Abdominal aortic calcific deposits are associated with increased risk for congestive heart failure: The Framingham Heart Study

Abdominal aortic calcific deposits are associated with increased risk for congestive heart failure: The Framingham Heart Study Craig R. Walsh, MD,a,c L. Adrienne Cupples, PhD,a,b Daniel Levy, MD,a,d,f Douglas P. Kiel, MD, MPH,a,e Marian Hannan, ScD,a,e Peter W. F. Wilson, MD,a and Christopher J. O’Donnell, MD, MPHa,c,f Framingham and Boston, Mass, and Bethesda, Md

Objectives We sought to determine the association of aortic atherosclerosis, detected by calcific deposits in the abdominal aorta seen on lateral lumbar radiographs, with risk for congestive heart failure (CHF).

Background Although the association between atherosclerotic coronary heart disease (CHD) and CHF has been extensively studied, there are limited prospective data regarding the association of extracoronary atherosclerosis with CHF.

Methods Lateral lumbar radiographs were obtained in 2467 Framingham Heart Study participants (1030 males and 1437 females) free of CHF in 1968. An abdominal aortic calcium (AAC) score was calculated for each subject based on the extent of calcium in the abdominal aorta. Proportional hazards models were used to test for associations between AAC score and CHF risk.

Results There were 141 cases of CHF in men and 169 cases in women. In men, the multivariable-adjusted risk for CHF was increased for the second (hazards ratio [HR] 1.5, 95% CI 0.9-2.5) and third (HR 2.2, 95% CI 1.3-3.7) tertiles compared with the lowest tertile. Similarly, in women, the multivariable-adjusted risk for CHF was increased for the second (HR 1.8, 95% CI 1.1-2.9) and third (HR 3.2, 95% CI 2.0-5.1) tertiles compared with the lowest tertile. After further adjustment for CHD occurring prior to the onset of CHF, risk remained significantly increased for both men and women. Conclusions Atherosclerosis of the abdominal aorta is an important risk factor for CHF, independent of CHD and other risk factors. Noninvasive detection and quantification of atherosclerosis may be useful in identifying high-risk individuals likely to benefit from strategies aimed at preventing CHF. The possibility of a link between AAC and vascular compliance deserves further study. (Am Heart J 2002;144:733-9.)

Atherosclerotic coronary heart disease (CHD) is associated with increased risk for congestive heart failure (CHF) independent of other CHF risk factors.1-5 However, data are sparse on the relationship between extracoronary atherosclerosis and CHF. Detection of aortic atherosclerosis identifies subjects at increased risk for CHD.6-8 The presence and extent of aortic athero-

From the aFramingham Heart Study, Framingham, bDepartment of Epidemiology and Biostatistics, Boston University School of Public Health, Boston, cCardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston, dDepartment of Medicine, Beth Israel-Deaconess Medical Center, Harvard Medical School, Boston, e

Hebrew Rehabilitation Center for Aged Research and Training Institute, Harvard Medical School, Division on Aging, Boston, Mass, and the fNational Heart, Lung, and Blood Institute, National Institute of Health, Bethesda, Md. Supported by the National Heart, Lung, and Blood Institute Framingham Heart Study, National Institutes of Health (NIH/NHLBI contract N01-HC-38038). Submitted August 30, 2001; accepted February 27, 2002. Reprint requests: Christopher J. O’Donnell, MD, MPH, Framingham Heart Study, 73 Mount Wayte Ave, Suite #2, Framingham, MA 01702. E-mail: [email protected] © 2002, Mosby, Inc. All rights reserved. 0002-8703/2002/$35.00 ⫹ 0 4/1/124404 doi:10.1067/mhj.2002.124404

sclerosis may therefore predict the risk of CHF consequent to ischemic heart disease. In addition, atherosclerosis of the aorta is associated with reduced aortic compliance,9,10 leading to a greater hydraulic load on the left ventricle.11 Increased pulse pressure and other measures of decreased vascular compliance have been associated with left ventricular hypertrophy12,13 and CHF.13-15 Atherosclerosis of the aorta may therefore be associated with CHF independent of CHD, because of reduced aortic compliance. Atherosclerosis develops in the aorta before its appearance in the femoral, carotid, or coronary arteries.16 Calcification of the thoracic aorta, detected by chest radiography, identifies individuals at increased risk for cardiovascular disease.8 Calcification of the distal abdominal aorta, which can be detected and quantified by lateral lumbar radiography,17 is correlated with atherosclerotic plaque at autopsy18 and is predictive of cardiovascular events.6,7 In this study we sought to determine the risk of CHF according to the severity of abdominal aortic calcific

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Table I. Criteria for CHF Major criteria Paroxysmal nocturnal dyspnea Neck-vein distention Rales Radiographic cardiomegaly (increasing heart size on chest x-ray) Acute pulmonary edema S3 gallop Increased central venous pressure (⬎16 cm water at right atrium) Hepatojugular reflux Pulmonary edema, visceral congestion, or cardiomegaly at autopsy Minor criteria Bilateral ankle edema Nocturnal cough Dyspnea on ordinary exertion Hepatomegaly Pleural effusion Decrease in vital capacity by one third from maximum recorded Tachycardia (rate ⱖ120/min) A diagnosis of CHF was made if at least 2 major criteria, or 1 major and 2 minor criteria were met.

deposits seen on lateral lumbar radiographs among the original subjects of the Framingham Heart Study who were followed for 22 years. We further sought to examine whether these associations are independent of other important risk factors for CHF.

Methods Study sample The Framingham Heart Study is a prospective epidemiologic cohort study that was established in 1948 to evaluate potential risk factors for CHD. The original cohort consisted of 5209 residents of Framingham, Mass, aged 28 to 62 years who have undergone follow-up evaluations every 2 years. The study design and entry criteria have been detailed elsewhere.19 As part of an osteoporosis survey, subjects had lateral lumbar radiographs performed at biennial examination 10 (1966-1970). Subjects with prevalent CHF or valvular heart disease at the baseline examination were excluded from this analysis. The present study followed the remaining 2467 subjects for the development of CHF over 22 years of follow-up.

Baseline measurements and definitions Medical histories were obtained and physical examinations were performed for each participant at every clinic visit. Systolic and diastolic blood pressures were measured twice in the left arm of each participant, and the average of the 2 readings was used for analyses. The diagnosis of hypertension was made on the basis of a systolic blood pressure of ⱖ140 mm Hg, a diastolic blood pressure of ⱖ90 mm Hg, or the current use of antihypertensive drugs.20 Blood tests performed at the time of the examination (or the examination immediately before or after the index examination) included measurement of total cholesterol and blood glucose. Highdensity lipoprotein (HDL) cholesterol was measured in 1837

subjects. Diabetes was defined on the basis of a nonfasting blood glucose level of ⱖ11.1 mmol/L (ⱖ200 mg/dL), a fasting blood glucose level of ⱖ7.8 mmol/L (ⱖ140 mg/dL), or the use of insulin or an oral hypoglycemic agent.21 Body mass index was calculated as the weight in kilograms divided by the square of the height in meters. Subjects who smoked cigarettes regularly within 1 year of the index examination were considered to be current smokers. The number of cigarettes smoked per day was recorded for current smokers. Electrocardiographic left ventricular hypertrophy was diagnosed if a subject had voltage criteria for left ventricular hypertrophy accompanied by lateral repolarization changes.22 Valvular heart disease was defined by auscultation criteria as any diastolic murmur or a ⬎2/6 systolic murmur at the Framingham Heart Study clinic examination. Diagnostic criteria for CHD, including angina pectoris, myocardial infarction, coronary insufficiency, and sudden, unexpected death, have been published.19

Measurement of abdominal aortic calcifications As previously described, the presence and extent of abdominal aortic calcific deposits on lateral lumbar spine radiography were coded.17 An abdominal aortic calcium (AAC) score was developed to grade the severity of calcification in the first through fourth lumbar regions. Aortic calcific deposits were assessed at each vertebral segment and were regarded as present if densities were visible in an area parallel to the lumbar spine and anterior to the lower part of the spine. Densities overlapping vertebrae were considered to represent aortic calcific deposits only if they extended from or formed a clear pattern with those of the lower part of the aorta. Calcific deposits were graded on a scale of 0 to 3 at each lumbar vertebral segment. A score of 0 denoted no aortic calcific deposits; 1, small scattered calcific deposits filling less than one third of the longitudinal wall of the aorta; 2, one third or more, but less than two thirds, of the longitudinal wall of the aorta was calcified; and 3, two thirds or more of the longitudinal wall of the aorta was calcified. A separate score was determined anteriorly and posteriorly, and the grades were summed across the 4 vertebrae, resulting in an AAC score that could range from 0 to 24 points. As previously published, correlation was 0.93 for interrater agreement and 0.98 for intrarater agreement.17

Outcome measurements The primary outcome of interest was incident CHF. Subjects were asked about symptoms and examined for signs of CHF at each biennial examination. Information about CHF was obtained with the aid of hospitalization records and by communication with personal physicians. All suspected new events were reviewed by a panel of 3 experienced investigators, who evaluated all pertinent medical and hospital records and pathology reports. Criteria for the diagnosis of CHF are summarized in Table I. A diagnosis of CHF was made if at least 2 major criteria, or 1 major and 2 minor criteria, were present. Minor criteria were acceptable only if they could not be attributed to another medical condition (eg, pulmonary hypertension, chronic lung disease, cirrhosis, ascites, or nephrotic syndrome).1 The criteria used to identify subjects with CHF in the Framingham Heart Study compare

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Table II. Baseline characteristics of the study males and females (1966-1970) Variable Age (y) Hypertension (%) SBP (mmHg) DBP (mmHg) Pulse pressure (mmHg) Hypertension treatment (%) CHD (%) Diabetes (%) Total cholesterol (mmol/L) [mg/dL] HDL cholesterol (mmol/L)* [mg/dL] Current smokers (%) Left ventricular hypertrophy (%) Body mass index (kg/m2)

Males (n ⴝ 1030)

Females (n ⴝ 1437)

60.4 ⫾ 7.8 24.5 138.6 ⫾ 21.6 81.3 ⫾ 11.3 57.2 ⫾ 16.8 11.4 14.3 5.5 5.7 ⫾ 1.0 [221.3 ⫾ 39.9] 1.2 ⫾ 0.3 [45.0 ⫾ 12.9] 36.8 2.4 26.2 ⫾ 3.4

60.8 ⫾ 8.0 29.0 140.4 ⫾ 24.5 80.1 ⫾ 11.5 60.3 ⫾ 19.2 16.7 7.4 4.5 6.3 ⫾ 1.1 [243.3 ⫾ 42.0] 1.5 ⫾ 0.4 [57.3 ⫾ 15.7] 32.3 1.9 25.3 ⫾ 4.1

Values presented as mean ⫾ SD unless otherwise noted. SBP, Systolic blood pressure; DBP, diastolic blood pressure; HDL, high-density lipoprotein. *HDL cholesterol measured in 777 men and 1060 women.

favorably with other clinically based criteria in identifying individuals with CHF23 and left ventricular systolic dysfunction.24

Statistical analysis Separate analyses were performed for men and women. Because approximately one third of subjects had an AAC score of 0, subjects were categorized according to AAC score tertile. Baseline risk factors were computed for each tertile. Pearson’s correlation coefficients were computed to determine the correlation of AAC score with systolic blood pressure and pulse pressure. Cox proportional hazards models25 were used to calculate age- and multivariable-adjusted hazards ratios (HRs) for CHF. The following variables were included in the multivariable-adjusted model: age, systolic blood pressure, hypertension treatment, diabetes, total cholesterol, smoking, electrocardiographic left ventricular hypertrophy, and body mass index. Subjects in the lowest AAC score tertile served as the reference group. To further characterize the effect of CHD on the association between AAC score and CHF risk, a second multivariable-adjusted model was constructed, adjusting for both prevalent CHD and intercurrent CHD as a time-dependent variable. As a secondary analysis, age- and multivariable-adjusted HRs for CHF were recalculated after exclusion of subjects with prevalent CHD at the time of the index examination. For all models, the proportional hazards assumption was tested and found to be appropriate. All statistical analyses were performed with SAS statistical software (SAS Institute Inc, Cary, NC).

Results Baseline characteristics The clinical characteristics of our study population are summarized in Table II. The mean age was 60.4

Figure 1

Age-adjusted incidence of congestive heart failure in 1030 men during 22 years of follow-up according to tertile of AAC score measured from lateral lumbar radiographs.

years in men and 60.8 years in women. In men, 25% were hypertensive, and 14% had CHD at the baseline examination. In women, 29% were hypertensive and 7% had CHD at baseline. Few subjects had diabetes or electrocardiographic left ventricular hypertrophy. In unadjusted analysis, AAC score was modestly correlated with systolic blood pressure (r ⫽ 0.3, P ⫽ .0001) and with pulse pressure (r ⫽ 0.3, P ⫽ .0001).

Abdominal aortic calcific deposits and risk for CHF Age-adjusted incidences of CHF according to AAC tertile for men and women are shown in Figures 1 and 2, respectively. In age-adjusted models, there was a stepwise increase in risk for CHF with increasing AAC in both men and women (Table III). These associations persisted after adjusting for multiple predictors of CHF (Table III, multivariable model 1). The association between CHF risk and AAC was modestly attenuated by further adjustment for CHD at baseline or CHD that had occurred before the development of CHF (Table III, multivariable model 2). However, even after adjustment for previous CHD, the hazard ratio for CHF associated with the third tertile of AAC was 1.9 (95% CI 1.1-3.2) for men and 2.5 (95% CI 1.6-4.0) for women, compared with the lowest tertile of AAC. HDL cholesterol measures were not available in 630 subjects at the baseline examination and were not included in the multivariable-adjusted models for the primary analysis. In a secondary analysis, we examined whether HDL cholesterol affected the observed association between AAC and CHF risk. We repeated the analysis in the 777 men and 1060 women who had

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Figure 2

3 (HR 2.2, 95% CI 1.3-3.8) compared with women in tertile 1 after adjustment for HDL cholesterol in addition to the variables included in multivariable model 2.

Discussion In our study, abdominal aortic calcific deposits on lateral lumbar radiographs, a measure of aortic atherosclerosis, were associated with increased risk for CHF, even after multivariable adjustment for CHF risk factors, including CHD, hypertension, diabetes, and electrocardiographic left ventricular hypertrophy. The presence of prevalent or intercurrent CHD did not explain the primary result.

Atherosclerosis and CHF Age-adjusted incidence of congestive heart failure in 1437 women during 22 years of follow-up according to tertile of AAC score measured from lateral lumbar radiographs.

HDL cholesterol measured at baseline, after including HDL cholesterol in the multivariable-adjusted models. Risk for CHF was increased in men in tertile 2 (HR 2.2, 95% CI 1.3-4.0) and tertile 3 (HR 2.9, 95% CI 1.65.5) compared with men in tertile 1 after adjustment for HDL cholesterol in addition to the variables included in multivariable model 2. Similarly, risk for CHF was increased in women in tertile 2 (HR 1.8, 95% CI 1.0-3.1) and tertile 3 (HR 3.0, 95% CI 1.7-5.2) compared with women in tertile 1 after adjustment for HDL cholesterol in addition to the variables included in multivariable model 2.

Abdominal aortic calcific deposits and risk for CHF in subjects free of CHD In our study sample, 883 men and 1331 women were free of CHD at the baseline examination. In ageadjusted models, there was a stepwise increase in risk for CHF with increasing AAC in both men and women (Table IV). These associations persisted after adjusting for multiple predictors of CHF (Table IV, multivariable model 1), including interim CHD occurring before the development of CHF (Table IV, multivariable model 2). Of subjects in our study sample who were free of CHD at the baseline examination, 677 men and 992 women had HDL cholesterol measured. Risk for CHF was increased in men in tertile 2 (HR 1.8, 95% CI 0.93.7) and tertile 3 (HR 2.3, 95% CI 1.2-4.5) compared with men in tertile 1 after adjustment for HDL cholesterol in addition to the variables included in multivariable model 2. Similarly, risk for CHF was increased in women in tertile 2 (HR 1.7, 95% CI 1.0-3.1) and tertile

The association between CHD and CHF is well established.26 However, most population-based studies of incident CHF1-5 have used clinically based criteria to identify subjects with CHD and may underestimate the effect of atherosclerosis on CHF risk. Using clinical criteria to diagnose CHD, most individuals with coronary atherosclerosis or extensive noncoronary atherosclerosis who have not had angina or a clinically recognized myocardial infarction will not be classified as having CHD. Our study demonstrates that individuals with extensive atherosclerosis of the abdominal aorta are at an increased risk for CHF independent of angina or clinically apparent myocardial infarction. Similarly, Gottdiener et al,5 in a report in 5888 participants in the Cardiovascular Health Study (average follow-up 5.5 years), found that carotid artery intimal-medial thickness was associated with risk for CHF independent of clinically recognized CHD at the baseline examinations. Our study extends these prior observations to show that subclinical atherosclerosis in the abdominal aorta identifies individuals at an increased risk for CHF independent of clinically apparent CHD. Myocardial infarction causes CHF through loss of contracting myocytes in the area of infarcted myocardium followed by progressive remodeling of the remaining viable myocardium.27 In our study, adjusting for antecedent CHD as well as interim CHD attenuated the association between aortic atherosclerosis and CHF risk, suggesting that the association is in part due to an increased risk of myocardial infarction among subjects with more extensive aortic atherosclerosis. However, after excluding subjects with prevalent CHD at the baseline examination and adjusting for intercurrent CHD events, AAC remained significantly associated with risk of CHF, suggesting that other mechanisms are responsible for the observed association. In this regard, severe coronary atherosclerosis can cause myocardial dysfunction through chronic28 or repeated29 episodes of ischemia in the absence of acute myocardial infarction. Atherosclerosis of the

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Table III. Risk for CHF associated with tertiles of AAC index in 1030 men and 1437 women during 22 years of follow up Age-adjusted model AAC tertile Men 1 2 3 Women 1 2 3

Multivariable-adjusted Model 1*

Multivariable-adjusted Model 2†

Incident CHF

At risk

Hazard ratio

95% CI

Hazard ratio

95% CI

Hazard ratio

95% CI

28 52 61

336 371 323

1.0 1.7 2.2

referent 1.0-2.6 1.4-3.6

1.0 1.5 2.2

referent 0.9-2.5 1.3-3.7

1.0 1.5 1.9

referent 0.9-2.4 1.1-3.2

32 46 91

601 397 439

1.0 2.2 3.8

referent 1.4-3.4 2.4-6.0

1.0 1.8 3.2

referent 1.1-2.9 2.0-5.1

1.0 1.7 2.5

referent 1.1-2.7 1.6-4.0

*Model 1: Adjusted for age, systolic blood pressure, hypertension treatment, diabetes, total cholesterol, smoking, electrocardiographic left ventricular hypertrophy, and body mass index. †Model 2: Adjusted for variables included in model 1 plus prevalent CHD and incident CHD as a time-dependent covariate.

Table IV. Risk for CHF associated with tertiles of AAC index in 883 men and 1331 women free of CHD at the baseline examination during 22 years of follow up Age-adjusted model AAC tertile Men 1 2 3 Women 1 2 3

Multivariable-adjusted Model 1*

Multivariable-adjusted Model 2†

Incident CHF

At risk

Hazard ratio

95% CI

Hazard ratio

95% CI

Hazard ratio

95% CI

21 36 39

308 313 262

1.0 1.3 2.5

referent 0.7-2.5 1.4-4.3

1.0 1.2 2.0

referent 0.7-2.3 1.2-3.6

1.0 1.2 1.8

referent 0.6-2.1 1.0-3.1

30 41 74

582 370 379

1.0 2.1 3.4

referent 1.3-3.6 2.1-5.4

1.0 1.7 2.7

referent 1.0-2.9 1.7-4.5

1.0 1.7 2.2

referent 1.0-2.8 1.3-3.5

*Model 1: Adjusted for age, systolic blood pressure, hypertension treatment, diabetes, total cholesterol, smoking, electrocardiographic left ventricular hypertrophy, and body mass index. †Model 2: Adjusted for variables included in model 1 plus incident CHD as a time-dependent covariate.

aorta correlates with coronary artery atherosclerosis.30 The increased risk of CHF in subjects with extensive AAC that we observed in our study may in part be attributable to coexisting coronary atherosclerosis in the absence of angina or recognized myocardial infarction. However, there remains a substantially increased risk for CHF that is not explained by traditional risk factors or clinically apparent CHD.

Atherosclerosis of the aorta and vascular compliance Studies of nonhuman primates fed atherogenic diets have reported that aortic compliance decreases with atheroma formation and increases with atheroma regression.31,32 Less is known about the relationship between atheroma formation and aortic compliance in humans. Using lateral lumbar radiographs, Witteman et al10 reported that calcific deposits in the abdominal

aorta are positively associated with pulse pressure, a crude measure of aortic vascular compliance. Consistent with this, we found a modest but statistically significant positive association between AAC score and pulse pressure in our study sample. Reduced aortic compliance increases the hydraulic load on the left ventricle, predisposing to left ventricular hypertrophy12,13 and CHF.13-15 Thus, the presence of calcific deposits in the abdominal aorta may identify individuals at risk for CHF due to decreased aortic compliance. A number of direct measures of aortic stiffness are now available for use, including pulse wave velocity by ultrasound33 and direct measure of phasic change by magnetic resonance imaging.34 Additional studies that used direct measures of aortic stiffness are needed to better clarify the interrelation of atherosclerosis, vascular compliance, and risk for CHF.

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Potential limitations In our study, we did not have pathologic data to confirm that aortic calcific deposits seen on plain radiographs were within atherosclerotic plaques. However, previous necropsy studies have reported that calcific deposits in the aorta detected by conventional radiographic techniques similar to those used in our study were due to calcium accumulation within the tunica intima at the site of complex atherosclerotic plaques.18 Mo ¨ nckeburg’s medial calcific sclerosis, which may also result in arterial calcium deposits detectable by conventional radiographic techniques, affects small and medium-sized muscular arteries and characteristically spares large elastic arteries such as the aorta.16 Although calcium accumulates within the tunica media of the aorta with advancing age, the total calcium content of the media typically is not sufficient to be detectable with conventional radiographic techniques.35 Thus, the available evidence suggests that aortic calcific deposits seen on plain radiographs represent atherosclerotic plaque in the aorta. Vascular calcific deposits seen on plain radiographs are more likely to represent advanced atherosclerotic plaque and may not detect early atherosclerotic lesions.21 Newer technologies provide more sensitive, quantitative measures of atherosclerosis and may better approximate the association between aortic atherosclerosis and CHF. Also, during the study interval, subjects were largely untreated for cardiovascular risk factors. Although this provides a unique insight into the longterm natural history of subclinical atherosclerosis, results may differ in the context of modern medical practice. Left ventricular function was not routinely measured on our study sample. Further study is warranted to determine the association between AAC and CHF due to systolic and diastolic dysfunction, respectively. Finally, the Framingham population is largely white and our findings may have limited generalizability to other populations.

Implications Our study has potential implications for the prevention of CHF. Individuals who have extensive aortic atherosclerosis are at increased risk for CHF independent of CHD. The elevated risks for CHF are largely independent of known CHF risk factors such as hypertension, diabetes mellitus, valvular heart disease, and electrocardiographic left ventricular hypertrophy. Noninvasive detection and quantification of atherosclerosis may identify individuals most likely to benefit from preventive therapies. Although our simple, “lowtechnology” method for detection of aortic atherosclerosis is highly reproducible,17 other noninvasive tests, such as abdominal ultrasound,36,37 are able to indirectly detect vascular calcifications. In addition, newer

high-resolution technologies, such as magnetic resonance imaging38 and computed tomography,39 are more sensitive and accurate for the detection and quantification of atherosclerosis and may better characterize CHF risk. Angiotensin-converting enzyme inhibitors have been shown to prevent CHF in persons with asymptomatic left ventricular dysfunction40 and after myocardial infarction.41 The recently published Heart Outcomes Prevention Evaluation (HOPE) trial,42 as well as retrospective analyses of the Studies of Left Ventricular Dysfunction (SOLVD)43 and Survival And Ventricular Enlargement (SAVE)44 trials suggest that the protective effects of angiotensin-converting enzyme inhibitors against CHF may be in part mediated through a reduction in coronary ischemic events. Among individuals with normal left ventricular systolic function who have CHD or who are at high risk for the development of CHD, the angiotensin-converting enzyme inhibitor ramipril decreases risk for CHF.42 Further studies are warranted to determine whether noninvasive detection and quantification of subclinical atherosclerosis may be used to identify asymptomatic individuals with extensive atherosclerosis who may benefit from treatment with angiotensin-converting enzyme inhibitors for the prevention of CHF.

Conclusions Atherosclerosis of the abdominal aorta, as detected by abdominal aortic calcification, is an important risk factor for CHF, independent of clinically recognized CHD and other major CHF risk factors. Noninvasive detection and quantification of atherosclerosis may be useful in identifying subjects likely to benefit from strategies aimed at preventing CHF. The possibility of a link between AAC and vascular compliance deserves further study.

References 1. McKee PA, Castelli WP, McNamara PM, et al. The natural history of congestive heart failure: the Framingham study. N Engl J Med 1971;285:1441-6. 2. Eriksson H, Svardsudd K, Larsson B, et al. Risk factors for heart failure in the general population: the study of men born in 1913. Eur Heart J 1989;10:647-56. 3. Remes J, Reunanen A, Aromaa A, et al. Incidence of heart failure in eastern Finland: a population-based surveillance study. Eur Heart J 1992;13:588-93. 4. Cowie MR, Wood DA, Coats AJ, et al. Incidence and aetiology of heart failure: a population-based study. Eur Heart J 1999;20: 421-8. 5. Gottdiener JS, Arnold AM, Aurigemma GP, et al. Predictors of congestive heart failure in the elderly: the Cardiovascular Health Study. J Am Coll Cardiol 2000;35:1628-37. 6. Wilson PW, Kauppila L, Kiel D, et al. Lumbar aortic calcification is an important predictor of vascular morbidity and mortality. Circulation 2001;103:1529-34.

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7. Witteman JC, Kok FJ, van Saase JL, et al. Aortic calcification as a predictor of cardiovascular mortality. Lancet 1986;2:1120-2. 8. Iribarren C, Sidney S, Sternfeld B, et al. Calcification of the aortic arch: risk factors and association with coronary heart disease, stroke, and peripheral vascular disease. JAMA 2000;283:2810-5. 9. Blankenhorn DH, Kramsch DM. Reversal of atherosis and sclerosis: the two components of atherosclerosis. Circulation 1989;79:1-7. 10. Witteman JC, Grobbee DE, Valkenburg HA, et al. J-shaped relation between change in diastolic blood pressure and progression of aortic atherosclerosis. Lancet 1994;343:504-7. 11. Nichols WW, O’Rourke MF. Input impedance as vascular load. McDonald’s blood flow in arteries. Theoretical, experimental, and clinical principles. 4th ed. New York: Oxford University Press; 1998. p. 284-92. 12. Saba PS, Roman MJ, Pini R, et al. Relation of arterial pressure waveform to left ventricular and carotid anatomy in normotensive subjects. J Am Coll Cardiol 1993;22:1873-80. 13. Rajkumar C, Cameron JD, Christophidis N, et al. Reduced systemic arterial compliance is associated with left ventricular hypertrophy and diastolic dysfunction in older people. J Am Geriatrics Soc 1997;45:803-8. 14. Chae CU, Pfeffer MA, Glynn RJ, et al. Increased pulse pressure and risk of heart failure in the elderly. JAMA 1999;281:634-43. 15. Hundley WG, Kitzman DW, Morgan TM, et al. Cardiac cycledependent changes in aortic area and distensibility are reduced in older patients with isolated diastolic heart failure and correlate with exercise intolerance. J Am Coll Cardiol 2001;38:796-802. 16. Pathobiological Determinants of Atherosclerosis in Youth (PDAY) Research Group. Natural history of aortic and coronary atherosclerotic lesions in youth. Findings from the PDAY Study. Arterioscler Thromb 1993;13:1291-8. 17. Kauppila LI, Polak JF, Cupples LA, et al. New indices to classify location, severity and progression of calcific lesions in the abdominal aorta: a 25-year follow-up study. Atherosclerosis 1997;132: 245-50. 18. Hyman JB, Epstein FH. A study of the correlation between roentgenographic and post-mortem calcification of the aorta. Am Heart J 1954;47:540-3. 19. Gordon T, Moore FE, Shurtleff D, et al. Some methodological problems in the long-term study of cardiovascular disease: observations on the Framingham Study. J Chronic Dis 1959;10:186206. 20. The sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med 1997;157:2413-46. 21. National Diabetes Data Group. Classification and diagnosis of diabetes mellitus and other categories of glucose intolerance. Diabetes 1979;28:1039-57. 22. Kannel WB, Gordon T, Offutt D. Left ventricular hypertrophy by electrocardiogram: prevalence, incidence, and mortality in the Framingham study. Ann Intern Med 1969;71:89-105. 23. Mosterd A, Deckers JW, Hoes AW, et al. Classification of heart failure in population based research: an assessment of six heart failure scores. Eur J Epidemiol 1997;13:491-502. 24. Marantz PR, Tobin JN, Wassertheil-Smoller S, et al. The relationship between left ventricular systolic function and congestive heart failure diagnosed by clinical criteria. Circulation 1988;77:607-12. 25. Cox DR. Regression models and life tables. J R Stat Soc B 1972; 34:187-220. 26. Gheorghiade M, Bonow RO. Chronic heart failure in the United

Walsh et al 739

27.

28. 29.

30.

31.

32.

33.

34.

35. 36.

37.

38. 39.

40.

41.

42.

43.

44.

States: a manifestation of coronary artery disease. Circulation 1998;97:282-9. Pfeffer MA, Braunwald E. Ventricular remodeling after myocardial infarction: experimental observations and clinical implications. Circulation 1990;81:1161-72. Braunwald E, Kloner RA. The stunned myocardium: prolonged, postischemic ventricular dysfunction. Circulation 1982;66:1146-9. Braunwald E, Rutherford JD. Reversible ischemic left ventricular dysfunction: evidence for the “hibernating myocardium.” J Am Coll Cardiol 1986;8:1467-70. Khoury Z, Schwartz R, Gottlieb S, et al. Relation of coronary artery disease to atherosclerotic disease in the aorta, carotid, and femoral arteries evaluated by ultrasound. Am J Cardiol 1997;80: 1429-33. Farrar DJ, Bond MG, Riley WA, et al. Anatomic correlates of aortic pulse wave velocity and carotid artery elasticity during atherosclerosis progression and regression in monkeys. Circulation 1991;83:1754-63. Wright JS, Cruickshank JK, Kontis S, et al. Aortic compliance measured by non-invasive Doppler ultrasound: description of a method and its reproducibility. Clin Sci 1990;78:463-8. Mohiaddin RH, Underwood SR, Bogren HG, et al. Regional aortic compliance studied by magnetic resonance imaging: the effects of age, training, and coronary artery disease. Br Heart J 1989;62:90-6. Shankar R, Bond MG. Correlation of noninvasive arterial compliance with anatomic pathology of atherosclerotic nonhuman primates. Atherosclerosis 1990;85:37-46. Sherebrin MH, Kim HL, Roach MR. Calcium mass in human aortas from autopsy. Physiol Meas 1994;15:281-9. Bridal SL, Fornes P, Bruneval P, et al. Correlation of ultrasonic attenuation (30 to 50 MHz) and constituents of atherosclerotic plaque. Ultrasound Med Biol 1997;23:691-703. Jarvisalo MJ, Jartti L, Nanto-Salonen K, et al. Increased aortic intima-media thickness: a marker of preclinical atherosclerosis in high-risk children. Circulation 2001;104:2943-7. Fayad ZA, Fuster V. Characterization of atherosclerotic plaques by magnetic resonance imaging. Ann N Y Acad Sci 2000;902:173-86. Takasu J, Takanashi K, Naito S, et al. Evaluation of morphological changes of the atherosclerotic aorta by enhanced computed tomography. Atherosclerosis 1992;97:107-21. The Studies of Left Ventricular Dysfunction Investigators. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. The SOLVD Investigators. N Engl J Med 1992;327:685-91. Kober L, Torp-Pedersen C, Carlsen JE, et al. A clinical trial of the angiotensin-converting-enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction. Trandolapril Cardiac Evaluation (TRACE) Study Group. N Engl J Med 1995;333:1670-6. Yusuf S, Sleight P, Pogue J, et al. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in highrisk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000;342:145-53. Yusuf S, Pepine CJ, Garces C, et al. Effect of enalapril on myocardial infarction and unstable angina in patients with low ejection fractions. Lancet 1992;340:1173-8. Pfeffer MA, Braunwald E, Moye LA, et al. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction: results of the Survival and Ventricular Enlargement Trial. The SAVE Investigators. N Engl J Med 1992; 327:669-77.