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Importance: There are limited data on the association of sex with the incidence of postoperative atrial fibrillation (poAF) and subsequent long-term mortality after cardiac surgery. Objective: To evaluate whether the incidence of poAF and associated long-term mortality after cardiac surgery differ by sex. Design, Setting, and Participants: This retrospective cohort study was conducted at 2 tertiary care centers in Massachusetts from January 1, 2002, until October 1, 2016, with follow-up until December 1, 2022. Adult (aged >20 years) women and men undergoing coronary artery bypass graft surgery, aortic valve surgery, mitral valve surgery, and combined procedures with cardiopulmonary bypass were examined using medical records. Patients who had data on poAF were included in data analyses. Exposures: Sex and poAF. Main Outcomes and Measures: Primary outcomes were the incidence of poAF and all-cause mortality. poAF was defined as any atrial fibrillation detected on electrocardiogram (EKG) during the index hospitalization in patients presenting for surgery in normal sinus rhythm. Data on poAF were obtained from EKG reports and supplemented by information from the Society of Thoracic Surgeons Adult Cardiac Surgery Database. All-cause mortality was assessed via hospital records. The hypotheses were formulated prior to data analysis. Results: Among 21â¯568 patients with poAF data (mean [SD] age, 66.5 [12.4] years), 2694 of 6601 women (40.8%) and 5805 of 14â¯967 men (38.8%) developed poAF. In a multivariable logistic regression model, women had lower risk of poAF (odds ratio [OR], 0.85; 95% CI, 0.79-0.91; P < .001). During the follow-up study period, 1294 women (50.4%) and 2376 men (48.9%) in the poAF group as well as 1273 women (49.6%) and 2484 men (51.1%) in the non-poAF group died. Cox proportional hazards analysis found that the association between poAF and mortality was significantly moderated (ie, effect modified) by sex. Compared with same-sex individuals without poAF, men with poAF had a 17% higher mortality hazard (hazard ratio [HR], 1.17; 95% CI, 1.11-1.25; P < .001), and women with poAF had a 31% higher mortality hazard (HR, 1.31; 95% CI, 1.21-1.42; P < .001). Conclusions and Relevance: In this retrospective cohort study of 21â¯568 patients who underwent cardiac surgery, women were less likely to develop poAF than men when controlling for other relevant characteristics; however, women who did develop poAF had a higher risk of long-term mortality than men who developed poAF. This observed elevated risk calls for a tailored approach to perioperative care in women undergoing cardiac surgery.
Subject(s)
Atrial Fibrillation , Cardiac Surgical Procedures , Postoperative Complications , Humans , Atrial Fibrillation/epidemiology , Atrial Fibrillation/etiology , Atrial Fibrillation/mortality , Male , Female , Retrospective Studies , Middle Aged , Aged , Cardiac Surgical Procedures/adverse effects , Cardiac Surgical Procedures/mortality , Sex Factors , Postoperative Complications/mortality , Postoperative Complications/epidemiology , Incidence , Risk Factors , Massachusetts/epidemiologyABSTRACT
Bicuspid aortic valve (BAV) is the most common congenital heart malformation in adults but can also cause childhood-onset complications. In multicenter study, we found that adults who experience significant complications of BAV disease before age 30 are distinguished from the majority of BAV cases that manifest after age 50 by a relatively severe clinical course, with higher rates of surgical interventions, more frequent second interventions, and a greater burden of congenital heart malformations. These observations highlight the need for prompt recognition, regular lifelong surveillance, and targeted interventions to address the significant health burdens of patients with early onset BAV complications.
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Bicuspid Aortic Valve (BAV) is the most common adult congenital heart lesion with an estimated population prevalence of 1%. We hypothesize that early onset complications of BAV (EBAV) are driven by specific impactful genetic variants. We analyzed whole exome sequences (WES) to identify rare coding variants that contribute to BAV disease in 215 EBAV families. Predicted pathogenic variants of causal genes were present in 111 EBAV families (51% of total), including genes that cause BAV (8%) or heritable thoracic aortic disease (HTAD, 17%). After appropriate filtration, we also identified 93 variants in 26 novel genes that are associated with autosomal dominant congenital heart phenotypes, including recurrent deleterious variation of FBN2, MYH6, channelopathy genes, and type 1 and 5 collagen genes. These findings confirm our hypothesis that unique rare genetic variants contribute to early onset complications of BAV disease.
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Bicuspid aortic valve (BAV), the most common congenital heart defect, is a major cause of aortic valve disease requiring valve interventions and thoracic aortic aneurysms predisposing to acute aortic dissections. The spectrum of BAV ranges from early onset valve and aortic complications (EBAV) to sporadic late onset disease. Rare genomic copy number variants (CNVs) have previously been implicated in the development of BAV and thoracic aortic aneurysms. We determined the frequency and gene content of rare CNVs in EBAV probands (n = 272) using genome-wide SNP microarray analysis and three complementary CNV detection algorithms (cnvPartition, PennCNV, and QuantiSNP). Unselected control genotypes from the Database of Genotypes and Phenotypes were analyzed using identical methods. We filtered the data to select large genic CNVs that were detected by multiple algorithms. Findings were replicated in cohorts with late onset sporadic disease (n = 5040). We identified 34 large and rare (< 1:1000 in controls) CNVs in EBAV probands. The burden of CNVs intersecting with genes known to cause BAV when mutated was increased in case-control analysis. CNVs intersecting with GATA4 and DSCAM were enriched in cases, recurrent in other datasets, and segregated with disease in families. In total, we identified potentially pathogenic CNVs in 8% of EBAV cases, implicating alterations of candidate genes at these loci in the pathogenesis of BAV.
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Objectives: It is uncertain whether concurrent mitral valve repair or replacement for moderate or greater secondary mitral regurgitation at the time of coronary artery bypass graft or aortic valve replacement surgery improves long-term survival. Methods: Patients undergoing coronary artery bypass graft and/or aortic valve replacement surgery with moderate or greater secondary mitral regurgitation were reviewed. The effect of concurrent mitral valve repair or replacement upon long-term mortality was assessed while accounting for patient and operative characteristics and mitral regurgitation severity. Results: Of 1,515 patients, 938 underwent coronary artery bypass graft or aortic valve replacement surgery alone and 577 underwent concurrent mitral valve repair or replacement. Concurrent mitral valve repair or replacement did not alter the risk of postoperative mortality for patients with moderate mitral regurgitation (hazard ratio = 0.93; 0.75-1.17) or more-than-moderate mitral regurgitation (hazard ratio = 1.09; 0.74-1.60) in multivariable regression. Patients with more-than-moderate mitral regurgitation undergoing coronary artery bypass graft-only surgery had a survival advantage from concurrent mitral valve repair or replacement in the first two postoperative years (P = 0.028) that did not persist beyond that time. Patients who underwent concurrent mitral valve repair or replacement had a higher rate of later mitral valve operation or reoperation over the five subsequent years (1.9% vs. 0.2%; P = 0.0014) than those who did not. Conclusions: These observations suggest that mitral valve repair or replacement for more-than-moderate mitral regurgitation at the time of coronary artery bypass grafting may be reasonable in a suitably selected coronary artery bypass graft population but not for aortic valve replacement, with or without coronary artery bypass grafting. Our findings are supportive of 2021 European guidelines that severe secondary mitral regurgitation "should" or be "reasonabl[y]" intervened upon at the time of coronary artery bypass grafting but do not support 2020 American guidelines for performing mitral valve repair or replacement concurrent with aortic valve replacement, with or without coronary artery bypass grafting.
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Importance: Nonsyndromic bicuspid aortic valve (nsBAV) is the most common congenital heart valve malformation. BAV has a heritable component, yet only a few causative genes have been identified; understanding BAV genetics is a key point in developing personalized medicine. Objective: To identify a new gene for nsBAV. Design, Setting, and Participants: This was a comprehensive, multicenter, genetic association study based on candidate gene prioritization in a familial cohort followed by rare and common association studies in replication cohorts. Further validation was done using in vivo mice models. Study data were analyzed from October 2019 to October 2022. Three cohorts of patients with BAV were included in the study: (1) the discovery cohort was a large cohort of inherited cases from 29 pedigrees of French and Israeli origin; (2) the replication cohort 1 for rare variants included unrelated sporadic cases from various European ancestries; and (3) replication cohort 2 was a second validation cohort for common variants in unrelated sporadic cases from Europe and the US. Main Outcomes and Measures: To identify a candidate gene for nsBAV through analysis of familial cases exome sequencing and gene prioritization tools. Replication cohort 1 was searched for rare and predicted deleterious variants and genetic association. Replication cohort 2 was used to investigate the association of common variants with BAV. Results: A total of 938 patients with BAV were included in this study: 69 (7.4%) in the discovery cohort, 417 (44.5%) in replication cohort 1, and 452 (48.2%) in replication cohort 2. A novel human nsBAV gene, MINDBOMB1 homologue MIB1, was identified. MINDBOMB1 homologue (MIB1) is an E3-ubiquitin ligase essential for NOTCH-signal activation during heart development. In approximately 2% of nsBAV index cases from the discovery and replication 1 cohorts, rare MIB1 variants were detected, predicted to be damaging, and were significantly enriched compared with population-based controls (2% cases vs 0.9% controls; P = .03). In replication cohort 2, MIB1 risk haplotypes significantly associated with nsBAV were identified (permutation test, 1000 repeats; P = .02). Two genetically modified mice models carrying Mib1 variants identified in our cohort showed BAV on a NOTCH1-sensitized genetic background. Conclusions and Relevance: This genetic association study identified the MIB1 gene as associated with nsBAV. This underscores the crucial role of the NOTCH pathway in the pathophysiology of BAV and its potential as a target for future diagnostic and therapeutic intervention.
Subject(s)
Bicuspid Aortic Valve Disease , Signal Transduction , Ubiquitin-Protein Ligases , Receptors, Notch/metabolism , Ubiquitin-Protein Ligases/genetics , Ubiquitin-Protein Ligases/metabolism , Genetic Association Studies , HumansABSTRACT
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 (P<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 (P<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 FGFR2, PPP2CA, and ADAM17 in human carotid artery smooth muscle cells and WNT5A, APP, and APC 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.
Subject(s)
Aortic Valve Stenosis , Atherosclerosis , Calcinosis , Extracellular Vesicles , MicroRNAs , Humans , Aortic Valve/pathology , Aortic Valve Stenosis/pathology , Multiomics , Calcinosis/metabolism , Cells, Cultured , MicroRNAs/metabolism , Atherosclerosis/pathology , Wnt Signaling Pathway , Extracellular Vesicles/metabolismABSTRACT
AIMS: Calcific aortic valve disease (CAVD) is the most common valve disease, which consists of a chronic interplay of inflammation, fibrosis, and calcification. In this study, sortilin (SORT1) was identified as a novel key player in the pathophysiology of CAVD, and its role in the transformation of valvular interstitial cells (VICs) into pathological phenotypes is explored. METHODS AND RESULTS: An aortic valve (AV) wire injury (AVWI) mouse model with sortilin deficiency was used to determine the effects of sortilin on AV stenosis, fibrosis, and calcification. In vitro experiments employed human primary VICs cultured in osteogenic conditions for 7, 14, and 21 days; and processed for imaging, proteomics, and transcriptomics including single-cell RNA-sequencing (scRNA-seq). The AVWI mouse model showed reduced AV fibrosis, calcification, and stenosis in sortilin-deficient mice vs. littermate controls. Protein studies identified the transition of human VICs into a myofibroblast-like phenotype mediated by sortilin. Sortilin loss-of-function decreased in vitro VIC calcification. ScRNA-seq identified 12 differentially expressed cell clusters in human VIC samples, where a novel combined inflammatory myofibroblastic-osteogenic VIC (IMO-VIC) phenotype was detected with increased expression of SORT1, COL1A1, WNT5A, IL-6, and serum amyloid A1. VICs sequenced with sortilin deficiency showed decreased IMO-VIC phenotype. CONCLUSION: Sortilin promotes CAVD by mediating valvular fibrosis and calcification, and a newly identified phenotype (IMO-VIC). This is the first study to examine the role of sortilin in valvular calcification and it may render it a therapeutic target to inhibit IMO-VIC emergence by simultaneously reducing inflammation, fibrosis, and calcification, the three key pathological processes underlying CAVD.
Subject(s)
Aortic Valve Stenosis , Calcinosis , Humans , Animals , Mice , Aortic Valve Stenosis/genetics , Aortic Valve/pathology , Calcinosis/metabolism , Constriction, Pathologic , Cells, Cultured , FibrosisABSTRACT
Acute postoperative pain (APOP) is often evaluated through granular parameters, though monitoring postoperative pain using trends may better describe pain state. We investigated acute postoperative pain trajectories in cardiac surgical patients to identify subpopulations of pain resolution and elucidate predictors of problematic pain courses. We examined retrospective data from 2810 cardiac surgical patients at a single center. The k-means algorithm for longitudinal data was used to generate clusters of pain trajectories over the first 5 postoperative days. Patient characteristics were examined for association with cluster membership using ordinal and multinomial logistic regression. We identified 3 subgroups of pain resolution after cardiac surgery: 37.7% with good resolution, 44.2% with moderate resolution, and 18.2% exhibiting poor resolution. Type I diabetes (2.04 [1.00-4.16], p = 0.05), preoperative opioid use (1.65 [1.23-2.22], p = 0.001), and illicit drug use (1.89 [1.26-2.83], p = 0.002) elevated risk of membership into worse pain trajectory clusters. Female gender (1.72 [1.30-2.27], p < 0.001), depression (1.60 [1.03-2.50], p = 0.04) and chronic pain (3.28 [1.79-5.99], p < 0.001) increased risk of membership in the worst pain resolution cluster. This study defined 3 APOP resolution subgroups based on pain score trend after cardiac surgery and identified factors that predisposed patients to worse resolution. Patients with moderate or poor pain trajectory consumed more opioids and received them for longer before discharge. Future studies are warranted to determine if altering postoperative pain monitoring and management improve postoperative course of patients at risk of moderate or poor pain resolution.
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Cellular heterogeneity of aortic valves complicates the mechanistic evaluation of the calcification processes in calcific aortic valve disease (CAVD), and animal disease models are lacking. In this study, we identify a disease-driver population (DDP) within valvular interstitial cells (VICs). Through stepwise single-cell analysis, phenotype-guided omic profiling, and network-based analysis, we characterize the DDP fingerprint as CD44highCD29+CD59+CD73+CD45low and discover potential key regulators of human CAVD. These DDP-VICs demonstrate multi-lineage differentiation and osteogenic properties. Temporal proteomic profiling of DDP-VICs identifies potential targets for therapy, including MAOA and CTHRC1. In vitro loss-of-function experiments confirm our targets. Such a stepwise strategy may be advantageous for therapeutic target discovery in other disease contexts.
Subject(s)
Aortic Valve Stenosis , Calcinosis , Animals , Aortic Valve/pathology , Cells, Cultured , Extracellular Matrix Proteins , Humans , Osteogenesis , ProteomicsABSTRACT
AIMS: Mitral valve prolapse (MVP) is a common valvular heart disease with a prevalence of >2% in the general adult population. Despite this high incidence, there is a limited understanding of the molecular mechanism of this disease, and no medical therapy is available for this disease. We aimed to elucidate the genetic basis of MVP in order to better understand this complex disorder. METHODS AND RESULTS: We performed a meta-analysis of six genome-wide association studies that included 4884 cases and 434 649 controls. We identified 14 loci associated with MVP in our primary analysis and 2 additional loci associated with a subset of the samples that additionally underwent mitral valve surgery. Integration of epigenetic, transcriptional, and proteomic data identified candidate MVP genes including LMCD1, SPTBN1, LTBP2, TGFB2, NMB, and ALPK3. We created a polygenic risk score (PRS) for MVP and showed an improved MVP risk prediction beyond age, sex, and clinical risk factors. CONCLUSION: We identified 14 genetic loci that are associated with MVP. Multiple analyses identified candidate genes including two transforming growth factor-ß signalling molecules and spectrin ß. We present the first PRS for MVP that could eventually aid risk stratification of patients for MVP screening in a clinical setting. These findings advance our understanding of this common valvular heart disease and may reveal novel therapeutic targets for intervention.
Subject(s)
Mitral Valve Prolapse , Adult , Genetic Loci/genetics , Genome-Wide Association Study , Humans , Latent TGF-beta Binding Proteins/genetics , Mitral Valve Prolapse/genetics , Proteomics , Risk FactorsABSTRACT
BACKGROUND: Long noncoding RNAs (lncRNAs) have been implicated in the pathogenesis of cardiovascular diseases. We aimed to identify novel lncRNAs associated with the early response to ischemia in the heart. METHODS AND RESULTS: RNA sequencing data gathered from 81 paired left ventricle samples from patients undergoing cardiopulmonary bypass was collected before and after a period of ischemia. Novel lncRNAs were validated with Oxford Nanopore Technologies long-read sequencing. Gene modules associated with an early ischemic response were identified and the subcellular location of selected lncRNAs was determined with RNAscope. A total of 2446 mRNAs, 270 annotated lncRNAs and one novel lncRNA differed in response to ischemia (adjusted p < 0.001, absolute fold change >1.2). The novel lncRNA belonged to a gene module of highly correlated genes that also included 39 annotated lncRNAs. This module associated with ischemia (Pearson correlation coefficient = -0.69, p = 1 × 10-23) and activation of cell death pathways (p < 6 × 10-9). A further nine novel cardiac lncRNAs were identified, of which, one overlapped five cis-eQTL eSNPs for the gene RWD Domain-Containing Sumoylation Enhancer (RWDD3) and was itself correlated with RWDD3 expression (Pearson correlation coefficient -0.2, p = 0.002). CONCLUSION: We have identified 10 novel lncRNAs, one of which was associated with myocardial ischemia and may have potential as a novel therapeutic target or early marker for myocardial dysfunction.
Subject(s)
Myocardial Ischemia/genetics , Myocardial Ischemia/metabolism , RNA, Long Noncoding/metabolism , Databases, Genetic , Gene Expression Regulation , Gene Regulatory Networks , Heart Ventricles/metabolism , High-Throughput Nucleotide Sequencing , Humans , Myocardium/metabolism , RNA, Messenger/metabolism , Sequence Analysis, RNAABSTRACT
Objective: Aortic valve (AV) leaflets rely on a precise extracellular matrix (ECM) microarchitecture for appropriate biomechanical performance. The ECM structure is maintained by valvular interstitial cells (VICs), which reside within the leaflets. The presence of pigment produced by a melanocytic population of VICs in mice with dark coats has been generally regarded as a nuisance, as it interferes with histological analysis of the AV leaflets. However, our previous studies have shown that the presence of pigment correlates with increased mechanical stiffness within the leaflets as measured by nanoindentation analyses. In the current study, we seek to better characterize the phenotype of understudied melanocytic VICs, explore the role of these VICs in ECM patterning, and assess the presence of these VICs in human aortic valve tissues. Approach and Results: Immunofluorescence and immunohistochemistry revealed that melanocytes within murine AV leaflets express phenotypic markers of either neuronal or glial cells. These VIC subpopulations exhibited regional patterns that corresponded to the distribution of elastin and glycosaminoglycan ECM proteins, respectively. VICs with neuronal and glial phenotypes were also found in human AV leaflets and showed ECM associations similar to those observed in murine leaflets. A subset of VICs within human AV leaflets also expressed dopachrome tautomerase, a common melanocyte marker. A spontaneous mouse mutant with no aortic valve pigmentation lacked elastic fibers and had reduced elastin gene expression within AV leaflets. A hyperpigmented transgenic mouse exhibited increased AV leaflet elastic fibers and elastin gene expression. Conclusions: Melanocytic VIC subpopulations appear critical for appropriate elastogenesis in mouse AVs, providing new insight into the regulation of AV ECM homeostasis. The identification of a similar VIC population in human AVs suggests conservation across species.
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Patients with bicuspid aortic valve (BAV) have an increased risk of aortic dilation and aortic dissection or rupture. The impact of physical training on the natural course of aortopathy in BAV patients remains unclear. The aim of this study was to evaluate the impact of regular physical activity on aortic diameters in a consecutive cohort of paediatric patients with BAV. Consecutive paediatric BAV patients were evaluated and categorized into two groups: physically active and sedentary subjects. Only the subjects with a complete 2-year follow-up were included in the study. To evaluate the potential impact of physical activity on aortic size, aortic diameters were measured at the sinus of Valsalva and mid-ascending aorta using echocardiography. We defined aortic diameter progression the increase of aortic diameter ≥ 10% from baseline. Among 90 BAV patients (11.5 ± 3.4 years of age, 77% males), 53 (59%) were physically active subjects. Compared to sedentary, physically active subjects were not significantly more likely to have > 10% increase in sinus of Valsalva (13% vs. 8%, p-value = 0.45) or mid-ascending aorta diameter (9% vs. 13%, p-value = 0.55) at 2 years follow-up, both in subjects with sinus of Valsalva diameter progression (3.7 ± 1.0 mm vs. 3.5 ± 0.8 mm, p-value = 0.67) and in those with ascending aorta diameter progression (3.0 ± 0.8 mm vs. 3.2 ± 1.3 mm, p-value = 0.83). In our paediatric cohort of BAV patients, the prevalence and the degree of aortic diameter progression was not significantly different between physically active and sedentary subjects, suggesting that aortic dilation is unrelated to regular physical activity over a 2-year period.
Subject(s)
Aortic Valve/pathology , Bicuspid Aortic Valve Disease/physiopathology , Disease Progression , Exercise , Adolescent , Aortic Valve/diagnostic imaging , Bicuspid Aortic Valve Disease/diagnostic imaging , Case-Control Studies , Child , Echocardiography , Female , Humans , Male , Retrospective StudiesABSTRACT
Calcific aortic valve disease (CAVD) occurs when subpopulations of valve cells undergo specific differentiation pathways, promoting tissue fibrosis and calcification. Lipoprotein particles carry oxidized lipids that promote valvular disease, but low-density lipoprotein-lowering therapies have failed in clinical trials, and there are currently no pharmacological interventions available for this disease. Apolipoproteins are known promoters of atherosclerosis, but whether they possess pathogenic properties in CAVD is less clear. To search for a possible link, we assessed 12 apolipoproteins in nonfibrotic/noncalcific and fibrotic/calcific aortic valve tissues by proteomics and immunohistochemistry to understand if they were enriched in calcified areas. Eight apolipoproteins (apoA-I, apoA-II, apoA-IV, apoB, apoC-III, apoD, apoL-I, and apoM) were enriched in the calcific versus nonfibrotic/noncalcific tissues. Apo(a), apoB, apoC-III, apoE, and apoJ localized within the disease-prone fibrosa and colocalized with calcific regions as detected by immunohistochemistry. Circulating apoC-III on lipoprotein(a) is a potential biomarker of aortic stenosis incidence and progression, but whether apoC-III also induces aortic valve calcification is unknown. We found that apoC-III was increased in fibrotic and calcific tissues and observed within the calcification-prone fibrosa layer as well as around calcification. In addition, we showed that apoC-III induced calcification in primary human valvular cell cultures via a mitochondrial dysfunction/inflammation-mediated pathway. This study provides a first assessment of a broad array of apolipoproteins in CAVD tissues, demonstrates that specific apolipoproteins associate with valvular calcification, and implicates apoC-III as an active and modifiable driver of CAVD beyond its potential role as a biomarker.
Subject(s)
Aortic Valve Stenosis/metabolism , Aortic Valve/pathology , Apolipoprotein C-III/metabolism , Calcinosis/metabolism , Aortic Valve/metabolism , Aortic Valve Stenosis/pathology , Apolipoprotein C-III/analysis , Calcinosis/pathology , Cells, Cultured , Humans , Inflammation/metabolism , Inflammation/pathology , Mitochondria/metabolism , Mitochondria/pathologyABSTRACT
OBJECTIVES: Functional mitral regurgitation (MR) is observed with ischaemic heart disease or aortic valve disease. Assessing the value of mitral valve repair or replacement (MVR/P) is complicated by frequent discordance between preoperative transthoracic echocardiographic (pTTE) and intraoperative transoesophageal echocardiographic (iTOE) assessment of MR severity. We examined the association of pTTE and iTOE with postoperative mortality in patients with or without MR, at the time of coronary artery bypass grafting (CABG) and/or aortic valve replacement without MVR/P. METHODS: Medical records of 6629 patients undergoing CABG and/or aortic valve replacement surgery with or without functional MR and who did not undergo MVR/P were reviewed. MR severity assessed by pTTE and iTOE were examined for association with postoperative mortality using proportional hazards regression while accounting for patient and operative characteristics. RESULTS: In 72% of 709 patients with clinically significant (moderate or greater) functional MR detected by pTTE, iTOE performed after induction of anaesthesia demonstrated a reduction in MR severity, while 2% of patients had increased severity of MR by iTOE. iTOE assessment of MR was better associated with long-term postoperative mortality than pTTE in patients with moderate MR [hazard ratio (HR) 1.31 (1.11-1.55) vs 1.02 (0.89-1.17), P-value for comparison of HR 0.025] but was not different for more than moderate MR [1.43 (0.96-2.14) vs 1.27 (0.80-2.02)]. CONCLUSIONS: In patients undergoing CABG and/or aortic valve replacement without MVR/P, these findings support intraoperative reassessment of MR severity by iTOE as an adjunct to pTTE in the prediction of mortality. Alone, these findings do not yet provide evidence for an operative strategy.
Subject(s)
Coronary Artery Bypass , Echocardiography, Transesophageal , Echocardiography , Heart Valve Prosthesis Implantation , Mitral Valve Insufficiency/diagnostic imaging , Aged , Heart Valve Prosthesis , Humans , Male , Middle Aged , Mitral Valve Insufficiency/surgery , Myocardial Ischemia/surgery , Proportional Hazards Models , Retrospective Studies , Treatment OutcomeABSTRACT
Extracellular vesicles (EVs) including plasma membrane-derived microvesicles and endosomal-derived exosomes aggregate by unknown mechanisms, forming microcalcifications that promote cardiovascular disease, the leading cause of death worldwide. Here, we show a framework for assessing cell-independent EV mechanisms in disease by suggesting that annexin A1 (ANXA1)-dependent tethering induces EV aggregation and microcalcification. We present single-EV microarray, a method to distinguish microvesicles from exosomes and assess heterogeneity at a single-EV level. Single-EV microarray and proteomics revealed increased ANXA1 primarily on aggregating and calcifying microvesicles. ANXA1 vesicle aggregation was suppressed by calcium chelation, altering pH, or ANXA1 neutralizing antibody. ANXA1 knockdown attenuated EV aggregation and microcalcification formation in human cardiovascular cells and acellular three-dimensional collagen hydrogels. Our findings explain why microcalcifications are more prone to form in vulnerable regions of plaque, regulating critical cardiovascular pathology, and likely extend to other EV-associated diseases, including autoimmune and neurodegenerative diseases and cancer.
ABSTRACT
BACKGROUND: Studies examining the role of factor V Leiden among patients at higher risk of atherothrombotic events, such as those with established coronary heart disease (CHD), are lacking. Given that coagulation is involved in the thrombus formation stage on atherosclerotic plaque rupture, we hypothesized that factor V Leiden may be a stronger risk factor for atherothrombotic events in patients with established CHD. METHODS: We performed an individual-level meta-analysis including 25 prospective studies (18 cohorts, 3 case-cohorts, 4 randomized trials) from the GENIUS-CHD (Genetics of Subsequent Coronary Heart Disease) consortium involving patients with established CHD at baseline. Participating studies genotyped factor V Leiden status and shared risk estimates for the outcomes of interest using a centrally developed statistical code with harmonized definitions across studies. Cox proportional hazards regression models were used to obtain age- and sex-adjusted estimates. The obtained estimates were pooled using fixed-effect meta-analysis. The primary outcome was composite of myocardial infarction and CHD death. Secondary outcomes included any stroke, ischemic stroke, coronary revascularization, cardiovascular mortality, and all-cause mortality. RESULTS: The studies included 69 681 individuals of whom 3190 (4.6%) were either heterozygous or homozygous (n=47) carriers of factor V Leiden. Median follow-up per study ranged from 1.0 to 10.6 years. A total of 20 studies with 61 147 participants and 6849 events contributed to analyses of the primary outcome. Factor V Leiden was not associated with the combined outcome of myocardial infarction and CHD death (hazard ratio, 1.03 [95% CI, 0.92-1.16]; I2=28%; P-heterogeneity=0.12). Subgroup analysis according to baseline characteristics or strata of traditional cardiovascular risk factors did not show relevant differences. Similarly, risk estimates for the secondary outcomes including stroke, coronary revascularization, cardiovascular mortality, and all-cause mortality were also close to identity. CONCLUSIONS: Factor V Leiden was not associated with increased risk of subsequent atherothrombotic events and mortality in high-risk participants with established and treated CHD. Routine assessment of factor V Leiden status is unlikely to improve atherothrombotic events risk stratification in this population.
Subject(s)
Coronary Disease/genetics , Factor V/genetics , Genotype , Thrombosis/genetics , Atherosclerosis , Clinical Trials as Topic , Coronary Disease/diagnosis , Coronary Disease/mortality , Genetic Predisposition to Disease , Humans , Polymorphism, Single Nucleotide , Precision Medicine , Prognosis , RiskABSTRACT
OBJECTIVE: Bicuspid aortic valve is a common risk factor for thoracic aortic aneurysm and dissection. Guidelines for elective ascending aortic intervention (AAI) in bicuspid aortic valve are derived from limited evidence, and the extent of practice variation due to patient and provider characteristics is unknown. Using data from 2 large cardiovascular registries, we investigated factors that influence decisions for AAI. METHODS: All bicuspid aortic valve cases with known aortic diameters and surgical status were included. We used multivariable logistic regression to profile predictors of isolated aortic valve replacement (AVR) or AVR+AAI, stratified by patient characteristics, surgical indications, and institution. RESULTS: We studied 2861 subjects at 18 institutions from 1996 to 2015. The median aortic diameter of patients who underwent AVR+AAI varied widely across institutions (39-52 mm). Aortic diameters were <45 mm in 38% of patients undergoing AVR+AAI. Patients who underwent AAI at <45 mm, compared with those managed nonoperatively, were younger (54 ± 13 vs 61 ± 15 years; P < .001) with more frequent aortic stenosis (53% vs 28%; P < .001) and regurgitation (52% vs 18%; P < .001). CONCLUSIONS: Clinical and institutional factors influence the timing of AAI and are associated with significant variability in ascending aortic diameter at AAI across institutions. More than one third of patients with a bicuspid aortic valve undergo AAI at aortic diameters <45 mm. Long-term outcomes of this subgroup of patients, who may manifest earlier and more severe disease, are needed to determine the risk-benefit ratio of routine aortic interventions at smaller diameters.