Changes in the ankle–brachial index and progression of white matter hyperintensities of presumed vascular origin in community-dwelling older adults: A prospective population study

Abstract

Keywords

ankle–brachial index (ABI)atherosclerosis cerebral small vessel disease longitudinal study peripheral artery disease

The ankle–brachial index (ABI) is utilized to recognize peripheral artery disease (PAD), a marker of atherosclerosis.¹ White matter hyperintensities (WMH) of presumed vascular origin are representative lesions of cerebral small vessel disease (cSVD).² An association between selective markers of atherosclerosis and increased presence of neuroimaging markers of cSVD has been suggested, but information is contradictory and mostly limited to cross-sectional studies.^3
–5 Since this relationship could have important prognostic and therapeutic implications, this study aims to determine whether large and small vessel disease progress interrelated or independently to each other.

Using the Atahualpa Project Cohort, this longitudinal prospective study included baseline and follow-up ABI determinations and brain magnetic resonance imaging (MRI) exams. Participants were identified by means of door-to-door surveys and signed comprehensive informed consents at enrollment and before follow-up exams. The design contemplated follow-up exams with sufficient exposure time that allowed enough statistical power to detect the hypothesized difference. The study was approved by the Ethics Committee of our institution.

Baseline and follow-up ABI determinations followed the recommendations of the American Heart Association (AHA).⁶ Specifically trained final-year medical students performed all tests, as suggested by the AHA. MRIs (baseline and follow up) were performed with a Philips Intera 1.5T, following a previously described protocol.⁷ ABI values ⩽ 0.9 were considered positive for PAD and values ⩾ 1.4 were representative of calcinosis. ABI progression was defined as a change in the ABI status from normal at baseline (0.91–1.3) to abnormal in the follow up. WMH were graded according to the modified Fazekas scale,⁸ and WMH progression was defined as the increase in at least one grade of this scale. To test intra-rater reliability of ABI determinations, the same personnel performed repeated exams in 20% of the population 2 weeks after the first evaluation (at baseline and follow up). Kappa coefficients for interrater agreement of WMH severity were 0.91 at baseline and 0.93 at follow up; discrepancies were resolved by consensus.

Demographics and cardiovascular risk factors were selected as relevant covariates. For this, we used the Life’s Simple 7 construct of the AHA.⁹ Data analysis was carried out using Stata Statistical Software, release 18 (College Station, TX, USA). Poisson regression models were fitted to estimate the rate of progression of WMH severity after considering ABI status at baseline, demographics, cardiovascular risk factors, and the time between baseline and follow-up exams. Logistic regression models, adjusted for the above-mentioned covariates, were fitted to estimate interrelations in the progression of WMH and deterioration in the ABI status.

Of 478 individuals aged ⩾ 60 enrolled in the Atahualpa Project Cohort between 2012 and 2019, 398 (83%) received a baseline brain MRI and ABI determinations. Of them, 251 (63%) had a follow-up MRI and ABI determinations and were included. The time between baseline and follow-up exams was 1631 person-years, and the mean follow up was 6.5 ± 1.4 years (range: 2.2–9.1 years). This follow up allowed the analysis to have at least 80% power to detect an incidence rate ratio of 1.75.

Of 251 participants who completed the study, 47 (19%) had ABI status deterioration and 96 (38%) had WMH progression. Characteristics of participants are detailed in the online Supplemental material. Of the total cohort, 127 (51%) individuals did not have deterioration in ABI status or progression in WMH severity, 28 (11%) showed deterioration in the ABI status but not progression in WMH severity, 77 (31%) showed progression in WMH severity but not deterioration in the ABI status, and 19 (8%) showed deterioration in both the ABI status and WMH progression. Using deterioration in the ABI status and WMH progression at follow up as dependent variables, logistic regression models did not show interrelated progression of these markers (Table 1).

Table 1.

Logistic regression model showing no interrelated progression of ankle–brachial index (ABI) determinations and white matter hyperintensities (WMH).

WMH progression	IRR	95% CI	p-value
ABI progression	0.91	0.44–1.91	0.816
ABI status at baseline	0.70	0.31–1.59	0.399
Age at baseline	1.12	1.06–1.18	< 0.001^a
Female sex	0.91	0.52–1.60	0.744
Body mass index ⩾ 30 kg/m²	0.69	0.34–1.41	0.305
Poor physical activity	0.34	0.08–1.57	0.168
Unhealthy diet	0.98	0.23–4.16	0.975
Blood pressure ⩾ 140/90 mmHg	0.98	0.55–1.75	0.950
Fasting glucose ⩾ 126 mg/dL	1.03	0.54–1.95	0.926
Total cholesterol ⩾ 240 mg/dL	0.34	0.42–1.69	0.762

Smoking status was not included in the model because of collinearity with other variables.

Statistically significant result.

IRR, incidence rate ratio.

There is inconclusive evidence of an improved benefit of statins in the context of cSVD.^10,11 The lack of association between ABI and WMH progression suggests that therapies considered first-line for one vascular condition may not apply to all others and helps explain why cholesterol-lowering therapies may not be useful in all patients with vascular diseases.

Limitations of this study include a relatively small sample size. We did not perform angiography to confirm PAD diagnosis. We only included individuals of Amerindian ancestry and results may not be generalizable to other ethnic groups. Likewise, some bias caused by mistakes at either baseline or follow-up determination cannot be definitively excluded despite the high intra-rater reliability observed. In addition, the large range of follow up (2.2–9.1 years) may have induced a bias in the findings of this study. Strengths include the longitudinal prospective population-based design, with high levels of inter- and intra-reader agreement as well as standardized methods for ABI and MRI collection at baseline and follow up.

In conclusion, study results suggest that progression of ABI and WMH are independent to each other despite sharing pathophysiologic mechanisms and risk factors.⁵ Further studies are needed to confirm our findings, which would allow early recognition of asymptomatic patients in need of additional work-up or medical therapy.

Supplemental Material

sj-pdf-1-vmj-10.1177_1358863X241256299 – Supplemental material for Changes in the ankle–brachial index and progression of white matter hyperintensities of presumed vascular origin in community-dwelling older adults: A prospective population study

Supplemental material, sj-pdf-1-vmj-10.1177_1358863X241256299 for Changes in the ankle–brachial index and progression of white matter hyperintensities of presumed vascular origin in community-dwelling older adults: A prospective population study by Maitri Patel, Robertino M Mera, Denisse A Rumbea and Oscar H Del Brutto in Vascular Medicine

Footnotes

Data availability statement

Data will be available upon reasonable request to the corresponding author.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

This study was supported by Universidad Espíritu Santo – Ecuador. The sponsor had no role in the design of the study nor in the collection or analysis of data.

ORCID iD

Oscar H Del Brutto

Supplementary material

The supplementary material is available online with the article.

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Supplementary Material

Please find the following supplemental material available below.

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