Identification of Key Non-coding RNAs and Transcription Factors in Calcific Aortic Valve Disease.

Background:Calcific aortic valve disease (CAVD) is one of the most frequently occurring valvular heart diseases among the aging population. Currently, there is no known pharmacological treatment available to delay or reverse CAVD progression. The regulation of gene expression could contribute to the initiation, progression, and treatment of CAVD. Non-coding RNAs (ncRNAs) and transcription factors play essential regulatory roles in gene expression in CAVD; thus, further research is urgently needed.Materials and Methods:The gene-expression profiles of GSE51472 and GSE12644 were obtained from the Gene Expression Omnibus database, and differentially expressed genes (DEGs) were identified in each dataset. A protein-protein-interaction (PPI) network of DEGs was then constructed using the Search Tool for the Retrieval of Interacting Genes/Proteins database, and functional modules were analyzed with ClusterOne plugin in Cytoscape. Furthermore, Gene Ontology-functional annotation and Kyoto Encyclopedia of Genes and Genomes-pathway analysis were conducted for each functional module. Most crucially, ncRNAs and transcription factors acting on each functional module were separately identified using the RNAInter and TRRUST databases. The expression of predicted transcription factors and key genes was validated using GSE51472 and GSE12644. Furthermore, quantitative real-time PCR (qRT-PCR) experiments were performed to validate the differential expression of most promising candidates in human CAVD and control samples.Results:Among 552 DEGs, 383 were upregulated and 169 were downregulated. In the PPI network, 15 functional modules involving 182 genes and proteins were identified. After hypergeometric testing, 45 ncRNAs and 33 transcription factors were obtained. Among the predicted transcription factors, CIITA, HIF1A, JUN, POU2F2, and STAT6 were differentially expressed in both the training and validation sets. In addition, we found that key genes, namely, CD2, CD86, CXCL8, FCGR3B, GZMB, ITGB2, LY86, MMP9, PPBP, and TYROBP were also differentially expressed in both the training and validation sets. Among the most promising candidates, differential expressions of ETS1, JUN, NFKB1, RELA, SP1, STAT1, ANCR, and LOC101927497 were identified via qRT-PCR experiments.Conclusion:In this study, we identified functional modules with ncRNAs and transcription factors involved in CAVD pathogenesis. The current results suggest candidate molecules for further research on CAVD.

The effects of levosimendan in patients undergoing transcatheter aortic valve replacement- a retrospective analysis.

Background: Aortic stenosis (AS) increases left ventricular afterload, leading to cardiac damage and heart failure (HF). Transcatheter aortic valve replacement (TAVR) is an effective therapy for AS. No inotropic agents including levosimendan have been evaluated in patients undergoing TAVR. Methods: A total of 285 patients underwent TAVR between 2014 and 2019; 210 were included in the matched analysis and 105 received 0.1 μg/kg body weight/min levosimendan immediately after the prosthesis had been successfully implanted. Medical history, laboratory tests, and echocardiography results were analyzed. Endpoints including 2-year all-cause mortality, stroke, or HF-related hospitalization, and a combination of the above were analyzed by Cox proportional hazard models. Results: The levosimendan group had no difference in 2-year mortality compared with the control group (hazard ratio [HR]: 0.603, 95% confidence interval [CI]: 0.197-1.844; p = 0.375). However, levosimendan reduced stroke or HF-related hospitalization (HR: 0.346; 95% CI: 0.135-0.884; p = 0.027) and the combined endpoint (HR: 0.459, 95% CI: 0.215-0.980; p = 0.044). After adjusting for multiple variants, levosimendan still reduced stroke or HF-related hospitalization (HR: 0.346, 95% CI: 0.134-0.944; p = 0.038). Conclusion: Prophylactic levosimendan administration immediately after valve implantation in patients undergoing TAVR can reduce stroke or HF-related hospitalization but does not lower all-cause mortality.

Sevelamer Attenuates Bioprosthetic Heart Valve Calcification.

Objective: Sevelamer hydrochloride is a phosphate binder used to treat hyperphosphatemia in chronic kidney disease (CKD) patients that can reduce valvular and vascular calcification. The aim of this study was to examine the effects of sevelamer treatment on calcification in bioprosthetic heart valves (BHVs). Methods: Wister rats were randomly divided into three groups according to sevelamer intake and implantation (sham-sham operation; implant-implantation and normal diet, implant+S implantation, and sevelamer diet). Two kinds of BHVs-bovine pericardium treated with glutaraldehyde (GLUT) or non-GLUT techniques-were implanted in rat dorsal subcutis at 4 weeks. After implantation, sevelamer was administered to the implant+S group. The animals were executed at days 0 (immediately after implantation), 7, 14, 28, and 56. Calcium levels were determined by atomic absorption spectroscopy and von Kossa staining. Serum biochemistry analysis, Western blotting, real-time quantitative polymerase chain reaction, alkaline phosphatase activity measurement, histopathologic analysis, immunohistochemistry, and enzyme-linked immunosorbent assay were conducted to identify the anti-calcification mechanism of sevelamer. Results: Non-GLUT crosslinking attenuates BHV calcification. Serum phosphate and calcium remained unreactive to sevelamer after a 14-day treatment. However, the mean calcium level in the implant+S group was significantly decreased after 56 days. In addition, the PTH level, inflammatory cell infiltration, system and local inflammation, and expression of Bmp2, Runx2, Alp, IL-1β, IL-6, and TNF-α were significantly reduced in the implant+S group. Conclusion: Sevelamer treatment significantly attenuated the calcification of BHVs and had anti-inflammation effects that were independent from serum calcium and phosphate regulation. Thus, sevelamer treatment might be helpful to improve the longevity of BHVs.

Current Status and Future Direction of Transcatheter Mitral Valve Replacement.

Identification of Key Non-coding RNAs and Transcription Factors in Calcific Aortic Valve Disease.

Background:Calcific aortic valve disease (CAVD) is one of the most frequently occurring valvular heart diseases among the aging population. Currently, there is no known pharmacological treatment available to delay or reverse CAVD progression. The regulation of gene expression could contribute to the initiation, progression, and treatment of CAVD. Non-coding RNAs (ncRNAs) and transcription factors play essential regulatory roles in gene expression in CAVD; thus, further research is urgently needed.Materials and Methods:The gene-expression profiles of GSE51472 and GSE12644 were obtained from the Gene Expression Omnibus database, and differentially expressed genes (DEGs) were identified in each dataset. A protein-protein-interaction (PPI) network of DEGs was then constructed using the Search Tool for the Retrieval of Interacting Genes/Proteins database, and functional modules were analyzed with ClusterOne plugin in Cytoscape. Furthermore, Gene Ontology-functional annotation and Kyoto Encyclopedia of Genes and Genomes-pathway analysis were conducted for each functional module. Most crucially, ncRNAs and transcription factors acting on each functional module were separately identified using the RNAInter and TRRUST databases. The expression of predicted transcription factors and key genes was validated using GSE51472 and GSE12644. Furthermore, quantitative real-time PCR (qRT-PCR) experiments were performed to validate the differential expression of most promising candidates in human CAVD and control samples.Results:Among 552 DEGs, 383 were upregulated and 169 were downregulated. In the PPI network, 15 functional modules involving 182 genes and proteins were identified. After hypergeometric testing, 45 ncRNAs and 33 transcription factors were obtained. Among the predicted transcription factors, CIITA, HIF1A, JUN, POU2F2, and STAT6 were differentially expressed in both the training and validation sets. In addition, we found that key genes, namely, CD2, CD86, CXCL8, FCGR3B, GZMB, ITGB2, LY86, MMP9, PPBP, and TYROBP were also differentially expressed in both the training and validation sets. Among the most promising candidates, differential expressions of ETS1, JUN, NFKB1, RELA, SP1, STAT1, ANCR, and LOC101927497 were identified via qRT-PCR experiments.Conclusion:In this study, we identified functional modules with ncRNAs and transcription factors involved in CAVD pathogenesis. The current results suggest candidate molecules for further research on CAVD.

The effects of levosimendan in patients undergoing transcatheter aortic valve replacement- a retrospective analysis.

Background: Aortic stenosis (AS) increases left ventricular afterload, leading to cardiac damage and heart failure (HF). Transcatheter aortic valve replacement (TAVR) is an effective therapy for AS. No inotropic agents including levosimendan have been evaluated in patients undergoing TAVR. Methods: A total of 285 patients underwent TAVR between 2014 and 2019; 210 were included in the matched analysis and 105 received 0.1 μg/kg body weight/min levosimendan immediately after the prosthesis had been successfully implanted. Medical history, laboratory tests, and echocardiography results were analyzed. Endpoints including 2-year all-cause mortality, stroke, or HF-related hospitalization, and a combination of the above were analyzed by Cox proportional hazard models. Results: The levosimendan group had no difference in 2-year mortality compared with the control group (hazard ratio [HR]: 0.603, 95% confidence interval [CI]: 0.197-1.844; p = 0.375). However, levosimendan reduced stroke or HF-related hospitalization (HR: 0.346; 95% CI: 0.135-0.884; p = 0.027) and the combined endpoint (HR: 0.459, 95% CI: 0.215-0.980; p = 0.044). After adjusting for multiple variants, levosimendan still reduced stroke or HF-related hospitalization (HR: 0.346, 95% CI: 0.134-0.944; p = 0.038). Conclusion: Prophylactic levosimendan administration immediately after valve implantation in patients undergoing TAVR can reduce stroke or HF-related hospitalization but does not lower all-cause mortality.

Sevelamer Attenuates Bioprosthetic Heart Valve Calcification.

Objective: Sevelamer hydrochloride is a phosphate binder used to treat hyperphosphatemia in chronic kidney disease (CKD) patients that can reduce valvular and vascular calcification. The aim of this study was to examine the effects of sevelamer treatment on calcification in bioprosthetic heart valves (BHVs). Methods: Wister rats were randomly divided into three groups according to sevelamer intake and implantation (sham-sham operation; implant-implantation and normal diet, implant+S implantation, and sevelamer diet). Two kinds of BHVs-bovine pericardium treated with glutaraldehyde (GLUT) or non-GLUT techniques-were implanted in rat dorsal subcutis at 4 weeks. After implantation, sevelamer was administered to the implant+S group. The animals were executed at days 0 (immediately after implantation), 7, 14, 28, and 56. Calcium levels were determined by atomic absorption spectroscopy and von Kossa staining. Serum biochemistry analysis, Western blotting, real-time quantitative polymerase chain reaction, alkaline phosphatase activity measurement, histopathologic analysis, immunohistochemistry, and enzyme-linked immunosorbent assay were conducted to identify the anti-calcification mechanism of sevelamer. Results: Non-GLUT crosslinking attenuates BHV calcification. Serum phosphate and calcium remained unreactive to sevelamer after a 14-day treatment. However, the mean calcium level in the implant+S group was significantly decreased after 56 days. In addition, the PTH level, inflammatory cell infiltration, system and local inflammation, and expression of Bmp2, Runx2, Alp, IL-1β, IL-6, and TNF-α were significantly reduced in the implant+S group. Conclusion: Sevelamer treatment significantly attenuated the calcification of BHVs and had anti-inflammation effects that were independent from serum calcium and phosphate regulation. Thus, sevelamer treatment might be helpful to improve the longevity of BHVs.

Current Status and Future Direction of Transcatheter Mitral Valve Replacement.