Prevalence of calcific aortic valve disease in the elderly and associated risk factors: a population-based study in a Mediterranean area

Abstract

Aims

To determine the prevalence of aortic valve sclerosis (ASC) and stenosis (AS) in the elderly in a Mediterranean area and to identify associated clinical factors.

Methods and Results

Population cross-sectional study in a random sample of 1068 people ≥65 years in a Mediterranean area. ASC was categorized as absent, mild-to-moderate, or moderate-to-severe depending on the severity of thickening and calcification. The relation between the severity of ASC and potential risk factors was assessed by multinomial logistic regression analysis. Some degree of thickening and/or calcification was present in 45.4%, of the sample, 73.5% in >85 years. AS prevalence was 3% for the total cohort and 7.4% in >85 years. Adjusting for gender it was found that age, smoking habit, hypertension, waist circumference, and ankle−brachial index <0.9 were associated with degrees of ASC. Except for waist circumference, there was a gradient between the magnitude of association and the severity of ASC. The OR for age was 1.56 (95% CI 1.39–1.76) for mild-to-moderate ASC and 2.03 (95% CI 1.72–2.4) for moderate-to-severe ASC, and for smoking habit 1.59 (95% CI 1.08–2.34) for mild-to-moderate ASC and 2.13 (95% CI 1.19–3.78) for moderate-to-severe ASC. Diabetes and renal impairment were associated with advanced but not with early stages of ASC.

Conclusions

The prevalence of ASC and AS in people ≥65 years is similar to that reported in other regions. The gradient in the association of cardiovascular risk factors with the severity of ASC suggests that they may be causally implied in the pathogenesis of the disease.

Aortic valve sclerosis, aortic valve stenosis, calcific aortic valve disease, cardiovascular risk factors

Introduction

The denomination calcific aortic valve disease (CAVD) encompasses from aortic valve sclerosis (ASC) in the first stages of the disease to acquired aortic valve stenosis (AS).^1–4 However, the relevance of ASC goes far beyond its role as a precursor of haemodynamically significant AS since it seems clear that ASC is independently associated with cardiac events and cardiovascular mortality.^5,6

Studies assessing the prevalence of ASC and AS report rates of 18−53% for ASC and 1.3−4.8% for AS.^7–10 Although there are some discrepancies between studies, the association of CAVD with classic atherosclerosis risk factors is the rule,^7–10 thus suggesting a link between atherosclerosis and CAVD.^10,11 However, these studies were carried out in countries with high atherosclerosis prevalence and cardiovascular mortality, such as the USA^5,7,9,10,12 and North-Europe.⁸ Prevalence studies are essential for implementing preventive measures.¹³ No study assessing the prevalence of CAVD and its risk factors has recently been conducted in the Mediterranean area. Given the plausible relationship between CAVD, atherosclerosis, and cardiovascular events, it may be that the ‘Mediterranean paradox’ (i.e. similar cardiovascular risk factors prevalence in northern Europe/USA areas and Mediterranean countries but higher ischaemic heart and cerebrovascular diseases in the former)¹⁴ could also affect the prevalence of CAVD as well as their associated risk factors in the Mediterranean area.

ASC has usually been considered as a condition with a two-stage status: presence or absence of thickening and/or calcification in aortic cusps. Rather, ASC represents a continuum ranging from mild to severe degrees of thickening and/or calcification. In this regard, it can be hypothesized that, if potential risk factors associated with ASC were actually so, a gradient in the magnitude of association could be present: the greater the severity of ASC, the higher the magnitude of association.

The aim of this study is to assess: (1) prevalences of ASC and AS in a contemporary unselected elderly population of a Mediterranean area; (2) the association of potential risk factors with CAVD; and (3) the gradient in the magnitude of association between potential risk factors and ASC severity.

Methods

Study design and participants

Individuals aged ≥65 years included in the lists of nine primary healthcare facilities of Barcelona (2008) represented the reference population (54,594 subjects ≥65; 16.5% of the total Barcelona population ≥65 years). A sample size of 1118 subjects was estimated based on an expected AS prevalence of 3%, with an absolute precision of 1% (relative precision 33%). Random sampling was age stratified according to the Barcelona demographic census into three strata: 65–74, 75–84, and ≥85 years. 2800 people were randomly selected from the primary care lists. They were consecutively contacted by phone and invited to participate until the three study sample strata were completed. Specifically, 1533 subjects were contacted and 391 (25.5%) refused to participate. There were no initial exclusion criteria other than previous implantation of aortic prosthesis valve, which occurred in six out of 1142 (0.05%). Therefore 1136 patients were finally included in the study and underwent clinical examination and echocardiogarphy.

Clinical and laboratory data

Demographic data and anthropometric measurements including weight, height, waist circumference, and systolic and diastolic blood pressure were collected by two trained research nurses according with the usual recommendations. Investigators were trained to perform ankle–brachial index (ABI) measurement according to recommendations.¹⁵ The ABI for each leg was calculated using a standardized Doppler ultrasonic device (Hadeco; Bidop ES-100V3). ABI ≤0.9 or ≥1.4 were considered abnormal.¹⁶

Cardiovascular risk factors, history of coronary and cerebrovascular disease, other comorbidities, and treatments prescribed were assessed by reviewing the medical records and by interviewing the patients during the visits.

All laboratory measurements from the previous 6 months, including total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, glucose, and creatinine were obtained from the primary care medical records.

Echocardiographic assessment

Transthoracic echocardiography was performed by a single experienced operator according with recommendations,¹⁷ with a portable ultrasound machine (Vivid I; General Electric; 3.4 MHz phased array probe). Studies were sent to the echocardiography laboratory at Vall d’Hebron Hospital for interpretation. Echocardiographic studies were judged technically adequate to assess ASC in 1068 out of 1136 patients (94%) and technically adequate to assess aortic atherosclerosis in 1016 patients (89%).

The morphology of the aortic valve was assessed by 2D echocardiography using left parasternal short and long axis views. ASC was first defined, similarly to previous studies, as the presence of calcification or thickening in at least one aortic leaflet without aperture restriction.^6,8–10 Calcification was defined in the presence of acoustic shadow. Thickening was considered to be present based on the echocardiographer’s judgment. Then, each aortic valve was graded on a scale of 0 to 3 for both thickening and calcification. Calcification was graded from 0 to 3 depending on the number of leaflets affected. Thickening was graded from 0 to 3 according to echocardographer judgment. Thus a value of ‘ASC degree’ ranging from 0 to 6 was assigned to each patient. Finally, ASC was stratified into three strata: absence of ASC (0 points of thickening and calcification), mild-to-moderate ASC (1−3 points), and moderate-to-severe ASC (4−6 points). An example is shown in Figure 1. To validate the stratification system, a random sample of 50 studies was selected and reanalysed by the same operator several weeks later and by a second operator in a blinded fashion. A weighted Kappa agreement of 0.61 (95% CI 0.41−0.8; p < 0.001) for the three strata classification indicated an adequate inter-observer agreement. The intra-observer weighted Kappa agreement was 0.66 (95% CI 0.48–0.84).

Figure 1.

Aortic valve sclerosis severity according with the degree of thickening and calcification: (A) absence; (B) mild-to-moderate; and (C) moderate-to-severe.

Peak transaortic flow velocities were measured by continuous-wave Doppler (average of triplicate measurements).¹⁰ A peak velocity >2.5 m/s indicated AS.⁹ Those patients with ASC and a jet velocity >2.5 m/s were classified for the manuscript purposes as AS.

Aortic atherosclerosis, defined as irregular intimal thickening ≥2 mm with increased echogenicity,¹⁰ was assessed in ascending thoracic aorta, (parasternal and suprasternal view), aortic arch (suprasternal view), and abdominal aorta (abdominal view). ‘Complicated atherosclerotic plaque’ was defined as a maximal plaque thickness ≥4 mm or associated with mobile debris. Aortic valve regurgitation was assessed as recommended.¹⁸

Statistical analysis

Continuous data are presented as mean ± standard deviation and categorical data as absolute number and percentage. Prevalences of ASC and AS were estimated in each age-strata group and standardized by the direct method for the European population age. Comparisons among the three study subgroups of ASC severity involving continuous data were performed using simple linear regression analysis. The objective was to assess if there was a linear association between the variable of interest and the severity of ASC. For discrete variables, the potential linear association was assessed by the linear-by-linear association test.

The association between potential cardiovascular risk factors and the severity of ASC was explored using multinomial logistic regression analysis (polytomous regression). The dependent variable has three categories: absence of ASC (the reference category), mild-to moderate ASC, and moderate-to-severe ASC. The objective was to estimate, for each potential predictor, the odds ratio (OR) of mild-to-moderate ASC vs. absence of ASC, and the OR of moderate-to-severe ASC vs. absence of ASC. Modelling process involved forward and backward stepwise methods with a threshold for exit set at p > 0.10 and for enter at p < 0.05. Once the initial set of variables was selected, we tested each one of the rest of covariates. Those variables inducing a change in β-coefficients >10% were retained in the model. First-order interactions between, on the one side, age and the rest of covariates and, on the other side, between gender and the rest of covariates were tested. They were retained in the model if statistically significant. Goodness of fit of the model was explored with Hosmer−Lemeshow test. Once the multinomial regression model was developed, we tested the assumption of proportional odds order across categories using ordinal logistic regression. All the variables of the initial multinomial model were included in an ordinal model. Goodness of fit for the ordinal model was evaluated by comparing the likelihood value with that obtained by fitting the model with the multinomial analysis. If the difference between the log-likelihood values of both (i.e. ordinal vs. multinomial) were nonstatistically significant it would support the assumption of ordinality.

Data were analysed using SPSS version 15.0 (SPSS, Chicago, IL, USA). Two-sided significance level was considered when p-values were <0.05.

Results

Table 1 shows the prevalence of ASC and AS relative to the study sample and standardized for the age-stratified European population. Some degree of sclerosis was present in 45.4% of the study sample, reaching 73.5% for those older than 85. AS prevalence also increased with age, with a maximum of 7.4% for those older than 85. As shown in Table 2, the severity of ASC was directly related with age and waist circumference. By contrast, height was inversely related with the severity of ASC. Thus, the greater the severity of ASC, the higher the rate of smoking habit, hypertension, hypercholesterolaemia, hypertriglyceridaemia, diabetes, renal impairment, and ankle–brachial pressure index <0.9. The same was true for myocardial infarction, heart failure, atrial fibrillation, stroke, and chronic pulmonary obstructive disease. There was a clear relationship between creatinine levels and the severity of ASC and an inverse linear relationship between HDL cholesterol and the ASC severity. The rates of drug therapies use were higher in those patients with a higher severity of ASC except for beta-blockers, insulin, fibrates, calcium, vitamin D, and bisphosphonates.

Table 1.

Prevalence of aortic sclerosis and aortic stenosis according with the age strata in both the study sample and standardized by the 2009 European population

65–75 years (n = 488, 45.7%)	76–85 years (n = 444, 41.6%)	>85 years (n = 136, 12.7%)	Total (n = 1068)
Sclerosis
Mild-to-moderate
Study sample	121 (24.8)	164 (36.9)	64 (47.1)	349 (32.7)
Standardized	24.8	36.9	47.6	31.7
Moderate-to-severe
Study sample	27 (5.5)	73 (16.4)	36 (26.5)	136 (12.7)
Standardized	5.5	16.4	26.2	11.8
Any
Study sample	148 (30.3)	237 (53.4)	100 (73.5)	485 (45.4)
Standardized	30.4	53.3	73.8	43.6
Stenosis
Study sample	3 (0.6)	19 (4.3)	10 (7.4)	32 (3)
Standardized	0.5	4.2	7.1	2.6

Values are n (%) or %.

Table 2.

Sample characteristics by severity of aortic sclerosis

Valid	Sample (n = 1068)	No aortic sclerosis (n = 583)	Mild-to-moderate (n = 349)	Moderate- to-severe (n = 136)	p-value
Demographics
Age (years)	1068	76.5 ± 6.7	74.5 ± 6	78.2 ± 6.7	80.5 ± 6.4	<0.001
Females	1068	637 (59.6)	359 (61.6)	203 (58.2)	75 (55.1)	0.31
Height (cm)	1064	157 ± 9.3	157.6 ± 9.1	156.7 ± 9.6	156.6 ± 9.2	0.03
Weight (kg)	1064	68.1 ± 11.9	69.1 ± 11.8	69 ± 12.4	69.5 ± 11.4	0.9
Body mass index (kg/m2)	1064	28.1 ± 4.4	27.8 ± 4.6	28.3 ± 4.2	28.4 ± 4.3	0.21
Waist circumference (cm)	1061	98.8 ± 9.9	97.8 ± 9.8	100 ± 9.6	99.9 ± 10.4	0.002
Systolic blood pressure (mmHg)	1063	144.7 ± 21.05	143.4 ± 19.2	146.3 ± 22.5	146.2 ± 24.2	0.1
Diastolic blood pressure (mmHg)	1063	79.1 ± 10.8	79.1 ± 10.1	79.2 ± 11.3	79 ± 12.3	0.99
Cardiovascular risk factors
Smoking habit (current or previous)	1068	368 (34.5)	182 (31.2)	130 (37.2)	56 (41.2)	0.036
Alcohol consumption	1068	411 (38.5)	218 (37.4)	142 (40.7)	51 (37.5)	0.6
Hypertension	1067	675 (63.3)	321 (55.2)	247 (70.8)	107 (78.7)	<0.001
Hypercholesterolaemia	1068	541 (50.7)	283 (48.5)	182 (52.1)	76 (55.9)	0.09
Hypertriglyceridaemia	1068	76 (7.1)	31 (5.3)	34 (9.7)	11 (8.1)	0.047
Diabetes	1068	234 (21.9)	117 (20.1)	72 (20.6)	45 (33.1)	0.007
Renal impairment	1068	57 (5.3)	20 (3.4)	21 (6)	16 (11.8)	<0.001
Dialysis	1068	2 (0.2)	0	1 (0.3)	1 (0.7)	0.066
Ankle − brachial pressure index <0.9	1068	104 (9.9)	39 (6.8)	43 (12.5)	22 (16.5)	<0.001
Cardiovascular history
Myocardial infarction	1068	59 (5.5)	25 (4.3)	24 (6.9)	10 (7.4)	0.066
Percutaneous revascularization	1068	48 (4.5)	24 (4.1)	17 (4.9)	7 (5.1)	0.52
Congestive heart failure	1068	29 (2.7)	13 (2.2)	9 (2.6)	7 (5.1)	0.1
Atrial fibrillation	1068	57 (5.3)	9 (1.5)	25 (7.2)	23 (16.9)	<0.001
Peripheral arteriopathy	1068	5 (0.9)	5 (1.4)	2 (1.5)	3 (2.2)	0.41
Stroke	1068	63 (6.4)	28 (4.8)	24 (6.9)	16 (11.8)	0.003
Other comorbidities
Chronic obstructive pulmonary disease	1068	106 (9.9)	46 (7.9)	42 (12)	18 (13.2)	0.018
Upper gastrointestinal haemorrhage history	1068	11 (1)	4 (0.7)	5 (1.4)	2 (1.5)	0.47
Lower gastrointestinal haemorrhage history	1068	26 (2.4)	11 (1.9)	10 (2.9)	5 (3.7)	0.17
Laboratory measurements
Glucose (mg/dl)	982	106.3 ± 27.9	105 ± 25.8	107.7 ± 32	107.7 ± 26	0.18
Creatinine (mg/dl)	978	0.96 ± 0.41	0.92 ± 0.42	1 ± 0.35	1.07 ± 0.49	<0.001
Total cholesterol (mg/dl)	999	207.1 ± 38.9	208.8 ± 38.7	206.3 ± 38.7	202 ± 39.6	0.07
LDL cholesterol (mg/dl)	900	126.9 ± 32.7	127.1 ± 31.6	127.6 ± 33	124.7 ± 36.5	0.6
HDL cholesterol (mg/dl)	949	56.3 ± 14.7	57.2 ± 13.4	55.3 ± 15.4	54.7 ± 14.3	0.03
Triglycerides (mg/dl)	970	120 ± 61.4	118.6 ± 63.7	121.1 ± 57.7	122.9 ± 60.3	0.41
Treatment prescribed
Oral antidiabetics	1068	143 (13.4)	66 (11.3)	48 (13.8)	29 (21.3)	0.004
Insulin	1068	32 (3)	16 (2.7)	13 (3.7)	3 (2)	0.92
Beta-blockers	1068	146 (13.7)	70 (12)	55 (15.8)	21 (15.4)	0.22
ACE inhibitors	1068	263 (24.6)	125 (21.4)	93 (26.6)	45 (33.1)	0.002
RAII inhibitors	1068	215 (20.1)	97 (16.6)	82 (23.5)	36 (26.5)	0.002
Furosemide	1068	96 (9)	31 (5.3)	43 (12.3)	22 (16.2)	<0.001
Thiazide diuretics	1068	351 (32.9)	162 (27.8)	129 (37)	60 (44.1)	<0.001
Nitrates	1068	49 (4.6)	23 (3.9)	14 (4)	12 (8.8)	0.049
Calcium-channel blockers	1068	151 (14.1)	75 (12.9)	46 (13.2)	30 (22.1)	0.024
Clopidogrel	1068	33 (3.1)	10 (1.7)	20 (5.7)	3 (2.2)	0.09
Aspirin	1068	212 (19.9)	107 (18.4)	67 (19.2)	38 (27.9)	0.032
Statins	1068	364 (34.1)	181 (31)	127 (36.4)	56 (41.2)	0.012
Fibrates	1068	24 (2.2)	15 (2.6)	6 (1.7)	3 (2.2)	0.6
Oral anticoagulants	1068	65 (6.1)	13 (2.2)	26 (7.4)	26 (19.1)	<0.001
Dopaminergics	1068	3 (0.3)	0	1 (0.3)	2 (1.5)	0.008
Calcium	1068	156 (14.6)	91 (15.6)	43 (12.3)	22 (16.2)	0.65
Vitamin D	1068	129 (12.1)	77 (13.2)	32 (9.2)	10 (14.7)	0.69
Bisphosphonates	1068	90 (8.4)	54 (9.3)	20 (5.7)	16 (11.8)	0.96

Values are mean ± standard deviation or n (%)

ACE, angiotensin-converting enzyme; HDL, high-density lipoprotein; LDL, low-density lipoprotein; RA, renin-angiotensin.

The relationship between the severity of ASC and other echocardiographic features is shown in Table 3. Patients with higher degrees of thickening and calcification had greater ventricular thickness (interventricular wall: 12.3 ± 2.1 in moderate-to-severe ASC vs. 11 ± 1.9 mm in no ASC; p < 0.001) and lower ejection fraction (64.5 ± 9.6 vs. 66.1 ± 7.2; p = 0.012). In addition, in this group there were more patients with aortic arch calcified plaques (18.9% vs. 4.7%; p < 0.001) and with abdominal aorta calcified plaques (37% vs. 14.9%; p < 0.001). Doppler flow velocities and gradients across aortic valve were linearly related with severity of ASC as well as aortic regurgitation degree.

Table 3.

Relationship between aortic sclerosis and other echocardiographic features

Valid	Sample (n = 1068)	No aortic sclerosis (n = 583)	Mild-to- moderate (n = 349)	Moderate-to- severe (n = 136)	p-value
Left ventricle end diastolic diameter (mm)	1067	44.8 ± 5.2	44.9 ± 4.8	44.6 ± 5.4	44.3 ± 5.9	0.42
Left ventricle end systolic diameter (mm)	1067	28.1 ± 4.7	27.9 ± 4.3	28.3 ± 4.8	28.8 ± 5.8	0.1
Interventricular wall (mm)	1068	11.4 ± 2	11 ± 1.9	11.7 ± 2	12.3 ± 2.1	<0.001
Posterior wall (mm)	1068	10.8 ± 1.8	10.5 ± 1.7	11 ± 1.8	11.5 ± 2	<0.001
Ejection fraction (%)	1059	65.6 ± 7.9	66.1 ± 7.2	65.1 ± 8.2	64.5 ± 9.6	0.012
Aortic ring diameter (mm)	1068	20.5 ± 2.2	20.5 ± 2.1	20.4 ± 2.3	21.15 ± 2.6	0.02
Aortic root diameter (mm)	1068	33.2 ± 4.1	32.9 ± 3.8	33.2 ± 4.3	34.1 ± 4.6	0.01
Sinotubular junction (mm)	1067	25.6 ± 3.6	25.5 ± 3.5	25.6 ± 3.6	26.4 ± 4.3	0.02
Ascending aorta diameter (mm)	1056	36.2 ± 4	35.5 ± 3.8	36.5 ± 3.9	38 ± 4.8	<0.001
Maximum valve aperture (mm)	1067	18.4 ± 12.6	19.3 ± 13.7	17.8 ± 11.3	15.8 ± 9.9	0.007
Ascending aorta calcified plaques	1003	16 (1.6)	5 (0.9)	9 (2.8)	2 (1.6)	0.17
Complicated	1003	12 (1.2)	5 (0.9)	6 (1.8)	1 (0.8)	0.43
Aortic arch calcified plaques	1008	95 (9.5)	26 (4.7)	46 (14.1)	24 (18.9)	<0.001
Complicated	1008	80 (7.9)	23 (4.2)	39 (11.9)	18 (14.2)	<0.001
Abdominal aorta calcified plaques	1016	235 (23.1)	84 (14.9)	104 (31.8)	47 (37)	<0.001
Complicated	1016	189 (18.6)	72 (12.8)	85 (26)	32 (25.2)	<0.001
Doppler
Maximum aortic flow velocity (m/s)	1068	1.45 ± 0.47	1.3 ± 0.34	1.47 ± 0.32	2 ± 0.76	<0.001
Mean aortic flow gradient (mmHg)	1068	4.9 ± 6.2	3.9 ± 6.1	4.7 ± 2.4	10.1 ± 9.6	<0.001
Maximum aortic flow gradient (mmHg)	1068	9.4 ± 10.1	7.4 ± 9.7	9.1 ± 4.6	18.6 ± 15.9	<0.001
Aortic regurgitation >I	1065	21 (2)	6 (1)	8 (2.3)	7 (5.2)	0.002

Values are mean ± standard deviation or n (%).

Table 4 shows the variables associated with ASC, adjusting for gender and according with the severity of thickening and calcification. Age, smoking habit, hypertension, waist circumference, and ABI <0.9 were associated with mild-to-moderate degrees of ASC. Moreover, except for waist circumference, there was a gradient between the magnitude of these associations and the severity of ASC. The OR for age was of 1.56 (95% CI 1.39–1.76) for mild-to-moderate ASC, and of 2.03 (95% CI 1.72–2.4) for moderate-to-severe ASC. Likewise, smoking habit had an OR for mild-to-moderate ASC of 1.59 (95% CI 1.08–2.34) and of 2.13 (95% CI 1.19–3.78) for moderate-to-severe ASC. Diabetes and renal impairment were associated with advanced but not early stages of thickening and calcification. Model calibration was acceptable as showed by Hosmer−Lemeshow calibration test, which it was 0.7 for the ‘mild-to-moderate’ logit and 0.41 for the ‘moderate-to-severe’ logit. The ordinal model fitted with the same variables of the multinomial model was statistically significant (p < 0.001) and there was a non-significant difference between its log-likelihood value and that of the multinomial model (p = 0.4) thus suggesting that ordinality could be assumed.

Table 4.

Predictors of aortic valve sclerosis in the multinomial analysis

OR	95% CI	p-value
Mild-to-moderate vs. no sclerosis
Age (5-year increase)	1.56	1.39–1.76	<0.001
Smoking habit (prior or current)	1.59	1.08–2.34	0.018
Hypertension	1.54	1.13–2.1	0.006
Waist circumference (3-cm increase)	1.25	1.09–1.45	0.002
Ankle−brachial index <0.9	1.93	1.06–3.51	0.03
Diabetes	0.88	0.6–1.26	0.49
Renal impairment	1.33	0.67–2.6	0.41
Gender (males)a	1.05	0.72–1.5	0.81
Moderate-to-severe vs. no sclerosis
Age (5-year increase)	2.03	1.72–2.4	<0.001
Smoking habit (prior or current)	2.13	1.19–3.78	0.014
Hypertension	1.91	1.19–3.1	0.008
Waist circumference (3-cm increase)	1.2	0.98–1.48	0.08
Ankle−brachial index <0.9	2.17	1.02–4.4	0.04
Diabetes	1.7	1.1–2.6	0.025
Renal impairment	2.36	1.1–5	0.027
Gender (males)a	1.1	0.6–1.9	0.72

a

The variable gender was forced into the model as a control variable.

Discussion

The present study shows a prevalence of ASC and AS in people ≥65 years in a Mediterranean area of 45.4% and 3%, respectively, which is similar to or even higher than that reported years ago in other settings. As in other scenarios, traditional cardiovascular risk factors such as age, hypertension, smoking habit, and diabetes were associated with ASC. Other determinants, not consistently found in other studies, were waist circumference, ABI < 0.9 and renal impairment. A remarkable finding was that, except for diabetes and renal impairment, a gradient in the magnitude of association between ASC and risk factors was found: the greater the severity of ASC the stronger the association with the corresponding risk factor.

Aortic valve calcification begins deep in the valvular tissue but, in advanced disease, it extends through the surfaces of the cusps (ASC stage). If calcification progresses valve function is finally affected leading to outflow obstruction (AS stage).¹ This process is at least partially triggered and supported by lipids,¹⁹ especially oxidized low-density lipoproteins .^20,21 This pathobiology suggests a link between CAVD and atherosclerosis, indirectly supported by the association between ASC and cardiovascular events.⁵ However, and partially conflicting with the biological rationale, the results of randomized clinical trials with lipid-lowering therapies in patients with ASC are controversial, suggesting that CAVD is probably a more complex process involving other risks factors and different valve responses to the same oxidative stimuli. For this reason, as recommended by scientific societies, the study of clinical risk factors for the distinct phases of CAVD to identify individuals at higher risk is mandatory.¹

In contrast to other studies, we decided to consider ASC as a continuum ranging from mild to severe degrees of thickening and calcification. The rationale for this strategy was the assumption that, if risk factors for ASC were actually implied in the causal chain, there would be a gradient in the magnitude of association depending on the severity of ASC. We observed a gradient for the majority of factors detected, except for waist circumference and for ABI < 0.9. These conditions were associated with ASC in a similar magnitude regardless the severity of thickening and calcification. They could represent a marker of general cardiovascular risk and thus are strongly associated with other variables that would be the true risk factors of ASC. By contrast, the gradient in the magnitude of association was greater for renal impairment and diabetes. However these were statistically associated only with the more severe stages of thickening and calcification. As these two conditions lead to an accelerated development of atherosclerosis, they may be associated with a more severe stage of ASC. In any case, association between ASC severity and risk factors could be related with the level of oxidative stress, which would be higher in those patients exposed either longer or more intensively to certain risk factors.¹ It does not necessary exclude the existence of different valve phenotypes (for instance different cardiac valve cell types proportions), which could lead to a different inflammatory response in presence of a oxidative stress stimuli.¹ The role that these two conditions are playing in the development of ASC should be focused on further studies.

We did not observe an association between total and LDL cholesterol and ASC. It may be because patients with moderate-to-severe ASC were on specific drug therapy much more often than those patients with mild-to-moderate degree of ASC or those without any degree or ASC. This was especially true in the case of statins but also with antithypertensive drugs. In any case, as reported previously, it is also true that the association with elevated LDL cholesterol is relatively weak in those >65 years old, the group at greatest risk of progressing to AS.¹ Unfortunately other lipid measurements such as Lp(a) were not available. As shown in other studies, they might have been associated with ASC.⁹

Excepting the Cardiovascular Health Study,^5,9 to our knowledge this is the largest community level study in the elderly aimed at assessing the ASC and AS prevalence and their determinants, and the only one carried out in a Mediterranean area. Based on the lower incidence of atherosclerotic complications in our context and on the well established clinicopathological link between atherosclerosis and CAVD^21,22 we initially hypothesized that the prevalence of CAVD would also be smaller than that observed in other scenarios. However, the similar ASC and AS rates in a Mediterranean area comparing with other countries indirectly supports that CAVD is likely to be a more complex process and that, although cardiovascular risk factors may play a role on the first stages of aortic valve distortion, disease progression may depend on other factors.²³ In this regard, the absence of any relevant effect of statins at high dose in CAVD shown in a clinical trial also supports the presence of other determinants.²³ These hypothetical determinants would likely act in a similar manner in areas with high or low cardiovascular risk factor complications.

Limitations

The observational nature and cross-sectional design prevent any causal inference. The study was limited to people ≥65 years and this may have influenced the magnitude of association between risk factors and CAVD. Of the subjects contacted by phone call, 25.5% refused to participate, and echocardiographic view was inadequate for proper thickening and calcification assessment in 5.99% of patients. This may have induced some selection bias. Since the nonresponding subjects are usually older and with higher comorbidities, the estimated prevalence of CAVD is probably slightly lower than it would otherwise have been.

Finally, the consistency of our findings is partially dependent on the accuracy of CAVD gradation. Although the system for thickening and calcification scoring employed for the purpose of this study is novel and not previously validated, the degree of inter- and intra-observer agreement that we calculated supports its adequacy.

Conclusions

The prevalence of ASC and AS in people ≥65 years in a Mediterranean area is similar to or even higher than that reported in other regions, the traditional cardiovascular risk factors being also associated with CAVD as previously reported in other scenarios. The finding of a gradient in the association of these factors with the severity of aortic sclerosis may be considered as an additional argument to support their implication in the causal chain for the development of the disease.

Funding

This work was supported by the Spanish Centro Nacional de Investigaciones Cardiovasculares (CNIC) [grant no. CNIC-09-2007].

Conflict of interest

None declared.