Remote Ischemic Conditioning: Promising Potential in Wound Repair in Diabetes?

Abstract

Remote ischemic conditioning involves the use of a blood pressure cuff or similar device to induce brief (3–5 min) episodes of limb ischemia. This, in turn, seems to activate a group of distress signals that has shown the potential ability to improve healing of the heart muscle and other organ systems. Until recently, this has not been tested in people with diabetic foot ulcers. The purpose of this review was to provide background on remote ischemic conditioning and recent data to potentially support its use as an adjunct to healing diabetic foot ulcers and other types of tissue loss. We believe that this inexpensive therapy has the potential to be deployed and incorporated into a variety of other therapies to prime patients for healing and to reduce morbidity in patients with this common, complex, and costly complication.

Noncommunicable diseases are now the leading cause of global mortality in the developed and developing world, having surpassed infectious diseases as recently as 2009. Diseases such as cardiovascular disease, cancer, diabetes, and other chronic conditions now constitute more than 60% of deaths worldwide. These noncommunicable diseases pose a staggering economic burden that is estimated to increase to a cumulative output loss of $47 trillion by 2030. [1] We have transitioned from communicable diseases to ‘‘diseases of decay’’ in which we need replacements for things such as cardiac muscle after a myocardial infarction, brain tissue after a stroke, and tissue loss after the onset of diabetes mellitus. Decay is indeed a natural phenomenon, but we must find ways to better delay the deleterious effects of decay.

The prevalence of diabetes in the United States in 2012 was 29.1 million, or 9.3% of the population. [2] Approximately 25% of those with diabetes will develop a diabetic foot ulcer (DFU) during their lifetime, with an annual population-based incidence ranging from 1% to 4%. [3] Foot ulcers and infections are the most common reason for the hospitalization of diabetic patients in the United States. [4]

One strategy to ‘‘delay decay’’ is to evaluate, understand, and harness intrinsic physiologic processes and distress signals designed to facilitate healing and tissue repair. [5] To that end, remote ischemic conditioning (RIC) creates just such a physiologic distress signal. This simple and remarkably inexpensive therapy is seen intrinsically in the heart with ischemic preconditioning (IPC). [6] Until very recently, we have been unaware of any reports in the literature that have discussed its use in diabetes and the diabetic foot. This, combined with the relative paucity of well-studied techniques and technologies available in healing and prevention in this area of medicine highlights a major therapeutic unmet need. [7,8] Therefore, the purpose of this review was to analyze the available literature and early findings and the potential application for RIC in the diabetic foot.

Remote ischemic conditioning was first identified as an endogenous phenomenon in which the application of brief cycles of ischemia and reperfusion to the heart reduced subsequent myocardial infarct size in canines. [9] Later, experimental studies found that RIC was not limited to the cardiovascular system and could constitute a form of systemic protection for many tissues and organs. A recent study of traumatic brain injury found that RIC using a standard blood pressure cuff applied to the arm was associated with a significant decrease in standard biomarkers of acute brain injury, unveiling the therapeutic role of RIC for the potential prevention of secondary brain injury in patients with traumatic brain injury. [10] This newfound approach translates well to the clinical setting by applying a blood pressure cuff on the upper arm or leg, which noninvasively induces the RIC stimulus. [11] Understanding the mechanisms by which neuronal, hormonal, and systemic responses react under brief cycles of ischemia can bring to light the specific pathways that can later be manipulated to promote quick and efficient healing of diabetic foot ulcers.

Methods

To determine the efficacy of RIC, a literature review was undertaken to evaluate the outcomes of RIC in a variety of experiments that target various tissues and organs. A systematic review of PubMed, the electronic database of the US National Library of Medicine, National Institutes of Health, was conducted with no restriction on data or language. An inclusive text word query for remote ischemic conditioning and diabetic remote ischemic conditioning was entered. Twenty-one articles were identified using this method, and the references in these original 21 articles were analyzed for the same inclusion criteria. After review, six articles were yielded that described RIC for diabetic patients, and one focused on the diabetic foot specifically.

Due to the novel nature of this intervention, little is published in the literature specifically on this topic for the treatment of diabetic foot ulcers or similar types of tissue loss. Therefore, extensive research was conducted on various review articles covering the effects of RIC on specific tissues and organs or organ systems that relate to DFUs. One article pertaining explicitly to RIC and DFU was found [5] and was used to bring together the information regarding the effects of RIC on DFU healing.

Timeline of Advancements in RIC Discoveries and Therapies

In 1993, McClanahan and coworkers [12] discovered that IPC of the myocardium need not be stimulated across various coronary arteries only but that applying cycles of nonlethal ischemia and reperfusion to an organ remote from the heart in rabbits could mimic the same process. Other studies displayed similar results in rats under hypothermic conditions but not under normothermic conditions, [13] suggesting that RIC of the renal arteries may be temperature sensitive.

In an effort to keep this process as noninvasive as possible, it was found that restricting blood flow to the skeletal muscles of the lower extremities of rabbits, specifically the gastrocnemius, before an acute coronary artery occlusion reduced the following myocardial infarct size by 65%. [14] The application of a tourniquet to the hind limb of rats to induce RIC demonstrated reduced reperfusion arrhythmias after a sustained ischemic insult. [15] The limb is a favored location for the purpose of applying a tourniquet to noninvasively stimulate RIC due to the location of the large femoral artery and has been shown to reduce injury of other organs in animals and humans. [16] The accessibility and convenience of using the limb to induce RIC facilitated the transition of this procedure to the clinical setting.

Remote ischemic conditioning provokes a systemic protective response by modulating immune cells either at the post-translational level or through transcriptional regulation. [17] In an experimental study on a septic mice model, those undergoing RIC have been shown to have better survival than controls. Further details of the study revealed that RIC is associated with a marked decrease in the levels of proinflammatory markers, ie, tumor necrosis factor a and interleukin 1b (Figure 1). [18] Healthy human volunteers who underwent brief forearm ischemia showed in their blood a suppression of proinflammatory genes encoding proteins involved in leukocyte chemotaxis, adhesion, migration, and exocytosis. Alternatively, anti-inflammatory genes, such as HSP70 and calpastatin, were upregulated and were found to be correlated with functional changes in human leukocytes. [19] This finding was in agreement with another study [20] showing reduced expression of neutrophil CD11b and platelet-neutrophil complexes in human volunteers who underwent forearm RIC.

Initially, RIC was demonstrated in the canine heart, [21] and its protective effect on the heart was later confirmed in humans. [11] Subsequent studies have shown that RIC protects muscle flaps, stomach, kidneys, lungs, and the liver from ischemic reperfusion injury. [22] Cerebrovascular injuries, such as strokes resulting from cerebral ischemia or intracranial hemorrhages, are the second leading cause of mortality and disability worldwide and contribute to the increasing global mortality of noncommunicable diseases. [1] Jensen et al [23] showed that remote IPC of the limb in pigs reduced brain edema, hemorrhage, and neuronal damage caused by hypothermic circulatory arrest and was associated with significantly improved neurologic function. The cytoprotective effect of RIC on muscle flaps has been shown in a variety of experimental studies focusing on tissue necrosis of epigastric adipocutaneous flaps and various skeletal muscles. [24,25] This protection was associated with improved endothelial function and microcirculation, reduced leukocyte adhesion and accumulation, and preserved adenosine 5’-triphosphate content. [25]

Vasdekis et al [26] concluded that this therapy is safe and could potentially constitute a promising innovate treatment for atherosclerosis in the future, but there seems to be no positive correlation between RIC and the resolution of atherosclerotic diseases such as peripheral artery disease. Another study found that this therapy did not improve walking distance or any variables of limb ischemia in patients with peripheral artery disease and intermittent claudication, [27] which is plausible based on the presumed mechanism of action of stimulating pluripotent cells to regenerate tissue, [28] not breaking up plaque.

The effect of RIC on the diabetic foot is presented in the study by Shaked et al [5] in which 40 patients with DFUs received standard wound care in a prospective, double-blind, randomized, sham procedure–controlled study. The ratio of patients who reached 75% reduction of their ulcer area was higher in the study group (14 of 22 [64%]) than in the control group (3 of 12 [25%]). The ratio of patients who reached complete healing of their ulcer was 9 of 22 (41%) in the study group compared with 0 of 12 in the control group (Figure 2). Furthermore, the mean ± SD residual ulcer area at the end of follow-up was significantly smaller in the study group (25% ± 6% of the initial area) compared with the control group (61% ± 10%) (Figure 3).

The growth capacity of small collateral vessels is reduced in patients with diabetic microangiopathy, and RIC in patients with DFU might be futile without an invasive therapeutic procedure of intra-arterial and intramuscular administration of bone marrow–derived mononuclear cells and the injection of CD34⁺-enriched cells directly into the diabetic wound. [5] Nevertheless, a previous study showed the capability of RIC in the extremities to increase the availability of CD34⁺ angiogenic progenitor cells while maintaining their ability to form vascular structures. [28] Remote ischemic conditioning can increase nitric oxide production, an angiogenic factor and potent vasodilator that has a protective effect against ischemic reperfusion injury, and further increase the recruitment of CD34⁺ cells. [29] More recently, several studies indicate that bone marrow–derived stem/progenitor cells could also significantly affect cutaneous homeostasis and wound healing in diabetic and nondiabetic animals through cell differentiation or the release of paracrine factors. [30] Previous reports demonstrate the effectiveness of RIC in cutaneous oxygen saturation, arterial capillary blood flow, and post-capillary venous filling pressure and its potential use with DFUs. [31]

Clinical Application and Conclusions

The ability to replicate RIC in human volunteers using a standard blood pressure cuff to induce brief suprasystolic cycles of ischemia and reperfusion in the arm has shown promise in its potential translation to the clinical setting. [5,11] Remote ischemic conditioning has been shown to be effective in protecting various organs from ischemic reperfusion injury while simultaneously manipulating endogenous pathways by recruiting various cells and inducing signals to promote tissue healing and quicker recovery (Figure 4). We believe that this therapy can be particularly beneficial as an adjunct to healing of DFUs. This can be achieved with a standard blood pressure cuff in the clinic while measuring vitals and conducting a general history and physical examination, and perhaps this inexpensive therapy can potentially be deployed and incorporated into a variety of other therapies to prime patients for healing to reduce morbidity in patients with this common, complex, and costly complication.