Therapeutic arteriogenesis in peripheral arterial disease: combining intervention and passive training

Abstract

The prevalence of peripheral arterial disease (PAD) is on the rise in an aging population, significantly affecting quality of life, morbidity and mortality. Besides medical treatment and surgical or interventional revascularization, supervised exercise programs are a primary treatment modality for PAD. Training may significantly increase pain-free walking time (+ 180 %) while avoiding the associated complications of (repeated) invasive revascularization. Training effects rely on an improvement of risk factor management, muscle function, economy of movement, hemorheology, vascular growth and collateral vessel growth. Exercise training upregulates pulsatile fluid shear stress on the vascular endothelium, prompting an improvement of endothelial function (eNOS, NO) and an outgrowth of preexistent collaterals (arteriogenesis) to functional conductance arteries outside the ischemic area at risk. However, the necessary intense minimum training intervals compromise patient compliance, and the impaired functional status of many PAD patients limits active exercise training. Strategies are necessary to a) increase training compliance, b) make the benefits of exercise training available to patients unable to exercise actively and c) therapeutically enhance the adaptive growth of biological bypasses (arteriogenesis). A modified form of “passive exercise training” derived from enhanced external counterpulsation (low-pressure ECP) which was originally developed for the therapy of heart failure, may prove to be an option for this group of patients. Therefore, this review article suggests a tailored combination therapy, consisting of a facilitating revascularization procedure to restore arterial inflow, succeeded by supervised exercise training, which has yielded promising therapeutic results in clinical trials. Further studies, using appropriate imaging methods and controls, are under way to (a) establish the efficacy of low-pressure EECP in PAD patients and (b) to directly correlate training-induced improvements of collateral flow to the functional improvements seen with exercise training.

Impact of a single session of intermittent pneumatic leg compressions on skeletal muscle and isolated artery gene expression in rats

“…If, as discussed above, increased circumferential stretch in collateral arteries and repeated forceful compressions of the muscles are also important, it would be appropriate to select a frequency that enhances the action of these mechanisms. Along these lines, alternative compression strategies that employ much higher frequencies, such as enhanced external counterpulsation, have begun to be tested in cohorts of patients with claudication (1,35). These initial studies indicate that the extremely high frequencies adopted in these devices are safe and seem to be associated with improved outcomes in these patients (35).…”

Vascular Growth in Health and Disease

“…During adaptive collateral growth the restoration of flow brought about by the growing collateral reduces FSS and prematurely terminates arteriogenesis. Exercise training maintains elevated FSS level, thus augmenting collateral proliferation (reviewed in Bondke Persson et al, 2011). External counterpulsation is currently under evaluation for the clinical use in patients who are unable to undergo the necessary long and intense training intervals, with promising first results (Buschmann et al, 2009; Thakkar et al, 2010).…”

Let ‘em grow: theYin andYang of vessel growth

“…) (Bondke Persson et al . ). With refined methods in imaging and molecular biology, we have looked again and more closely into the different stages of vascular growth and have detected interesting, unexpected overlaps: Angiogenesis and neurogenesis share common guidance cues (Carmeliet & Tessier‐Lavigne ) (Safar & Struijker‐Boudier ).…”

“…Among the potential immediate effects of exercise training are an improvement of risk factor management, optimization of muscular function and the economy of movement, of hemorheology and capillary as well as collateral vessel growth [reviewed in Bondke Persson et al . ()]. Differential assessment of vascular growth processes may aditionally benefit studies of exercise effects on postischemic recovery (Matsuda et al .…”