The CNP/NPR-B/cGMP Axis is a Therapeutic Target in Calcific Aortic Stenosis.
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ABSTRACT:
SUBMITTER: Armstrong DWJ
PROVIDER: S-EPMC8733674 | biostudies-literature | 2021 Dec
REPOSITORIES: biostudies-literature
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The CNP/NPR-B/cGMP Axis is a Therapeutic Target in Calcific Aortic Stenosis.
Armstrong David W J DWJ Gupta Deepak K DK Lindman Brian R BR Merryman W David WD
JACC. Basic to translational science 20211227 12
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Project description:Calcific aortic stenosis (AS) is the most prevalent heart valve disorder in developed countries. It is characterized by progressive fibro-calcific remodelling and thickening of the aortic valve leaflets that, over years, evolve to cause severe obstruction to cardiac outflow. In developed countries, AS is the third-most frequent cardiovascular disease after coronary artery disease and systemic arterial hypertension, with a prevalence of 0.4% in the general population and 1.7% in the population >65 years old. Congenital abnormality (bicuspid valve) and older age are powerful risk factors for calcific AS. Metabolic syndrome and an elevated plasma level of lipoprotein(a) have also been associated with increased risk of calcific AS. The pathobiology of calcific AS is complex and involves genetic factors, lipoprotein deposition and oxidation, chronic inflammation, osteoblastic transition of cardiac valve interstitial cells and active leaflet calcification. Although no pharmacotherapy has proved to be effective in reducing the progression of AS, promising therapeutic targets include lipoprotein(a), the renin-angiotensin system, receptor activator of NF-?B ligand (RANKL; also known as TNFSF11) and ectonucleotidases. Currently, aortic valve replacement (AVR) remains the only effective treatment for severe AS. The diagnosis and staging of AS are based on the assessment of stenosis severity and left ventricular systolic function by Doppler echocardiography, and the presence of symptoms. The introduction of transcatheter AVR in the past decade has been a transformative therapeutic innovation for patients at high or prohibitive risk for surgical valve replacement, and this new technology might extend to lower-risk patients in the near future.
| S-EPMC5127286 | biostudies-literature
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| S-EPMC5928500 | biostudies-literature
Project description:Calcific aortic stenosis (AS) is the most common form of valve disease in the Western world and affects over 2.5 million individuals in North America. Despite the large burden of disease, there are no medical treatments to slow the development of AS, due at least in part to our incomplete understanding of its causes. The Cohorts for Heart and Aging Research in Genetic Epidemiology extra-coronary calcium consortium reported a genome-wide association study demonstrating that genetic variants in LPA are strongly associated with aortic valve (AV) calcium and clinical AS. Using a Mendelian randomization study design, it was demonstrated that the effect of this genetic variant is mediated by plasma lipoprotein (a) [Lp(a)], directly implicating elevations in Lp(a) as a cause of AV calcium and progression to AS. This discovery has sparked intense interest in Lp(a) as a modifiable cause for AV disease. Herein, we will review the mounting epidemiological and genetic findings in support of Lp(a)-mediated valve disease, discuss potential mechanisms underlying this observation, and outline the steps to translate this discovery to a much needed novel preventive and/or therapeutic strategy for AV disease.
| S-EPMC4878194 | biostudies-literature
Project description:Calcific aortic valve stenosis (CAVS) is a major health problem facing aging societies. The identification of osteoblast-like and osteoclast-like cells in human tissue has led to a major paradigm shift in the field. CAVS was thought to be a passive, degenerative process, whereas now the progression of calcification in CAVS is considered to be actively regulated. Mechanistic studies examining the contributions of true ectopic osteogenesis, nonosseous calcification, and ectopic osteoblast-like cells (that appear to function differently from skeletal osteoblasts) to valvular dysfunction have been facilitated by the development of mouse models of CAVS. Recent studies also suggest that valvular fibrosis, as well as calcification, may play an important role in restricting cusp movement, and CAVS may be more appropriately viewed as a fibrocalcific disease. High-resolution echocardiography and magnetic resonance imaging have emerged as useful tools for testing the efficacy of pharmacological and genetic interventions in vivo. Key studies in humans and animals are reviewed that have shaped current paradigms in the field of CAVS, and suggest promising future areas for research.
| S-EPMC3150727 | biostudies-literature
Project description:Background: Calcific aortic stenosis is the most prevalent valvular abnormality in the Western world. Factors commonly associated with calcific aortic stenosis include advanced age, male sex, hypertension, diabetes and impaired renal function. This review synthesises the existing literature on genetic associations with calcific aortic stenosis. Methods: A systematic search was conducted in the PubMed, Ovid and Cochrane libraries from inception to 21 July 2024 to identify human studies investigating the genetic factors involved in calcific aortic stenosis. From an initial pool of 1392 articles, 78 were selected for full-text review and 31 were included in the final qualitative synthesis. The risk of bias in these studies was assessed using the Newcastle Ottawa Scale. Results: Multiple genes have been associated with calcific aortic stenosis. These genes are involved in different biological pathways, including the lipid metabolism pathway (PLA, LDL, APO, PCSK9, Lp-PLA2, PONS1), the inflammatory pathway (IL-6, IL-10), the calcification pathway (PALMD, TEX41) and the endocrine pathway (PTH, VIT D, RUNX2, CACNA1C, ALPL). Additional genes such as NOTCH1, NAV1 and FADS1/2 influence different pathways. Mechanistically, these genes may promote a pro-inflammatory and pro-calcific environment in the aortic valve itself, leading to increased osteoblastic activity and subsequent calcific degeneration of the valve. Conclusions: Numerous genetic associations contribute to calcific aortic stenosis. Recognition of these associations can enhance risk stratification for individuals and their first-degree relatives, facilitate family screening, and importantly, pave the way for targeted therapeutic interventions focusing on the identified genetic factors. Understanding these genetic factors can also lead to gene therapy to prevent calcific aortic stenosis in the future.
| S-EPMC11508093 | biostudies-literature
Project description:GWAS on Calcific Aortic Valve Stenosis
| PRJNA420788 | ENA
Project description:GWAS on Calcific Aortic Valve Stenosis
| PRJNA420787 | ENA
Project description:BACKGROUND:Aortic stenosis (AS) is a chronic inflammatory disease, and calcification plays an important role in the progression of the disease. Galectin-3 (Gal-3) is a proinflammatory molecule involved in vascular osteogenesis in atherosclerosis. Therefore, we hypothesized that Gal-3 could mediate valve calcification in AS. METHODS AND RESULTS:Blood samples and aortic valves (AVs) from 77 patients undergoing AV replacement were analyzed. As controls, noncalcified human AVs were obtained at autopsy (n=11). Gal-3 was spontaneously expressed in valvular interstitial cells (VICs) from AVs and increased in AS as compared to control AVs. Positive correlations were found between circulating and valvular Gal-3 levels. Valvular Gal-3 colocalized with the VICs markers, alpha-smooth muscle actin and vimentin, and with the osteogenic markers, osteopontin, bone morphogenetic protein 2, runt-related transcription factor 2, and SRY (sex-determining region Y)-box 9. Gal-3 also colocalized with the inflammatory markers cd68, cd80 and tumor necrosis factor alpha. In vitro, in VICs isolated from AVs, Gal-3 induced expression of inflammatory, fibrotic, and osteogenic markers through the extracellular signal-regulated kinase 1 and 2 pathway. Gal-3 expression was blocked in VICs undergoing osteoblastic differentiation using its pharmacological inhibitor, modified citrus pectin, or the clustered regularly interspaced short palindromic repeats/Cas9 knockout system. Gal-3 blockade and knockdown decreased the expression of inflammatory, fibrotic, and osteogenic markers in differentiated VICs. CONCLUSIONS:Gal-3, which is overexpressed in AVs from AS patients, appears to play a central role in calcification in AS. Gal-3 could be a new therapeutic approach to delay the progression of AV calcification in AS.
| S-EPMC5210369 | biostudies-literature
Project description:The antiphospholipid syndrome is defined by antiphospholipid antibodies (aPL) together with arterial and/or venous thromboembolism and/or obstetric morbidities. aPL are overrepresented in SLE and acute myocardial infarction, but it is unknown whether aPL are associated with calcific aortic valve stenosis (CAVS) in the general population. The prevalence of aPL and other SLE-associated autoantibodies and their impact on aortic valve transcriptomics were therefore determined. A total of 233 tricuspid CAVS cases (median age 74, 69% male) and an age- and sex-matched control population were included. aPL were measured as anti-cardiolipin and anti-β2Glycoprotein-I of IgG/M/A isotypes. Resilient, thickened and calcified aortic valve (AV) tissue derived from five aPL positive and five matched aPL negative CAVS patients undergoing surgical aortic valve replacement were analysed by microarrays. The prevalence of positivity for any aPL (IgG/M/A) in patients with CAVS was 6.4% (95% CI 3.6% - 10.4%: n = 233). aPL IgG was significantly more prevalent in CAVS cases vs controls (4.6% vs 0.6%, P = 0.04). AV tissue from aPL IgG/IgM-positive patients was negatively enriched in pathways related to interferon signalling. One hundred differentially expressed genes could predict local AV CAVS progression with supervised machine learning algorithms. aPL IgG was more common in CAVS patients compared with matched controls and aPL positivity was associated with altered AV transcriptomics related to local disease progression and interferon pathways. Further studies should aim to establish aPL as a possible risk marker and/or causal factor for CAVS and could offer new precision therapeutic targets.
| S-EPMC9977117 | biostudies-literature
Project description:BackgroundProprotein convertase subtilisin/kexin type 9 (PCSK9), 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), cholesteryl ester transfer protein (CETP) and apolipoprotein C3 (APOC3) are pivotal regulators of lipid metabolism, with licensed drugs targeting these genes. The use of lipid-lowering therapy via the inhibition of these genes has demonstrated a reduction in the risk of cardiovascular disease. However, concerns persist regarding their potential long-term impact on aortic diseases and calcific aortic valve disease (CAVS). This study aims to investigate causal relationships between genetic variants resembling these genes and aortic disease, as well as calcific aortic valve disease using Mendelian randomization (MR).MethodsWe conducted drug-target Mendelian randomization employing summary-level statistics of low-density lipoprotein cholesterol (LDL-C) to proxy the loss-of-function of PCSK9, HMGCR, CETP and APOC3. Subsequently, we investigated the association between drug-target genetic variants and calcific aortic valve stenosis and aortic diseases, including thoracic aortic aneurysm (TAA), abdominal aortic aneurysm (AAA), and aortic dissection (AD).ResultsThe genetically constructed variants mimicking lower LDL-C levels were associated with a decreased risk of coronary artery disease, validating their reliability. Notably, HMGCR inhibition exhibited a robust protective effect against TAA (odds ratio (OR): 0.556, 95% CI: 0.372-0.831, p = 0.004), AAA (OR: 0.202, 95% CI: 0.107-0.315, p = 4.84 × 10-15), and AD (OR: 0.217, 95% CI: 0.098-0.480, p = 0.0002). Similarly, PCSK9, CETP and APOC3 inhibition proxies reduced the risk of AAA (OR: 0.595, 95% CI: 0.485-0.730, p = 6.75 × 10-7, OR: 0.127, 95% CI: 0.066-0.243, p = 4.42 × 10-10, and OR: 0.387, 95% CI: 0.182-0.824, p = 0.014, respectively) while showing a neutral impact on TAA and AD. Inhibition of HMGCR, PCSK9, and APOC3 showed promising potential in preventing CAVS with odds ratios of 0.554 (OR: 0.554, 95% CI: 0.433-0.707, p = 2.27 × 10-6), 0.717 (95% CI: 0.635-0.810, p = 9.28 × 10-8), and 0.540 (95% CI: 0.351-0.829, p = 0.005), respectively. However, CETP inhibition did not demonstrate any significant benefits in preventing CAVS (95% CI: 0.704-1.544, p = 0.836). The consistency of these findings across various Mendelian randomization methods, accounting for different assumptions concerning genetic pleiotropy, enhances the causal inference.ConclusionsOur MR analysis reveals that genetic variants resembling statin administration are associated with a reduced risk of AAA, TAA, AD and CAVS. HMGCR, PCSK9 and APOC3 inhibitors but not CETP inhibitors have positive benefits of reduced CAVS. Notably, PCSK9, CETP and APOC3 inhibitors exhibit a protective impact, primarily against AAA, with no discernible benefits extending to TAA or AD.
| S-EPMC11367000 | biostudies-literature