**1. Introduction**

Of all deaths caused by major non-communicable diseases (coronary disease, type 2 diabetes, breast, and colon cancer), a considerable share of up to 10 percent results from physical inactivity [1]. That results in 5.3 million out of 57 million deaths worldwide per year [1]. Approximately one-third of the global population does not fulfil the minimum requirements for physical activity to maintain health [2,3]. However, retrospective studies have suggested that regular physical activity is associated with a lower risk of cardiovascular mortality and morbidity [4,5]. Prospective studies provide direct

evidence that adopting a physically active lifestyle delays all-cause mortality, extends longevity [6], and reduces risk for cardiovascular mortality by 42 to 44 percent [7,8]. Several vascular diseases such as arteriosclerosis, thrombosis, embolic diseases, accidental vascular damages, or dissections are known risk factors for LEAD [9]. Beyond that, smoking, diabetes, dyslipidemia, hypertension, and, in particular, physical inactivity are major risk factors for LEAD [10,11]. Exercising and physical activity are, thus, of grea<sup>t</sup> relevance in the context of LEAD.

Peripheral arterial disease is characterized by limited blood flow through the arteries supplying the (usually lower) extremities. Peripheral arterial disease commonly refers to stenosis or occlusion of the peripheral arteries. The global prevalence was estimated to be 202 million [11]. Approximately 30 percent of these individuals suffer from intermittent claudication and subsequent impairment of mobility [12]. Major assessable impacts include impaired performance in lower extremity performance tests and, due to its effect on everyday activities, a significant impairment of health-related quality of life [13,14]. The walking performance of these patients is 50 percent or less lower [15]. In addition, a lower peak oxygen uptake is approximately 50 percent lower in patients with intermittent claudication as compared with the normal population [15]. There is clear evidence that supervised exercise therapies aimed at improving lower extremity performance, including supervised exercise programs, home-based walking interventions, and resistance training, improve lower limb symptoms and quality of life among LEAD patients [13,14,16]. The training is effective if it takes place at least two times per week over a period of three months [17]. A single training session should be approximately 45 min to achieve cardiovascular adjustments [13]. A well-established screening tool for individuals with LEAD, even when it is still in a mild asymptomatic state, is the measurement of ankle-brachial index (ABI). In order to diagnose most individuals with LEAD, regular measurements of the ankle-brachial index (ABI) in the whole population starting at an age of about 40 years seem to be useful [18].

The clinical manifestation and the clinical course of LEAD are heterogenous. Symptoms of varying severity occur depending on the degree of stenosis and insufficiency of blood (i.e., oxygen) supply to the distal tissues [19]. At a low grade of stenosis, LEAD usually remains clinically asymptomatic and individuals do not have any adverse effects in their everyday activities. As the disease progresses, LEAD is characterized by leg pain, induced during exercise or when walking (intermittent claudication) [20]. At a higher grade of LEAD, the patients suffer from resting pain in the affected leg, and in end stage from ulceration and gangrene of the foot (critical limb ischemia) [20]. Peripheral arterial disease is a major cause of decreased mobility, functional capacity, quality of life, and increases the risks of amputation or death [21,22]. This risk is triggered by the prevalence of atherosclerotic manifestations in the coronary and cerebral circulation [22,23]. That leads to a high cardiovascular mortality risk [24]. Therefore, the early identification and treatment of LEAD patients is one of the key elements in LEAD therapy. According to international guidelines, any patient suffering from LEAD should receive the best medical treatment (BMT), whereas in Fontaine stage I or IIA/B (Rutherford 1–3), conservative treatment by BMT and exercise training is recommended [10,25]. In higher stages of LEAD, surgical or interventional treatment could be indicated.

Skeletal muscle is constantly adapting to its environment [26]. It responds to stress by stimulating muscle development, and it responds to disuse with atrophy [27]. Traditional training methods use loads greater than 70 percent of one repetition maximum (1RM) to stimulate muscle hypertrophy [26,28]. This is not be safe for all patients and healthy people who are unable to tolerate high-load resistance due to stress, for example, placed on the joints and soft tissues. Therefore, there is adapted low-load resistance training that can also stimulate the anabolic pathway. This training method with lower loads, additionally, uses a blood flow restriction (BFR) to receive a similar stimulus than high-load training. The BFR is, thereby, artificially induced, usually by applying a blood pressure cuff. The cuff is attached at the origin of the target extremity (arms or legs). Low-load resistance training alone has not been shown to promote muscle development, but when combined with BFR, positive effects have been demonstrated to occur. A meta-analysis investigating 20 studies showed that low-load BFR training was more effective at increased muscle strength as compared with low-load training alone [29]. In healthy populations, training under reduced blood flow aims to reach low-loaded training e ffects comparable to those under high-loaded conditions. To achieve systematic e ffects during BFR, a resistance load lower than that in classic (resistance/strength) training without using BFR is used. An intensity of 20 percent of the one repetition maximum (the weight which can be moved once over the total range of motion, 1RM) and a reduced training time of about four to eight weeks have been demonstrated to have systematic e ffects on muscle hypertrophy and muscular strength [30]. More specifically, BFR training with a reduced load can lead to the same results as resistance training with significantly higher loads (at 65% 1RM) and longer intervention time. In particular, increases in muscle thickness and strength gains are comparable between these two strategies [31,32]. A wide variety of suggested, known, and potential mechanisms of how BFR during exercise leads to training benefits is given.

Both BFR and exercising with LEAD seems to elicit physical benefits over exercising e ffects solely and combined with the reduced blood flow. This makes BFR a promising model for studying exercise e ffects in LEAD patients without putting the vulnerable target population at an undue risk of (for example) adverse events. There is a multitude of known, potential, and suggested mechanisms of exercising during BFR or with LEAD, and therefore designing a study to prove one or more similarities or di fferences is of importance in order to collect and present all known mechanisms. This could lead, in a second step, to the selection of outcomes for experimental confirmatory studies.

Against this background, it is important (1) to identify the exercise-induced e ffects under both blood flow reduced conditions (disease vs. external application) and (2) to compare the underlying mechanism to point out di fferences and similarities. With this review on systematic reviews and original data publications, we aim to describe the current evidence of vascular adaption due to training under blood flow restriction.

#### **2. Materials and Methods**

This review adopts a narrative (focus) comparative design. A priori systematic literature research was performed to find and select suitable evidence. We followed up-to-date guidelines for systematic literature research.

#### *2.1. Search Strategy*

In July 2019, systematic literature research was performed. For that purpose, the peer review-based bibliographic database MEDLINE (PubMed) was used. Two investigators (JV, KT) independently searched for relevant primary and secondary analyses using the following predefined Boolean search syntax, especially adaptable to PubMed): ("peripheral arterial disease" [All Fields] OR "intermittent claudication" [All Fields] OR "blood flow restriction" [All Fields] OR "reduced blood flow" [All Fields]) AND ("e ffects" [All Fields] OR "exercise response" [All Fields] OR "mechanism" [All Fields] OR "vascular adaption" [All Fields]) AND ("training" [All Fields]). An initial exploratory electronic database search was conducted by the two reviewers to define the final search terms. Both reviewers independently conducted the main research afterwards. The herewith identified studies were screened for eligibility using (1) titles and (2) abstracts. The remaining full texts were assessed to ascertain whether they are fulfilling the inclusion and not fulfilling the exclusion criteria. The search was restricted to peer-review publications authored in English or German (publication date: 01.01.2010 to 02.07.2019). The references of all manuscripts included were screened for further sources with potential relevance for the review.

#### *2.2. Participants' Inclusion Criteria*

Both male and female adults (>18 years of age) were considered eligible. Participants had to be healthy or LEAD patients. On participant level, no further inclusion criteria were applied.

#### *2.3. Study Inclusion Criteria*

Primary and secondary data studies (RCTs, CTs, systematic reviews or meta-analyses, cohort and case-control studies) were considered eligible if they adopted an (exercise, training, physical activity, and movement) intervention that consisted of exercises without additional specific treatment. Position papers, consensus papers, letters to the editor, and editorials were excluded. Primary aim (of the studies to be included) had to be training with reduced blood flow due to disease or external superficial (non-invasive) application.

#### *2.4. Study Selection*

All studies initially found were individually screened for relevance. Final inclusion (or exclusion) into the review followed a standardized procedure: for each of the messages found in the literature, the publication with the highest level of evidence (Oxford Centre for Evidence-Based Medicine, Levels of Evidence) and the highest relevance was selected and included. The description of the results and findings were, thus, preferably selected from systematic reviews, randomized controlled trials, controlled trials, and cohort and case-control studies. The order followed a decrease in the evidence levels, starting from Level 1 (meta-analyses and systematic reviews on RCTs) downwards to Level 5 (narrative reviews and consensus papers). The relevance rating was conducted based on the special focus on vascular adaption and arteriogenesis. All types of controls were included; and no restrictions were undertaken for outcomes.

#### **3. Results and Discussion**

#### *3.1. Study Selection*

We identified 416 manuscripts. After inclusion and exclusion criteria application and study selection (evidence slope), *n* = 39 manuscripts were included in the vascular adaption part.

#### *3.2. Evidence on LEAD and Exercise*

As the major e ffect, exercise improves walking in patients with LEAD. More specifically, the walking distance until pain occurs and the maximum walking distance can be improved with exercise therapy. Beyond the general exercise e ffects, a variety of involved mechanisms for the e ffect of exercise on walking ability have been proposed in studies investigating exercise in populations exposed to LEAD risk factors such as suppression of inflammation, as shown by a decrease in circulating chemokines (interleukin (IL)-8 and monocyte chemoattractant protein-1) after endurance training [33]. A decrease in number of proinflammatory immune cells (leucocytes, monocytes, and neutrophils) has been observed in overweight participants [34,35].

Furthermore, an improvement in the endothelial function in hypertensive patients [36] was attributed to an improved endothelium-dependent vasorelaxation. The latter was triggered through an increase in the release of nitric oxide. A remodeling of the involved skeletal muscles during strength training in LEAD patients [37,38] a ffects not only muscle histology but also their metabolism. The remodeling characteristics in skeletal muscle are as follows: change in capillary density, alterations in the ratio of type I to type II muscle fibers, arteriogenesis, and increases in mitochondrial activity [37,39].
