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Circulation Aug 2023Fewer than 50% of patients who develop aortic valve calcification have concomitant atherosclerosis, implying differential pathogenesis. Although circulating...
BACKGROUND
Fewer than 50% of patients who develop aortic valve calcification have concomitant atherosclerosis, implying differential pathogenesis. Although circulating extracellular vesicles (EVs) act as biomarkers of cardiovascular diseases, tissue-entrapped EVs are associated with early mineralization, but their cargoes, functions, and contributions to disease remain unknown.
METHODS
Disease stage-specific proteomics was performed on human carotid endarterectomy specimens (n=16) and stenotic aortic valves (n=18). Tissue EVs were isolated from human carotid arteries (normal, n=6; diseased, n=4) and aortic valves (normal, n=6; diseased, n=4) by enzymatic digestion, (ultra)centrifugation, and a 15-fraction density gradient validated by proteomics, CD63-immunogold electron microscopy, and nanoparticle tracking analysis. Vesiculomics, comprising vesicular proteomics and small RNA-sequencing, was conducted on tissue EVs. TargetScan identified microRNA targets. Pathway network analyses prioritized genes for validation in primary human carotid artery smooth muscle cells and aortic valvular interstitial cells.
RESULTS
Disease progression drove significant convergence (<0.0001) of carotid artery plaque and calcified aortic valve proteomes (2318 proteins). Each tissue also retained a unique subset of differentially enriched proteins (381 in plaques; 226 in valves; q<0.05). Vesicular gene ontology terms increased 2.9-fold (<0.0001) among proteins modulated by disease in both tissues. Proteomics identified 22 EV markers in tissue digest fractions. Networks of proteins and microRNA targets changed by disease progression in both artery and valve EVs revealed shared involvement in intracellular signaling and cell cycle regulation. Vesiculomics identified 773 proteins and 80 microRNAs differentially enriched by disease exclusively in artery or valve EVs (q<0.05); multiomics integration found tissue-specific EV cargoes associated with procalcific Notch and Wnt signaling in carotid arteries and aortic valves, respectively. Knockdown of tissue-specific EV-derived molecules , , and in human carotid artery smooth muscle cells and , , and in human aortic valvular interstitial cells significantly modulated calcification.
CONCLUSIONS
The first comparative proteomics study of human carotid artery plaques and calcified aortic valves identifies unique drivers of atherosclerosis versus aortic valve stenosis and implicates EVs in advanced cardiovascular calcification. We delineate a vesiculomics strategy to isolate, purify, and study protein and RNA cargoes from EVs entrapped in fibrocalcific tissues. Integration of vesicular proteomics and transcriptomics by network approaches revealed novel roles for tissue EVs in modulating cardiovascular disease.
Topics: Humans; Aortic Valve; Aortic Valve Stenosis; Multiomics; Calcinosis; Cells, Cultured; MicroRNAs; Atherosclerosis; Wnt Signaling Pathway; Extracellular Vesicles
PubMed: 37427430
DOI: 10.1161/CIRCULATIONAHA.122.063402 -
Journal of the American College of... Nov 2023The American College of Cardiology/American Heart Association guidelines recommend the assessment and grading of severity of aortic stenosis (AS) as mild, moderate, or...
BACKGROUND
The American College of Cardiology/American Heart Association guidelines recommend the assessment and grading of severity of aortic stenosis (AS) as mild, moderate, or severe, per echocardiogram, and recommend aortic valve replacement (AVR) when the AS is severe.
OBJECTIVES
The authors sought to describe mortality rates across the entire spectrum of untreated AS from a contemporary, large, real-world database.
METHODS
We analyzed a deidentified real-world data set including 1,669,536 echocardiographic reports (1,085,850 patients) from 24 U.S. hospitals (egnite Database, egnite). Patients >18 years of age were classified by diagnosed AS severity. Untreated mortality and treatment rates were examined with Kaplan-Meier (KM) estimates, with results compared using the log-rank test. Multivariate hazards analysis was performed to assess associations with all-cause mortality.
RESULTS
Among 595,120 patients with available AS severity assessment, the KM-estimated 4-year unadjusted, untreated, all-cause mortality associated with AS diagnosis of none, mild, mild-to-moderate, moderate, moderate-to-severe, or severe was 13.5% (95% CI: 13.3%-13.7%), 25.0% (95% CI: 23.8%-26.1%), 29.7% (95% CI: 26.8%-32.5%), 33.5% (95% CI: 31.0%-35.8%), 45.7% (95% CI: 37.4%-52.8%), and 44.9% (95% CI: 39.9%-49.6%), respectively. Results were similar when adjusted for informative censoring caused by treatment. KM-estimated 4-year observed treatment rates were 0.2% (95% CI: 0.2%-0.2%), 1.0% (95% CI: 0.7%-1.3%), 4.2% (95% CI: 2.0%-6.3%), 11.4% (95% CI: 9.5%-13.3%), 36.7% (95% CI: 31.8%-41.2%), and 60.7% (95% CI: 58.0%-63.3%), respectively. After adjustment, all degrees of AS severity were associated with increased mortality.
CONCLUSIONS
Patients with AS have high mortality risk across all levels of untreated AS severity. Aortic valve replacement rates remain low for patients with severe AS, suggesting that more research is needed to understand barriers to diagnosis and appropriate approach and timing for aortic valve replacement.
Topics: Humans; Treatment Outcome; Heart Valve Prosthesis Implantation; Aortic Valve Stenosis; Aortic Valve; Echocardiography; Severity of Illness Index; Risk Factors; Transcatheter Aortic Valve Replacement
PubMed: 37877909
DOI: 10.1016/j.jacc.2023.09.796 -
Heart Failure Reviews Sep 2023Acute decompensation often represents the onset of symptoms associated with severe degenerative aortic stenosis (AS) and usually complicates the clinical course of the... (Review)
Review
Acute decompensation often represents the onset of symptoms associated with severe degenerative aortic stenosis (AS) and usually complicates the clinical course of the disease with a dismal impact on survival and quality of life. Several factors may derange the faint balance between left ventricular preload and afterload and precipitate the occurrence of symptoms and signs of acute heart failure (HF). A standardized approach for the management of this condition is currently lacking. Medical therapy finds very limited application in this setting, as drugs usually indicated for the control of acute HF might worsen hemodynamics in the presence of AS. Urgent aortic valve replacement is usually performed by transcatheter than surgical approach whereas, over the last decades, percutaneous balloon valvuloplasty gained renewed space as bridge to definitive therapy. This review focuses on the pathophysiological aspects of acute advanced AS and summarizes current evidence on its management.
Topics: Humans; Quality of Life; Balloon Valvuloplasty; Aortic Valve Stenosis; Aortic Valve; Heart Valve Prosthesis; Heart Failure; Treatment Outcome
PubMed: 37083966
DOI: 10.1007/s10741-023-10312-7 -
Cardiovascular Research Jul 2023Although evidence indicates the association of lipoprotein(a) [Lp(a)] with atherosclerosis, the link with calcific aortic valve disease (CAVD) is unclear. This... (Meta-Analysis)
Meta-Analysis
Although evidence indicates the association of lipoprotein(a) [Lp(a)] with atherosclerosis, the link with calcific aortic valve disease (CAVD) is unclear. This systematic review and meta-analysis explores the connection between Lp(a) and aortic valve calcification and stenosis (AVS). We included all relevant studies, indexed in eight databases, up to February 2023. A total of 44 studies (163 139 subjects) were included, with 16 of them being further meta-analysed. Despite considerable heterogeneity, most studies support the relationship between Lp(a) and CAVD, especially in younger populations, with evidence of early aortic valve micro-calcification in elevated-Lp(a) populations. The quantitative synthesis showed higher Lp(a) levels, by 22.63 nmol/L (95% CI: 9.98-35.27), for patients with AVS, while meta-regressing the data revealed smaller Lp(a) differences for older populations with a higher proportion of females. The meta-analysis of eight studies providing genetic data, revealed that the minor alleles of both rs10455872 and rs3798220 LPA gene loci were associated with higher risk for AVS (pooled odds ratio 1.42; 95% CI: 1.34-1.50 and 1.27; 95% CI: 1.09-1.48, respectively). Importantly, high-Lp(a) individuals displayed not only faster AVS progression, by a mean difference of 0.09 m/s/year (95% CI: 0.09-0.09), but also a higher risk of serious adverse outcomes, including death (pooled hazard ratio 1.39; 95% CI: 1.01-1.90). These summary findings highlight the effect of Lp(a) on CAVD initiation, progression and outcomes, and support the early onset of Lp(a)-related subclinical lesions before clinical evidence.
Topics: Female; Humans; Aortic Valve; Aortic Valve Stenosis; Hyperlipidemias; Lipoprotein(a); Risk Factors
PubMed: 37078819
DOI: 10.1093/cvr/cvad062 -
The International Journal of... Feb 2024At the present time, right ventricular function in patients with aortic stenosis is insufficiently taken into account in the decision-making process of aortic valve...
At the present time, right ventricular function in patients with aortic stenosis is insufficiently taken into account in the decision-making process of aortic valve replacement. The aim of our study was to evaluate significance of right ventricular dysfunction in patients with severe aortic stenosis by modern 3D echocardiographic methods. This is prospective analysis of 68 patients with severe high and low-gradient aortic stenosis. We evaluated function of left and right ventricle on the basis of 3D reconstruction. Enddiastolic, endsystolic volumes, ejection fraction and stroke volumes of both chambers were assessed. There were more patients with right ventricular dysfunction in low-gradient group (RVEF < 45%) than in the high-gradient group (63.6% vs 39%, p = 0.02). Low-gradient patients had worse right ventricular function than high-gradient patients (RVEF 36% vs 46%, p = 0.02). There wasn't any significant correlation between the right ventricular dysfunction and pulmonary hypertension (r = - 0.25, p = 0.036). There was significant correlation between left and right ejection fraction (r = 0.78, p < 0.0001). Multiple regression analysis revealed that the only predictor of right ventricular function is the left ventricular function. According to our results we can state that right ventricular dysfunction is more common in patients with low-gradient than in high-gradient aortic stenosis and the only predictor of right ventricular dysfunction is left ventricular dysfunction, probably based on ventriculo-ventricular interaction. Pulmonary hypertension in patients with severe AS does not predict right ventricular dysfunction.
Topics: Humans; Hypertension, Pulmonary; Ventricular Dysfunction, Right; Predictive Value of Tests; Aortic Valve Stenosis; Ventricular Function, Left; Stroke Volume; Aortic Valve; Severity of Illness Index; Treatment Outcome
PubMed: 37950827
DOI: 10.1007/s10554-023-02986-9 -
European Heart Journal Sep 2023Heyde syndrome is the co-occurrence of aortic stenosis, acquired von Willebrand syndrome, and gastrointestinal bleeding. Aortic valve replacement has been demonstrated... (Meta-Analysis)
Meta-Analysis
AIMS
Heyde syndrome is the co-occurrence of aortic stenosis, acquired von Willebrand syndrome, and gastrointestinal bleeding. Aortic valve replacement has been demonstrated to resolve all three associated disorders. A systematic review and meta-analysis were performed to obtain best estimates of the effect of aortic valve replacement on acquired von Willebrand syndrome and gastrointestinal bleeding.
METHODS AND RESULTS
A literature search was performed to identify articles on Heyde syndrome and aortic valve replacement up to 25 October 2022. Primary outcomes were the proportion of patients with recovery of acquired von Willebrand syndrome within 24 h (T1), 24-72 h (T2), 3-21 days (T3), and 4 weeks to 2 years (T4) after aortic valve replacement and the proportion of patients with cessation of gastrointestinal bleeding. Pooled proportions and risk ratios were calculated using random-effects models. Thirty-three studies (32 observational studies and one randomized controlled trial) on acquired von Willebrand syndrome (n = 1054), and 11 observational studies on gastrointestinal bleeding (n = 300) were identified. One study reported on both associated disorders (n = 6). The pooled proportion of Heyde patients with acquired von Willebrand syndrome recovery was 86% (95% CI, 79%-91%) at T1, 90% (74%-96%) at T2, 92% (84%-96%) at T3, and 87% (67%-96%) at T4. The pooled proportion of Heyde patients with gastrointestinal bleeding cessation was 73% (62%-81%). Residual aortic valve disease was associated with lower recovery rates of acquired von Willebrand syndrome (RR 0.20; 0.05-0.72; P = 0.014) and gastrointestinal bleeding (RR 0.57; 0.40-0.81; P = 0.002).
CONCLUSION
Aortic valve replacement is associated with rapid recovery of the bleeding diathesis in Heyde syndrome and gastrointestinal bleeding cessation. Residual valve disease compromises clinical benefits.
Topics: Humans; Aortic Valve; Angiodysplasia; Aortic Valve Stenosis; von Willebrand Diseases; Gastrointestinal Hemorrhage; Syndrome; von Willebrand Factor
PubMed: 37555393
DOI: 10.1093/eurheartj/ehad340 -
Australian Journal of General Practice Jul 2023Severe aortic stenosis (AS) is a condition that commonly affects elderly Australians. Once symptomatic, severe AS has a poor prognosis if untreated. Transcatheter aortic...
BACKGROUND
Severe aortic stenosis (AS) is a condition that commonly affects elderly Australians. Once symptomatic, severe AS has a poor prognosis if untreated. Transcatheter aortic valve implantation (TAVI) is a percutaneous procedure that is now the recommended treatment for elderly patients with severe AS who are suitable for intervention.
OBJECTIVE
This article provides a contemporary review of the diagnosis and management of severe AS in the elderly.
DISCUSSION
Management options for severe AS include TAVI, surgical aortic valve replacement (SAVR), or medical/palliative therapy. In elderly adults, TAVI improves mortality, symptoms and quality of life compared with medical therapy, and is superior to SAVR. The decision regarding which management option is most appropriate for an individual patient is made using a collaborative multidisciplinary approach. General practitioners play key roles in providing information to risk stratify patients when considering intervention, caring for patients after the procedure and/or providing medical and palliative treatment for those deemed unsuitable for intervention.
Topics: Adult; Humans; Aged; Transcatheter Aortic Valve Replacement; Quality of Life; Risk Factors; Australia; Aortic Valve Stenosis
PubMed: 37423243
DOI: 10.31128/AJGP-08-22-6527 -
Journal of the American Heart... May 2024Large observational studies have demonstrated a clear inverse association between renal function and risk of aortic stenosis (AS). Whether this represents a causal,...
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], =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], =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.
Topics: Humans; Mendelian Randomization Analysis; Renal Insufficiency, Chronic; Glomerular Filtration Rate; Genome-Wide Association Study; Aortic Valve Stenosis; Cystatin C; Risk Factors; Kidney; Genetic Predisposition to Disease; Creatinine; Risk Assessment; Polymorphism, Single Nucleotide; Biomarkers; Blood Urea Nitrogen
PubMed: 38639330
DOI: 10.1161/JAHA.123.034102 -
Biomedicine & Pharmacotherapy =... Jul 2023Calcified aortic valve disease (CAVD) is a common cardiovascular disease in elderly individuals. Although it was previously considered a degenerative disease, it is, in... (Review)
Review
Calcified aortic valve disease (CAVD) is a common cardiovascular disease in elderly individuals. Although it was previously considered a degenerative disease, it is, in fact, a progressive disease involving multiple mechanisms. Aortic valve endothelial cells, which cover the outermost layer of the aortic valve and are directly exposed to various pathogenic factors, play a significant role in the onset and progression of CAVD. Hemodynamic changes can directly damage the structure and function of valvular endothelial cells (VECs). This leads to inflammatory infiltration and oxidative stress, which promote the progression of CAVD. VECs can regulate the pathological differentiation of valvular interstitial cells (VICs) through NO and thus affect the process of CAVD. Under the influence of pathological factors, VECs can also be transformed into VICs through EndMT, and then the pathological differentiation of VICs eventually leads to the formation of calcification. This review discusses the role of VECs, especially the role of oxidative stress in VECs, in the process of aortic valve calcification.
Topics: Humans; Aged; Aortic Valve; Aortic Valve Stenosis; Calcinosis; Endothelial Cells; Cells, Cultured; Oxidative Stress
PubMed: 37116353
DOI: 10.1016/j.biopha.2023.114775 -
Clinical Epigenetics Mar 2024Aortic valve stenosis (AVS) is the most prevalent cardiac valve lesion in developed countries, and pathogenesis is closely related to aging. DNA methylation-based...
BACKGROUND
Aortic valve stenosis (AVS) is the most prevalent cardiac valve lesion in developed countries, and pathogenesis is closely related to aging. DNA methylation-based epigenetic clock is now recognized as highly accurate predictor of the aging process and associated health outcomes. This study aimed to explore the causal relationship between epigenetic clock and AVS by conducting a bidirectional Mendelian randomization (MR) analysis.
METHODS
Summary genome-wide association study statistics of epigenetic clocks (HannumAge, HorvathAge, PhenoAge, and GrimAge) and AVS were obtained and assessed for significant instrumental variables from Edinburgh DataShare (n = 34,710) and FinnGen biobank (cases = 9870 and controls = 402,311). The causal association between epigenetic clock and AVS was evaluated using inverse variance weighted (IVW), weighted median (WM), and MR-Egger methods. Multiple analyses (heterogeneity analysis, pleiotropy analysis, and sensitivity analysis) were performed for quality control assessment.
RESULTS
The MR analysis showed that the epigenetic age acceleration of HorvathAge and PhenoAge was associated with an increased risk of AVS (HorvathAge: OR = 1.043, P = 0.016 by IVW, OR = 1.058, P = 0.018 by WM; PhenoAge: OR = 1.058, P = 0.005 by IVW, OR = 1.053, P = 0.039 by WM). Quality control assessment proved our findings were reliable and robust. However, there was a lack of evidence supporting a causal link from AVS to epigenetic aging.
CONCLUSION
The present MR analysis unveiled a causal association between epigenetic clocks, especially HorvathAge and PhenoAge, with AVS. Further research is required to elucidate the underlying mechanisms and develop strategies for potential interventions.
Topics: Humans; DNA Methylation; Genome-Wide Association Study; Mendelian Randomization Analysis; Aortic Valve Stenosis; Acceleration; Epigenesis, Genetic
PubMed: 38475866
DOI: 10.1186/s13148-024-01647-5