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. Author manuscript; available in PMC: 2012 Jan 1.
Published in final edited form as: Vasc Med. 2011 Jun 27;16(4):253–259. doi: 10.1177/1358863X11408640

Relationship Between Central and Peripheral Atherosclerosis and Left Ventricular Dysfunction in a Community Population

Connie W Tsao 1, Philimon Gona 2,3, Carol Salton 1, Joanne M Murabito 2,3, Noriko Oyama 1,5, Peter G Danias 1, Christopher J O’Donnell 3,4, Warren J Manning 1, Susan B Yeon 1
PMCID: PMC3249244  NIHMSID: NIHMS325487  PMID: 21708875

Abstract

We aimed to determine the relationships between resting left ventricular (LV) wall motion abnormalities (WMAs), aortic plaque, and PAD in a community cohort. 1726 Framingham Heart Study Offspring Cohort participants (806 males, 65±9 years) underwent cardiovascular magnetic resonance with quantification of aortic plaque volume and assessment of regional LV systolic function. Claudication, lower extremity revascularization, and ankle-brachial index (ABI) were recorded at Examination 7. WMAs were associated with greater aortic plaque burden, decreased ABI, and claudication in age- and sex-adjusted analyses (all p<0.001), which were not significant after adjustment for cardiovascular risk factors. In age- and sex-adjusted analyses, both the presence (p<0.001) and volume of aortic plaque were associated with decreased ABI (p<0.001). After multivariable adjustment, ABI≤0.9 or prior revascularization was associated with a three-fold odds of aortic plaque (p=0.0083). Plaque volume significantly increased with decreasing ABI in multivariable-adjusted analyses (p<0.0001). In this free-living population, associations of WMAs with aortic plaque burden and clinical measures of PAD were attenuated after adjustment for coronary heart disease risk factors. Aortic plaque volume and ABI remained strongly negatively correlated after multivariable adjustment. Our findings suggest that the association between coronary heart disease and non-coronary atherosclerosis is explained by cardiovascular risk factors. Aortic atherosclerosis and PAD remain strongly associated after multivariable adjustment suggesting shared mechanisms beyond those captured by traditional risk factors.

Keywords: Aortic atherosclerosis, peripheral arterial disease, left ventricular wall motion abnormality, epidemiology, MRI

Central and peripheral arterial disease (PAD) are manifestations of cardiovascular disease (CVD) that carry significant morbidity and mortality. In prospective, population-based studies, the presence and extent of atherosclerotic plaques in the carotid and femoral arteries are associated with increased CVD death.1,2 Decreased ankle-brachial index (ABI) is associated with increased risk of congestive heart failure (CHF), coronary heart disease (CHD), and CVD death,3,4 and confers increased morbidity and mortality for each category of Framingham Risk score (FRS).5 CVD risk increases with greater extent of atherosclerosis across multiple vascular territories.6

Myocardial ischemia and infarction resulting from CHD is a major cause of resting left ventricular (LV) wall motion abnormalities (WMAs). Echocardiographic resting WMAs correlate with significant coronary stenoses by cardiac catheterization.7 In participants with known CHD and LV dysfunction, the presence and severity of resting WMAs are associated with increased morbidity and mortality.8,9 In subjects without overt CVD, WMAs may be a marker of silent CHD.10

Cardiovascular magnetic resonance (CMR) facilitates both qualitative and quantitative measures of LV systolic function, as well as aortic plaque burden. While the extent of polyvascular atherosclerotic disease has been reported,6 there are few studies that examine the inter-relatedness of WMAs, aortic atherosclerosis, and PAD in an unselected population, particularly including subjects without prevalent CVD. As atherosclerosis has a prolonged subclinical course and correlates with future adverse CVD events,3,4 early intervention may prevent the development of overt CVD or recurrent events, provided that similar mechanisms produce atherosclerosis in different vascular beds. We hypothesized that measures of aortic and peripheral atherosclerosis would be associated both with WMAs and with each other in a free-living population.

METHODS

Participants

Study participants included a subset of participants attending Examination 7 (1998-2001) of the Framingham Heart Study (FHS) Offspring Cohort, which has been described previously.11 At evaluation every 3-4 years beginning with Examination 1 (1971-1975), participants underwent routine medical history and physical, anthropometry, and assessment of CVD risk factors. Participants were excluded from the CMR substudy if they were not in sinus rhythm, had a contraindication to CMR (e.g., pacemaker), or did not live in a state contiguous with Massachusetts. CMR scanning (2002-2006) was incomplete in 32 participants (claustrophobia, n=13; scanner dysfunction, n=7; metallic devices, n=10; miscellaneous, n=2). A total of 1726 participants (65±9 years, 806 Men) completed CMR with analyzable images. Ankle-brachial index (ABI) data were available in 1671 of these participants. The study was approved by the institutional review boards of both the Boston University Medical Center and the Beth Israel Deaconess Medical Center. All participants provided written informed consent.

CMR Imaging

Supine CMR imaging was performed using a 1.5T CMR scanner (Gyroscan NT, Philips Medical Systems, Best, The Netherlands) with a 5-element commercial cardiac array coil for radiofrequency signal reception. Following localizing scans to determine the position and orientation of the heart within the thorax, end-expiratory breath-hold, ECG-gated cine steady state free precession images were acquired in 2-chamber, 4-chamber, and contiguous short axis orientations (temporal resolution 39 ms, repetition time = R-R interval, echo time 9 ms, flip angle 30 degrees, field of view 400 mm, matrix size 208×256, slice thickness 10 mm, gap=0).

Aortic plaque imaging included 36 transverse slices from the aortic arch to the aortoiliac bifurcation using a free-breathing, ECG-gated, fat-suppressed, black blood T2-weighted turbo spin-echo sequence12 with 5-mm slice thickness and in-plane spatial resolution of 1.03 × 0.64 mm (10-mm and 5-mm slice gaps for thoracic and abdominal aorta, respectively).

Image Analysis of LV function and Aortic Plaque

CMR image analysis was performed using dedicated software (EasyVision 5.1, Philips Medical Systems, Best, The Netherlands) by an observer (C.S.) blinded to all clinical data. LV wall motion was analyzed according to a 17-segment model.13 WMAs noted by the observer were confirmed by two additional reviewers blinded to all clinical data (C.T., S.Y). Global and regional wall motion score was computed using a 5-point scale (1=normal, 2= hypokinetic, 3=akinetic, 4=dyskinetic, 5=aneurysm), with the normal sum of all segments scoring 17. Wall motion score index (WMSI) was calculated as the total wall motion score divided by number of segments, with a WMSI ≥19/17 (WMSI>1.12, WMA) considered abnormal (≥2 contiguous hypokinetic segments, and/or one akinetic or dyskinetic segment).10 Quantitative measures of LV systolic function and mass (LVM) were obtained by manually tracing epicardial and endocardial LV borders at end-diastole and end-systole, as previously described.11 LV end-diastolic volume (EDV) and end-systolic volume (ESV) were computed using the summation of discs method. LV ejection fraction (LVEF) was computed by (EDV-ESV)/EDV. LVM was determined by summing myocardial volume and multiplying by myocardial density (1.05 g/ml). LVM was indexed to body surface area (BSA). LVM index (LVMI), relative wall thickness (RWT), LVM/LVEDV, and LVEF were tabulated.

CMR images were analyzed with commercial software (MASS v 6.1, QT-MEDIS) for descending thoracic and abdominal aortic atherosclerotic plaque by a single expert reviewer (N.O.) blinded to all clinical data.12 Images analyzed were perpendicular to the aorta with >50% of the inner circumference of the aortic wall visualized. Atherosclerotic plaque was defined as luminal protrusions of ≥1 mm in radial thickness12 that were visually distinguished from the minimal residual blood signal of each plaque. By visually tracing the plaque border, the cross-sectional area of plaque was measured, and total plaque volume was calculated. Inter- and intra-reader replicate measurements were made to determine reproducibility.12

Clinical Variables and Assessment of PAD

Participants underwent routine physical examination, anthropometry, and laboratory assessment of CVD risk factors at Examination 7 (1998-2001). Resting systolic (SBP) and diastolic blood pressure (DBP) were measured in the right arm seated position. Plasma glucose, and total and high-density lipoprotein cholesterol were measured on morning samples after an 8-hour fast. Hypertension was defined as SBP ≥140 mm Hg or DBP ≥90 mm Hg or use of antihypertensive medications. Dyslipidemia was defined as a total cholesterol ≥200 mg/dL or the use of lipid-lowering therapy. Diabetes mellitus was defined as fasting glucose ≥126 mg/dl or the use of insulin or oral hypoglycemic medications. A history of coronary heart disease (CHD) and congestive heart failure (CHF) were determined by physician end-point review.14 CHD was defined as recognized or unrecognized myocardial infarction (with diagnostic electrocardiography), angina, or coronary insufficiency. CHF was identified by clinical signs and symptoms.

The presence of intermittent claudication at any clinic examination visit was defined by a physician-administered questionnaire, in which participants reported exertional leg discomfort related to degree of walking that was relieved with rest, verified by an endpoint review panel of three investigators.15 Ankle-brachial SBP measurements, repeated twice, were obtained by trained technicians using a standard protocol at Examination 7 (average 4.4 years from CMR study).15 ABI was calculated for each leg as the ratio of average SBP in the ankle divided by average SBP in the higher arm. The lower of the two ABIs calculated for each lower extremity was used for analysis. If ABI was missing for one lower extremity, data was used from the other extremity. A reported history of lower extremity revascularization, including percutaneous angioplasty, placement of stent, or vascular bypass surgery, was recorded and validated by medical record review. Three categories of ABI were defined: ABI<0.9 or history of lower extremity revascularization (significant PAD); 0.9 ≤ ABI ≤ 1.0; and 1.0 < ABI ≤ 1.4. Participants with ABI > 1.4 were excluded as these values may represent medial arterial calcification with associated increased mortality.16

Statistical Analysis

Participants were categorized by the presence or the absence of a WMA. Plaque volume was natural log-transformed due to a non-normal distribution and reported as median (interquartile range). Descriptive statistics for all covariates are presented as percentages or means ± SD. Differences in characteristics between the groups with and without WMAs were evaluated using two-sample t tests and analysis of covariance (ANCOVA) for continuous variables, and Chi-squared test and logistic regression for binary variables. Age- and sex-adjusted and multivariable-adjusted ANCOVA and logistic regression models were constructed to assess the association of aortic plaque, natural log-transformed plaque volume, claudication, and ABI (as both continuous and categorical variables, using ABI >1.0 to ≤1.4 as the referent group) to the presence or absence of a WMA. Odds ratios and 95% confidence intervals were calculated for the association of categorical variables with WMAs. Covariates in the multivariable model were determined at Examination 7: age, sex, body mass index, tobacco pack-years, SBP, total cholesterol/HDL ratio, and histories of hypertension treatment, dyslipidemia treatment, and diabetes mellitus. Similar models were generated to assess the relationship of aortic plaque to ABI severity. An age- and sex-adjusted Pearson correlation coefficient was used to determine the linear association between the presence and quantity of aortic plaque with ABI. All analyses were performed with SAS 8.0 (SAS Institute, Cary, NC). A two-sided p-value <0.05 was considered statistically significant.

The authors had full access to and take full responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.

RESULTS

The demographics and characteristics of the study sample are shown in Table 1. WMAs were present in 106 (6%) of the total population. Compared to participants without a WMA, those with WMAs had a greater prevalence of all cardiovascular risk factors, particularly male sex, diabetes, and hypertension, and a greater prevalence of CHD or CHF (all p<0.001). However, 53% of participants with WMAs had no history of CHD or CHF. Participants with WMAs also had greater LVMI and LVEDV, and lower LVEF (all p<0.0001).

Table 1.

Clinical characteristics of the study population

No WMAs (n=1620) WMAs (n=106) P Value
Risk factors and clinical events
Age (yrs) 64.5±9.0 67.7±9.1 0.0005
Male (%) 45 78 <0.0001
BMI (kg/m2) 27.6±5.3 29.3±5.0 0.0037
Obesity (%) 32.3 46.2 0.0033
Diabetes (%) 8.8 24.5 <0.0001
Systolic blood pressure (mm Hg) 124.9±17.6 128.6±13.9 0.0364
Diastolic blood pressure (mm Hg) 74.0±9.4 75.1±11.3 0.3253
Hypertension (%) 50.5 78.3 <0.0001
Tobacco use (pack-years) 13.4±19.3 29.4±28.2 <0.0001
Current or former cigarette smoker, (%) 59.8 72.6 0.0085
Total cholesterol/HDL 4.0±1.3 4.4±1.3 0.0216
Dyslipidemia (%) 79.5 87.7 0.04
FRS 7.64±4.06 9.95±3.86 <0.0001
CHD or CHF 6.7% 47.2% <0.0001
CMR measurements
WMSI 1.00±0.01 1.56±0.43
LVMI (g/m2) 54.2±11.1 68.3±14.3 <0.0001
LVEDV (ml) 123±29 162±36 <0.0001
LVEF (%) 68.1±5.7 53.6±9.1 <0.0001
Aortic plaque measurements
Aortic plaque, N (%) 771 (48) 60 (57) 0.072
Aortic plaque volume, cm2 (IQR) 0.0 (0.0-0.4) 0.1 (0.0 -1.2) <0.001
Clinical PAD
Intermittent claudication, % 31 (2) 9 (9) <0.001
ABI, mean (SD) 1.11±0.15 1.14±0.10 <0.001
ABI ≤0.9/revascularization, % 34 (2) 8 (8) <0.001
ABI 0.9 to 1.0, % 68 (4) 8 (8) <0.001
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BMI: body mass index. CHD: myocardial infarction, angina pectoris, or coronary insufficiency. CHF: congestive heart failure. Dyslipidemia: total cholesterol ≥200 mg/dl or on lipid-lowering therapy. FRS: Framingham Coronary Risk Score. LVEDV: left ventricular end-diastolic volume. LVEF: left ventricular ejection fraction. LVMI: left ventricular mass index. Obesity: BMI>30. Tobacco: any smoking during Examinations 1-7. WMA = WMSI >1.12. WMSI: wall motion score index.

The prevalence of aortic plaque and measures of clinical PAD are presented in Table 1. Aortic plaque was present in 48% of the cohort. The majority of participants with aortic plaque (93%) had normal LV wall motion. Plaque volume was greater in participants with WMAs compared to those with normal wall motion (p<0.001). This difference persisted after age- and sex-adjustment (p=0.001) but was attenuated after multivariable adjustment (p=0.22).

Participants with WMAs had a greater prevalence of both claudication and decreased ABI. Claudication was associated with a nearly four-fold odds of having a WMA in age- and sex-adjusted analysis (OR=3.78, 95% CI 1.68-8.52, p=0.001); this association was attenuated after multivariable adjustment (OR 1.69, 95% CI 0.66-4.37, p=0.276). Mean ABI was not significantly lower in participants with a WMA in multivariable adjusted analyses (mean±SD: 1.11±0.15 vs. 1.14±0.10, p=0.12). ABI ≤0.9 or revascularization was present in 42 (2.5%) participants, ABI 0.91 to 1.0 was present in 76 (4.5%) participants, and ABI>1.0 to 1.4 was present in 1553 (92.9%) participants. There was a significant increase in the proportion of participants with WMAs across decreasing levels of ABI (5.5% among ABI >1.0 to 1.4, 10.5% among ABI 0.91-1.0, and 19.0% among ABI ≤0.9 or revascularization, p<0.001 for linear trend). In age- and sex-adjusted analyses, ABI ≤0.9 or revascularization was associated with a nearly three-fold risk of WMA (OR 2.94, 95% CI 1.28-6.76, p=0.01) and ABI 0.9 to 1.0 was associated with an elevated risk for WMAs (OR 2.58, 95% CI 1.13-5.84, p=0.02) compared to ABI >1.0 and ≤1.4. However, the association between ABI level and WMA was not significant after multivariable adjustment (OR for WMA 1.9, 95% CI 0.78-4.40, p=0.843, for ABI ≤0.9 or revascularization; OR for WMA 0.90, 95% CI 0.32-2.52, p=0.163 for ABI 0.9 to 1.0) (Figure 1).

Figure 1.

Figure 1

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Odds of a WMA associated with peripheral arterial disease (PAD).

Boxes represent Odds Ratio for a WMA; lines represent 95% CI. Claudication, ABI ≤0.9 or revascularization, and ABI 0.9-1.0 were associated with increased odds of a WMA in age- and sex-adjusted analyses. These associations were attenuated after multivariable adjustment.

Aortic plaque and ABI were significantly inversely associated. In participants with aortic plaque, ABI was significantly lower compared to those without plaque (ABI=1.12±0.11 vs. 1.15±0.09, p<0.0001). The prevalence of aortic plaque increased with decreasing ABI category (Figure 2). ABI≤ 0.9 or a history of revascularization was associated with five-fold increase in the odds of aortic plaque in age- and sex-adjusted analyses (OR 4.99, 95% CI 2.184-11.414, p=0.0014) and a three-fold increase in the odds after multivariable adjustment (OR 3.23, 95% CI 1.35-7.73, p=0.0083). Likewise, median aortic plaque burden also increased with decreasing ABI group, from 0 cm3 (IQR 0.0-0.39 cm3) among ABI >1.0 to 1.4, to 0.34 cm3 (IQR 0.0-1.49 cm3) among ABI 0.91-1.0, to 2.2 cm3 (IQR 0.23-4.10 cm3) among ABI≤ 0.9 or a history of revascularization. This relationship was significant in age- and sex-adjusted analysis (Spearman r= -0.28, p=0.001), and persisted after multivariable adjustment (p<0.0001).

Figure 2.

Figure 2

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Relationship of aortic plaque prevalence with ABI groups.

The prevalence of aortic plaque increased with decreasing ABI group (p<0.001).

DISCUSSION

To our knowledge, this is the first population-based study to evaluate the relationship of LV WMAs, a likely surrogate for CHD, with other measures of systemic atherosclerosis. Notably, a significant proportion of participants with WMAs were free of prevalent CHD or CHF. The associations between extent of aortic plaque and clinical PAD with LV WMAs seen in age- and sex-adjusted analyses were not significant after multivariable adjustment. However, aortic plaque and ABI remained strongly inversely correlated after adjustment for CHD risk factors.

In our community-based population, CMR evidence of aortic plaque was common. Though many participants without WMAs had aortic plaque, this group had a lower overall plaque volume. The high prevalence of aortic plaque in both groups with and without WMAs is consistent with the high prevalence of CVD risk factors, notably hypertension, history of tobacco use, and dyslipidemia throughout the population. The association of increased plaque volume in participants with WMAs was attenuated in multivariable analysis, suggesting that these mechanisms of atherosclerosis in the aorta and coronary arteries have in common traditional CVD risk factors including obesity, smoking, diabetes, hypertension, and dyslipidemia. However, our results are consistent with transesophageal echocardiographic data showing an association of aortic plaque thickness with CHD22 and increased incidence of CHD and CVD morbidity in those with aortic calcification.23-26

Significant clinical PAD was uncommon in our cohort (2.4% with ABI ≤0.9 or revascularization and only 2.3% with claudication), despite the prevalence of CVD risk factors. This is similar to the 2-4% prevalence of ABI ≤0.9 reported previously in an earlier, larger subset of the FHS Offspring Cohort15, in the Atherosclerosis Risk in Communities (ARIC) Study17, and the Multi-Ethnic Study of Atherosclerosis18. The 8-9% prevalence of significant PAD among those with a WMA was greater than those with normal LV wall motion. The fact that ABI and WMAs were associated in age- and sex-adjusted analyses but not upon multivariable adjustment in our study suggests that both ABI and WMAs may be influenced by traditional CVD risk factors. A similar relationship was seen between claudication and WMAs in multivariable analyses.

While attenuated in multivariable analyses, the association between PAD and WMAs is consistent with that between decreased ABI and both prevalence and incident development of CHD in the ARIC studies.17,19 While an ABI ≤0.9 is used as the cutoff for significant PAD,5 an ABI 0.9-1.0 may reflect an intermediate risk, as this group still had a nearly three-fold odds of WMA in age- and sex-adjusted analysis. These results are consistent with reports of both an increased prevalence of CHD15,17 and both cohort and meta-analysis studies demonstrating greater risk for cardiovascular events and mortality with progressive decreases in ABI.5,20 Notably also in the Cardiovascular Health Study, decreased ABI in participants free of clinical cardiovascular disease was associated with echocardiographic segmental WMAs.27

In contrast, both the prevalence and burden of aortic plaque demonstrated a strong inverse relationship with groups of ABI independently of traditional CVD risk factors. The stronger association of measures of non-coronary atherosclerosis with each other than with WMAs could reflect that WMAs are the result of a clinical event which may not correlate with absolute degree of atherosclerosis. This is consistent with past angiographic evidence that often angiographic severity may result from lesser grade, rather than highly stenotic, lesions.21 Alternatively, factors promoting atherosclerosis in coronary as compared with non-coronary beds may have different mechanisms. Consistent with this possibility, members of the Reduction of Atherothrombosis for Continued Health (REACH) cohort with PAD had a markedly greater prevalence of polyvascular disease than did those with CAD (60% vs. 25%, respectively).6

CMR is advantageous as it is not limited by acoustic windows, generates standard imaging planes, and defines wall motion at the apex with higher precision than echocardiography.28 We were able to assess LV wall motion in 99% of all participants and complete aortic plaque analysis in 96% of participants. This technique has been well-validated in the assessment of LV function29 and imaging atherosclerotic plaque.12

Limitations of this study include a relatively small number of participants with clinical PAD and WMAs, which may have limited the power to detect associations between PAD and WMAs. In addition, Examination 7 data and CMR data were not obtained concurrently. While there was an average of 4.4 years between Examination 7 and the CMR test, this time interval would be more likely to bias true associations towards the null. Furthermore, assessment of regional WMAs remains largely observer-dependent, though CMR allows superior endocardial border definition and thus excellent interobserver agreement.30 While the majority of WMAs (94%) reflected regional rather than global LV dysfunction, 6% of WMAs were global. This minority of WMAs could represent non-ischemic cardiomyopathy with no significant coronary artery disease. Finally, the FHS Offspring Cohort is a predominantly middle aged and older Caucasian population. Thus, our results may not be generalizable to other races or ethnicities or age groups.

In conclusion, in this community-based population, incidentally detected WMAs which likely reflect CHD were associated with measures of aortic and peripheral atherosclerosis in age- and sex-adjusted, but not multivariable adjusted models. The prevalence and burden of aortic plaque were strongly and independently associated with peripheral arterial disease in both age- and sex- and multivariable-adjusted analyses. WMAs and peripheral atherosclerosis share common CVD risk factors. However, aortic atherosclerosis and PAD remain strongly associated after multivariable adjustment, suggesting shared mechanisms beyond those captured by traditional risk factors.

Acknowledgments

The Framingham Heart Study is supported by Grant N01-HC-25195 from the National Heart, Lung and Blood Institute, Bethesda, Maryland. This work is also partially supported by a grant from the National Institutes of Health (RO1 HL70279) and a National Institutes of Health training grant (T32 HL07374 to CWT).

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