Thoracic Aortic Calcification
Introduction
Section titled “Introduction”Thoracic aortic calcification (TAC) refers to the deposition of calcium within the walls of the thoracic aorta, the largest artery in the chest. This calcification is a manifestation of atherosclerosis, a chronic inflammatory disease characterized by the buildup of plaque in arterial walls. TAC is considered a marker of subclinical atherosclerosis, indicating the presence of arterial disease before the onset of overt symptoms.[1]
Biological Basis
Section titled “Biological Basis”The biological basis of TAC involves a complex interplay of factors that lead to the calcification of the arterial wall. This process is often initiated by endothelial dysfunction, followed by the accumulation of lipids and inflammatory cells within the intima, forming atherosclerotic plaques. Over time, these plaques can undergo calcification, where calcium phosphate crystals are deposited. This process is active, involving osteoblast-like differentiation of vascular smooth muscle cells, and is influenced by systemic factors such as chronic inflammation, dyslipidemia, and imbalances in calcium and phosphate metabolism.
Clinical Relevance
Section titled “Clinical Relevance”Clinically, TAC is recognized as an important indicator of cardiovascular risk. Its presence is associated with an increased likelihood of developing adverse cardiovascular events, including myocardial infarction, stroke, and heart failure. As a measure of subclinical atherosclerosis, TAC provides prognostic information independent of traditional cardiovascular risk factors. Imaging techniques, particularly multidetector computed tomography (MDCT), are commonly used to detect and quantify aortic calcification, allowing for risk stratification in asymptomatic individuals. The Framingham Heart Study has utilized MDCT to assess other forms of subclinical atherosclerosis, such as abdominal and coronary artery calcification, noting their heritability and predictive value for future cardiovascular disease.[1]
Social Importance
Section titled “Social Importance”The social importance of TAC lies in its potential to identify individuals at higher risk for cardiovascular disease, a leading cause of morbidity and mortality worldwide. By detecting TAC early, healthcare providers can implement targeted preventive strategies, such as lifestyle modifications and pharmacotherapy, to mitigate future cardiovascular events. Understanding the genetic and environmental factors contributing to TAC can also inform public health initiatives aimed at reducing the burden of atherosclerosis across populations. Research into genetic variants associated with subclinical atherosclerosis, including calcification in other arterial beds like the abdominal aorta and coronary arteries, aims to further refine individual risk assessment and develop personalized prevention strategies.[1]
Methodological and Statistical Considerations
Section titled “Methodological and Statistical Considerations”The studies on subclinical atherosclerosis phenotypes, including arterial calcification, were conducted in a moderate-sized community-based sample.[1]For specific phenotypes like abdominal aortic calcification, the number of participants with available measures was relatively small, ranging from 673 to 680 individuals.[1]This sample size may limit the statistical power to detect genetic effects of modest magnitude, particularly given the extensive multiple testing inherent in a genome-wide association study.[2] As a consequence, no associations met the stringent criteria for genome-wide significance, indicating that further validation studies are essential to confirm any observed associations.[1] The genetic coverage provided by the Affymetrix 100K gene chip used in these studies was partial, which means that the array may not have captured all relevant genetic variations within certain gene regions, potentially leading to an inability to identify all true associations.[1] This limited coverage also posed challenges for replicating previously reported findings.[2] Furthermore, distinguishing genuine genetic associations from potential false-positive results, especially for moderately strong associations, remains a fundamental challenge in genome-wide studies, underscoring the critical need for external replication in independent cohorts to validate and prioritize findings.[3]
Phenotypic Measurement and Generalizability
Section titled “Phenotypic Measurement and Generalizability”The assessment of subclinical atherosclerosis phenotypes, such as arterial calcification, relies on imaging modalities that primarily focus on fixed anatomic components like calcific plaque, rather than capturing dynamic or metabolically active aspects of the disease.[1] While these represent state-of-the-art non-invasive imaging methods for population studies, this inherent limitation means the full biological complexity of the condition may not be entirely characterized. Additionally, for some echocardiographic traits, averaging measurements over a span of up to twenty years and using different equipment over time could introduce misclassification and potentially obscure age-dependent genetic effects by assuming a consistent influence of genes and environmental factors across a wide age range.[2] A significant limitation concerning the generalizability of these findings is that the study population was exclusively composed of individuals of white, European descent.[2] Therefore, the applicability of the identified genetic associations and the overall findings to other ethnicities or populations with distinct genetic architectures and environmental exposures is currently unknown.[2]Given that the occurrence and distribution of arterial calcification and other subclinical atherosclerosis phenotypes can vary across different racial or environmental backgrounds, the results from this study may not be directly extrapolated to non-white populations.[1]
Gene-Environment Interactions and Remaining Knowledge Gaps
Section titled “Gene-Environment Interactions and Remaining Knowledge Gaps”The studies did not undertake an investigation of gene-environmental interactions, which are known to play a crucial role in modulating how genetic variants influence complex phenotypes.[2] Genetic associations can be context-specific, meaning that environmental factors, such as dietary salt intake, might influence the effects of genes like ACE and AGTR2 on traits.[2] The lack of such analyses means that potential gene-environment confounders or intricate interactions that could explain additional phenotypic variability in arterial calcification were not explored, leaving a gap in understanding the full etiological picture.
Despite the comprehensive genome-wide association approach, which aims to identify novel genetic variants without prior hypotheses, relatively little is known about the specific genetic factors that contribute to the inter-individual variability in quantitative measures of subclinical atherosclerosis.[1] The current findings primarily generate new candidate SNP hypotheses, rather than definitively identifying causal variants.[1] Further extensive research and validation studies are therefore warranted to confirm these initial associations and to comprehensively elucidate the genetic architecture underlying arterial calcification.
Variants
Section titled “Variants”Genetic variants play a significant role in an individual’s susceptibility to various cardiovascular conditions, including thoracic aortic calcification. Research has identified several single nucleotide polymorphisms (SNPs) across diverse genes that are associated with subclinical atherosclerosis measures, providing insights into the complex genetic architecture of vascular health.[1] These variants often influence fundamental cellular processes, from lipid metabolism to extracellular matrix integrity, which collectively contribute to the development and progression of arterial calcification.
Variants affecting lipid transport and metabolic regulation, such as rs58674255 in the VPS13A gene and rs148988294 and rs144740773 in CDKAL1, are of particular interest. The VPS13A gene encodes a protein involved in lipid transport and mitochondrial function, processes critical for maintaining cellular health and preventing lipid accumulation and oxidative stress in the arterial walls. Variants like rs58674255 could potentially alter lipid processing or mitochondrial efficiency, thereby influencing the vulnerability of aortic tissues to calcification. Similarly, CDKAL1is recognized for its role in pancreatic beta-cell function and glucose metabolism, with variants likers148988294 and rs144740773 being associated with Type 2 Diabetes risk.[4]Given that diabetes is a major risk factor for accelerated atherosclerosis and vascular calcification, theseCDKAL1variants may indirectly contribute to thoracic aortic calcification by impacting glucose homeostasis and metabolic pathways that affect vascular cell function.
Other variants influence critical signaling pathways and the structural integrity of blood vessels. For example, rs12352759 in the GNA14 gene affects a G protein alpha subunit, which is essential for mediating cellular responses to various extracellular signals. Altered GNA14function due to this variant could disrupt signal transduction pathways involved in vascular smooth muscle cell proliferation, migration, or inflammation, all of which are central to the calcification process. Concurrently,rs115249592 in COL6A6is located within a gene encoding a subunit of Collagen VI, a crucial component of the extracellular matrix that provides structural support to tissues, including the aortic wall. Variants in collagen genes can impact the mechanical properties and elasticity of arteries, potentially leading to increased stiffness and a propensity for mineral deposition, thereby contributing to thoracic aortic calcification.[1] Beyond protein-coding genes, non-coding RNA regions also harbor variants with potential implications for vascular calcification. The variant rs187916214 in the LIN28AP1 - CACYBPP2 region, which includes pseudogenes, may affect regulatory elements that influence nearby functional genes involved in calcium signaling or cell proliferation. Similarly, rs60620535 in the LINC02498 - MIR572 region involves a long intergenic non-coding RNA and a microRNA, both known to regulate gene expression and cellular processes such as inflammation and cell differentiation. Lastly, rs6902719 in RNF217-AS1, an antisense RNA, could modulate the expression of its sense gene RNF217, which is involved in ubiquitination pathways crucial for protein degradation and cellular stress responses. These non-coding variants can fine-tune gene expression, influencing the complex interplay of factors that promote or inhibit calcification within the thoracic aorta .
Key Variants
Section titled “Key Variants”Defining Aortic Calcification and its Measurement
Section titled “Defining Aortic Calcification and its Measurement”Aortic calcification refers to the deposition of calcium within the walls of the aorta, a large artery central to the circulatory system. This phenomenon is considered a marker of subclinical atherosclerosis, indicating the presence of arterial disease before clinical symptoms manifest.[1] In research settings, a calcified lesion within the aorta is precisely defined as an area consisting of at least three connected pixels with a CT attenuation greater than 130 Hounsfield Units, identified using 3D connectivity criteria.[1] This operational definition allows for consistent identification and quantification of calcium deposits through imaging techniques such as multidetector computed tomography (MDCT).[1]
Terminology and Quantification Approaches
Section titled “Terminology and Quantification Approaches”While the general term “aortic calcification” describes calcium deposits in the aorta, specific anatomical segments are often distinguished for diagnostic and research purposes. The provided studies primarily focus on abdominal aortic calcification (AAC), which refers to calcification specifically within the abdominal segment of the aorta.[1] AAC is quantified by multiplying the area of a calcified lesion by a weighted CT attenuation score, which depends on the maximal CT attenuation (Hounsfield Units) within that lesion.[1]This method is a modification of the original Agatston Score, initially developed for electron beam CT, and has been adapted for MDCT scan protocols used in numerous studies to score both AAC and coronary artery calcification (CAC).[1]
Clinical Significance and Classification of Aortic Calcification
Section titled “Clinical Significance and Classification of Aortic Calcification”The presence and extent of aortic calcification, particularly AAC, are recognized as important predictors of vascular morbidity and mortality.[5] The quantification methods, such as the modified Agatston score for AAC, provide a dimensional approach to classifying the burden of calcification, allowing for severity gradations based on the calculated score.[1]This quantitative assessment contributes to understanding an individual’s cardiovascular risk profile and tracking disease progression, although specific categorical classifications or nosological systems beyond the score itself are not detailed in the researchs for AAC.
Causes of Thoracic Aortic Calcification
Section titled “Causes of Thoracic Aortic Calcification”Thoracic aortic calcification, a manifestation of subclinical atherosclerosis, results from a complex interplay of genetic predispositions, lifestyle choices, cardiometabolic conditions, and age-related changes. Its development is not attributed to a single factor but rather a cumulative effect of multiple pathways contributing to arterial wall stiffening and mineral deposition.
Genetic Predisposition
Section titled “Genetic Predisposition”Genetic factors play a significant role in an individual’s susceptibility to aortic calcification, as evidenced by the heritability of subclinical atherosclerosis measures like abdominal aortic calcification (AAC) and coronary artery calcification (CAC).[1]Genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) associated with these calcification phenotypes, though results have not always reached genome-wide significance, suggesting that many genes with modest influences contribute to this complex trait.[1] For instance, specific SNPs such as rs10488813 have been linked to AAC, and variants like rs10483853 , rs10507130 , rs10519394 , and rs10520541 to CAC, highlighting potential genetic markers for arterial calcification.[1] Further research is warranted to validate these associations and elucidate the functional mechanisms through which these genetic variants influence the calcification process.
Beyond specific SNPs, a polygenic risk, involving numerous genes with small effects, likely contributes to the overall genetic architecture of aortic calcification. While some candidate genes, including F5, MTHFR, REN, APOB, CX3CR1, GATA2, EDN1, CTGF, VEGF, PON1, MMP3, SCARB1, ALOX5AP, CETP, ITGB3, NOS2A, APO3, and MMP9, have been investigated, their associations with subclinical atherosclerosis measures have shown varying degrees of significance.[1] The limited coverage of genetic variation in some candidate genes by current genotyping arrays underscores the need for more comprehensive studies to fully uncover the genetic underpinnings of arterial calcification .
Lifestyle and Cardiometabolic Risk Factors
Section titled “Lifestyle and Cardiometabolic Risk Factors”Lifestyle and cardiometabolic factors are major drivers in the development and progression of aortic calcification. Traditional cardiovascular risk factors, such as high systolic blood pressure, elevated body mass index (BMI), and current cigarette smoking status, are strongly associated with increased arterial calcification.[1] Conditions like diabetes, dyslipidemia (indicated by total-to-HDL cholesterol ratio and log triglycerides), and the use of anti-hypertensive or lipid-lowering therapies also reflect underlying physiological dysregulations that promote arterial damage and calcification.[1] These factors contribute to the inflammatory and oxidative stress pathways that initiate and propagate atherosclerotic plaque formation, eventually leading to the deposition of calcium in the arterial walls.
Age and Hormonal Influences
Section titled “Age and Hormonal Influences”Age is an independent and potent risk factor for thoracic aortic calcification, with its prevalence and severity increasing significantly with advancing years.[1]The cumulative exposure to various damaging factors over a lifetime, along with cellular senescence and impaired repair mechanisms, contributes to the progressive mineralization of arterial tissues. Furthermore, hormonal factors, particularly menopausal status and the use of hormone therapy in women, are considered important covariates influencing the risk of arterial calcification.[1]These hormonal changes can affect lipid metabolism, vascular inflammation, and bone mineral density, indirectly impacting the propensity for calcium deposition in the aorta.
Gene-Environment Interactions
Section titled “Gene-Environment Interactions”The development of thoracic aortic calcification is not solely determined by genetic or environmental factors in isolation, but also by the intricate interplay between them. Genetic predispositions can interact with environmental triggers, modulating an individual’s risk in a context-specific manner. For example, specific genetic variants might confer higher susceptibility to calcification only when an individual is exposed to particular dietary patterns or lifestyle habits . Although the direct investigation of such gene-environment interactions for subclinical atherosclerosis measures like aortic calcification was not undertaken in some studies, the concept remains a crucial aspect of understanding the full spectrum of causal factors . Future research focusing on these complex interactions will be essential to fully unravel the personalized risk profiles for thoracic aortic calcification.
Biological Background
Section titled “Biological Background”Thoracic aortic calcification refers to the deposition of calcium phosphate minerals within the walls of the thoracic aorta, the largest artery in the body that originates from the heart and extends down to the abdomen. This process is a significant indicator of subclinical atherosclerosis, a condition where arteries harden and narrow due to plaque buildup, and serves as a strong predictor for future cardiovascular events independent of traditional risk factors.[1]While the provided studies predominantly discuss abdominal aortic calcification (AAC) and coronary artery calcification (CAC), the underlying biological mechanisms for calcification in major arterial territories, including the thoracic aorta, are largely shared.
The Nature and Clinical Significance of Arterial Calcification
Section titled “The Nature and Clinical Significance of Arterial Calcification”Arterial calcification, encompassing forms like thoracic, abdominal, and coronary calcification, is not merely a passive accumulation of calcium but an active, regulated biological process resembling bone formation. These calcific deposits are typically detected and quantified using multidetector computed tomography (MDCT), where a calcified lesion is defined as an area with a CT attenuation greater than 130 Hounsfield Units.[1]The presence and extent of calcification in arteries, such as the abdominal aorta, are critical predictors of vascular morbidity and mortality, highlighting their clinical importance in assessing cardiovascular health.[5]Furthermore, measures of subclinical atherosclerosis, including calcification, have been shown to be heritable traits, indicating a significant genetic component in an individual’s susceptibility to this condition.[1]
Cellular and Molecular Pathways in Calcification
Section titled “Cellular and Molecular Pathways in Calcification”The development of arterial calcification involves complex molecular and cellular pathways, primarily driven by vascular smooth muscle cells (VSMCs) within the arterial wall. These cells can undergo a phenotypic switch, transforming into osteoblast-like cells that actively produce bone matrix proteins and facilitate mineral deposition. This process is influenced by various signaling pathways, including those regulating inflammation, oxidative stress, and metabolic dysregulation, which disrupt normal homeostatic mechanisms within the vasculature. Key biomolecules, such as calcium and phosphate ions, along with regulatory proteins and enzymes, play crucial roles in initiating and propagating this pathological mineralization. For instance, an imbalance in calcium and phosphate metabolism can trigger calcification, while various growth factors and cytokines can promote the osteogenic differentiation of VSMCs.
Genetic Predisposition and Regulatory Networks
Section titled “Genetic Predisposition and Regulatory Networks”Genetic mechanisms significantly contribute to an individual’s susceptibility to arterial calcification. Genome-wide association studies (GWAS) aim to identify specific genetic variants, such as single nucleotide polymorphisms (SNPs), that are associated with the quantitative measures of atherosclerosis, including calcification.[1]While many candidate genes have been explored, the precise regulatory networks governing calcification are still being elucidated. The heritability of subclinical atherosclerosis measures like abdominal aortic calcification and coronary artery calcification suggests that inherited genetic variations influence gene expression patterns and cellular functions critical to arterial health. Although numerous genes were evaluated in previous research, some, such asF5, MTHFR, REN, APOB, CX3CR1, GATA2, EDN1, CTGF, VEGF, PON1, MMP3, SCARB1, ALOX5AP, CETP, ITGB3, NOS2A, APO3, and MMP9, did not show significant associations with subclinical atherosclerosis in certain studies.[1] Conversely, other genes and their regulatory elements may play a more direct role in modulating calcification risk.
Systemic Factors and Disease Pathophysiology
Section titled “Systemic Factors and Disease Pathophysiology”Arterial calcification is intricately linked to systemic pathophysiological processes and interactions at the tissue and organ level. Traditional cardiovascular risk factors, including age, elevated systolic blood pressure, high body mass index (BMI), cigarette smoking, diabetes, dyslipidemia (abnormal HDL and total cholesterol levels, and triglycerides), menopausal status, and hormone therapy, are strongly associated with the development and progression of arterial calcification.[1]These systemic conditions disrupt the delicate balance within the arterial wall, promoting inflammation, endothelial dysfunction, and the accumulation of lipids, which are hallmarks of atherosclerosis. The presence of calcification in one arterial territory, such as the thoracic aorta, often reflects a broader systemic atherosclerotic burden, indicating generalized vascular disease. Compensatory responses within the body may attempt to mitigate these changes, but sustained exposure to risk factors often overwhelms these protective mechanisms, leading to progressive arterial stiffening and increased cardiovascular risk.
Genetic Architecture and Transcriptional Regulation
Section titled “Genetic Architecture and Transcriptional Regulation”The development of thoracic aortic calcification, like other forms of arterial calcification, is significantly influenced by genetic predisposition, as evidenced by the heritability of abdominal aortic calcific deposits.[1] and coronary artery calcium quantity.[6]Genome-wide association studies (GWAS) have been instrumental in identifying genetic variants that contribute to subclinical atherosclerosis, including calcification, by uncovering previously unrecognized genes.[1] For instance, specific genetic variants in genes such as CFH and NOS1APhave been implicated in subclinical atherosclerosis.[1], [7], [8] These genetic factors likely regulate the transcription of genes essential for vascular cell function, extracellular matrix remodeling, and the initiation of mineralization processes within the arterial wall, influencing the overall susceptibility to calcification.
Cellular Signaling and Mineral Homeostasis
Section titled “Cellular Signaling and Mineral Homeostasis”Intracellular signaling cascades are central to the pathogenesis of arterial calcification. For example, the disruption of the CFTRchloride channel has been shown to alter the mechanical properties and cAMP-dependent chloride transport in mouse aortic smooth muscle cells, thereby affecting cellular functions critical for vascular integrity.[9] The presence of CFTR expression and chloride channel activity in human endothelia.[10]further suggests its broad influence on vascular cell physiology and its potential role in calcification. Receptor activation by molecules such as Angiotensin II can also dysregulate signaling pathways, specifically by increasing phosphodiesterase 5A expression in vascular smooth muscle cells.[11] which antagonizes cGMP signaling and promotes vascular remodeling. The intricate regulation of phosphodiesterase 5.[12] underscores the complexity of intracellular messaging that, when perturbed, can contribute to pathological mineral deposition. The precise control of mineral homeostasis within the vascular wall involves specific proteins like osteocalcin, a marker for bone turnover that participates in calcium regulation.[13] The functional activity of osteocalcinis subject to post-translational modification, specifically carboxylation, which is dependent on adequate vitamin K status.[13] This metabolic regulation of osteocalcin represents a key mechanism that links nutritional factors to the control of mineral deposition, and its dysregulation can directly contribute to the pathological calcification observed in the arterial wall.
Metabolic Dysregulation and Systemic Influences
Section titled “Metabolic Dysregulation and Systemic Influences”Metabolic pathway dysregulation significantly contributes to the initiation and progression of arterial calcification. Alterations in lipid metabolism, including total cholesterol, high-density lipoprotein cholesterol, and triglycerides, are recognized risk factors for cardiovascular disease and subclinical atherosclerosis.[14], [15], [16]Elevated serum uric acid levels also represent a metabolic risk factor for cardiovascular disease, metabolic syndrome, and hypertension.[17], [18], [19] with the GLUT9 gene influencing these levels.[20]thereby establishing a direct metabolic link to vascular pathology. Endocrine factors exert broader systemic control over vascular health, influencing metabolic flux and contributing to the calcification process. Endogenous sex hormones are associated with cardiovascular disease incidence in men.[21]while thyroid dysfunction is linked to total cholesterol levels.[22] These hormonal influences can modulate cellular processes and protein modifications, such as the phosphorylation of Heat Shock Protein-90 by TSH.[23]which impacts protein stability and cellular stress responses. Furthermore, systemic inflammation, indicated by C-reactive protein levels, is modulated by genetic polymorphisms.[14] integrating inflammatory responses into the complex network interactions that drive arterial calcification.
Pathway Crosstalk and Disease Progression
Section titled “Pathway Crosstalk and Disease Progression”The progression of arterial calcification is an emergent property resulting from extensive pathway crosstalk and intricate network interactions within the vascular system. For instance, the Angiotensin II signaling pathway, a key regulator of blood pressure and vascular remodeling, directly interacts with and antagonizes cGMP signaling by increasing phosphodiesterase 5A expression.[11] This interaction forms a feedback loop that promotes vasoconstriction and exacerbates the calcification process, illustrating a hierarchical regulation where systemic hormonal signals translate into localized cellular responses. The overall dysregulation of these interconnected pathways, including those governing platelet aggregation.[1] and hemostatic factors.[24]contributes to the broader pathogenesis of atherosclerosis.[25]a condition where calcification is a critical and often debilitating feature. Understanding these complex network interactions is crucial for identifying potential therapeutic targets to effectively modulate disease progression and mitigate the impact of arterial calcification.
Prognostic Indicator of Cardiovascular Risk
Section titled “Prognostic Indicator of Cardiovascular Risk”Aortic calcification, particularly abdominal aortic calcification(AAC) as investigated in research, is recognized as a significant predictor of future vascular morbidity and mortality. The presence and extent of these calcific deposits serve as important markers for adverse cardiovascular outcomes, independent of traditional risk factors. Quantitative assessment of calcification through methods like multidetector computed tomography (MDCT) provides valuable insights into an individual’s long-term cardiovascular prognosis.[5]
Diagnostic Utility and Risk Assessment
Section titled “Diagnostic Utility and Risk Assessment”The detection of aortic calcification, specifically AAC, offers a non-invasive diagnostic approach for identifying subclinical atherosclerosis. MDCT-based scoring, which quantifies calcified lesions by multiplying the area of a lesion with a weighted CT attenuation score, enables precise measurement of the calcific burden. This objective measure enhances risk stratification by helping to identify individuals at higher risk for cardiovascular events, thereby supporting the development of personalized prevention strategies.[1]The quantity of calcification observed in the aorta, such as AAC, exhibits significant heritability, suggesting that genetic factors play a role alongside environmental influences in its development and progression. Understanding these genetic predispositions can further refine cardiovascular risk prediction models and guide more targeted interventions for high-risk populations.[1]
Associations with Systemic Atherosclerosis
Section titled “Associations with Systemic Atherosclerosis”Aortic calcification, exemplified by AAC, is a manifestation of widespread systemic atherosclerosis and frequently coexists with subclinical atherosclerosis in other arterial territories. Research indicates associations between AAC and other markers of vascular disease, includingcoronary artery calcification (CAC), carotid intimal medial thickness (IMT), and ankle-brachial index(ABI). These interconnections highlight the systemic nature of atherosclerosis and underscore the utility of evaluating multiple vascular beds for a comprehensive assessment of cardiovascular health and potential complications.[1] Despite these associations, there are often incomplete correlations between calcification in different vascular beds, suggesting that various arterial segments may reflect distinct aspects or stages of the atherosclerotic process. This complexity emphasizes the importance of a multi-modal approach to fully characterize an individual’s overall atherosclerotic burden and its implications for related conditions.[1]
References
Section titled “References”[1] O’Donnell CJ et al. “Genome-wide association study for subclinical atherosclerosis in major arterial territories in the NHLBI’s Framingham Heart Study.” BMC Med Genet 2007.
[2] Vasan RS et al. “Genome-wide association of echocardiographic dimensions, brachial artery endothelial function and treadmill exercise responses in the Framingham Heart Study.” BMC Med Genet 2007.
[3] Benjamin, Emelia J. et al. “Genome-wide association with select biomarker traits in the Framingham Heart Study.” BMC Medical Genetics, vol. 8, suppl. 1, 2007, p. S2.
[4] Wallace C et al. “Genome-wide association study identifies genes for biomarkers of cardiovascular disease: serum urate and dyslipidemia.” Am J Hum Genet 2008.
[5] Wilson, P. W. et al. “Abdominal aortic calcific deposits are an important predictor of vascular morbidity and mortality.”Circulation, vol. 103, 2001, pp. 1529-1534.
[6] Peyser, P. A., et al. “Heritability of coronary artery calcium quantity measured by electron beam computed tomography in asymptomatic adults.” Circulation, vol. 106, no. 24, 2002, pp. 304-308.
[7] Klein, R. J., et al. “Complement factor H polymorphism in age-related macular degeneration.”Science, vol. 308, no. 5720, 2005, pp. 385-389.
[8] Post, W., et al. “Determinants of coronary artery and aortic calcification in the Old Order Amish.” Circulation, vol. 115, no. 6, 2007, pp. 717-724.
[9] Robert, R., et al. “Disruption of CFTR chloride channel alters mechanical properties and cAMP-dependent Cl-transport of mouse aortic smooth muscle cells.”Journal of Physiology (London), vol. 568, no. Pt 2, 2005, pp. 483-495.
[10] Tousson, A., et al. “Characterization of CFTR expression and chloride channel activity in human endothelia.” American Journal of Physiology. Cell Physiology, vol. 275, no. 6, 1998, pp. C1555-C1564.
[11] Kim, D., et al. “Angiotensin II increases phosphodiesterase 5A expression in vascular smooth muscle cells: a mechanism by which angiotensin II antagonizes cGMP signaling.”Journal of Molecular and Cellular Cardiology, vol. 38, no. 1, 2005, pp. 175-184.
[12] Lin, C. S., et al. “Expression, distribution and regulation of phosphodiesterase 5.” Current Pharmaceutical Design, vol. 12, no. 27, 2006, pp. 3439-3457.
[13] Gundberg, C. M., et al. “Osteocalcin: isolation, characterization, and detection.”Methods in Enzymology, vol. 107, 1984, pp. 516-544.
[14] Kathiresan, S., et al. “Contribution of clinical correlates and 13 C-reactive protein gene polymorphisms to interindividual variability in serum C-reactive protein level.”Circulation, vol. 113, no. 11, 2006, pp. 1415-1423.
[15] Willer, C. J., et al. “Newly identified loci that influence lipid concentrations and risk of coronary artery disease.”Nature Genetics, vol. 40, no. 2, 2008, pp. 161-169.
[16] Keavney, B., et al. “Lipid-related genes and myocardial infarction in 4685 cases and 3460 controls: discrepancies between genotype, blood lipid concentrations, and coronary disease risk.”International Journal of Epidemiology, vol. 33, no. 5, 2004, pp. 1002-1013.
[17] Hayden, M. R., and S. C. Tyagi. “Uric acid: A new look at an old risk marker for cardiovascular disease, metabolic syndrome, and type 2 diabetes mellitus: The urate redox shuttle.”Nutrition & Metabolism (London), vol. 1, no. 1, 2004, p. 10.
[18] Johnson, R. J., et al. “Is there a pathogenetic role for uric acid in hypertension and cardiovascular and renal disease?”Hypertension, vol. 41, no. 6, 2003, pp. 1183-1190.
[19] Puig, J. G., and L. M. Ruilope. “Uric acid as a cardiovascular risk factor in arterial hypertension.”Journal of Hypertension, vol. 17, no. 7, 1999, pp. 869-872.
[20] Li, S., et al. “The GLUT9 gene is associated with serum uric acid levels in Sardinia and Chianti cohorts.”PLoS Genetics, vol. 4, no. 11, 2008, p. e1000242.
[21] Arnlov, J., et al. “Endogenous sex hormones and cardiovascular disease incidence in men.”Annals of Internal Medicine, vol. 145, no. 3, 2006, pp. 176-184.
[22] Kanaya, A. M., et al. “Association between thyroid dysfunction and total cholesterol level in an older biracial population: the health, aging and body composition study.”Archives of Internal Medicine, vol. 162, no. 7, 2002, pp. 773-779.
[23] Ginsberg, J., et al. “Phosphorylation of Heat Shock Protein-90 by TSH in FRTL-5 Thyroid Cells.” Thyroid, vol. 16, no. 8, 2006, pp. 737-742.
[24] Yang, Q., et al. “Genome-wide association and linkage analyses of hemostatic factors and hematological phenotypes in the Framingham Heart Study.”BMC Medical Genetics, vol. 8, no. Suppl 1, 2007, p. S12.
[25] Fuster, V., et al. “The pathogenesis of coronary artery disease and the acute coronary syndromes (1).”New England Journal of Medicine, vol. 326, no. 4, 1992, pp. 242-250.