The Inverse Association of Muscular Strength with Carotid Intima-Media and Extra-Media Thickness in Women

Abstract

The purpose of this study was to determine the relationship between strength and atherosclerotic cardiovascular disease (CVD) risk in young women. Carotid intima-media thickness (IMT) and extra-media thickness (EMT) were used as measures of subclinical atherosclerosis and CVD risk. Muscular strength, IMT, and EMT were measured in 70 young women (mean age = 21 ± 4 years). Strength was determined using a handgrip dynamometer and expressed relative to body mass. IMT and EMT were measured using ultrasonography of the left common carotid artery. Objectively measured moderate-vigorous physical activity (MVPA) was assessed with accelerometry. Higher relative handgrip strength was associated with lower IMT (r = −0.23; p<0.05) and lower EMT (r = −0.27; p<0.05). Associations between relative handgrip strength and IMT (r = −0.24) as well as EMT (r = −0.25) remained significant after adjusting for potential confounders including traditional CVD risk factors and MVPA (p<0.05). These results show that there is an inverse association between handgrip strength with carotid IMT and EMT in young women. Muscular strength may reduce CVD risk in young women via favorable effects on subclinical carotid atherosclerosis independent of physical activity.

INTRODUCTION

Cardiovascular Disease (CVD) is the leading cause of death in the United States, as well as worldwide [1]. Heart disease accounts for 1 of every 4 deaths in the U.S. each year. CVD is also the primary cause of mortality for women in the U.S., accounting for 1 of every 3 female deaths [1]. There is currently a rise in CVD events seen in younger women and this is alarming [2]. Cardiorespiratory fitness in young adulthood is beneficial for cardiovascular health later in life and low cardiorespiratory fitness is a powerful predictor of higher CVD mortality [3]. A lesser appreciated aspect of physical fitness related to cardio-protection is muscular strength [4]. Greater muscular strength is inversely associated with CVD risk factors such as abdominal adiposity, blood pressure, insulin resistance, and as such is associated with lower mortality risk [5, 6]. Conversely, lower muscular strength in late adolescence/early adulthood (i.e. age 18 years) is a significant predictor of the development of heart failure [7] and CVD events later in life, independent of cardiorespiratory fitness [8]. The great majority of studies exploring the cardiovascular health benefits of muscular strength have been done exclusively in men [9-13]. There are established sex-differences in muscle mass, neuromuscular strength and cardiovascular function and these differences change across the lifespan. Therefore, exploration of the sex-specific association between muscular strength and cardiovascular health in women is warranted.

As much as traditional CVD risk factors are associated with CVD risk, their ability to predict overt CVD and future cardiovascular events in all populations is suboptimal [14]. Direct measures of subclinical atherosclerosis may offer insight into CVD risk extending beyond traditional CVD risk factors as subclinical measures capture direct vascular damage and subsequent vascular remodeling [15]. Carotid intima-media-thickness (IMT) is a measure of subclinical atherosclerosis influenced by both fatty deposition, plaque formation and smooth-muscle hyperplasia/ hypertrophy. IMT is measured non-invasively via carotid ultrasonography and is an established measure of vascular damage and predictor of future CVD events [15]. An emerging measure of subclinical atherosclerosis also obtained from carotid ultrasonography is extra-media thickness (EMT) [16]. EMT captures structure of the arterial adventitia and perivascular adipose tissue [17, 18]. EMT provides additional insight into vascular damage and CVD risk separate from that provided by IMT [19, 20]. Muscular strength has been shown to be inversely associated with IMT in children and older adults [21, 22]. Whether muscular strength is favorably associated with carotid IMT and EMT in younger women remains unknown.

Given the lack of studies focusing on the relationship between muscular strength and CVD risk in women, and the rise of CVD events occurring in younger women [2], we chose to focus our study on the examination of muscular strength as it relates to subclinical atherosclerosis in young women. Specifically, the purpose of this study was to examine the relationship between muscular strength (assessed as handgrip strength) and subclinical atherosclerosis (assessed and carotid IMT and EMT) in young women. We hypothesized that there would be an inverse association between muscular strength with IMT and EMT.

METHODS

Participants

Seventy young, healthy women (mean ± SD, age = 21 ± 4 yrs, range: 18-35 yrs; 17% Black/African American, 34% Hispanic/Latina) were recruiting from the broader university community for participation in this study. Exclusion criteria included any health issue that might alter the relationship between strength and CVD risk and this included: self-reported CVD, respiratory disease, metabolic disease (including hypertension, diabetes, hyperlipidemia, etc.), renal disease, sickle cell disease, mild cognitive impairment, use of any medications known to affect heart rate (HR) and blood pressure (BP), orthopedic injury affecting ambulation and/or grip strength, and habitual cigarette smoking. Women on oral contraceptives (OC) were included in this study (n = 20). Female participants were scheduled during the early follicular phase of their menstrual cycles to control for the effects of female sex hormones on vascular measures. All participants signed a written informed consent approved by the Institutional Review Board of Syracuse University. This study adheres to ethical standards in sport and exercise science research as recommended by the International Journal of Sports Medicine.[23]

Protocol

Each participant completed two visits to the laboratory. For Visit 1, participants were instructed to arrive after a 3-hour fast and were asked to abstain from alcohol and caffeine for 12 hours. Participants were also directed to refrain from exercising 12 hours before testing. Height and weight were measured in the standing position using a stadiometer and electronic scale, respectively. Body composition was assessed using air displacement plethysmography (BodPod, COSMED). Handgrip strength was tested using a handgrip dynamometer for 3 consecutive trials. The maximal force generated (expressed relative to body mass) was used for subsequent statistical analyses. Cardiorespiratory fitness was estimated using a 3-minute YMCA Step Test. During this test, participants would step up and down on a 12-inch block to the cadence of a metronome set to 96 bpm. Participants wore a heart rate monitor placed just below their xiphoid process (Polar, Polar Electro, Bethpage NY USA) and HR was monitored at rest (quiet sitting), during stepping exercise (peak), and during 1-minute of recovery (quiet sitting). VO₂max was estimated using the equation 65.81 - (0.1847 * recovery heart rate in bpm) [24].

Participants reported back to the lab for Visit 2 approximately nine days later. Visit 2 was conducted following an overnight fast. Participants were once again asked to abstain from alcohol, caffeine and exercise for 24 hours. Serum lipoproteins and fasting plasma glucose were assessed using a finger stick. Total cholesterol, high density lipoprotein (HDL), triglycerides, low density lipoprotein (LDL), and glucose levels were determined using a point-of-care device (Cholestech Alere Medical Analyzer, Waltham MA). Resting blood pressure was assessed in the brachial and carotid artery (described below). Wall thickness of the left carotid artery was also evaluated using ultrasonography (described below).

Objective physical activity assessment:

Following Visit 1, participants were fitted with an ActiGraph GT3X+ accelerometer (ActiGraph LLC, Pensacola, FL, USA). Participants were instructed to wear the accelerometer at the waist on an elasticized belt positioned directly below the right mid-axillary line for 24 hours a day (except if participating in water-related activities) for nine consecutive days. Data from the GT3X+ device were downloaded using the low frequency filter from the ActiLife software (version 6.13, ActiGraph LLC). For data analysis, raw accelerometer data were converted to counts and summed over a 60 sec epoch. A previously validated algorithm was applied to the AG accelerometer data to separate sleep wear time from awake wear time [25]. Furthermore, periods of non-wear were defined as consecutive blocks of at least 60 min of 0 activity counts, including up to 2 consecutive minutes of activity counts less than 100, in line with the National Health and Nutrition Examination Survey (NHANES) criteria [26]. A complete day of acclerometer use was defined as at least 10 hours of wear time while awake, which is consistent with the minimum set by the NHANES [26]. A minimum of 4 days of wear data were necessary in order for participants to be included in data analysis. A cut point of 2020 activity counts/min was used to determine the amount of time in minutes spent at a physical activity level of moderate-to-vigorous intensity (MVPA) [26].

Blood pressure measurement:

Brachial systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP) were measured using an oscillometric cuff (Omron Blood Pressure Monitor, Kyoto Japan). Measures were initiated after 10 minutes of rest in the supine position. Measurements were taken in duplicate and averaged for subsequent analyses. Using applanation tonometry (SphygmoCor, Atcor Medical, Sydney Australia) at the right carotid artery, calibrations were made to brachial MAP and DBP to provide a carotid SBP measurement. Carotid pulse pressure (PP) was calculated using the equation carotid SBP – DBP. Carotid PP was included in statistical adjustments since regional pulsatile pressure in the carotid artery may be more associated with carotid atherosclerosis compared with MAP or PP measured in the brachial artery [27].

Carotid Ultrasonography:

Images of the left common carotid artery were obtained using Doppler ultrasound and 5.0–13.0 MHz linear-array probe (ProSound 7; Hitachi Aloka, Tokyo, Japan). IMT was assessed from a longitudinal view of the far wall of the common carotid artery (CCA), below the carotid bulb, as the distance from the intima lumen interface to the media adventitial border. EMT was assessed from the near wall of the same image. EMT was measured from the media adventitia border to the jugular lumen interface (see Figure 1). Both IMT and EMT measurements were completed using digital calipers during diastole, determined from simultaneous ECG gating [20].

Figure 1.

Sample ultrasound image of the common carotid artery. Note continuous lines (top) represent the extra-media thickness while dashed lines (bottom) represent the intima-media thickness.

Reproducibility analyses were completed separately on images obtained from this study population. Images were analyzed in triplicate for 10 different randomly selected participant images (assessed on two separate days). Raters were blinded to the participant ID. Intra-rater reliability assessed as intra-class correlation coefficients (ICCs) was 0.83 for EMT and 0.96 for IMT. We used values analyzed from a single researcher for all statistical analyses.

Statistical Analysis

Descriptive statistics were calculated for all variables as mean ± standard deviation (SD). Pearson correlation coefficients were used to explore univariate associations between variables of interest. Partial correlations were used to explore the associations between muscular strength with IMT and EMT after controlling for traditional CVD risk factors (age, total cholesterol, HDL-cholesterol, glucose, BMI) and other factors previously shown to associate with muscular strength (estimated VO₂max and MVPA) and factors that may influence IMT and EMT (OC use, race/ethnicity and carotid PP). Hierarchical/blockwise multiple regression was used to explore muscular strength as a predictor of IMT and EMT (in separate models) after adjusting for aforementioned covariates. Covariates were entered into the first block with grip strength entered in a second separate block. We include the standardized β and R² change as results. Statistical significance was set at p<0.05.

RESULTS

Participant characteristics and cardiovascular measures are shown in Table 1 and Table 2, respectively. 17% of women self-identified as non-Hispanic Black, 43% as non-Hispanic White and 34% as Hispanic. 29% of women self-reported use of oral contraceptives. All participants met requirements for accelerometer wear time (100%) to be included in analyses. Average accelerometer wear time was 6.5 ± 0.8 days for 909.1 ± 69.8 mins/day.

Table 1.

Participant Characteristics (n=70).

Variables	Mean ± SD
Age (yrs)	21 ± 4
Height (cm)	164.3 ± 0.07
Weight (kg)	66.5 ± 10.7
Body mass index (kg/m2)	24.5 ± 3.9
Body Fat (%)	29.6 ± 7.7
Total Cholesterol (mg/dL)	167 ± 34
HDL Cholesterol (mg/dL)	62 ± 18
Triglycerides (mg/dL)	93 ± 45
LDL Cholesterol (mg/dL)	92 ± 31
Glucose (mg/dL)	87 ± 8
Maximal Relative Handgrip	0.47 ± .11
Mean Relative Handgrip	0.44 ± .09
MVPA (Min/day)	53 ± 20
Estimated VO2Max (mL/kg/min)	49.5 ± 3.9

MVPA, moderate-vigorous physical activity; LDL, low-density lipoprotein

Table 2.

Cardiovascular Measures (n = 70).

Variables	Mean ± SD
Brachial Systolic BP (mmHg)	110 ± 9
Brachial Diastolic BP (mmHg)	71 ± 7
Brachial Pulse Pressure (mmHg)	38 ± 7
Mean Arterial Pressure (mmHg)	84 ± 7
Carotid Systolic BP (mmHg)	102 ± 9
Carotid Diastolic BP (mmHg)	72 ± 7
Carotid Pulse Pressure (mmHg)	31 ± 6
Intima Media Thickness (mm)	0.39 ± .06
Extra Media Thickness (mm)	0.74 ± .18

BP, blood pressure

A correlation matrix is displayed in Table 3. There was a positive relationship between handgrip strength and: estimated VO₂max (p=0.011) and MVPA (p=0.023). There were no associations between IMT and EMT (p=0.22). IMT was associated with age (p=0.005). Neither IMT nor EMT were associated with any other traditional measure of CVD risk (BMI, total cholesterol, HDL-cholesterol, fasting glucose; p>.05 for all, data not shown).

Table 3.

Univariate Associations Between Vascular Measures and Fitness Measures.

	HG	EMT	IMT	VO2 Max	MVPA
EMT	−0.27 *
IMT	−0.23 *	−0.15
VO2 Max	0.27 *	0.08	−0.06
MVPA	0.24 *	0.04	−0.29 *	0.37 *
Body Fat	−0.60 *	0.22 *	0.10	−0.32 *	−0.27 *

HG, handgrip; EMT, extra-media thickness; IMT, intima-media thickness; MVPA, moderate-vigorous physical activity.

^*significant association, p<0.05

Handgrip strength was inversely associated with IMT (p=0.010). Associations remained after adjusting for potential confounders described above (r = −.24; p=0.038). According to multiple regression, handgrip strength approached significance as a predictor of IMT (standardized β=−0.26, t = −2.0) after controlling for covariates, explaining an additional 5% of the variance in IMT (p=0.06). Handgrip strength was inversely associated with EMT (p=.010). Associations remained after adjusting for potential confounders (r = −.25; p=0.032). According to multiple regression, handgrip strength was a significant predictor of EMT (standardized β=−0.30, t = −2.2) after controlling for covariates, explaining an additional 6.5% of the variance in EMT (p=0.035).

DISCUSSION

This study is among the first to examine the relationship between muscular strength with measures of subclinical carotid atherosclerosis in young women and found that greater handgrip strength is associated with lower IMT and EMT. These inverse relationships between handgrip strength and IMT and EMT remained significant even after adjusting for potential confounders including traditional CVD risk factors, oral contraceptive use, race/ethnicity, MVPA and estimated VO₂max. Our findings suggest that muscular strength is inversely associated with atherosclerotic CVD risk in young women, independently of physical activity levels and estimated cardiorespiratory fitness.

Carotid IMT is an extensively studied measure of subclinical atherosclerosis and important prognostic measure of vascular damage and CVD risk in both men and women [28]. IMT was inversely associated with muscular strength, supporting an independent cardio-protective role of muscular fitness in women. The cardio-protective effects of muscular strength cover the lifespan. Muscular strength has been shown to inversely associate with IMT in children between the ages of 11-12 years old [21]. Moreover, young men (age 18 years) with higher muscular strength have a lower risk of developing CVD later in life [7, 8]. Our findings extend the cardio-protective effects of muscular strength to young women and note a favorable association of handgrip strength with established markers of vascular damage and subclinical atherosclerosis.

EMT is an emerging measure of vascular damage and subclinical atherosclerosis that is unique from IMT. Indeed, we noted no association between EMT and IMT in our study. IMT captures an “inside-out” processes related to the atherosclerotic process (i.e., endovascular inflammation, lipid oxidation, fatty /cholesterol deposition) as well as pathophysiological adaptations to local hemodynamic forces causing smooth muscle hypertrophy and possibly increased vascular tone. EMT reflects “outside-in” processes related to perivascular fat accumulation and adventitial remodeling (i.e., glycation, calcification) [18, 19]. Precise mechanisms explaining the association between muscular strength with EMT and IMT are unknown. Muscular strength was likely not working through traditional CVD risk factors as associations remained after adjusting for CVD risk factors. One possibility may be related to body composition. Perivascular fat is a prominent component of EMT and as such systemic adiposity has been suggested to play a role in modulating EMT [18, 20]. In support of this, there was an inverse association between handgrip strength and body fat and a positive association between body fat and EMT in our study. Moreover, controlling for body fat attenuated the relationship between grip strength and EMT (r=−.17, p>0.05). Thus, individuals with higher strength that maintain a leaner body mass (lower body fat) maintain lower EMT. Body fat was not associated with IMT once again reaffirming that each vascular measure captures a distinct aspect of carotid structure and function. Strength may be working through other physiological pathways (e.g., inflammation, oxidative stress, autonomic balance) to impact endothelial function and smooth muscle tone, thus favorably modifying IMT. More research is needed to examine mechanisms governing the cardio-protective effects of muscular strength on the carotid wall.

Our cohort of young women were physically active with ~96% of participants meeting current physical activity recommendations (and 74% achieving double the weekly recommended MVPA levels). Moreover, according to estimated VO₂max values, all participants were categorized as having above average to excellent cardiorespiratory fitness. It is important to underscore that even in women meeting and exceeding physical activity guideline recommendations with higher levels of cardiorespiratory fitness, muscular strength was associated with lower subclinical carotid atherosclerosis. Thus, muscular strength offers additional cardio-protection extending beyond physical activity and cardiorespiratory fitness levels. Even highly active women with higher cardiorespiratory fitness can appreciate additional CV health benefits from having higher muscular strength.

Our findings were not related to strength training per se. According to self-report, ~49% of women in this study engaged in habitual strength training. Interestingly, there were no differences in handgrip strength between women that self-reported engaging in habitual strength training versus those that did not (0.48±0.1 vs 0.45±0.08, p=.16) nor were there differences in body fat (28±7 vs 31±7, p=.12). As such, there were no differences in IMT or EMT between women who strength trained vs those that did not (p>.05). Self-report of exercise behavior is not without flaw owing to inaccuracy of self-report. It has been suggested that when surveying risk for CVD, one should look to the outcome of the lifestyle behavior (i.e., strength) rather than the behavior itself (i.e., self-reported strength training). Dankel et al. has shown that strength is a more important predictor of all-cause mortality than self-reported strength training [29]. With respect to self-report, participants may overestimate intensity of the bout and/or not accurately recall frequency. This is analogous to studies that highlight that cardiorespiratory fitness is a better predictor of CVD risk than self-reported leisure-time exercise [30, 31]. Thus, a practical extension of present findings would suggest that for improving cardiovascular health, young women should engage in strength training at a sufficiently high enough volume and intensity to yield physiological adaptation (i.e., strength gains).

One strength of our study was inclusion of a multi-ethnic/racial group of young women. The association of muscular strength with EMT and IMT remained significant after adjusting for race/ethnicity. This finding may have important implications for health disparities as racial/ethnic minorities are less likely to engage in healthy lifestyle behaviors and risk for atherosclerotic CVD is higher in Hispanic women and non-Hispanic Black women compared to non-Hispanic white women [32]. Thus, maintenance of muscular strength may be an important means of maintaining cardiovascular health and abrogating risk for atherosclerotic CVD with advancing age for women of different races and ethnicities.

Limitations to our study should be acknowledged. VO₂max was estimated from HR response to submaximal exercise. Additional research is needed to explore the relationship between cardiorespiratory fitness and EMT using gold standard approaches of assessing maximal oxygen consumption (e.g., metabolic gas analyses). EMT was measured on the near wall and IMT on the far wall of the common carotid artery thus not capturing subclinical atherosclerosis on the same aspect of the vessel wall. This decision was made as EMT is conventionally measured on the near wall using the jugular vein as an anatomical reference point [19]. Conversely, IMT measurement is conventionally performed on the far wall owing to improved boundary clarity [28]. Body composition was assessed using air displacement plethysmography. Future studies using duel-energy X-ray absorptiometry (DXA) are needed to explore the important mediating role of visceral adiposity as well as offer insight into atherosclerotic burden of other vascular beds (via assessment of aortic calcification).[33] Overall, correlations were small suggesting somewhat weak associations between handgrip strength and subclinical carotid atherosclerosis. Thus, readers are encouraged to interpret results with caution. It is still notable that handgrip strength was associated with IMT and EMT even after adjusting for several traditional and emerging CVD risk factors, explaining an additional 5-6% of the variance in each outcome.

In conclusion, we demonstrate weak inverse associations between muscular strength with carotid IMT and EMT in young women, independent of physical activity levels and estimated cardiorespiratory fitness. Our findings suggest that muscular strength may be modestly associated with lower subclinical atherosclerotic risk in young women. The benefits of muscular strength for cardiovascular health extend beyond cardio-protection afforded by physical activity and apply to women of different race/ethnicities.