BLOOD PRESSURE AND VASCULAR CALCIFICATION

Abstract

The aim of this study was to determine the associations between the presence and extent of calcified atherosclerosis in multiple vascular beds and systolic blood pressure, diastolic blood pressure, pulse pressure, mean arterial pressure, isolated systolic hypertension, and hypertension. 9,510 patients (42.5% women) underwent electron beam computed tomography scanning as part of a routine health maintenance screening. At the same visit, blood pressure was measured with the participant in the seated position using a mercury sphygmomanometer. Mean age was 58±11.4 years and body mass index was 27.1±4.5. The prevalence of any calcification in the carotids, coronaries, subclavians, thoracic aorta, abdominal aorta, and iliacs were 31.9, 57.2, 31.7, 37.0, 54.3, and 48.8% respectively. In separate multivariable logistic models containing traditional cardiovascular disease risk factors, pulse pressure and systolic blood pressure were significantly associated with presence of calcification in all vascular beds except the iliacs and subclavians, respectively, with pulse pressure having stronger magnitudes of the associations for most of the vascular beds. Age stratified analyses indicated that these associations were stronger in those over 60 years of age, compared to subjects less than 60 years of age, and gender stratified analyses demonstrated that men had a greater association compared to women. Also, the magnitudes of the associations for isolated systolic hypertension were, in general, larger than those for hypertension. Pulse pressure and isolated systolic hypertension are robust and important correlates for calcified atherosclerosis in different vascular beds. Isolated systolic hypertension may be clinically relevant in diagnosing or preventing calcified atherosclerosis.

Introduction

Epidemiologic studies suggest that elevated blood pressure (BP) is an independent and strong predictor of cardiovascular disease (CVD).¹ Controversy exists as to which BP measure is the best predictor of CVD events. Recent data suggests that aortic stiffness is an independent predictor of future heart disease in older individuals.² Increases in aortic stiffness are believed to be closely linked to increases in pulse pressure, thereby placing a higher after-load on the left ventricle.³ Thus, pulse pressure (PP) may be relevant in the pathophysiology of coronary heart disease. ⁴

Calcium is deposited early in the formation of the atherosclerotic plaque and can be used as a marker of the atherosclerotic process.⁵ The use of electron beam computed tomography (EBCT) affords the opportunity to noninvasively construct cross-sectional images of arteries to detect the presence and extent of calcium due to atherosclerosis in different vascular beds.⁶ The coronary calcium score is significantly predictive of future cardiac events.⁷

There are many risk factors associated with atherosclerotic calcification including hypertension (HTN).⁸ Previous reports have not typically explored the association between different measures of BP and calcification in multiple vascular beds. Accordingly, the aim of the study was to determine which measures of blood pressure (systolic blood pressure [SBP], diastolic blood pressure [DBP], mean arterial pressure [MAP], pulse pressure [PP], hypertension [HTN] and isolated systolic hypertension [ISH]) were associated with arterial calcification in six different vascular beds (carotids, coronaries, subclavians, thoracic aorta, abdominal aorta and iliacs).

Methods

Subjects

From October 1999 to July 2003, 9,510 ambulatory patients presented for preventive medicine services at a private, university affiliated disease prevention center in La Jolla, California. Most patients were asymptomatic and self-referred or referred by their primary physician as a supplement to their routine medical care. All patients completed a detailed health history questionnaire prior to undergoing the whole body scanning procedure. Smoking status was defined as current, former, or never. Family history of coronary heart disease (CHD) was defined as a CHD event prior to age of 55 years in a first-degree relative. Patients who had a history of coronary heart disease-related surgery (stent placement, coronary artery bypass graft) were excluded from the study.

The study protocol complies with the Declaration of Helsinki and was approved by the committee for protection of human subjects at the University of California San Diego who granted a waiver for informed consent because we analyzed existing data from a clinical population.

Imaging

All 9,510 patients had EBCT scans of the heart with an Imatron C-150 scanner (GE, San Francisco, CA, USA). Of these, 6,456 had “whole body scans” which entailed scanning from the base of the skull to the pubic symphysis. From this scan, we obtained measurements of calcified atherosclerosis in the following vascular beds: carotids, subclavians, thoracic aorta, abdominal aorta and iliac arteries, as previously described. ⁹ The coronary and carotid images were analyzed at the time of the EBCT scan. For the other vascular beds, images were retrospectively analyzed for calcified atherosclerosis. Calcium scoring were performed using the method described by Agatston et al.¹⁰ The coronary calcium score consisted of calcified lesions in the left main, left anterior descending, left circumflex and right coronary arteries. Data from the left and right sides were combined to give the extent of calcium in the carotid, subclavian and iliac beds. The thoracic aorta was defined as the segment above the diaphragm, while the abdominal aorta was the segment below the diaphragm to the aortic bifurcation. The right and left subclavian arteries were evaluated from their take-off points from the brachiocephalic artery and aorta, respectively, to the apex of the vessels as they began to arch over the top of the lung.

Blood Pressure

After the patient had rested for 5 minutes in the seated position, trained technicians used a standardized protocol to obtain SBP and DBP in the right upper extremity using a stethoscope and a sphygmomanometer. Blood pressure was assessed once at the clinic visit. PP was calculated as the difference between the SBP and DBP, whereas MAP was defined as DBP+1/3 (SBP–DBP). ISH was defined as a SBP of at least 140 mm Hg and a DBP below 90 mm Hg and no reported use of HTN medication. HTN was defined as SBP greater than or equal to 140 and DBP greater than or equal to 90 and/or use of HTN medication.

Laboratory

Casual serum lipid and glucose measurements were obtained by finger stick, using the Cholestec LDX system. Weight was assessed with the patient lightly clothed and without shoes. BMI was calculated as the weight (kg) divided by the height (m²). Body fat measurement was conducted using bioimpedence on the OMRON™ HBF-300.

Diabetes was defined by current use of physician-prescribed antiglycemic medications or a casual glucose level >200 mg/dL. Individuals with a total to HDL cholesterol ratio >5 or who reported the use of a medication to treat high cholesterol were classified as dyslipidemic.

Statistical Analysis

The outcome variables for this study were the presence and extent of calcium due to atherosclerosis in the carotids, subclavians, coronaries, thoracic aorta, abdominal aorta and iliac arteries. Six measures of BP were the primary predictor variables: SBP, DBP, PP, MAP, ISH and HTN. Covariates included age, gender, BMI, smoking, dyslipidemia, diabetes, family history of CHD and HTN medication. HTN medication was included in the definition of ISH and HTN.

The differences in the distributions of the baseline characteristics were determined by t-tests or chi-square tests, as appropriate. For the primary analysis, calcium scores were dichotomized as either the presence or absence of calcified plaques and logistic regression analysis was used to determine odds ratios. In analyses limited to those with calcium in the given vascular bed, multivariable linear regression was used to determine the associations between measures of BP and the extent of vascular calcium in distinct vascular beds. In order to make β coefficients more interpretable and units comparable, all BP parameters used for statistical analyses were defined by dividing the means of the following variables PP, SBP, DBP, MAP by their SD.

We established a-priori that the relationship between age and BP measures as well as sex and BP measures may potentially influence the outcome. Therefore, we stratified the cohort by age (≥60 and <60 years) and separately for gender and repeated our analyses as described above. For each outcome variable (calcium scores in each vascular bed) we did not impute data but rather used the lowest common denominator of subjects for each analysis after accounting for missing values. For example, subclavian calcium scores were analyzed in 1477 subjects while coronary calcium was analyzed in 9510 subjects. All P values were two-tailed, with a P value of less than 0.05 considered to indicate statistical significance. All statistical analyses were conducted using SPSS (Version 16.0; SPSS, Inc., Chicago, IL, USA).

Results

The total number of subjects examined for presence of calcium in the carotids, coronaries, subclavians, thoracic aorta, abdominal aorta and iliacs were 4487, 9510, 1477, 4606, 4606, and 4604, respectively. The number of subjects varied because the images of the thoracic and abdominal aorta as well as the subclavians and iliacs were analyzed retrospectively. This, combined with differences in resources available during the timeframes when each of the vascular beds was analyzed, lead to the different number of analyzed scans for each bed.

The characteristics of all the study subjects (n=9510) are provided in Table 1. Men comprised 57.5% of the study sample. More than 20% of the sample had a family history of CHD, 37.5% had smoked or were currently smoking, 28.3% had hypertension, 8.2% had ISH, and 2.6% had diabetes. The prevalence of any calcium was highest in the coronaries (57.2%) while the lowest prevalence was found in the carotid and subclavian arteries (31.9% and 31.7%, respectively).

Table 1.

Baseline cohort Characteristics

Characteristics	All Patients n=9510	<60yrs. n=5520	≥60yrs. n=3990	P- Value
Age, mean (SD) years	58 (11.4)	50.2 (6.9)	68.8 (6.6)	<0.01
BMI, mean (SD) kg/m2	27.1 (4.5)	27.1 (7.2)	27.0 (4.2)	0.05
Total BF%, mean (SD)	29.6 (7.5)	27.8 (7.2)	32.4 (7.0)	<0.01
Total Cholestrol, mean (SD)	208.1 (42.1)	209.6 (43.0)	205.6 (40.5)	<0.01
TC/HDL ratio, mean (SD)	4.4 (1.8)	4.5 (1.7)	4.3 (2.1)	<0.01
DBP, mean (SD) mmHg	78.4 (12.9)	78.6 (14.4)	78.1 (10.3)	0.12
SBP, mean (SD) mmHg	126.4 (17.5)	123.5 (16.8)	131 (17.8)	<0.01
PP, mean (SD)	48.3 (18.4)	45.3 (20.0)	53.0 (17.8)	<0.01
MAP, mean (SD)	94.4 (13.3)	93.6 (14.4)	95.7 (11.3)	<0.01
Females, No. (%)	4041 (42.5)	2145 (38.9)	1896 (47.5)	<0.01
Ever Smoker, No.(%)	3563 (37.5)	1956 (35.5)	1607 (40.2)	<0.01
ISH, No. (%)	567 (8.2)	244 (5.8)	323 (12.1)	<0.01
Hypertension, No.(%)	2690 (28.3)	1351 (24.5)	1339 (33.5)	<0.01
Diabetes Mellitus, No. (%)	244 (2.6)	112 (2.0)	132 (3.3)	<0.01
Family History CHD, No. (%)	2067 (21.7)	1295 (23.5)	772 (19.3)	<0.01
Calcium No. (%)
Carotid (>0)	1432 (31.9)	444 (16.4)	986 (55.7)	<0.01
Coronary (>0)	5435 (57.2)	2525 (45.8)	2910 (72.9)	<0.01
Subclavian (>0)	468 (31.7)	176 (20.4)	292 (47.5)	<0.01
Distal Aorta (>0)	2501 (54.3)	962 (34.6)	1539 (84.1)	<0.01
Proximal Aorta (>0)	1705 (37.0)	464 (16.7)	1241 (68.0)	<0.01
Iliac (>0)	2247 (48.8)	898 (32.3)	1349 (73.8)	<0.01

T-test and chi square tests were used to determine differences between age groups for all baseline characteristics

p<0.01 is significant

After stratifying the cohort by 60 years of age, the ≥60 group had a higher SBP, PP, and MAP compared to the <60 group (p<0.01) (Table 1). Additionally, the ≥60 age group had a greater prevalence of ISH (12.1% compared to 5.8%, p<0.01). The prevalence of calcification was highest in the abdominal aorta followed by the iliacs and coronaries (84.2%, 73.9%, 72.9% respectively) for those ≥60 years. Conversely, the <60 age group had the greatest prevalence of calcification in the coronaries followed by the abdominal aorta (45.8% and 34.6%, respectively).

Table 2 shows the age-adjusted differences in patient characteristics between those patients with calcium compared to patients without calcium in different vascular beds. In general, there were significant differences in patient characteristics between those with and without calcium. The differences between the two groups were often seen in age, SBP, PP, smoking and HTN. In the coronaries, there were significant differences between the groups for all characteristics listed.

Table 2.

Differences in the cohort characteristics between those with calcium and those without calcium in different vascular beds^‡

Carotid	Calcium	Calcium		Thoracic Aorta	Calcium	Calcium
Characteristics	NO	YES	P value	Characteristics	NO	YES	P value
	n=3055	n=1432			n=2901	n=1705
Age, mean (years)	54.00	65.00	<0.01*	Age, mean (years)	50.40	63.30	<0.01*
BMI, mean (kg/m2)	26.8	27.5	<0.01*	BMI, mean (kg/m2)	27.20	27.20	0.96
TC/HDL ratio, mean	4.3	4.6	<0.01*	TC/HDL ratio, mean	4.30	4.40	<0.01*
DBP, mean (mmHg)	77.5	79	0.04†	DBP, mean (mmHg)	78.20	77.70	0.50
SBP, mean (mmHg)	123	131	0.44	SBP, mean (mmHg)	120.00	133.00	0.16
PP, mean	45	51	<0.01*	PP, mean	45.60	48.50	<0.01*
MAP, mean	92.5	95.2	<0.01*	MAP, mean	93.40	94.00	0.37
Gender (female), %	48.9	30.7	<0.01*	Gender (female),%	43.40	42.00	0.50
Ever Smoker, %	39	53	<0.01*	Ever Smoker, %	40.00	49.40	<0.01*
ISH, %	6.5	9.8	<0.01*	ISH, %	6.80	8.90	0.08
Hypertension, %	10.1	18.5	<0.01*	Hypertension, %	11.70	16.30	<0.01*
Diabetes Mellitus, %	1.6	5.1	<0.01*	Diabetes Mellitus, %	2.30	4.30	<0.01*
Family History CHD, %	24	27	0.08	Family History CHD, %	23.20	27.70	0.01*
Coronaries	Calcium	Calcium		Abdominal Aorta	Calcium	Calcium
Characteristics	NO	YES	P value	Characteristics	NO	YES	P value
	n=4075	n=5435			n=2105	n=2501
Age, mean (years)	53.60	61.30	<0.01*	Age, mean (years)	52.30	66.00	<0.01*
BMI, mean (kg/m2)	26.30	27.80	<0.01*	BMI, mean (kg/m2)	27.00	27.40	0.08
TC/HDL ratio, mean	4.00	4.70	<0.01*	TC/HDL ratio, mean	4.10	4.50	<0.01*
DBP, mean (mmHg)	76.70	79.70	<0.01*	DBP, mean (mmHg)	77.40	78.50	0.09
SBP, mean (mmHg)	128.00	130.00	<0.01*	SBP, mean (mmHg)	124.10	132.00	0.40
PP, mean	45.90	50.70	<0.01*	PP, mean	45.00	48.00	<0.01*
MAP, mean	92.30	95.80	<0.01*	MAP, mean	92.50	94.50	<0.01*
Gender (female), %	58.50	30.40	<0.01*	Gender (female), %	50.00	37.10	<0.01*
Ever Smoker, %	33.60	40.70	<0.01*	Ever Smoker, %	31.00	54.30	<0.01*
ISH, %	6.30	9.70	<0.01*	ISH, %	6.90	8.10	0.23
Hypertension, %	12.00	16.30	<0.01*	Hypertension, %	9.30	16.80	<0.01*
Diabetes Mellitus, %	1.40	3.90	<0.01*	Diabetes Mellitus, %	2.20	3.80	0.01*
Family History CHD, %	19.70	23.40	<0.01*	Family History CHD, %	23.30	26.20	0.07
Subclavians	Calcium	Calcium		Iliacs	Calcium	Calcium
Characteristics	NO	YES	P value	Characteristics	NO	YES	P value
	n=1009	n=468			n=2357	n=2247
Age, mean (years)	55.10	63.10	<0.01*	Age, mean (years)	52.10	63.00	<0.01*
BMI, mean (kg/m2)	27.20	26.20	<0.01*	BMI, mean (kg/m2)	26.70	27.60	<0.01*
TC/HDL ratio, Mean	4.21	4.20	0.95	TC/HDL ratio, mean	4.10	4.60	<0.01*
DBP, mean (mmHg)	80.40	79.50	0.19	DBP, mean (mmHg)	76.90	78.90	<0.01*
SBP, mean (mmHg)	126.10	127.00	0.51	SBP, mean (mmHg)	123.30	133.00	0.25
PP, mean	45.80	47.60	0.03†	PP, mean	45.50	47.40	<0.01*
MAP, mean	95.70	95.40	0.65	MAP, mean	92.10	94.70	<0.01*
Gender (female), %	45.80	39.20	0.02†	Gender (female), %	55.30	32.50	<0.01*
Ever Smoker, %	43.20	55.00	<0.01*	Ever Smoker, %	34.60	52.50	<0.01*
ISH, %	8.40	10.20	0.32	ISH, %	6.60	8.10	0.11
Hypertension, %	10.10	13.10	0.11	Hypertension, %	12.00	14.50	0.02†
Diabetes Mellitus, %	2.30	2.60	0.72	Diabetes Mellitus, %	2.10	4.00	<0.01*
Family History CHD, %	24.50	27.30	0.27	Family History CHD, %	23.00	27.20	<0.01*

^*p<0.01

^†p<0.05

^‡age adjusted

Table 3 shows the odds of having calcium scores > 0. In separate multivariable logistic models containing traditional CVD risk factors (age, sex, BMI, smoking, dyslipidemia, diabetes, family history of CVD and HTN medication), PP and SBP were significantly associated with calcification in all of the vascular beds except the iliacs and subclavians, respectively, with PP having the stronger magnitudes of the associations for most of the vascular beds. Similarly, and compared to HTN, a diagnosis of ISH was associated with a greater odds of calcification in a majority of the vascular beds.

Table 3.

Odds ratios of the presence of calcium in different vascular beds by different measures of blood pressure ^‡

	Carotid	Coronary	Subclavian	Thoracic Aorta	Abdominal Aorta	Iliac
BP measures	OR	OR	OR	OR	OR	OR
Total  Subjects
SBP	1.28*	1.35*	1.17	1.15*	1.23*	1.19*
DBP	1.05	1.19*	0.96	0.98	1.02	1.07†
PP	1.49*	1.24*	1.36*	1.34*	1.34*	1.09
MAP	1.17*	1.25*	1.06	1.06	1.09†	1.14*
ISH§	1.48†	1.58*	1.37	1.28	1.26	1.22
HTN§	1.63*	1.34*	1.14	1.13	1.47*	1.14
≥60 years
SBP	1.27*	1.39*	1.31†	1.20*	1.27*	1.29*
DBP	1.02	1.25*	1.07	1.03	1.14	1.30*
PP	1.38*	1.43*	1.41*	1.32*	1.34*	1.18
MAP	1.17†	1.40*	1.24	1.15	1.23†	1.38*
ISH§	1.46†	1.67*	1.36	1.46	1.32	1.4
HTN§	1.48*	1.28*	1.53†	1.23	1.56*	1.15
< 60 years
SBP	1.30*	1.32*	1.08	1.09	1.19*	1.11
DBP	1.04	1.12*	0.92	0.93	1.02	1.04
PP	1.60*	1.15*	1.28	1.39*	1.40*	1.05
MAP	1.12†	1.18*	0.99	1.02	1.08	1.07
ISH§	1.41	1.50*	1.3	1.02	1.23	1.07
HTN§	1.68*	1.14*	1.14	1.03	1.52*	1.15

^*p<0.01

^†p<0.05

^‡Adjusted for age, sex, BMI, smoking, dyslipidemia, diabetes, family history of CHD and HTN medication

^§HTN medication was not used as a covariate for HTN or ISH

These analyses were repeated and stratified by age (Table 3). In the ≥60 group, there were significant associations between both SBP and PP and vascular bed calcification in all of the different sites. In general, the odds for the presence of calcium for both PP and SBP were greater in the ≥60 group compared to the <60 group. Lastly, compared to those without ISH, those with ISH had a greater magnitude of association with calcified atherosclerosis among all vascular beds in the ≥60 group compared to the <60 group. In this regard, there were significant interactions between age and PP, SBP and ISH for all vascular beds (p ≤ 0.01 for all).

Table 4 illustrates gender differences for the odds of calcium > 0. These data, suggest that men have a greater odds of calcification in all vascular beds compared to women. Additionally, higher PP, as well as a diagnosis of ISH and HTN, were associated with a higher odds of calcification in all vascular beds. Notably, in women, ISH appears to be more strongly associated with calcification, whereas in men, HTN is associated with a higher odds of calcification to a greater magnitude. There were significant interactions between gender and BP variables (SBP, PP, ISH, HTN).

Table 4.

Gender-specific odds ratios for the presence of calcium in different vascular beds by different measures of blood pressure ^*

	Carotid	Coronary	Subclavian	Thoracic Aorta	Abdominal Aorta	Iliac
BP measures:	OR	OR	OR	OR	OR	OR
Males
SBP	1.36	1.39	1.34	1.14	1.21	1.15
DBP	1.14	1.27	0.99	1.02	1.08	1.15
PP	1.57	1.43	1.55	1.37	1.35	1.09
MAP	1.15	1.19	1.08	1.02	1.09	1.08
ISH†	1.54	1.62	1.40	1.09	1.34	1.06
HTN†	1.94	1.24	1.94	1.55	1.61	1.14
Females
SBP	1.00	1.00	1.02	1.00	1.15	1.23
DBP	1.04	1.08	0.99	1.02	1.01	1.11
PP	1.36	1.12	1.12	1.24	1.25	1.14
MAP	1.05	1.07	1.01	1.04	1.03	1.06
ISH†	1.46	1.56	1.28	1.74	1.21	1.51
HTN†	1.31	1.20	0.70	0.94	1.89	0.89

^*Adjusted for age, BMI, smoking, dyslipidemia, diabetes, family history of CHD and HTN medication

^†HTN was not used as a covariate for HTN or ISH

Multivariable linear regression models were used to determine the associations with the extent of calcium in each vascular bed (Table 5) among subjects with any calcification. A 1-SD increase in SBP and PP corresponded to the greatest increases in the extent of calcium in the thoracic aorta. Additionally, a diagnosis of ISH was associated with the largest magnitudes of the associations for increasing calcium in the thoracic aorta and coronaries, whereas, HTN had the largest magnitudes of associations in the subclavians and carotids (Table 5). In a majority of cases, these increases in association tended to be greater in the ≥60 group. In these analyses, there were significant interactions between age and the following BP variables: SBP, PP and ISH variables (p ≤ 0.01for all).

Table 5.

Associations of different blood pressure measures with the extent of calcification in different vascular beds among subjects with any calcification ^†

	Carotids	Coronaries	Subclavians	Thoracic Aorta	Abdominal Aorta	Iliacs
BP Measures	Beta	Beta	Beta	Beta	Beta	Beta
Total   Subjects
SBP	7.25	1.11	13.20	20.80*	0.40	0.20
DBP	0.80	−1.09	−3.34	11.63*	0.30	−3.15
PP	8.76	1.31	1.82	21.41*	20.08*	1.92
MAP	2.22	1.01	0.60	10.19*	3.87	1.11
ISH (yes/no)‡	32.31	31.65*	31.00	39.10*	15.49	42.62
HTN (yes/no)‡	37.44*	30.60*	62.58*	20.10*	33.51	18.77
≥60 years
SBP	15.49	12.64*	15.49	22.14*	5.07	0.20
DBP	−2.86	−4.30	−2.86	10.52	4.92	−3.63
PP	13.66	24.61*	19.01	20.10*	25.61*	11.63
MAP	2.94	0.70	4.39	10.19	3.87	1.31
ISH (yes/no)‡	59.84*	34.72	38.26	48.43*	5.87	47.85*
HTN (yes/no)‡	29.56*	36.62*	58.10*	28.27*	20.08	15.60
<60 years
SBP	5.16	0.40	5.16	15.03*	8.44	9.86
DBP	−2.37	5.34	−2.37	9.42	−0.20	1.71
PP	2.27	0.30	3.56	24.48*	10.30	22.26
MAP	1.31	2.74	-5.16	8.22	5.65	1.51
ISH (yes/no)‡	38.43	26.24	27.25	4.81	19.01	28.66
HTN (yes/no)‡	60.96*	27.25*	100.57*	2.74	71.1*	28.15

Multivariable linear regression

^*p<0.05

^†Model included CVD risk factors and hypertension medication, excludes individuals without calcification

1SD increase in BP measure is associated with a % increase or decrease in calcification

The categorical BP measures are compared to the reference group (=no)

^‡HTN medication was not used as a covariate for HTN or ISH

We also determined the associations by gender among subjects with any calcification (Table 6). The results were similar to the previous findings in that SBP and PP corresponded to the greatest increases in the extent of calcium in the thoracic aorta for continuous variables in both men and women and there were significant interactions between gender and the same BP variables.

Table 6.

Gender-specific associations of different blood pressure measures with the extent of calcification in different vascular beds among subjects with any calcification ^†

	Carotids	Coronaries	Subclavians	Thoracic Aorta	Abdominal Aorta	Iliacs
BP Measures	Beta	Beta	Beta	Beta	Beta	Beta
Male
SBP	9.3	8.4*	7.4	11.6*	5.4*	3.4
DBP	−2.5	−0.3	−4.3	4.6	−1.2	−0.8
PP	2.9	11.6*	12.4*	10.5*	7.3*	4.8
MAP	−1	3.8*	0.8	8.9	1.8	1.2
ISH (yes/no)‡	1.4	2.5	4.7	5.1	1.61	4.4
HTN (yes/no)‡	8.7*	5.4*	11.9*	5.2	8.5*	5.7*
Female
SBP	2	−0.2	1.6	15.9*	6.6*	−3.5
DBP	5.2	0.4	0.6	7.1	2.7	−2.6
PP	6.5	−0.1	−0.2	10.3*	9.6*	10.8*
MAP	7.9	0.1	0.6	11.6	6.4	1.3
ISH (yes vs. no)‡	5.4	3.4	10.5	9.6*	−0.5	12.1*
HTN (yes vs. no)‡	8.1	6.2*	17.9*	4.2	3.8	0.8

Multivariable linear regression

^*p<0.05

^†Model included CVD risk factors and hypertension medication, excludes individuals without calcification

1SD increase in BP measure is associated with a % increase or decrease in calcification

The categorical BP measures are compared to the reference group (= no)

^‡HTN medication was not used as a covariate for HTN or ISH

Discussion

Prior to our study, there has been only limited information on the presence of atherosclerotic calcification in non-coronary vascular beds.¹¹ A previous study demonstrated that the detection of extra-coronary atherosclerosis, potentially helps to indentify individuals more likely to develop new calcified coronary disease.¹² Furthermore, controversy exists as to which BP components are the best predictors of CVD events, and which components of BP are most strongly associated with calcium in non-coronary vascular beds. Our study is unique in that we analyzed the associations between multiple measures of BP and calcification in distinct vascular beds. Overall, for continuous variables, we found that SBP and PP had the greatest odds of calcification across all vascular beds. Furthermore, the BP parameters SBP and PP, corresponded with the greatest magnitude of associations in the thoracic aorta. ISH had a greater magnitude of association in the thoracic aorta and coronaries when compared to a diagnosis of HTN.

Previous studies have determined that BP components have age-dependent roles in the prediction of CAC,¹³ and that SBP, DBP, MAP and PP¹⁴ are age-dependent predictors of CVD risk.¹⁵ In this regard, with increasing age, arterial compliance decreases and arterial stiffness increases¹⁵, leading to increases in SBP, decreases in DBP and a widening of PP.¹⁶ In our study and among those ≥60 years SBP and PP were elevated and more subjects had ISH. Conversely, in those under 60 years , HTN had stronger associations with calcification compared to ISH and both HTN and ISH were more variable in women. Similarly, in the Rochester Family Heart Study, SBP and PP were independent predictors of the presence and quantity of coronary artery calcification in the ≥50 years of age group.¹³ Taken together, these results suggest that the relevance of PP and ISH (and perhaps SBP) increases with age, particularly in the 6^th and 7^th decade of life.

Many epidemiologic studies have focused on the presence of significant associations between PP and coronary atherosclerosis ¹⁷ and determined that PP was more highly correlated with atherosclerosis when compared with SBP or DBP levels. Furthermore, previous studies indicated that SBP and PP may be better predictors of CVD risk than other measures of BP.¹⁸ Our data indicates that PP is significantly associated with vascular calcification in other, non-coronary vascular beds except the iliacs and subclavians, and the magnitudes of associations are generally stronger than for SBP and DBP.

Atherosclerotic calcification may lead to arterial stiffness, a significant risk factor for CVD.¹⁹ Notably, ISH reflects an elevated PP, which is considered a crude estimate of arterial stiffness, which is a powerful predictor of cardiovascular events.²⁰ Our results for these two measurements showed significant associations with calcium in the thoracic aorta and the magnitudes of the associations differed significantly by age group. Notably, in the elderly, ISH is associated with increased aortic stiffness, early return of reflected waves, and as a result smaller PP amplification.²¹ Our results support the relevance of PP and ISH in the pathophysiology of cardiovascular disease in those ≥60 years.

Individuals with ISH have an increased risk for stroke, coronary heart disease, and congestive heart failure.²² The prevalence of ISH increases among older subjects, as does the magnitude of the association of ISH with calcification and aortic stiffness.²³ Importantly, studies suggests that aortic calcification may play an important role in the development of ISH in humans, as is the case in animal models of vascular calcification,²⁴ in which drug-induced vascular calcification leads to the development of ISH.²⁵ In this way, vascular calcification may be relevant in the development of ISH rather than ISH leading to calcification. Clearly, prospective studies on the association between aortic calcification and ISH in humans are needed to clarify this relationship and to determine whether HTN promotes calcifications or calcifications promote stiffness and therefore increases in SBP and PP.

The strengths of our study include the large sample size, the ascertainment of calcification measures in multiple vascular beds and the use of multiple measures of BP for analytical purposes. Our study has some limitations. The results of this study may not be generalizable to all community-based populations as the subjects for this study were self-selected. However, the 10-year Framingham risk score from our study cohort was comparable to the Framingham cohort,²⁶ which was similar in ethnic distribution to ours. For instance, after calculating the 10-year Framingham risk score for our study cohort, we determined that men had a 10% risk of developing CHD and women had a 2% risk of developing CHD, which was similar to the original cohort where men had a risk of 8.0% followed by women who had a risk of 2.8%. Additionally, small differences in our data resulted in significance, presumably due to our large sample size, thus significance may not ensure clinical relevance. Another potential limitation is that computed tomography cannot determine whether calcium is in the intima or media of the arterial wall. Calcium in the intimal layer of the artery is associated with atherosclerotic plaque and is a predictor of cardiac events.²⁷ In contrast, Mönckeberg’s sclerosis, or calcification of the tunica media layer, is associated with metabolic, electrolyte, and pH abnormalities. Mönckeberg’s calcification is also frequently associated with renal disease or diabetes mellitus.²⁸ However, we had few subjects with diabetes in our study and thus, we believe that the possibility of misclassification is small. Also, although kidney function influences blood pressure, history of chronic kidney disease was not collected. Importantly, previous studies have not found a significant association between kidney function and vascular calcification.²⁹

In conclusion, the current study demonstrates that different measures of blood pressure are associated with significant calcification in multiple vascular beds, and that these associations vary with age. Our study also highlights the differences between the more distal vascular beds (iliacs and subclavians) versus the more central vascular beds (thoracic and abdominal aorta). That is, PP and SBP, as well as a diagnosis of ISH, had the greatest magnitudes of association in the thoracic aorta. From a blood pressure perspective, the vascular beds studied appear to be physiologically distinct, which may potentially explain these differences. We also assessed the extent of calcification at multiple sites to test the relation of the number of diseased sites with BP measures. We determined that there were no significant findings after adjusting for CVD risk factors, which may imply bed specificity in the BP-calcification relationship. The results presented underscore the importance of assessing PP and ISH in the prevention of cardiovascular disease.

Perspectives

Potentially, our findings may be used to optimize clinical protocols for the diagnosis of atherosclerosis and the prevention of ischemic heart disease and stroke. Also, measuring multiple vascular beds may be a reasonable risk reduction strategy to reduce CVD. Hopefully, data from future studies will provide additional insight that suggests that screening multiple vascular beds may have clinical relevance and that screening multiple BP components will be useful in improving CVD risk assessment.