Publication
Research Article
Arterial stiffness is associated with aging, obesity, comorbidities, and cardiovascular disease in the general population and needs to be further studied in people with MS.
Background: Multiple sclerosis (MS) is a chronic, immune-mediated, neurodegenerative disease of the central nervous system with prevalent vascular comorbidities and associated vascular dysfunction involving arterial stiffness. This study examined the difference in arterial stiffness between people with MS and controls and whether the difference was accounted for by anxiety, depression, and walking endurance, variables not usually included in other studies of arterial stiffness in MS.
Methods: The sample included 129 people with MS (age, 48.5 [10.8] years; 70.5% female; Expanded Disability Status Scale score median, 4) and 51 controls without MS (age, 48.7 [11.3] years; 78.4% female) who completed arterial stiffness, anxiety, and depression assessments and the 6-Minute Walk Test (6MWT).
Results: There were significant differences between groups in arterial stiffness (P = .05; d = –.0354), anxiety (P = .009; d = –0.438) and depressive symptoms (P < .001; d = –0.927), and walking endurance (P < .001; d = 1.618). The bivariate correlations were significant between arterial stiffness and age, body mass index (BMI), mean arterial pressure (MAP), and 6MWT distance (all P < .05). The difference in arterial stiffness between groups remained when controlling for age, BMI, MAP, anxiety and depression symptoms, and 6MWT distance.
Conclusions: Our results indicate that people with MS have higher levels of arterial stiffness compared with controls, but this difference is not explained by age, BMI, MAP, anxiety, depression, or walking endurance.
From the Integrative Physiology Lab (SRD, NGD, BF, RWM) and the Department of Kinesiology and Nutrition (SRD, NGD, RWM), College of Applied Health Sciences, University of Illinois Chicago, Chicago, IL; Interdisciplinary School of Health Sciences, University of Ottawa, Ottawa, ON, Canada (LAP); Manning College of Nursing and Health Sciences, University of Massachusetts Boston, Boston, MA (BF). Correspondence: Sydney R. DeJonge, MS, College of Applied Health Sciences, 1919 W Taylor St, Suite 545, Chicago, IL, 60612; email: sdejon3@uic.edu.
Multiple sclerosis (MS) is a chronic, immune-mediated neurodegenerative disease of the central nervous system (CNS) with a prevalence of nearly 1 million adults in the United States.1 A hallmark feature of MS includes CNS lesions that are the primary source of disability. Another noteworthy disease feature is comorbidity, defined as a coexisting supplementary disease that is not a direct outcome of MS itself.2 Over 50% of people with MS present with 1 or more comorbidities,3 and vascular comorbidity (eg, hypertension, hyperlipidemia, diabetes, ischemic heart disease)4,5 is exceedingly prevalent in MS and associated with worse disease outcomes.4,6,7
The vascular system represents a focal point for understanding vascular comorbidity in MS, as impairment of vascular function may represent an initial marker for the development of vascular comorbidity.8-13 The functions of the vascular system include maintaining adequate blood flow, blood pressure, and exchange of metabolic byproducts and gases throughout the body.14 Arterial stiffness reflects the structural and mechanical properties of the arterial wall that influence changes in blood pressure and flow15,16 and can be measured as carotid-femoral pulse wave velocity (cfPWV) using noninvasive techniques.16
There is emerging evidence that people with MS have impaired vascular function, particularly arterial stiffness, compared with controls,17 and the difference in arterial stiffness remains when controlling for covariates such as age, sex, body mass index (BMI), and aerobic fitness.18 Arterial stiffness has also been associated with cognitive processing speed,12 fatigue,19 and physical activity11 in MS. There is no explanation for increased levels of arterial stiffness in people with MS compared with control groups, and there are notable limitations within this research, including small samples of MS and control participants and a lack of consideration of other common outcomes, including anxiety, depression, and walking endurance, along with other covariates such as mean arterial pressure (MAP) when comparing MS and control samples.2,20-23 Prior evidence in controls has demonstrated that people with increased anxiety and depression have higher levels of arterial stiffness,22,24 and due to the prevalence of anxiety and depression in MS, we suggest this could account for the difference.25 Similarly, there are noticeable differences in walking endurance between people with MS and controls,26 and this has not previously been identified as a covariate.
The present study is a secondary analysis of data combined from 3 separate studies measuring arterial stiffness using cfPWV in people with MS and control participants (Table S1, presented in a PDF at the bottom of the online article with other supplemental materials).11,27,28 The large combined data set permitted further examination of differences between participants with MS and control participants in arterial stiffness, namely cfPWV, and whether other variables might account for the differences in arterial stiffness between the groups. We hypothesized a priori that arterial stiffness would be higher in people with MS than in control participants, even after accounting for other variables, including anxiety, depression, and walking endurance, as they have been associated with measures of arterial stiffness in control participants.
Participants
We conducted a secondary analysis of data combined from 3 previously published studies that included participants with MS and control participants.11,27,28 The procedures were approved by the University of Illinois Urbana-Champaign and the University of Illinois Chicago institutional review boards, and all participants provided written informed consent. The secondary analysis included 129 participants with MS and 51 controls without MS.
Age and sex were self-reported, and BMI was based on height and weight recorded from a stadiometer and scale. Disability status was based on the Expanded Disability Status Scale (EDSS) score generated from an examination performed by a Neurostatus-certified examiner (n = 98) and EDSS scores converted from Patient-Determined Disease Steps scale scores (n = 31).29 We further captured the disease course and duration based on self-report.
Vascular Function: Primary Outcome
Vascular function was assessed via applanation tonometry using a high-fidelity strain gauge pressure transducer (SphygmoCor; ATCOR Medical). All participants rested in the supine position for 10 minutes before the assessment. Aortic stiffness was assessed using the gold-standard procedure, cfPWV. Arterial stiffness was calculated from the time delay between pressure waves measured at the common carotid artery to the femoral artery and the distance between the carotid and femoral arteries. Radial artery pressure waveforms were collected through a noninvasive blood pressure measurement and applanation tonometry (SphygmoCor). A generalized transfer function was applied to calculate central pressure waveforms such as central systolic blood pressure (cSBP), central diastolic blood pressure (cDBP), and MAP.30 These variables, particularly MAP, are essential as pressure strongly influences arterial stiffness.16
Measurements
The 6-Minute Walk Test (6MWT) measured aerobic or walking endurance and was performed in an accessible hallway with 4 corridors that allowed participants to walk without any obstacles or restrictions. Participants walked as far and as fast as possible within the limits of safety and stability for 6 minutes,31 and we permitted the use of an assistive device if needed. The 6MWT distance was measured in feet (6MWD).31
Anxiety and depression symptoms were measured by the Hospital Anxiety and Depression Scale (HADS).32 The HADS questionnaire has 14 items, 7 aligning with anxiety (HADS-A) and 7 with depression (HADS-D), and each item was rated on a scale of 0 (most of the time) to 3 (not at all). The negatively worded items were reverse-scored, and the scores from the 7 items were summed into a composite score of anxiety and depression subscales over the previous 4-week period. Scores range from 0 to 21, with higher scores suggesting a greater occurrence of anxiety and depression symptoms.
Statistical Analysis
Data analyses were performed using IBM SPSS Statistics version 28.0. Descriptive statistics are provided as mean (SD), median (IQR), or frequency (%), based on the measurement properties per outcome. We compared samples on demographic variables using independent-samples t tests and χ2 tests. We performed independent-samples t tests on measurements of vascular function, 6MWD, and summary scores of anxiety and depression; the magnitude of differences was expressed as Cohen d, with guidelines of 0.2, 0.5, and greater than 0.8 as small, moderate, and large differences, respectively. We examined associations among vascular function and other variables using bivariate Pearson correlations for identifying possible covariates. We did a regression analysis examining whether vascular function differed between groups even after controlling for covariates using a stepwise entry of variables (ie, group in step 1 and covariates in subsequent steps). We selected variables that either differed between groups or had bivariate correlations with cfPWV. Significance for all analyses was set at P less than .05.
Study participant demographic and clinical characteristics are provided in Table 1. There were no significant differences in age, sex, or BMI between groups. Participants with MS largely had a relapsing-remitting course with moderate disease duration and level of disability and had not experienced a relapse within the previous 30 days.
Table 1. Demographic and Clinical Characteristics of the Sample
Descriptive data, P values from independent-samples t tests for vascular parameters, HADS subscale scores, and 6MWD are presented in Table 2. There were statistically significant differences between MS and control participants in cfPWV (P < .05; d = –0.354), HADS-A (P < .01; d = –0.438), HADS-D (P < .001; d = –0.927), and 6MWD (P < .001; d = 1.618). There were no significant differences between groups in cSBP, cDBP, or MAP.
Table 2. Between-Group Comparison of Vascular Function, Anxiety, Depression, and 6-Minute Walk Distance
There were statistically significant correlations between cfPWV with age (r = 0.349), BMI (r = 0.315), MAP (r = 0.400), and 6MWD (r = –0.154). Based on scatterplots (Figure, Figure S1), cfPWV was higher in those who were older and had a higher BMI and MAP but was lower in those with greater walking endurance in the overall sample of participants with MS and control participants.
Figure. Significant Bivariate Correlations Among cfPWV and Age, BMI, MAP, and 6MWD
Table 3 presents the regression analysis examining whether group differences in cfPWV were accounted for by HADS-A, HADS-D, age, BMI, MAP, or 6MWD. The inclusion of group in step 1 explained 2.8% of the variance in cfPWV, and the effect of group was statistically significant (P < .05). Group remained a statistically significant predictor of cfPWV even when age, BMI, MAP, and HADS-A entered the regression in steps 2 through 5.
Table 3. Regression Analysis of Vascular Function Between Groups After Controlling for Covariates
Participants with MS had higher cfPWV and worse anxiety and depression symptoms and shorter 6MWD than control participants in this large, combined data set. We further demonstrated that the differences in cfPWV between groups were not influenced by age, BMI, MAP, 6MWD, and anxiety or depressive symptoms. These findings align with other research using smaller samples that demonstrated higher cfPWV in people with MS than in control participants but without substantial control for covariates.11,12,18 This overall difference in arterial stiffness aligns with vascular dysfunction and might be an early precursor of vascular comorbidities in MS. Arterial stiffness is a strong predictor of cardiovascular disease and overall mortality in the general population,16,33 and our results and prior research demonstrate increased arterial stiffness in MS, which could indicate an increased risk in cardiovascular disease and even death for people with MS.34
Some researchers have examined possible covariates of the difference in arterial stiffness between participants with MS and control participants. For example, findings from one study reported that people with MS engaged in lower amounts of physical activity than controls, and those lower physical activity levels accounted for the difference in arterial stiffness between the 2 groups.11 Results from another study found that aerobic capacity is lower in people with MS than in control participants, but it did not account for the difference in cfPWV between the groups.18 Our study findings report that age, BMI, MAP, anxiety, depression, and 6MWD do not account for the difference in cfPWV between participants with MS and control participants. Collectively, these results underscore the established difference in arterial stiffness between participants with MS and control participants and imply that blood pressure does not contribute to the difference in cfPWV, despite the significant role that it has on stiffness. To date, we have not solidified the core reasons for the differences in vascular function; however, these results contribute to the current literature by identifying factors that do not account for the differences between participants with and without MS.
Our study does have limitations. The studies we combined were not all designed a priori to compare vascular function between people with MS and control participants. A major limitation of our analysis was that there were no comorbidities or related medications in these studies. Also, not including other measurements of vascular function, such as ankle-brachial index and pulse volume recording, is a limitation, as these measures could help aid in the understanding of increased cfPWV in people with MS. On average, participants in this secondary analysis did not meet the usually accepted cutoff subscale scores for elevated anxiety and depression on the HADS questionnaire. This indicates they were not experiencing clinically elevated anxiety or depressive symptoms; this is a limiting factor, as these symptoms are covariates in our analysis. In addition, we cannot conclude whether people were being treated for anxiety or depression with medication or other therapeutic mechanisms, as this information was not initially collected. The sample of people with MS recruited for the original studies primarily had a relapsing-remitting clinical course and a low average EDSS score, which may limit the generalizability of these results. Disease course and duration were self-reported, and this also represents a limitation based on possible inaccuracy in reporting.
Our results might highlight measuring markers of vascular function throughout the arterial tree, in addition to including measurements such as ankle-brachial index and flow-mediated dilation, as directions for future research in MS. Including measurements of potential mechanisms for vascular dysfunction, such as autonomic function and biomarkers (eg, cytokines, C-reactive protein), would be important as well, as these outcomes are generally consequences of MS. Levels of physical activity in combination with arterial stiffness could be considered, as there have been prior data to confirm this association in MS. Future studies should include subpopulations of people with MS who have other comorbid conditions (ie, those with hypertension, diabetes, and anxiety or depression disorders) when examining arterial stiffness. Finally, a medication history would be beneficial when considering data in these subpopulations. Such endeavors will further our understanding of vascular dysfunction in MS and perhaps its sources and influences for future intervention.
Findings from this study demonstrate that people with MS had higher arterial stiffness compared with control participants and that this difference was not explained by age, BMI, MAP, anxiety and depression symptoms, or walking endurance. These results further suggest that arterial stiffness may be associated with etiology and progression of MS and not factors such as anxiety, depression, MAP, or 6MWD.
Acknowledgments: We would like to thank and acknowledge those who collected data from the previously published studies and all the participants who made these data analyses possible. A special thanks to the committee of the Integrative Physiology of Exercise Conference for allowing these results to be presented as a poster abstract at their conference in November 2024.
Prior Presentation: We presented these results as a poster at theIntegrative Physiology of Exercise Conference from November 20 to 22, 2024, in University Park, Pennsylvania.
Conflicts of Interest: The authors have declared no relevant conflicts of interest.
Funding: This study includes data that were collected through research projects funded by the National Multiple Sclerosis Society (RG 4702A1/2) and the University of Illinois Urbana-Champaign Research Board. This research was supported by a predoctoral F31 Fellowship from the National Cancer Institute (1F31CA295016-01).
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