Aortic Valve Calcification

Background

Aortic valve calcification (AVC) is a common age-related condition characterized by the deposition of calcium in the aortic valve leaflets, leading to their stiffening and thickening. This process, often initially termed aortic sclerosis, is not merely a benign degenerative condition but an active process that precedes the development of clinical aortic stenosis (AS).^[1]While considered an important early phenotype for valvular heart disease, AVC is associated with progression to severe AS and significantly increased cardiovascular morbidity and mortality.^[1] Currently, there are no established medical treatments to prevent or slow the progression of AVC.^[1]

Biological Basis

The biological basis of AVC involves complex mechanisms that share similarities with atherosclerosis, including inflammation, lipid accumulation, and active calcification processes within the valve tissue. Genetic factors play a significant role in susceptibility to AVC, with studies demonstrating familial aggregation of calcific aortic valve stenosis.^[2]Genome-wide association studies (GWAS) have identified specific genetic loci associated with AVC. A key finding is the association of a single nucleotide polymorphism (SNP),rs10455872 , located within the LPAgene (lipoprotein(a) gene) on chromosome 6, with a strong predisposition to aortic valve calcification.^[1]This association is mediated by genetically determined levels of lipoprotein(a) (Lp(a)), indicating a causal role for lifelong elevated Lp(a) levels in the development of AVC.^[1] Beyond LPA, other genes have been implicated in the pathogenesis of AVC and AS. Mutations in the NOTCH1gene are known to cause aortic valve disease.^[3]and polymorphisms in the vitamin D receptor (VDR) gene have been linked to an increased risk of calcific aortic valve stenosis.^[4]Further research has identified associations between apolipoprotein E (APOE) alleles and calcific valvular heart disease.^[5] and an oestrogen receptor alpha gene polymorphism has been related to aortic valve sclerosis in postmenopausal women.^[6] More recent integrative genomic analyses have further expanded the list of candidate causal genes, including PALMD.^[7] PRRX1, ATP13A3, and TWIST1.^[7] highlighting the complex genetic architecture underlying this condition.

Clinical Relevance

The clinical relevance of aortic valve calcification stems from its role as a precursor to aortic stenosis, which can severely impede blood flow from the heart to the body. As AVC progresses, it can lead to moderate to severe aortic stenosis.^[1] necessitating interventions such as aortic valve replacement, including transcatheter aortic valve implantation (TAVI) for severe cases.^[8] The genetic predisposition, particularly through the LPA locus, has been linked to an increased risk of incident clinical aortic stenosis and the need for aortic valve replacement.^[1] Understanding the genetic determinants of AVC is crucial for identifying individuals at higher risk, potentially enabling earlier detection and the development of targeted preventative or therapeutic strategies.

Social Importance

Aortic valve calcification and its progression to aortic stenosis represent a significant public health challenge, particularly in aging populations. The absence of effective pharmacological treatments to halt or reverse AVC progression means that surgical or transcatheter interventions are currently the only options for severe cases, imposing a substantial burden on healthcare systems and affecting the quality of life for millions. Knowledge of the genetic determinants of valvular calcification is socially important because it can illuminate the underlying mechanisms of valvular heart disease, potentially fostering the development of novel therapies that could prevent or slow the disease’s progression.^[1]Such advancements would have a profound impact on reducing cardiovascular morbidity and mortality, improving patient outcomes, and alleviating the healthcare burden associated with this prevalent condition.

Challenges in Study Design and Statistical Power

The statistical power of genome-wide association studies (GWAS) for aortic valve calcification presents a significant limitation, particularly in non-White populations, despite notable efforts to increase ancestral diversity.^[9] While some studies achieved large sample sizes for discovery, the power for replication in smaller, independent cohorts or specific ancestry groups often remained limited. This can lead to certain associations, such as that of rs6493062 (CDAN1), failing to meet significance thresholds or showing inconsistent replication across diverse populations, thereby raising questions about the robustness and broader generalizability of these findings.^[9]Methodological choices, such as evaluating only genome-wide significant SNPs in replication stages due to sample size constraints, may also inadvertently overlook other true genetic associations with more modest effect sizes.^[1] Sensitivity analyses further illustrate these power limitations, where some previously genome-wide significant loci, such as those near SLMAP and MECOM, lost their significance when specific subgroups (e.g., individuals with aortic insufficiency) were excluded.^[9] Although the effect estimates for these variants remained largely unchanged, the loss of statistical significance underscores the delicate balance between cohort refinement and maintaining adequate power for robust detection. Inconsistent replication, as observed for variants like rs17659543 and rs13415097 near IL1F9, across different cohorts further highlights the need for larger, well-powered studies to validate initial findings and confirm their broader applicability.^[1]

Phenotypic Definition and Precision

The precise definition and of aortic valve calcification present notable challenges that can influence genetic association studies. Diagnostic codes, such as ICD-9, may not always accurately differentiate between calcific aortic stenosis (CAS) and other conditions like aortic insufficiency, leading to potential misclassification of cases.^[9] Instances where individuals initially identified as CAS cases were later clarified to have aortic insufficiency highlight the importance of rigorous phenotyping beyond administrative codes, as such inaccuracies can introduce noise and potentially dilute true genetic signals or lead to spurious associations.^[9]This phenotypic overlap necessitates further research to determine if mixed aortic valve disease represents a distinct pathological entity requiring separate investigation.

Furthermore, while the use of subclinical phenotypes, such as valvular calcium detected by CT scanning, can be advantageous for identifying early disease processes, it also means that genetic associations may relate more to the predisposition for calcification rather than to clinically overt aortic stenosis.^[1]The distinction between an early protophenotype and a fully developed clinical disease state is crucial for interpreting the clinical relevance of identified genetic loci. Although deep phenotyping can reduce heterogeneity, it also implies that the direct translation of findings to the mechanisms underlying symptomatic, severe aortic stenosis might require additional validation in cohorts specifically characterized by advanced clinical disease.

Generalizability and Confounding Factors

The generalizability of genetic findings for aortic valve calcification is constrained by the demographic characteristics of the studied cohorts. Many discovery stages have historically focused predominantly on individuals of White European ancestry, and even large multi-ancestry studies, like the Million Veteran Program, have acknowledged limited statistical power in non-White populations.^[9] This ancestral imbalance, coupled with the Million Veteran Program’s predominantly male population, limits the direct applicability of findings to broader, more diverse populations, including women and various non-European ancestral groups, potentially obscuring ancestry-specific genetic effects or gene-environment interactions.^[9] Future research with greater representation from diverse ancestries and sexes is essential to fully elucidate the genetic architecture of the condition.

Environmental and lifestyle factors, as well as comorbid conditions, act as significant confounders that can modulate genetic associations with aortic valve calcification. While some studies have attempted to adjust for factors like body mass index (BMI) or other atherosclerotic traits such as coronary artery disease (CAD) and peripheral artery disease (PAD), the intricate interplay between genes and these environmental influences may not be fully captured.^[9] For example, the attenuated effect estimates for LPAvariants after adjusting for CAD and PAD suggest a shared genetic etiology or confounding by these comorbidities, complicating the isolation of specific genetic contributions to aortic valve calcification.^[9] A comprehensive understanding of gene-environment interactions and the full spectrum of relevant confounders remains a critical knowledge gap.

Variants

Genetic variations play a crucial role in an individual’s susceptibility to aortic valve calcification (AVC) and subsequent aortic stenosis (AS). These variants can influence gene expression, protein function, and biological pathways involved in inflammation, lipid metabolism, and cellular differentiation, all of which contribute to the progressive hardening and narrowing of the aortic valve. Understanding these genetic factors provides insights into disease mechanisms and potential therapeutic targets.

One of the most significant genetic loci associated with aortic valve calcification is theLPAgene, which encodes apolipoprotein(a), a key component of lipoprotein(a) [Lp(a)]. The variantrs10455872 located within intron 25 of LPA on chromosome 6 is strongly associated with an increased risk of incident aortic stenosis, with a hazard ratio of 1.68 per risk allele, and also with aortic-valve replacement.^[1]This variant significantly increases the odds of aortic-valve calcification by approximately two-fold.^[1] Studies indicate that rs10455872 is strongly associated with elevated plasma Lp(a) levels, and these elevated levels causally mediate the effect of the variant on aortic valve calcification.^[1]This suggests that lifelong elevations in Lp(a) contribute substantially to the development of aortic valve disease.

Inflammation is a critical process in the progression of aortic valve calcification, with key genes likeIL6 playing a central role. The IL6gene produces interleukin 6, a cytokine that regulates immune responses and inflammation. Variants such asrs1474347 and rs2069832 are located near IL6 and may influence its expression or activity. Colocalization experiments suggest that variants like rs1474347 and rs13311155 , which is located in the MTCYBP42 - TOMM7 region, can influence the expression of IL6-AS1, a long non-coding RNA that transcriptionally regulates IL6.^[9] While elevated plasma IL6levels are linked to increased mortality in aortic stenosis patients, increased tissue-specificIL6 expression has been associated with a decreased risk of calcific aortic stenosis, highlighting the complex role of this pathway.^[9] The variant rs1800797 , also associated with this inflammatory pathway, might impact the regulation of IL6 or other nearby genes like STEAP1B, which is involved in iron transport and oxidative stress, thereby influencing the inflammatory milieu within the valve.

Long non-coding RNAs (lncRNAs) like LINC01708 and TEX41 are increasingly recognized for their regulatory roles in gene expression, impacting cellular processes relevant to calcification. Variants such as rs6702619 , rs11166276 , and rs7543130 within or near LINC01708 may alter its regulatory functions. For instance, rs6702619 acts as a significant expression quantitative trait locus (eQTL) for PALMDin aortic valve tissue, suggesting its role in regulating genes involved in muscle development and cell adhesion, which are relevant to valve integrity and remodeling.^[10] Similarly, rs72854462 and rs2246363 are associated with TEX41, an lncRNA for which rs72854462 is a prominent eQTL in the aortic valve, implying its influence on TEX41 expression and potentially on downstream pathways affecting calcification.^[10] Other variants like rs1016819 and rs2150026 in PRRX1, a gene encoding a homeobox protein important for craniofacial and limb development, may impact cell differentiation and tissue remodeling in the valve. Variants rs682112 and rs665770 near IPO9-AS1 and NAV1 may influence neuronal development and intracellular transport, processes that could indirectly affect valve health. Lastly, rs10770612 , located in the TCP1P3 - LINC02468region, might affect protein folding or lncRNA-mediated regulation, contributing to the complex genetic landscape of aortic valve calcification.

Key Variants

RS ID	Gene	Related Traits
rs10455872	LPA	myocardial infarction lipoprotein-associated phospholipase A(2) response to statin lipoprotein A parental longevity
rs6702619 rs11166276 rs7543130	LINC01708	aortic valve calcification bulb of aorta size aortic stenosis magnetic resonance imaging of the heart heart failure
rs72854462	TEX41	diastolic blood pressure red blood cell density erythrocyte count systolic blood pressure aortic valve calcification
rs1800797	IL6, STEAP1B, IL6-AS1	asthma level of myocilin in blood systemic lupus erythematosus aortic stenosis aortic valve calcification
rs1474347 rs2069832	IL6	aortic valve calcification
rs1016819 rs2150026	PRRX1	aortic valve calcification
rs682112 rs665770	IPO9-AS1, NAV1	coronary atherosclerosis aortic valve calcification
rs13311155	MTCYBP42 - TOMM7	atrial fibrillation aortic valve calcification serum albumin amount
rs10770612	TCP1P3 - LINC02468	bulb of aorta size pulse pressure systolic blood pressure aortic valve calcification
rs2246363	TEX41	hemoglobin brain attribute aortic valve calcification

Causes

Aortic valve calcification is a complex condition influenced by a combination of genetic predispositions, metabolic imbalances, inflammatory processes, and environmental factors. It is understood as a progressive inflammatory process with overlapping risk factors with atherosclerotic cardiovascular disease.^[9] Understanding these diverse causal pathways is crucial for identifying individuals at risk and developing potential interventions.

Genetic Predisposition

Genetic factors play a significant role in determining an individual’s susceptibility to aortic valve calcification, with evidence of familial aggregation suggesting a heritable component.^[11]Genome-wide association studies (GWAS) have identified specific genetic variants associated with this condition. Notably, a single nucleotide polymorphism (SNP)rs10455872 within the LPAgene, which encodes apolipoprotein(a), has shown genome-wide significance for aortic valve calcification.^[1]Genetically determined elevations in lipoprotein(a) levels, as predicted byLPAgenotype, are causally linked to an increased prevalence of aortic valve calcification and incident aortic stenosis. Other candidate genes likePALMD, PRRX1, ATP13A3, and TWIST1 have also been implicated as susceptibility genes or loci for calcific aortic valve stenosis through transcriptome-wide association studies and Mendelian randomization analyses.^[7] While some studies have reported associations with polymorphisms in genes such as the Vitamin D receptor and apolipoprotein E alleles, large-scale independent replication is essential to confirm these findings.^[4]

Atherosclerotic and Metabolic Risk Factors

Aortic valve calcification shares many risk factors with general atherosclerotic cardiovascular disease, highlighting its metabolic underpinnings. Long-term and early adult exposure to traditional atherosclerosis risk factors, such as dyslipidemia, significantly contributes to the development of aortic valve calcium.^[12] Age is a predominant non-modifiable risk factor, with the prevalence of calcific aortic stenosis increasing substantially in adults over 70 years of age.^[9]Elevated levels of lipoprotein(a) are not only genetically influenced but also act as a significant metabolic risk factor, promoting the calcification process within the valve leaflets.^[1]Other factors like body-mass index (BMI) and current smoking status are also considered and adjusted for in studies, indicating their role as contributing lifestyle-related risk factors.^[1]Comorbidities such as chronic kidney disease are also recognized in the context of aortic valve calcification, suggesting systemic influences on valve health.^[7]

Hormonal and Inflammatory Pathways

Hormonal influences and inflammatory processes contribute to the pathogenesis of aortic valve calcification, often interacting with genetic and environmental factors. Research indicates that the amount of calcium-deficient hexagonal hydroxyapatite in aortic valves can be influenced by gender.^[4] Specifically, polymorphisms in the Oestrogen receptor αgene have been linked to aortic valve sclerosis in postmenopausal women, suggesting a role for estrogen signaling in valve health.^[6] The inflammatory nature of calcific aortic stenosis is well-established, with it being described as a progressive inflammatory process.^[9]

Gene-Environment Interactions and Lifestyle

The development of aortic valve calcification is often a result of complex interactions between an individual’s genetic makeup and various environmental or lifestyle factors. For instance, the predictive power of lipoproteins for aortic valve calcification can be influenced by age, illustrating a gene-environment interaction where genetic predisposition to certain lipoprotein profiles interacts with the aging process.^[12] Similarly, the association of the FTO gene (rs11647020 ) with calcific aortic stenosis can be clarified by adjusting for BMI, suggesting an interplay between genetic variants influencing adiposity and obesity-related environmental factors. Geographic influences and socioeconomic factors are also suggested to play a role, as evidenced by the heterogeneous distribution of patients with aortic valve stenosis.^[13] These broader environmental contexts can modulate the expression of genetic predispositions and influence exposure to other risk factors.

Biological Background

Aortic valve calcification is a complex and progressive disease, distinct from simple degenerative wear-and-tear, characterized by the active remodeling and calcification of the aortic valve leaflets. This condition, particularly calcific aortic stenosis (CAS), is the most common form of valvular heart disease globally, affecting millions and carrying a high mortality risk if left untreated.^[9] Understanding the intricate biological processes underlying this calcification is crucial, as current medical therapies have not been successful in preventing or reversing its progression.^[7]The disease involves a confluence of genetic predispositions, molecular and cellular dysregulation, and systemic risk factors that collectively drive the mineralization of valve tissue.

Aortic Valve Calcification as a Progressive Disease

Calcific aortic stenosis (CAS) represents the most prevalent structural heart disorder caused by hemodynamic obstruction at the aortic valve, affecting millions globally and posing a significant mortality risk if left untreated.^[9] Contrary to being a simple degenerative process, CAS is now understood as a progressive inflammatory condition characterized by active remodeling and calcification of the aortic valve leaflets.^[7]This complex disease progresses through a long asymptomatic phase, offering a potential window for therapeutic intervention, yet current cardiovascular medications like statins and angiotensin-converting-enzyme inhibitors have proven ineffective in halting its progression.^[7]Early manifestations, such as aortic sclerosis, are not benign but rather precursors to clinical aortic stenosis, associated with increased cardiovascular morbidity and mortality.^[14]

Cellular and Molecular Drivers of Calcification

The calcification of the aortic valve involves a sophisticated interplay of cellular functions and molecular pathways, leading to the fibrotic and calcific remodeling of valve tissue .

Core Signaling and Regulatory Pathways

Several specific signaling pathways and regulatory mechanisms are central to the pathogenesis of aortic valve calcification. Mutations in theNOTCH1gene are a known cause of aortic valve disease, serving as a susceptibility locus for bicuspid aortic valve and accelerated valvular calcification.^[3]The Bone Morphogenetic Protein (BMP) signaling pathway, particularly involvingSMAD9, is also implicated, with variations in this pathway potentially influencing calcification processes, similar to its role in bone metabolism.^[15]Furthermore, the vitamin D receptor genotype has been shown to predispose individuals to the development of calcific aortic valve stenosis, highlighting the role of vitamin D metabolism and its downstream signaling in valve health.^[16] Other genes, such as ALPL(alkaline phosphatase),NAV1, PALMD (Palmdelphin), and ATP13A3, have been identified through genomic studies as susceptibility genes for CAVS, suggesting their involvement in diverse regulatory mechanisms including phosphate metabolism, neural navigation, cellular scaffolding, and polyamine transport, respectively.^[10]These genetic associations underscore the complex interplay of various regulatory pathways in disease initiation and progression.

Systems-Level Integration and Disease Mechanisms

The progression of aortic valve calcification is not driven by isolated pathways but by a complex interplay of multiple interconnected networks, representing a systems-level integration of diverse biological processes. Pathway crosstalk is evident in the shared risk factors for CAVS and atherosclerotic cardiovascular disease, including circulating lipoproteins, blood pressure, and inflammation, which collectively contribute to the disease phenotype.^[10] For instance, dysregulation in lipid metabolism, as seen with Lp(a), can exacerbate inflammatory responses, creating a vicious cycle that accelerates calcification.^[1] Hierarchical regulation is also observed, where master transcription factors like PRRX1 and TWIST1 orchestrate broad changes in gene expression, leading to profound cellular transdifferentiation and extracellular matrix remodeling.^[17] These factors operate within positive feedback loops that can bistably activate fibroblasts, thereby maintaining a pro-calcific state.^[18] Understanding these emergent properties from network interactions is crucial for identifying novel therapeutic targets, as current pharmacological interventions, such as statins, have not proven effective in slowing or reversing CAVS progression.^[7]

Prognostic Value and Disease Progression

Aortic valve calcification (AVC) serves as a critical indicator of future cardiovascular events and disease progression, establishing itself as an important precursor to clinical valve disease.^[1]Its presence is strongly associated with increased cardiovascular morbidity and mortality, particularly in elderly populations.^[1] Furthermore, AVC is a significant predictor for the development of incident aortic stenosis (AS) and the subsequent requirement for aortic valve replacement (AVR), highlighting its prognostic utility in identifying individuals at risk for progressive valvular dysfunction.^[1]Longitudinal studies have also elucidated clinical, echocardiographic, and exercise predictors that help stratify outcomes in asymptomatic valvular aortic stenosis, emphasizing the need for comprehensive monitoring strategies.^[7]

Genetic Predisposition and Risk Stratification

Genetic factors significantly contribute to the susceptibility and progression of aortic valve calcification, offering valuable insights for risk stratification and personalized medicine approaches.^[1] A key finding is the robust association of the rs10455872 single nucleotide polymorphism within theLPAlocus with AVC, with genetically determined lipoprotein(a) [Lp(a)] levels demonstrating a causal role.^[1] This LPA genotype further predicts incident aortic stenosis and the need for aortic valve replacement, indicating its utility in identifying high-risk individuals for early intervention.^[1] Beyond LPA, mutations in genes such as NOTCH1, variations in the Vitamin D receptor, and susceptibility genes like PALMD and MYRF have been identified, underscoring the complex genetic architecture underlying valvular calcification and aortic stenosis.^[1]The observed familial aggregation of calcific aortic valve stenosis and evidence for a heritable component in valve-related mortality highlight the potential for genetic screening in identifying at-risk relatives.^[1] Multi-ancestry genome-wide association studies (GWAS) have replicated these genetic associations across diverse populations, reinforcing their clinical utility and paving the way for more comprehensive risk models.^[1] Integrating these genetic insights allows for enhanced risk stratification, potentially enabling targeted prevention strategies and earlier monitoring for individuals with a strong genetic predisposition to AVC and its progression to severe aortic stenosis.^[9]

Clinical Assessment, Comorbidities, and Therapeutic Considerations

The clinical assessment of aortic valve calcification primarily relies on computed tomography (CT) scanning, which precisely identifies and quantifies calcific lesions within the aortic valve leaflets using standardized Agatston methods.^[1]This diagnostic utility allows for objective of calcification burden, which is crucial for monitoring disease progression and informing clinical decisions.^[1]AVC frequently coexists with other calcific cardiovascular pathologies, such as mitral annular calcification (MAC) and coronary artery calcification (CAC), suggesting shared underlying mechanisms and highlighting the systemic nature of vascular calcification.^[1]The presence of MAC itself is a known predictor of adverse cardiovascular morbidity and mortality, further emphasizing the interconnectedness of these conditions.^[1]Aortic valve calcification is associated with traditional atherosclerosis risk factors, and the presence of oxidized low-density lipoprotein has been observed in nonrheumatic stenotic aortic valves.^[1]This suggests overlapping pathological processes that may influence disease progression and potential therapeutic targets. While intensive lipid-lowering therapy has been evaluated in aortic stenosis, its impact on halting calcification progression requires careful consideration.^[7]For advanced disease, Transcatheter Aortic Valve Implantation (TAVI) represents a significant therapeutic option for severe aortic stenosis, demonstrating the evolution of treatment strategies for this condition.^[7] Understanding these associations and therapeutic pathways is vital for comprehensive patient care and developing effective management and prevention strategies.^[9]

Frequently Asked Questions About Aortic Valve Calcification

These questions address the most important and specific aspects of aortic valve calcification based on current genetic research.

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1. If my family has heart valve problems, will I get it too?

Yes, if close family members have had calcific aortic valve stenosis, you have a higher chance of developing it. Studies show that this condition can run in families, suggesting a significant genetic predisposition. Your genes play a role in determining your susceptibility.

2. Can I take medicine to stop my heart valves from getting stiff?

Currently, there are no established medical treatments or medications that can prevent or slow down the progression of aortic valve calcification. While researchers are actively investigating new therapies, the main interventions for severe cases involve valve replacement procedures. Understanding your genetic risk can help with earlier monitoring.

3. I watch my cholesterol; does that protect my heart valves?

While a healthy diet and managing your overall cholesterol are crucial for general heart health, some risks for valve calcification are more tied to specific genetic factors. Elevated levels of lipoprotein(a) (Lp(a)), which is largely genetically determined and not easily influenced by diet, are strongly linked to valve calcification. So, while good habits are always important, some valve risks are more tied to your specific genes.

4. Do my heart valves just naturally get stiff as I get older?

Aortic valve calcification is a very common age-related condition, but it’s not simply inevitable wear and tear. It’s an active biological process similar to atherosclerosis. While aging is a major factor, your genetics also play a significant role in how prone your valves are to calcifying over time.

5. Is a DNA test useful to know my valve risk?

A DNA test can be useful for understanding your risk, especially for certain genetic markers. For example, variations in the LPAgene are strongly linked to an increased predisposition to aortic valve calcification due to genetically determined high lipoprotein(a) levels. Knowing this could help your doctor monitor you more closely, though it doesn’t mean you will definitely develop the condition.

6. Can a healthy lifestyle stop my valves from stiffening if it runs in my family?

A healthy lifestyle is always beneficial for your overall cardiovascular health. However, genetic factors play a significant role in aortic valve calcification, and some predispositions, like those linked to theLPAgene, are quite strong. While lifestyle can mitigate some general risks, it may not completely override a strong genetic susceptibility to valve stiffening.

7. Will I feel anything if my heart valves are getting stiffer?

In the early stages of aortic valve calcification, you typically won’t feel any symptoms because the valve is only mildly stiff. Symptoms usually appear much later when the calcification has progressed to significant aortic stenosis, severely impeding blood flow. These later symptoms might include chest pain, shortness of breath, or dizziness, which would prompt medical evaluation.

8. Does being a woman change my risk for stiff heart valves?

Yes, being a woman can influence your risk, especially after menopause. Research has linked a specific polymorphism in the oestrogen receptor alpha gene to aortic valve sclerosis in postmenopausal women. This suggests that hormonal changes and certain genetic variations related to hormone pathways can play a role in the development of valve calcification.

9. Does my ethnic background affect my heart valve risk?

Yes, your ethnic background can affect your risk. Research on aortic valve calcification has shown that genetic risk factors might vary or be less understood in different ancestry groups. Studies have noted limitations in statistical power, particularly in non-White populations, highlighting the importance of diverse research to fully understand these differences.

10. Can I find out my risk before my valves get really bad?

Yes, understanding your genetic risk can help. Genetic factors, such as those associated with the LPAgene, are linked to an increased risk of developing aortic valve calcification and potentially needing valve replacement later in life. Identifying these genetic predispositions can help doctors pinpoint individuals at higher risk, potentially allowing for earlier detection and closer monitoring, even before severe symptoms appear.

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This FAQ was automatically generated based on current genetic research and may be updated as new information becomes available.

Disclaimer: This information is for educational purposes only and should not be used as a substitute for professional medical advice. Always consult with a healthcare provider for personalized medical guidance.

References

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[2] Probst, V. et al. “Familial aggregation of calcific aortic valve stenosis in the western part of France.” Circulation, vol. 113, 2006, pp. 856–860.

[3] Garg, V. et al. “Mutations in NOTCH1 cause aortic valve disease.”Nature, vol. 437, 2005, pp. 270–274.

[4] Ortlepp, J. R. et al. “The amount of calcium-deficient hexagonal hydroxyapatite in aortic valves is influenced by gender and associated with genetic polymorphisms in patients with severe calcific aortic stenosis.” Eur Heart J, vol. 25, 2004, pp. 514–522.

[5] Novaro, G. M. et al. “Association between apolipoprotein E alleles and calcific valvular heart disease.”Circulation, vol. 108, 2003, pp. 1804–1808.

[6] Nordström, P. et al. “Oestrogen receptor α gene polymorphism is related to aortic valve sclerosis in postmenopausal women.” J Intern Med, vol. 254, 2003, pp. 140–146.

[7] Theriault, S. et al. “A transcriptome-wide association study identifies PALMD as a susceptibility gene for calcific aortic valve stenosis.” Nat Commun, vol. 9, 2018, p. 988.

[8] Sehatzadeh, S., et al. “Transcatheter aortic valve implantation (TAVI) for treatment of aortic valve stenosis: an evidence update.” Ontario Health Technology Assessment Series, vol. 13, no. 1, 2013, pp. 1-40.

[9] Small, A. M. et al. “Multiancestry Genome-Wide Association Study of Aortic Stenosis Identifies Multiple Novel Loci in the Million Veteran Program.” Circulation, 2023, PMID: 36802703.

[10] Theriault, S. et al. “Integrative genomic analyses identify candidate causal genes for calcific aortic valve stenosis involving tissue-specific regulation.” Nat Commun, vol. 15, 2024, p. 2380.

[11] Horne, B. D. et al. “Evidence for a heritable component in death resulting from aortic and mitral valve diseases.” Circulation, vol. 110, 2004, pp. 3143–3148.

[12] Owens, D. S. et al. “Interaction of age with lipoproteins as predictors of aortic valve calcification in the Multi-Ethnic Study of Atherosclerosis.”Arch Intern Med, vol. 168, 2008, pp. 1200–1207.

[13] Le Gal, G. et al. “Heterogeneous geographic distribution of patients with aortic valve stenosis: arguments for new aetiological hypothesis.” Heart, vol. 91, 2005, pp. 247–249.

[14] Otto, C. M. et al. “Association of aortic-valve sclerosis with cardiovascular mortality and morbidity in the elderly.”N Engl J Med, vol. 341, 1999, pp. 142–147.

[15] Gregson, C. L., et al. “A Rare Mutation in SMAD9 Associated With High Bone Mass Identifies the SMAD-Dependent BMP Signaling Pathway.”Journal of Bone and Mineral Research, vol. 30, no. 12, 2015, pp. 2187–95.

[16] Ortlepp, J. R. et al. “The vitamin D receptor genotype predisposes to the development of calcific aortic valve stenosis.”Heart, vol. 85, 2001, pp. 635–638.

[17] Lee, K. W. et al. “PRRX1 is a master transcription factor of stromal fibroblasts for myofibroblastic lineage progression.” Nat. Commun., vol. 13, 2022, p. 2793.

[18] Yeo, S. Y., et al. “A positive feedback loop bi-stably activates fibroblasts.” Nature Communications, vol. 9, no. 1, 2018, p. 3016.