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Obstetrics & Gynecology:
doi: 10.1097/AOG.0b013e318206c8cb
Original Research

The Association of Breast Arterial Calcification and Coronary Heart Disease

Schnatz, Peter F. DO; Marakovits, Kimberly A.; O'Sullivan, David M. PhD

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Author Information

From the Departments of Obstetrics and Gynecology and Internal Medicine, The Reading Hospital and Medical Center, Reading, Pennsylvania; the Departments of Obstetrics and Gynecology and Internal Medicine, Jefferson Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania; and the School of Osteopathic Medicine, Philadelphia College of Osteopathic Medicine, Philadelphia, Pennsylvania.

Funded by the research budgets of the Reading Hospital and Medical Center and Hartford Hospital.

Presented in abstract form at the 2009 Annual Meeting of the North American Menopause Society, October 1, 2009, San Diego, California.

Corresponding author: Peter F. Schnatz, DO, FACOG, FACP, NCMP, Associate Chairman and Residency Program Director, The Reading Hospital and Medical Center, Department of ObGyn-R1; PO Box 16052, Reading, PA 19612-6052; e-mail: schnatzp@readinghospital.org.

Financial Disclosure The authors did not report any potential conflicts of interest.

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Abstract

OBJECTIVE: To estimate whether mammography can be an early, valid tool for predicting the development of coronary heart disease (CHD) in women.

METHODS: Women presenting for routine mammograms between June and August 2004 were recruited for the study. Baseline data collected included risk factors and family history of heart disease, as well as any cardiac events experienced by the patient. Similar follow-up data were collected during subsequent years, and these patient-completed surveys were correlated with the baseline mammograms screened for breast arterial calcifications.

RESULTS: Throughout the 5-year follow-up, CHD was present in 20.8% of women who screened positive for breast arterial calcification and in 5.4% of who screened negative for breast arterial calcification (P<.001). Among women who did not have CHD at baseline, breast arterial calcification-positive women were more likely to develop CHD or a stroke than those who were breast arterial calcification-negative (6.3% compared with 2.3%, P=.003; and 58.3% compared with 13.3%, P<.001), respectively. These results remained significant even when controlling for age.

CONCLUSION: The presence of breast arterial calcifications on mammograms indicates a significantly increased risk of developing CHD or a stroke. These results suggest that breast arterial calcifications should be routinely reported on mammograms and viewed as a marker for the development of CHD.

LEVEL OF EVIDENCE: II

Coronary heart disease (CHD) is the leading cause of death among women and is responsible for almost half a million deaths per year.1 It is clear that CHD prevalence and mortality rates increase with age,1,2 especially after age 50.2 Independent of age, the prevalence of CHD increases after menopause.2–7 Women of advanced age with histories of smoking, diabetes, high blood pressure, obesity, and hypercholesterolemia, along with a family history of coronary disease and a sedentary lifestyle, are at increased risk for developing CHD.8–10 Women are more likely to have atypical symptoms, so it is essential that risk screening and preventive education be maximized.

The results of previous studies have shown an increased prevalence of radiographically demonstrable calcification, found in the intimal layer of large vessels, in persons with CHD.11–13 Medial arterial calcifications are characterized by diffuse, fine, and granular deposits along the circumference of small to medium-sized muscular arteries that appear as parallel lines or a ring of calcification depending on the radiographic angle. Whereas intimal calcifications are strongly associated with morbidity and mortality from CHD, medial arterial calcifications have unknown clinical significance.14–16

Breast arterial calcifications, therefore, are medial calcifications of the breast arteries that often appear on mammograms. The reported prevalence of breast arterial calcifications on mammography is 3–29.4%.16–24 A benign nature of these medial calcifications has been suggested; therefore, they are inconsistently reported on mammography although they are common findings.

Previous clinical study findings, however, have determined a strong association between the presence of breast arterial calcifications on mammography and CHD (odds ratios [ORs] range from 1.32–6.20).16–20,23–25 Whether the presence of breast arterial calcifications in a woman without CHD predicts her future development of coronary atherosclerosis is not known. The results of a recent study found that 76% of women with breast arterial calcifications on their baseline mammogram developed coronary artery calcifications (a marker for CHD) within 6–11 years, independent of age (OR 2.0). Comparably, only 49% of women without breast arterial calcifications at baseline showed coronary artery calcifications during the follow-up period.19 Another study, with a sample size of 307 women, reported an odds ratio of 8.13 (confidence interval [CI]: 2.7–24.6) for breast arterial calcifications in predicting women with CHD.26 The relatively small sample sizes along with the methodologies, however, limit the conclusiveness of these recent findings.19,26 Furthermore, the first study analyzed a marker for CHD, not CHD itself. The second study, as with most studies on this topic, looked at the association in those who already had CHD. A better understanding of the predictive relationship between breast arterial calcification and CHD is therefore needed.

The use of mammography to predict CHD risk may allow for earlier detection and preventive interventions. Even if a woman does not exhibit the typical CHD risk factors, theoretically, her risk could be increased based solely on her annual screening mammogram. Although screening mammography recommendations have recently changed, the new guidelines would be unlikely to affect any potential role in CHD screening. Although mammograms are no longer recommended for women under age 50 years,27 the risk of a major cardiovascular event in women age 45–54 years is approximately 0.3%1; therefore, the later age of screening would not influence the effectiveness of using mammography as a CHD screening tool.

Evidence for a connection between breast arterial calcification and CHD remains controversial and a prospective predictive relationship needs to be studied. Therefore, the current 5-year prospective cohort study was designed to further elucidate the possible association between breast arterial calcification and CHD. Results from the baseline population were reported, confirming an association between breast arterial calcification and CHD16 and a lower prevalence of breast arterial calcification in hormonal therapy users.28 The current analysis reports the 5-year results.

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METHODS

This study was approved by the Reading Hospital and Medical Center Institutional Review Board. Women presenting for routine breast cancer screening mammography between June and August 2004, inclusive, at four outpatient radiology facilities were given an explanation of the research project and offered the opportunity to participate. Of the 2,082 consecutive women invited to join the study, 87 women (4.2%) refused to participate. Reasons for not participating included lack of time (34 women, 39.1%), anxiety about the upcoming procedure (12 women, 13.8%), and unspecified reasons (41 women, 47.1%). The only exclusion criterion was male gender. A total of 1,995 women were enrolled, and each woman gave consent to complete a questionnaire and have her mammogram analyzed for the presence of breast arterial calcification. Complete baseline data, including questionnaire responses and breast arterial calcification reports, were obtained for 1,919 women.

The baseline questionnaire collected demographic information such as name, date of birth, race or ethnicity (white non-Hispanic, Hispanic, African American non-Hispanic, or other), and contact information. Risk factors for CHD also were assessed, including the presence of hypertension, diabetes mellitus, a family history of CHD, hypercholesterolemia, along with smoking history and exercise habits. Hypertension was defined as 1) a medical history or diagnosis of hypertension, 2) use of an antihypertensive medication, or 3) awareness of a systolic pressure of at least 140 mm Hg, or a diastolic pressure of at least 90 mm Hg, on at least two occasions. Diabetes mellitus was defined as using insulin or oral diabetic medications, or adhering to a prescribed diabetic diet. Participants were classified as smokers if they currently smoked cigarettes or smoked cigarettes within the previous 12 months. Hypercholesteremia was defined as having a medical history of high cholesterol or use of a lipid-lowering agent. A positive family history of CHD included a first-degree relative, younger than 55 years old if male and younger than 65 years old if female, who had a cardiac event (angina, myocardial infarction, coronary artery bypass graft, or stroke). Questions asked for a self-reported personal history of CHD, which was defined as ever having had angina pectoris, myocardial infarction, abnormal coronary angiography, coronary artery bypass graft, or stroke.

The questionnaire also asked for menopause status, date of menopause onset, history of hormonal therapy use, and history of breast cancer. Menopause was defined as the absence of a menstrual period for more than 12 months. In the event that women gave only the year of their last menstrual period, July 1 of that year was used to approximate the month. Current hormonal therapy use was defined as a minimum of 3 consecutive months of therapeutic hormonal therapy at the time the questionnaire was administered. Previous hormonal therapy use was defined as a minimum of 3 months of therapeutic hormonal therapy, but not within 3 months preceding the administration of the questionnaire. Information regarding birth weight also was obtained.

Women were asked whether or not they would like to be contacted for a follow-up questionnaire in subsequent years of the study; 146 women (7.3%) declined to be contacted for participation in follow-up years.

After patients were enrolled and consented at the radiology sites, trained research personnel and staff at each site presented the questionnaire, which took approximately 10 minutes to complete. The questionnaire was offered in English and Spanish according to the patient's preference. The availability of a questionnaire in other languages was available but never required.

Mammograms were analyzed for the presence of breast arterial calcification by one of 21 radiologists at the four radiology practices in the greater Hartford, CT, area. All radiologists were blinded to the results of the questionnaire. A mammogram was determined to be breast arterial calcification-positive if breast arterial calcifications were present on one of the two views on either the right, left, or both breasts.15,16 Because there is no consensus on what constitutes more or less severe breast arterial calcification, or what significance a greater or lower quantity of calcifications would mean, consistent with previous studies, the severity or quantity of calcification was not specified. To ensure intra-observer reliability among the 21 radiologists, each radiologist completed a prestudy review and calibration of 20 standardized mammograms, 12 of the mammograms were breast arterial calcification-negative and 8 were breast arterial calcification-positive. Each radiologist, during the pretest and the study, was given the following definition to ensure that the same criteria were being utilized. Breast arterial calcification was defined as the presence of two parallel linear calcium deposits along the periphery of tapered structures (in a longitudinal image of an arterial wall) or a calcific ring configuration (in an en face image of an arterial wall) typical of arteries and distinct from breast ducts.14,15,29,30 The prestudy quality control demonstrated a 96% simple agreement for the 420 cases (mean plus or minus standard deviation [SD] of correct interpretations=19.2±1.0; minimum=17, maximum=20).16

Each woman was followed prospectively for 5 years following the baseline data collection. A similar questionnaire to the baseline questionnaire was mailed to each participant in the second, fourth, and fifth years of the study to obtain follow-up data and record any change in CHD status. Patients who did not respond to the mailing were contacted by phone, and exhaustive efforts were made to account for all participants. If a participant had died, research personnel communicated with family or attempted to verify the cause of death when able. Participants were excluded from the prospective study based only on the inability to contact the patient for follow-up.

Of the total 1,995 participants in the baseline database, 496 were not included in the follow-up study. Eleven women declined to participate when called for the follow-up survey, 60 women lacked breast arterial calcification information on mammography, and 425 women were unable to be contacted for the follow-up survey.

Therefore, 1,499 participants were considered in the follow-up study. Of these, 1,454 women had at least partial data for analysis from year 5 of the follow-up survey collection, and 45 had died. Of these deaths, 1 was CHD-related, 27 were confirmed to be unrelated to CHD, and 17 were of unknown cause.

The prospective data were analyzed for each participant to estimate the overall prevalence of CHD in those with, compared with those without, breast arterial calcification at baseline. We also determined the prevalence of new CHD over time in those with, compared with those without, breast arterial calcification over the course of this 5-year study. We recognized that there may be a difference between peripheral vascular disease (represented by stroke in this study) and systemic arterial disease (represented by angina pectoris, a myocardial infarction, an abnormal coronary angiography, or a coronary artery bypass graft in this study). For this reason, we additionally analyzed peripheral vascular disease and systemic arterial disease separately.

Our a priori power analysis was based on the work of Crystal et al and their reported breast arterial calcification prevalence of 17.5%.31 Anecdotal evidence from the general patient population suggested that patients in this sample would report the presence, history, or occurrence of certain risk factors (specifically, abnormal coronary angiography, coronary bypass surgery and stroke) far less frequently than they would others (eg, diabetes, menopause, smoking). Therefore, the study was powered to detect differences (should any be apparent) in variables with lower prevalence between women with breast arterial calcification-positive screenings and women with breast arterial calcification-negative screenings.

Group sample sizes of 159 and 746, a total of 905 individuals, would achieve 80% power to detect a difference of 0.05 between the null hypothesis that both group proportions were 0.07 and the alternative hypothesis that the proportion in the breast arterial calcification-negative group was 0.02, using a two-sided χ2 test with continuity correction and with a significance level of 0.05.

Descriptive statistics comprised means and SDs for continuous data (eg, age). All data were checked for normality with use of a p-p graph before comparing differences between the breast arterial calcification-positive and breast arterial calcification-negative groups. Percentages were used for categorical data (participants with hypertension, diabetes, etc).

Inferential statistics included Student t test for comparing continuous data at baseline. Continuity-corrected χ2 tests were used to compare differences in categorical variables between baseline groups. This analytical test also was used to compare group differences between baseline percentages and corresponding values after 5 years of follow-up. To evaluate the contribution of variables in the manifestation of CHD, a logistic regression model was created using variables that showed significant differences with univariable statistics. A forward, conditional model was used, including variables that were P<.05 and excluding them at P≥.10. Odds ratios (ORs) and 95% CIs were generated for each variable that demonstrated a significant contribution in the model.

The age-matched group was created by sorting on participant age and then selecting the first breast arterial calcification-negative and first breast arterial calcification-positive record until the limiting factor (breast arterial calcification-negative) was exhausted. A check of balanced age was ensured by performing a paired t test of the cases and controls, which resulted in no significant difference (P=.300) between the groups. For this matched group, a McNemar's χ2 test was used to compare differences in 5-year CHD incidence.

All analyses were performed using SPSS 17.0. An a priori alpha level of 0.05 was used such that all results yielding P<.05 were deemed statistically significant.

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RESULTS

Among the 1,919 women analyzed in the original baseline data,16 1,454 (75.8%) had 5-year prospective data available for analysis. At baseline, the mean age (plus or minus SD) of this population was 56.3±12.1 years, 60.9% of whom were menopausal (72.1% had reached menopause by the end of the study), and 69.5% reported exercising at least 30 minutes per week (see Table 1).

Table 1
Table 1
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The race or ethnicity for this cohort included 1,370 (94.7%) who identified themselves (at baseline) as white, 27 (1.9%) as Hispanic, 31 (2.1%) as African American, and 19 (1.3%) who identified themselves as “other” (7 women did not provide a response). There were 19 people who answered using at least two choices, and these cases were excluded from the analysis. Of the 1,454 in this prospective arm of the study, 237 (16.3%) had breast arterial calcifications detected on mammography testing. Women with breast arterial calcification were significantly older at baseline than women without breast arterial calcification, 68.7±10.7 years compared with 54.3±11.1 years, respectively (P<.001; see Table 1).

Among the 1,454 individuals, four of the six major cardiovascular risk factors were significantly more prevalent (except smoking and family history) in the breast arterial calcification-positive population at the conclusion of the study (P≤.014, Table 2). The breast arterial calcification-positive group also had a significantly higher mean number (plus or minus SD) of CHD risk factors (0.12±0.41 compared with 0.03±0.25, P=.003).

Table 2
Table 2
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In the total population, among all eligible women, the overall prevalence of CHD in those who were breast arterial calcification-positive compared with those who were breast arterial calcification-negative, throughout the course of the 5 years of follow-up, was 20.8% compared with 5.4% (P<.001; Fig. 1). Looking more specifically at the prospective development of CHD, that is, among women who did not have CHD at baseline, women who were breast arterial calcification-positive at baseline had a significantly higher likelihood of developing CHD compared with women who were breast arterial calcification-negative at baseline (6.3% compared with 2.3%, respectively; P=.003; Fig. 2.

Fig. 1
Fig. 1
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Fig. 2
Fig. 2
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To address the possibility that these findings could be due to the higher mean age in the breast arterial calcification-positive group, several separate analyses were performed to control for age. Among an age-matched (differing by a mean of less than 1 year, P=.300) comparison group of participants who were breast arterial calcification-positive and breast arterial calcification-negative at baseline, those who were breast arterial calcification-positive had a higher likelihood of developing CHD compared with those women who were breast arterial calcification-negative at baseline (6.3% compared with 1.1%; P=.046; Fig. 3). When we evaluated the development of any CHD after 5 years, among those who were CHD-negative at baseline and controlling for age, we found that women who were breast arterial calcification-positive had a 3.5-fold increased risk for CHD (OR=3.54, 95% CI 2.28–5.50, P<.001). Further evaluation of the development of any CHD after 5 years, among those who were CHD-negative at baseline and controlling for age as well as all five of the CHD risk factors, there were three other variables that showed statistical significance. Women with hypertension had a greater than 2.8-fold increased risk for CHD (OR=2.84, 95% CI=1.84–4.37, P<.001); women with hypercholesterolemia had a 2.4-fold increased risk for CHD (OR=2.42, 95% CI=1.58–3.72, P<.001), and women with family history of CHD had a 1.7-fold increased risk for CHD (OR=1.66, 95% CI=1.06–2.60, P=.026; Fig. 4).

Fig. 3
Fig. 3
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Fig. 4
Fig. 4
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Looking separately at the development of peripheral vascular disease and arterial disease yielded additional findings. Among those who had not suffered a stroke at baseline, comparing breast arterial calcification-positive with breast arterial calcification-negative participants over the course of 5 years, 58.3% compared with 13.3% developed a stroke, respectively (P<.001). Among those who were negative for arterial disease at baseline, comparing breast arterial calcification-positive with breast arterial calcification-negative participants over the course of 5 years, 27.8% compared with 12.6% developed arterial disease, respectively (P=.056).

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DISCUSSION

The debate has been going on for years about the possible association between breast arterial calcification and CHD. Many studies,17–19,23–25 including our own,16 have shown an association, but others have argued the link is due to confounding variables associated with CHD risk factors,14,18,32,33 especially age.14,33 In other words, although it seems clear that women with breast arterial calcification have a higher prevalence of CHD, breast arterial calcification is more common with advanced age and therefore may be illustrating the well-known CHD risk factor of increasing age.

In our previous report, we controlled for age and still found that within three narrower age ranges (younger than 55 years, 55–64 years, and older than 64 years), the prevalence of CHD was greater in those with breast arterial calcification. For the younger, middle, and older groups, the prevalence of CHD in women with breast arterial calcification was 6.7%, 10.4%, and 18.9%, respectively, while the prevalence of CHD in women without breast arterial calcification was 1.1%, 3.8%, and 10.1%, respectively.28 In a separate logistic regression analysis, when controlling for the possible confounder of age, patients with breast arterial calcification still had a significantly higher prevalence of CHD.16 In a study looking prospectively at the development of coronary artery calcifications, patients with breast arterial calcification were more likely to have coronary artery calcification and breast arterial calcification was significantly associated with coronary artery calcification (OR 3.3, 95% CI: 1.7–6.0). They also found a statistically significant association between breast arterial calcification and age, similar to our previous results.19 Looking at patients with breast arterial calcification compared with those without breast arterial calcification, and whether there is a difference in the prospective development of CHD, is the most relevant type of study to answer the question of whether breast arterial calcification is not only associated with higher rates of current CHD (ie, a risk indicator), but is a marker (or risk factor) for the future development of CHD. In addition to looking at a larger sample size, our report also added CHD as an independent prospective outcome variable. These findings, therefore, add further confidence to the belief that breast arterial calcification is a risk factor for the future development of CHD.

Among those women who were CHD-negative at baseline, when we controlled for hypertension, hypercholesterolemia, diabetes mellitus, smoking, family history, and menopause, being breast arterial calcification-positive and having hypertension resulted in a higher risk for developing CHD at some point during the next 5 years. Hypertension actually posed the greatest risk, 3.2 times, followed by being breast arterial calcification-positive (2.2 times). Interestingly, none of the other four well-documented CHD risk factors played a significant role in determining whether a woman would develop CHD. When looking at the statistically significant contributors to the 5-year incidence of CHD (Fig. 4), four variables were identified (breast arterial calcification, hypertension, hypercholesterolemia, and family history of CHD). It is important to highlight that although all were significant, breast arterial calcification had the highest OR for predicting CHD after 5 years. Of note, the age of menopausal women, a continuous variable with a wide range and one that almost always is significant, was not significant. When using breast arterial calcification (and hypertension) as potential factors, the role of age is much less (if any), and certainly not a statistically significant indicator of association with CHD. These findings, given the controversy over age in the literature, are very important. When looking at the CHD risk factors over time (Table 1), the prevalence of a positive family history was not significantly different between women negative and those positive for breast arterial calcification at either time point. However, the prevalence in both breast arterial calcification-negative and –positive groups significantly increased over time, demonstrating the high rate of CHD in family members of our postmenopausal women.

When looking at the development of peripheral vascular disease and arterial disease, the prospective development of arterial disease in those who were positive for breast arterial calcification was nearly double that of women negative for breast arterial calcification. Although the finding was borderline significant (P=.056), the lower numbers, and hence power, may have influenced this. Of note, however, was the dramatic increase in peripheral vascular disease (strokes) in those who were breast arterial calcification-positive compared with breast arterial calcification-negative at baseline (58.3% compared with 13.3%, respectively, P<.001). This finding certainly warrants further investigation.

Our results suggest that even when controlling for age, patients with breast arterial calcification have a higher likelihood of developing CHD or a stroke. Until this point, the clinical significance of breast arterial calcification as detected by mammography has been in question, and therefore has not been routinely reported. Based on these findings, we suggest that breast arterial calcification should be reported consistently to help alert patients and their clinicians to the increased risks associated with this condition. Furthermore, a consistent reporting of this will allow enhanced accumulation of data for further research on this topic.

Limitations to the current study include the inability to determine the cause of death for some patients who died, although in the 28 (62.2%) for whom the cause was known, 96.4% of the cases were unrelated to CHD. Another limitation is the primarily white, non-Hispanic participant population. Although our data may not be applicable to women of other races or ethnicities, similar studies have shown comparable results among diverse populations in areas such as Brazil,26 Israel,32 and the Netherlands.19 Additionally, determination of CHD in this study was identified by patient report, which leaves open the possibility of recall bias. Fortunately, these items have clear definitions that were well known and recognized by our patients, and care was given to ensure the accuracy of the data in conjunction with our trained personnel.

Prospective research on the predictive relationship between breast arterial calcification and CHD must be continued to further clarify the significance of breast arterial calcification. Further investigations should include a diverse study sample. For now, these results suggest that the presence of breast arterial calcifications on screening mammography indicates a significantly increased risk of developing CHD. Furthermore, we suggest that breast arterial calcifications should be routinely reported on mammograms and viewed as a marker for the development of CHD. Clinicians noting the presence of breast arterial calcifications on a mammogram report, during a patient encounter, should notify patients that this may be a marker of increased risk, encourage behavior modification (diet, exercise, smoking cessation, etc), and appropriately screen patients for modifiable CHD risk factors (hypertension, diabetes, hypercholesterolemia, obesity, and the metabolic syndrome).

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© 2011 by The American College of Obstetricians and Gynecologists.

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