RNA Expression Profile of Calcified Bicuspid, Tricuspid and Normal Human Aortic Valves by RNA Sequencing
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE76718 | GEO | 2016/09/22
SECONDARY ACCESSION(S): PRJNA308447
REPOSITORIES: GEO
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Project description:The molecular mechanisms leading to premature development of aortic valve stenosis (AS) in individuals with a bicuspid aortic valve are unknown. The objective of this study was to identify genes differentially expressed between calcified bicuspid aortic valves (BAVc) and tricuspid valves with (TAVc) and without (TAVn) AS using RNA sequencing (RNA-Seq). We collected 10 human BAVc and nine TAVc from men who underwent primary aortic valve replacement. Eight TAVn were obtained from men who underwent heart transplantation. mRNA levels were measured by RNA-Seq and compared between valve groups. Two genes were upregulated, and none were downregulated in BAVc compared with TAVc, suggesting a similar gene expression response to AS in individuals with bicuspid and tricuspid valves. There were 462 genes upregulated and 282 downregulated in BAVc compared with TAVn. In TAVc compared with TAVn, 329 genes were up- and 170 were downregulated. A total of 273 upregulated and 147 downregulated genes were concordantly altered between BAVc vs. TAVn and TAVc vs. TAVn, which represent 56 and 84% of significant genes in the first and second comparisons, respectively. This indicates that extra genes and pathways were altered in BAVc. Shared pathways between calcified (BAVc and TAVc) and normal (TAVn) aortic valves were also more extensively altered in BAVc. The top pathway enriched for genes differentially expressed in calcified compared with normal valves was fibrosis, which support the remodeling process as a therapeutic target. These findings are relevant to understand the molecular basis of AS in patients with bicuspid and tricuspid valves.
| S-EPMC6195654 | biostudies-literature
Project description:The objective of this study was to identify genes differentially expressed between calcified bicuspid aortic valves (BAV) and tricuspid valves with (TAVc) and without (TAVn) aortic valve stenosis. Ten human BAV and nine TAVc were collected from male who underwent primary aortic valve replacement. Eight TAVn were obtained from male who underwent heart transplantation. mRNA levels were measured using Illumina HumanHT-12 v4 Expression BeadChip and compared between valve groups.
2016-09-22 | GSE83453 | GEO
Project description:Purpose: The molecular mechanisms leading to premature development of aortic valve stenosis (AS) in individuals with a bicuspid aortic valve (BAV) are unknown. The objective of this study was to identify genes differentially expressed between calcified BAV and tricuspid valves with (TAVc) and without (TAVn) calcification using RNA sequencing (RNA-Seq). Methods: Ten human calcified BAV and nine TAVc were collected from men who underwent aortic valve replacement. Eight TAVn were obtained from men who underwent heart transplantation. mRNA levels were measured using the Illumina HiSeq 2000 system. Reads were aligned with TopHat. Cuffdiff, DESeq, edgeR, and SAMSeq were used to compare gene expression. Genes with adjusted P < 0.05 in the four methods were called differentially expressed. Pathway analysis was performed with IPA. Results: Two genes were up-regulated and none were down-regulated in BAV compared to TAVc. There were 462 genes up-regulated and 282 down-regulated in BAV compared to TAVn. Compared to TAVn, 329 genes were up- and 170 were down-regulated in TAVc. Conclusions: This is the first transcriptome study on calcified and normal aortic valves using RNA-Seq. BAV and TAVc have a highly similar expression profile. These results contribute to our molecular understanding of AS and the identification of new therapeutic targets that are urgently needed to prevent, slow the development or treat AS in patients with bicuspid and tricuspid valves.
2016-09-22 | GSE76717 | GEO
Project description:Purpose: The molecular mechanisms leading to premature development of aortic valve stenosis (AS) in individuals with a bicuspid aortic valve (BAV) are unknown. The objective of this study was to identify genes differentially expressed between calcified BAV and tricuspid valves with (TAVc) and without (TAVn) calcification using RNA sequencing (RNA-Seq). Methods: Ten human calcified BAV and nine TAVc were collected from men who underwent aortic valve replacement. Eight TAVn were obtained from men who underwent heart transplantation. mRNA levels were measured using the Illumina HiSeq 2000 system. Reads were aligned with TopHat. Cuffdiff, DESeq, edgeR, and SAMSeq were used to compare gene expression. Genes with adjusted P < 0.05 in the four methods were called differentially expressed. Pathway analysis was performed with IPA. Results: Two genes were up-regulated and none were down-regulated in BAV compared to TAVc. There were 462 genes up-regulated and 282 down-regulated in BAV compared to TAVn. Compared to TAVn, 329 genes were up- and 170 were down-regulated in TAVc. Conclusions: This is the first transcriptome study on calcified and normal aortic valves using RNA-Seq. BAV and TAVc have a highly similar expression profile. These results contribute to our molecular understanding of AS and the identification of new therapeutic targets that are urgently needed to prevent, slow the development or treat AS in patients with bicuspid and tricuspid valves.
2016-09-22 | GSE76712 | GEO
Project description:Purpose: Calcific aortic valve stenosis (AS) is a fatal disease with currently no medical therapy. Some genes were associated with AS, but the genetic architecture of the disease has yet to be discovered. The objective of this study was to combine genome-wide association studies (GWAS) and gene expression in human valve tissues to identify new susceptibility genes of AS. Methods: A meta-analysis was performed combining the results of two independent GWAS in 474 patients that underwent aortic valve replacement from Quebec city and 486 echocardiography cases from France. The controls consisted of 3,151 publically available individuals of European ancestry. Sixty-nine SNPs selected from the meta-analysis (p < 1 x 10-4) were followed-up for replication in a third cohort of 395 cases and 404 controls. Single marker and gene set association analyses were performed. The mRNA expression levels of susceptibility genes were evaluated in 19 human aortic valves with (n=9) and without (n=10) AS by RNA sequencing. Results: Single marker analysis identified 15 SNPs with p values lower than 1 x 10-6 in the meta-analysis near the FAR2 gene on chromosome 12. At the replication stage, none of these SNPs were confirmed and three other SNPs on chromosomes 2 and 5 reached p < 0.05. Gene set analysis revealed more meaningful association with the calcium signaling pathway enriched for genes mapped to disease-associated SNPs. Genes in this pathway including F2R, GNA14, HTR4, P2RX6, and TNNC1 were found differentially expressed in valves with and without AS. Conclusions: This integrative genomic study identified new AS susceptibility genes expressed in human valve tissue. Moderate but coordinated genetic association and expression patterns were observed for genes implicated in the calcium signaling pathway and may provide new therapeutic targets to treat this frequent and rising life-threatening disease. Samples of aortic valves were collected from 19 male patients undergoing aortic valve replacement surgery. RNA sequencing was performed using the Illumina Hiseq 2000. Three pairwise comparison among the two kind of valves were made.
2015-12-09 | E-GEOD-55492 | biostudies-arrayexpress
Project description:Purpose: Calcific aortic valve stenosis (AS) is a fatal disease with currently no medical therapy. Some genes were associated with AS, but the genetic architecture of the disease has yet to be discovered. The objective of this study was to combine genome-wide association studies (GWAS) and gene expression in human valve tissues to identify new susceptibility genes of AS. Methods: A meta-analysis was performed combining the results of two independent GWAS in 474 patients that underwent aortic valve replacement from Quebec city and 486 echocardiography cases from France. The controls consisted of 3,151 publically available individuals of European ancestry. Sixty-nine SNPs selected from the meta-analysis (p < 1 x 10-4) were followed-up for replication in a third cohort of 395 cases and 404 controls. Single marker and gene set association analyses were performed. The mRNA expression levels of susceptibility genes were evaluated in 19 human aortic valves with (n=9) and without (n=10) AS by RNA sequencing. Results: Single marker analysis identified 15 SNPs with p values lower than 1 x 10-6 in the meta-analysis near the FAR2 gene on chromosome 12. At the replication stage, none of these SNPs were confirmed and three other SNPs on chromosomes 2 and 5 reached p < 0.05. Gene set analysis revealed more meaningful association with the calcium signaling pathway enriched for genes mapped to disease-associated SNPs. Genes in this pathway including F2R, GNA14, HTR4, P2RX6, and TNNC1 were found differentially expressed in valves with and without AS. Conclusions: This integrative genomic study identified new AS susceptibility genes expressed in human valve tissue. Moderate but coordinated genetic association and expression patterns were observed for genes implicated in the calcium signaling pathway and may provide new therapeutic targets to treat this frequent and rising life-threatening disease.
2015-12-09 | GSE55492 | GEO
Project description:RNA Expression Profile of Calcified Bicuspid, Tricuspid and Normal Human Aortic Valves by RNA Sequencing
| PRJNA308447 | ENA
Project description:OBJECTIVE:To determine whether the leaflets of bicuspid aortic valve (BAV) experience increased strain when compared to tricuspid aortic valve (TAV) leaflets. BACKGROUND:The population at highest risk of aortic valve calcification (AVC) are individuals with BAVs. Currently, efforts to medically treat AVC are hampered by a limited understanding of the biomechanical forces involved in the molecular pathogenesis of AVC. METHODS:Surgically created BAVs and control TAVs were placed into a left heart simulator. Strains were calculated by comparing the distances between points on the aortic valve (AoV) leaflet during various time points during a simulated cardiac cycle. RESULTS:The fused leaflets of BAVs experience significantly more strain during systole when compared to TAVs. Specifically, BAVs experience 24% strain (P < .0001) in the radial direction, parallel to the direction of blood flow, as compared to TAVs. There was peak difference of 4% (P < .001) in the circumferential direction. DISCUSSION:Based upon the data presented here, we are in the process of identifying how increased strain activates calcification-associated pathways in AoV cells. Future studies will examine whether these stretch responsive pathways can be blocked to inhibit calcification of BAVs.
| S-EPMC6261454 | biostudies-other
Project description:ObjectiveTo determine long-term survival and reoperation rate in patients with a bicuspid aortic valve (BAV) and patients with a tricuspid aortic valve (TAV) after stentless aortic valve replacement (AVR)/aortic root replacement (ARR).MethodsBetween 1992 and 2014, 1293 patients underwent first AVR/ARR with a stentless aortic valve using the modified inclusion operating technique, including 741 patients with a TAV and 552 with a BAV. Using propensity scoring with 26 variables, 330 matched pairs were identified with AVR with or without ascending aorta/arch replacement. Data were obtained through chart review, surveys, and the National Death Index.ResultsPatient demographics were similar in the propensity score-matched groups. Both groups had similar cardiopulmonary bypass, cross-clamp, and hypothermia circulatory arrest times, cerebral protection strategies, and rate of aortic arch replacement. The median size of implanted valves was similar (BAV: 27 mm [range, 25-29 mm] vs TAV: 27 mm [range, 25-27 mm]). Compared with the TAV group, the BAV group had a shorter hospital stay (6 days vs 7 days; P = .001) but similar 30-day mortality (1.8% vs 1.2%). The BAV group had better long-term (15-year) survival (46% vs 33%; P = .002) but a higher cumulative incidence of reoperation for structural valve deterioration (15-year: 15% vs 11%; P = .048). Cox proportional hazard analysis identified a BAV as a protective factor for long-term mortality (hazard ratio [HR], 0.71; 95% CI, 0.56-0.91; P = .006), but a risk factor for reoperation due to structural valve deterioration (HR, 1.4 [95% CI, 0.8-2.6; P = .27] in the matched cohort and 2.2 [95% CI, 1.3-3.7; P = .004] in the unmatched cohort).ConclusionsThe BAV patients had better long-term survival but a higher reoperation rate compared with TAV patients after stentless AVR. Our findings suggest caution in the use of bioprostheses for BAV patients.
| S-EPMC9390591 | biostudies-literature
Project description:ObjectiveTo determine the long-term survival and rate of reoperation after surgical treatment of infective endocarditis (IE) in patients with a bicuspid aortic valve (BAV) and patients with a tricuspid aortic valve (TAV).MethodsBetween 1997 and 2017, 210 patients underwent surgical treatment for native aortic valve endocarditis, including 51 patients with BAV (24%) and 159 patients with TAV (76%). Data were obtained from the Society of Thoracic Surgeons data warehouse and hospital medical record review, supplemented with surveys and national death index data for more complete follow-up.ResultsCompared with the TAV IE group, the BAV IE group was significantly younger (42 years vs 54 years) and had lower incidence rates of hypertension, coronary artery disease, and congestive heart failure (CHF). There were no significant between-group differences in postoperative stroke, sepsis, pacemaker requirement, or in-hospital mortality (2.0% vs 4.4%). Liver disease was a risk factor for operative mortality (odds ratio [OR], 13; 95% CI, 3.3-30; P = .0002). The 10-year survival rate was 64% for the BAV group versus 46% for the TAV group (P = .0191). Significant risk factors for long-term mortality were intravenous drug use (hazard ratio [HR], 4.5; P < .0001), preoperative renal failure requiring dialysis (HR, 4.13; P < .0001), CHF (HR, 1.7; P = .04), and liver disease (HR, 2.6; P = .02). The HR for BAV was 0.67 (95% confidence interval [CI], 0.3-1.4). The 10-year postoperative cumulative incidence of reoperation was significantly higher in the BAV patients compared with the TAV patients (5.7% vs 4.5%; P = .045) with an HR of 2.4 (95% CI, 0.8-7.1; P = .11) for BAV.ConclusionsBAV patients develop IE requiring surgery at a younger age than TAV patients, but have significantly better long-term survival. Early detection of BAV is important to prevent IE and provide aggressive surgical treatment should IE occur.
| S-EPMC9390515 | biostudies-literature