Materiały źródłowe

• #1 Aortic Valve Disease – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK542205/

  Aortic valve disease consists of regurgitations comprising retrograde flow throw the aortic valve and stenosis or narrowing of the orifice limiting the anterograde flow through the valve. […] While the pathology may develop over many years, symptoms may not appear until the condition is severe; at this point, the morbidity and mortality of aortic valvular disease are very high. […] Aortic regurgitation leads to retrograde blood flow from the aorta into the left ventricle, increased left ventricular volume, and chamber dilation. […] Narrowing the valve in aortic stenosis occurs due to the fusion of the leaflets or calcifications that cause the valve to have decreased mobility and obstruct the orifice. […] Calcified aortic stenosis occurs via progressive endothelial damage that can initially cause inflammation and infiltration of macrophages and other inflammatory cells.

• #1 Pathogenesis and Molecular Immune Mechanism of Calcified Aortic Valve Disease

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8734655/

  Calcified aortic valve disease (CAVD) was previously regarded as a passive process associated with valve degeneration and calcium deposition. However, recent studies have shown that the occurrence of CAVD is an active process involving complex changes such as endothelial injury, chronic inflammation, matrix remodeling, and neovascularization. […] CAVD is often associated with aging, degenerative changes, and calcium deposition and is regarded as an irreversible passive process. However, in recent years, it has been gradually recognized that CAVD is an active process involving endothelial injury, lipid infiltration, chronic inflammation, matrix remodeling, fibrosis, cell differentiation, progressive calcification, and neovascularization. […] Accumulating evidence has shown that calcified aortic valve disease is an active inflammatory disease caused by various factors. The pathological mechanism is complex and includes endothelial injury, inflammatory reactions, and oxidative stress that cause changes in cell composition in the valve, which is characterized by local thickening of the valve, the deposition of calcium salt, and the formation of calcium nodules, resulting in dysfunctional valve activity and hemodynamic changes.

• #1 Pathogenesis and Molecular Immune Mechanism of Calcified Aortic Valve Disease

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8734655/

  The progression of calcified aortic valve disease is divided into two stages. The first stage is aortic valve sclerosis, in which extracellular matrix secretion is increased and some inflammatory cells infiltrate; the second stage is called aortic valve calcification, in which a large amount of calcium salts are deposited, forming calcium nodules, extracellular matrix components are abnormally increased, the valve leaflet is stiff and deformed, the number of interstitial cells in the valve is reduced, and neovascularization occurs. […] The role of inflammatory factors in regulating CAVD development and progression. Endothelial injury induces lipid particles (ApoB and ApoE), T lymphocytes and macrophages into the valve and releases large inflammatory factors, such as TNF-a, IL-1, TGF1, and VEGF. VEGF induces neovascularization. These inflammatory factors lead to osteoblast-like cells, ultimately inducing calcium deposition.

• #1

  https://link.springer.com/article/10.1007/s00395-022-00935-6

  The current proposed pathophysiological process of CAVD is divided into an initiation and a propagation phase. The initiation phase starts by damage and stimulation of the VECs, which can be initiated by oxidative or mechanical stress. […] The inflammatory milieu promotes VECs, VICs and macrophages to secrete extracellular vesicles, and induces apoptosis of macrophages and VICs, which release apoptotic bodies. […] The pathogenesis of calcific aortic valve disease. In the initiation phase, valvular endothelial cells (VECs) are activated by oxidative, mechanical or shear stress, leading to increased valvular permeability. […] The chronic inflammation stimulates apoptosis of macrophages and VICs and the release of extracellular vesicles, including apoptotic bodies, which both promote the continuous deposition of microcalcifications and crystals.

• #1 Pathophysiology, emerging techniques for the assessment and novel treatment of aortic stenosis | Open Heart

  https://openheart.bmj.com/content/10/1/e002244

  The precise pathological mechanism behind the stenosis of the aortic valve remains unresolved. Nonetheless, advancements in technology and research have changed our insight. A once considered passive, degenerative process due to ageing is now understood to be active, similar in its molecular underpinning to atherosclerosis and its associated inflammatory response. […] The initiation stage is analogous to that found in atherosclerosis. Initial endothelial insult results in the infiltration of low-density lipoproteins (LDLs) and Lp(a) into the valve, depositing within the fibrosa. […] Following this, reactive oxygen species modify the lipids into oxidised LDLs (OxLDLs). OxLDLs stimulate the extravasation of monocytes into the valve interstitium which consequently differentiate into macrophages. At this stage, the inflammatory cascade initiates; macrophages capture the OxLDLs to form foam cells, enhancing the influx of immune cells through a greater expression of adhesion molecules E-selectin and intercellular adhesion molecule 1, thus perpetuating the cycle.

• #1 Models for calcific aortic valve disease in vivo and in vitro | Cell Regeneration | Full Text

  https://cellregeneration.springeropen.com/articles/10.1186/s13619-024-00189-8

  Genetically modified animal models serve as crucial tools to replicate human disease traits, aiding the study of underlying mechanisms and therapeutic avenues. […] Mechanical injury models involve applying stress or damage to valve leaflets, initiating an inflammatory response and pathological tissue remodeling leading to CAVD. […] While each model describes different aspects of CAVD development, no single animal model consistent completely represents human CAVD with its wide spectrum of risk factors and heterogeneity. […] With regard to in vitro models, mimicking aortic valve structure and modeling the progression of CAVD dynamics are key issues that need to be addressed. […] The isolation of VECs and VICs is an essential step in studying CAVD in vitro. […] VICs are crucial contributors to the pathogenesis of calcific aortic valve disease by transforming into activated myofibroblasts-like cells.

• #1 Pathogenesis and Molecular Immune Mechanism of Calcified Aortic Valve Disease

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8734655/

  Under the stimulation of inflammatory mediators, chemokines, growth factors, and cathepsins released by inflammatory cells, normal collagen fibers and elastic fibers in the aortic valve are destroyed. Furthermore, fibroblasts in the aortic valve are induced to differentiate into myofibroblasts and are activated for a long time, producing a large amount of collagen. […] Myofibroblasts in the aortic valve are phenotypically between smooth muscle cells and fibroblasts and have dual properties. Under the stimulation of TGF-1, bone matrix protein and other cytokines, myofibroblasts differentiate into osteoblast-like cells, and then heterotopic calcification occurs in the valve. […] Neovascularization not only creates conditions for the infiltration of inflammatory cells and plasma lipids but also promotes endochondral osteogenesis in valves.

• #1 Calcific aortic valve disease: mechanisms, prevention and treatment | Nature Reviews Cardiology

  https://www.nature.com/articles/s41569-023-00845-7

  Calcific aortic valve disease (CAVD) is the most common disorder affecting heart valves and is characterized by thickening, fibrosis and mineralization of the aortic valve leaflets. […] Analyses of surgically explanted aortic valve leaflets have shown that dystrophic mineralization and osteogenic transition of valve interstitial cells co-occur with neovascularization, microhaemorrhage and abnormal production of extracellular matrix. […] Genetic and molecular studies have identified that the NOTCH, WNT-catenin and myocardin signalling pathways are involved in the control and commitment of valvular cells to a fibrocalcific lineage. […] Complex interactions between valve endothelial and interstitial cells and immune cells promote the remodelling of aortic valve leaflets and the development of CAVD.

• #1

  https://link.springer.com/article/10.1007/s00395-022-00935-6

  The role of the innate immune system is well established in the pathophysiology of ASCVD. Monocyte-derived macrophages are the principal immune cell type in atherosclerotic plaques and are involved in its initiation, progression and destabilization. […] Despite the differences between CAVD and ASCVD, the profound commonalities in risk factors and similarities in (early) pathological features suggest overlap in pathophysiology, including a key role for inflammation and activation of the innate immune system. […] Inflammation in CAVD occurs on several levels. Besides local inflammation in the aortic valves, inflammation can be observed in the circulation, by activated immune cells and increased inflammatory proteins. […] CAVD develops by an active inflammatory process driven by infiltrated lipoproteins and immune cells.

• #1 Aortic stenosis – Wikipedia

  https://en.wikipedia.org/wiki/Aortic_stenosis

  The human aortic valve normally consists of three cusps or leaflets and has an opening of 3.0-4.0 square centimeters. When the left ventricle contracts, it forces blood through the valve into the aorta and subsequently to the rest of the body. When the left ventricle expands again, the aortic valve closes and prevents the blood in the aorta from flowing backward (regurgitation) into the left ventricle. In aortic stenosis, the opening of the aortic valve becomes narrowed or constricted (stenotic) (e.g., due to calcification). Degenerative (the most common variety), and bicuspid aortic stenosis both begin with damage to endothelial cells from increased mechanical stress. […] Inflammation is thought to be involved in the earlier stages of the pathogenesis of AS and its associated risk factors are known to promote the deposition of LDL cholesterol and lipoprotein(a), a highly damaging substance, into the aortic valve, causing significant damage and stenosis over time. Infiltration of inflammatory cells (macrophages, T lymphocytes), followed by the release of inflammatory mediators such as interleukin-1-beta and transforming growth factor beta-1 occurs. Subsequently, fibroblasts differentiate into osteoblast-like cells, which results in abnormal bone matrix deposition leading to progressive valvular calcification and stenosis.

• #1 Aortic Stenosis: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/150638-overview

  When the aortic valve becomes stenotic, resistance to systolic ejection occurs and a systolic pressure gradient develops between the left ventricle and the aorta. This outflow obstruction leads to an increase in left ventricular (LV) systolic pressure. As a compensatory mechanism to normalize LV wall stress, LV wall thickness increases by parallel replication of sarcomeres, producing concentric hypertrophy. At this stage, the chamber is not dilated and ventricular function is preserved, although diastolic compliance is reduced. […] Eventually, however, LV end-diastolic pressure (LVEDP) rises, which causes a corresponding increase in pulmonary capillary arterial pressures and a decrease in cardiac output due to diastolic dysfunction. The contractility of the myocardium may also diminish, which leads to a decrease in cardiac output due to systolic dysfunction. Ultimately, heart failure develops.

• #1 Aortic Stenosis: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/150638-overview

  In most patients with aortic stenosis, LV systolic function is preserved and cardiac output is maintained for many years despite an elevated LV systolic pressure. Although cardiac output is normal at rest, it often fails to increase appropriately during exercise, which may result in exercise-induced symptoms. […] Diastolic dysfunction may occur as a consequence of impaired LV relaxation and/or decreased LV compliance, as a result of increased afterload, LV hypertrophy, or myocardial ischemia. LV hypertrophy often regresses following relief of valvular obstruction. However, some individuals develop extensive myocardial fibrosis, which may not resolve despite regression of hypertrophy. […] In patients with severe aortic stenosis, atrial contraction plays a particularly important role in diastolic filling of the LV. Thus, development of atrial fibrillation in aortic stenosis often leads to heart failure due to an inability to maintain cardiac output.

• #1 Aortic Stenosis: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/150638-overview

  Increased LV mass, increased LV systolic pressure, and prolongation of the systolic ejection phase all elevate the myocardial oxygen requirement, especially in the subendocardial region. Although coronary blood flow may be normal when corrected for LV mass, coronary flow reserve is often reduced. […] Myocardial perfusion is thus compromised by the relative decline in myocardial capillary density and by a reduced diastolic transmyocardial (coronary) perfusion gradient due to elevated LV diastolic pressure. Therefore, the subendocardium is susceptible to underperfusion, which results in myocardial ischemia. […] Angina results from a concomitant increased oxygen requirement by the hypertrophic myocardium and diminished oxygen delivery secondary to diminished coronary flow reserve, decreased diastolic perfusion pressure, and relative subendocardial myocardial ischemia.

• #1 Aortic Valve Disease – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK542205/

  The most common consequences of aortic stenosis stem from decreased anterograde flow from the left ventricle into the aorta, leading to a backup of blood in the left ventricle and increased left ventricular pressures. […] Aortic insufficiency occurs due to inadequate aortic valve closure during diastole, leading to retrograde blood flow from the aorta into the left ventricle. […] Aortic regurgitation can occur in a chronic or acute setting. […] The same pathologies most commonly cause chronic aortic regurgitation in developing countries, such as aortic stenosis, calcific disease, congenital bicuspid valve issues, and Marfan syndrome. […] Aortic stenosis is a condition more prevalent in the elderly population (fifth through eighth decades). […] The prognosis of patients with severe symptomatic aortic valve disease who do not undergo valve replacement is very poor, with survival at 3 years ranging from approximately 40 to 60%.

• #1 Physical examination in aortic valve disease: do we still need it in the modern era?

  https://www.escardio.org/Journals/E-Journal-of-Cardiology-Practice/Volume-18/physical-examination-in-aortic-valve-disease-do-we-still-need-it-in-the-modern

  Aortic valve disease, especially aortic stenosis (AS), has an increasing prevalence worldwide, so a good screening tool for the selection of patients being referred for further testing and surgical or interventional procedure is always needed. […] The classic signs such as a „parvus et tardus” carotid pulse, a loud late-peaking systolic murmur in the aortic area or a diminished A2 correlate with the severity of aortic stenosis, while wide pulse pressure and a holodiastolic regurgitant murmur are the hallmark findings in significant chronic aortic regurgitation. […] The intensity of the murmur reflects the velocity of blood flow across the valve, so a very loud murmur (grade 4 or greater) has a high specificity for severe AS. […] As aortic stenosis worsens, it takes longer for blood to be ejected through the valve.

• #1 Calcific aortic valve disease: mechanisms, prevention and treatment | Nature Reviews Cardiology

  https://www.nature.com/articles/s41569-023-00845-7

  Genetic studies are revealing the polygenic architecture of CAVD, and the risk loci identified so far have emphasized the importance of lipids and cell signalling related to fibrosis, mineralization and inflammation in its pathogenesis. […] Evidence suggests that decreasing the plasma levels of lipids such as lipoprotein(a) might be most effective for preventing the onset of aortic valve mineralization. […] Inflammation and mechanical stress stimulate osteogenic differentiation of human aortic valve interstitial cells. […] Lack of periostin leads to suppression of Notch1 signaling and calcific aortic valve disease. […] Tumor necrosis factor- accelerates the calcification of human aortic valve interstitial cells obtained from patients with calcific aortic valve stenosis via the BMP2-Dlx5 pathway. […] Macrophages promote aortic valve cell calcification and alter STAT3 splicing.

• #1 Calcific Aortic Valve Disease: Molecular Mechanisms and Therapeutic Approaches | ECR Journal

  https://www.ecrjournal.com/articles/calcific-aortic-valve-disease-molecular-mechanisms-and-therapeutic-approaches?language_content_entity=en

  The processes of aortic valve stenosis and calcification share many similarities with atherosclerosis, and the pathologies of both conditions have similar risk factors and histopathology. […] Activation of VICs and pathways of calcific aortic stenosis is the result of mechanical and shear stress, endothelial damage and deposition of LDLs, triggering inflammatory events and attracting inflammatory cells (monocytes, macrophages and T cells). […] VICs activated by the inflammatory process are designated myofibroblasts. […] These cells will develop angiogenic activity and produce matrix metalloproteinases, proteins that are involved in tissue remodelling and support VIC activation and transformation. […] During this process activated VICs differentiate into osteoblasts. […] The molecular mechanism underlying bicuspid aortic valve calcification was solved. Mutations in the transcriptional regulator NOTCH1 resulted in aortic valve anomalies and severe calcification, owing to impaired repression of the osteoblast stimulator runt-related transcription factor 2 (RUNX2).

• #1 Calcific Aortic Valve Disease: Molecular Mechanisms and Therapeutic Approaches | ECR Journal

  https://www.ecrjournal.com/articles/calcific-aortic-valve-disease-molecular-mechanisms-and-therapeutic-approaches?language_content_entity=en

  Calcific aortic valve disease (CAVD) is a slow, progressive disorder that ranges from mild valve thickening without obstruction of blood flow, termed aortic sclerosis, to severe calcification with impaired leaflet motion, termed aortic stenosis. […] The presence of osteoblasts in atherosclerotic vascular lesions and in CAVD implies that calcification is an active, regulated process akin to atherosclerosis, with lipoprotein deposition and chronic inflammation. […] CAVD is currently considered as an actively regulated and progressive disease, characterised by a cascade of cellular changes that initially cause fibrotic thickening, followed by extensive calcification of the aortic valve leaflets. […] Recent evidence suggests that CAVD is the result of an active inflammatory process affecting the valve and leading to osteoblastic transformation with bone formation of VICs by activation of the receptor activator of nuclear factor- B (RANK).

• #1 Novel Nitric Oxide-Mediated Mechanism Facilitates Calcific Aortic Valve Disease – Pediatrics Nationwide

  https://pediatricsnationwide.org/2021/03/02/novel-nitric-oxide-mediated-mechanism-facilitates-calcific-aortic-valve-disease/

  The novel pathway could be targeted to prevent or reverse aortic valve calcification in humans. […] Researchers have recently described a novel nitric oxide-mediated mechanism in calcific aortic valve disease that involves the ubiqutin-proteasome pathway, and its modulation in animal models was shown to cause aortic valve calcification. […] The proposed mechanisms are initiated by injury of the endothelial cells lining the aortic valve leaflets that ultimately drives a gene expression program within the valve cells leading to calcification, says Dr. Garg. […] In a series of experiments, the team showed that the novel mechanism works via a post-translational S-nitrosylation of the USP9X protein, which deubiquitinates and stabilizes a NOTCH1 ligand found in endothelial cells of the heart valve called MIB1.

• #1 Aortic valve sclerosis: Pathogenesis, clinical manifestations, diagnosis and management – UpToDate

  https://www.uptodate.com/contents/aortic-valve-sclerosis-pathogenesis-clinical-manifestations-diagnosis-and-management

  Aortic valve sclerosis is important clinically because it progresses to aortic stenosis in a minority of patients and is associated with increased cardiovascular risk, although this association does not appear to be causal. […] This topic will discuss the pathogenesis of aortic sclerosis and calcific aortic stenosis and the diagnosis, prevalence, clinical significance, and management of aortic sclerosis. […] Aortic sclerosis is defined as irregular thickening and/or calcification of the valve leaflets without stenosis (ie, antegrade transvalvular velocity is ≤2 m/s). […] The prevalence of aortic valve sclerosis detected by echocardiography increases with age from <10 percent at mean age less than 60 years to 35 percent between 75 and 84 years of age and approximately 50 percent of those over age 80.

• #1 Aortic Stenosis: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/150638-overview

  There may exist a causal association between LDL-C-related genetic variants and aortic valve disease. In a community-based study consisting of 6942 subjects with data on aortic valve calcium and more than 28,000 subjects with aortic stenosis (follow-up, 16 y), Smith et al found that genetic predisposition toward elevations in low-density lipoprotein cholesterol (LDL-C) (as indicated by genetic risk scores [GRSs]) but not elevated high-density lipoprotein cholesterol (HDL-C) or triglycerides GRSs were associated with the presence of aortic valve calcium and the incidence of aortic stenosis.

• #1 Calcified aortic valve disease complicated with and without diabetes mellitus: the underlying pathogenesis

  https://www.imrpress.com/journal/RCM/23/1/10.31083/j.rcm2301007/htm

  Aortic valve calcification may be related to the osteoblasts differentiation from endothelial cells. CAVD is a closely regulated process similar to bone osteogenesis. […] Aortic valve calcification may also be caused by lipid accumulation, including lipoprotein (a) and its associated oxidized phospholipids. […] Inflammation may be associated with remodeling of calcified aortic valve. […] Normal heart valves are avascular and absorb oxygen mainly through blood diffusion. During the onset of the disease, the expression of angiogenic factors leading to neovascularization affects the progress of valvular disease. […] Previous studies have shown that diabetes can not only accelerate the initiation of CAVD, but also promote the progress of CAVD. […] One of the common features of DM is chronic hyperglycemia which has been related to vascular and inflammatory cell interactions with AGEs.

• #1 Cross Talk between NOTCH Signaling and Biomechanics in Human Aortic Valve Disease Pathogenesis

  https://www.mdpi.com/2308-3425/1/3/237

  Aortic valve disease is a burgeoning public health problem associated with significant mortality. Loss of function mutations in NOTCH1 cause bicuspid aortic valve (BAV) and calcific aortic valve disease. […] The underlying pathogenesis remains largely unknown, and the interaction between molecular and mechanical contributing factors is poorly understood. […] Congenital aortic valve malformations such as bicuspid aortic valve (BAV) underlie the majority of cases of calcific AVD, and can be caused by loss of function mutations in NOTCH1. […] NOTCH signaling also plays a role in arterial remodeling and has direct effects upon elastin. […] The objective of this study was to develop a feasible and reliable experimental approach to exploring the role of NOTCH in the mechanobiology of human AVICs. […] NOTCH LOF in the setting of OSS activated ACTA2 expression in AVICs and significantly decreased ELN content, consistent with the hypothesis that NOTCH dysregulation combined with OSS plays a role in AVD processes.

• #1 Calcified aortic valve disease complicated with and without diabetes mellitus: the underlying pathogenesis

  https://www.imrpress.com/journal/RCM/23/1/10.31083/j.rcm2301007

  As the most prevalent valvular heart disease, calcific aortic valve disease (CAVD) is a major health problem with risk of severe morbidity and mortality in the absence of effective medical treatment beyond surgical or interventional aortic valve replacement. The pathology involved in CAVD is multifactorial, including valvular endothelial cells damage, valvular interstitial cells differentiation, extracellular matrix remodeling, inflammation, fibrosis and calcification. […] Recently, diabetes mellitus has also been shown to accelerate the progression of CAVD. CAVD patients complicated with diabetes mellitus may benefit from early aortic valve replacement when compared with those without diabetes mellitus. Hence, diabetes mellitus is considered as an independent risk factor for CAVD. Therefore, in-depth understanding of the pathogenesis of these two diseases and their relationship may help us find appropriate prevention and therapeutic strategies for CAVD patients complicated with diabetes mellitus.

• #1 Multi-Omics Approaches to Define Calcific Aortic Valve Disease Pathogenesis – Perfusfind

  https://perfusfind.com/en/multi-omics-approaches-to-define-calcific-aortic-valve-disease-pathogenesis/

  Calcific aortic valve disease sits at the confluence of multiple world-wide epidemics of aging, obesity, diabetes, and renal dysfunction, and its prevalence is expected to nearly triple over the next 3 decades. […] This substantial gap in care is largely because of our still-limited understanding of both normal aortic valve biology and the key regulatory mechanisms that drive disease initiation and progression. […] One promising and rapidly evolving tactic is the application of multiomics approaches to fully define disease pathogenesis. […] We also discuss recent forays toward the omics-based characterization of valvular (patho)biology at single-cell resolution; these efforts promise to shed new light on cellular heterogeneity in healthy and diseased valvular tissues and represent the potential to efficaciously target and treat key cell subpopulations. […] Last, we discuss systems biology- and network medicine-based strategies to extract meaning, mechanisms, and prioritized drug targets from multiomics datasets.

• #1 Pathophysiology, emerging techniques for the assessment and novel treatment of aortic stenosis | Open Heart

  https://openheart.bmj.com/content/10/1/e002244

  Hypertrophy itself can be maladaptive, contributing to diastolic dysfunction. […] The dilated heart can be visualised by multiple imaging modalities however CMR imaging can identify the underlying fibrosis at an earlier stage. […] There are no efficacious pharmacological treatments proven to slow CAS progression. However, multiple therapeutics have been repurposed or developed to decrease mortality without the associated complications of valve replacement. […] Novel treatments targeting Lp(a) show promise due to the molecules known structure and role in CAS pathophysiology; associated genetics and role as a monitorable biomarker.

• #1 Enhancing aortic valve drug delivery with PAR2-targeting magnetic nano-cargoes for calcification alleviation | Nature Communications

  https://www.nature.com/articles/s41467-024-44726-0

  Calcific aortic valve disease is a prevalent cardiovascular disease with no available drugs capable of effectively preventing its progression. […] However, due to the rapid blood flow rate associated with aortic valve stenosis and the lack of specific markers, achieving targeted drug delivery for calcific aortic valve disease has proved to be challenging. […] Here we find that protease-activated-receptor 2 (PAR2) expression is up-regulated on the plasma membrane of osteogenically differentiated valvular interstitial cells. […] Hence, cell membrane markers highly expressed in osteogenically differentiated VICs could represent a potential TDDS targeting site for treating CAVD. […] Notably, PAR3 (i.e., F2RL2-encoded protein) does not respond to synthetic peptides that mimic the putative tethered ligand.

• #1 Novel Nitric Oxide-Mediated Mechanism Facilitates Calcific Aortic Valve Disease – Pediatrics Nationwide

  https://pediatricsnationwide.org/2021/03/02/novel-nitric-oxide-mediated-mechanism-facilitates-calcific-aortic-valve-disease/

  Current evidence in the field demonstrates that nitric oxide prevents calcification through the cyclic GMP pathway. […] This is the first time the ubiquitin-proteasome pathway has been linked to calcific aortic valve disease. Importantly, this pathway is targetable; studies of cancer patients are already testing drug targets in this pathway, which with further investigation may ultimately be applicable in calcific aortic valve disease, says Dr. Majumdar.

• #1 Enhancing aortic valve drug delivery with PAR2-targeting magnetic nano-cargoes for calcification alleviation | Nature Communications

  https://www.nature.com/articles/s41467-024-44726-0

  Taken together, these results demonstrate that PAR2-ligand functionalization enhances the affinity of nanoparticles for osteogenically and myofibrogenically differentiated hVICs. […] These results demonstrate that the PAR2-targeted XCT790-loaded magnetic nanoparticles significantly inhibit the osteogenic differentiation of VICs, preventing the progression of aortic calcification in mice.

• #1 A new transcatheter heart valve concept | Mechanical Engineering – UCL – University College London

  https://www.ucl.ac.uk/mechanical-engineering/case-studies/2022/oct/new-transcatheter-heart-valve-concept

  Open heart surgical replacement of the aortic valve was previously an effective option for treating patients with heart valve disease. However, demographic changes mean that this surgery is not usually the best option anymore. The most relevant heart valve disease has now become aortic valve calcification, which is a mostly the age related stiffening of the valve leaflets, affecting more than 10% of people aged over 75. […] Transcatheter aortic valve implantation (TAVI), allows the delivery of a specially designed collapsible artificial valve through the vascular system, avoiding the need of open-heart surgery and its associated risks. […] Moreover, it is suitable for a wider range of aortic valve diseases than current TAVI. […] In addition, the use of polymer for the leaflets can reduce calcification. This is the main cause of structural degeneration in current prosthetic valves, meaning the new valves may also result in extended durability. […] Our research effort has resulted in a solution that has confirmed potential to improve safety, procedural simplification and reduced costs in replacing aortic valves, Professor Burriesci says.

• #1 Aortic Valve Disease | Frankel Cardiovascular Center | Michigan Medicine

  https://www.umcvc.org/conditions-treatments/aortic-valve-disease

  Aortic valve disease can also be caused by age-related buildup of calcium that causes the valve to become narrow and stiff (stenosis). […] Heart conditions such as a prior heart attack or high blood pressure can damage the aortic valve. […] High-dose radiation from cancer treatment can also lead to aortic valve disease. […] Infections such as rheumatic fever or infective endocarditis (an infection of inner lining of the heart that can also involve the heart valves) can cause aortic valve disease. […] During TAVR, the doctor uses a catheter to insert a replacement valve inside the diseased valve. […] During open surgery, the aortic valve can be replaced or repaired. Patients with stenosis typically require valve replacement. Leaky valves can often be repaired or replaced. […] Because replacement valves have a limited lifespan, surgeons prefer to repair a diseased aortic valve if possible, especially in younger patients.

• #2 Pathogenesis and Molecular Immune Mechanism of Calcified Aortic Valve Disease

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8734655/

  Calcified aortic valve disease (CAVD) was previously regarded as a passive process associated with valve degeneration and calcium deposition. However, recent studies have shown that the occurrence of CAVD is an active process involving complex changes such as endothelial injury, chronic inflammation, matrix remodeling, and neovascularization. […] CAVD is often associated with aging, degenerative changes, and calcium deposition and is regarded as an irreversible passive process. However, in recent years, it has been gradually recognized that CAVD is an active process involving endothelial injury, lipid infiltration, chronic inflammation, matrix remodeling, fibrosis, cell differentiation, progressive calcification, and neovascularization. […] Accumulating evidence has shown that calcified aortic valve disease is an active inflammatory disease caused by various factors. The pathological mechanism is complex and includes endothelial injury, inflammatory reactions, and oxidative stress that cause changes in cell composition in the valve, which is characterized by local thickening of the valve, the deposition of calcium salt, and the formation of calcium nodules, resulting in dysfunctional valve activity and hemodynamic changes.

• #2 Heart valve disease module 2: pathophysiology – The British Journal of Cardiology

  https://bjcardio.co.uk/2016/03/heart-valve-disease-module-2-pathophysiology-2/

  This is perhaps best exemplified by calcific aortic stenosis. Once believed to be the result of prolonged wear and tear and an inevitable consequence of ageing, this common condition is now recognised to be an active, highly-regulated inflammatory condition with common risk factors and similar pathological characteristics to atherosclerosis. […] Progressive narrowing of the aortic valve results from increased thickening and stiffness of the valve leaflets, which restricts their opening and imposes an increased afterload on the left ventricle. Mechanical stress is believed to act as the initiating trigger. This causes damage to the endothelium on the aortic aspect of the valve, facilitating the infiltration of inflammatory cells and lipid. This is believed to be a two stage process, with an initiation phase resulting from endothelial injury and inflammatory cell infiltration and a propagation phase resulting in progressive calcification.

• #2 Extracellular Matrix in Calcific Aortic Valve Disease: Architecture, Dynamic and Perspectives

  https://www.mdpi.com/1422-0067/22/2/913

  Pathophysiology of CAVD includes a disease continuum from sclerosis to chronic inflammation and then leaflet calcification, which ultimately can account for aortic stenosis (AS). CAVD was for a long time considered a degenerative disease, with a gradual accumulation of the calcium in the valve leaflets. It is now clear that it is instead the result of some active and complex cellular processes, firstly coordinated by valve interstitial cells (VICs), vascular endothelial cells (VECs) and inflammatory cells, which account for extracellular matrix (ECM) reorganization. […] In this work, the authors provide an extensive review of the literature concerning the role of ECM in the establishment of the two major hallmarks of CAVD: fibrosis and mineralization. […] Although for a long time CAVD pathogenesis has been described as a degenerative process with passive calcium deposition, recently many active processes have been implicated in the progressive calcification of the aortic valve.

• #2 Pathophysiology, emerging techniques for the assessment and novel treatment of aortic stenosis | Open Heart

  https://openheart.bmj.com/content/10/1/e002244

  The precise pathological mechanism behind the stenosis of the aortic valve remains unresolved. Nonetheless, advancements in technology and research have changed our insight. A once considered passive, degenerative process due to ageing is now understood to be active, similar in its molecular underpinning to atherosclerosis and its associated inflammatory response. […] The initiation stage is analogous to that found in atherosclerosis. Initial endothelial insult results in the infiltration of low-density lipoproteins (LDLs) and Lp(a) into the valve, depositing within the fibrosa. […] Following this, reactive oxygen species modify the lipids into oxidised LDLs (OxLDLs). OxLDLs stimulate the extravasation of monocytes into the valve interstitium which consequently differentiate into macrophages. At this stage, the inflammatory cascade initiates; macrophages capture the OxLDLs to form foam cells, enhancing the influx of immune cells through a greater expression of adhesion molecules E-selectin and intercellular adhesion molecule 1, thus perpetuating the cycle.

• #2 Pathophysiology, emerging techniques for the assessment and novel treatment of aortic stenosis | Open Heart

  https://openheart.bmj.com/content/10/1/e002244

  The propagation phase of CAS is characterised by repeated fibrosis and calcification. Inflammation activated VICs induce fibrosis by the secretion of matrix metalloproteinases through a myofibroblastic phenotype. […] This scarred tissue acts as a nidus for calcification in which inflammation-induced apoptosis of VICs leads to diffuse microcalcification through the release of apoptotic bodies. […] As the disease progresses, stiffening of the valve prompts further apoptosis, resulting in the calcific mechanisms superseding the immunological pathway in propagating CAS. […] The macroscopic manifestations of CAS, as a result of cellular pathological processes, affect the aortic valve and surrounding myocardium. Initially, valve disease is difficult to detect. […] Valvular narrowing increases myocardial burden, precipitating morphological maladaptation.

• #2 Aortic stenosis – Wikipedia

  https://en.wikipedia.org/wiki/Aortic_stenosis

  The human aortic valve normally consists of three cusps or leaflets and has an opening of 3.0-4.0 square centimeters. When the left ventricle contracts, it forces blood through the valve into the aorta and subsequently to the rest of the body. When the left ventricle expands again, the aortic valve closes and prevents the blood in the aorta from flowing backward (regurgitation) into the left ventricle. In aortic stenosis, the opening of the aortic valve becomes narrowed or constricted (stenotic) (e.g., due to calcification). Degenerative (the most common variety), and bicuspid aortic stenosis both begin with damage to endothelial cells from increased mechanical stress. […] Inflammation is thought to be involved in the earlier stages of the pathogenesis of AS and its associated risk factors are known to promote the deposition of LDL cholesterol and lipoprotein(a), a highly damaging substance, into the aortic valve, causing significant damage and stenosis over time. Infiltration of inflammatory cells (macrophages, T lymphocytes), followed by the release of inflammatory mediators such as interleukin-1-beta and transforming growth factor beta-1 occurs. Subsequently, fibroblasts differentiate into osteoblast-like cells, which results in abnormal bone matrix deposition leading to progressive valvular calcification and stenosis.

• #2

  https://link.springer.com/article/10.1007/s00395-022-00935-6

  The role of the innate immune system is well established in the pathophysiology of ASCVD. Monocyte-derived macrophages are the principal immune cell type in atherosclerotic plaques and are involved in its initiation, progression and destabilization. […] Despite the differences between CAVD and ASCVD, the profound commonalities in risk factors and similarities in (early) pathological features suggest overlap in pathophysiology, including a key role for inflammation and activation of the innate immune system. […] Inflammation in CAVD occurs on several levels. Besides local inflammation in the aortic valves, inflammation can be observed in the circulation, by activated immune cells and increased inflammatory proteins. […] CAVD develops by an active inflammatory process driven by infiltrated lipoproteins and immune cells.

• #2 Models for calcific aortic valve disease in vivo and in vitro | Cell Regeneration | Full Text

  https://cellregeneration.springeropen.com/articles/10.1186/s13619-024-00189-8

  Myofibroblast-like cells play a pivotal role in extracellular matrix remodeling during the pathogenesis of aortic valve calcification. […] Despite relatively rapid development of in vitro 3D models of CAVD in recent years, there are still some limitations. […] Overall, 3D aortic valve calcification tissue models are still in their nascent stages, but their potential applications hold immense promise.

• #2

  https://link.springer.com/article/10.1007/s00395-022-00935-6

  The differentiation of VICs into myofibroblasts or osteoblast-like cells is stimulated by cytokines, including TGF-1 or TNF, IFN-, IL-6 and receptor activator of NF-B ligand (RANKL). […] The role of macrophages in ASCVD is well established and shows many similarities with the pathogenesis of CAVD. Monocyte-derived macrophages are the main immune cell type found in the atherosclerotic plaque and play a central role in all stages of atherogenesis. […] The crucial role of lipoproteins is further demonstrated in the Reserva mouse model in which rapid normalization of circulating cholesterol after a period of hyperlipidemia leads to a normalization of valvular oxidative stress, suppression of pro-osteogenic signalling, and a prevention of disease progression. […] The prolonged presence of monocytes with a trained hyperresponsive phenotype is explained by the fact that training occurs at the level of myeloid precursors in the bone marrow.

• #2 Calcific Aortic Valve Disease: Molecular Mechanisms and Therapeutic Approaches | ECR Journal

  https://www.ecrjournal.com/articles/calcific-aortic-valve-disease-molecular-mechanisms-and-therapeutic-approaches?language_content_entity=en

  The processes of aortic valve stenosis and calcification share many similarities with atherosclerosis, and the pathologies of both conditions have similar risk factors and histopathology. […] Activation of VICs and pathways of calcific aortic stenosis is the result of mechanical and shear stress, endothelial damage and deposition of LDLs, triggering inflammatory events and attracting inflammatory cells (monocytes, macrophages and T cells). […] VICs activated by the inflammatory process are designated myofibroblasts. […] These cells will develop angiogenic activity and produce matrix metalloproteinases, proteins that are involved in tissue remodelling and support VIC activation and transformation. […] During this process activated VICs differentiate into osteoblasts. […] The molecular mechanism underlying bicuspid aortic valve calcification was solved. Mutations in the transcriptional regulator NOTCH1 resulted in aortic valve anomalies and severe calcification, owing to impaired repression of the osteoblast stimulator runt-related transcription factor 2 (RUNX2).

• #2 Identification of key genes and pathways in calcific aortic valve disease by bioinformatics analysis – Zhang – Journal of Thoracic Disease

  https://jtd.amegroups.org/article/view/33939/html

  Histological studies suggested that the early lesion of CAVD was an active inflammatory process shared some similarities with atherosclerosis, such as lipid deposition, macrophage and T-cell infiltration, and basement membrane disruption. […] Various molecular, cellular, and biomechanical mechanisms had been found involved in the progression of CAVD, such as bicuspid aortic valve, osteogenic mechanisms, endocrine mechanisms, dysregulated mineral metabolism, osteoclast deficiency, and developmental signaling. […] Inflammation is involved in the development and progression of CAVD, and calcification of the aortic valve was considered an inflammation-dependent process. […] The gene cluster containing HLA-DPA1, HLA-DRA, HLA-DMA, HLA-DMB, and CD74 detected by MCODE also suggested the role of immune response in CAVD. […] The present study suggested that the expression of ALDH2 was down-regulated in CAVD, however, the role of ALDH2 in CAVD had not been reported yet. It has been demonstrated that dysregulation of antioxidant mechanisms led to increased oxidative stress, which contributed to the progression of CAVD.

• #2 Aortic valve disease – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/aortic-valve-disease/symptoms-causes/syc-20355117

  Aortic valve stenosis is a thickening and narrowing of the valve between the heart’s main pumping chamber and the body’s main artery, called the aorta. The narrowing creates a smaller opening for blood to pass through. This reduces or blocks blood flow from the heart to the rest of the body. […] In aortic valve stenosis, the aortic valve opening is narrowed, as shown in the top image. The heart must work harder to pump blood across the smaller opening. This increases pressure within the heart. Eventually the strain reduces the hearts ability to pump blood to the body. This is like placing smaller and smaller nozzles on the end of a garden hose, as shown on the bottom image. The narrower the nozzle is, the slower the flow of water. This results in pressure buildup within the garden hose. […] The valve may become thick and stiff or the valve may not close properly.

• #2 Aortic stenosis – Wikipedia

  https://en.wikipedia.org/wiki/Aortic_stenosis

  As a consequence of this stenosis, the left ventricle must generate a higher pressure with each contraction to effectively move blood forward into the aorta. Initially, the LV generates this increased pressure by thickening its muscular walls (myocardial hypertrophy). The type of hypertrophy most commonly seen in AS is known as concentric hypertrophy, in which the walls of the LV are (approximately) equally thickened. […] In the later stages, the left ventricle dilates, the wall thins, and the systolic function deteriorates (resulting in impaired ability to pump blood forward).

• #2 Novel Nitric Oxide-Mediated Mechanism Facilitates Calcific Aortic Valve Disease – Pediatrics Nationwide

  https://pediatricsnationwide.org/2021/03/02/novel-nitric-oxide-mediated-mechanism-facilitates-calcific-aortic-valve-disease/

  Current evidence in the field demonstrates that nitric oxide prevents calcification through the cyclic GMP pathway. […] This is the first time the ubiquitin-proteasome pathway has been linked to calcific aortic valve disease. Importantly, this pathway is targetable; studies of cancer patients are already testing drug targets in this pathway, which with further investigation may ultimately be applicable in calcific aortic valve disease, says Dr. Majumdar.

• #2 Aortic valve sclerosis and pathogenesis of calcific aortic stenosis – UpToDate

  https://www.uptodate.com/contents/aortic-valve-sclerosis-and-pathogenesis-of-calcific-aortic-stenosis

  Aortic valve thickening (sclerosis) without stenosis is common in older adults. It is often detected either as a systolic murmur on physical examination or on echocardiography or computed tomography (CT) performed for some other reason. Aortic valve sclerosis is important clinically because it can progress to aortic stenosis and is associated with increased cardiovascular risk. […] The pathobiology of aortic sclerosis and early calcific aortic valve disease shares similarities with atherosclerosis involving lipid accumulation, inflammation, and calcification. Calcification predominates in more advanced stages of aortic stenosis driving valve stiffness and narrowing. The pathobiology of calcific aortic valve disease is an area of active research, and our understanding of the cellular and molecular mechanisms of disease is in flux.

• #2 Aortic Stenosis Overview | American Heart Association

  https://www.heart.org/en/health-topics/heart-valve-problems-and-disease/heart-valve-problems-and-causes/problem-aortic-valve-stenosis

  Aortic stenosis mainly affects older people as a result of scarring and calcium buildup in the valve cusp (flap or fold). Age-related AS usually begins after age 60, but often it doesn’t show symptoms until ages 70 or 80. […] Bicuspid aortic valve is a birth defect where only two cusps grow instead of the normal three. This can lead to aortic stenosis. Another cause may be that the valve opening doesn’t grow along with the heart. This makes the heart work harder to pump blood to the restricted opening. Over the years the defective valve often becomes stiff and narrow because of calcium buildup.

• #2 Calcified aortic valve disease complicated with and without diabetes mellitus: the underlying pathogenesis

  https://www.imrpress.com/journal/RCM/23/1/10.31083/j.rcm2301007/htm

  DM is a kind of chronic and low-grade inflammatory reaction. […] ROS mediated oxidative stress plays an important role in the pathophysiology of CAVD. […] Aortic valve calcification in diabetic patients may be accomplished through different pathways. […] Overall, it is certain that molecules and pathways under CAVD and DM are numerous.

• #2 Enhancing aortic valve drug delivery with PAR2-targeting magnetic nano-cargoes for calcification alleviation | Nature Communications

  https://www.nature.com/articles/s41467-024-44726-0

  Calcific aortic valve disease is a prevalent cardiovascular disease with no available drugs capable of effectively preventing its progression. […] However, due to the rapid blood flow rate associated with aortic valve stenosis and the lack of specific markers, achieving targeted drug delivery for calcific aortic valve disease has proved to be challenging. […] Here we find that protease-activated-receptor 2 (PAR2) expression is up-regulated on the plasma membrane of osteogenically differentiated valvular interstitial cells. […] Hence, cell membrane markers highly expressed in osteogenically differentiated VICs could represent a potential TDDS targeting site for treating CAVD. […] Notably, PAR3 (i.e., F2RL2-encoded protein) does not respond to synthetic peptides that mimic the putative tethered ligand.

• #2 Pathophysiology, emerging techniques for the assessment and novel treatment of aortic stenosis | Open Heart

  https://openheart.bmj.com/content/10/1/e002244

  Hypertrophy itself can be maladaptive, contributing to diastolic dysfunction. […] The dilated heart can be visualised by multiple imaging modalities however CMR imaging can identify the underlying fibrosis at an earlier stage. […] There are no efficacious pharmacological treatments proven to slow CAS progression. However, multiple therapeutics have been repurposed or developed to decrease mortality without the associated complications of valve replacement. […] Novel treatments targeting Lp(a) show promise due to the molecules known structure and role in CAS pathophysiology; associated genetics and role as a monitorable biomarker.

• #2 Enhancing aortic valve drug delivery with PAR2-targeting magnetic nano-cargoes for calcification alleviation | Nature Communications

  https://www.nature.com/articles/s41467-024-44726-0

  Moreover, PAR2 has been implicated in atherosclerosis, which shares similar initial pathological features with CAVD. […] To further confirm that PAR2 expression is upregulated in osteogenically differentiated VICs as well as in calcified valve tissue in vivo, the protein expression pattern of PAR2 was examined in non-calcified and calcified aortic valves. […] Taken together, these data suggest that PAR2, as a membrane protein upregulated in calcified leaflets and osteogenically differentiated hVICs, might be an effective target for a CAVD TDDS. […] These results suggest that F2RL1-positive cells are disease-causing cells that can cause valve fibrosis and calcification, further supporting the design of targeted interventions against valve cells with high PAR2 expression. […] To verify the feasibility of PAR2 as a binding site of calcified valves for nanocarriers, FDA-approved materials with strong clinical translational potential are more appropriate.

• #3 Aortic valve sclerosis and pathogenesis of calcific aortic stenosis – UpToDate

  https://www.uptodate.com/contents/aortic-valve-sclerosis-and-pathogenesis-of-calcific-aortic-stenosis

  Aortic valve thickening (sclerosis) without stenosis is common in older adults. It is often detected either as a systolic murmur on physical examination or on echocardiography or computed tomography (CT) performed for some other reason. Aortic valve sclerosis is important clinically because it can progress to aortic stenosis and is associated with increased cardiovascular risk. […] The pathobiology of aortic sclerosis and early calcific aortic valve disease shares similarities with atherosclerosis involving lipid accumulation, inflammation, and calcification. Calcification predominates in more advanced stages of aortic stenosis driving valve stiffness and narrowing. The pathobiology of calcific aortic valve disease is an area of active research, and our understanding of the cellular and molecular mechanisms of disease is in flux.

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