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Critical Role of Coaptive Strain in Aortic Valve Leaflet Homeostasis: Use of a Novel Flow Culture Bioreactor to Explore Heart Valve Mechanobiology

View Article: PubMed Central - PubMed

ABSTRACT

Background: Aortic valve (AV) disease presents critical situations requiring surgery in over 2% of the US population and is increasingly the reason for cardiac surgery. Throughout the AV cycle, mechanical forces of multiple types and varying intensities are exerted on valve leaflets. The mechanisms whereby forces regulate leaflet homeostasis are incompletely understood. We used a novel flow bioreactor culture to investigate alteration of AV opening or closure on leaflet genes.

Methods and results: Culture of rat AV was conducted in a flow bioreactor for 7 days at 37°C under conditions approximating the normal stroke volume. Three force condition groups were compared: Cycling (n=8); always open (Open; n=3); or always closed (Closed; n=5). From each culture, AV leaflets were pooled by force condition and RNA expression evaluated using microarrays. Hierarchical clustering of 16 transcriptome data sets from the 3 groups revealed only 2 patterns of gene expression: Cycling and Closed groups clustered together, whereas Open AV were different (P<0.05). Sustained AV opening induced marked changes in expression (202 transcripts >2‐fold; P<0.05), whereas Closed AV exhibited similar expression pattern as Cycling (no transcripts >2‐fold; P<0.05). Comparison with human sclerotic and calcific AV transcriptomes demonstrated high concordance of >40 Open group genes with progression toward disease.

Conclusions: Failure of AV to close initiates an extensive response characterized by expression changes common to progression to calcific aortic valve disease. AV coaptation, whether phasic or chronic, preserved phenotypic gene expression. These results demonstrate, for the first time, that coaptation of valve leaflets is a fundamentally important biomechanical cue driving homeostasis.

No MeSH data available.


Related in: MedlinePlus

Integrated analysis of gene expression patterns. The data table (A) indicates the number of differentially regulated transcripts as a function of the fold‐change cut‐off value for the 3 comparison groups. Venn diagrams depict the transcripts with overlapping expression among the 3 culture conditions at a 2‐fold change level (B) and a 4‐fold change level (C) in the study group (1‐way ANOVA corrected P≤0.05). The overlap in the Venn diagrams indicates the transcripts present in both comparisons.
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jah31655-fig-0004: Integrated analysis of gene expression patterns. The data table (A) indicates the number of differentially regulated transcripts as a function of the fold‐change cut‐off value for the 3 comparison groups. Venn diagrams depict the transcripts with overlapping expression among the 3 culture conditions at a 2‐fold change level (B) and a 4‐fold change level (C) in the study group (1‐way ANOVA corrected P≤0.05). The overlap in the Venn diagrams indicates the transcripts present in both comparisons.

Mentions: A summary of the up‐ and downregulated genes and their fold‐change cutoff are listed in Figure 4A. We identified 202 genes in the Open valve group (fold >2.0; P<0.05, t test, followed by Benjamini and Hochberg FDR correction) that were differentially regulated compared with Cycling valves, and 211 genes in Open group versus Closed group comparison (Figure 4A). However, no significant differential expression was observed between the Cycling and Closed groups at the P<0.05 cutoff for >2‐fold difference, indicating significant homogeneity of the 2 groups. Furthermore, the data of Figure 4A confirm the very high degree of overlap in expression values between Cycling and Closed valves. Table S1 lists the gene transcripts expressed >2‐fold in the Open condition compared with the other 2 culture conditions. As shown in the Venn diagrams (Figure 4B and 4C), 190 differentially expressed transcripts were common between these 2 force condition groups (Figure 4B), and the majority of genes were upregulated. When Open valves were compared with either the Closed or Cycling valves, more than 90% of the >2‐fold regulated transcripts were common to both groups. A similar high level of concordance was observed in the subsets of genes expressed at >4‐fold (Figure 4A and 4C) and >10‐fold changes. To further assess the homogeneity of the Closed and Cycling group transcriptomes, we compared the 28 transcripts regulated in the >1.2‐ to <2‐fold change level and confirmed that the few differences between the 2 groups were of no apparent biological significance.


Critical Role of Coaptive Strain in Aortic Valve Leaflet Homeostasis: Use of a Novel Flow Culture Bioreactor to Explore Heart Valve Mechanobiology
Integrated analysis of gene expression patterns. The data table (A) indicates the number of differentially regulated transcripts as a function of the fold‐change cut‐off value for the 3 comparison groups. Venn diagrams depict the transcripts with overlapping expression among the 3 culture conditions at a 2‐fold change level (B) and a 4‐fold change level (C) in the study group (1‐way ANOVA corrected P≤0.05). The overlap in the Venn diagrams indicates the transcripts present in both comparisons.
© Copyright Policy - creativeCommonsBy-nc
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5015277&req=5

jah31655-fig-0004: Integrated analysis of gene expression patterns. The data table (A) indicates the number of differentially regulated transcripts as a function of the fold‐change cut‐off value for the 3 comparison groups. Venn diagrams depict the transcripts with overlapping expression among the 3 culture conditions at a 2‐fold change level (B) and a 4‐fold change level (C) in the study group (1‐way ANOVA corrected P≤0.05). The overlap in the Venn diagrams indicates the transcripts present in both comparisons.
Mentions: A summary of the up‐ and downregulated genes and their fold‐change cutoff are listed in Figure 4A. We identified 202 genes in the Open valve group (fold >2.0; P<0.05, t test, followed by Benjamini and Hochberg FDR correction) that were differentially regulated compared with Cycling valves, and 211 genes in Open group versus Closed group comparison (Figure 4A). However, no significant differential expression was observed between the Cycling and Closed groups at the P<0.05 cutoff for >2‐fold difference, indicating significant homogeneity of the 2 groups. Furthermore, the data of Figure 4A confirm the very high degree of overlap in expression values between Cycling and Closed valves. Table S1 lists the gene transcripts expressed >2‐fold in the Open condition compared with the other 2 culture conditions. As shown in the Venn diagrams (Figure 4B and 4C), 190 differentially expressed transcripts were common between these 2 force condition groups (Figure 4B), and the majority of genes were upregulated. When Open valves were compared with either the Closed or Cycling valves, more than 90% of the >2‐fold regulated transcripts were common to both groups. A similar high level of concordance was observed in the subsets of genes expressed at >4‐fold (Figure 4A and 4C) and >10‐fold changes. To further assess the homogeneity of the Closed and Cycling group transcriptomes, we compared the 28 transcripts regulated in the >1.2‐ to <2‐fold change level and confirmed that the few differences between the 2 groups were of no apparent biological significance.

View Article: PubMed Central - PubMed

ABSTRACT

Background: Aortic valve (AV) disease presents critical situations requiring surgery in over 2% of the US population and is increasingly the reason for cardiac surgery. Throughout the AV cycle, mechanical forces of multiple types and varying intensities are exerted on valve leaflets. The mechanisms whereby forces regulate leaflet homeostasis are incompletely understood. We used a novel flow bioreactor culture to investigate alteration of AV opening or closure on leaflet genes.

Methods and results: Culture of rat AV was conducted in a flow bioreactor for 7&nbsp;days at 37&deg;C under conditions approximating the normal stroke volume. Three force condition groups were compared: Cycling (n=8); always open (Open; n=3); or always closed (Closed; n=5). From each culture, AV leaflets were pooled by force condition and RNA expression evaluated using microarrays. Hierarchical clustering of 16 transcriptome data sets from the 3 groups revealed only 2 patterns of gene expression: Cycling and Closed groups clustered together, whereas Open AV were different (P&lt;0.05). Sustained AV opening induced marked changes in expression (202 transcripts &gt;2&#8208;fold; P&lt;0.05), whereas Closed AV exhibited similar expression pattern as Cycling (no transcripts &gt;2&#8208;fold; P&lt;0.05). Comparison with human sclerotic and calcific AV transcriptomes demonstrated high concordance of &gt;40 Open group genes with progression toward disease.

Conclusions: Failure of AV to close initiates an extensive response characterized by expression changes common to progression to calcific aortic valve disease. AV coaptation, whether phasic or chronic, preserved phenotypic gene expression. These results demonstrate, for the first time, that coaptation of valve leaflets is a fundamentally important biomechanical cue driving homeostasis.

No MeSH data available.


Related in: MedlinePlus