Microvascular Function and Ambulatory Capacity in Peripheral Artery Disease

Abstract

Background: Patients with peripheral artery disease experience walking impairment that is incompletely explained by large-artery atherosclerotic occlusive disease and abnormal ankle-brachial index (ABI). Microvascular dysfunction is associated with adverse outcomes, including amputation, but its effect on ambulation is unknown. We tested the hypothesis that skeletal muscle microvascular function directly associates with walking distance, is a more sensitive indicator of walking distance than conduit artery blood inflow, and correlates with ambulatory improvement following peripheral artery disease interventions.

Methods: Sixty-eight participants, including 50 with peripheral artery disease (ABI ≤0.85) and 18 healthy controls, underwent vascular function assessment after sphygmomanometer cuff-induced calf ischemia using magnetic resonance imaging measures of blood oxygenation level-dependent reactivity and arterial spin labeling perfusion reactivity. Functional status was assessed using the 6-minute walk test. A subgroup of patients with peripheral artery disease underwent repeat testing after supervised exercise therapy (n=14) or revascularization (n=14). Multivariable linear regression models were used to assess the association of macrovascular reactive hyperemic blood inflow within the conduit arteries, skeletal muscle microvascular blood oxygenation level-dependent reactivity, and walking distance.

Results: Resting large-artery pressure by ABI (R=0.74; P<0.001), macrovascular blood inflow (R=0.40; P<0.001), and skeletal muscle microvascular blood oxygenation level-dependent reactivity (R=0.66; P<0.001) significantly correlated with the 6-minute walk test distance in univariable vascular testing. In multivariable analysis of each vascular parameter, however, calf skeletal muscle microvascular reactivity was most strongly associated with the 6-minute walk test (β=825.3; P=0.023). In those with repeat testing after intervention, the change in microvascular reactivity, but not ABI or macrovascular blood inflow, significantly correlated with the change in the 6-minute walk test distance (R=0.46; P=0.014).

Conclusions: Microvascular reactivity after ischemia directly associates with walking distance and was a stronger predictor of walking distance than macrovascular blood inflow and ABI. After supervised exercise therapy or revascularization, improvements in microvascular function, but not macrovascular inflow or ABI, correlate with improvement in walking distance. Further study of microvascular dysfunction as a mechanistic driver of ambulatory function is warranted.

Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03490968.

Keywords: blood vessels; capillary resistance; magnetic resonance imaging; microcirculation; peripheral arterial disease; peripheral vascular diseases.

Figure 1.. Association Between Vascular Measures and Six-Minute Walk Test.

Across all 18 control and 50 peripheral artery disease participants at enrollment, ankle brachial index (A), blood oxygenation level-dependent (BOLD) reactivity in the large conduit artery region (i.e., macrovascular blood inflow) (B), and microvascular BOLD reactivity (C) correlated with function, quantified as the six-minute-walk-test.

Figure 2.. Calf Microvascular Reactivity in PAD (BOLD & Perfusion)

Mean blood oxygenation level-dependent (BOLD) and perfusion responses across the 11 min assessment (rest: 1 min; cuff occlusion: 5 min; post-occlusion release: 5 min). Reactivity changes for both metrics are correlated (p<0.001; see Results) and exhibit similar trends indicative of higher skeletal muscle reactivity in control versus peripheral artery disease participants, as well as delayed vascular responses in peripheral artery disease participants. The perfusion assessment (B) provides additional confirmation that the calk skeletal muscle drops from 5–15 ml/100g/min at rest to null by the conclusion of the 5 min occlusion. The BOLD time course (left) is shown in signal intensity arbirtrary units (a.u.), whereas the perfusion time course is shown in perfusion units of ml blood / 100g skeletal muscle tissue / minute.

Figure 3:. Microvascular Reactivity Change Predicts Post-Treatment Walking Gains

Following intervention with either exercise (n=14) or revascularization (n=14) therapy, neither change in ankle brachial index (A) nor change in macrovascular blood inflow (B) correlate with the change in ambulatory function, quantified as the six-minute-walk-test. There was a significant association between microvascular BOLD reactivity (C) and six-minute-walk-test.