubiquitina-Proteína Ligases , Ubiquitinação , Proteína Forkhead Box O1/metabolismo , Proteína Forkhead Box O1/genética , Animais , Valva Aórtica/metabolismo , Valva Aórtica/patologia , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Camundongos , Humanos , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina-Proteína Ligases/genética , Calcinose/metabolismo , Calcinose/patologia , Calcinose/genética , Estenose da Valva Aórtica/metabolismo , Estenose da Valva Aórtica/patologia , Estenose da Valva Aórtica/genética , Masculino , Osteogênese/genética , Modelos Animais de Doenças , Diferenciação CelularRESUMO
Background: Matrix metalloproteinase (MMP) enzyme gene polymorphisms MMP-2-1575G/A and MMP-9-1562C/T promoter polymorphism, their serum levels, and activity are associated with aortic valve calcification (AVC). Materials and Methods: The synergistic link between the risk of AVC and the alleles T and A of MMP-9 and MMP-2 was investigated, respectively. Ninety-two cases with AVC and 92 healthy individuals from the west of Iran were included, and MMP- 2-1575G/A and MMP-9-1562C/T promoter polymorphisms were detected using PCR-RFLP. The serum levels and activity of MMP-2 and -9 were assessed using ELISA and gelatin zymography methods, respectively. In addition, serum biochemical markers, including FBS, urea and creatinine, cholesterol, triglyceride, HDL, LDL, calcium, phosphorus, and blood pressure: systolic blood pressure and diastolic blood pressure were measured. Results: Heart valve calcification disease was associated with a comparatively higher frequency of the A allele of the MMP2-1575 variation (p = 0.002). In addition, the frequency of T allele of the MMP9-1562 variant was higher than the control group (p = 0.007). Conclusion: MMP-2 and MMP-9 serum levels and activities were observed to be considerably higher in the experimental group than in the control group (p < 0.001). Patients are more susceptible to cardiovascular disease than the control group due to elevated serum levels and activity of MMP-2 and MMP-9.
Assuntos
Estenose da Valva Aórtica , Valva Aórtica , Calcinose , Predisposição Genética para Doença , Metaloproteinase 2 da Matriz , Metaloproteinase 9 da Matriz , Regiões Promotoras Genéticas , Humanos , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/sangue , Calcinose/genética , Calcinose/sangue , Feminino , Masculino , Irã (Geográfico) , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/sangue , Valva Aórtica/patologia , Regiões Promotoras Genéticas/genética , Pessoa de Meia-Idade , Estenose da Valva Aórtica/genética , Estenose da Valva Aórtica/sangue , Polimorfismo de Nucleotídeo Único/genética , Idoso , Adulto , Alelos , Estudos de Casos e Controles , Frequência do Gene/genética , Doenças das Valvas Cardíacas/genética , Doenças das Valvas Cardíacas/sangue , GenótipoRESUMO
Calcific aortic valve stenosis (CAVS) is characterized by increasing inflammation and progressive calcification in the aortic valve leaflets and is a major cause of death in the aging population. This study aimed to identify the inflammatory proteins involved in CAVS and provide potential therapeutic targets. We investigated the observational and causal associations of 92 inflammatory proteins, which were measured using affinity-based proteomic assays. Firstly, the case-control cohort identified differential proteins associated with the occurrence and progression of CAVS. Subsequently, we delved into exploring the causal impacts of these associated proteins through Mendelian randomization. This involved utilizing genetic instruments derived from cis-protein quantitative loci identified in genome-wide association studies, encompassing a cohort of over 400,000 individuals. Finally, we investigated the gene transcription and protein expression levels of inflammatory proteins by single-cell and immunohistochemistry analysis. Multivariate logistic regression and spearman's correlation analysis showed that five proteins showed a significant positive correlation with disease severity. Mendelian randomization showed that elevated levels of two proteins, namely, matrix metallopeptidase-1 (MMP1) and sirtuin 2 (SIRT2), were associated with an increased risk of CAVS. Immunohistochemistry and single-cell transcriptomes showed that expression levels of MMP1 and SIRT2 at the tissue and cell levels were significantly higher in calcified valves than in non-calcified control valves. These findings indicate that MMP1 and SIRT2 are causally related to CAVS and open up the possibility for identifying novel therapeutic targets.
Assuntos
Estenose da Valva Aórtica , Valva Aórtica , Valva Aórtica/patologia , Biomarcadores , Calcinose , Mediadores da Inflamação , Metaloproteinase 1 da Matriz , Análise da Randomização Mendeliana , Proteômica , Humanos , Estenose da Valva Aórtica/metabolismo , Estenose da Valva Aórtica/sangue , Estenose da Valva Aórtica/patologia , Estenose da Valva Aórtica/genética , Calcinose/genética , Calcinose/metabolismo , Calcinose/sangue , Calcinose/patologia , Valva Aórtica/metabolismo , Masculino , Feminino , Idoso , Estudos de Casos e Controles , Biomarcadores/sangue , Mediadores da Inflamação/metabolismo , Mediadores da Inflamação/sangue , Metaloproteinase 1 da Matriz/genética , Metaloproteinase 1 da Matriz/metabolismo , Pessoa de Meia-Idade , Fatores de Risco , Índice de Gravidade de Doença , Idoso de 80 Anos ou mais , Predisposição Genética para Doença , Proteínas Sanguíneas/genética , Proteínas Sanguíneas/análise , FenótipoAssuntos
Estenose da Valva Aórtica , Valva Aórtica , Calcinose , MicroRNAs , RNA Longo não Codificante , RNA Longo não Codificante/genética , MicroRNAs/genética , Humanos , Calcinose/genética , Valva Aórtica/diagnóstico por imagem , Valva Aórtica/patologia , Valva Aórtica/cirurgia , Estenose da Valva Aórtica/genética , Estenose da Valva Aórtica/cirurgia , Masculino , Animais , FemininoRESUMO
AIMS: Cohort studies have demonstrated associations between calcific aortic valve disease (CAVD) and Lp(a). As Lp(a) is almost entirely genetically determined, in this study, we aim to determine whether Lp(a), when predicted from genetic data, is associated with CAVD and major adverse cardiovascular events (MACEs). METHODS AND RESULTS: Patients undergoing coronary angiography between January 2012 and May 2013 were invited to participate in the study. Of 752 analysable participants, 446 had their Lp(a) measured and 703 had a calculable LPA genetic risk score (GRS). The primary outcomes were the presence of CAVD at baseline and MACE over a 7-year follow-up. The GRS explained 45% of variation in Lp(a). After adjustment for cardiac risk factors and coronary artery disease (CAD), the odds of CAVD increased with increasing Lp(a) [odds ratio (OR) 1.039 per 10-unit increase, 95% confidence interval (CI) 1.022-1.057, P < 0.001] and GRS (OR 1.054 per 10-unit increase, 95% CI 1.024-1.086; P < 0.001). Lipoprotein(a) and the GRS as continuous variables were not associated with subsequent MACEs. A dichotomized GRS (>54) was associated with MACE, but this relationship became non-significant when CAD classification was added into the model (OR 1.333, 95% CI 0.927-1.912; P = 0.12). CONCLUSION: An LPA GRS can explain 45% of variation in Lp(a) levels, and both Lp(a) and the GRS are associated with CAVD. An elevated GRS is associated with future cardiac events in a secondary risk setting, but, if the CAD status is known, it does not provide additional prognostic information.
Lipoprotein (a) [Lp(a)] is a type of cholesterol that is determined almost entirely by genetics. It is associated with heart disease and also stiffening of the heart valves. Recent advancements have made it possible to predict Lp(a) levels by analysing a person's DNA. This study examines the association between genetically predicted Lp(a) and adverse outcomes.Genetically predicted Lp(a) accounts for 45% of the variability in the actual Lp(a) level.Both actual and genetically predicted Lp(a) are associated with heart valve disease and adverse heart outcomes. If the degree of narrowing of the arteries in the heart is already known, genetically predicted Lp(a) does not help further predict risk.
Assuntos
Estenose da Valva Aórtica , Valva Aórtica , Calcinose , Estratificação de Risco Genético , Lipoproteína(a) , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valva Aórtica/diagnóstico por imagem , Valva Aórtica/patologia , Estenose da Valva Aórtica/genética , Estenose da Valva Aórtica/diagnóstico por imagem , Estenose da Valva Aórtica/epidemiologia , Calcinose/genética , Calcinose/diagnóstico por imagem , Angiografia Coronária , Lipoproteína(a)/sangue , Lipoproteína(a)/genética , Prognóstico , Medição de Risco , Fatores de TempoRESUMO
BACKGROUND: Large observational studies have demonstrated a clear inverse association between renal function and risk of aortic stenosis (AS). Whether this represents a causal, reverse causal or correlative relationship remains unclear. We investigated this using a bidirectional 2-sample Mendelian randomization approach. METHODS AND RESULTS: We collected summary statistics for the primary analysis of chronic kidney disease (CKD) and AS from genome-wide association study meta-analyses including 480 698 and 653 867 participants, respectively. We collected further genome-wide association study summary statistics from up to 1 004 040 participants for sensitivity analyses involving estimated glomerular filtration rate (eGFR) derived from creatinine, eGFR derived from cystatin C, and serum urea nitrogen. Inverse-variance weighted was the primary analysis method, with weighted-median, weighted-mode, Mendelian randomization-Egger, and Mendelian randomization-Pleiotropy Residual Sum and Outlier as sensitivity analyses. We did not find evidence of a causal relationship between genetically predicted CKD liability as the exposure and AS as the outcome (odds ratio [OR], 0.94 per unit increase in log odds of genetic liability to CKD [95% CI, 0.85-1.04], P=0.26) nor robust evidence of AS liability as the exposure and CKD as the outcome (OR, 1.04 per unit increase in log odds of genetic liability to AS [95% CI, 0.97-1.12], P=0.30). The sensitivity analyses were neutral overall, as were the analyses using eGFR derived from creatinine, eGFR derived from cystatin C, and serum urea nitrogen. All positive controls demonstrated strong significant associations. CONCLUSIONS: The present study did not find evidence of a substantial effect of genetically predicted renal impairment on risk of AS. This has important implications for research efforts that attempt to identify prevention and treatment targets for both CKD and AS.
Assuntos
Estenose da Valva Aórtica , Estudo de Associação Genômica Ampla , Taxa de Filtração Glomerular , Análise da Randomização Mendeliana , Insuficiência Renal Crônica , Humanos , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/fisiopatologia , Insuficiência Renal Crônica/epidemiologia , Taxa de Filtração Glomerular/genética , Estenose da Valva Aórtica/genética , Estenose da Valva Aórtica/fisiopatologia , Cistatina C/sangue , Cistatina C/genética , Fatores de Risco , Rim/fisiopatologia , Predisposição Genética para Doença , Creatinina/sangue , Medição de Risco , Polimorfismo de Nucleotídeo Único , Biomarcadores/sangue , Nitrogênio da Ureia SanguíneaRESUMO
Calcific aortic valve disease (CAVD) and osteoarthritis (OA) are common diseases in the ageing population and share similar pathogenesis, especially in inflammation. This study aims to discover potential diagnostic and therapeutic targets in patients with CAVD and OA. Three CAVD datasets and one OA dataset were obtained from the Gene Expression Omnibus database. We used bioinformatics methods to search for key genes and immune infiltration, and established a ceRNA network. Immunohistochemical staining was performed to verify the expression of candidate genes in human and mice aortic valve tissues. Two key genes obtained, leucine rich repeat containing 15 (LRRC15) and secreted phosphoprotein 1 (SPP1), were further screened using machine learning and verified in human and mice aortic valve tissues. Compared to normal tissues, the infiltration of immune cells in CAVD tissues was significantly higher, and the expressions of LRRC15 and SPP1 were positively correlated with immune cells infiltration. Moreover, the ceRNA network showed extensive regulatory interactions based on LRRC15 and SPP1. The authors' findings identified LRRC15 and SPP1 as hub genes in immunological mechanisms during CAVD and OA initiation and progression, as well as potential targets for drug development.
Assuntos
Estenose da Valva Aórtica , Valva Aórtica , Calcinose , Biologia Computacional , Osteoartrite , Osteopontina , Animais , Humanos , Camundongos , Valva Aórtica/patologia , Valva Aórtica/metabolismo , Valvopatia Aórtica/genética , Valvopatia Aórtica/metabolismo , Estenose da Valva Aórtica/genética , Estenose da Valva Aórtica/metabolismo , Estenose da Valva Aórtica/patologia , Calcinose/genética , Calcinose/metabolismo , Calcinose/patologia , Redes Reguladoras de Genes , Osteoartrite/genética , Osteoartrite/metabolismo , Osteoartrite/patologia , Osteopontina/genética , Osteopontina/metabolismoRESUMO
Aortic stenosis (AS) and hypertrophic cardiomyopathy (HCM) are distinct disorders leading to left ventricular hypertrophy (LVH), but whether cardiac metabolism substantially differs between these in humans remains to be elucidated. We undertook an invasive (aortic root, coronary sinus) metabolic profiling in patients with severe AS and HCM in comparison with non-LVH controls to investigate cardiac fuel selection and metabolic remodeling. These patients were assessed under different physiological states (at rest, during stress induced by pacing). The identified changes in the metabolome were further validated by metabolomic and orthogonal transcriptomic analysis, in separately recruited patient cohorts. We identified a highly discriminant metabolomic signature in severe AS in all samples, regardless of sampling site, characterized by striking accumulation of long-chain acylcarnitines, intermediates of fatty acid transport across the inner mitochondrial membrane, and validated this in a separate cohort. Mechanistically, we identify a downregulation in the PPAR-α transcriptional network, including expression of genes regulating fatty acid oxidation (FAO). In silico modeling of ß-oxidation demonstrated that flux could be inhibited by both the accumulation of fatty acids as a substrate for mitochondria and the accumulation of medium-chain carnitines which induce competitive inhibition of the acyl-CoA dehydrogenases. We present a comprehensive analysis of changes in the metabolic pathways (transcriptome to metabolome) in severe AS, and its comparison to HCM. Our results demonstrate a progressive impairment of ß-oxidation from HCM to AS, particularly for FAO of long-chain fatty acids, and that the PPAR-α signaling network may be a specific metabolic therapeutic target in AS.
Assuntos
Estenose da Valva Aórtica , Cardiomiopatia Hipertrófica , Humanos , Receptores Ativados por Proliferador de Peroxissomo , Cardiomiopatia Hipertrófica/genética , Hipertrofia Ventricular Esquerda/genética , Estenose da Valva Aórtica/genética , Ácidos Graxos/metabolismoRESUMO
Calcific aortic valve disease (CAVD) is a heart valve disorder characterized primarily by calcification of the aortic valve, resulting in stiffness and dysfunction of the valve. CAVD is prevalent among aging populations and is linked to factors such as hypertension, dyslipidemia, tobacco use, and genetic predisposition, and can result in becoming a growing economic and health burden. Once aortic valve calcification occurs, it will inevitably progress to aortic stenosis. At present, there are no medications available that have demonstrated effectiveness in managing or delaying the progression of the disease. In this study, we mined four publicly available microarray datasets (GSE12644 GSE51472, GSE77287, GSE233819) associated with CAVD from the GEO database with the aim of identifying hub genes associated with the occurrence of CAVD and searching for possible biological targets for the early prevention and diagnosis of CAVD. This study provides preliminary evidence for therapeutic and preventive targets for CAVD and may provide a solid foundation for subsequent biological studies.
Assuntos
Estenose da Valva Aórtica , Valva Aórtica/patologia , Calcinose , Doenças das Valvas Cardíacas , Humanos , Estenose da Valva Aórtica/genética , Estenose da Valva Aórtica/diagnóstico , Estenose da Valva Aórtica/epidemiologia , Doenças das Valvas Cardíacas/genética , Calcinose/genéticaRESUMO
There is currently no medical therapy to prevent calcific aortic valve stenosis (CAVS). Multi-omics approaches could lead to the identification of novel molecular targets. Here, we perform a genome-wide association study (GWAS) meta-analysis including 14,819 cases among 941,863 participants of European ancestry. We report 32 genomic loci, among which 20 are novel. RNA sequencing of 500 human aortic valves highlights an enrichment in expression regulation at these loci and prioritizes candidate causal genes. Homozygous genotype for a risk variant near TWIST1, a gene involved in endothelial-mesenchymal transition, has a profound impact on aortic valve transcriptomics. We identify five genes outside of GWAS loci by combining a transcriptome-wide association study, colocalization, and Mendelian randomization analyses. Using cross-phenotype and phenome-wide approaches, we highlight the role of circulating lipoproteins, blood pressure and inflammation in the disease process. Our findings pave the way for the development of novel therapies for CAVS.
Assuntos
Estenose da Valva Aórtica , Valva Aórtica , Valva Aórtica/patologia , Calcinose , Humanos , Valva Aórtica/metabolismo , Estudo de Associação Genômica Ampla , Estenose da Valva Aórtica/genética , GenômicaRESUMO
The senescence of aortic valve interstitial cells (VICs) plays a critical role in the progression of calcific aortic valve disease (CAVD). However, the precise mechanisms underlying the senescence of VICs remain unclear, demanding the identification of a novel target to mitigate this process. Previous studies have highlighted the anti-aging potential of morusin. Thus, this study aimed to explore the therapeutic potential of morusin in CAVD. Cellular experiments reveal that morusin effectively suppresses cellular senescence and cause a shift toward osteogenic differentiation of VICs in vitro. Mechanistically, morusin activate the Nrf2-mediated antiaging signaling pathway by downregulating CCND1 expression and aiding Keap1 degradation through Trim 25. This activation lead to the upregulated expression of antioxidant genes, thus reducing reactive oxygen species production and thereby preventing VIC osteogenic differentiation. In vivo experiments in ApoE-/- mice on a high-fat Western diet demonstrate the positive effect of morusin in mitigating aortic valve calcification. These findings emphasize the antiaging properties of morusin and its potential as a therapeutic agent for CAVD.
Assuntos
Estenose da Valva Aórtica , Calcinose , Senescência Celular , Flavonoides , Transdução de Sinais , Animais , Humanos , Masculino , Camundongos , Valva Aórtica/metabolismo , Valva Aórtica/patologia , Estenose da Valva Aórtica/metabolismo , Estenose da Valva Aórtica/genética , Estenose da Valva Aórtica/patologia , Calcinose/metabolismo , Calcinose/genética , Senescência Celular/efeitos dos fármacos , Ciclina D1/metabolismo , Ciclina D1/genética , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Fator 2 Relacionado a NF-E2/metabolismo , Fator 2 Relacionado a NF-E2/genética , Osteogênese/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Flavonoides/administração & dosagemRESUMO
Calcific aortic valve disease (CAVD) is a progressive cardiovascular disorder involving multiple pathogenesis. Effective pharmacological therapies are currently unavailable. Sirtuin6 (SIRT6) has been shown to protect against aortic valve calcification in CAVD. The exact regulatory mechanism of SIRT6 in osteoblastic differentiation remains to be determined, although it inhibits osteogenic differentiation of aortic valve interstitial cells. We demonstrated that SIRT6 was markedly downregulated in calcific human aortic valves. Mechanistically, SIRT6 suppressed osteogenic differentiation in human aortic valve interstitial cells (HAVICs), as confirmed by loss- and gain-of-function experiments. SIRT6 directly interacted with Runx2, decreased Runx2 acetylation levels, and facilitated Runx2 nuclear export to inhibit the osteoblastic phenotype transition of HAVICs. In addition, the AKT signaling pathway acted upstream of SIRT6. Together, these findings elucidate that SIRT6-mediated Runx2 downregulation inhibits aortic valve calcification and provide novel insights into therapeutic strategies for CAVD.
Assuntos
Estenose da Valva Aórtica , Valva Aórtica/patologia , Calcinose , Sirtuínas , Humanos , Valva Aórtica/metabolismo , Regulação para Baixo , Osteogênese/genética , Células Cultivadas , Estenose da Valva Aórtica/genética , Estenose da Valva Aórtica/metabolismo , Estenose da Valva Aórtica/patologia , Sirtuínas/genética , Sirtuínas/metabolismoRESUMO
Importance: Polygenic risk scores (PRSs) have proven to be as strong as or stronger than established clinical risk factors for many cardiovascular phenotypes. Whether this is true for aortic stenosis remains unknown. Objective: To develop a novel aortic stenosis PRS and compare its aortic stenosis risk estimation to established clinical risk factors. Design, Setting, and Participants: This was a longitudinal cohort study using data from the Million Veteran Program (MVP; 2011-2020), UK Biobank (2006-2010), and 6 Thrombolysis in Myocardial Infarction (TIMI) trials, including DECLARE-TIMI 58 (2013-2018), FOURIER (TIMI 59; 2013-2017), PEGASUS-TIMI 54 (2010-2014), SAVOR-TIMI 53 (2010-2013), SOLID-TIMI 52 (2009-2014), and ENGAGE AF-TIMI 48 (2008-2013), which were a mix of population-based and randomized clinical trials. Individuals from UK Biobank and the MVP meeting a previously validated case/control definition for aortic stenosis were included. All individuals from TIMI trials were included unless they had a documented preexisting aortic valve replacement. Analysis took place from January 2022 to December 2023. Exposures: PRS for aortic stenosis (developed using data from MVP and validated in UK Biobank) and other previously validated cardiovascular PRSs, defined either as a continuous variable or as low (bottom 20%), intermediate, and high (top 20%), and clinical risk factors. Main Outcomes: Aortic stenosis (defined using International Classification of Diseases or Current Procedural Terminology codes in UK Biobank and MVP or safety event data in the TIMI trials). Results: The median (IQR) age in MVP was 67 (57-73) years, and 135â¯140 of 147â¯104 participants (92%) were male. The median (IQR) age in the TIMI trials was 66 (54-78) years, and 45â¯524 of 59â¯866 participants (71%) were male. The best aortic stenosis PRS incorporated 5â¯170â¯041 single-nucleotide variants and was associated with aortic stenosis in both the MVP testing sample (odds ratio, 1.41; 95% CI, 1.37-1.45 per 1 SD PRS; P = 4.6 × 10-116) and TIMI trials (hazard ratio, 1.44; 95% CI, 1.27-1.62 per 1 SD PRS; P = 3.2 × 10-9). Among genetic and clinical risk factors, the aortic stenosis PRS performed comparably to most risk factors besides age, and within a given age range, the combination of clinical and genetic risk factors was additive, providing a 3- to 4-fold increased gradient of risk of aortic stenosis. However, the addition of the aortic stenosis PRS to a model including clinical risk factors only improved risk discrimination of aortic stenosis by 0.01 to 0.02 (C index in MVP: 0.78 with clinical risk factors, 0.79 with risk factors and aortic stenosis PRS; C index in TIMI: 0.71 with clinical risk factors, 0.73 with risk factors and aortic stenosis PRS). Conclusions: This study developed and validated 1 of the first aortic stenosis PRSs. While aortic stenosis genetic risk was independent from clinical risk factors and performed comparably to all other risk factors besides age, genetic risk resulted in only a small improvement in overall aortic stenosis risk discrimination beyond age and clinical risk factors. This work sets the stage for further development of an aortic stenosis PRS.
Assuntos
Estenose da Valva Aórtica , Infarto do Miocárdio , Humanos , Masculino , Idoso , Feminino , Estratificação de Risco Genético , Estudos Longitudinais , Predisposição Genética para Doença , Fatores de Risco , Estenose da Valva Aórtica/genéticaRESUMO
Background: The mechanism and medical treatment target for degenerative aortic valve disease, including aortic stenosis, is not well studied. In this study, we investigated the effect of clonal hematopoiesis of indeterminate potential (CHIP) on the development of aortic valve sclerosis (AVS), a calcified aortic valve without significant stenosis. Methods: Participants with AVS (valves ≥2 mm thick, high echogenicity, and a peak transaortic velocity of <2.5 m/sec) and an age- and sex-matched control group were enrolled. Twenty-four CHIP genes with common variants in cardiovascular disease were used to generate a next-generation sequencing panel. The primary endpoint was the CHIP detection rate between the AVS and control groups. Inverse-probability treatment weighting (IPTW) analysis was performed to adjust for differences in baseline characteristics. Results: From April 2020 to April 2022, 187 participants (125 with AVS and 62 controls) were enrolled; the mean age was 72.6±8.5 yrs, and 54.5% were male. An average of 1.3 CHIP variants was observed. CHIP detection, defined by a variant allele frequency (VAF) of ≥0.5%, was similar between the groups. However, the AVS group had larger CHIP clones: 49 (39.2%) participants had a VAF of ≥1% (vs. 13 [21.0%] in the control group; P=0.020), and 25 (20.0%) had a VAF of ≥2% (vs. 4 [6.5%]; P=0.028). AVS is independently associated with a VAF of ≥1% (adjusted odds ratio: 2.44, 95% confidence interval: 1.11-5.36; P=0.027). This trend was concordant and clearer in the IPTW cohort. Conclusions: Participants with AVS more commonly had larger CHIP clones than age- and sex-matched controls. Further studies are warranted to identify causality between AVS and CHIP.