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. Author manuscript; available in PMC: 2020 Apr 1.
Published in final edited form as: Curr Opin Endocrinol Diabetes Obes. 2019 Apr;26(2):96–102. doi: 10.1097/MED.0000000000000471

Risk Factors for Valvular Calcification

Hao Yu Chen 1,2, James C Engert 1,2,3, George Thanassoulis 1,2
PMCID: PMC6873465  NIHMSID: NIHMS1059492  PMID: 30694830

Abstract

Purpose of Review:

Recent literature is examined to identify established and emerging risk factors for valvular calcification, specifically aortic valve disease and mitral annular calcification.

Recent Findings:

Strong evidence implicates older age, male sex, cigarette smoking, elevated blood pressure, dyslipidemia, adiposity, and mineral metabolism as risk factors for calcific aortic valve disease. Emerging evidence suggests family history and lipoprotein(a) are additional risk factors. Recently, large-scale genome-wide analyses have identified robust associations for LPA, PALMD, and TEX41 with aortic stenosis. Factors predisposing to mitral annular calcification are less well characterized. Older age, cigarette smoking, increased body mass index, kidney dysfunction, and elevated triglycerides are associated with greater risk of mitral annular calcification, but conflicting evidence exists for sex and C-reactive protein.

Summary:

Established and emerging risk factors for calcific aortic valve disease, including some that overlap with atherosclerosis, may represent targets for pharmacological intervention. Mitral annular calcification is comparatively less well understood though some atherosclerosis risk factors do appear to increase risk.

Keywords: Calcific Aortic Valve Disease, Aortic Stenosis, Mitral Annular Calcification, Risk Factor, Genomics

Introduction

In calcific aortic valve disease (CAVD), valvular calcification is observed on the cusps of the aortic valve and ranges from aortic sclerosis, when calcific nodule formation and leaflet thickening are relatively mild and individuals are asymptomatic, to aortic stenosis, where substantial nodular development and stiffened leaflets lead to severe obstruction of blood flow through the valve and individuals become symptomatic. Prognosis is poor: aortic sclerosis is associated with 68% higher risk of coronary events, 69% higher risk of cardiovascular mortality, and 36% higher risk of all-cause mortality (1), and without aortic valve replacement, less than one-third of patients with severe aortic stenosis survive beyond 5 years (2,3).

In developed nations, CAVD is the most prevalent valvular heart disease among the elderly (4). Aortic sclerosis afflicts between 2.3% and 51.7% of older individuals, with the prevalence of sclerosis increasing dramatically with age (1). Aortic stenosis is observed in 1.7% of individuals 65 years or older (5) but 12.4% of individuals greater than 75 years of age (6). The prevalence of aortic stenosis demonstrates a similar dependency on age (7) and is expected to more than double by the year 2040 and triple by the year 2060 (8) due to the ageing population. Healthcare costs are expected to increase in tandem and in the United States, the cost of medically-managed severe aortic stenosis is already estimated to be $1.3 billion per year (2).

Mitral annular calcification (MAC) is a less common form of valvular calcification that occurs at the fibrous base of the mitral valve. It affects 9-20% of the population (9,10) and likewise increases in prevalence with age. MAC has been associated with 50% greater risk of incident cardiovascular disease, 60% greater risk of cardiovascular death, and 30% greater risk of all-cause death, adjusted for cardiovascular risk factors (11). Individuals with MAC are also more likely to have severe coronary artery disease (12) and to sustain a stroke (13).

Currently, no medical therapy exists for either CAVD or MAC. Epidemiological studies spanning the last three decades have implicated a number of risk factors which associate with valve calcification. Recent studies, including large-scale genome-wide studies, have identified novel risk factors. In this review, we discuss established and emerging risk factors for both CAVD and MAC.

Established Risk Factors for CAVD

Older Age

Due to the advanced ages of CAVD patients, the disease was thought to be a degenerative condition acquired due to ageing. Although this view has been overturned, age remains a strong risk factor for CAVD. Each 10-year increase in age among participants of the Cardiovascular Health Study (CHS) was associated with double the odds of CAVD (odds ratio [OR], 2.18; 95% confidence interval [CI], 2.15-2.20; p<0.001), adjusted for clinical factors (14). In the Multi-Ethnic Study of Atherosclerosis (MESA), the risk for aortic valve calcium (AVC) more than doubled per decade (risk ratio [RR], 2.19; 95% CI, 1.84-2.61; p<0.001) (15).

Male Sex

With the exception of Boon et al (16), male sex has been consistently associated with increased risk for AVC and aortic stenosis. Relative to women, men in the Framingham Offspring Study (FOS) had 56% higher odds of AVC (95% CI, 1.15-2.13; p=0.005) in models adjusted for atherosclerotic risk factors (9). Similarly, men were more likely than women to have aortic sclerosis or stenosis in the CHS (OR, 2.03; 95% CI, 1.7, 2.5; p<0.001), independent of other clinical factors (14).

Cigarette Smoking

Smoking has been strongly associated with increased risk of CAVD. In the FOS, greater cigarette use was associated with elevated odds for AVC (OR per standard deviation [SD] of cigarettes per day, 1.22; 95% CI, 1.06-1.39; p=0.005), adjusted for other cardiovascular factors (9). In the MESA, current smokers more than doubled their risk of incident AVC relative to never smokers independent of other clinical factors (RR, 2.49; 95% CI, 1.49-4.15; p=0.001), though smoking was not associated with the progression of calcification (15). Current smokers also had higher odds for aortic stenosis in the CHS (OR, 1.35; 95% CI 1.1-1.7; p=0.006) (14).

Blood Pressure and Vascular Stiffness

A number of studies have demonstrated an association between hypertension and CAVD. In the Helsinki Ageing Study, hypertension was associated with AVC independent of the effects of age and body mass index (OR, 1.74; 95% CI, 1.19-2.55; p=0.005) (17). A more modest effect was observed in the CHS, which accounted for additional clinical factors (OR, 1.23; 95% CI, 1.1-1.4; p=0.002). Within the MESA, a graded correlation was observed between the stages of hypertension, as defined by the Joint National Committee 7, and AVC: calcification was observed in 6% of normotensive individuals, 11% of borderline hypertensive individuals, 17% of individuals with stage I hypertension, and 16% of individuals with stage II hypertension The association of hypertension with prevalent AVC was also modified by age (interaction p=0.041), such that hypertensive individuals doubled their odds of calcification, but only before 65 years of age (adjusted OR, 2.31; 95% CI, 1.35-3.94).

Hypertension has also been associated with more rapid progression of CAVD. Peak aortic jet velocity, a measure of aortic stenosis progression, increased more rapidly in hypertensive versus non-hypertensive individuals (annualized change in velocity, 0.26±0.23 m/s versus 0.17±0.20 m/s; p<0.01) in a retrospective, echocardiography study (18). Faster progression was also observed among individuals with systolic hypertension in the PROGRESSA study (2-year change in median [25th-75th percentile] AVC, 370 [126-824] versus 157 [58-303] among normotensives; p=0.007), and this association persisted following adjustment for clinical factors and baseline AVC (19).

In the MESA, a comparison of blood pressure measures and their association with prevalent AVC demonstrated that the largest effect was observed for pulse pressure (OR per 10 mmHg, 1.41; 95% CI, 1.21-1.64 among individuals <65 years old and 1.14; 95% CI, 1.05-1.23 among individuals ≥65 years old) (20). Pulse pressure is a measure of arterial stiffness and wave reflection, suggesting that abnormal hemodynamics may promote calcification. Consistent with this hypothesis, greater wave reflection, as represented by the augmentation index, was associated with elevated odds for moderate to severe diffuse AVC independent of demographic variables and glomerular filtration rate in the Cardiac Abnormalities and Brain Lesions cohort (OR per 1% increase in augmentation index, 1.08; 95% CI, 1.02-1.14; p=0.005) (21). Increased wave reflection leads to greater tensile stress on the cusps of the aortic valve, and exposure of porcine aortic valve interstitial cells to such stress initiates extracellular matrix remodelling (22), which precedes thickening and calcification of the aortic valve.

Dyslipidemia

Whether elevated low-density lipoprotein cholesterol (LDL-C) is a risk factor for CAVD remains controversial in light of apparently discrepant findings between observational studies and randomized controlled trials. An immunohistological study found that apolipoprotein B and apolipoprotein(a) co-localized with calcium in the lesions of stenotic valves, but neither apolipoprotein was detected in normal valves (23). The distribution of apolipoprotein B was also more diffuse than that of apolipoprotein(a), suggesting LDL-C is found in the diseased aortic valve in addition to lipoprotein(a) (see section on lipoprotein[a]). This finding was supported by observations in the CHS that higher levels of LDL-C were associated with greater odds of developing aortic sclerosis (OR, 1.00; 95% CI, 1.00-1.01; p=0.002) (24) and increased odds for prevalent aortic sclerosis or stenosis (OR per mg/dl, 1.12; 95% CI, 1.03-1.23; p=0.008) (14), adjusted for other clinical factors. In the FOS, levels of total cholesterol, which correlate highly with levels of LDL-C, in early adulthood strongly predicted the presence of AVC in later life (adjusted OR per SD, 1.81; 95% CI, 1.55-2.11; p<0.0001) (9). Retrospective studies have also shown that aortic stenosis patients treated with statins progressed less rapidly (25-27).

Building upon this body of evidence, three randomized controlled trials investigated the use of lipid-lowering therapies in delaying or reversing aortic stenosis progression. In the Scottish Aortic Stenosis and Lipid Lowering Trial, Impact on Regression (SALTIRE), 155 patients randomized to either atorvastatin (80 mg) or placebo were followed for a median of 25 months (28). The Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial followed 1,873 patients with mild to moderate, asymptomatic aortic stenosis for a median of 52.2 months following randomization to simvastatin (40 mg) plus ezetimibe (10 mg) or placebo daily (29). In the Aortic Stenosis Progression Observation: Measuring Effects of Rosuvastatin (ASTRONOMER) trial, 269 patients were randomized to rosuvastatin (40 mg) or placebo daily and followed for a median of 3.5 years. No reductions in aortic stenosis progression were observed in any of these trials.

Although the results of these trials were disappointing, it would be premature to dismiss the therapeutic potential of statins for CAVD. In all three trials, patients had relatively advanced disease with elevated transaortic pressure gradients and mean aortic valve areas ≤1.5 cm2. Lipids may exert a larger influence on the initiation of the disease process and earlier intervention, perhaps among patients with aortic sclerosis, may be more effective. Mendelian randomization analysis performed in the Malmö Diet and Cancer Study demonstrated that genetically-elevated levels of LDL-C, reflecting a lifetime exposure to higher LDL-C, were causally associated with the incidence of aortic stenosis (hazard ratio [HR] per genetic risk score unit, 2.78; 95% CI, 1.22-6.37; p=0.02) (30). Moreover, individuals were not eligible to participate in the trials if they had clinical indications for cholesterol lowering, but these individuals would benefit most from intensive lipid-lowering therapies and their exclusion could underestimate the effectiveness of such regimens. While lipid-lowering therapies may be ineffective at delaying progression in advanced aortic stenosis cases, additional studies are warranted to assess the effectiveness of statins in early stage CAVD.

Adiposity

Several adiposity measures have been associated with greater risk for CAVD. In the MESA, metabolic syndrome and diabetes separately increased odds of developing AVC (OR, 1.67; 95% CI, 1.21-2.31 and 2.06; 95% CI, 1.39-3.06, respectively), adjusted for clinical factors, but neither were associated with progression among participants with calcification at baseline (31). Diabetes was also associated with greater risk of incident aortic stenosis in the Cardiovascular Health in Ambulatory Care Research Team cohort, which featured a 13-year median follow-up period (HR, 1.49; 95% CI, 1.44-1.54; p<0.001) (32). Long-term mean of body mass index in adulthood was associated with the presence of AVC (OR per SD, 1.21; 95% CI, 1.05-1.40; p=0.008) in the FOS, adjusted for clinical factors. Being overweight or obese also conferred increased risk of incident aortic stenosis relative to normal weight (HR, 1.24; 95% CI, 1.05-1.48 and 1.81; 95% CI, 1.47-2.23, respectively). These findings indicate that increased adiposity confers risk for CAVD, but additional work is required to identify possible mechanisms, such as dysglycemia or dyslipidemia.

Kidney Dysfunction and Mineral Metabolism

CAVD is commonly observed among patients with renal failure, with AVC reported in 28% of individuals ≤70 years old with end stage renal disease (33). Kidney dysfunction has also been linked to more rapid progression of, and more severe, disease. Aortic stenosis patients undergoing dialysis progress more rapidly (change in valve area in cm2/year, −0.19; range, −1.45 to 0.20 versus −0.07; range, −1.1 to 0.37; p<0.001), and dialysis remains an independent predictor of annualized changes in aortic valve area following adjustment for clinical variables (cm2/year, −0.92; p=0.02) (34). Calcium, phosphate, and the calcium × phosphate product were elevated among end-stage renal disease patients with AVC (all p<0.05) (33). Among aortic stenosis patients treated with hemodialysis, greater serum calcium levels predicted faster progression (OR, 6.08; 95% CI, 1.28-28.8; p=0.02). In community cohorts, higher serum phosphate has also been associated with greater risk for AVC (RR per mg/dl, 1.3; 95% CI, 1.1-1.5; p<0.001) (35) as well as aortic sclerosis (OR per 0.5 mg/dl, 1.17; 95% CI 1.04-1.31; p=0.01) (36).

Emerging Risk Factors for CAVD

Family History

Recently, a few studies have suggested that aortic stenosis has a familial component. Using national registry data on 6.1 million Swedish siblings, including 13,442 cases of aortic stenosis, Martinsson and colleagues observed that 4.8% of aortic stenosis patients had a sibling with aortic stenosis, compared to 0.5% among the general population (37). Following adjustment for age, sex, family size, and comorbidities, individuals with a sibling history of aortic stenosis had more than three times the risk (HR, 3.41; 95% CI, 2.23-5.21). In contrast, having a spouse with aortic stenosis was associated with a smaller increase in risk (HR, 1.16; 95% CI, 1.05-1.28 for husbands and 1.18; 95% CI, 1.07-1.30 for wives), suggesting that shared environment in adulthood explains less risk than genetics. Using the Utah Population Database, which features linkage of genealogical records with death certificates, Horne and colleagues demonstrated that individuals who died of non-rheumatic aortic stenosis were on average more related than the average relatedness observed among matched controls (genealogical index of familiality, 3.44 in cases versus 2.62 in controls; p<0.001) (38). When restricted to deaths before 65 years of age, the higher relatedness among cases was more pronounced, consistent with other partially heritable disorders (genealogical index of familiality, 8.47 in cases versus 2.43 in controls; p<0.001). In regions of France with little population movement, the distribution of aortic stenosis cases who undergo aortic valve replacement is heterogeneous and some families have a higher than expected disease prevalence (39,40), but these lines of evidence are weaker.

Lipoprotein(a)

A rapidly-growing body of evidence points to lipoprotein(a) as an important, potentially causal contributor to CAVD. A genome-wide association study (GWAS) performed in the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium associated a variant at the LPA locus, rs10455872, with both prevalent AVC (OR per G allele, 2.05; 95% CI, 1.66-2.53; p=2.8×10−11) and incident aortic stenosis (HR per G allele, 1.68; 95% CI, 1.32-2.15; p=3×10−5) (41). The association of this variant with aortic stenosis has since been robustly demonstrated in a number of cohorts (42-45). The LPA gene codes for apolipoprotein(a), and >90% of the variation in lipoprotein(a) levels has been attributed to genetic variation in LPA (46). The association of LPA with AVC and aortic stenosis therefore implicates elevated lipoprotein(a) as a risk factor for CAVD. Mendelian randomization studies have confirmed that this association is likely causal (41,43), pointing to lipoprotein(a) as a therapeutic target. Lipoprotein(a)-lowering agents are currently in development and randomized controlled trials have demonstrated remarkable reductions in lipoprotein(a) levels (47,48), paving the way for future trials investigating lipoprotein(a)-targeting therapeutics for arresting aortic stenosis progression.

Findings from Large-Scale Genetic Association Studies

Two large-scale GWAS for aortic stenosis have been reported in the years following the discovery of LPA. A study in the deCODE cohort and a transcriptome-wide association study in the QUEBEC-Calcific Aortic Valve Stenosis cohort independently identified a variant in the PALMD locus as associated with aortic stenosis, with each copy of the risk allele conferring 20-28% greater odds for the disease (49,50). The genome-wide association study in deCODE additionally identified the TEX41 variant rs1830321, which was associated with 15% greater odds for aortic stenosis per T allele (95% CI, 1.11-1.20; p=1.8×10−13). Both the PALMD and TEX41 variants were also associated with bicuspid aortic valves and atrial septal defects (all p≤5.9×10−3), implicating congenital cardiac malformations as a mechanism for CAVD.

Risk Factors for MAC

Our understanding of the risk factors for MAC remains poor due to the relatively low prevalence of MAC in the general population leading to very few adequately-powered cohorts. As observed for CAVD, the most critical risk factor is older age. In the MESA, each 10-year increase was associated with 3.58 times the odds of MAC adjusted for clinical factors (95% CI, 3.18-4.03; p<0.01) (10). Body mass index and cigarette smoking also conferred elevated odds for MAC in both the MESA and the FOS, while diabetes was only associated in the MESA (adjusted OR, 1.58; 95% CI, 1.25-1.99) (9,10). In the FOS, chronic kidney disease was associated with 60% greater odds for MAC independent of clinical factors (95% CI, 1.03-2.5; p<0.05) (51).

Unlike CAVD, women may be more likely than men to have MAC. In the MESA, the odds were 41% higher for women (95% CI, 1.15-1.75) (10). However, female sex was not a predictor of MAC in the FOS (9). Conversely, C-reactive protein was associated with MAC in the FOS (adjusted OR per SD, 1.29; 95% CI, 1.10-1.52; p=0.002) but not in the MESA, though it has not been associated with AVC in either cohort (9,15). Also notable was the lack of association for MAC with LDL-C. Rather, Mendelian randomization analyses supported a causal association with triglycerides in the Cohorts for Heart and Aging Research in Genomic Epidemiology cohort (OR per genetic risk score unit, 1.73; 95% CI, 1.24-2.41; p=0.0013) that persisted in sensitivity analyses accounting for genetic pleiotropy or the inclusion of Hispanic-Americans (52). This finding suggests that triglycerides may represent a new therapeutic target for the treatment or prevention of MAC.

Conclusion

Valvular calcification, manifesting as either CAVD or MAC, is particularly prevalent among the elderly. Strong evidence implicates atherosclerotic risk factors as increasing the risk of CAVD, and emerging evidence indicates family history, lipoprotein(a), and some genetic variants are also likely contributors. Risk factors for MAC overlap with those for CAVD, suggesting a shared aetiology, but female sex, C-reactive protein, and triglycerides may be more important for MAC. Among these are risk factors with potential for therapeutic targeting, though a better characterization of their contributions is warranted given the failure of statins in randomized controlled trials for aortic stenosis. Large-scale genetic analyses and Mendelian randomization may provide valuable insight in this regard.

Table 1.

Summary of Evidence for Risk Factors for Calcific Aortic Valve Disease.

Risk Factor Strength of Evidence
Observational Studies Genetic Studies
Established Risk Factors
 Older Age +++ n/a
 Male Sex +++ n/a
 Cigarette Smoking ++ n/a
 Blood Pressure and Vascular Stiffness ++ n/a
 Dyslipidemia +a +++
 Adiposity ++ n/a
 Kidney Dysfunction and Mineral Metabolism ++ n/a
Emerging Risk Factors
 Family History + n/a
 Lipoprotein(a) ++ +++
 Findings from Large-Scale Genetic Association Studies n/a ++
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+++, strong evidence of increased risk; ++, moderate evidence of increased risk; +, weak evidence of increased risk; n/a, not available.

a

Discrepant findings between observational studies and randomized controlled trials.

Table 2.

Summary of Evidence for Risk Factors for Mitral Annular Calcification.

Risk Factor Strength of Evidence
Observational Studies Genetic Studies
Established Risk Factors
 Older Age +++ n/a
 Adiposity + n/a
 Cigarette Smoking ++ n/a
 Triglycerides n/a ++
Emerging Risk Factors
 Kidney Dysfunction + n/a
 Female Sex + n/a
 C-Reactive Protein + n/a
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+++, strong evidence of increased risk; ++, moderate evidence of increased risk; +, weak evidence of increased risk; n/a, not available.

Key Points.

  • Atherosclerotic risk factors have been well established as increasing the risk of calcific aortic valve disease

  • Emerging risk factors for calcific aortic valve disease include a family history of the disease, lipoprotein(a), and genetic variants

  • Large-scale genetic analyses and Mendelian randomization studies have identified risk loci with strong evidence of association with aortic stenosis

  • Current understanding of the risk factors for mitral annular calcification is limited. While a subset of atherosclerotic risk factors has been shown to increase mitral annular calcification risk, the evidence was inconsistent for some others and non-atherosclerotic risk factors have not been well studied

Acknowledgments

Financial Support and Sponsorship

H.Y.C. is supported by studentships from the Research Institute of the McGill University Health Centre, the McGill University Faculty of Medicine, and the McGill University Health Centre Foundation.

Abbreviations

AVC

Aortic Valve Calcium

CAVD

Calcific Aortic Valve Disease

CHS

Cardiovascular Health Study

CI

Confidence Interval

FOS

Framingham Offspring Study

HR

Hazard Ratio

LDL-C

Low-Density Lipoprotein Cholesterol

MAC

Mitral Annular Calcification

MESA

Multi-Ethnic Study of Atherosclerosis

OR

Odds Ratio

RR

Risk Ratio

SD

Standard Deviation

Footnotes

Conflicts of Interest

G.T. has received consulting fees from Ionis Pharmaceuticals and has participated in advisory boards for Amgen and Sanofi. The other authors report no relevant disclosures.

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