Study Population

The study cohort was derived from the Cardiac Abnormalities and Brain Lesions (CABL) study, whose participants were drawn from the Northern Manhattan Study (NOMAS). NOMAS is a population-based study designed to evaluate the incidence, risk factors, and clinical outcomes of stroke in the population of northern Manhattan. Study design and methodologies of NOMAS have been previously published in detail. Briefly, subjects were eligible if they (1) had never been diagnosed with stroke, (2) were ≥ 40 years of age, and (3) resided for ≥ 3 months in a household with a telephone in northern Manhattan. Beginning in September 2005, NOMAS subjects > 50 years of age who voluntarily agreed to undergo brain magnetic resonance imaging and more extensive cardiovascular assessments were included in the CABL study, which is designed to investigate the relationship between subclinical cardiovascular disease and subclinical brain disease. Participants in CABL who had complete data sets of pulse wave analysis and evaluation of AVC constituted the cohort of the present study.

The study was approved by the institutional review boards of Columbia University Medical Center and the University of Miami. Written informed consent was obtained from all study participants.

Risk Factor Assessment

Hypertension was defined as systolic BP ≥ 140 mm Hg or diastolic BP ≥ 90 mm Hg at the time of the visit or a patient’s self-reported history of hypertension or antihypertensive medication use. Diabetes mellitus was defined by the patient’s self-report, current use of insulin or hypoglycemic agents, or a fasting blood glucose level ≥ 126 mg/dL on two or more occasions in each participant. Hypercholesterolemia was defined as total serum cholesterol > 240 mg/dL, a patient’s self-report of hypercholesterolemia, or the use of lipid-lowering medication. Smoking status was defined as cigarette smoking at any time in the past or present. Body mass index was calculated as weight in kilograms divided by the square of height in meters. The estimated glomerular filtration rate was calculated using the four-variable Modification of Diet in Renal Disease equation.

Assessment of AVC

Transthoracic echocardiography was performed by trained registered sonographers according to a standardized protocol with a commercially available system (iE33; Philips Medical Systems, Andover, MA) equipped with a 2.5- to 3.5-MHz transducer. Two-dimensional images of the aortic valve were obtained and stored on digital media for subsequent offline analysis. AVC was defined as bright dense echoes > 1 mm in size on one or more cusps. Each valve leaflet was graded on a scale ranging from 0 (normal) to 3 (severe calcification). We excluded 51 subjects with suboptimal images for the assessment and those with bicuspid aortic valves or aortic valve stenosis (defined as peak flow velocity ≥ 2.0 m/sec) and 10 subjects for whom aortic valve peak flow velocity was not available. Severity of AVC was defined on the basis of the maximum score of calcification among the three leaflets: a maximum score of 0 was considered to indicate no AVC, a score of 1 mild AVC, and a score of ≥ 2 moderate to severe AVC. In mild AVC, the presence of calcified deposits of score 1 on one cusp only was considered as focal and on two or more cusps was defined as diffuse. Likewise, in moderate to severe AVC, the presence of calcified deposits of score ≥ 2 on one cusp only was considered as focal and on two or more cusps was defined as diffuse ( Figure 1 ). Participants were then divided into the following four categories of increasing AVC severity: (1) none or mild focal AVC, (2) mild diffuse AVC, (3) moderate to severe focal AVC, and (4) moderate to severe diffuse AVC. All images were interpreted by a single experienced echocardiographer (S.I.) blinded to subject characteristics and risk factors.

Representative images for each category of AVC from a parasternal short-axis view. Arrowheads indicate mild calcification, and arrows indicate moderate to severe calcification. (A) Mild focal AVC, (B) mild diffuse AVC, (C) moderate to severe focal AVC, and (D) moderate to severe diffuse AVC.

Pulse Wave Analysis

In the same session, after the performance of the echocardiographic examination, pulse wave analysis of the radial artery by applanation tonometry was performed using a commercially available device (SphygmoCor, Pulse Wave Analysis System; AtCor Medical, Sydney, Australia). A detailed description of the technique and reproducibility data have been previously published. Estimated central systolic, diastolic, and pulse pressure (PP) were calculated from the radial pulse wave by a validated generalized transfer function. The ratio of central PP to left ventricular stroke volume index was used as an indicator of arterial stiffness. Total arterial compliance was calculated using the area method illustrated by Liu et al . Aortic augmentation pressure from the reflected wave was measured as the difference between the peak systolic central pressure and the pressure at the onset of the reflected wave from the peripheral reflecting sites. The aortic augmentation index was calculated as the ratio between the augmentation pressure and the central PP and expressed as a percentage. Time to the beginning of the reflected wave (time to reflection) was also measured. Only studies with acceptable quality scores (operator index > 80%) were included in the analysis.

Statistical Analysis

Data are presented as mean ± SD for continuous variables and as proportions for categorical variables. Differences among groups were assessed by one-way analysis of variance for continuous variables and by Pearson χ ² tests for proportions. Analysis of covariance was performed separately for each variable derived from pulse wave analysis to assess differences among the four categories of AVC after adjustment for covariates, which were selected on the basis of their univariate associations with AVC severity (the threshold for inclusion in the multivariate models was set at a P value of < .05). The Tukey-Kramer procedure was used for multiple comparisons in one-way analysis of variance and analysis of covariance. In addition, multivariate logistic regression analyses using moderate to severe diffuse AVC as outcome were carried out. Inter- and intraobserver agreement for AVC categorization was assessed using κ statistics. P values < .05 were considered statistically significant. Statistical analyses were performed using SAS version 9.3 (SAS Institute Inc, Cary, North Carolina).

Study Cohort

Of 1,004 participants enrolled in the CABL study, 867 (mean age, 71 ± 9 years) who had both AVC assessment and pulse wave analysis available constituted the sample for the present study, including 339 men (39.1%), 123 non-Hispanic whites (14.1%), 141 non-Hispanic blacks (16.3%), 583 Hispanics (67.2%), and 20 of other ethnicities (2.3%). Of the 867 subjects, 685 had hypertension (79.0%), 248 had diabetes mellitus (28.6%), 582 had hypercholesterolemia (67.2%), and 452 were ever smokers (52.1%).

Assessment of AVC

The demographics and clinical characteristics in the four categories of AVC are listed in Table 1 . Of the 867 subjects, 155 (17.9%) were classified as having none or mild focal AVC, 592 (68.3%) as having mild diffuse AVC, 89 (10.3%) as having moderate to severe focal AVC, and 31 (3.6%) as having moderate to severe diffuse AVC. Both of the AVC categories of moderate to severe focal and moderate to severe diffuse AVC showed higher age and higher frequency of male sex compared with the other two categories. Race/ethnicity and estimated glomerular filtration rate were also significantly different among the four categories. The moderate to severe diffuse AVC category showed significantly higher aortic valve peak flow velocities compared with any of the other three AVC categories.

For the categorization of AVC, the κ statistic for interobserver agreement was 0.73 (95% confidence interval [CI], 0.49–0.97) with 80% agreement (95% CI, 62.4%–97.5%), and the κ statistic for intraobserver agreement was 0.87 (95% CI, 0.69–1.0), with 90% agreement (95% CI, 76.9%–100%).

Central BP, Arterial Stiffness, and Wave Reflection Parameters Associated with AVC

Parameters derived from pulse wave analysis are shown in Table 2 . Neither central systolic BP nor central diastolic BP was significantly different among the four categories, whereas central PP was higher in more advanced categories of AVC. The ratio of PP to stroke volume index, an indicator of arterial stiffness, was higher and total arterial compliance was lower with more advanced AVC. Greater amplitude of wave reflection was observed with more advanced AVC, whereas time to reflection was not significantly different among the four categories. After adjusting for pertinent covariates (age, sex, race/ethnicity, and estimated glomerular filtration rate), significant differences remained in the variables of wave reflection, including augmentation pressure and augmentation index ( Table 3 ). The AVC category of moderate to severe diffuse showed greater amplitude of wave reflection compared with any of the other three AVC categories. Central PP, central PP/stroke volume index, and total arterial compliance were no longer significantly associated with the severity of AVC. Even when brachial systolic and diastolic BPs and antihypertensive medication use were added to the model as covariates, augmentation pressure and augmentation index remained associated with the severity of AVC ( P < .01 for both).

Table 2

Central BP, arterial stiffness, and wave reflection parameters in relation to the severity of AVC

Variable	AVC				P value
	None/mild focal	Mild diffuse	Moderate to severe focal	Moderate to severe diffuse
cSBP (mm Hg)	121.7 ± 21.5	119.3 ± 18.0	120.6 ± 20.6	125.1 ± 19.0	.225
cDBP (mm Hg)	72.7 ± 10.5	72.2 ± 10.1	70.8 ± 10.3	67.9 ± 9.6	.069
cPP (mm Hg)	49.0 ± 18.4	47.1 ± 14.6	49.8 ± 16.1	57.2 ± 17.3 ∗ , † , ‡	.003
cPP/SVi (mm Hg m 2 /mL)	1.48 ± 0.75	1.41 ± 0.53	1.59 ± 0.56	1.71 ± 0.64 †	.003
Total arterial compliance (mL/mm Hg)	1.19 ± 0.57	1.19 ± 0.55	1.06 ± 0.51 †	0.91 ± 0.33 ∗ , †	.014
Augmentation pressure (mm Hg)	14.2 ± 8.7	14.4 ± 7.6	15.4 ± 8.2	19.9 ± 9.1 ∗ , † , ‡	.002
Augmentation index (%)	27.4 ± 9.6	29.3 ± 9.5 ∗	29.4 ± 9.5	33.6 ± 8.9 ∗ , † , ‡	.008
Augmentation index at HR 75 beats/min (%)	24.7 ± 8.0	25.5 ± 8.3	25.4 ± 9.6	29.1 ± 8.1	.073
Time to reflection (msec)	135.5 ± 10.7	135.9 ± 9.9	136.6 ± 10.5	131.6 ± 10.2	.112

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