Subclinical atherosclerosis and risk factors in relation to autonomic indices in the general population

INTRODUCTION

Orthostatic hypotension is one common manifestation of cardiovascular autonomic dysfunction that affects a substantial proportion of the population [1]. The incidence of orthostatic hypotension increases with age and the presence of orthostatic hypotension is associated with neurologic disorders as well as cardiovascular risk factors and disease [2,3]. Apart from the adverse outcomes of manifest orthostatic hypotension and the morbidity and mortality in conjunction with fall injuries [4], even subtle indices of autonomic dysfunction can be the first signs of disease and predict future adverse cardiovascular events [1–3,5,6]. This may be in the form of an abnormal orthostatic blood pressure response that does not fulfil the criteria for manifest orthostatic hypotension, but cardiovascular autonomic dysfunction may also be indicated by an elevated resting heart rate (RHR). Of note, an elevated RHR has been shown to be strongly associated with adverse cardiovascular events [6,7].

Whereas markers of cardiovascular autonomic dysfunction, such as orthostatic hypotension and elevated RHR, are associated with adverse cardiovascular outcomes, it is not known how these factors relate to subclinical cardiovascular disease in the general population. One measurement of vascular ageing and adverse cardiovascular risk is arterial stiffness [8,9]. With increasing age, the walls of large elastic arteries undergo adverse structural and functional changes, leading to arteriosclerosis and arterial stiffness [10]. Arterial stiffness can be determined by various indices, of which carotid to femoral pulse wave velocity (PWV) is the most widely validated [11].

Another potential marker of vascular ageing and subclinical atherosclerosis is coronary artery calcification score (CACS) according to Agatson, which is assessed by computed tomography (CT). Recent studies have suggested that CACS is of predictive value, particularly in asymptomatic individuals [12–16] and may reclassify individuals at risk of coronary artery disease events [17].

In this study, we examined signs of cardiovascular autonomic dysfunction in the general population and their association with cardiovascular risk factors including subclinical atherosclerosis and arterial stiffness. We specifically hypothesized that an abnormal orthostatic blood pressure response as well as elevated RHR in middle-aged individuals are associated with subclinical cardiovascular disease in the form of increased arterial stiffness, coronary and carotid atherosclerosis.

MATERIALS AND METHODS Study population

The current study was based on the population-based Swedish CArdioPulmonary-bio-Image Study (SCAPIS) from which we used data from the sub-cohort recruited in Malmö, Sweden. The Malmö SCAPIS cohort (6251 individuals, 53% participation rate of invited individuals) included blood samples, questionnaires, anthropometric and haemodynamic measurements, including complete recordings on orthostatic blood pressure reactions, coronary artery calcium score as well as carotid to femoral PWV. The SCAPIS project has been previously described in detail [18,19].

Figure 1 depicts the procedure of exclusion in our current study population. Firstly, individuals with missing recordings of orthostatic blood pressure (BP) reactions (n = 251) were excluded. Of the remaining 6000 individuals, 259 were excluded due to missing information on carotid-femoral PWV. Of these, 5741 individuals, 179 were further excluded due to missing information on CACS and 69 more for missing information of any blood samples. In total, 5493 individuals constituted the final study population. These individuals had complete data on anthropometric measurements, that is weight, height, BMI and waist circumference, smoking status, BP and pulse pressure (PP) and RHR.

F1FIGURE 1:

Flow chart for the selection of the final study population. The selection of the final study population. PWV, pulse wave velocity; SCAPIS, The Swedish CArdioPulmonary bioImage Study.

Written informed consent was obtained from all participants. The SCAPIS project was approved by the Regional Ethical Review Board in Umeå (2010–228–31 M) and Lund (2016/1031), respectively.

Basic examination

Computed tomography was used to determine CACS, and the calcium content in each artery was summed utilizing the Agatston scoring system [20,21].

Arterial stiffness was determined by the parameter carotid-femoral artery PWV in metres per second. The methods for assessing CACS and PWV in the SCAPIS study were described in detail previously [18]. Height, weight, waist circumference and BMI were obtained and measured in meters and kilograms.

Brachial SBP and DBP readings were taken in supine position after 5 min of rest. BP readings were then taken after 3 min of standing to obtain systolic and diastolic orthostatic BP reactions by subtracting the BP after standing from the BP in supine position (i.e. positive values correspond to a BP decrease on standing).

Orthostatic hypotension was defined according to the international consensus as a decrease in SBP of 20 mmHg or more and/or a decrease in DBP of 10 mmHg or more. We also created another variable for orthostatic hypotension that included a drop in SBP to below 90 mmHg 3 min after standing up (OH90). Fasting venous blood samples were collected for analysis of glycated haemoglobin (HbA1c), plasma lipids, creatinine and CRP. Smoking and antihypertensive drug treatment were assessed from self-reported data from a questionnaire. Smoking status was categorized as current smoker, former smoker and never-smoker, respectively. Pack-years of smoking was calculated for current smokers (n = 813) and former smokers. Individuals were classified as having diabetes based on responses in the questionnaire or by an elevated fasting plasma glucose sample. Detailed information on the methods used in the Malmö cohort of SCAPIS are found elsewhere [18,19].

Statistical analysis

More than 50% of the participants had a calcium score of zero, resulting in skewed data. To classify the distribution (Fig. 2), CACS was classified into four categories using cut offs: 0, 1–100, 101–300 and more than 300.

F2FIGURE 2:

Distribution of coronary artery calcification score in the study population. Distribution of coronary artery calcification score in the study population. The score corresponds to Agatson score measured by computed tomography. CACS, coronary artery calcification score.

The participants were categorized into quartiles according to orthostatic BP decrease, that is Q1 included the individuals with the least decrease (or even increase in BP upon standing) and Q4 those with the most fall in BP upon standing.

The characteristics of the study population were explored and described as mean ± SD for normal distributions. Due to skewed distribution, CACS was described as median and interquartile range.

Differences across the various characteristics were tested using χ2 for categorical variables, analysis of variance (ANOVA) for continuous and normally distributed variables and Kruskal–Wallis test and Mann–Whitney test for nonnormal-distributed variables. Furthermore, linear regression models were constructed with CACS and PWV, respectively, as dependent variables and orthostatic hypotension as well as covariates age, sex, smoking, diabetes mellitus, low-density lipoprotein (LDL) and antihypertensive treatment as independent variables. All analyses were carried out using SPSS version 25 (IBM Corp, Armonk, New York, USA). A P value of less than 0.05 was regarded as statistically significant.

RESULTS Characteristics of the study population

Characteristics of the study population are presented in Table 1. In short, the participants were between 50 and 64 years of age, and 46.6% of participants were men. In the population, 43% were overweight (BMI greater than 25 kg/m2) and 22% were obese (BMI greater than 30 kg/m2). This distribution is depicted in a pie chart in the supplement (Supplementary figure 1, https://links.lww.com/HJH/C143). Diabetes mellitus was prevalent in 7.7%. The mean (SD) orthostatic SBP and DPB reactions upon standing was −3.8 (10.2) and −9.5 (6.4) mmHg, respectively (i.e. both SBP and DBP increased on average in the population). Manifest orthostatic hypotension was present in 95 of 5493 recordings, that is 1.7% and 124, that is 2.3% when also accounting for a drop of SBP to under 90 mmHg (OH90).

TABLE 1 - Study population characteristics Orthostatic SBP reaction Characteristics N Q1 (Increase > 10 mmHg) Q2 (Increase 10 to 4 mmHg) Q3 (Increase 4 mmHg to decrease 3 mmHg) Q4 (Decrease > 3 mmHg) P b Number of individuals (n, %) 5493 1478 (26.9%) 1306 (23.8%) 1363 (24.8%) 1346 (24.5%) 0.000 Age (years) 57.5 (±4.3) 58 (±4.3) 57.1 (±4.3) 57.1 (±4.3) 57.6 (±4.3) 0.000 Male sex (n, %) 2561 (46.6%) 42.8% 45.3% 48.7% 50% 0.000 BMI (kg/m2) 27 (±4.3) 27.5 (±4.6) 26.9 (±4.2) 26.8 (±4.3) 26.8 (±4.2) 0.000 Weight (kg) 79.9 (±15.7) 80 (±15.9) 79.5 (±15.4) 79.8 (±16.9) 80.3 (±15.7) 0.570 Height (cm) 171.6 (±9.7) 170.3 (±9.6) 171.5 (±9.6) 172.1 (±9.8) 172.9 (±9.7) 0.000 Waist circumference (cm) 94.8 (±12.7) 95.7 (±12.8) 94.5 (±12.5) 94.4 (±12.7) 94.7 (±12.7) 0.019 Resting heart rate (beats per minute) 61 (±9) 61 (±9) 61 (±9) 61 (±9) 61 (±9) 0.743 SBP (mmHg) 123 (±16) 121 (±16) 120 (±16) 122 (±16) 128 (±17) 0.000 DBP (mmHg) 76 (±10) 76 (±9) 76 (±10) 76 (±10) 78 (±10) 0.000 Pulse pressure (mmHg) 46 (±10) 45 (±10) 44 (±9) 46 (±9) 50 (±10) 0.000 Carotid plaque (%) 3278 (59.9%) 59.3% 56.6% 60.6% 62.8% 0.012 Coronary artery calcium scorea 0 (28) 0 (30) 0 (23) 0 (27) 0 (32) 0.045 Pulse wave velocity (m/s) 8.34 (±1.26) 8.36 (±1.29) 8.19 (±1.19) 8.28 (±1.2) 8.53 (±1.31) 0.000 Pack-years 27 (±34) 28 (±36) 27 (±31) 28 (±34) 26 (±32) 0.310 Haemoglobin level (g/dl) 143 (±12) 142 (±12) 142 (±12) 143 (±12) 143 (±12) 0.091 Creatinine level (mmol/l) 77 (±15) 77 (±16) 77 (±15) 78 (±15) 78 (±15) 0.030 Triglyceride level (mg/dl) 1.3 (±0.8) 1.3 (±0.8) 1.3 (±0.8) 1.2 (±0.8) 1.2 (±0.7) 0.213 Cholesterol level (mg/dl) 5.5 (±1) 5.5 (±1) 5.5 (±1) 5.4 (±1) 5.4 (±1) 0.009 HDL (mmol/l) 1.7 (±0.5) 1.7 (±0.5) 1.7 (±0.5) 1.7 (±0.5) 1.7 (±0.5) 0.441 LDL (mmol/l) 3.6 (±0.9) 3.6 (±0.9) 3.6 (±1) 3.6 (±0.9) 3.6 (±1) 0.068 Cholesterol/HDL ratio 3.6 (±1.3) 3.6 (±1.4) 3.6 (±1.2) 3.5 (±1.2) 3.6 (±1.2) 0.424 CRP (mg/l) 2.4 (±4.4) 2.6 (±4.9) 2.2 (±3.8) 2.4 (±5.4) 2.1 (±3.1) 0.012 HbA1c (%) 36.9 (±6.8) 36.8 (±5.9) 36.7 (±5.8) 36.8 (±6.6) 37.3 (±8.8) 0.150 Plasma glucose level (mmol/l) 5.5 (±1.2) 5.5 (±1.1) 5.5 (±1.2) 5.5 (±1.1) 5.6 (±1.5) 0.014 Diabetes (n, %) 423 (7.7%) 8.4% 6.2% 7.5% 8.6% 0.079 Current smokers (n, %) 813 (14.8%) 15.9% 16.6% 14.3% 12.3% 0.009 Antihypertensive drugs (n, %) 1100 (20%) 23.8% 17.5% 19.3% 19% 0.001

Values expressed are means (±SD) or percentages unless specified otherwise.CRP, C-reactive protein; HDL, high-density lipoprotein cholesterol; LDL, low-density lipoprotein cholesterol.

aExpressed as median (third quartile) due to skewed distribution.

bP value is for difference across the quartiles of Delta SBP.

The distribution of the CACS in the population is depicted in Fig. 2. Approximately 55% had no signs of coronary artery calcification on cardiac computerized tomography, while about 6% had severe calcification of their coronary arteries (CACS >300).

Measurements on carotid-femoral PWV in our study (mean 8.34 m/s; SD 1.26) resembled findings for the same age group found in other studies [22,23]. Haemodynamic parameters and blood samples had normal values on average.

Cardiovascular risk factors and orthostatic hypotension

The distribution of cardiovascular risk factors in relation to manifest orthostatic hypotension is depicted in Table 2. The factors that differed according to orthostatic hypotension were age (P = 0.021), SBP (P < 0.001), DBP (P < 0.001), PP (P < 0.001), CACS (P < 0.001), PWV (P = 0.004) as well as HbA1c (P < 0.001) and plasma glucose levels (P = 0.035). The occurrence of carotid plaque did not differ according to orthostatic hypotension (Table 2).

TABLE 2 - Cardiovascular risk factors according to manifest orthostatic hypotension in the population Orthostatic hypotension Yes No P Individuals, n (%) 95 (1.7) 5398 (98.3) N/A Age 58.4 (4.3) 57.4 (4.3) 0.021 Male sex % 48.4% 46.6% 0.756 BMI 26.9 (3.8) 27 (4.4) 0.686 Weight (kg) 80.3 (15.1) 79.9 (15.7) 0.827 Height (cm) 172.5 (9) 171.6 (9.7) 0.408 WC (cm) 94.7 (11.1) 94.8 (12.7) 0.927 RHR (bpm) 61 (9) 61 (10.6) 0.906 SBP (mmHg) 139 (19) 122 (16) <0.001 DBP (mmHg) 82 (10) 76 (10) <0.001 PP (mmHg) 56 (13) 46 (10) <0.001 Carotid plaque 59.7% 66.3% 0.195 CACSa 9 (89) 0 (27) <0.001 PWV 8.7 (1.4) 8.3 (1.3) 0.004 Pack-years 27 (30) 27 (34) 0.985 Haemoglobin 142 (13) 143 (12) 0.632 Creatinine 78 (14) 77 (15) 0.868 Triglycerides 1.2 (0.8) 1.3 (0.8) 0.541 Cholesterol 5.4 (1) 5.5 (1) 0.629 HDL 1.7 (0.5) 1.7 (0.5) 0.507 LDL 3.5 (0.9) 3.6 (1) 0.441 Chol/HDL 3.5 (1.2) 3.6 (1.3) 0.451 CRP 2.2 (3.6) 2.4 (4.4) 0.774 HbA1c 39 (13) 37 (7) 0.000 Glucose 5.8 (2.1) 5.5 (1.2) 0.035 DM 11.6% 7.6% 0.170 Smoking 10.5% 14.9% 0.306 HTD treatment 25.3% 19.9% 0.417

Values expressed are means (±SD) or percentages.Bpm, beats per minute; CACS, Coronary artery calcification score; Chol, cholesterol; DM, diabetes mellitus; HTD, hypertensive drug; N, Total number of participants; PP, pulse pressure; PWV, pulse wave velocity; RHR, resting heart rate; WC, waist circumference.

aExpressed as median and third quartile due to skewed distribution.

In multivariable linear regression models, orthostatic hypotension was associated with PWV (beta 0.27; P = 0.023) but not with CACS (P = 0.26).

The distribution of cardiovascular risk factors in relation to OH90 is shown in Supplementary Table 1, https://links.lww.com/HJH/C143. Of note, individuals with normal orthostatic reactions demonstrated higher values of variables associated with obesity, that is they had higher BMI (P = 0.007), weight (P = 0.035) and waist circumference (P = 0.004). The association with haemodynamic parameters according to OH90 was similar to that of orthostatic hypotension, with the exception of PWV, which did not associate with OH90 (P = 0.375).

Orthostatic blood pressure reactions and cardiovascular risk factors

The second (Q2) and third (Q3) quartiles of systolic orthostatic BP reaction included normal orthostatic BP reactions, whereas Q1 indicates an increase in SBP during orthostatic provocation (more than 10 mmHg) and Q4 include a decrease in SBP during orthostatic provocation of 3 mmHg and more, that is including orthostatic hypotension.

Orthostatic SBP and DBP reactions were associated with CACS (P = 0.045 and P < 0.001, respectively) as were PP (P < 0.001). There was an association between CACS and PWV (P < 0.001) (see Figures 3a-c and Supplementary Figure 2A, https://links.lww.com/HJH/C143, respectively).

F3FIGURE 3: (a--c) Prevalence of coronary calcification and arterial stiffness according to quartiles of orthostatic blood pressure reactions. Coronary artery calcification score (a) and arterial stiffness (b) according to quartiles of orthostatic SBP reaction and coronary artery calcification score according to quartiles of orthostatic DBP reaction (c). Quartiles for orthostatic SBP reaction are shown in Table 1. Quartiles for orthostatic DBP reaction were Q1: increase of 13.5 to 38.5 mmHg; Q2: increase of 9.5 to 13 mmHg; Q3: increase of 5.5 to 9 mmHg; Q4: decrease 26.5 mmHg to increase 5 mmHg. CACS, coronary artery calcification score; ORDBP, orthostatic DBP reaction; ORSBP, orthostatic SBP reaction.

A number of cardiovascular risk factors were distributed according to systolic orthostatic BP reaction in a U-shaped pattern (see Table 1; Fig. 3 and Supplementary Figure 2, https://links.lww.com/HJH/C143), that is they were most pronounced in the quartiles with either the most pronounced orthostatic BP increase (Q1) or decrease (Q4). A significant difference across quartiles of systolic orthostatic BP reactions was found for age (P < 0.001), CACS (P = 0.045) and PWV (P < 0.001) (Fig. 3 a,b). The occurrence of carotid plaque differed according to quartiles of orthostatic SBP reactions (P = 0.012); however, this was not the case for diabetes mellitus (P = 0.079).

For anthropometric measurements, there was an association between orthostatic BP and BMI (P < 0.001) and waist circumference (P = 0.019), where specifically an increase in orthostatic BP seemed to correlate with higher BMI and waist circumference.

Height was associated with orthostatic SBP decrease (P < 0.001), with the largest heights seen in the quartile with the most pronounced orthostatic BP decrease.

Higher SBP, DBP and larger PP (P < 0.001 for all) were observed in the quartile with the most pronounced systolic orthostatic BP decrease.

Resting heart rate and cardiovascular risk factors

Resting heart rate was divided into quartiles Q1 to Q4: less than 56, 56–60, 61–66 and more than 66 bpm, respectively.

There were no significant differences in CACS according to quartiles of RHR (P = 0.137). Visually, an S-formed pattern was observed as depicted in Fig. 4a.

F4FIGURE 4:

(a,b) Coronary artery calcification and arterial stiffness according to quartiles of resting heart rate. Coronary artery calcification score (a) and arterial stiffness (b) according to quartiles of resting heart rate. Quartiles for resting heart rate were Q1: <56 bpm; Q2: 56–60 bpm; Q3: 61–66 bpm and Q4: >66 bpm. CACS, coronary artery calcification score.

Significant differences according to RHR were found for PWV (P < 0.001), age (P = 0.011), SBP (P < 0.001) and DBP (P < 0.001), and the anthropometric parameters BMI (P < 0.001), weight (P < 0.001), height (P < 0.001), waist circumference (P < 0.001). A number of biochemical values differed as well, including creatinine (P < 0.001), triglycerides (P < 0.001), HDL (P < 0.001), cholesterol (P = 0.026), blood glucose levels (P < 0.001), CRP (P < 0.001) and HbA1c (P < 0.001).

There was no significant association between RHR and PP (P = 0.132) and LDL (P = 0.089).

For the haemodynamic parameters, the lowest mean SBP and DBP were observed in the quarter with lowest RHR and highest SBP and DBP in the quarter with highest RHR (see Supplementary Figure 2B, https://links.lww.com/HJH/C143).

The same pattern was seen for PWV (Fig. 4b) and the anthropometric parameters weight, BMI and waist circumference (Supplementary Figure 2C, https://links.lww.com/HJH/C143), except for height, where the pattern was inverted (the quarter with the lowest RHR were on average taller, and the quarter with the highest RHR were on average shorter (Supplementary Figure 2D, https://links.lww.com/HJH/C143).

The use of antihypertensive drug treatment was higher in those with higher RHR (P < 0.001). The same pattern was seen for the prevalence of diabetes mellitus (P < 0.001). Smoking status did not differ according to RHR (P = 0.358).

DISCUSSION

In this study, we tested the hypothesis that an abnormal orthostatic BP response as well as elevated RHR in middle-aged individuals are associated with subclinical cardiovascular disease in the form of increased arterial stiffness, carotid and coronary atherosclerosis. We show that:

(1) The prevalence of manifest orthostatic hypotension is low in the general population at middle age; however, a number of conventional cardiovascular risk factors are associated with this condition already at this age. (2) There seems to be a U-shaped association between BP reaction upon standing and markers of atherosclerosis and vascular status, including coronary calcium deposits and carotid-femoral PWV. Both an excessive BP increase and decrease upon standing seem to be associated with markers of vascular aging.

The prevalence of orthostatic hypotension and other potential manifestations of cardiovascular autonomic dysfunction increases with age, in parallel with cardiopulmonary disease. Previous studies have shown that orthostatic hypotension as well as other features of cardiovascular autonomic dysfunction are associated with adverse cardiovascular disease outcomes [2,7,24,25]; however, the association between subtle markers of cardiovascular autonomic dysfunction and subclinical cardiovascular disease and risk factors in the general population has been less well explored.

Generalization of the findings from the current study population

The SCAPIS study enrolled a substantial part of urban age groups 50–64 years of age, with a participation rate over 50%. Hence, findings should be representative for the middle-aged general population in Sweden. Over 20% were obese and more than 7% had DM.

As mentioned, the prevalence of manifest orthostatic hypotension was found to be quite low in our study compared with a similar Swedish study population (The Malmö Preventive Project) that was enrolled some decades earlier [5]. It may be that better control of cardiovascular risk factors in recent decades, with smoking as the most notable difference (45 vs. 15% in our current study), has actually improved vascular health, and thus reduced the prevalence of orthostatic hypotension.

Cardiovascular disease risk factors associated with cardiovascular autonomic dysfunction

Firstly, we found that a number of cardiovascular risk factors, including age, SBP and DBP, PP, coronary calcium, PWV as well as HbA1c and blood glucose levels were associated with manifest orthostatic hypotension. In contrast, we did not find any significant association between orthostatic hypotension and diabetes, antihypertensive drug treatment and current smoking.

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