The effects of oral inorganic nitrate supplementation on lower limb perfusion and metabolism during exercise in patients with Peripheral Arterial Disease (PAD)

Biomedical Engineering and Bioengineering; Cardiovascular Medicine; Exercise Physiology

To determine mechanisms of ambulation improvements in PAD+IC following inorganic nitrate supplementation by performing graded plantar flexion exercise while undergoing magnetic resonance imaging

Peripheral arterial disease (PAD) is a highly prevalentand costly condition.  Intermittent claudication (IC), defined as ischemic leg pain that occurswith walking, results in functional impairment, reduced daily physical activity, and a lowerquality of life.  Although the mechanismscontributing to functional impairment are not fully delineated, currentevidence suggests that the uncoupling of skeletalmuscle cellular metabolism from tissue perfusion may be responsible for exerciseintolerance. 

We have previously shown that acute increases in plasma inorganic nitrite, viaoral nitrate, produced clinically significant increases exercise performance inpatients with PAD+IC.  This increasedfunctional benefit endured even when administered over 12 weeks in conjunctionwith an exercise rehabilitation program. The increases in performancewere accompanied by a reduction in fractional oxygen extraction at the workingtissues, measured by near infra-red spectroscopy (NIRS)  suggesting increased perfusion to workingtissues. 

Unfortunately, while NIRS data during aphysiological challenge is indicative, it is also relatively imprecise -NIRSmeasures only relative oxygenation/deoxygenation for the whole tissue-bed.  Inthis study we aim to utilize much more precise Magnetic Resonance Imagingduring graded plantar flexion exercise and/or limb cuff occlusion.  Specifically will give 15 patients with PAD+IC6.4mmol of inorganic nitrate (or placebo) for 3-5 days, in a randomized,double-blind, cross over study.  We willutilize Pulsed Arterial Spin Labelling (PASL) coupled with a cuff occlusion or stressto create tissue perfusion maps and differentiate between specificgastrocnemius muscle compartments in a spatial and temporally resolved fashion.  Additionally, we will use Creatine ExchangeSaturation transfer (CrCEST) to measure PCr recovery kineticsafter exhaustive exercise or until subjects symptoms limit their exercisetolerance.  These techniques incombination will allow us to differentiate deficits in tissue perfusion andmetabolism (mitochondrial function) for specific compartments of thegastrocnemius muscle before and after intervention.  Maximal graded treadmill exercise and 6 minutewalk testing will be performed to determine ambulatory function under eachtreatment condition.


Desired outcomes

1) Determine between treatment differences (Inorganic Nitrate v PL) in peakexercise, maximal hyperemia in different lower limb compartments (anterior,lateral, gastrocnemius, soleus and deep compartments) by Pulsed Arterial Spin Labeling (PASL)

2) Determine between treatment differences (Inorganic Nitrate v PL) inphosphocreatine recovery time constant (PCr) measured by Creatine chemicalExchange Saturation Transfer (CrCREST).

3) Determine relations in between treatment changes in walking performanceand lower limb compartmental perfusion characteristics (outcome 1) and phosphocreatinerecover kinetics (outcome 2).

If successful, this study would provide a unique insight into potentialinterventional and pharmacological targets for new therapeutic approaches toPAD+IC, with the capacity to provide clinically meaningful changes in exercisecapacity beyond the current best practice option.  Ultimately these approaches could significantlyreduce the burden of exercise participation and rehabilitation for PAD+IC.