Assessing causal relationship between non-alcoholic fatty liver disease and risk of atrial fibrillation.

Association between remnant cholesterol and progression of bioprosthetic valve degeneration.

AIMS:Remnant cholesterol (RC) seems associated with native aortic stenosis. Bioprosthetic valve degeneration may share similar lipid-mediated pathways with aortic stenosis. We aimed to investigate the association of RC with the progression of bioprosthetic aortic valve degeneration and ensuing clinical outcomes.METHODS AND RESULTS:We enrolled 203 patients with a median of 7.0 years (interquartile range: 5.1-9.2) after surgical aortic valve replacement. RC concentration was dichotomized by the top RC tertile (23.7 mg/dL). At 3-year follow-up, 121 patients underwent follow-up visit for the assessment of annualized change in aortic valve calcium density (AVCd). RC levels showed a curvilinear relationship with an annualized progression rate of AVCd, with increased progression rates when RC >23.7 mg/dL (P = 0.008). There were 99 deaths and 46 aortic valve re-interventions in 133 patients during a median clinical follow-up of 8.8 (8.7-9.6) years. RC >23.7 mg/dL was independently associated with mortality or re-intervention (hazard ratio: 1.98; 95% confidence interval: 1.31-2.99; P = 0.001).CONCLUSION:Elevated RC is independently associated with faster progression of bioprosthetic valve degeneration and increased risk of all-cause mortality or aortic valve re-intervention.

Genetic association of lipids and lipid-lowering drug target genes with non-alcoholic fatty liver disease.

BACKGROUND:Some observational studies found that dyslipidaemia is a risk factor for non-alcoholic fatty liver disease (NAFLD), and lipid-lowering drugs may lower NAFLD risk. However, it remains unclear whether dyslipidaemia is causative for NAFLD. This Mendelian randomisation (MR) study aimed to explore the causal role of lipid traits in NAFLD and evaluate the potential effect of lipid-lowering drug targets on NAFLD.METHODS:Genetic variants associated with lipid traits and variants of genes encoding lipid-lowering drug targets were extracted from the Global Lipids Genetics Consortium genome-wide association study (GWAS). Summary statistics for NAFLD were obtained from two independent GWAS datasets. Lipid-lowering drug targets that reached significance were further tested using expression quantitative trait loci data in relevant tissues. Colocalisation and mediation analyses were performed to validate the robustness of the results and explore potential mediators.FINDINGS:No significant effect of lipid traits and eight lipid-lowering drug targets on NAFLD risk was found. Genetic mimicry of lipoprotein lipase (LPL) enhancement was associated with lower NAFLD risks in two independent datasets (OR1 = 0.60 [95% CI 0.50-0.72], p1 = 2.07 × 10-8; OR2 = 0.57 [95% CI 0.39-0.82], p2 = 3.00 × 10-3). A significant MR association (OR = 0.71 [95% CI, 0.58-0.87], p = 1.20 × 10-3) and strong colocalisation association (PP.H4 = 0.85) with NAFLD were observed for LPL expression in subcutaneous adipose tissue. Fasting insulin and type 2 diabetes mediated 7.40% and 9.15%, respectively, of the total effect of LPL on NAFLD risk.INTERPRETATION:Our findings do not support dyslipidaemia as a causal factor for NAFLD. Among nine lipid-lowering drug targets, LPL is a promising candidate drug target in NAFLD. The mechanism of action of LPL in NAFLD may be independent of its lipid-lowering effects.FUNDING:Capital's Funds for Health Improvement and Research (2022-4-4037). CAMS Innovation Fund for Medical Sciences (CIFMS, grant number: 2021-I2M-C&T-A-010).

Prognostic value of calcium and phosphorus status in elderly heart disease patients with tricuspid regurgitation.

Can Measuring the 'Dual Anchors of Aorta' Enhance the Success Rate of TAVR?-A Single-Center Experience.

INTRODUCTION:Chronic severe aortic regurgitation (AR) has a poor long-term prognosis, especially among old-age patients. Considering their advancing age, the surgical approach of aortic valve replacement may not always be the best alternative modality of treatment in such patients. Therefore, this study's primary goal was to provide an initial summary of the medium- and short-term clinical effectiveness of transcatheter aortic valve replacement (TAVR) guided by accurate multi-detector computed tomography (MDCT) measurements in patients with severe and chronic AR, especially in elderly patients.METHODS:The study enrolled retrospectively and prospectively patients diagnosed with severe AR who eventually underwent TAVR procedure from January 2019 to September 2022 at Fuwai cardiovascular Hospital, Beijing. Baseline information, MDCT measurements, anatomical classification, perioperative, and 1-year follow-up outcomes were collected and analyzed. Based on a novel anatomical categorization and dual anchoring theory, patients were divided into four categories according to the level of anchoring area. Type 1, 2, and 3 patients (with at least two anchoring regions) will receive TAVR with a transcatheter heart valve (THV), but Type 4 patients (with zero or one anchoring location) will be deemed unsuitable for TAVR and will instead receive medical care (retrospectively enrolled patients who already underwent TAVR are an exception).RESULTS:The mean age of the 37 patients with severe chronic AR was 73.1 ± 8.7 years, and 23 patients (62.2%) were male. The American Association of Thoracic Surgeons' score was 8.6 ± 2.1%. The MDCT anatomical classification included 17 cases of type 1 (45.9%), 3 cases of type 2 (8.1%), 13 cases of type 3 (35.1%), and 4 cases of Type 4 (10.8%). The VitaFlow valve (MicroPort, Shanghai, China) was implanted in 19 patients (51.3%), while the Venus A valve (Venus MedTech, Hangzhou, China) was implanted in 18 patients (48.6%). Immediate TAVR procedural and device success rates were 86.5% and 67.6%, respectively, while eight cases (21.6%) required THV-in-THV implantation, and nine cases (24.3%) required permanent pacemaker implantation. Univariate regression analysis revealed that the major factors affecting TAVR device failure were sinotubular junction diameter, THV type, and MDCT anatomical classification (p < 0.05). Compared with the baseline, the left ventricular ejection fraction gradually increased, while the left ventricular end-diastolic diameter remained small, and the N-terminal-pro hormone B-type natriuretic peptide level significantly decreased within one year.CONCLUSION:According to the results of our study, TAVR with a self-expanding THV is safe and feasible for patients with chronic severe AR, particularly for those who meet the criteria for the appropriate MDCT anatomical classification with intact dual aortic anchors, and it has a significant clinical effect for at least a year.

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.

Assessing causal relationship between non-alcoholic fatty liver disease and risk of atrial fibrillation.

Association between remnant cholesterol and progression of bioprosthetic valve degeneration.

AIMS:Remnant cholesterol (RC) seems associated with native aortic stenosis. Bioprosthetic valve degeneration may share similar lipid-mediated pathways with aortic stenosis. We aimed to investigate the association of RC with the progression of bioprosthetic aortic valve degeneration and ensuing clinical outcomes.METHODS AND RESULTS:We enrolled 203 patients with a median of 7.0 years (interquartile range: 5.1-9.2) after surgical aortic valve replacement. RC concentration was dichotomized by the top RC tertile (23.7 mg/dL). At 3-year follow-up, 121 patients underwent follow-up visit for the assessment of annualized change in aortic valve calcium density (AVCd). RC levels showed a curvilinear relationship with an annualized progression rate of AVCd, with increased progression rates when RC >23.7 mg/dL (P = 0.008). There were 99 deaths and 46 aortic valve re-interventions in 133 patients during a median clinical follow-up of 8.8 (8.7-9.6) years. RC >23.7 mg/dL was independently associated with mortality or re-intervention (hazard ratio: 1.98; 95% confidence interval: 1.31-2.99; P = 0.001).CONCLUSION:Elevated RC is independently associated with faster progression of bioprosthetic valve degeneration and increased risk of all-cause mortality or aortic valve re-intervention.

Genetic association of lipids and lipid-lowering drug target genes with non-alcoholic fatty liver disease.

BACKGROUND:Some observational studies found that dyslipidaemia is a risk factor for non-alcoholic fatty liver disease (NAFLD), and lipid-lowering drugs may lower NAFLD risk. However, it remains unclear whether dyslipidaemia is causative for NAFLD. This Mendelian randomisation (MR) study aimed to explore the causal role of lipid traits in NAFLD and evaluate the potential effect of lipid-lowering drug targets on NAFLD.METHODS:Genetic variants associated with lipid traits and variants of genes encoding lipid-lowering drug targets were extracted from the Global Lipids Genetics Consortium genome-wide association study (GWAS). Summary statistics for NAFLD were obtained from two independent GWAS datasets. Lipid-lowering drug targets that reached significance were further tested using expression quantitative trait loci data in relevant tissues. Colocalisation and mediation analyses were performed to validate the robustness of the results and explore potential mediators.FINDINGS:No significant effect of lipid traits and eight lipid-lowering drug targets on NAFLD risk was found. Genetic mimicry of lipoprotein lipase (LPL) enhancement was associated with lower NAFLD risks in two independent datasets (OR1 = 0.60 [95% CI 0.50-0.72], p1 = 2.07 × 10-8; OR2 = 0.57 [95% CI 0.39-0.82], p2 = 3.00 × 10-3). A significant MR association (OR = 0.71 [95% CI, 0.58-0.87], p = 1.20 × 10-3) and strong colocalisation association (PP.H4 = 0.85) with NAFLD were observed for LPL expression in subcutaneous adipose tissue. Fasting insulin and type 2 diabetes mediated 7.40% and 9.15%, respectively, of the total effect of LPL on NAFLD risk.INTERPRETATION:Our findings do not support dyslipidaemia as a causal factor for NAFLD. Among nine lipid-lowering drug targets, LPL is a promising candidate drug target in NAFLD. The mechanism of action of LPL in NAFLD may be independent of its lipid-lowering effects.FUNDING:Capital's Funds for Health Improvement and Research (2022-4-4037). CAMS Innovation Fund for Medical Sciences (CIFMS, grant number: 2021-I2M-C&T-A-010).

Prognostic value of calcium and phosphorus status in elderly heart disease patients with tricuspid regurgitation.

Can Measuring the 'Dual Anchors of Aorta' Enhance the Success Rate of TAVR?-A Single-Center Experience.

INTRODUCTION:Chronic severe aortic regurgitation (AR) has a poor long-term prognosis, especially among old-age patients. Considering their advancing age, the surgical approach of aortic valve replacement may not always be the best alternative modality of treatment in such patients. Therefore, this study's primary goal was to provide an initial summary of the medium- and short-term clinical effectiveness of transcatheter aortic valve replacement (TAVR) guided by accurate multi-detector computed tomography (MDCT) measurements in patients with severe and chronic AR, especially in elderly patients.METHODS:The study enrolled retrospectively and prospectively patients diagnosed with severe AR who eventually underwent TAVR procedure from January 2019 to September 2022 at Fuwai cardiovascular Hospital, Beijing. Baseline information, MDCT measurements, anatomical classification, perioperative, and 1-year follow-up outcomes were collected and analyzed. Based on a novel anatomical categorization and dual anchoring theory, patients were divided into four categories according to the level of anchoring area. Type 1, 2, and 3 patients (with at least two anchoring regions) will receive TAVR with a transcatheter heart valve (THV), but Type 4 patients (with zero or one anchoring location) will be deemed unsuitable for TAVR and will instead receive medical care (retrospectively enrolled patients who already underwent TAVR are an exception).RESULTS:The mean age of the 37 patients with severe chronic AR was 73.1 ± 8.7 years, and 23 patients (62.2%) were male. The American Association of Thoracic Surgeons' score was 8.6 ± 2.1%. The MDCT anatomical classification included 17 cases of type 1 (45.9%), 3 cases of type 2 (8.1%), 13 cases of type 3 (35.1%), and 4 cases of Type 4 (10.8%). The VitaFlow valve (MicroPort, Shanghai, China) was implanted in 19 patients (51.3%), while the Venus A valve (Venus MedTech, Hangzhou, China) was implanted in 18 patients (48.6%). Immediate TAVR procedural and device success rates were 86.5% and 67.6%, respectively, while eight cases (21.6%) required THV-in-THV implantation, and nine cases (24.3%) required permanent pacemaker implantation. Univariate regression analysis revealed that the major factors affecting TAVR device failure were sinotubular junction diameter, THV type, and MDCT anatomical classification (p < 0.05). Compared with the baseline, the left ventricular ejection fraction gradually increased, while the left ventricular end-diastolic diameter remained small, and the N-terminal-pro hormone B-type natriuretic peptide level significantly decreased within one year.CONCLUSION:According to the results of our study, TAVR with a self-expanding THV is safe and feasible for patients with chronic severe AR, particularly for those who meet the criteria for the appropriate MDCT anatomical classification with intact dual aortic anchors, and it has a significant clinical effect for at least a year.

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.