Edited by: Jean-Pierre Montani, University of Fribourg, Switzerland
Reviewed by: Alun Hughes, University College London, UK; Carolyn J. Barrett, University of Auckland, New Zealand; Sofia Ahmed, University of Calgary, Canada
*Correspondence: Ovidiu C. Baltatu
This article was submitted to Integrative Physiology, a section of the journal Frontiers in Physiology
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Carotid atherosclerosis is characterized by increased intima-media thickness (IMT) and presence of atheromatous plaques in the arterial wall (Stein et al.,
Atherosclerosis of the carotid and aortic baroreceptors may be associated with cardiac autonomic dysfunction due to a decreased baroreflex sensitivity. Carotid atherosclerosis may induce these effects through both structural and biochemical mechanisms. Carotid atherosclerotic plaques are commonly found in the carotid sinus (Milei et al.,
Gianaros et al. associated intima–media thickness in the carotid bulb with reduced baroreflex sensitivity in patients enrolled in the REActivity and Cardiovascular risk Trial (REACT) to study preclinical atherosclerosis (Gianaros et al.,
Heart rate variability (HRV) analysis is a commonly used noninvasive method to measure alterations in baroreflex and autonomic tone (Campos et al.,
This was a prospective cross-sectional observational study. We enrolled 101 consecutive subjects who presented to the Cardiology outpatient clinic for a routine visit and agreed to have a noninvasive carotid artery duplex ultrasonography at Heart Institute of Santa Casa Charity (IACOR), Fernandopolis, Brazil, from June 2015 to February 2016. The study was approved by the Ethics Committee of Camilo Castelo Branco University in accordance with resolution 466/2012 and 340/2004 of the National Health Council (Ministry of Health) for research on human subjects (CAAE: 01328712.0.0000.5244, permit no. 18326). Written informed consent was obtained from all subjects.
Asymptomatic patients aged 18 years and older with at least one cardiovascular risk factor, including hypertension, diabetes, obesity, smoking, hypercholesterolemia, without a history of transient ischemic attack, stroke, or other neurologic signs or symptoms were selected to participate in the study. Patients with symptomatic carotid artery stenosis were excluded if the patient had transient or permanent focal neurologic symptoms corresponding to the ipsilateral retina or the cerebral hemisphere (Lanzino et al.,
Clinical characteristics such as diabetes mellitus, hypertension, obesity, smoking, were documented together with the lipid profile (total cholesterol, triglycerides, LDL and HDL).
Carotid arteriosclerotic disease was evaluated through measuring the IMT. The subclinical vascular disease scanning protocol for evaluation of common carotid IMT and detection of carotid plaques was done according to the standardized protocol of the American Society of Echocardiography (Stein et al.,
Quantitative testing of the cardiac autonomic function was performed during deep breathing test (Low et al.,
All data processing was performed while blinded to the level of deep breathing testing and analysis. The characteristics of study participants were depicted using standard descriptive statistics, overall and stratified by quartiles of SDNN. Chi-square (χ2) test of independence for categorical (nominal) variables and Analysis of variance (ANOVA) test for continuous variables were used to analyze the covariates of interest and their association with SDNN and other measures of HRV (RMSSD, CV, PNN50, SD1, and SD2).
Multivariable linear regression models were used to assess the association between heart rate variability parameters from the deep breathing test and mean carotid IMT.
The goodness of curve fit was assessed with the
The models were adjusted for relevant confounding variables, including demographics (age, sex, race/ethnicity), traditional CVD risk factors (hypertension, diabetes, smoking, total cholesterol, and high density lipoprotein) grouped into atherosclerotic cardiovascular disease (ASCVD) risk score, body mass index (BMI), waist-hip-ratio (WHR), and left ventricular ejection fraction (LVEF). Sequential multivariable models for each outcome were created based on our assessment of the covariates likelihood of being a confounder in the relationship between heart rate variability and subclinical carotid disease. Residual plots were used to confirm model assumptions.
All statistical tests were 2 sided, and
A total of 101 study participants met the eligibility criteria and performed the deep breathing test. The mean age was 60.4 ± 13.4(SD) years, and 46% were men. Characteristics of study participants distributed according to quartiles of one of the HRV parameters (standard deviation of all RR intervals (SDNN) from the deep breathing test) are summarized in Table
SDNN (ms) | 53.5 ± 32.7 | 19.7 ± 5.1 | 36.5 ± 5.9 | 57.7 ± 6.2 | 100.9 ± 22.2 | |
Age (years) | 60.4 ± 13.4 | 70.6 ± 10.9 | 61.6 ± 11.7 | 59.4 ± 9.3 | 49.9 ± 13.2 | <0.001 |
Men, n % | 46 (45.5) | 7 (28.0) | 12 (46.2) | 13 (52.0) | 14 (56.0) | 0.20 |
Race, n % | 0.80 | |||||
White | 96 (95.0) | 24 (96.0) | 25 (96.2) | 24 (96.0) | 23 (92.0) | |
Black | 4 (4.0) | 1 (4.0) | 1 (3.8) | 1 (4.0) | 1 (4.0) | |
Other | 1 (1.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (4.0) | |
BMI (kg/m2) | 27.7 ± 4.4 | 28.4 ± 4.9 | 28.3 ± 4.3 | 27.3 ± 4.5 | 27.0 ± 3.9 | 0.58 |
WHR | 0.9 ± 0.1 | 0.9 ± 0.1 | 0.9 ± 0.1 | 0.9 ± 0.1 | 0.9 ± 0.1 | 0.62 |
Smoking | 16 (15.8) | 4 (16.0) | 6 (23.1) | 4 (16.0) | 2 (8.0) | 0.54 |
HTN | 48 (47.5) | 16 (64.0) | 12 (48.0) | 12 (48.0) | 8 (32.0) | 0.16 |
DM | 17 (16.8) | 6 (24.0) | 4 (15.4) | 5 (20.0) | 2 (8.0) | 0.47 |
SBP supine (mmHg) | 137.0 ± 17.6 | 145.7 ± 18.8 | 137.8 ± 19.2 | 135.5 ± 13.3 | 129.0 ± 15.1 | 0.007 |
SBP standing (mmHg) | 129.1 ± 17.0 | 135.2 ± 16.8 | 130.0 ± 20.1 | 127.5 ± 15.1 | 123.5 ± 14.1 | 0.09 |
DBP (mmHg) | 78.4 ± 10.5 | 79.3 ± 10.7 | 78.3 ± 13.0 | 78.3 ± 9.7 | 78.0 ± 8.2 | 0.97 |
LVEF (%) | 67.8 ± 4.4 | 69.5 ± 5.4 | 65.9 ± 3.9 | 68.7 ± 3.9 | 67.1 ± 3.3 | 0.01 |
TC (mg/dl) | 191.2 ± 39.4 | 190.7 ± 41.3 | 191.4 ± 38.5 | 189.4 ± 39.9 | 193.3 ± 40.2 | 0.99 |
HDL (mg/dl) | 46.3 ± 9.6 | 47.3 ± 10.5 | 43.1 ± 8.1 | 48.0 ± 10.2 | 47.0 ± 9.0 | 0.25 |
LDL (mg/dl) | 113.0 ± 35.9 | 110.5 ± 35.3 | 113.6 ± 33.7 | 108.8 ± 38.6 | 119.2 ± 37.2 | 0.75 |
ASCVD risk score | 16.4 ± 17.5 | 27.3 ± 17.2 | 19.0 ± 22.3 | 10.9 ± 10.3 | 8.2 ± 10.7 | <0.001 |
IMT (mm) | 0.80 ± 0.20 | 0.90 ± 0.19 | 0.82 ± 0.21 | 0.81 ± 0.16 | 0.68 ± 0.19 | 0.001 |
The participants had a carotid intima media thickness mean 0.80 ± 0.20 mm with a median [IQR] 0.80 [0.65–0.93] mm. The characteristics of HRV parameters are depicted in Table
SDNN (ms) | 47.3 [26.5–69.4] |
CV | 5.3 [3.1–7.7] |
RMSSD (ms) | 27.5 [17.5–51.1] |
PNN50 | 7.3 [1.2–26.7] |
SD1 | 19.4 [12.4–36.2] |
SD2 | 63.8 [34.7–90.4] |
Scatterplot distribution of IMT by SDNN from the deep breathing test is shown in Figure
The median carotid media thickness was highest (0.90 ± 0.19 mm) in the first quartile of SDNN (19.7 ± 5.1 ms) and progressively declined in each subsequent quartile to 0.82 ± 0.21 mm, 0.81 ± 0.16 mm, and 0.68 ± 0.19 in quartiles 2 (36.5 ± 5.9 ms), 3 (57.7 ± 6.2 ms) and 4 (100.9 ± 22.2 ms), respectively (
SDNN (ms) | −0.003 | −0.004 to −0.002 | <0.001 | −0.002 | −0.003 to −0.001 | 0.005 |
CV | −0.025 | −0.035 to −0.016 | <0.001 | −0.016 | −0.026 to −0.006 | 0.002 |
RMSSD (ms) | −0.003 | −0.005 to −0.001 | <0.001 | −0.002 | −0.003 to −0.000 | 0.03 |
PNN50 | −0.004 | −0.006 to −0.001 | 0.002 | −0.002 | −0.004 to −0.000 | 0.1 |
SD1 | −0.004 | −0.006 to −0.002 | <0.001 | −0.002 | −0.005 to −0.000 | 0.03 |
SD2 | −0.002 | −0.003 to −0.001 | <0.001 | −0.001 | −0.002 to 0.000 | 0.004 |
In this cohort of individuals with subclinical carotid atherosclerosis and at increased cardiovascular risk, carotid IMT as a marker of subclinical atherosclerosis was associated with alterations of HRV indicating an impaired cardiac autonomic control. This association was found to be independent of atherosclerotic cardiovascular disease (ASCVD) risk score (to include age, gender, race, HDL, and total cholesterol, diabetes, systolic blood pressure, hypertension treatment and smoking), body mass index (BMI), waist-hip-ratio (WHR), left ventricular ejection fraction (LVEF). By demonstrating a significant inverse relationship between carotid IMT and HRV, our results are in line with the hypothesis that carotid atherosclerotic lesions are associated with impaired ANS function.
We previously investigated the relationship between carotid IMT and cardiovagal dysfunction assessed through frequency (Pereira et al.,
Our study indicates that carotid IMT as marker of subclinical atherosclerosis is associated with impaired cardiac autonomic control as represented by a decrease in HRV indices. Moreover, the relationship between deep breathing HRV and subclinical carotid disease was maintained after adjustment for relevant confounding variables, including traditional CVD risk factors (age, sex, race, hypertension, diabetes, smoking, total cholesterol, and high density lipoprotein) grouped into the atherosclerotic cardiovascular disease (ASCVD) risk score, body mass index (BMI), waist-hip-ratio (WHR), and left ventricular ejection fraction.
HRV has been studied in conjunction with clinical autonomic tests, of which the most used are the Valsalva maneuver, head-up tilt, and deep breathing tests (
This study has several strengths, including concurrent assessment of bilateral common carotid and internal carotid artery media thickness, in conjunction with several indices related to cardiac autonomic function during deep breathing test, including SDNN, RMSSD, CV, pNN50, SD1, and SD2, and along with several cardiovascular risk factors. In the present study, multivariable regression analysis revealed a significant inverse association between carotid IMT and HRV that is independent of several cardiovascular risk factors. The cross-sectional design of our study was also appropriate to examine several cardiovascular risk factors related with HRV. To quantify autonomic dysfunction, we utilized comprehensive, portable and easy to use heart rate variability analyzing system that can be easily carried out in any patient setting. HRV deep breathing test is a fast and convenient method to quantify autonomic dysfunction. HRV measures have been suggested for initial screening of cardiovascular risk as it is noninvasive, economical and easy to use in clinical practice (Jelinek et al.,
This study has several limitations. First, this is a cross-sectional analysis and causality cannot be inferred. Second limitation relates to selection bias, given the nature of high risk patients referred directly from the Cardiology clinic. Furthermore, the results are only applicable to adults with at least one cardiovascular risk factor. Finally, these analyses are based on a sample of patients referred for single measurement of carotid IMT; whether changes in IMT over time add incremental predictive value to the development of cardiac autonomic dysfunction will need further study.
In summary, our study indicates that subclinical carotid atherosclerosis is associated with impairment in the cardiac autonomic control in individuals with at least one cardiovascular disease risk factor, regardless of the confounding effects of cardiovascular risk factors.
Study conception and design: OB, VP, and LC. Performed the study: VP, Sd and JF. Analyzed de data: MD, AB, and VP. Drafting of manuscript: OB, LC. Critical revision: MD, AB, VP, and CO.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
The authors gratefully acknowledge Ana Paula do Prado Cardoso, nurse for coordination and providing support of all clinical visits. This research was supported by São Paulo Research Foundation (FAPESP 13/14724-0; FAPESP 14/10985-7). OB is supported by the National Counsel of Technological and Scientific Development (CNPq 301706/2013-1). We thank the reviewers for their constructive comments, which helped us to improve the manuscript.