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Abstract

Background

Abdominal aortic calcifications were already ubiquitous in ancient populations from all continents. Although nowadays generally considered as an innocent end stage of stabilised atherosclerotic plaques, increasing evidence suggests that arterial calcifications contribute to cardiovascular risk. In this review we address abdominal aortic calcification from an evolutionary perspective and review the literature on histology, prevalence, risk factors, clinical outcomes and pharmacological interventions of abdominal aortic calcification.

Design

The design of this study was based on a literature review.

Methods

Pubmed and Embase were systematically searched for articles on abdominal aortic calcification and its synonyms without language restrictions. Articles with data on histology, prevalence, risk factors clinical outcomes and/or pharmacological interventions were selected.

Results

Abdominal aortic calcification is highly prevalent in the general population and prevalence and extent increase with age. Prevalence and risk factors differ between males and females and different ethnicities. Risk factors include traditional cardiovascular risk factors and decreased bone mineral density. Abdominal aortic calcification is shown to contribute to arterial stiffness and is a strong predictor of cardiovascular events and mortality. Several therapies to inhibit arterial calcification have been developed and investigated in small clinical trials.

Conclusions

Abdominal aortic calcification is from all eras and increasingly acknowledged as an independent contributor to cardiovascular disease. Large studies with long follow-up must be carried out to show whether inhibition of abdominal aortic calcification will further reduce cardiovascular risk.

Keywords

Abdominal aorta calcification mummy histology epidemiology aneurysm treatment

Introduction

Why do calcifications in the aorta develop and why are they so ubiquitous? Nowadays many physicians seem to think that aorta calcifications are an innocent finding on imaging. Cardiovascular disease reduction focuses on treatment of hyperlipidaemia, thrombosis and inflammation. Apart from the vascular interventionist, who experiences problems from calcifications because they may prevent entering the vessel and make procedures more difficult, most physicians ignore calcifications as an innocent end stage of stabilised atherosclerotic plaques. But are they right?

There have been several hypotheses over past decades as to why calcifications occur and whether there is a positive or negative effect on survival. In 1957, Williams¹ postulated that arterial calcifications could be the result of antagonistic pleiotropy: the tendency of certain genes to be beneficial for an organism in the early or reproductive years, but detrimental in later life. For example, bone fractures at a young age can result in death in the era of hunters and collectors and fast calcification of fractures might therefore aid survival.² Yet, later in life, a strong tendency towards calcification might express itself in the calcification of the connective tissue of arteries.

Another hypothesis, proposed by Demer et al.³ stated that the calcification process could have evolved as a useful adaptive response in the protection against chronic (parasitic) infections. These calcifications are thought to insulate the noxious focus and might have aided survival in a pre-antibiotic era. Nowadays this appears to occur as a maladaptive response to inflammatory lipoprotein particles resembling infectious particles.

In recent years, calcification of the arteries is increasingly regarded as a protective factor which can be seen as a response to injury to prevent plaque rupture in the coronaries or further aneurysm growth in the abdominal aorta.^4,5 Accordingly, mechanisms that promote the manifestations of atherosclerosis also increase the risk of calcification.⁶ However, on the antagonistic spectrum, when aortic calcifications become more severe they might cause adverse health outcomes. Circular calcifications involving the entire arterial wall affect the normal physiology of the aorta by inhibiting the Windkessel function, required for the dampening of pulsatile energy from the heart to the periphery and for decreasing left cardiac ventricle load.⁷

Epidemiological studies in several populations show that (progression of) aortic calcification is associated with cardiovascular events and mortality independent of coronary calcium score and that circularity of the calcifications independently adds to the risk.^8–10 Probably, aortic calcifications were a once-needed repair mechanism and the propensity of the human body to calcify has been beneficial in former populations. In our aging population the detrimental effects may become more evident. In past decades, the development of lipid-lowering drugs, blood pressure control, anti-thrombotic and anti-inflammatory therapies have led to an enormous reduction of cardiovascular risk. However, for further risk reduction, studies into the causative role of calcification in cardiovascular disease and pharmacological interventions in calcification formation might be crucial to further decrease the huge residual cardiovascular risk.

The ancient and forgotten history of aortic calcifications

Nowadays, the unhealthy modern lifestyle and diet are considered important contributors to cardiovascular disease. However, ancient Egyptians already suffered from coronary artery disease. The ancient Egyptian medical text, the ‘Papyrus Ebers', that dates back to 1500 BC, describes the following symptoms: ‘When thou examine a man for illness in his cardia, he has pain in his arm, in his breast, on the side of his cardia, […] it is death which approaches him'.¹¹ This is a clear description of angina pectoris.

In the HORUS study, named after the Egyptian deity,¹² the prevalence of arterial calcifications in ancient mummies from four different geographical regions has been investigated. Using whole-body computed tomography (CT) scanning, arterial calcification was quantified in 76 ancient Egyptian, 51 ancient Peruvian, five ancestral Puebloans and five Unangan hunter gatherers. Arterial calcifications were seen in 34% of the 137 mummies studied. Twenty per cent of the mummies had aortic calcification whereas coronary calcification was seen in only 4%. Mummies with arterial calcification where older and their better survival was correlated with the number of calcified arterial beds. This shows that arterial calcifications were already highly prevalent in ancient populations and that calcific aortic disease is not characteristic of any specific diet or lifestyle.

Methods

For literature on the histology and epidemiology of abdominal aortic calcification (AAC), Pubmed and Embase were systematically searched for articles on AAC and its synonyms without language restrictions. Articles with data on histology, prevalence, risk factors, clinical outcomes and/or pharmacological interventions were selected. All articles were screened on title and abstract and the full text of relevant articles was evaluated on eligibility. In addition, a manual search through the references of the selected articles was performed to identify additional relevant articles.

Histology of AAC

Atherosclerotic plaques already develop in childhood and their extent increases with age. Although coronary artery calcification has been extensively studied, atherosclerosis develops at a younger age in the aorta. In the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) study, the presence and extent of atherosclerotic lesions were studied on histology in 1532 deceased persons from 15–34 years. In the youngest age group (15–19 years old), 100% of the abdominal aortas had atherosclerotic lesions, whereas these lesions were found in only 50% of the coronary arteries. AACs developed later, but were already present in 14% in the oldest age group (30–34 years old).¹³

Calcifications occur in the intimal and in the medial layer of the arterial wall. Intimal calcification is present in atherosclerotic lesions and is common in the coronary arteries. Medial arterial calcification seems to be an independent process from atherosclerosis. It is considered a metabolic disease that starts around the internal elastic lamina and expands into the medial layer. Medial calcification is related to aging, diabetes, chronic kidney disease and several rare monogenetic diseases,¹⁴ and is common in the peripheral arteries.^15,16 Data on the exact histologic localization of aortic calcifications and their development with age are limited. It has been shown that medial calcification can be found in the aortic wall and increases during ageing, especially when investigated with dedicated staining or micro-incineration.^17,18 Despite the lack of data it is generally assumed that aortic calcifications are predominant atherosclerotic in nature.

The epidemiology of AAC and its relation to outcomes

Prevalence

Calcifications in the abdominal aorta as seen on CT scans develop early in life, and the prevalence and extent increase with age. In the Framingham Heart Study, the prevalence of AAC and the difference between male and females was investigated in 3285 participants and in a subgroup of 1656 participants without any cardiovascular risk factors. AAC was present in 22.4% of the male and 16.4% of the female participants under 45 years. In the subgroup without any cardiovascular risk factors, AAC was already present in 15.5% of males and 7.8% in females in the age group under 45 years. In both groups, the prevalence increased to 100% in both males and females over 75 years old. Agatston-like scores were higher in males in all age categories.¹⁹

The Multi-Ethnic Study of Atherosclerosis (MESA) investigated the difference in AAC prevalence between different ethnicities. In the 1957 participants with a mean age of 65 years, calcification was present in 80% of whites, 74% of Chinese, 68% of Hispanics and 63% of African Americans.²⁰ When adjusted for cardiovascular risk factors, Hispanics and African Americans, but not Chinese Americans, had a significantly lower risk for the presence of AAC than whites. So, although AAC is highly prevalent and prevalence increases to 100% in older populations, differences between males and females and different ethnicities exist.

Risk factors of AAC

Calcifications in the abdominal aorta increase with age and are associated with traditional cardiovascular risk factors.^21,22 In addition, age, baseline AAC, diabetes mellitus, body mass index (BMI), systolic blood pressure and pulse pressure are independently associated with progression of AAC.^23–25 Risk factors appear to differ between males and females. In a Korean study comparing risk factors between males and females, smoking was associated with AAC in men, whereas diabetes and hypertension were associated with AAC in females.²⁶

European Americans have higher prevalence and extent, but lower density of AAC, when compared to Hispanics, African Americans and Chinese Americans,²⁷ and risk factors differ between these ethnicities.²⁰ In the MESA study it was found that in European Americans, age, male gender, (history of) smoking, hypertension and use of cholesterol medication are risk factors for AAC. In Hispanics, risk factors were age, smoking and low-density lipoprotein (LDL) cholesterol, in African Americans, age, smoking and hypertension, whereas in Chinese Americans, only age was significantly associated with AAC.²⁰ These differences in risk factors suggest ethnic differences in the arterial calcification process.

Conflicting results regarding the association between AAC and adipose tissue have been found and the association therefore remains inconclusive (Supplemental Material 1). Epidemiological studies consistently report associations between AAC and osteoporosis, accelerated bone loss and vertebral and hip fractures (Supplemental Material 1). Despite this consistent inverse association, the mechanism behind this bone-vascular axis is complex and not completely elucidated.²⁸ Although long-term exposure to air pollution has been associated with cardiovascular disease morbidity and mortality, no overall association was found between fine-matter air pollution or residential proximity to major roads and prevalence and progression of thoracic aortic calcification or AAC.^29,30

AAC and vascular function

Calcification contributes to arterial stiffness and affects normal arterial physiology by impacting on the Windkessel function.³¹ AAC is associated with vascular function tests including pulse wave velocity (PWV)^31,32 and low ankle brachial index (ABI)³³ and the length of AAC on X-ray is associated with the height of PWV.³⁴ In addition, AAC was independently associated with left ventricular mass and mitral annular early diastolic velocity, a measure for diastolic dysfunction, in elderly men with hypertension³² and with left ventricular mass in patients with chronic kidney disease (CKD),³⁵ which suggests that aortic calcification and stiffness impact on cardiac load.

AAC and clinical outcomes

Several epidemiological studies have shown that AAC is associated with cardiovascular disease and cardiovascular mortality,^36,37 incident coronary heart disease,¹⁰ myocardial infarction³⁸ and stroke.³⁹ A meta-analysis of 10 longitudinal studies showed that AAC was associated with an increased relative risk of coronary events (relative risk (RR) 1.81, 95% confidence interval (CI) 1.54–2.14), cerebrovascular events (RR 1.37, 95% CI 1.22–3.34), all cardiovascular events (RR 1.64, 95% CI 1.24–2.17) and cardiovascular death (RR 1.72 95% CI 1.03–2.86).⁴⁰

Recently, AAC was shown to be a better predictor of cardiovascular events than the Framingham risk score.³⁷ The MESA study investigated the difference between AAC and coronary artery calcification (CAC) on cardiovascular outcomes. When compared, both AAC and CAC are independent predictors of coronary heart disease and cardiovascular disease. However, AAC, but not CAC was associated with cardiovascular disease mortality and AAC was a stronger predictor for all-cause mortality than CAC.⁴¹ In a follow-up study, AAC volume was associated with all-cause mortality and a trend towards an association with cardiovascular disease was found after adjustment for cardiovascular risk factors. In contrast, a non-significant trend towards an inverse relation between calcification density and all-cause mortality was found.⁴² This suggests that dense calcifications might protect against cardiovascular events, an observation confirmed in the coronary arteries.⁴³ These results emphasise the difference between calcification volume and density and show that AAC might add to cardiovascular risk classification.

Role of AAC in cardiovascular risk classification

Currently, the 10-year risk of cardiovascular mortality is most commonly estimated based on traditional cardiovascular risk factors including, age, sex, cholesterol levels, blood pressure and smoking status. Risk categories are classified in low risk (<1%), moderate risk (1–5%), high risk (5–10%) and very high risk (>10%).⁴⁴ No imaging markers are part of most risk classifications, although CAC score, carotid intima media thickness and ankle brachial index are considered as risk modifiers.⁴⁴ AAC is currently not included in the guidelines of the European Society of Cardiology (ESC) and differing results as to whether it improves risk (re)classification have been found. In the Framingham Heart Study, AAC did not significantly improve risk (re)classification, when compared to the Framingham risk score, but CAC score did.³⁶ Another longitudinal study in 829 asymptomatic patients who underwent CT colonography screening found that AAC did improve reclassification when compared to the Framingham risk score.³⁷ Therefore, despite a consistent association between AAC and cardiovascular events and mortality, more evidence on its role in risk (re)classification, management consequences and outcome improvement is needed.

Calcification in abdominal aortic aneurysm and consequences for interventions

Abdominal aortic aneurysms (AAAs) are progressive dilatations of the infrarenal aorta. Aneurysm size is the most important predictor of growth and rupture and surgical repair is usually undertaken when the aortic diameter approximates the point when the risk of rupture it thought to outweigh the perioperative risks, which is when the aortic diameter exceeds 5.5 cm.⁴⁵ Histological examination of AAA biopsies has shown that the pathophysiology involves all layers of the arterial wall and involve degradation of extracellular collagen and elastin, a reduction in vascular smooth muscle cells and infiltration of macrophages.⁴⁶ Calcification of AAA is frequently observed and is speculated to stabilise progression of AAA dilatation. Indeed, some epidemiological studies have found lower expansion rates in calcified when compared to non-calcified AAAs,^47,48 whereas others found no such associations.⁴⁹ Diabetes is negatively associated with abdominal aneurysm growth and it is speculated that calcification plays a role in this association.⁵⁰ Despite this potential positive effect on growth, AAA calcification was shown to be associated with increased rupture risk,⁵¹ especially on the junction between calcium deposits and the fibrous matrix.⁵² A possible mechanism involves increased peak wall stress and diminished mechanical stability of the arterial wall at calcified sites.⁵³

Ultrasound is the preferred imaging modality for screening for AAAs. The current guidelines of the Society of Vascular Surgery advice a one-time screening for AAAs in persons between 65–75 years with a smoking history, in persons >75 years and in good health with a smoking history and in first degree relatives aged 65–75 years, or >75 years and in good health, of patients with an AAA.⁵⁴ Currently, the size of the AAA is used as the estimate for rupture risk. A retrospective study on 24,000 autopsies has shown that 118 of the 473 nonresected AAAs were ruptured. Forty per cent of the AAAs with a diameter >5.0 mm were ruptured. However, 40% of the AAAs between 7–10 cm were unruptured, whereas 13% of aneurysms below 5 cm were.⁵⁵ This shows that aneurysm size is not the sole predictor for rupture risk and emphasises the need for better risk stratification. AAA calcification might add to the risk assessment and it may modify the growth rate if follow-up imaging is considered.^47,48 Currently, however, methods to measure the peak wall stress and peak wall rupture index for AAA risk stratification are being developed.⁵⁶ Since the increased rupture risk seen in calcified AAAs is thought to be mediated by peak wall stress, this might be a better predictor for rupture risk. In past decades, AAA treatment has shifted from open surgical repair to endovascular aneurysm repair (EVAR). Although EVAR results in lower perioperative mortality than open repair, this advantage diminishes after longer follow-up⁵⁷ and some studies even report lower long-term mortality after open surgery.⁵⁸ Not much literature is available about the role of aortic calcifications in AAA repair. Calcification at the proximal attachment zone is speculated to impair fixation between stent graft and the aortic wall. This potentially leads to endoleaks, migration and increased risk of thromboembolism.⁵⁹ Some studies did find an association between neck calcification and re-interventions^59,60 and endograft limb occlusion.⁶¹ In general, however, no association between (extent of) calcification and clinical failure, graft migration or endoleaks are found.^62,63

Aortic calcification: is it a treatable disease?

Arterial calcifications have long been thought to be an irreversible endpoint of atherosclerotic disease. However, increasing evidence suggests that it is an actively regulated process that can be halted or even reversed. This has prompted the search for therapeutics that might interfere in the calcification process and several possible treatments have been identified, developed and are being studied in a clinical setting.⁶⁴

Bisphosphonates

Although currently used for the treatment of osteoporosis, bisphosphonates were initially developed for the treatment of ectopic mineralization. Their chemical structure resembles the chemical structure of inorganic pyrophosphate, an important inhibitor of calcification.⁶⁵ In several genetic syndromes affecting the homeostasis of inorganic pyrophosphate, the old bisphosphonate etidronate was shown to inhibit and even reverse arterial calcifications in the abdominal aorta.^66,67 Although the newer bisphosphonates including alendronate⁶⁸ and ibandronate have shown no significant effect on arterial calcification in the abdominal aorta,^68,69 several small clinical trials have shown that etidronate does affect arterial calcification in more general populations as well. In patients on haemodialysis, etidronate was shown to inhibit and reverse progression of AAC⁷⁰ whereas it decreased abdominal aortic wall thickness on magnetic resonance imaging (MRI) in patients with hypercholesterolaemia.⁷¹ A large cohort study⁷² and meta-analysis⁷³ have shown that bisphosphonate use is associated with lower cardiovascular events and cardiovascular mortality, but the causal link between reduction of arterial calcification and a reduction of cardiovascular events remains to be established.

Calcium antagonists

Already some decades ago, several calcium antagonists were shown to reduce and prevent aortic calcification in rats.^74,75 Some small clinical trials have confirmed these results in the coronary arteries in humans. In placebo-controlled trials, nifedipine was shown to reduce the number of newly formed coronary lesions in early stage coronary artery disease,⁷⁶ but not instable angina pectoris,⁷⁷ and to slow down coronary artery calcification when compared to co-amizolide in patients with hypertension.⁷⁸ Azelnidipine compared to the diuretic indapamide was shown to improve arterial stiffness in patients with hypertension.⁷⁹ In addition, a significant reduction in circulating osteoprotegerin, matrix metalloproteinase 2 and high sensitive C-reactive protein was found in the azelnidipine-treated arm, which suggests that the effect of calcium antagonist might be mediated through bone turnover and inflammation. No literature on the effect of calcium antagonists on aortic calcification in humans exists.

Vitamin K

Vitamin K is an important co-factor for the carboxylation and activation of several vitamin K dependent proteins including the calcification inhibitor matrix Gla protein (MGP). Several epidemiological studies have found association between high circulation inactive MGP and PWV, coronary, aortic and femoral artery calcification, and cardiovascular events and mortality.⁸⁰ Despite vitamin K supplementation being consequently shown to decrease circulating levels of inactive MGP, differing results regarding its effect on calcification progression have been found. In a randomised controlled clinical trial, vitamin K was shown to have a positive effect on PWV, but other trials found no effect on calcification of the coronary or femoral arteries.^81,82 No literature on the effect of vitamin K supplementation on aortic calcification exists.

Magnesium

Meta-analyses of prospective cohort studies have shown that dietary magnesium intake and serum magnesium are inversely associated with the risk of cardiovascular disease and mortality.⁸³ Although the mechanism remains largely unclear, in vitro and animal studies have shown that magnesium interferes in the calcification process.⁸⁴ Two small clinical trials have shown that it halts progression of carotid intima-media thickness and arterial calcification in CKD patients on haemodialysis.^85,86 However, larger studies in more general populations are warranted to elucidate the role of magnesium in arterial calcification and its potential as a therapeutic agent.

Conclusions

Despite the general view of atherosclerosis as a consequence of modern lifestyle, arterial calcifications were already highly prevalent in ancient populations from different continents. Possibly a once-needed repair mechanism that aided survival, nowadays these calcifications are increasingly acknowledged as independent contributors to cardiovascular disease. They can also make interventions more complex and lead to complications. Risk factors for AAC differ between males and females and between different ethnicities and include traditional cardiovascular risk factors and decreased bone mineral density. AAC is associated with cardiovascular events and mortality and this association might be mediated through the effect of calcification on vascular functioning and arterial stiffness. Causal investigations into the role of aorta calcification in cardiovascular diseases must shed light on the pathophysiological mechanisms driving these associations. Several therapies to inhibit arterial calcification have been developed and investigated in small clinical trials. Larger studies with longer follow-up might now show whether inhibition of aorta calcification will further decrease cardiovascular risk.

Supplemental Material

sj-pdf-1-cpr-10.1177_2047487320919895 - Supplemental material for Abdominal aortic calcification: from ancient friend to modern foe

Supplemental material, sj-pdf-1-cpr-10.1177_2047487320919895 for Abdominal aortic calcification: from ancient friend to modern foe by Jonas W Bartstra, Willem PThM Mali, Wilko Spiering and Pim A de Jong: on behalf of the International Headache Society Global Patient Advocacy Coalition in European Journal of Preventive Cardiology

Footnotes

Author contribution

JB contributed to the conception, design, acquisition, analysis and interpretation of the data and drafted the manuscript. WM, WS and PdJ contributed to the conception and design of the study, interpretation of the data and critically revised the manuscript. All authors gave final approval and agree to be accountable for all aspects of the work ensuring integrity and accuracy.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship and/or publication of this article.

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