Impacts of Metabolic Syndrome Scores on Cerebrovascular Conductance Are Mediated by Arterial Stiffening

Abstract

BACKGROUND

Individuals with metabolic syndrome (MetS) exhibit reduced cerebral blood flow. The mechanisms of this reduction remain unknown but arterial stiffening has been implicated as a contributor. We determined if MetS was associated with reduced cerebral blood flow at midlife, and if so, whether arterial stiffness was responsible for mediating their relation.

METHODS

Middle-aged (40–60 years) community dwelling adults (n = 83) were studied. MetS score was calculated for each subject. Middle cerebral artery hemodynamics was measured using transcranial Doppler ultrasound. Indices of aortic, systemic, and carotid artery stiffness were derived.

RESULTS

Subjects had subclinical MetS pathology (MetS score = 19.8 ± 10.4) that was inversely associated with cerebrovascular conductance (CVC: r = −0.261, P = 0.02). Carotid-femoral pulse wave velocity (cfPWV) (r = −0.188, P = 0.09), brachial-ankle pulse wave velocity (baPWV) (r = −0.161, P = 0.15), and carotid artery distensibility (r = −0.10, P = 0.37) abrogated the direct association of MetS score and CVC, demonstrating full mediation. Nonparametric bootstrapping further indicated significant indirect effects of cfPWV, baPWV, and carotid artery distensibility, fully mediating reductions of CVC exerted from sublcinical MetS. Carotid artery distensibility demonstrated the greatest effect on CVC (B = −0.0019, SE = 0.0012, −0.0050 to −0.0002 95% confidence interval).

CONCLUSIONS

Arterial stiffness, particularly the stiffness of the carotid artery, mediated reductions in CVC related to MetS.

Metabolic syndrome (MetS) is a clustering of preclinical cardiovascular risk factors within a single individual that raises an individual’s risk for cardiometabolic diseases.¹ Although these risk factors can occur and act independently, when an individual accrues 3 or more, they are deemed to have acquired MetS. While using predefined classifications allows for the clinical diagnosis of MetS, MetS exists on a spectrum of heterogeneous pathophysiology with ranging negative effects. Accordingly, the MetS score was developed to place MetS into a spectrum by using a scoring system commensurate with severity of each risk factor that improves the prediction of diabetes development beyond that of traditional risk classification.² The added predictability from the MetS score may also strengthen its sensitivity to arterial stiffness as insulin resistance synergistically exacerbates age-related arterial stiffness.³

Affecting over a third of the US adult population, the consequences of MetS extend beyond increased risk of cardiometabolic diseases. MetS has been strongly associated with vascular dementia.^4,5 The physiological mechanisms behind these deleterious outcomes may partially lie within increased arterial stiffness and the resultant reduction in cerebral perfusion.^6,7 Additionally, MetS, reduced cerebral blood flow, and arterial stiffness have all been associated with signs of brain disease such as white matter hyperintensities related to dementia.^8–11 With dementia prevalence increasing and Alzheimer’s disease now elevated to the 6^th leading cause of death in the United States, understanding the pathophysiological mechanisms leading to dementia is a critical issue facing ever increasing older populations.¹² Indeed, cardiovascular risk factors and vascular dysfunction have been implicated in a vascular hypothesis of dementia development through insufficient sufficient blood flow to the brain.^13–15 Individuals with dementia may already have arterial dysfunction and impaired cerebral perfusion too great to recover, making the observation of cognitively intact individuals without existing cognitive impairment critical.

Therefore, the goal of the present investigation was to determine if midlife MetS score is associated with brain blood flow and if arterial stiffness accounted for its effect. Transcranial Doppler of the middle cerebral artery was used to determine brain blood flow velocity (BFV) and cerebrovascular conductance (CVC). Arterial stiffness was measured in multiple segments of the arterial tree to characterize systemic arterial stiffness. Central stiffness was assessed with carotid-femoral pulse wave velocity (cfPWV), aortic and peripheral arterial stiffness was determined by brachial-ankle pulse wave velocity (baPWV), and distensibility characterized carotid artery stiffness. We hypothesized that MetS score would be negatively associated with BFV and CVC and arterial stiffness would mediate this relationship.

METHODS

Subjects

From the Austin, Texas community, 83 adults aged 40–60 years were recruited. To be eligible, individuals had to be without overt cardiovascular disease (e.g., coronary artery disease, transient ischemic attack, myocardial infarction, heart failure, or cardiac surgery), or neurological disease (e.g., stroke, Parkinson’s disease, and clinically significant traumatic brain injury). Subjects were free of cognitive impairment evidenced by scoring >24 on the Mini Mental Status Exam. Informed consent was obtained from all subjects. The local institutional review board approved this study.

Metabolic syndrome characterization

Subjects reported to a climate-controlled laboratory (22–24 °C) in the morning following an overnight fast of at least 8 hours. Subjects abstained from exercise, alcohol, and caffeine for ≥24 hours prior to their visit. Height and body weight were recorded using a stadiometer and digital scale for the calculation of BMI. Waist circumference was determined using a nonelastic measuring tape placed around the trunk at the top of the iliac crest.¹⁶ A blood sample was taken from the antecubital vein by a certified phlebotomist via venipuncture. Blood concentrations of triglycerides, high-density lipoprotein cholesterol, and glucose were determined with standard enzymatic techniques. Blood pressure was measured using the automatic oscillometric method (VP-2000; Omron Healthcare, Kyoto, Japan) in the supine position after resting comfortably for 15 minutes.

Metabolic syndrome score

The MetS score was constructed from the parameters based off MetS risk factors using the method described by Macchia et al.² This diagnostic score places cardiometabolic risks associated with MetS into a continuous score rather than simply categorizing the number of risks. Risk points are assigned to each cardiometabolic risk factor with increasing severity. The precise methodology in which risk points are assigned based on risk factors to create the MetS score is shown in Supplementary Table S1.

Cerebrovascular hemodynamics

To assess cerebrovascular hemodynamics, transcranial color-coded duplex ultrasonography (iE 33 Ultrasound System, Philips, Bothell, WA) was performed at the left middle cerebral artery. The middle cerebral artery was insonated from the left posterior temporal window using a 1.6 MHz transcranial Doppler probe, which was mounted on a custom-made probe fixation device attached to commercially available headgear (Dia Mon, DWL Compumedics, Charlotte, NC).^17,18 Beat-by-beat blood pressure was measured by Portapres (Finapres Medical, Amsterdam, Netherlands). BFV was recorded for 3 minutes during spontaneous breathing after at least 15 minutes of rest in the supine position. Ten consecutive BFV waveforms were used to determine mean BFV. CVC was calculated by dividing mean BFV by mean arterial pressure.

Arterial stiffness

Arterial stiffness was assessed with 3 independent methods to characterize the stiffening of different segments of the arterial tree.¹⁹ Applanation tonometry of the carotid and femoral arteries was performed with an array of 15 micropiezoresistive transducers that captured pulse pressure waveforms (VP-1000 Plus; Omron Healthcare, Bannocburn, IL).²⁰ An automated vascular testing device measured pulse wave transit time between the 2 tonometers based on the foot-to-foot method. Using an inelastic tape measure, the straight distance between the 2 recording sites was measured. CfPWV was determined as the pulse travel distance divided by the transit time.²¹

BaPWV determined systemic arterial stiffness.²² Bilateral brachial and posttibial arterial pressure waveforms were stored for 10 seconds by extremities cuffs wrapped on both arms and ankles that were connected to a plethysmographic sensor and an oscillometric pressure sensor. BaPWV was calculated for the right and left side using the distance between the 2 upper and lower arterial recording sites divided by their respective transit times. Again, transit time was determined from the time delay between the proximal and distal “foot” waveforms. BaPWV from the left and right sides was averaged to yield a single variable.

Carotid artery distensibility was measured to assess arterial stiffness most closely related to the cerebral vasculature. An iE 33 Ultrasound System (Philips, Bothell, WA) equipped with a high-resolution linear-array transducer was used to collect a longitudinal B-mode image of the common carotid artery. The image was captured perpendicularly to the blood vessel 1–2 cm proximal to the carotid bulb with the near and far wall interfaces presenting clearly. Ultrasound images were saved in DICOM format and analyzed with image-analysis software (Vascular Research Tool Carotid Analyzer, Medical Imaging Applications, Coralville, IA). A single investigator blinded to subject characteristics performed all image analysis. Recordings of pulse pressure waveforms from the contralateral common carotid artery were obtained simultaneously with arterial applanation tonometry (VP-2000; Omron Healthcare, Kyoto, Japan). Arterial distensibility was calculated as the change in diameter for a given step in pressure normalized to baseline diameter (ΔD/ΔP * D).²³

Statistical analyses

Physiological variables were evaluated with descriptive characteristics and presented as means ± SD. Frequencies are presented for categorical variables. MetS Score, BFV, CVC, and arterial stiffness indices were examined for normality with the Shapiro–Wilk test. Spearman’s rank correlation analysis was used to determine their respective associations due to some naturally skewed distributions. MetS score risk components, including sex as a dichotomous variable with 0 representing female and 1 representing male, were added to ascertain their individual contributions to the research aim. Independent samples t-tests compared outcome variables between individuals with MetS determined by the traditional definition of ≥3 components outlined by the NHLBI and individuals with 0 MetS components.¹ This comparison was repeated using the MetS score stratifying groups by the cutoff of <28 as non-MetS and ≥28 as MetS to assess differences between the traditional MetS criteria and the MetS score.² These 2 stratification approaches were also used for moderation analysis to determine if MetS moderated the relationship between arterial stiffness and BFV or CVC.

Mediation analysis was performed first with parametric regression analysis and confirmed with a nonparametric approach. In the classic mediation model, the direct association between x and y must be significant in the absence of proposed mediators. Upon introduction of a mediator to the model, the association of the direct path is either significantly reduced (partial mediation) or abrogated (full mediation). In our analysis, the direct path was MetS score to cerebrovascular hemodynamic outcomes. In the event of a significant direct association, arterial stiffness measures would be added as potential mediators. An alpha of P < 0.05 was considered significant for Spearman’s rank correlations and parametric regression analyses.

Bias-corrected bootstrapped linear regression using 5,000 samples determined the direct effect of MetS score on cerebrovascular outcomes. A nonparametric bootstrapping technique using the PROCESS macro was then performed.²⁴ This procedure requires a significant direct association between the independent and dependent variables to be present. This procedure takes 5,000 samples at random with replacement from the obtained data and calculates the indirect effect for each sample. The distributions of obtained scores determine 95% confidence intervals (CIs) while correcting for bias due to the underlying distribution. Cerebrovascular outcomes served as the dependent variables with MetS score serving as the independent variable. Arterial stiffness indices served as potential mediators. A 95% bias-corrected CI excluding 0 was considered significant. Arterial stiffness indices were entered simultaneously to determine which segment of stiffening vasculature has the greatest effect on cerebrovascular hemodynamics from MetS score. SPSS version 24 (SPSS; IBM, Armonk, NY) was used for all statistical analyses.

RESULTS

Subject characteristics

Subject descriptive characteristics are enumerated in Table 1. Sex was evenly represented and individuals were middle-aged. Subjects on average did not reach diagnosable cutoffs for MetS using either traditional diagnostic criteria or the MetS score (≥28 points), indicating subclinical MetS pathology.²

Table 1.

Selected subject characteristics

	Mean ± SD
Descriptive
Age, years	48.7 ± 5.6
Sex, M/F	42/41
Education, years	15.7 ± 2.5
Height, cm	169 ± 9
Body weight, kg	79.8 ± 14.8
BMI, kg/m2	27.9 ± 5.1
Systolic BP, mm Hg	119 ± 12
Diastolic BP, mm Hg	73 ± 9
Mean BP, mm Hg	89 ± 11
Total cholesterol, mg/dl	203 ± 44
HDL-cholesterol, mg/dl	52 ± 17
LDL-cholesterol mg/dl	130 ± 39
Triglycerides, mg/dl	110 ± 60
Glucose, mg/dl	97 ± 21
MetS components, n	1.6 ± 1.3
MetS score, AU	19.8 ± 10.4
Arterial stiffness
Carotid-femoral PWV, cm/s	1,025 ± 164
Brachial-ankle PWV, cm/s	1,293 ± 184
Arterial distensibility, 1,000 × mm Hg−1	1.8 ± 0.6
Cerebrovascular hemodynamics
BFV, cm/s	53.0 ± 14.3
CVC, cm/s/mm Hg	0.60 ± 0.17
Ethnicity
Caucasian, n (%)	55 (66.3)
African American, n (%)	5 (6.0)
Latino, n (%)	17 (20.5)
Asian, n (%)	4 (4.8)
Other, n (%)	2 (2.4)
Medications
Antihypertensive, n (%)	15 (18.1)
Anticholesterol, n (%)	12 (14.5)
Insulin, n (%)	2 (2.4)

Abbreviations: BMI, body mass index; BFV, blood flow velocity; BP, blood pressure; CVC, cerebrovascular conductance; F, female; HCL, high-density lipoprotein; LDL, low-density lipoprotein; M, male; MetS, metabolic syndrome; PWV, pulse wave velocity.

Associations

Spearman’s rank correlation analysis of traditional MetS and MetS score with cerebrovascular hemodynamics, arterial stiffness, and MetS score components are delineated in Table 2. Traditional MetS status was associated with MetS score (rs = 0.524, P < 0.05) and distensibility (rs = −0.272, P < 0.05). MetS score was associated with CVC (rs = −0.243, P < 0.05) but not BFV (rs = −0.133, P > 0.05). BFV and CVC were highly correlated (rs = 0.887, P < 0.01). CfPWV was associated with baPWV (rs = 0.629, P < 0.01) and distensibility (rs = −0.346, P < 0.05). BaPWV was associated with distensibility (rs = −0.424, P < 0.01). MetS score was associated with baPWV (rs = 0.431, P < 0.01) and distensibility (rs = −0.428, P < 0.01) but not cfPWV (rs = 0.193, P > 0.05). CVC was associated with cfPWV (rs = −0.428, P < 0.01), baPWV (rs = −0.320, P < 0.01), and distensibility (rs = 0.387, P < 0.01), whereas BFV was not (all P > 0.05).

Table 2.

Spearman’s rho correlation coefficients of MetS, MetS score, cerebrovascular hemodynamics, arterial stiffness, and risk components

	MetS	MetS score	BFV	CVC	cfPWV	baPWV	Distensibility	Sex	Age	SBP	WC	TRG	HDL-C	Glucose
MetS	1	0.524†	ns	ns	ns	ns	−0.272*	0.331†	ns	ns	0.559†	0.428†	−0.294†	0.482†
MetS score	–	1	ns	−0.243*	ns	0.431†	−0.428†	0.486†	ns	0.337†	0.553†	0.411†	−0.401†	0.887†
BFV	–	–	1	0.887†	ns	ns	ns	−0.331†	ns	ns	ns	ns	0.341†	ns
CVC	–	–	–	1	−0.364†	−0.320†	.387†	−0.248*	−0.241*	ns	ns	ns	0.274*	ns
cfPWV	–	–	–	–	1	0.629†	−0.346†	ns	0.324†	0.531†	ns	ns	ns	ns
baPWV	–	–	–	–	–	1	−0.424†	ns	0.273*	0.548†	ns	0.267*	ns	0.379†
Distensibility	–	–	–	–	–	–	1	ns	−0.383†	−0.520†	−0.323†	−0.264*	ns	−0.407†
Sex	–	–	–	–	–	–	–	1	ns	ns	0.287†	0.222*	−0.517†	0.348†
Age	–	–	–	–	–	–	–	–	1	ns	ns	ns	ns	ns
SBP	–	–	–	–	–	–	–	–	–	1	0.222*	0.327†	ns	0.295†
WC	–	–	–	–	–	–	–	–	–	–	1	0.424†	ns	0.329†
TRG	–	–	–	–	–	–	–	–	–	–	–	1	−0.332†	0.360†
HDL-C	–	–	–	–	–	–	–	–	–	–	–	–	1	−0.265*
Glucose	–	–	–	–	–	–	–	–	–	–	–	–	–	1

Abbreviations: baPWV, brachial-ankle pulse wave velocity; BFV, blood flow velocity; C, cholesterol; CVC, cerebrovascular conductance; cfPWV, carotid-femoral pulse wave velocity; HDL, high-density lipoprotein; MetS, metabolic syndrome; ns, nonsignificant; SBP, systolic blood pressure; TRG, triglycerides; WC, waist circumference.

*P < 0.05; ^†P < 0.01.

In relation to MetS score components, MetS was associated with male sex, waist circumference, triglycerides, high-density lipoprotein, and glucose (all P < 0.05). MetS score shared the same associations but was further related to systolic blood pressure (P < 0.01). BFV and CVC were associated with high-density lipoprotein cholesterol with CVC also negatively associated with age (all P < 0.05). All arterial stiffness measures were associated with age and systolic blood pressure (all P < 0.05). BaPWV and distensibility were further associated with triglycerides and glucose (all P < 0.05) with distensibility also showing relations to waist circumference (P < 0.01). Blood glucose and triglycerides were associated with all MetS score risk components other than age (all P < 0.05). Systolic blood pressure was also associated with waist circumference (P < 0.05). High-density lipoprotein was associated with triglycerides, and glucose (all P < 0.05).

Group comparisons

Differences between individuals with and without MetS using traditional criteria and MetS score are shown in Table 3. Using traditional criteria, compared with individuals absent of MetS components, individuals with MetS had greater MetS components (0.0 ± 0.0 vs. 3.4 ± 0.6, P < 0.01), MetS score (11.2 ± 4.6 vs. 30.3 ± 10.4, P < 0.01), and lower distensibility (2.2 ± 0.7 vs. 1.5 ± 0.6, P < 0.01). Compared with individuals with MetS score <28, individuals with MetS exhibited more MetS components (1.2 ± 1.0 vs. 3.0 ± 1.0, P < 0.01), and MetS score (15.4 ± 0.0 vs. 35.7 ± 6.8, P < 0.01). These individuals also displayed reduced CVC (0.62 ± 0.18 vs. 0.53 ± 0.12, P < 0.05) with greater cfPWV (1,006 ± 140 vs. 1,092 ± 223, P < 0.05), baPWV (1,272 ± 181 vs. 1,369 ± 178, P < 0.05), and lower distensibility (1.9 ± 0.6 vs. 1.5 ± 0.4, P < 0.01). Presence of MetS using either traditional MetS criteria or MetS score to determine MetS status was incapable of moderating the relationships of arterial stiffness to CVC (95% CI straddled 0).

Table 3.

Comparisons of cerebral hemodynamics and arterial stiffness between individuals with MetS and healthy controls using traditional MetS criteria and the MetS score

	0 Components (n = 18)	≥3 Components (n = 20)	P value	MetS score <28 (n = 65)	MetS score ≥28 (n = 18)	P value
MetS components, n	0.0 ± 0.0	3.4 ± 0.6	<0.01	1.2 ± 1.0	3.0 ± 1.0	<0.01
MetS score, AU	11.2 ± 4.6	30.3 ± 10.4	<0.01	15.4 ± 6.0	35.7 ± 6.8	<0.01
BFV, cm/s	51.4 ± 14.1	49.5 ± 12.6	0.65	54.3 ± 15.2	48.5 ± 9.2	0.13
CVC, cm/s/mm Hg	0.62 ± 0.16	0.55 ± 0.14	0.14	0.62 ± 0.18	0.53 ± 0.12	<0.05
cfPWV, cm/s	971 ± 119	1050 ± 195	0.15	1006 ± 140	1092 ± 223	<0.05
baPWV, cm/s	1213 ± 119	1316 ± 203	0.06	1272 ± 181	1369 ± 178	<0.05
Distensibility, 1,000 × mm Hg−1	2.2 ± 0.7	1.5 ± 0.4	<0.01	1.9 ± 0.6	1.5 ± 0.4	<0.01

Data are means ± SD. Abbreviations: ba, brachial-ankle; BFV, blood flow velocity; cf, carotid-femoral; CVC, cerebrovascular conductance; MetS, metabolic syndrome; PWV, pulse wave velocity.

Mediation

Using parametric statistics, the direct path of MetS score to CVC was significant (r = −0.261, P = 0.017), but not to BFV (r = 0.139, P = 0.212). Shown in Figure 1, cfPWV fully mediated the relation of MetS to CVC with the direct path abolished (r = −0.188, P = 0.09). The indirect paths of MetS to cfPWV (r = 0.250, P = 0.02) and cfPWV to CVC (r = −0.365, P < 0.01) were significant. BaPWV fully mediated the relation of MetS to CVC with the direct path abrogated (r = −0.161, P < 0.15), and the indirect paths of MetS score to baPWV (r = 0.394, P < 0.01) and baPWV to CVC (r = −0.305, P < 0.01) significant. The indirect paths of MetS score to distensibility (r = −0.428, P < 0.001) and distensibility to CVC (r = 0.415, P < 0.001) were significant while the direct path lost significance (r = −0.102, P = 0.365), showing full mediation.

Figure 1.

Parametric mediation models showing the (a) direct path model of the effect of MetS score on CVC. Arterial stiffness mediates the reductions of CVC through (b) aortic stiffness via cfPWV, (c) systemic arterial stiffness via baPWV, and (d) carotid artery stiffness via arterial distensibility as evidenced by complete abrogation of direct path significance. Abbreviations: ba, brachial-ankle; cf, carotid-femoral; brachial-ankle; MetS, metabolic syndrome; PWV, pulse wave velocity.

Parametric mediation analysis was confirmed with bias-corrected nonparametric analyses with effects and CIs of direct and indirect paths outlined in Table 4. Each arterial stiffness index cfPWV, baPWV, and distensibility fully mediated the effect of MetS score on CVC. When cfPWV, baPWV, and distensibility were entered simultaneously as mediators, distensibility had the largest indirect effect (B = −0.0019, SE = 0.0012, −0.0063 to −0.0007 95% CI) on CVC compared with either cfPWV (B = −0.0011, SE = 0.007, −0.0028 to −0.0001 95% CI) or baPWV (B = 0.0000, SE = 0.0009, −0.0017 to 0.0021 95% CI).

Table 4.

Summary of bias-corrected nonparametric bootstrapped models of arterial stiffness mediating reduced CVC with increasing MetS score

				95% CI
Measure	Effect	β	SE	Lower limit	Upper limit
cfPWV	Direct	−0.0030	0.0017	−0.0064	0.0005
	Indirect	−0.0013	0.0007	−0.0030	−0.0003
baPWV	Direct	−0.0027	0.0019	−0.0065	0.0010
	Indirect	−0.0015	0.0008	−0.0036	−0.0002
Distensibility	Direct	−0.0017	0.0018	−0.0053	0.0020
	Indirect	−0.0026	0.0012	−0.0059	−0.0009

Abbreviations: ba, brachial-ankle; cf, carotid-femoral; CI, confidence interval; PWV, pulse wave velocity.

DISCUSSION

Critical findings from the current investigation are as follows: MetS score was significantly inversely associated with CVC. This relationship was observed in a middle-aged population with average MetS scores below diagnostic cutoff indicating that MetS negatively and subclinically affect CVC at midlife. The relationship between MetS score and CVC was mediated by arterial stiffness measured at various segments of the arterial tree with carotid artery stiffening demonstrating the greatest effect. Collectively, these findings suggest that arterial stiffness, particularly of the carotid artery, mediates the impact of subclinical MetS in promoting cerebral hypoperfusion. Neither the traditional classification of MetS nor classification with the MetS score moderated the association of arterial stiffness and CVC. However, determining MetS status via the MetS score showed differences between CVC, cfPWV, baPWV, and distensibility, whereas the traditional method only showed differences in distensibility. While statistical power may have influenced this result, MetS classification via MetS score detected more MetS related changes in cerebrovascular hemodynamics and arterial stiffening. Finally, based on associative data, glucose is likely the most important individual MetS score risk component influencing the observed moderation, with sex possibly playing a role.

Arterial stiffness differs systemically, with peripheral and muscular vessels presenting as stiffer compared with the ascending or abdominal aorta.^25,26 For example, the carotid artery has lower vessel distensibility compared with the aorta.²⁶ MetS components contribute to arterial stiffening to varying degrees, and hypertension and type-2 diabetes induce greater arterial stiffening in the aorta than in the carotid or more distal arteries (femoral-brachial).^27,28 Because the aorta may be more vulnerable to stiffening from MetS components, we hypothesized that the effects would show up more clearly in cfPWV. However, we observed the larger effect of carotid artery distensibility on CVC from MetS score than cfPWV or baPWV. The carotid artery is directly connected to the cerebral circulation and the stiffening of this arterial segment may therefore be more relevant to the pathogenesis of cerebral hypoperfusion.

Our observed positive associations between arterial stiffness and MetS agree with previous studies.^29,30 One investigation found MetS was independently associated with impaired cerebral vasomotor reactivity.³¹ Contrary to our hypothesis, MetS score and arterial stiffness indices were unrelated to middle cerebral artery BFV. This is not an isolated finding as a previous cross-sectional study found no association between baPWV and BFV under normocapnia in a pooled young and old cohort, but showed a negative association between arterial stiffness and CVC under resting conditions.³² Our findings closely mirror that investigation as we found no association of arterial stiffness with BFV, yet stiffness was related to CVC. Although BFV and CVC are highly correlated and cerebral blood flow is tightly regulated, the brain is a high flow low impedance organ giving perfusion pressure an important role.³³ Therefore, controlling for blood pressure and observing CVC may have added descriptive value than BFV alone.

The associations between MetS score, CVC, and arterial stiffness found in the present study were relatively modest. These mild effects might be explained by the subject population that was middle-aged and healthy, as individuals did not achieve clinically diagnosable MetS on average. Additionally, the effects of MetS score on cerebrovascular hemodynamics may only be beginning to appear in this population. We would hypothesize that these associations would be stronger in individuals with greater MetS scores. Nonetheless, these associations were statistically significant with MetS scores that were subclinical on average. This particular finding demonstrates the early insidious nature of cardiometabolic risk factors on initiating cerebral hypoperfusion and emphasizes the importance of early intervention to combat these modifiable risks. MetS risks and arterial stiffening can be mitigated through lifestyle modifications such as diet and exercise.^34,35 As primary and secondary prevention strategies, lifestyle interventions could reduce the impact of MetS and arterial stiffness on conferring impaired cerebrovascular hemodynamics.

The influence of individual risk factors and sex on the observed mediation can be inferred from their associations with MetS and arterial stiffness measures. Previous work showed that cfPWV was greater in older adult men than women and was associated with fasting glucose after controlling for mean arterial pressure.³⁶ While we did not control mean arterial pressure in our analyses, hypertension minimally and variably contributes to MetS score based on which arterial stiffness measures are used.¹⁹ Nevertheless, mean arterial pressure may have influenced our findings because of its relations to MetS and arterial stiffening. In our data, blood glucose had the greatest association with MetS score among all MetS risk components and was significantly related to arterial distensibility. Systolic blood pressure was related to all arterial stiffness measures and MetS scores. However, blood glucose was more strongly interrelated to other MetS risk components than systolic pressure. Male sex was related to MetS, MetS score, cerebrovascular hemodynamics, and a number of individual components, suggesting that men may be more vulnerable to reductions in CVC from MetS pathology mediated by arterial stiffness.

This investigation had strengths and limitations that should be discussed. The characterization of arterial stiffness in various segments of the arterial tree enabled the ascertainment of their relative contributions to mediating the effects of MetS score on cerebrovascular hemodynamics. We also used parametric and nonparametric statistical approaches to confirm our findings. However, this investigation was cross-sectional in nature. While we were able to demonstrate statistical mediation of reduced CVC with increasing MetS score, longitudinal or intervention data are necessary to confirm our findings.

We provided evidence of a novel mediation path model by which subclinical MetS pathology reduces CVC conferred through arterial stiffening. Our findings suggest that stiffening of the carotid artery may have a greater effect in reducing CVC than the abdominal aorta or peripheral vasculature. The importance of subclinical MetS pathology in promoting arterial stiffness and reductions in CVC was reinforced by the inability of MetS classification systems to moderate this relationship. These findings are of clinical importance as reductions in CVC likely occur prior to diagnosable MetS or cerebrovascular disease. Future studies should target reducing MetS components through interventions that include lifestyle changes to confirm if arterial stiffness is responsible for conferring reductions of CVC from MetS pathology.

SUPPLEMENTARY MATERIAL

Supplementary data are available at American Journal of Hypertension online.

DISCLOSURE

The authors declared no conflict of interest.