The High Prevalence of Subclinical Atherosclerosis in Patients With Ankylosing Spondylitis Without Clinically Evident Cardiovascular Disease

Abstract

We conducted the present study to determine whether subclinical macrovascular atherosclerotic disease was present in patients with ankylosing spondylitis (AS) without clinical history of cardiovascular disease. We also sought to establish whether demographic or clinical features of the disease may influence the development of subclinical atherosclerotic disease in a series of patients with AS seen at a community hospital. We recruited 64 patients who fulfilled the modified New York diagnostic criteria for AS from Hospital Xeral-Calde, Lugo, Spain. We excluded patients seen during the recruitment period who had cardiovascular disease or renal insufficiency. We also studied 64 matched controls. Carotid artery intima-media thickness (IMT) and carotid plaques were measured in the right common carotid artery. The study was performed using high-resolution B-mode ultrasound.

Patients with AS exhibited greater carotid IMT than did matched controls (mean ± SD, 0.74 ± 0.21 mm vs. 0.67 ± 0.14 mm; p = 0.01; differences of means, 0.077; 95% confidence interval, 0.016-0.139). Carotid plaques were more commonly observed in patients with AS than in controls (19 [29.7%] vs. 6 [9.4%], respectively; p = 0.03). The best predictors for carotid plaques in patients with AS were erythrocyte sedimentation rate (ESR) at time of disease diagnosis (odds ratio [OR], 1.18; 95% confidence intervals [CI], 1.04-1.33; p = 0.01) and duration of disease (OR, 1.39; 95% CI, 1.01-1.92; p = 0.05). In contrast, there was no significant correlation between carotid IMT and either ESR or C-reactive protein in this study. Results of the present study show that patients with AS without clinically evident cardiovascular disease have a high prevalence of subclinical macrovascular disease in the form of increased carotid IMT and carotid plaques compared to matched controls.

Abbreviations: AS = ankylosing spondylitis, BASDAI = Bath Ankylosing Spondylitis Disease Activity Index, BASFI = Bath Ankylosing Spondylitis Functional Index, CI = confidence intervals, CRP = C-reactive protein, ESR = erythrocyte sedimentation rate, IMT = intima-media thickness, IQ = interquartile, NSAID = nonsteroidal antiinflammatory drug, OR = odds ratio, RA = rheumatoid arthritis, SD = standard deviation, TNF = tumor necrosis factor.

INTRODUCTION

Patients with inflammatory arthritis have an increased risk of cardiovascular events and cardiovascular mortality.²⁰ Studies on rheumatoid arthritis (RA), the most commonly studied inflammatory polyarthritis, have disclosed that the high incidence of cardiovascular events observed in patients with this chronic disease can not be completely explained by the presence of traditional cardiovascular risk factors.⁵ In this regard, an association between the magnitude and severity of the inflammatory response and the presence of subclinical atherosclerosis and cardiovascular events has been found in patients with RA.^6,11,12 Likewise, patients with spondyloarthropathies are also associated with increased cardiovascular mortality, which can be only partly explained by the presence of classic cardiovascular risk factors.²¹

Ankylosing spondylitis (AS), the prototype of spondyloarthropathy, has been associated with a 1.5-2.0 increased mortality rate compared to that in the general population, which is largely due to cardiovascular complications.^22,26 While cardiac disease such as aortic regurgitation; cardiomyopathy, including myocardial failure due to left ventricular dysfunction; and conduction defects were noted to be increased in the AS cohorts,^21,22 accelerated atherosclerotic disease was considered to play the major role in the increased mortality associated with AS. In this regard, a recent population-based study has disclosed that the prevalence rate for myocardial infarction in Dutch individuals with AS was increased approximately 2- to 3-fold compared to the rate in the general population.²⁷

In keeping with other chronic inflammatory rheumatic diseases, accelerated atherosclerotic disease is now considered to play a major role in the increased cardiovascular morbidity observed in these patients. Inflammation seems to have a pivotal role in the mechanisms leading to accelerated atherogenesis in patients with spondyloarthropathies. The presence of a chronic inflammatory process in these patients may contribute to all stages of atherosclerosis, including early atheroma formation, plaque instability, and thrombus development responsible for the development of cardiovascular events in these patients. We note that in a previous study,¹⁷ endothelial dysfunction, an early step in the atherosclerosis process, was observed in patients with psoriatic arthritis without clinically evident cardiovascular disease or classic cardiovascular risk factors of atherosclerosis at the time of the study. In patients with this chronic inflammatory polyarthritis included in the group of spondyloarthropathies, a significant correlation between C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) levels at the time of disease diagnosis and the presence of endothelial dysfunction was found.¹⁷ This observation emphasizes the importance of inflammation in the development of atherogenesis and cardiovascular events in patients with spondyloarthropathies.

An important step forward in our understanding of whether AS is associated with increased cardiovascular morbidity and mortality due to atherosclerosis may be to determine the presence of subclinical data of atherosclerosis disease in patients with AS without overt cardiovascular complications. At present several noninvasive imaging techniques offer an opportunity to study the relation of surrogate markers to the development of atherosclerosis. The use of these techniques may help identify high-risk individuals who may benefit from active therapy to prevent clinical disease. One of these surrogate markers is the presence of endothelial dysfunction. We note that impaired endothelial function has recently been observed in patients with AS.^30,33

Carotid intima-media wall thickness (IMT) of the common carotid artery, determined by high-resolution B-mode ultrasound of the common carotid artery, is another useful noninvasive surrogate marker of atherosclerosis disease. Case-control studies have shown that increased common carotid artery IMT determined by high-resolution B-mode ultrasound is a good indicator of generalized atherosclerosis and coronary artery disease,^1,31 providing early information of atherosclerosis in subclinical stages of the disease in individuals at risk.^23,28 The IMT corresponds to the width of the vessel intima and media, which consists of endothelium, connective tissue, and smooth muscle.²⁸ This is also the site of lipid deposition and plaque formation.²⁹ A recent (2009) study¹⁶ has shown that carotid IMT has a high predictive power for the development of cardiovascular events over a 5-year follow-up period in patients with RA. However, information related to the value of ultrasonographic studies of the carotid artery in patients with AS is limited and contradictory,^3,24,30 probably due to the small number of patients and controls assessed in most of these series.^3,30

In the present study we assessed whether carotid IMT was increased in a cohort of patients with AS without overt cardiovascular disease seen at a community hospital. We also aimed to establish if the frequency of carotid plaques, considered to be the best expression of severe macrovascular disease, was increased in patients with AS compared to matched controls.

PATIENTS AND METHODS

Patients and Controls

We assessed a series of patients with AS and the same number of matched controls (described below). The patient group comprised consecutive patients attending hospital outpatient clinics seen over 4 months (March to June 2008), who fulfilled the modified New York diagnostic criteria for AS.³² They were treated by the same group of rheumatologists and were recruited from the Hospital Xeral-Calde, Lugo, Spain. This hospital is the single referral center for rheumatic diseases for a well-defined, stable and ethnically homogenous, mixed rural and urban, white population living in the region of Lugo, central Galicia (northwestern Spain).^8,9 The main characteristics of the Lugo population have previously been reported.^10,11

Inclusion Criteria

Only patients who had been treated for at least 1 year at the outpatient rheumatology clinic at the time of the study were included. We excluded patients seen during the recruitment period who had experienced cardiovascular disease, including ischemic heart disease (angina or myocardial infarction electrocardiographically confirmed), heart failure, cerebrovascular events (transient ischemic attacks or strokes confirmed by magnetic resonance imaging and/or computerized tomography brain scan) or peripheral arterial disease (confirmed by Doppler and/or arteriography), or renal insufficiency (serum creatinine values in all individuals included in the study had to be <1.3 mg/dL, which is considered the upper normal range in our laboratory).

Definitions of classic (traditional) cardiovascular risk factors (hypertension, diabetes mellitus, and dyslipidemia) have already been reported.¹¹ Patients were considered to have dyslipidemia if they had hypercholesterolemia and/or hypertriglyceridemia (defined as diagnosis of hypercholesterolemia or hypertriglyceridemia by the patients' family physicians before the diagnosis of AS, or total cholesterol and/or triglyceride levels in fasting plasma >240 mg/dL and 160 mg/dL, respectively, at the time of disease diagnosis or over the extended follow-up).¹¹ Patients were considered to have hypertension if before the diagnosis of AS they had been diagnosed as having hypertension by their family physicians, or if at the time of disease diagnosis or over the extended follow-up they had blood pressure >150/90 mm Hg in 2 different examinations performed on different days.¹¹ Patients with AS were considered to have diabetes mellitus if before disease diagnosis they had been diagnosed as having diabetes mellitus by their family physicians or if 2 fasting plasma glucose levels on different days at the time of disease diagnosis or over the extended follow-up were >125 mg/dL.¹¹ Obesity was defined if at the time of the study the body mass index (calculated as weight in kilograms divided by height in squared meters) was greater than 30.¹¹ With regard to smoking, we established 2 categories: 1) current smokers, comprising patients who smoked at the time of the study or who had smoked within the 10 years before the carotid artery study, and 2) the remaining patients (former or never smokers), comprising those who had never smoked or had stopped smoking at least 10 years before the ultrasonographic assessment.^11,13

Sixty-four patients with AS fulfilled the inclusion criteria described above. Another 4 patients with AS were excluded, based on the exclusion criteria described above.

A clinical index of disease activity (Bath Ankylosing Spondylitis Disease Activity Index [BASDAI], range 0-10)⁷ and functional status (Bath Ankylosing Spondylitis Functional Index [BASFI], score 0-10)² were evaluated in all patients at the time of the carotid ultrasonographic study. Also, at that time clinical information on hip involvement, history of synovitis or enthesitis in other peripheral joints, history of anterior uveitis, presence of syndesmophytes, and HLA-B27 status (typed by cell cytotoxicity) was assessed. We assessed CRP (by a latex immunoturbidity method), ESR-Westergren, serum glucose, total cholesterol, high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol, and triglycerides (fasting overnight determinations) in all patients at the time of study. Information about CRP (by nephelometry) and ESR at the time of disease diagnosis was also reviewed.

All patients included in the current study had begun treatment with nonsteroidal antiinflammatory drugs (NSAIDs) immediately after the disease diagnosis. Most of them were still being treated with these drugs at the time of the study. They were treated with ibuprofen: 1800-2400 mg/d, naproxen: 500-1000 mg/d, diclofenac: 100-150 mg/d or indomethacin: 100-150 mg/d. Forty-one had received or were receiving treatment with sulfasalazine (range, 2-3 g/d). At the time of the study, 21 patients were being treated with tumor necrosis factor (TNF)-α blockers (18 with infliximab and 3 with adalimumab) because of severe disease refractory to at least 3 NSAIDs.

Control Group

Controls (n = 64) were community based. They were recruited from family physician health centers of the Lugo region. They were age ± 2 years and sex and ethnically matched controls without family history of AS, psoriasis, psoriatic arthritis, RA, or any other inflammatory rheumatic diseases. None of the controls included in the study had a history of cardiovascular disease such as heart failure, myocardial infarction, angina, cerebrovascular events and peripheral arteriopathy, or renal insufficiency. Furthermore, they were frequency-matched for the presence of classic atherosclerosis risk factors.

Informed consent was obtained from all cases and controls. The local institutional committee approved the study.

Ultrasonographic Study

Carotid IMT was measured in the right common carotid artery as previously reported.^14,15 Until now the most widely available approach for performing carotid IMT measurements was by means of manually positioned cursors-a subjective, laborious, and slow process. However, for the purpose of the present study, QLAB's IMT-quantification software measurement plug-in (Philips Healthcare, DA Best, The Netherlands) was used to increase the consistency and reliability of IMT measurements, reduce the effort required to carry out IMT measurements successfully, and minimize the time needed to complete an IMT study. Atherosclerotic plaque in the common carotid artery was defined as a distinct protrusion, greater than 1.5 mm, into the vessel lumen.^14,18 The study was performed using high-resolution B-mode ultrasound (iE33 Philips ultrasound system, Philips Ultrasound, Bothell, WA) with a 10-MHz linear transducer. A single cardiologist (CG-J) who was blinded to clinical information performed all the studies in all cases.

The reproducibility of the IMT measurements was evaluated in 17 patients and 17 controls within 1 week of the first ultrasonographic examination. The correlation coefficient for carotid IMT was 0.98.

Statistical Analysis

Continuous data were expressed as the mean ± standard deviation (SD), median, and interquartile (IQ) range; categorical variables were expressed as percentages. Continuous variables were compared using the Student t test or the Mann-Whitney U test. Proportions were compared by chi-square test or the Fisher exact test.

Correlation between carotid IMT and continuous variables was tested via estimation of the Pearson partial correlation coefficient (r) adjusting for age at the time of the study, sex, and classic atherosclerosis risk factors. A multivariable analysis using backward stepwise logistic regression was performed to determine the best model for predicting carotid plaques in patients with AS. The relationship between the main clinical and ultrasonographic variables and carotid plaques in AS patients estimated by unadjusted logistic regression was expressed in odds ratios (ORs) and 95% confidence intervals (CI). Our study had 80% power to detect a difference in carotid IMT equal to 70% of the SD, and 61% power to detect an OR = 3 in the association between carotid plaques and a dichotomic exposure.

Two-sided p values ≤ 0.05 were considered to indicate statistical significance. Analyses were performed using Stata 10/SE (StataCorp, College Station, TX).

RESULTS

Clinical Characteristics of AS Patients

We studied 64 patients with AS (51 men and 13 women). The mean ages at the onset of symptoms and at the time of the carotid ultrasonographic study were 34.3 and 52.6 years, respectively. The mean AS duration was 19.1 years. Forty-seven (73.4%) of the 64 patients were HLA-B27 positive. Laboratory markers of inflammatory response (CRP and ESR natural-log-transformed) at the time of AS diagnosis and at the time of the study, as well as glucose and lipid profile data at the time of the study, are shown in Table 1.

TABLE 1: Demographic, Laboratory, and Carotid Ultrasonographic Findings of 64 Patients With AS and 64 Matched Controls

Eleven (17.2%) had hip involvement and 18 (28.1%) had experienced synovitis or enthesitis in other peripheral joints over the course of the disease. Twelve (18.8%) had suffered anterior uveitis, and at the time of the study 21 (32.8%) showed syndesmophytes on plain radiographs. The clinical index of disease activity (BASDAI) and the functional status (BASFI) at the time of the study are shown in Table 2.

TABLE 2: Main Clinical Findings of 64 Patients With AS

Differences Between AS Patients and Controls

We performed a cross-sectional study to establish clinical and ultrasonographic differences between patients and controls (see Table 1). Patients with AS exhibited greater carotid IMT than did matched controls (mean ± SD, 0.74 ± 0.21 mm vs. 0.67 ± 0.14 mm, respectively; p = 0.01; differences of means, 0.077; 95% CI, 0.016-0.139) (Figure 1). In addition, carotid plaques were more commonly observed in patients with AS than in controls (19 [29.7%] vs. 6 [9.4%], respectively; p = 0.03) (see Table 1).

FIGURE 1: Carotid ultrasonographic study in patients with AS and controls. Individual and mean values (horizontal lines) are expressed as carotid IMT in mm.

Correlation Between Carotid Artery IMT and Epidemiologic, Functional, and Laboratory Variables in AS Patients

Partial correlation of carotid IMT thickness with age at onset of symptoms, disease duration, ESR, and CRP adjusting for age at time of study, sex, and classic cardiovascular risk factors in this series of 64 patients with AS is shown in Table 3. No significant correlation between carotid IMT and these continuous variables was found. Likewise, no significant correlation between BASDAI and BASFI at the time of study and carotid IMT was observed (see Table 3).

TABLE 3: Partial Correlation of Carotid Artery IMT With Selected Continuous Variables Adjusting by Age at Time of Study, Sex, and Classic Cardiovascular Risk Factors in 64 Patients With AS

Differences Between AS Patients Undergoing Treatment With TNF-α Blockers or Not

Since some of the patients with AS were undergoing treatment with TNF-α blockers, we stratified patients based on their treatment regimens (TNF-α inhibitors or not) and then assessed for differences in the carotid IMT and in ESR or CRP levels at the time of study. No statistically significant differences were observed (Table 4).

TABLE 4: Differences Between AS Patients Undergoing Treatment With TNF-α Blockers or Not

Differences Between AS Patients With and Without Carotid Plaques

To further investigate the severity of the macrovascular atherosclerotic disease in patients with AS without clinically evident cardiovascular complications, we assessed whether AS patients with carotid plaques had some clinical differences compared with those without carotid plaques (Table 5). As expected, patients with carotid plaques were older and had significantly greater carotid IMT (age, 65.8 ± 10.3 yr and carotid IMT, 0.94 ± 0.19 mm) compared with AS patients without plaques (age, 47.0 ± 12.4 yr and carotid IMT, 0.66 ± 0.15 mm) (p < 0.001 for both comparisons). Moreover, AS patients with carotid plaques had longer disease duration than those without carotid plaques (26.8 ± 13.6 yr vs. 15.8 ± 8.2 yr; p = 0.002). Also, AS patients with plaques more commonly had hip involvement (31.6%) than those without plaques (11.1%) but the difference was not statistically significant (p = 0.07).

TABLE 5: Main Clinical and Ultrasonographic Differences Between AS Patients With and Without Carotid Plaques

We observed no significant differences in the HLA-B27 status or in the index of disease activity (BASDAI) and the functional status (BASFI) at the time of the study between AS patients with carotid plaques and those without carotid plaques (see Table 5).

It is noteworthy that AS patients with carotid plaques showed higher values of ESR at the time of disease diagnosis than patients without plaques (29.4 ± 18.4 mm/1st h vs. 18.8 ± 13.8 mm/1st h, respectively; p = 0.03). This was also true for ESR measured at the time of the study (25.0 ± 18.7 mm/1st h for patients with plaques vs. 14.8 ± 12.4 mm/1st h for patients without plaques; p = 0.01). Moreover, patients with carotid plaques had a trend for higher CRP values at the time of disease diagnosis than those who did not exhibit carotid plaques in the ultrasonographic assessment (20.9 ± 22.0 mg/L vs. 11.8 ± 12.8 mg/L, respectively; p = 0.09).

Relationship Between the Main Clinical and Ultrasonographic Variables and Carotid Plaques in AS Patients

The patient's age at the time of the study (OR, 1.12; 95% CI, 1.06-1.19) and the duration of the disease (OR, 1.11; 95% CI, 1.04-1.19) were associated with increased risk of developing carotid plaques (Table 6). Moreover, the degree of carotid IMT (each 0.1 mm) increased the risk of developing carotid plaques (OR, 2.87; 95% CI, 1.68-4.91). This was also the case for CRP at the time of disease diagnosis (OR, 1.03; 95% CI, 1.00-1.07) and ESR at the time of the study (OR, 1.05; 95% CI, 1.01-1.09) and at the time of disease diagnosis (OR, 1.04; 95% CI, 1.01-1.08).

TABLE 6: Relationship Between the Main Clinical and Ultrasonographic Variables and Carotid Plaques in Patients With AS*

Predictive Model for Carotid Plaques in AS Patients

Since carotid plaques constitute the best morphologic expression of severe macrovascular atherosclerotic disease, the search for predictive factors for plaques in patients with AS without clinical evidence of cardiovascular disease is of major importance to establish the cardiovascular outcome of these patients. Thus, we assessed the best predictive model of carotid plaques corrected for age at time of study, sex and classic (traditional) cardiovascular risk factors in this series of patients with AS. The best predictors of carotid plaques were the ESR at time of disease diagnosis (OR, 1.18; 95% CI, 1.04-1.33; p = 0.01), and the duration of disease from onset of symptoms (OR, 1.39; 95% CI, 1.01-1.92; p = 0.05).

DISCUSSION

Results of the present study show that patients with AS without clinically evident cardiovascular disease have a high prevalence of subclinical macrovascular atherosclerotic disease in the form of increased carotid artery IMT and carotid plaques compared to ethnically matched controls. The disease duration and the systemic inflammatory response expressed by the ESR levels observed at the time of disease diagnosis were found to be the best predictors of severe subclinical atherosclerotic disease, manifested by the presence of carotid plaques at the time of the ultrasonographic assessment. These results may help explain the increased cardiovascular mortality observed in patients with AS.^21,22,26

A recent (2009) report by van Eijk et al³³ disclosed the presence of endothelial dysfunction in 15 patients with AS. These authors found that patients with active AS had impaired microvascular endothelium-dependent vasodilatation and capillary recruitment in the skin, which improved following TNF-α blocking therapy.³³ This observation is of great relevance to explain the increased incidence of cardiovascular events in patients with AS, since endothelial dysfunction is an early step in the atherogenesis process that may precede for many years the development of macrovascular disease and cardiovascular events. In keeping with these authors, we also found endothelial dysfunction in patients with psoriatic arthritis, another disease included within the group of spondyloarthropathies.¹⁷

Arterial wall thickening has a strong prognostic value for cardiovascular events, in particular myocardial infarction and stroke. Carotid IMT assessment allows convenient stratification of patients at risk for cardiovascular disease, and it has proved to be a good marker for the efficacy of antiatherogenic drugs. However, until now studies of carotid ultrasonography to determine the presence of subclinical macrovascular disease could not conclusively emphasize the importance of this technique as a useful surrogate marker of cardiovascular disease in patients with AS. In this regard, in a report³ on 28 young patients with AS (mean age at time of study, 31.8 yr) with short disease duration (mean, 5 yr), no statistically significant differences were found compared to 27 matched controls. Similarly, in a 2006 study³⁰ that encompassed 54 young patients with AS (mean age at time of study, 37 yr) and 31 controls, no differences in the carotid IMT were observed. However, an impaired endothelial function was found in patients with AS from that series.³⁰ More recently (2008), a trend toward increased carotid IMT was observed in a series of 60 AS patients with long-standing disease (mean, 11 yr) compared to 60 controls.²⁴ In keeping with our results, the authors of that study²⁴ did not find a correlation between carotid IMT and the CRP levels measured at the time of the study. We feel that the larger number of patients with long-standing AS assessed in our study may explain the significant differences in the carotid artery IMT observed between the group of patients with AS and the matched controls.

An important difference between the current study and those previously reported^3,24,30 was the specific analysis of the prevalence of carotid plaques in AS patients with long-standing disease. This is of major relevance as our results show that disease duration and ESR at the time of disease diagnosis are predictors of severe macrovascular disease, manifested by the presence of carotid plaques, in patients with AS without clinically evident cardiovascular disease.

The reasons for the accelerated atherosclerosis in patients with chronic rheumatic diseases are not completely understood. Besides the presence of traditional cardiovascular risk factors and the potential influence of some genetic factors, there is a growing body of evidence that inflammation plays a major role in the progression of atherosclerosis in patients with chronic inflammatory rheumatic diseases. In this regard, the duration of a persistent chronic inflammation may be of major importance to explain this accelerated atherogenesis. With respect to this, we previously observed a longer disease duration in RA patients with carotid plaques compared to those without plaques.¹⁸ Also, a persistent chronic systemic inflammation during the course of the disease was associated with increased carotid IMT in patients with RA.^6,12 More importantly, del Rincon et al⁴ disclosed that in patients with RA, the duration of this chronic inflammatory disease augments the effect of age on atherosclerosis. These authors found that the rate at which the carotid IMT increased per unit of age steepened in proportion to the RA duration.⁴ They confirmed that in patients with RA, the systemic inflammation amplifies the age-related risk of cardiovascular disease.⁴ These observations may offer a good explanation for the potential role of both the ESR as a marker of systemic inflammation and the duration of the disease in the development of carotid plaques in our series of long-standing AS patients.

In line with the above, in a study of mortality in 398 AS patients with long-standing disease, a higher ESR was observed in the group of patients with AS who died compared to those who survived.²²

A potential limitation of the current study was that most patients with AS were exposed to NSAIDs. Therefore, we cannot exclude the fact that the effect on carotid IMT increase can be partially attributed to the use of these drugs. With respect to this, NSAIDs are associated with increased risk of serious cardiovascular events.²⁵ This potential risk is particularly due to effects on prostacyclin. In this regard, NSAIDS used by our patients with AS, especially diclofenac, have been found to increase the risk of cardiovascular events.²⁵ However, in a recent study by Goodson et al,¹⁹ patients with inflammatory polyarthritis who took NSAIDs did not appear to have an excess risk of dying from cardiovascular events. The authors explored whether NSAID use was associated with heart-related death in 923 patients newly diagnosed with inflammatory polyarthritis. The average length of NSAID use was 4 years, and patients were followed a median of about 10 years.¹⁹ We note that the use of these drugs at the start of the study was associated with a 46% lower risk of dying from cardiovascular disease.¹⁹ Having ever used NSAIDs during follow-up was also significantly associated with a reduced risk of cardiovascular death.¹⁹

Although the current study includes the largest series of patients with AS assessed by carotid ultrasonography to our knowledge, the relatively small number of patients may still be a potential limitation. However, in view of the exclusion and inclusion criteria and matching of controls, our results do indeed confirm the presence of increased subclinical atherosclerotic macrovascular disease in patients with AS. In this regard, our data support the conclusion that AS should be considered a high-risk condition for cardiovascular disease.