Insights into calcific aortic valve stenosis: a comprehensive overview of the disease and advancing treatment strategies

Aortic valve stenosis is a disease characterized by thickening and narrowing of the aortic valve (AV), most commonly due to calcification, which leads to left ventricular outflow obstruction called calcific aortic valve disease (CAVD). CAVD presents as a progressive clinical syndrome with cardiorespiratory symptoms, often with rapid deterioration. The modern-day pathophysiology of CAVD involves a complex interplay of genetic factors, chronic inflammation, lipid deposition, and valve calcification, with early CAVD stages resembling atherosclerosis. Various imaging modalities have been used to evaluate CAVD, with a recent trend of using advanced imaging to measure numerous AV parameters, such as peak jet velocity. Significant improvements in mortality have been achieved with transcatheter AV repair, but numerous therapeutics and modalities are being researched to delay the progression of CAVD. This article aims to provide a comprehensive review of CAVD, explore recent developments, and provide insights into future treatments with various novel modalities.


Introduction
Aortic valve sclerosis is characterized by thickening of the aortic valve (AV), typically accompanied by mild calcification without a significant pressure gradient (defined as an aortic jet velocity <2 m/s) [1] .The clinical importance lies in the fact that it is the most frequent cause of left ventricular (LV) outflow obstruction in both children and adults [1] .This condition primarily arises from three underlying causes: a congenital valve abnormality, often with additional calcification (unicuspid or bicuspid valves), calcific disease affecting a trileaflet valve, and rheumatic heart disease (RHD).
As AV leaflet thickening and calcification progress, the increased stiffness of the valve leads to obstruction at the valve level and a transition from aortic sclerosis to aortic stenosis (AS) [2] , which is referred to as calcific aortic valvular disease (CAVD).Numerous well-documented complications associated with CAVD include heart failure, sudden cardiac death, pulmonary hypertension, arrhythmias, and an increased propensity for bleeding [3][4][5][6][7][8][9][10] .For asymptomatic patients, there are currently no established medical treatments proven to delay the advancement of valve leaflet disease [11] .Although earlier retrospective studies appear promising regarding the use of statin therapy, a recent large-scale randomized prospective study revealed that statin therapy does not effectively halt disease progression [12] .In a recent investigation conducted by Lee et al. [13] , it was discovered that dipeptidyl peptidase-4 (DPP-4) inhibitors possessing favorable pharmacokinetic and pharmacodynamic properties were linked to a reduced risk of AS progression.In this study of 212 patients, the occurrence of severe AS progression was less common in the group receiving favorable heart-to-plasma DPP-4 inhibitor concentrations (7.1%) compared to the unfavorable DPP-4 inhibitor concentrations group (29.0%;P = 0.03) or the non-user group (29.6%;P = 0.01).After accounting for age, baseline renal function, and AS severity in Cox regression analysis, the group with favorable concentration of DPP-4 inhibitors exhibited a significantly reduced risk of severe AS development [hazard ratio (HR) 0.116, 95% confidence interval (CI) 0.024 to 0.551, P = 0.007].According to the 2021 European Society of Cardiology (ESC)/European Association for Cardio-Thoracic Surgery (EACTS) guidelines for the management of valvular heart disease, the sole effective intervention for severe symptomatic AS is aortic valve replacement (AVR) [14] .
This review aims to shed light on promising emerging therapeutic modalities employed in the management of CAVD.Furthermore, to highlight the urgent need to integrate such novel modalities, our review comprehensively covers the epidemiology, pathobiology, clinical features, diagnostic modalities, current management guidelines, and prognosis of CAVD.
The current review also aims to provide physicians with an indepth resource that ensures accurate diagnosis and management of patients, thus mitigating the risks of coronary artery and cardiovascular diseases in the context of CAVD, which are frequently associated with poor prognosis and increased morbidity and mortality rates.

Methodology
We conducted a search in the PubMed/MEDLINE, EMBASE, Google Scholar, and Scopus databases from inception until October 2023.Keywords and medical subject heading (MeSH) terms included 'Aortic valve disease,' 'calcific aortic stenosis,' 'senile aortic stenosis,' 'aortic valve calcinosis,' and 'calcification of aortic valve.' Boolean operators 'AND' and 'OR' were utilized to combine these MeSH terms.Our study encompassed all randomized controlled trials, observational studies, narrative reviews, and case reports investigating CAVD.Covidence facilitated the reviewing process, with two independent reviewers (A.G. and S.A.S.) screening titles and abstracts of retrieved studies to determine relevance.Full texts of potentially relevant studies were obtained and further assessed for eligibility.

Epidemiology
The reported incidence of CAVD has been found to vary between countries.In a study conducted in the year 2019, the highest number of reported cases has been reported in the United States (n = 117 080), followed by Japan (n = 71 837), which therefore increases concerns regarding the prevalence of CAVD [3] .According to the study, the prevalence of CAVD does not only vary amongst different nations but is also found to be notably higher among males and showed an upward trend with advancing age rather than females and younger age groups, accordingly [3] .In developed nations, after coronary artery disease and systemic arterial hypertension, CAVD is the third most common cardiovascular disease and affects the heart valves.According to a Norwegian study, there are 4.9 instances per 1000 people per year of CAVD cases.Projections show that due to present incidence rates and demographic changes, the number of patients with CAVD in wealthy countries over the age of 70 or 75 years will double or even triple in the next 50 years.However, because rheumatic fever (RF) and RHD are more common in developing nations, the epidemiology of AS differs [15] .In 2017, CAVD caused an estimated 12.6 million cases and 102 700 deaths worldwide.The disability-adjusted life years (DALYs) related to CAVD increased by 101% between 1990 and 2017.High-income areas, including Western Europe, the United States, Canada, Chile, Argentina, Australia, and New Zealand, had the highest death rates [16] .
While the prevalence of CAVD is 0.4% in the general population, it significantly increases to 1.7% in those over 65 years, with an estimated 3.4% prevalence of severe AS in people 75 years and older, frequently accompanied by symptoms [15] .Deaths attributed to CAVD have consistently increased over the past two decades, primarily affecting older adults in high-income countries.Children's range from 0.5% to 1%.Nevertheless, it accounts for more than half of the CAVD cases, which necessitates surgical intervention.This contributes considerably to the AV issues.A noteworthy difference between those with bicuspid and tricuspid valves is that people with bicuspid valves frequently develop CAVD one to two decades earlier [15] .With a prevalence of 1841 per 100 000 individuals worldwide in 2017 for men aged at least 70 years, it is noteworthy that men are disproportionately afflicted [16] .

Risk factors
Risk factors for AS include a sedentary lifestyle, obesity, dyslipidemia, DM, and hypertension.The risk of developing CAVD is enhanced by several risk factors such as metabolic syndrome, RF, and RHD.High blood pressure, obesity, and type 2 DM are modifiable risk factors.Intricate interactions between valve endothelial and interstitial cells, immune cells, and modifications to the hemostatic system, including platelet function, result in the development of CAVD.Risk evaluation is made more difficult by

HIGHLIGHTS
• Ataciguat, eplerenone, pelacarsen, PCSK9 inhibitors, colchicine, denosumab, pioglitazone, folic acid, and alendronic acid are emerging drugs that show potential in the management and progression of calcific aortic valve stenosis (CAVS).• Novel non-invasive ultrasound therapy may be an effective therapeutic modality for patients with CAVS.• Extensive research is currently underway to develop reliable biomarkers that can effectively track the progression of CAVS in patients, given its association with increased mortality and complications such as stroke.Among these biomarkers are the T50 test, high-sensitivity cardiac troponin, growth/differentiation factor 15, ST2 protein, and microRNAs (miRNAs).
hemodynamic risk factors including reduced cardiac output and LV systolic dysfunction [17] .Hereditary factors are believed to have an impact on regional variations in the prevalence of CAVD, which are characterized by clustering.The importance of signaling pathways, such as NOTCH, Wnt-catenin, and myocardin, in steering valvular cells toward a fibrocalcific lineage has been demonstrated by genetic and molecular research.The polygenic nature of CAVD has been demonstrated by ongoing genetic research, with a focus on lipid metabolism and cell signaling pathways connected to fibrosis, mineralization, and inflammation [15] .
Smoking and sedentary lifestyle are behavioral risk factors that have an impact on CAVD development.When age and sex were taken into account, a study indicated that sedentary activity elevated the risk of CAVD by 5.9 times, while hypertension, obesity, and DM were linked to 1.9, 1.8, and 1.6 times greater chances, respectively.These elements work together to create a complex environment for CAVD, making it a major public health concern [18] .
Cardiac risk factors have also been explored in multiple studies regarding their association with AS.Yan et al. [4] examined a group of over 1.12 million Canadians in an observational study and followed them up for more than a decade, and they have demonstrated a significant association between common cardiovascular risk factors such as hypertension, DM, and dyslipidemia and the likelihood of developing severe AS.Compared with other risk factors, hypertension was found to have the highest attributed risk.The study also demonstrated that the impact of cardiac risk factors on the development of AS was consistent between females and males, although a higher incidence of AS was noted in the latter group [4] .The incidence rate of ischemic stroke was 13.3 per 1000 person-years in the control group, whereas it increased to 30.4 per 1000 person-years in patients with AV stenosis, indicating a significantly higher risk among patients with AV stenosis compared to the control group across all age groups [4] .Similarly, another study has also demonstrated that AS consistently poses an elevated risk of cardiovascular events [5] .Since there is a high prevalence and potentially poorer management of CAVD risk factors in countries with lower income, including hypertension, there could be a higher risk imposed on such nations.

Molecular mechanisms of development
The etiology of AS has evolved significantly over the 20th century.Historically, RF was the main cause; however, in the modern world, AS is characterized by late-life onset and involves lipid deposition and inflammation in the AV.Genetic and environmental factors contribute to its development, with genome-wide association studies identifying key genetic polymorphisms related to factors such as lipoprotein metabolism, calcium signaling pathways, and genes such as RUNX2 and CACNA1C.Individuals with multiple affected siblings had a higher risk of AS, suggesting potential genetic factors.Mutations in NOTCH1 may also play a role, especially in families with a congenital bicuspid aortic valve (BAV) [19] .
CAVD has distinct initiation and propagation phases.The initiation phase shares similarities with atherosclerosis and involves endothelial damage, inflammation, and risk factors such as age, male sex, body mass index, smoking, hypertension, and elevated lipid levels.Mechanical stress plays a key role in the initiation of CAVD.The propagation phase is characterized by fibrosis, accelerated calcification, and a shift toward pro-osteogenic mechanisms.Factors such as reduced nitric oxide (NO) expression and upregulation of the renin-angiotensin system contribute to this phase.Valvular interstitial cells (VICs) undergo a phenotypic switch to osteoblast-like cells.Matrix Gla protein (MGP), a vitamin K-dependent protein, inhibits calcification, but vitamin K antagonist (VKA) drugs can exacerbate it [20] .
Recent research has identified genetic risk loci such as interleukin-6 (IL-6), ALPL, and NAV1 in CAVD.NAV1 exhibits a strong association between risk alleles and elevated NAV1 expression in the AV, which is associated with cardiovascular traits.IL-6 promotes valve mineralization, particularly through a specific SNP (rs1800795) in its promoter region.ALPL indirectly affects CAVD by influencing bone mineral density, whereas NAV1, linked to actin binding and expressed in the aorta, may play a role in vascular function [21] .
In AS and CAVD, modern-day pathophysiology involves a complex interplay of genetic factors, chronic inflammation, lipid deposition, and valve calcification.Early CAVD stages resemble atherosclerosis, with inflammation involving immune cell activation, leading to CAVD and obstruction of blood flow.Inflammation is driven by factors such as oxidized low-density lipoprotein (ox-LDL) and IL-6.Epigenetic factors and the microbiome may also contribute to this, and endothelial dysfunction is closely linked to calcific lesions.Lipid accumulation precedes inflammation, and lipoproteins (a) [Lp(a)] and oxidized phospholipids (OxPLs) contribute to inflammation and mineralization.Antioxidative endothelial cells release NO to inhibit valve interstitial cell differentiation into osteoblast-like cells; however, oxidative stress impairs NO production.Regulation of DPP-4 and insulin growth factor-1 (IGF-1) are implicated in calcification, and inhibition of BMP-2 and Notch signaling may offer therapeutic approaches.In CAVD, antigen-presenting cells (APCs), including macrophages and dendritic cells, play a pivotal role in inflammation.The imbalance between M1-like and M2 macrophages intensifies inflammation, whereas T lymphocytes, cytokines, and mechanical forces contribute to immune activation.NOTCH1 mutations are associated with CAVD pathogenesis, offering potential therapeutic targets along with the BGN-TLR3-IFNAR1 axis, which governs AV calcification [22][23][24][25][26][27][28][29] .
CAVD is a complex condition influenced by genetics and epigenetics.Genome-wide association studies have identified specific genetic variants linked to valvular calcification and AS, such as the LPA variant (rs10455872) and variants near PALMD, TEX41, GATA4, IL-6, and ALPL.Epigenetic modifications such as DNA methylation and long non-coding RNA H19 contribute to AV calcification via Notch-signaling pathways.Lp(a)-derived metabolites, such as lysophosphatidic acid, affect DNA methylation and PLPP3 activity, inducing pro-osteogenic effects.Multiomics has transformed CAVD research, with RNA sequencing (RNA-seq) revealing differential gene expression, especially in endothelia, and highlighting NOTCH1 haploinsufficiency networks.Proteomics identifies genes such as GFAP as specific VIC markers, whereas metabolomics unveils changes in metabolites and diverse valvular cell types.Research has explored the role of Runx2-expressing cells in CAVD and suggested potential therapeutic avenues.Oxidative stress is significant in CAVD and is driven by OxPLs that activate the NF-kB pathway and promote osteogenesis in VICs.Oxidative stress also reduces the NO levels and promotes osteogenesis.Asymmetric dimethylarginine, uric acid, and serotonin metabolism exacerbate oxidative stress.Oxidative stress is prominent in BAVs and affects disease progression.Capsaicin, with its anti-inflammatory and antioxidant properties, shows promise as a CAVD treatment.Studies on CAVD have identified differentially expressed genes, including circRNAs, lncRNAs, microRNAs (miRNAs), and mRNAs.Immune cell patterns revealed an increase in M0 macrophages and memory B cells as potential therapeutic targets.Research on rats has linked vascular calcification to chaperone genes and ER stress due to nicotine and vitamin D. Another study involving transcatheter aortic valve implantation (TAVI) in severe AS patients emphasized the role of microparticles in vascular health assessment [30][31][32][33][34][35][36][37][38] .

Classic clinical features
Most patients with CAVD are asymptomatic and are often discovered on diagnostic testing [39] .The initial presentation of the disease is often delayed until the valve orifice is narrowed to less than 1 cm 2 .Most patients with CAVD remain asymptomatic until the 7th to 8th decade of life in cases of CAVD as the hypertrophied LV can maintain cardiac output in the latent period.Anatomical abnormalities of the valve, such as a unicuspid or bicuspid AV, or the presence of metabolic diseases, such as alkaptonuria, can hasten the development of the disease and present in the 5th to 6th decades of life [40][41][42] .In symptomatic individuals, CAVD presents as a progressive clinical syndrome of cardiorespiratory symptoms with rapid deterioration.The cardinal features observed in cases of CAVD are angina pectoris, exertional dyspnea, and syncope [43] .Moreover, structural heart changes secondary to valvular obstruction can lead to the development of paroxysmal or recurrent arrhythmias that present as palpitations.
While severity is defined based on diagnostic tests, the onset of symptoms is associated with an overall poorer prognosis in patients with CAVD.Other late features of CAVD include heart failure, such as orthopnea, paroxysmal nocturnal dyspnea, and dyspnea due to pulmonary edema [44] .Symptoms of right heart failure and pulmonary hypertension may also develop in patients with AS; however, such cases are less common.

Subclinical features
As most patients with calcific AS are asymptomatic, it is necessary to define the subclinical features of CAVD.The presence of AV calcification, as well as increased calcium in the AV identified on echocardiographic studies, has been linked to the development of structural changes in the heart, such as increased LV size and atrial dilatation [45] .These structural changes indicate that the presence of AV calcifications can serve as a precursor to the development of heart failure, which is often seen as the endpoint of CAVD.Even without the development of stenotic AVs, simple calcification of the AVs has been linked to a higher incidence of non-fatal myocardial infarctions and non-fatal cerebrovascular accidents [46] .Furthermore, new-onset cognitive impairment could be a presenting feature of subclinical AV calcification, indicating the effect of CAVD on the overall vasculature of the body [47] .

Atypical presentations
Any deviation from the widely accepted natural course of the disease constitutes atypical presentation.While CAVD is generally present in the 7th or 8th decade of life, cases with much earlier presentations have been noted.These cases are generally associated with hereditary conditions or systemic inflammation, which hasten stenosis development.The unicuspid aortic valve is a rare entity that has been shown to present with AV calcifications as early as 3rd or 4th decade of life and is commonly misdiagnosed as a bicuspid aortic valvular disease [48] .Homozygous familial hypercholesterolemia is also a disease with varied clinical presentations, and even with appropriate treatment, it has been reported to present with an accelerated course of AV calcification and stenosis [49] .In children, a case of tuberous xanthoma initially presenting as CAVD has been noted, highlighting that the disease is not limited to the elderly [50] .Moreover, it is well documented that alkaptonuria presents with AV calcification, a condition popularly referred to as cardiac ochronosis [51] .Rare hereditary syndromes such as Singleton Merten syndrome must be considered when investigating familial cases of AS, as they present with difficult-to-group clinical features [52] .Aside from hereditary conditions, early-onset chronic renal disease with impaired calcium metabolism has been shown to present with rapidly progressive AV stenosis [53] .
A case of transient ischemic attack secondary to CAVD, possibly secondary to calcific emboli affecting the cerebral arteries, has been reported [54] .Heyde syndrome, a well-known cardiac manifestation of CAVD, has been reported to present with iron deficiency anemia, possibly due to chronic gastrointestinal blood loss from the angiodysplasias that develop due to the disease [55] .A case of recurrent ventricular arrhythmias has been noted in association with a calcified AV, which demonstrated resolution after AV reimplantation, indicating that such arrhythmias could be sequelae of AV calcifications [56] .A similar case of syncope due to paroxysmal AV block was also noted to be associated with calcified AV.An interesting case was reported in which a patient with CAVD presented with infertility.Upon further investigation, the cause was demonstrated to be calcifications of the bilateral vas deferens, thus highlighting a possible link between cardiac diseases and infertility [57] .

Non-cardiac features
In addition to its usual cardiac features, AS can have systemic manifestations.One of the most well-described non-cardiac manifestations of AS is that of Heyde syndrome, which presents as a triad of AS, angiodysplasias with associated bleeding, and acquired von Willebrand syndrome [58,59] .Iron deficiency anemia can also be observed in patients with AS, either secondary to longstanding gastrointestinal bleeds or due to other lesser-understood mechanisms [60] .AS has also been associated with the development of cognitive impairment in rigorous clinical testing, which improves with disease resolution.Moreover, CAVD can present as embolic stroke secondary to calcified embolus derived from AV calcifications [61,62] .

Clinical examination
As most cases of AS are asymptomatic until late in the disease course, a detailed clinical examination provides great help in screening for the disease.The findings of clinical examinations can be categorized as follows:

Palpation
Palpatory findings are more prominent later in the disease course.Structural changes in the heart result in a laterally displaced apical impulse due to LV hypertrophy, and in some cases, a double apical impulse may also be noted.Pulsus parvus et tardus, or a slow-rising carotid pulse with a delayed peak, may be palpated as the disease progresses and is one of the pathognomonic signs of the disease [63] .A case of visible pulsus parvus and tardus has also been reported [64] .

Auscultation
Although lacking specificity or sensitivity, auscultatory findings are one of the first signs noticed whenever AS is suspected.In fact, a comparative study demonstrated that auscultation is comparable, if not superior, in identifying stenotic valvular lesions [65] .The classic murmur of AS is a systolic, crescendo-decrescendo murmur often heard best in the second right intercostal space, which radiates to the carotid arteries [63] .A murmur with musical quality heard prominently at the apex (Gallavardin phenomenon), which may be confused with the murmur of mitral regurgitation (MR), may accompany the basal murmur in a minority of cases.This murmur must be differentiated from MR, which has a harsh holosystolic characteristic.Paradoxical splitting of the second heart sound may also be achieved with appropriate maneuvers [63] .In patients with BAV, an early systolic ejection murmur may be heard prior to the development of AS [66] .

Complications of CAVD
CAVD is associated with increased cardiovascular mortality and morbidity.Untreated disease can lead to significant complications ranging from sudden cardiac death to infective endocarditis.Sudden cardiac death may occur, even in asymptomatic individuals with no classic clinical features of the disease [8] .Calcification of the valve and the resulting stress lead to an increased predilection for the development of infective endocarditis in these patients.
Even after catheter-based valve replacement, the rate of heart failure development was higher in patients with CAVD.Myocardial ischemia and myocardial infarction are also observed in untreated patients and have an overall worse prognosis than those without coexisting AS [67] .Emboli from calcified AV can lead to the development of embolic stroke in these patients.

Investigations and imaging
Patients with AS typically present with a triad of symptoms, including angina pectoris, syncope, and dyspnea [68] .The presence of left-predominant features may indicate heart failure.Murmurs similar to those observed in AS may be heard in patients with pulmonic stenosis and hypertrophic obstructive cardiomyopathy; therefore, multiple clinical maneuvers are commenced for investigation and appropriate management [69] .Auscultation during inspiration increases murmurs in the case of pulmonary valve stenosis; innocent murmurs, on the contrary, would be decreased after standing in the supine position for a minute [70] , showing that innocent murmurs were found in approximately 65-85% of young school-aged children [70,71] .The Valsalva maneuver, forcing expiration against a closed glottis, may be used because it reduces preload and end-diastolic volume, which aids in differentiating between AS and hypertrophic obstructive cardiomyopathy, since murmurs are accentuated in response to the Valsalva maneuver in the latter, due to reduced end-diastolic volume [72] .

Chest X-ray
The initial diagnosis of AS is usually confirmed by chest radiography (CXR), especially in symptomatic undiagnosed patients.However, radiographic findings may not be significant in the initial stages due to a lack of compensatory mechanisms, yet they are typically found in cases of advancement and when heart failure occurs.Therefore, since CXR is a nonspecific tool, it is not recommended as a sufficient diagnostic tool for AS, despite its role in the initial diagnosis [73] .

Electrocardiography
A study by Cohen-Shelly et al. [74] used electrocardiography (ECG) with artificial intelligence (AI) for AS screening and successfully identified patients with moderate to severe AS.ECG is found to be an essential tool in detecting comorbidities such as coronary heart disease, yet it is not deemed a sufficient diagnostic tool for AS [72] .LV hypertrophy may be indicated, yet not reliably, through ECG by the Sokolow-Lyon voltage positive finding (Sv1 + RV5 or 6 > 3.5 mV) and strain pattern, which were both found to be associated with AS, according to a study conducted by Mino et al. [75] .

Echocardiography
Echocardiography remains a tool for definitive and confirmed diagnosis of AS [42,44] .Echocardiographic imaging provides a reliable evaluation of valve anatomy, motion, and the extent of obstruction and is hence considered the gold standard for AS diagnosis.Nevertheless, AS severity could be underestimated or, contrastingly, less often overestimated in hypertensive patients; therefore, imaging must be conducted under controlled blood pressure conditions to avoid the influence of confounding flow effects [42,44] .Clinical decision-making pertaining to AS patients is as follows: (1) maximum aortic velocity, (2) mean pressure gradient (Bernoulli equation is employed for calculation), (3) valve area (continuity equation is employed for calculation), (4) ratio of velocity in the LV outflow tract proximal to the AV, and (5) velocity in a narrowed aortic orifice, when discrepancies in the aforementioned measurements or in other clinical/imaging data are encountered [42,76] .
The American College of Cardiology (ACC)/American Heart Association (AHA) 2020 guidelines recommend the following routine for patients with asymptomatic AS and normal LV function [42] (Table 1).

CT scan
Cardiac computed tomography (CCT) imaging provides insights into the diagnosis of AS and provides deeper details of preinterventional planning [73] .Valvular calcification scored through CCT could further aid in assessing the severity of the patient's case, since it is found to be a predictor for the progression and prognosis of AS.Moreover, non-contrast calcium scoring of the aortic valve (CT-AVC) is recommended to evaluate AS severity, especially when echocardiography measurements are discordant [77] .In up to 40% of cases, patients have discordant echocardiographic assessments of AS, therefore warranting clinical uncertainty, highlighting the role CT-AVC plays, especially because of its imperative advantage of being independent of hemodynamic status.Nevertheless, it is crucial to acknowledge that the first-line and gold standard assessment of AS is Doppler echocardiography [78] .Meanwhile, contrast CT is considered the gold standard anatomical assessment prior to transcatheter AV intervention [78,79] .

Magnetic resonance imaging scan
Cardiac magnetic resonance (CMR) imaging is a useful, nonirradiating, non-invasive modality to assess the severity of AS through two parameters: (1) planimetry of the valve area and (2) peak velocity across the AV, the first being a faster procedure [80] .Therefore, CMR is considered an effective alternative to invasive techniques, such as transesophageal echocardiography and cardiac catheterization, in the context of AS, although echocardiography remains the cornerstone for AS evaluation [81] .Different CMR modalities are compared in Table 2, adapted from the American Heart Association [81] .
Although endomyocardial biopsy is considered the gold standard for assessing myocardial fibrosis, a hallmark of severe AS with an important prognostic role, the presence of focal or diffuse fibrosis could be non-invasively evaluated using CMR [81] .

Definitive diagnosis of CAVD
The diagnosis of CAVD is primarily based on echocardiographic examinations, which aid in visualizing the valve anatomy and severity of valve calcification.Longitudinal systolic strain imaging is a more sensitive indicator of LV function and is effective in anticipating unfavorable outcomes such as mortality [82] .Doppler echocardiography serves as the primary modality for assessing AS severity.However, in cases where the echocardiography results are inconclusive or conflicting, cardiac catheterization may be employed to confirm the hemodynamic severity of the stenosis.Cardiac catheterization facilitates the measurement of cardiac blood pressure and flow, aiding in precise diagnosis [42] .
CMR imaging is valuable in scenarios where echocardiographic data are suboptimal or contradictory to the clinical evaluation of AS severity.CMR is effective in distinguishing between bicuspid and trileaflet valve anatomies while also providing an accurate assessment of peak jet velocity.Furthermore, CMR is beneficial for evaluating the anatomy of the aortic root and ascending aorta, particularly in patients with a bicuspid valve [83] .
CT imaging offers an alternative approach for assessing valve area through planimetry and provides quantitative measurements of valve calcification.For patients undergoing transcatheter aortic valve replacement (TAVR), a multimodal imaging approach includes CT assessment of the aortic annulus size and shape, leaflet length, and the distance between the annulus and coronary ostia.
The standard criteria used to assess the severity of AS include the maximum velocity (V max ) across the stenotic valve, the mean transaortic pressure gradient (ΔP mean ) calculated using the Bernoulli equation, and the functional aortic valve area (AVA) determined using the continuity equation.Notably, echocardiographic calculations of ΔP mean and AVA have been rigorously validated against invasive measurements and are now considered the established clinical practice standards [42] .
The international clinical guidelines endorse the evaluation of AS severity using both echocardiography and CT-AVC scoring when echocardiographic assessments yield discordant results.CT-AVC has emerged as an alternative means of assessing AS severity, offering a structural assessment that is independent of flow, focusing on the quantification of the calcium burden within the valve.When employing sex-specific thresholds, CT-AVC demonstrates good accuracy compared with echocardiography and provides significant prognostic information.Additionally, 18F-sodium fluoride uptake in the AV, as observed through positron emission tomography (PET), aids in identifying active tissue calcification.Moreover, it predicts changes in AV calcification on follow-up CT scans conducted 1-2 years later.

Treatment
The management spectrum of CAVD is evolving constantly.Treatment modalities range from surgical interventions and medical management to palliative and transient relief services, such as aortic balloon valvuloplasty [84,85] .Simvastatin and ezetimibe combination therapy reduces ischemic events in mild-tomoderate AS but not in severe cases [12] .Elevated Lp(a) levels are known to potentiate the atherosclerotic process of CAVD.Pharmacological interventions targeting Lp(a), such as proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, slow the progression of CAVD and reduce the dependence on surgical treatment.However, interventions remain the gold standard of treatment for symptomatic patients with CAVD [84,85] .
Although the role of valvuloplasty has significantly reduced considering the development of TAVR, it is known to cause a modest increase in the AV area and reduce transvalvular pressure, providing short-term relief to patients.It neither improves the mortality rate nor offers any survival advantage.Aortic balloon dilatation is performed in children to avoid disrupting growth before definitive surgical valve replacement [86] .
The indications for AVR include symptomatic patients, asymptomatic patients with severe AS, patients undergoing cardiac surgery for any other cause, classic and low-flow low-gradient AS, or decreased blood flow velocity across the AV by at least 0.3 m/s per year [86] .
Artificial valves can be bioprosthetic or mechanical.The choice of valve depends on the patient's age and well-being.Mechanical valves, such as balls and cages and bi-leaflets, are more durable but can predispose to thrombosis and embolism; thus, there is a need for lifelong anticoagulant therapy.Bioprosthetic valves employed in AVR could either be balloon-expanding, such as Sapien, or self-expanding, such as CoreValve [87] .They could either be allografts or xenografts.The Ross procedure is generally employed for congenital AS, where the diseased AV is replaced with the patient's own pulmonary valve (autograft) and the pulmonary valve is replaced with an aortic or pulmonary allograft.The most commonly used xenografts were bovine and porcine pericardial valves [88] .
The major advantage of bioprosthetic valves is their ability to improve hemodynamics and blood flow considerably, postoperatively with no lifelong need for anticoagulants.However, they are less durable and prone to calcification on the valve leaflets [88] .
Due to the current technological advancements, more durable, less thrombogenic, and better hemodynamic stability-oriented valves are being researched.Obtained from the skin graft of burn victims, tissue-engineered heart valves are also infection-resistant. Culturing techniques may even reveal the tendency of these valves to repair themselves [88] .
AVR can be performed either via open-heart surgery or catheter insertion.Surgical AVR (SAVR) involves cardiopulmonary bypass (CPB) and cardioplegic arrest.Performed under general anesthesia, SAVR is the conventional treatment for patients with low or intermediate surgical risk.The damaged AV was replaced with either a mechanical or a biological artificial valve.Owing to the risks involved in performing open-heart surgery and associated complications postoperatively, a minimally invasive technique was sought after, which led to the development of TAVR [87] .
TAVR is performed percutaneously under general or local anesthesia depending on the route of insertion.The most common route is the transfemoral approach, which is performed under general anesthesia.TAVR involves the placement of a collapsible bioprosthetic AV inside the valve.During the expansion of the new valve, the narrowed valve was pushed outward, taking charge of the blood flow from the LV to the aorta [87] .
Other routes, such as transthoracic or transapical, can be employed when the femoral artery cannot be used due to any abnormalities in the vasculature factors, such as size, tortuosity, or possible chance of calcification.TAVR was originally developed for patients at high surgical risk, such as those with advanced age, comorbidities, or patient rejection.It is now widely accepted by patients across the entire spectrum of severity owing to better clinical outcomes and minimally invasive interventions [87] .Guideline recommendations should aid in the treatment of associated cardiac conditions such as heart failure, atrial fibrillation, and hypertension.In cases of resistant hypertension with concomitant atrial fibrillation or heart failure, renal denervation might be a suitable modality choice to prevent the worsening of symptoms of AS and acute decompensation due to the superimposition of multiple pathologies in a single patient [89] .

Therapies
The therapies are summarized in Table 3. Ataciguat (HMR1766) is a guanylyl cyclase activator [90] used in the management of pulmonary hypertension [91] because of its relaxant effects.Ataciguat may be useful in reducing blood pressure in patients with moderate CAVD (Clinicaltrials.govID: NCT02049203).An ongoing clinical trial (Clinicaltrials.govID: NCT04913870) evaluated the efficacy of angiotensin receptor blockers (ARBs) on mild-to-moderate AS and to slow AS progression and LV remodeling.Antifibrotic therapy (spironolactone and dihydralazine) is being evaluated in a phase-3 trial, Reduce-MFA, to assess their effect on the regression of myocardial fibrosis after TAVI using ECV-derived matrix volume (measured by CMR) (Clinicaltrials.gov ID: NCT05230901).Eplerenone, a selective aldosterone receptor antagonist, has been studied as a potential therapeutic agent in patients with impaired cardiac hemodynamics after TAVR (Clinicaltrials.govID: NCT03923530).
EPISODE trial, in its 3rd phase, assesses the effect of PCSK9 inhibitors on CAVD (Clinicaltrials.govID: NCT04968509) based on the established reduction in atherogenic lipoprotein cholesterol-carrying particles such as Lp(a) [92] with the use of PCSK9 inhibitors.The results of this ongoing trial might necessitate potential therapeutic alterations to the current guidelines for AS management.Another lipid-lowering medication, pelacarsen (TQJ230), is being used to assess the impact of reducing Lp (a) in patients with CAVD and to measure the change in AV calcium score (Clinicaltrials.govID: NCT05646381).
Although Pawade et al. [93] concluded that denosumab and alendronic acid did not affect the progression of AV calcification in patients with CAVD, their trial was based on studies showing that bone turnover and osteoblastic differentiation of VICs are significant contributors to the pathogenesis of CAVD.Li et al. [94] reported significant reductions in serum C-terminal telopeptide, a measure of bone turnover, with the use of denosumab and alendronic acid, but no significant changes were observed in the AV calcium score.Potentially larger and longer multicenter trials might conclude some efficacy of osteoporosis drugs in slowing AS progression.
COPAS-Pilot is an ongoing trial assessing the effect of colchicine on valvular calcification activity using aortic valvular NaF uptake (Clinicaltrials.govID: NCT05253794).CAVD mouse models have established the role of targeted PTPN22 inhibition in reducing the progression of CAVD and, therefore, might be a potential therapeutic agent in humans with CAVD [95] .Myeloid cell reprogramming in AS is another area of interest (NCT04717219), which currently focuses on the role of activation of the innate immune system in CAVD.The outcomes of this trial will provide potential immune checkpoints, the inhibition or modulation of which might guide future CAVD research in developing these targeted therapies.
Pioglitazone, an antidiabetic medication, is being evaluated in a phase-2 trial (Clinicaltrials.govID: NCT05875675) to slow the progression of AV calcification because pioglitazone has antiinflammatory and antioxidant effects that may prevent cardiovascular diseases.Another antidiabetic medication, evogliptin, is in a phase-4 trial to assess the progression of AV calcification in patients with T2DM with mild-to-moderate CAVD (Clinicaltrials.govID: NCT04521452).Similarly, folic acid (Clinicaltrials.govID: NCT05861648) and vitamin K2 (menaquinone) (Clinicaltrials.govID: NCT04429035) have been evaluated in clinical trials to slow the progression of AV calcification.One phase-3 ongoing trial, REDOX-TAVI (Clinicaltrials.gov ID: NCT04171726), is investigating the efficacy of edoxaban in reducing the incidence of leaflet thickening.The results of REDOX-TAVI will provide therapeutic insights into the anticoagulant agents for TAVI.
To reduce cerebral embolic complications in TAVR, an ongoing phase-1 trial is evaluating the safety and efficacy of the F2 device, which is positioned in the aorta and covers the three great cerebral vessels during TAVR (Clinicaltrials.govID: NCT05866640).Other similar cerebroprotective devices being tested are AorticLab FLOWer system (Clinicaltrials.govID: NCT04704258) and EMBLOK EPS (Clinicaltrials.govID: NCT05295628).Another trial assessed the outcomes of transcatheter AV flushing with CO 2 (TAVI-CO 2 ) versus standard saline flushing of valves (TAVI-S), as CO 2 use in cardiac interventions has shown beneficial effects (Clinicaltrials.govID: NCT05146037).
To reduce paravalvular regurgitation (PVR) after TAVR, the WITAVI-REAL clinical trial (Clinicaltrials.govID: NCT03728049) evaluated the efficacy of point-of-care testing of von Willebrand factor as an alternative to a transesophageal echocardiogram at the time of minimally invasive TAVR in reducing PVR post-TAVR.Porcine calcified-aortic models have been demonstrated to reverse elastin-specific medial vascular calcification (Monckeberg's sclerosis) by local periadventitial delivery of chelating agents, such as disodium ethylenediaminetetraacetic acid (EDTA), loaded into poly (lactic-co-glycolic acid) nanoparticles [94] .Successful reversal of calcification in human aortic tissue may have massive clinical implications.Future research should focus on developing therapeutics that can reverse calcification, which will lead to major progress in the management and improvement of the prognosis of CAVD.Further research needs to be conducted on upcoming therapies in cardiovascular medicine, such as bempedoic acid and PCSK9 inhibitors like inclisiran, to determine their potential role in managing CAVD [96] .

Modalities
The incorporation of digital technology into AS is a recent trend.An ongoing clinical trial (Clinicaltrials.govID: NCT05230225) has assessed the impact of electronic physician notification letters on the likelihood of AVR utilization in patients with a clinical indication for severe AS.Novel CAVD biomarker kits are being prepared to assess the severity and prognosis of AV stenosis (Clinicaltrials.govID: NCT04312139) using multiplexed enzyme-linked immunosorbent assay (ELISA) kits.Novel non-invasive ultrasound therapy (NIUT) with Valvosoft is being evaluated for safety in patients with severe CAVD (Clinicaltrials.govID: NCT05235568).The outcomes of this trial assessing NIUT with Valvosoft could potentially provide data that reduce the necessity of TAVR in certain severe CAVD cases.
The ART-VR trial is an ongoing trial that estimates the effect of an immersive virtual reality (VR) environment on reducing procedural anxiety in patients undergoing TAVR (Clinicaltrials.govID: NCT05069987).With advances in AI, computerized stethoscopes (©VoqX) are undergoing clinical trials to diagnose structural cardiac pathologies (Clinicaltrials.gov ID: NCT04960280).©VoqX is being compared with the current gold standard testing, such as echocardiography or invasive cardiac catheterization.An ongoing trial tested the HUAWEI smartwatch to facilitate early discharge in patients following TAVR by assessing conduction disturbances, daily activity levels, heart rates, oxygen saturation, and sleep patterns (Clinicaltrials.govID: NCT04454177).
PET imaging with 18F-NaF has been demonstrated to quantify disease activity; since disease activity is a predictive marker of future disease progression, PET-CT has now become crucial for prognostication of CAVD [97] .Doris et al. [98] optimized 18F-NaF PET by reconstructing parameters and cardiac motion correction and demonstrated improvements in signal-to-noise ratio, which consecutively led to improvements in blurring from cardiac motion [98] .
The search for novel radiotracers that target inflammation, thrombus formation, and fibrosis is crucial for reducing the complications of CAVD.18F-GP1 is a novel tracer for PET imaging that binds to glycoprotein IIb/IIIa receptors on activated platelets during thrombotic depositions [99] .Another upcoming tracer is 68Ga-DOTATATE, which targets the somatostatin receptor expressed on activated macrophages during the pathogenesis of atherosclerotic inflammation [97,100] ..Endothelial failure in valvular endothelial cells is the first sign of calcification and is caused by several risk factors, including mechanical/shear stress, lipid accumulation, ROS, and inflammation.The progression phase, which follows the initial inflammatory phase, begins with the conversion of VICs into myofibroblastic and osteoblastic phenotypes, a process governed by the cytokines produced by immune cells [11] .Women display less severe inflammatory and fibrotic responses than men when it comes to cardiac remodeling.When triggered by interferon-α, female VICs show a tendency to be less prone to calcification.This distinction is related to sex-specific apoptotic pathways such as the PI3K/Akt survival pathway [100] .Lower levels of calcification in female AVs may be caused by variations in the secretion of important factors, such as IL-6, BMP-2, and MMP-1.Interferon-gamma (IFN)-induced proangiogenic, pro-inflammatory, and pro-calcific actions have a greater impact on male VICs.Women also exhibit reduced profibrotic TGF expression and a milder inflammatory response [17] .
As such, the balance between inhibitors and promoters is critical for calcification development owing to near-supersaturated calcium and phosphate concentrations.A primary systemic inhibitor, fetuin-A, prevents calcification by generating soluble protein-mineral nanoparticles.Low fetuin-A levels reduce calcification inhibition, leading to calcification when excessive.Koos et al. [101,102] linked fetuin-A serum levels with AV calcification progression and clinical outcomes independent of renal function and inflammation.Fetuin-A levels can be utilized as a useful parameter with defined levels for clinical protocols, because higher levels are associated with better survival.
Numerous prospective studies have been conducted to increase the predictability of disease progression, particularly in AS.However, because each of these studies had a substantial margin of error, it was difficult to predict the progression of AS.Pasch et al. [103] developed a novel in-vitro blood test, the T50 test, which assesses calcification propensity by monitoring the maturation time of calcium particles.Particularly, in patients with aortic sclerosis, this test is promising as a biomarker for predicting future arterial calcifications (Clinicaltrials.govID: NCT02241109).Another approach, known as PET-MDCT, combines anatomical and molecular imaging to evaluate the uptake of 18F-sodium fluoride by valvular tissue, which reveals the presence of active mineralization processes within the valve.This predicts the progression of AS and correlates with the severity of the condition [16] .Emerging blood biomarkers, including high-sensitivity cardiac troponin, growth/differentiation factor 15, ST2 protein, and miRNAs, also have the potential to identify myocardial dysfunction, although further research is required to determine their relevance beyond that of already established indicators [11] .It is critical to keep in mind that these markers are not very specific and can be affected by other health issues such as hypertension, DM, and coronary artery disease.Despite their shortcomings, these techniques present new opportunities to improve the prognosis of AS progression and associated cardiac events.
Regarding AS diagnosis and classification, valve anatomy, hemodynamic severity, LV response, and symptoms were considered.AS can range in severity from mild to severe with or without symptoms [104] .The primary method for determining AS severity is Doppler echocardiography.If the results are unclear, cardiac catheterization, which measures heart blood flow and pressure, may be employed, although this is hazardous.Peak aortic jet velocity, mean gradient, and AVA are the three variables used by Doppler to gauge the severity of AS.As a result of the faster flow (higher peak velocity) and pressure loss (increased mean gradient) caused by the calcific AS, the AVA gradually decreased.An increased peak velocity/mean gradient along with thicker AV leaflets with constrained opening are diagnostic indicators of AS.Echocardiography aids in determining how AS affects the LV shape and functionality.Patients with mild-tomoderate AS typically do not have any symptoms unless other conditions are present.They had a peak velocity of less than 4 m/ s, a mean gradient between 25 and 40 mmHg, and an AVA between 1 and 1.5 cm 2 .Patients with severe AS, commonly defined as a peak velocity of 4 m/s, mean gradient of 40 mmHg, and an AVA of 1 cm 2 , may or may not have symptoms and require more frequent clinical and Doppler monitoring.Doppler echocardiography is a useful method for assessing AS severity because it can calculate the maximal instantaneous and mean AV gradients using continuous-wave Doppler velocity across the valve [104] .

Quality of life
With the increasing prevalence of the disease and significant mortality rates, CAVD caused 1.5 million (95% uncertainty interval 1.4 million-1.6million) DALYs globally in the year 2017.The percentage change in DALYs in 2017 compared with 1990 was 101% [104] .
Heart failure is the most common complication associated with severe AS, causing significant morbidity and commonly presenting with fatigue, shortness of breath, orthopnea, and pedal edema as valvular disease progresses.This significantly impairs quality of life (QoL) by decreasing the overall functional capacity, especially in elderly patients [105] .The overall QoL may vary in the elderly due to associated morbidities, such as DM, obesity, and renal diseases, which by themselves are risk factors for CAVD, as previously mentioned [106] , or due to frailty [107] .It also contributes to the surgical risk in patients requiring AVR [108] .The psychosocial impact of this disease should not be overlooked.Patients can develop anxiety and depression owing to limited physical activity and the risk of sudden cardiac events [108] .
With the availability of AVR, there have been substantial improvements in QoL and survival rates in patients with severe aortic valvular disease and heart failure.TAVR has become the treatment of choice in patients at high risk of SAVR because of its minimally invasive technique, lower complications, and better overall long-term outcomes.Some patients may experience symptoms of residual heart failure due to diastolic dysfunction with preserved ejection fraction, but they are comparatively less severe [109] .
Several considerations must be made while determining the potential benefits of AVR, including pre-procedure symptom severity due to valvular disease and health status.Identifying the lesion and considering AVR early before the development of irreversible cardiac changes improves the prognosis and QoL [110] .AVR increases long-term risks for subclinical leaflet thrombosis [111] and infective endocarditis [112] , leading to embolism, including stroke, and further increasing morbidity.Based on these indications, the use of oral anticoagulants for thrombosis [111] and the case-by-case use of antibiotic prophylaxis [112] help prevent potentially life-threatening complications.Comprehensive care, support networks, and social interventions should address the psychosocial aspects to improve QoL.Exercise training-based cardiac rehabilitation is known to improve functional capacity in frail patients who have undergone AVR, thus improving their QoL [109] .Theoretically, high-dose eicosapentaenoic acid slows disease progression [106] , but its clinical benefits need to be studied.Further research is required to identify the factors affecting pre-AVR and post-AVR QoL and to explore other therapies, particularly those focusing on non-cardiac variables.

Challenges in the myriad of CAVD
Innovative diagnostic approaches have emerged in response to the challenges posed by CAVD and coexisting heart valve issues.These methods incorporate advanced technologies and target CAVD-specific biomarkers to enhance the effectiveness of TAVR treatment.Traditional echocardiography, designed for singlevalve issues, can be misleading when multiple valve diseases coexist with CAVD.The precise assessment of conditions such as MR, mitral stenosis (MS), and aortic regurgitation (AR) is crucial.Stress echocardiography aids in distinguishing genuinely severe AS from potentially less severe cases.CCT calculates AV calcium scores, while CMR assesses regurgitant lesions, and heart chamber changes, and detects replacement fibrosis through late gadolinium enhancement (LGE) and ECV measurement, offering crucial prognosis insights.A complete imaging approach is crucial for precise diagnosis and treatment guidance in patients with AS [113] .TAVR patients in the United States are now younger and healthier, benefiting from improved short-term outcomes due to better devices and procedures.Patient characteristics play a larger role in 1-year outcomes.TAVR programs have expanded due to volume requirements and procedural excellence, with experience showing a learning curve.Comprehensive metrics beyond 30-day mortality are essential for assessing quality of care.Collaboration and best practices should strengthen low-volume TAVR programs, considering patient-centered outcomes such as QoL.Technological advancements have resulted in improved TAVR results [114] .
BNP and troponin levels aid in assessing heart failure severity and maladaptive remodeling in patients with AS.Targeted therapies include lipid-lowering strategies, RAAS inhibitors, and metabolic agents.NO-cGMP signaling modifiers, interventions targeting the NOTCH pathway, and non-coding RNAs provide additional avenues for therapeutic development.Efforts to manage mineral metabolism and break the calcification cycle are underway, with bisphosphonate and vitamin K2 supplementation being explored.Controlling hypertension and heart rate may play a role in slowing CAVD progression [85,116,119] .
Studies including machine learning algorithms to identify novel biomarkers, investigations into the role of MMP9 in mitochondrial dysfunction, DUSP26 inhibition as a therapeutic strategy, apoC-III as a contributor to valvular calcification, and the potential role of copeptin as a risk stratifier offer further insights into CAVD management [28,[120][121][122] .

Conclusions
In developed countries, following coronary artery disease and systemic arterial hypertension, CAVD is the third most prevalent cardiovascular disease affecting the heart valves.DALYs associated with CAVD have continued to increase over the decades, and our understanding of their causes has evolved significantly during the 20th century.Modern world risk factors for CAVD include sedentary lifestyle, obesity, dyslipidemia, DM, and hypertension.Despite the rising prevalence of CAVD, surprisingly, most patients do not experience symptoms until the 7th or 8th decade of life.In individuals who exhibit symptoms, angina pectoris, exertional dyspnea, and syncope are hallmark features, although AS can also present in atypical ways, such as paroxysmal or recurrent arrhythmias.Although various diagnostic methods are available, echocardiography remains the definitive tool for confirming the diagnosis of AS.A comprehensive imaging approach is crucial to ensure precise diagnosis and guide treatment for individuals with AS.
The management approach for CAVD has developed continuously over time.Available treatments encompass a wide range, including surgical procedures, medical care, and palliative measures to provide temporary relief.AVR is considered to be the benchmark approach, whether through surgical or interventional procedures.As the field of cardiology continues to evolve, ongoing research has led to the investigation of several drugs showing promise in CAVD management, including PCSK9 inhibitors, ataciguat, pelacarsen, and pioglitazones.Recent advances in new TAVR systems have shown promising results in terms of mortality and complication reduction.The deployment of upcoming cerebroprotective devices has reduced the incidence of stroke post-TAVR.Extensive research is currently underway to develop reliable biomarkers that can effectively track the progression of CAVD in patients, given its association with increased mortality and complications, such as stroke.Among these biomarkers are the T50 test, high-sensitivity cardiac troponin, growth/differentiation factor 15, ST2 protein, and miRNAs.Unfortunately, these biomarkers currently lack the specificity required to be entirely reliable.With ongoing research efforts, the future of diagnostic and management options for CAVD appears promising, enabling cardiologists to offer more effective guidance to patients during challenging times.

Ethical approval
No ethical approval was required due to the review nature of the study.

Consent
No consent was required due to the retrospective review nature of the study based on public information.

Table 1
Frequency of ECG in asymptomatic AS patients with normal LV function a Patients with mixed valvular disease may require multiple evaluations at earlier intervals.The guideline intervals above do not consider the etiology of valve disease.

Table 2
CMR modalities' advantages and limitations

Table 3
Ongoing drug trials for calcific aortic valve diseaseCAVD is divided into two separate stages.The first stage involves lipid accumulation and endothelial failure, and the second stage involves calcification, fibrosis, and inflammation