Abstract
Objective
Numerous studies have reported an association between common carotid artery (CCA) parameters and atherosclerotic cardiovascular disease (CVD). However, the association between CCA parameters and hemodynamic stress on the left ventricle in elderly patients remains unclear.
Methods
We assessed CCA parameters, including the height-adjusted CCA interadventitial diameter (diameter/height), mean intima-media thickness (IMT), number of plaques, plaque score, resistance index (RI), and pulsatility index (PI) with ultrasonography, using serum N-terminal pro-brain natriuretic peptide (NT-proBNP) levels as a marker for hemodynamic stress on the left ventricle in 1,315 participants ≥70 years old without CVD. Of these participants, 706 had hypertension, defined as taking antihypertensive medications, having a systolic blood pressure ≥140 mmHg, and/or having a diastolic blood pressure ≥90 mmHg.
Results
After adjusting for the confounding factors, the CCA interadventitial diameter/height was significantly associated with the log NT-proBNP in both the normotensive group (β=0.125, p=0.002) and hypertensive group (β=0.080, p=0.029). The RI was significantly associated with the log NT-proBNP in the hypertensive group (β=0.176, p<0.001) but not in the normotensive group. In addition, the PI was significantly associated with the log NT-proBNP in the hypertensive group (β=0.156, p<0.001) but not in the normotensive group. However, no significant association was observed between the mean IMT, number of plaques, and plaque score and log NT-proBNP.
Conclusion
CCA measurements may be useful markers for hemodynamic stress on the left ventricle in elderly patients.
Keywords: brain natriuretic peptide, carotid artery, elderly, resistance index, pulsatility index
Introduction
Interaction between the systemic arterial tree and heart has been suggested to play an important role in the development of atherosclerotic cardiovascular disease (CVD) and heart failure (1,2). The common carotid artery (CCA) is part of the elastic arterial tree that is believed to reflect aortic hemodynamics (3). Numerous studies have reported that morphologic parameters of the CCA are associated with atherosclerotic CVD (4-7). However, available data regarding the hemodynamic link between the CCA morphology and heart are limited (8,9). Furthermore, the association of CCA flow parameters, including the resistance index (RI) and pulsatility index (PI) (10), with hemodynamic stress on the left ventricle has not been studied. Because the RI and PI of the CCA reflect vascular resistance of small blood vessels in cerebral arterial trees distal to the measurement point in the CCA (11), these parameters represent, at least in part, vascular resistance of the systemic vascular trees and the cardiac afterload.
N-terminal pro-brain natriuretic peptide (NT-proBNP), an established marker for heart failure (12), is released from the myocardium in response to increased cardiac wall stress due to volume and pressure overload (13,14) and thus reflects hemodynamic stress on the left ventricle in individuals without cardiac disease (15,16).
In the present study, we investigated whether or not CCA parameters, including interadventitial diameter, intima-media thickness (IMT), plaque number, plaque score, RI, and PI, were associated with the serum NT-proBNP levels in elderly participants without CVD, considering the differences between normotensive and hypertensive subjects.
Materials and Methods
Study participants
To investigate the CCA parameters and serum NT-proBNP levels, we recruited a total of 1,484 participants ≥70 years old following general health examinations from January 2015 to September 2017 at the Health Management and Promotion Center of the Hiroshima Atomic Bomb Casualty Council, Hiroshima, Japan. Data were collected regarding the participants' regular medications and medical histories (e.g. treatment for hypertension, diabetes mellitus, dyslipidemia, and CVDs) as well as drinking and smoking habits.
Among these participants, 16 were excluded because they did not complete the CA ultrasonographic measurements, 15 because of the presence of atrial fibrillation, 18 because of renal dysfunction (defined as serum creatinine ≥1.5 mg/dL), and 120 because they were being treated for or had a history of CVD (including coronary heart disease and stroke). In total, 1,315 participants [666 men and 649 women; mean age ± standard deviation (SD), 74.1±3.1 years; and mean body mass index (BMI) ± SD, 22.9±3.1 kg/m2] were included in our study. Of these, 706 participants (54%) had hypertension [defined as taking antihypertensive medications (n=491), having a systolic BP (SBP) ≥140 mmHg, and/or having a diastolic BP (DBP) ≥90 mmHg] (17); 232 (18%) had diabetes mellitus (defined as taking antidiabetic medications and/or having HbA1c ≥6.5); 846 (64%) had dyslipidemia (defined as taking antihyperlipidemic medications and/or having low density lipoprotein (LDL)-C ≥140 mg/dL, high density lipoprotein (HDL)-C <40 mg/dL, and/or triglyceride ≥150 mg/dL); 90 (7%) were current smokers (defined as having a current smoking habit, regardless of the number of cigarettes smoked per day); and 422 (32%) were habitual drinkers (defined as drinking alcohol for ≥5 days/week, regardless of the amount consumed).
Informed consent was obtained from all participants. The study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki and was approved by the Hiroshima Atomic Bomb Casualty Council committee.
CA ultrasonographic measurements
CA ultrasonography was performed by a blinded, experienced echographer using standard techniques with a HITACHI HIVISON Preirus (Hitachi Medical, Tokyo, Japan) equipped with a 7.5-MHz linear-array transducer. The participants were examined in the supine position with their head turned 45° from the site being scanned. The CCA interadventitial diameter was measured during the late phase of vascular contraction (end-diastolic phase) on the longitudinal scan at a point 10 mm proximal from the beginning of the carotid bulb. The CCA interadventitial diameter was defined as the distance between the adventitia-media interface on the near wall and the media-adventitia interface on the far wall. We calculated the height-adjusted index for the CCA interadventitial diameter as the CCA interadventitial diameter/height (mm/m) (9). The IMT was defined as the distance between the lumen-intima and media-adventitia interfaces. The greatest IMT was detected by scanning the CCA in the longitudinal axis view, and 2 measurements of IMT were performed at 10 mm proximal and 10 mm distal to the site of the greatest IMT. The mean IMT was then calculated as the mean of the IMT values at these three points (18).
Localized elevated lesions with a maximum thickness of >1 mm and a point of inflection on the surface of the intima-media complex were defined as plaques. Blood flow parameters, including the peak systolic velocity (PSV), end-diastolic velocity (EDV), and mean blood flow velocity (V mean), were measured with the sample volume located at the center of the CCA. An insonation angle ≤60° was maintained for all Doppler measurements, and RI was automatically calculated as (PSV-EDV)/PSV. Furthermore, the PI was automatically calculated as (PSV - EDV) / Vmean. In the subsequent analyses of this study, we used the measurements of the left CCA as the height-adjusted CCA diameter, mean IMT, RI, and PI. The number of plaques was counted in the left CCA and left internal CA. We calculated the plaque score by totaling the maximum thickness of all plaques in the same area (19).
We estimated the reliability of the ultrasonographic measurements from 134 pairs of scans performed up to a year apart, and the estimated correlation between the scans was 0.850 for the CCA interadventitial diameter, 0.854 for the mean IMT, 0.836 for the number of plaques, 0.948 for the plaque score, 0.698 for the RI, and 0.691 for the PI.
Blood sample and blood pressure measurements
We collected blood samples from all participants for measuring hemoglobin concentration and serum levels of creatinine and NT-proBNP. NT-proBNP was measured by a chemiluminescent enzyme immunoassay using a Cobas e601 analyzer (Roche Diagnostics, Tokyo, Japan) (20). A high NT-proBNP level was defined as NT-proBNP ≥ 125 pg/mL (21). Using a digital, automatic blood pressure (BP)-measuring instrument (Terumo, Tokyo, Japan or Omron Healthcare, Kyoto, Japan), BP was measured with the patient in a seated position on a chair with back and arm support at the heart level after resting for >5 minutes when the participants underwent health examinations.
Statistical analyses
Continuous variables are expressed as the mean ± standard deviation or median (interquartile range, 25-75%). The differences between the normotensive and hypertensive groups were compared using Wilcoxon's rank-sum test. Categorical variables were summarized as percentages and analyzed using the chi-squared test. Because the serum NT-proBNP level showed a skewed distribution, logarithmic transformation was carried out before the subsequent analyses. The relationships between individual CCA parameters and the log NT-proBNP were evaluated using Spearman's rank correlation. To adjust for the confounding factors that were correlated significantly with the log NT-proBNP, as determined by Spearman's rank correlation, the following two multivariable regression models were used: model 1 included the age, sex, BMI, hemoglobin concentration, SBP, DBP, and the presence of diabetes and dyslipidemia; model 2 included the pulse pressure (PP) instead of SBP and DBP in model 1. Consequently, we stratified the participants into subgroups based on sex to investigate the association between individual CCA parameters and log NT-proBNP using models 1 and 2.
We considered p<0.05 as statistically significant. All statistical analyses were performed using the JMP 10 statistical software program (SAS Institute, Cary, USA).
Results
Participants' characteristics and parameters of ultrasonographic measurements of the CCA are summarized in Table 1. The median (interquartile range, 25-75%) NT-proBNP level was 68 pg/mL (range, 41-103 pg/mL) and 71.5 pg/mL (range, 43-119 pg/mL) in the normotensive and hypertensive groups, respectively. All CCA parameters, including the CCA interadventitial diameter/height, mean IMT, number of plaques, plaque score, RI, and PI, were significantly higher in the hypertensive group than in the normotensive group.
Table 1.
Clinical Characteristics of Participants.
| All | Normotensive | Hypertensive | p | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| N | 1,315 | 609 | 706 | |||||||
| Mean age | (years) | 74.1±3.1 | 73.8±2.8 | 74.3±3.3 | 0.012 | |||||
| Female | [n (%)] | 649 (49) | 327 (54) | 322 (46) | 0.003 | |||||
| BMI | (kg/m2) | 22.9±3.1 | 22.1±2.7 | 23.7±3.2 | <0.001 | |||||
| Hemoglobin | (g/dL) | 13.8±1.3 | 13.7±1.2 | 13.9±1.3 | <0.001 | |||||
| Creatinine | (mg/dL) | 0.77±0.18 | 0.75±0.16 | 0.79±0.19 | <0.001 | |||||
| SBP | (mmHg) | 132±17 | 122±11 | 139±16 | <0.001 | |||||
| DBP | (mmHg) | 75±11 | 71±9 | 79±12 | <0.001 | |||||
| PP | (mmHg) | 56±13 | 51±10 | 61±14 | <0.001 | |||||
| HbA1c | (%) | 6.1±0.6 | 6.0±0.6 | 6.1±0.7 | 0.068 | |||||
| LDL-C | (mg/dL) | 122±29 | 125±28 | 120±29 | <0.001 | |||||
| HDL-C | (mg/dL) | 65±17 | 67±17 | 63±16 | <0.001 | |||||
| TG | (mg/dL) | 129±93 | 121±70 | 136±109 | <0.001 | |||||
| Current smoker | [n (%)] | 90 (7) | 39 (6) | 51 (7) | 0.557 | |||||
| Habitual drinker | [n (%)] | 422 (32) | 167 (27) | 255 (36) | <0.001 | |||||
| Diabetes | [n (%)] | 232 (18) | 96 (16) | 136 (19) | 0.096 | |||||
| Dyslipidemia | [n (%)] | 846 (64) | 387 (64) | 459 (65) | 0.580 | |||||
| NT-proBNPa | (pg/mL) | 69 (42–113) | 68 (41–103) | 71.5 (43–119) | 0.035 | |||||
| Log NT-proBNPa | 4.23 (3.74–4.73) | 4.18 (3.71–4.63) | 4.28 (3.76–4.78) | 0.035 | ||||||
| Ultrasonographic measurements of the common carotid artery | ||||||||||
| Diameter | (mm) | 7.4±0.8 | 7.1±0.8 | 7.6±0.8 | <0.001 | |||||
| Diameter/height | (mm/m) | 4.68±0.51 | 4.52±0.47 | 4.82±0.50 | <0.001 | |||||
| Mean IMT | (mm) | 0.9±0.2 | 0.8±0.2 | 0.9±0.2 | <0.001 | |||||
| Number of plaques | (n) | 1.9±1.2 | 1.8±1.2 | 2.1±1.3 | <0.001 | |||||
| Plaque score | 2.8±2.1 | 2.5±1.9 | 3.1±2.2 | <0.001 | ||||||
| RI | 0.74±0.06 | 0.73±0.05 | 0.75±0.05 | <0.001 | ||||||
| PI | 1.64±0.35 | 1.57±0.32 | 1.71±0.36 | <0.001 | ||||||
Data are expressed as mean±standard deviation or as number and percentage.
aData are provided as the median values (interquartile range, 25–75%).
BMI: body mass index, DBP: diastolic blood pressure, IMT: intima-media thickness, NT-proBNP: N-terminal pro-brain natriuretic peptide, PI: pulsatility index, PP: pulse pressure, RI: resistance index, SBP: systolic blood pressure
Fig. 1 shows the association of individual CCA parameters with the log NT-proBNP in the normotensive group. The CCA interadventitial diameter/height was significantly associated with the log NT-proBNP (ρ=0.155, p<0.001). However, the mean IMT (ρ=0.025, p=0.547), number of plaques (ρ=0.050, p=0.214), plaque score (ρ=0.042, p=0.299), RI (ρ=−0.053, p=0.193), and PI (ρ=−0.078, p=0.056) were not significantly associated with the log NT-proBNP. Fig. 2 shows the association of individual CCA parameters with the log NT-proBNP in the hypertensive group. The CCA interadventitial diameter/height was significantly associated with the log NT-proBNP (ρ=0.132, p<0.001). In addition, both the RI (ρ=0.154, p<0.001) and PI (ρ=0.092, p=0.014) were significantly associated with the log NT-proBNP. However, the mean IMT (ρ=0.062, p=0.099), number of plaques (ρ=−0.010, p=0.801), and plaque score (ρ=0.003, p=0.938) were not significantly associated with the log NT-proBNP.
Figure 1.
The association of individual CCA parameters with the log NT-proBNP in the normotensive group. IMT: intima-media thickness, NT-proBNP: N-terminal pro-brain natriuretic peptide, PI: pulsatility index, RI: resistance index, ρ: Spearman’s rank correlation coefficient
Figure 2.
The association of individual CCA parameters with the log NT-proBNP in the hypertensive group. IMT: intima-media thickness, NT-proBNP: N-terminal pro-brain natriuretic peptide, PI: pulsatility index, RI: resistance index, ρ: Spearman’s rank correlation coefficient
Table 2 shows the Spearman's rank correlations between the clinical characteristics and log NT-proBNP. The age, gender, SBP, and PP were positively associated with the log NT-proBNP, whereas the BMI, hemoglobin concentration, DBP, and presence of diabetes and dyslipidemia were negatively associated with the log NT-proBNP.
Table 2.
Spearman’s Rank Correlation between Clinical Characteristics of Participants and Log NT-proBNP.
| Variables | Log NT-proBNP | |||
|---|---|---|---|---|
| ρ | p | |||
| Age, year | 0.145 | <0.001 | ||
| Female | 0.137 | <0.001 | ||
| BMI, kg/m2 | -0.170 | <0.001 | ||
| Hemoglobin, g/dL | -0.251 | <0.001 | ||
| Creatinine, mg/dL | -0.012 | 0.676 | ||
| SBP, mmHg | 0.092 | <0.001 | ||
| DBP, mmHg | -0.058 | 0.036 | ||
| PP, mmHg | 0.178 | <0.001 | ||
| Current smoker, yes or no | 0.020 | 0.461 | ||
| Habitual drinker, yes or no | 0.009 | 0.743 | ||
| Anti-hypertensive medication, yes or no | -0.013 | 0.643 | ||
| Diabetes, yes or no | -0.091 | 0.001 | ||
| Dyslipidemia, yes or no | -0.086 | 0.002 | ||
BMI: body mass index, DBP: diastolic blood pressure, NT-proBNP: N-terminal pro-brain natriuretic peptide, PP: pulse pressure, SBP: systolic blood pressure
Table 3 shows the results of the multiple linear regression analysis. After adjusting for the confounding factors, including SBP and DBP (model 1), the CCA interadventitial diameter/height was significantly associated with the log NT-proBNP in both the normotensive group (β=0.125, p=0.002) and hypertensive group (β=0.080, p=0.029). In addition, both the RI and PI were significantly associated with the log NT-proBNP in the hypertensive group (β=0.176, p<0.001 and β=0.156, p<0.001, respectively) but not in the normotensive group. Similar results were obtained in model 2, which included PP.
Table 3.
Multiple Linear Regression Analysis for Log NT-proBNP in Normotensive and Hypertensive
| Variables | β | p | β | p | β | p | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Normotensive (n=609) | ||||||||||||
| Model 1 | ||||||||||||
| Age, year | 0.076 | 0.057 | 0.104 | 0.008 | 0.104 | 0.008 | ||||||
| Female | 0.044 | 0.363 | 0.031 | 0.536 | 0.028 | 0.578 | ||||||
| BMI, kg/m2 | -0.114 | 0.006 | -0.088 | 0.033 | -0.089 | 0.032 | ||||||
| Hemoglobin, g/dL | -0.250 | <0.001 | -0.263 | <0.001 | -0.264 | <0.001 | ||||||
| Diabetes, yes or no | 0.115 | 0.003 | 0.222 | 0.005 | 0.111 | 0.004 | ||||||
| Dyslipidemia, yes or no | 0.014 | 0.721 | 0.013 | 0.749 | 0.012 | 0.758 | ||||||
| SBP, mmHg | 0.090 | 0.058 | 0.102 | 0.043 | 0.100 | 0.043 | ||||||
| DBP, mmHg | -0.082 | 0.083 | -0.082 | 0.106 | -0.081 | 0.106 | ||||||
| Diameter/height, mm/m | 0.125 | 0.002 | ||||||||||
| RI | 0.015 | 0.738 | ||||||||||
| PI | 0.022 | 0.621 | ||||||||||
| Model 2 | ||||||||||||
| Age, year | 0.076 | 0.057 | 0.104 | 0.008 | 0.104 | 0.008 | ||||||
| Female | 0.044 | 0.363 | 0.031 | 0.536 | 0.028 | 0.578 | ||||||
| BMI, kg/m2 | -0.115 | 0.006 | -0.088 | 0.032 | -0.089 | 0.030 | ||||||
| Hemoglobin, g/dL | -0.252 | <0.001 | -0.263 | <0.001 | -0.264 | <0.001 | ||||||
| Diabetes, yes or no | 0.114 | 0.003 | 0.111 | 0.005 | 0.111 | 0.004 | ||||||
| Dyslipidemia, yes or no | 0.014 | 0.728 | 0.012 | 0.750 | 0.012 | 0.759 | ||||||
| PP, mmHg | 0.080 | 0.040 | 0.088 | 0.038 | 0.087 | 0.037 | ||||||
| Diameter/height, mm/m | 0.124 | 0.002 | ||||||||||
| RI | 0.015 | 0.733 | ||||||||||
| PI | 0.022 | 0.618 | ||||||||||
| Hypertensive (n=706) | ||||||||||||
| Model 1 | ||||||||||||
| Age, year | 0.128 | <0.001 | 0.128 | <0.001 | 0.133 | <0.001 | ||||||
| Female | 0.023 | 0.583 | -0.022 | 0.613 | -0.024 | 0.586 | ||||||
| BMI, kg/m2 | -0.141 | <0.001 | -0.139 | <0.001 | -0.140 | <0.001 | ||||||
| Hemoglobin, g/dL | -0.267 | <0.001 | -0.195 | <0.001 | -0.200 | <0.001 | ||||||
| Diabetes, yes or no | 0.070 | 0.048 | 0.078 | 0.027 | 0.076 | 0.031 | ||||||
| Dyslipidemia, yes or no | 0.070 | 0.054 | 0.072 | 0.047 | 0.069 | 0.058 | ||||||
| SBP, mmHg | 0.206 | <0.001 | 0.150 | <0.001 | 0.168 | <0.001 | ||||||
| DBP, mmHg | -0.126 | 0.005 | -0.051 | 0.287 | -0.070 | 0.136 | ||||||
| Diameter/height, mm/m | 0.080 | 0.029 | ||||||||||
| RI | 0.176 | <0.001 | ||||||||||
| PI | 0.156 | <0.001 | ||||||||||
| Model 2 | ||||||||||||
| Age, year | 0.127 | <0.001 | 0.126 | <0.001 | 0.131 | <0.001 | ||||||
| Female | 0.023 | 0.588 | -0.020 | 0.643 | -0.022 | 0.615 | ||||||
| BMI, kg/m2 | -0.141 | <0.001 | -0.136 | <0.001 | -0.138 | <0.001 | ||||||
| Hemoglobin, g/dL | -0.161 | <0.001 | -0.176 | <0.001 | -0.183 | <0.001 | ||||||
| Diabetes, yes or no | 0.072 | 0.044 | 0.081 | 0.021 | 0.079 | 0.025 | ||||||
| Dyslipidemia, yes or no | 0.070 | 0.054 | 0.072 | 0.047 | 0.069 | 0.057 | ||||||
| PP, mmHg | 0.173 | <0.001 | 0.124 | 0.001 | 0.139 | <0.001 | ||||||
| Diameter/height, mm/m | 0.080 | 0.028 | ||||||||||
| RI | 0.165 | <0.001 | ||||||||||
| PI | 0.147 | <0.001 | ||||||||||
BMI: body mass index, DBP: diastolic blood pressure, NT-proBNP: N-terminal pro-brain natriuretic peptide, PI: pulsatility index, PP: pulse pressure, RI: resistance index. SBP: systolic blood pressure, β: standardized partial regression coefficient
Table 4 shows the results of the sex-stratified analysis. In the hypertensive group, the CCA interadventitial diameter/height was significantly associated with the log NT-proBNP in men but not in women. Conversely, the RI and PI were significantly associated with the log NT-proBNP in both men and women.
Table 4.
Sex-stratified Analysis in Multiple Linear Regression for Log NT-proBNP.
| Model 1 | Model 2 | |||
|---|---|---|---|---|
| β | p | β | p | |
| Normotensive | ||||
| Male (n=282) | ||||
| Diameter/height, mm/m | 0.121 | 0.035 | 0.122 | 0.035 |
| RI | 0.017 | 0.765 | 0.016 | 0.177 |
| PI | 0.035 | 0.540 | 0.033 | 0.561 |
| Female (n=327) | ||||
| Diameter/height, mm/m | 0.125 | 0.034 | 0.121 | 0.037 |
| RI | 0.034 | 0.583 | 0.036 | 0.559 |
| PI | 0.025 | 0.684 | 0.026 | 0.666 |
| Hypertensive | ||||
| Male (n=384) | ||||
| Diameter/height, mm/m | 0.108 | 0.029 | 0.108 | 0.029 |
| RI | 0.181 | <0.001 | 0.175 | <0.001 |
| PI | 0.149 | 0.003 | 0.144 | 0.004 |
| Female (n=322) | ||||
| Diameter/height, mm/m | 0.038 | 0.497 | 0.043 | 0.438 |
| RI | 0.146 | 0.014 | 0.128 | 0.027 |
| PI | 0.140 | 0.017 | 0.123 | 0.032 |
Model 1 included age, sex, body mass index, hemoglobin, SBP, DBP, and the presence of diabetes and dyslipidemia. Model 2 included pulse pressure instead of SBP and DBP in model 1.
DBP: diastolic blood pressure, NT-proBNP: N-terminal pro-brain natriuretic peptide, PI: pulsatility index, RI: resistance index, SBP: systolic blood pressure
Discussion
In this study, the mean IMT, number of plaques, and plaque score in the CCA were not associated with the serum NT-proBNP levels in the elderly participants without CVD, suggesting that the local development of atherosclerosis in the CCA has no hemodynamic impact on the left ventricle. Conversely, the height-adjusted CCA interadventitial diameter was positively associated with the serum NT-proBNP level, suggesting that there is a significant hemodynamic linkage between CCA remodeling and the left ventricle in elderly participants with and without hypertension. Furthermore, the RI and PI of the CCA, which are markers for vascular resistance distal to the measurement point (10,11), were positively associated with the serum NT-proBNP level in the elderly hypertensive participants but not in the elderly normotensive participants, suggesting that these flow parameters may be useful markers for hemodynamic stress on the left ventricle in elderly hypertensive individuals.
Although numerous studies have reported that CCA morphologic parameters, such as the IMT and interadventitial diameter, are associated with atherosclerotic CVD (4-7), little is known about the hemodynamic linkage between CCA morphology and the heart. Recently, a few studies have reported that the CCA luminal diameter is associated with the serum NT-proBNP levels and the prevalence of left ventricular hypertrophy in middle-aged individuals (8,9). Scuteri et al. reported that the central SBP was significantly higher in patients with observed wall thickening and lumen dilatation in the CCA than in those without wall thickening or lumen dilatation in the CCA (22), suggesting a hemodynamic linkage between CCA remodeling and the left ventricle. Consistent with these findings, the present study showed that the height-adjusted CCA interadventitial diameter was positively associated with the serum NT-proBNP level in elderly participants. Conversely, the mean IMT, number of plaques, and plaque score were not associated with the serum NT-proBNP levels in this study. NT-proBNP exerts compensatory effects for the increased afterload through the induction of vasodilation, increasing sodium excretion, and inhibition of the sympathetic nervous system and renin-angiotensin-aldosterone system (23). In addition, NT-proBNP is involved in the adipose tissue function, such as via the modulation of the release of adipokines (24,25), and the serum NT-proBNP level is inversely associated with the total cholesterol and low-density lipoprotein cholesterol levels (26). These compensatory effects of NT-proBNP may have attenuated the development of arteriosclerosis and plaque formation, thereby reducing the association of the number of plaques as well as the plaque score with the serum NT-proBNP level for arterial stiffness.
The RI is simply calculated using two-point flow parameters (PSV and EDV) and has been reported to be a marker for stroke prevalence (27). The PI, the which is calculated based on the mean blood flow velocity during the cardiac cycle, is more frequently used for assessing the cerebral hemodynamic status and risk of stroke than RI (28,29). Lee et al. reported that the RI and PI of the CCA correlated with Framingham risk scores in patients with hypertension, suggesting that these CCA flow parameters reflect future coronary heart disease risk (30). However, no studies have investigated the association between these CCA flow parameters and hemodynamic stress on the left ventricle. In this study, we demonstrated that the RI and PI of the CCA were positively associated with the serum NT-proBNP level in elderly hypertensive participants but not in normotensive participants. These findings indicate that the presence of hypertension is a key element involved in the hemodynamic linkage between the heart and vascular resistance of small blood vessels in cerebral arterial trees.
In the present study, we assessed the association between CCA parameters and the serum NT-proBNP level by adjusting for confounding factors, including the age, sex (31), BMI (32), hemoglobin concentration (33), and indices of blood pressure (34). The sex-related differences in the serum NT-proBNP level are well known (31), and consistent with previous reports, we confirmed the significantly higher serum NT-proBNP level in women than in men in this study (data not shown). However, the sex-stratified analysis revealed that these sex-related differences did not affect the association between the CCA parameters and the serum NT-proBNP level, except for the height-adjusted CCA interadventitial diameter in hypertensive women. We were unable to evaluate any age-related differences because only elderly patients ≥70 years of age were included in the study. The vascular resistance of small blood vessels and the pulsatile load in the elastic arterial tree increase with age and can significantly contribute to the hemodynamic linkage between CCA remodeling and the left ventricle stress. A previous study reported that hypertension significantly influenced both the vessel diameter and wall thickness in participants who were >50 years of age. Such a relationship was not observed in younger participants (35). The association between CCA parameters and the NT-proBNP level may thus become significant in elderly individuals.
At present, approximately 50% of all heart failure patients are considered to have heart failure with a preserved ejection fraction (HFpEF), and its prevalence continues to increase with the growth of the elderly population (36). Although the pathophysiology of HFpEF is partially understood, the interaction between the systemic arterial tree and heart may play an important role in the underlying mechanisms (37). Liao et al. reported the gradual enlargement of the CCA lumen diameter from a healthy to a hypertensive status and finally to HFpEF, suggesting that the CCA lumen diameter is useful for identifying HFpEF patients (38). Overall, our results suggest that CCA flow parameters and diameter have a significant hemodynamic linkage with the heart in elderly hypertensive participants at risk of HFpEF (36). In clinical practice, these CCA measurements may be useful markers for detecting an increased risk of heart failure in elderly patients, given that these CCA parameters are easily assessed by ultrasonography.
Several limitations associated with the present study warrant mention. First, because of its cross-sectional study design, a causal relationship between CCA measurements and NT-proBNP may not be inferred. Second, the types of antihypertensive agents used were not assessed in participants being treated for hypertension, although the effects on the cardiac function may differ among antihypertensive agents. Finally, we excluded participants with cardiac disease; however, we were unable to rule out the possibility that our study population may have included participants with subclinical cardiac disease, as we did not assess the cardiac geometry or function using objective methods. In particular, subclinical aortic regurgitation can increase the RI, PI, and left ventricular volume overload, leading to increased serum NT-proBNP level.
In conclusion, our study showed that the height-adjusted CCA interadventitial diameter was positively associated with the serum NT-proBNP level in elderly participants with and without hypertension. The RI and PI of the CCA were also positively associated with the serum NT-proBNP levels in hypertensive patients. These parameters may shed light on the effects of hemodynamic stress on the left ventricle in elderly people.
The authors state that they have no Conflict of Interest (COI).
Acknowledgement
The authors thank Naomi Yuzono for her technical and secretarial assistance.
References
- 1. Vlachopoulos C, Aznaouridis K, O'Rourke MF, Safar ME, Baou K, Stefanadis C. Prediction of cardiovascular events and all-cause mortality with central haemodynamics: a systematic review and meta-analysis. Eur Heart J 31: 1865-1871, 2010. [DOI] [PubMed] [Google Scholar]
- 2. Chirinos JA, Kips JG, Jacobs DR Jr, et al. Arterial wave reflections and incident cardiovascular events and heart failure: MESA (Multiethnic Study of Atherosclerosis). J Am Coll Cardiol 60: 2170-2177, 2012. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3. Boutouyrie P, Bussy C, Lacolley P, Girerd X, Laloux B, Laurent S. Association between local pulse pressure, mean blood pressure, and large-artery remodeling. Circulation 100: 1387-1393, 1999. [DOI] [PubMed] [Google Scholar]
- 4. OLeary DH, Polak JF, Kronmal RA, Manolio TA, Burke GL, Wolfson SK Jr. Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. Cardiovascular Health Study Collaborative Research Group. N Engl J Med 340: 14-22, 1999. [DOI] [PubMed] [Google Scholar]
- 5. Terry JG, Tang R, Espeland MA, et al. Carotid arterial structure in patients with documented coronary artery disease and disease-free control subjects. Circulation 107: 1146-1151, 2003. [DOI] [PubMed] [Google Scholar]
- 6. Baldassarre D, Hamsten A, Veglia F, et al. Measurements of carotid intima-media thickness and of interadventitia common carotid diameter improve prediction of cardiovascular events: results of the IMPROVE (Carotid Intima Media Thickness [IMT] and IMT-Progression as Predictors of Vascular Events in a High Risk European Population) study. J Am Coll Cardiol 60: 1489-1499, 2012. [DOI] [PubMed] [Google Scholar]
- 7. Fujihara K, Suzuki H, Sato A, et al. Comparison of the Framingham risk score, UK Prospective Diabetes Study (UKPDS) Risk Engine, Japanese Atherosclerosis Longitudinal Study-Existing Cohorts Combine (JALS-ECC) and maximum carotid intima-media thickness for predicting coronary artery stenosis in patients with asymptomatic type 2 diabetes. J Atheroscler Thromb 21: 799-815, 2014. [DOI] [PubMed] [Google Scholar]
- 8. Chien CY, Liu CC, Po HL, et al. The relationship among carotid artery remodeling, cardiac geometry, and serum N-terminal pro-B-type natriuretic peptide level in asymptomatic Asians: sex-differences and longitudinal GEE study. PLoS One 10: e0131440, 2015. eCollection 2015. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9. Yang Y, Wang Y, Xu J, Gao P. Association between common carotid artery diameter and target organ damage in essential hypertension. J Hypertens 36: 537-543, 2018. [DOI] [PubMed] [Google Scholar]
- 10. Gosling RG, King DH. Arterial assessment by Doppler-shift ultrasound. Proc R Soc Med 67: 447-449, 1974. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11. Legarth J, Nolsoe C. Doppler blood velocity waveforms and the relation to peripheral resistance in the brachial artery. J Ultrasound Med 9: 449-453, 1990. [DOI] [PubMed] [Google Scholar]
- 12. Troughton RW, Frampton CM, Brunner-La Rocca HP, et al. Effect of B-type natriuretic peptide-guided treatment of chronic heart failure on total mortality and hospitalization: an individual patient meta-analysis. Eur Heart J 35: 1559-1567, 2014. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13. Mukoyama M, Nakao K, Hosoda K, et al. Brain natriuretic peptide as a novel cardiac hormone in humans. Evidence for an exquisite dual natriuretic peptide system, atrial natriuretic peptide and brain natriuretic peptide. J Clin Invest 87: 1402-1412, 1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14. Vanderheyden M, Goethals M, Verstreken S, et al. Wall stress modulates brain natriuretic peptide production in pressure overload cardiomyopathy. J Am Coll Cardiol 44: 2349-2354, 2004. [DOI] [PubMed] [Google Scholar]
- 15. Yoshimura M, Yasue H, Okumura K, et al. Different secretion patterns of atrial natriuretic peptide and brain natriuretic peptide in patients with congestive heart failure. Circulation 87: 464-469, 1993. [DOI] [PubMed] [Google Scholar]
- 16. Hirata Y, Matsumoto A, Aoyagi T, et al. Measurement of plasma brain natriuretic peptide level as a guide for cardiac overload. Cardiovasc Res 51: 585-591, 2001. [DOI] [PubMed] [Google Scholar]
- 17. Shimamoto K, Ando K, Fujita T, et al. The Japanese Society of Hypertension guidelines for the management of hypertension in 2014 (JSH 2014). Hypertens Res 37: 253-390, 2014. [DOI] [PubMed] [Google Scholar]
- 18. Mita T, Watada H, Shimizu T, et al. Nateglinide reduces carotid intima-media thickening in type 2 diabetic patients under good glycemic control. Arterioscler Thromb Vasc Biol 27: 2456-2462, 2007. [DOI] [PubMed] [Google Scholar]
- 19. Handa N, Matsumoto M, Maeda H, Hougaku H, Kamada T. Ischemic stroke events and carotid atherosclerosis. Results of the Osaka Follow-up Study for Ultrasonographic Assessment of Carotid Atherosclerosis (the OSACA Study). Stroke 26: 1781-1786, 1995. [DOI] [PubMed] [Google Scholar]
- 20. Yeo KT, Wu AH, Apple FS, et al. Multicenter evaluation of the Roche NT-proBNP assay and comparison to the Biosite Triage BNP assay. Clin Chim Acta 338: 107-115, 2003. [DOI] [PubMed] [Google Scholar]
- 21. Doi Y, Ninomiya T, Hata J, et al. N-terminal pro-brain natriuretic peptide and risk of cardiovascular events in a Japanese community: the Hisayama study. Arterioscler Thromb Vasc Biol 31: 2997-3003, 2011. [DOI] [PubMed] [Google Scholar]
- 22. Scuteri A, Chen CH, Yin FC, Chih-Tai T, Spurgeon HA, Lakatta EG. Functional correlates of central arterial geometric phenotypes. Hypertension 38: 1471-1475, 2001. [DOI] [PubMed] [Google Scholar]
- 23. Richards AM. Natriuretic peptides: update on Peptide release, bioactivity, and clinical use. Hypertension 50: 25-30, 2007. [DOI] [PubMed] [Google Scholar]
- 24. Gruden G, Landi A, Bruno G. Natriuretic peptides, heart, and adipose tissue: new findings and future developments for diabetes research. Diabetes Care 37: 2899-2908, 2014. [DOI] [PubMed] [Google Scholar]
- 25. Tanaka A, Yoshida H, Kawaguchi A, et al. N-terminal pro-brain natriuretic peptide and associated factors in the general working population: a baseline survey of the Uranosaki cohort study. Sci Rep 7: 5810, 2017. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26. Sanchez OA, Duprez DA, Bahrami H, et al. The associations between metabolic variables and NT-proBNP are blunted at pathological ranges: the Multi-Ethnic Study of Atherosclerosis. Metabolism 63: 475-483, 2014. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27. Bai CH, Chen JR, Chiu HC, Pan WH. Lower blood flow velocity, higher resistance index, and larger diameter of extracranial carotid arteries are associated with ischemic stroke independently of carotid atherosclerosis and cardiovascular risk factors. J Clin Ultrasound 35: 322-330, 2007. [DOI] [PubMed] [Google Scholar]
- 28. Lee KY, Sohn YH, Baik JS, Kim GW, Kim JS. Arterial pulsatility as an index of cerebral microangiopathy in diabetes. Stroke 31: 1111-1115, 2000. [DOI] [PubMed] [Google Scholar]
- 29. Chuang SY, Cheng HM, Bai CH, Yeh WT, Chen JR, Pan WH. Blood pressure, carotid flow pulsatility, and the risk of stroke: a community-based study. Stroke 47: 2262-2268, 2016. [DOI] [PubMed] [Google Scholar]
- 30. Lee MY, Wu CM, Chu CS, Lee KT, Sheu SH, Lai WT. Association of carotid hemodynamics with risk of coronary heart disease in a Taiwanese population with essential hypertension. Am J Hypertens 21: 696-700, 2008. [DOI] [PubMed] [Google Scholar]
- 31. Raymond I, Groenning BA, Hildebrandt PR, et al. The influence of age, sex and other variables on the plasma level of N-terminal pro brain natriuretic peptide in a large sample of the general population. Heart 89: 745-751, 2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32. Krauser DG, Lloyd-Jones DM, Chae CU, et al. Effect of body mass index on natriuretic peptide levels in patients with acute congestive heart failure: a ProBNP Investigation of Dyspnea in the Emergency Department (PRIDE) substudy. Am Heart J 149: 744-750, 2005. [DOI] [PubMed] [Google Scholar]
- 33. Desai AS, Bibbins-Domingo K, Shlipak MG, Wu AH, Ali S, Whooley MA. Association between anemia and N-terminal pro-B-type natriuretic peptide (NT-proBNP): findings from the Heart and Soul Study. Eur J Heart Fail 9: 886-891, 2007. [DOI] [PubMed] [Google Scholar]
- 34. Sasaki N, Yamamoto H, Ozono R, Fujiwara S, Kihara Y. Association of N-terminal pro B-type natriuretic peptide with blood pressure and pulse pressure in elderly people: a cross-sectional population study. Circ J 82: 2049-2054, 2018. [DOI] [PubMed] [Google Scholar]
- 35. Sasaki R, Yamano S, Yamamoto Y, et al. Vascular remodeling of the carotid artery in patients with untreated essential hypertension increases with age. Hypertens Res 25: 373-379, 2002. [DOI] [PubMed] [Google Scholar]
- 36. Owan TE, Hodge DO, Herges RM, Jacobsen SJ, Roger VL, Redfield MM. Trends in prevalence and outcome of heart failure with preserved ejection fraction. N Engl J Med 355: 251-259, 2006. [DOI] [PubMed] [Google Scholar]
- 37. Sharma K, Kass DA. Heart failure with preserved ejection fraction: mechanisms, clinical features, and therapies. Circ Res 115: 79-96, 2014. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38. Liao ZY, Peng MC, Yun CH, et al. Relation of carotid artery diameter with cardiac geometry and mechanics in heart failure with preserved ejection fraction. J Am Heart Assoc 1: e003053, 2012. [DOI] [PMC free article] [PubMed] [Google Scholar]