Coronary calcification among 3477 asymptomatic and symptomatic individuals

Abstract

Background

Coronary artery calcification (CAC) can be detected by cardiac computed tomography (CT), is associated to cardiovascular risk, and common in asymptomatic individuals and patients referred for cardiac CT.

Design

CAC was evaluated in asymptomatic individuals and symptomatic patients referred for cardiac CT, to assess whether differences in CAC may be explained by symptoms or traditional cardiovascular risk factors.

Methods

The presence and extent of CAC, gender, family history of coronary artery disease, hypertension, hyperlipidaemia, diabetes and tobacco were compared in 1220 asymptomatic individuals aged 49–61 years and 2257 age-matched symptomatic patients referred for cardiac CT with suspected coronary artery disease.

Results

Symptomatic individuals had a higher frequency of a family history of coronary artery disease (46% vs. 23%, p < 0.001), hypertension (38% vs. 21%, p < 0.001), hyperlipidaemia (42% vs. 12%, p < 0.001), a trend for more diabetes (6% vs. 5%, p = 0.05), but no significant difference was observed for the presence of CAC (Agatston > 0; 45% vs. 45%, p = 0.94) or severe calcifications (Agatston > 400; 6% vs. 5%, p = 0.36). In multivariate analyses age (odds ratio (OR) 1.09–1.18), male gender (OR 3.5–6.43), hypertension (OR 1.42–1.79), hyperlipidaemia (OR 1.86–2.09) and tobacco use (OR 1.83–2.01) were predictors for the presence and extent of CAC, whereas symptoms were not predictive for the presence of (Agatston > 0, OR 0.70 (0.59–0.83)), mild (Agatston ≥ 10; OR 0.85 (0.71–1.02)), moderate (Agatston ≥ 100; OR 0.99 (0.79–1.24)) or severe calcifications (Agatston ≥ 400; OR 0.93 (0.65–1.33)).

Conclusion

No difference in the presence or severity of coronary calcifications was observed between asymptomatic and symptomatic middle-aged individuals. After adjusting for cardiovascular risk factors, symptoms were not predictive for the presence or extent of CAC.

Introduction

Coronary artery calcification (CAC) as assessed by cardiac computed tomography (CT) has been extensively evaluated.^1–4 In asymptomatic and symptomatic individuals the extent of CAC is associated with increased risk of cardiovascular events and death, whereas the absence of CAC portends a favourable prognosis.^4,5 Furthermore, CAC provides incremental prognostic value in addition to traditional risk factors.^6–13 Although the mortality related to coronary artery disease (CAD) has declined in western countries during the last years, cardiovascular diseases still constitute a major public health problem worldwide.^14,15

While coronary calcifications in asymptomatic individuals and in patients referred for cardiac CT are quite common, a comparison of these groups taking traditional cardiovascular risk factors into account has not previously been thoroughly evaluated. Thus, we investigated the presence and severity of CAC in asymptomatic individuals and patients referred for cardiac CT with symptoms suggestive of CAD, to evaluate whether any potential difference in coronary calcification may be explained by the presence of symptoms or by traditional cardiovascular risk factors.

Methods

Study cohorts

A random selected sample of 1825 men and women aged 50 and 60 years living in the southern part of Denmark was invited to participate in a cardiovascular screening programme with evaluation of medical history, assessment of cardiovascular risk factors and CAC scanning in 2009 as previously described.³ From this cohort 1220 individuals without symptoms or a history of cardiovascular disease (i.e. stroke, myocardial infarction, percutaneous coronary intervention or coronary artery bypass surgery) underwent a CAC scan. The protocol was approved by the regional scientific ethical committee (S-20080140) and conducted according to the Declaration of Helsinki. All participants gave written informed consent. From the same geographical area prospectively entered data on cardiovascular risk factors and CAC were retrieved from a clinical database with patients undergoing cardiac CT due to symptoms suggestive of CAD. Participating imaging centres use similar guidelines for referral to cardiac CT in patients with symptoms suggestive of and without previous history of CAD: low-to-intermediate pre-test likelihood of CAD, regular heartbeat, and normal or near normal renal function.¹⁶ From 2009 to 2013 complete data on 2257 symptomatic patients referred for cardiac CT for clinical reasons with stable suspected and not known history of CAD aged 50–60 years were included for comparative analyses.

A family history of CAD was defined as any first-degree male or female relative with CAD before the age of 55 or 65 years old, respectively. Hypertension was defined as use of anti-hypertensive medication(s) or blood pressure ≥140/90 mmHg. Hyperlipidaemia was defined as use of lipid lowering medication(s) or total cholesterol ≥5 mmol/l. Diabetes mellitus was defined as use of anti-diabetic medication(s) or fasting glucose ≥7.0 mmol/l. Tobacco use was defined as current use of tobacco.

Cardiac CT

Coronary calcium scans were acquired during inspiratory breath hold as non-contrast enhanced prospective ECG-gated scans triggered at 50–75% of R-R interval, using 2.5 or 3.0 mm collimation with gantry rotation time 330–500 ms, tube current 150–200 mA and tube voltage of 120 kV. CAC was assessed using the Agatston (Ag) score.¹⁷

Statistical analyses

Cardiovascular risk factors including age, gender, family history of CAD, hypertension, hyperlipidaemia, diabetes mellitus, tobacco use and Ag scores are presented as frequencies, mean (±standard deviation) and median (range) as appropriate. Comparisons between groups were performed using Fisher’s exact test and Mann–Whitney U-test as appropriate. In a sub-analysis of patients with a detailed symptom description, Kruskal–Wallis rank test was used to evaluate any differences in Ag scores according to symptom classification as non-anginal, atypical and typical angina.¹⁸ In the univariate and multivariate analyses, symptoms were defined as present or absent. The presence of symptoms and cardiovascular risk factors were evaluated in univariate and multivariate logistic regression analyses as predictors for the presence (Ag > 0) and extent of coronary calcification (Ag ≥ 10, ≥100, and ≥400) with multiple analyses per CAC level. Regression analyses are presented as odds ratios (ORs) with 95% confidence intervals (CIs). All tests were two-tailed using a significance level of 5%. Analyses were performed using STATA 10.0 (StataCorp, Texas, USA).

Results

In the cohort of 3477 individuals, no difference between asymptomatic (n = 1220) and symptomatic (n = 2257) individuals was observed in gender or tobacco use. Symptomatic individuals more frequently presented with a family history of CAD, hypertension, hyperlipidaemia and a trend towards more diabetes (Table 1). We observed a higher proportion of symptomatic patients with Ag ≥ 10 and ≥100, but no significant difference was observed for the presence of (Ag > 0) or severe coronary calcifications (Ag ≥ 400) (Table 1). A detailed symptom description was available in 709 of 2257 patients (31%), with 274 patients with non-anginal chest pain, 197 with atypical angina and 238 with typical angina. The median (interquartile range, range) Agatston score was: non-anginal chest pain 0 ((0; 26), 0–1081), atypical angina 0 ((0; 51), 0–6300), and typical angina 0 ((0; 31), 0–1504), without any significant difference between groups (p = 0.57).

Univariate and multivariate analyses

In univariate and multivariate analyses age, male gender, hypertension, hyperlipidaemia and tobacco use were associated with Ag > 0, ≥10, ≥100 and ≥400 (Tables 2 and 3). In univariate analyses symptoms were associated with Ag ≥ 10 and Ag ≥ 100, however, after adjusting for cardiovascular risk factors symptoms were not associated with Ag ≥ 10, ≥100, or ≥400, and in fact inversely related to the presence of CAC (Ag > 0). There was a significant relation between Ag > 0, Ag > 10, Ag > 100, Ag > 400 (Table 2) and the numbers of risk factors. We found a significant relation between coronary calcification and the numbers of risk factors for both asymptomatic individuals and symptomatic patients (p < 0.001 for both).

Discussion

The major findings in the present study are: 1) the proportions of individuals with any coronary calcification (Ag > 0) or severe coronary calcification (Ag ≥ 400) are similar in middle-aged, randomly selected, asymptomatic individuals compared with patients referred for cardiac CT with symptoms suggestive of CAD, and 2) no clear association between symptoms and the presence or severity of CAC in middle-aged men and women.

Not surprisingly, traditional cardiovascular risk factors including age, male gender, hypertension, hyperlipideamia, tobacco use, and the number of risk factors were all associated with the presence and severity of CAC. In fact, age and male gender were the most powerful predictors of any level of CAC with ORs ranging from 2.4 to 5.2 per 10 years of age and from 3.5 to 6.4 for male gender. After adjusting for the traditional cardiovascular risk factors, symptoms were not related to Ag ≥ 10, ≥100 or ≥400, and in fact inversely related to the presence of CAC (Ag > 0). Furthermore, there was no relation between symptom severity and CAC in the sub-group of patients where a detailed symptom description was available. These observations underline the impact of traditional cardiovascular risk factors for the development of atherosclerosis and as predictors for coronary calcification. A possible explanation for the apparent inverse relation between symptoms and the presence of CAC (Ag > 0), may be the left skewed distribution of CAC (most individuals had no CAC) combined with a likely more rigorous analysis of the presence or absence of small amounts of calcification in a scientific study versus a clinical setting.¹⁹

The absence of significant difference in the proportion of patients with at least mild (Ag ≥ 10), moderate (Ag ≥ 100) or severe (Ag ≥ 400) calcifications in asymptomatic and symptomatic middle-aged men and women is intriguing. Approximately half of the asymptomatic middle-aged men and women have subclinical atherosclerosis. This observation is well established and may be of public health concern; however, its clinical implication in relation to treatment remains unsolved.^2,3 Limited scientific evidence and no clear recommendations are available as to whether these individuals should or would benefit from medical preventive treatment or intensive risk factor handling.^16,20 Furthermore, middle-aged patients with suspected CAD who are evaluated with a cardiac CT scan have no more CAC than age-matched supposedly healthy volunteers. This is surprising since these individuals would intuitively be expected to have more atherosclerosis, thus more coronary artery disease, causing symptoms (angina). Potential explanations for this finding may be that the atherosclerotic plaque causing symptoms is either not calcified, or that the symptoms leading the patients to cardiac CT scan are of non-coronary origin. In favour of the latter interpretation is the fact that the selection of patients for cardiac CT according to current guidelines is based on age, sex and symptoms, recommending cardiac CT primarily for patients with low intermediate (15–50%) pre-test likelihood of significant CAD.¹⁶ An evaluation of CAC in relation to coronary CTA may provide valuable information. Although the absence of CAC (approximately half of the symptomatic patients in the present study) does not exclude coronary stenosis or obviates the need for further evaluation,²¹ a decrease in diagnostic specificity of coronary CTA combined with an increased prevalence of significant stenosis in patients with an Ag score >400 makes it reasonable not to proceed with the coronary CTA as outlined in the recent European Guidelines.¹⁶

Coronary calcification is not only a sign of coronary atherosclerosis, but also an indicator of the total coronary atherosclerotic plaque burden.²² Indeed, coronary calcification has an incremental prognostic value when added to cardiovascular risk factors,^{4,6–8,12,13,23} and a graded relation between coronary atherosclerosis and cardiovascular risk has been established.^11,24–26 Hypertension, hyperlipidaemia and tobacco are modifiable risk factors and thus amenable to primary and secondary prevention; however, the risk factors most strongly associated (age and gender) with coronary calcifications are unfortunately not amenable to cardiovascular risk prevention. It would thus make sense to include an assessment of coronary calcification in order to improve risk stratification, to possibly identify patients where a more rigorous risk factor handling or even medical preventive therapy could be valuable. A total risk estimation using multiple risk factors (such as SCORE) is recommended for asymptomatic adults without evidence of cardiovascular disease.²⁷ The majority (78%) of the asymptomatic individuals in the present study were as previously reported at low (<5%) 10-year risk of a fatal cardiovascular disease event.³ Furthermore, 37% of individuals with >5% 10-year risk of fatal event were as previously reported without any signs of coronary calcifications.³ Whether these findings warrant up-grade or down-grade in overall risk assessment, and should have implications for primary risk prevention including medical therapy, remains unclear and warrants further investigations.

Limitations

This is a retrospectively designed observational cohort study. We did not have a detailed symptom description in all patients and any inference considering the relation between symptom severity and coronary calcification should be made with caution. It should be recognized that the symptomatic patients included in the present analyses represent the core of patients referred for cardiac CT, and the association of cardiovascular risk factors and symptoms may be different in patients with more severe CAD. Furthermore, data on the presence of angiographic stenosis was not available. Patients with a coronary stenosis would be expected to have a larger extent of coronary calcification,²⁸ thus, excluding these patients would not only introduce a selection bias, but is also unlikely to enforce an association of symptoms and CAC. Finally, at this stage, follow-up data cannot be provided to evaluate whether coronary calcifications have different prognostic significance in asymptomatic and symptomatic individuals.

Conclusion

In middle-aged men and women, coronary calcification is common, and primarily related to age and male gender followed by hypertension, hyperlipidaemia and tobacco use. In middle-aged patients referred for cardiac CT with symptoms suggestive of CAD, age, male gender, hypertension, hyperlipidaemia and tobacco use, but not symptoms, were associated with the presence or extent of coronary calcification.

Funding

The Danrisk study was supported by Region Syddanmark (grant number 08-17862) and Odense University Hospital, Denmark.

Conflict of interest

The authors declare that there is no conflict of interest.

References