Emerging evidence (Barbalho et al., 2019; Cerqueira et al., 2020) indicates that the intermittent application of BFR passively in the absence of muscle contraction mitigates losses in muscle and strength that occur during immobilization. Barbalho and colleagues (Barbalho et al., 2019) demonstrated that the addition of BFR to passive mobilization reduced rates of muscle wasting in older adults admitted to the ICU with coma. Compared to a control limb receiving passive mobilization alone, the addition of a tourniquet cuff to the proximal thigh during once daily passive mobilization decreased the rate of quadriceps muscle loss by 6% over an 11 day period. Other reports, which have been previously reviewed (Cerqueira et al., 2020), indicate that a BFR-P protocol consisting of 5 sets of 5 min restriction and 3 min reperfusion performed twice daily diminished disuse of the knee extensors by 11% following anterior crucial ligament reconstruction (Takarada et al., 2000) and prevented strength losses during 2 weeks of simulated cast immobilization in healthy adults (Kubota et al., 2008; Kubota et al., 2011). Although the mechanisms underlying these effects are largely unknown, it has been hypothesized (Loenneke et al., 2012a) that cellular swelling as a result of venous pooling may enhance muscle retention by inhibiting protein breakdown and/or increasing protein synthesis.

Neuromuscular electrical stimulation (NMES) is a technique that consists of generating involuntary muscle contractions using low level electrical currents delivered through electrodes applied to the skin. The addition of NMES to standard care (Liu et al., 2020) in critically ill patients reduces the rate of muscle loss, improves muscle strength, shortens length of stay in the hospital, and improves ability to perform activities of daily living. Some evidence (Natsume et al., 2015; Gorgey et al., 2016; Slysz and Burr, 2018) indicates that low-intensity NMES combined with BFR promotes more robust effects on muscle size and strength than low-intensity NMES or BFR-P performed alone. For example, Gorgey and colleagues (Gorgey et al., 2021) reported that 6 weeks of BFR-NMES in individuals living with spinal cord injury increased wrist extensor muscle cross-sectional area and improved electronically evoked wrist extensor torque. Changes in wrist extensor cross-sectional area were 17% greater in the treatment limb receiving BFR-NMES compared to a control limb receiving NMES alone. In another report (Natsume et al., 2015), BFR-NMES performed twice daily (5 days/week) in the lower-body increased quadriceps muscle thickness and maximal knee extension strength after 2 weeks of training in young males. No changes were observed in a control limb performing NMES alone which is consistent with related reports (Slysz and Burr, 2018).

Endothelial dysfunction has been suggested to be a major pathogenic mechanism of COVID-19 (Del Turco et al., 2020; Bonaventura et al., 2021) and persists for months beyond acute infection (Serviente et al., 2022). Endothelial dysfunction is associated with numerous chronic diseases (Hadi et al., 2005) as well as risk of future cardiovascular events (Green et al., 2011) and likely contributes to long-term symptoms in COVID-19 survivors (Charfeddine et al., 2021). In a systematic review and meta-analysis including 292 participants, Gu and colleagues (Gu et al., 2021) reported that BFR-P protocols, referred to as ischemic preconditioning, augment endothelial function via increased flow mediated dilation. Several authors (Jeffries et al., 2018; Rytter et al., 2020) have also reported enhanced microvascular function when implementing similar protocols. Like BFR-P protocols discussed previously, ischemic preconditioning involves the cyclical application of blood flow restriction and reperfusion, however, tourniquets are applied at higher pressures that result in complete arterial occlusion. A large body of evidence (Stokfisz et al., 2017) demonstrates that ischemic preconditioning protects tissues from subsequent ischemia and reperfusion injury and that these effects also occur in remote tissues (i.e., remote ischemic conditioning) that are not directly subject to the localized ischemic preconditioning stimulus. Indeed, lung and cardiovascular injury (Guzik et al., 2020) are common with severe COVID-19 illness and ischemic preconditioning may confer a systemic protective effect. The use of ischemic preconditioning in COVID-19 patients has been previously suggested (Incognito et al., 2021; Cahalin et al., 2023). Additionally, COVID-19 patients display impaired hemostasis (Hanff et al., 2020) which is characterized by overactivation in the coagulation system with reduced fibrinolytic activity. Accordingly, thrombotic complications are common in COVID-19. Longstanding evidence indicates that vascular compression stimulates the fibrinolytic system without elevating the coagulation cascade (Holemans, 1963; Robertson et al., 1972; Stegnar and Pentek, 1993; Kohro et al., 2005). Accordingly, when applied in COVID-19 patients, various BFR-P approaches could potentially help to reduce risk for thrombotic complications. While there is extensive literature supporting the application of BFR-P and its effects on numerous organ systems, reports implementing BFR-NMES are limited. To the best of our knowledge, only one report has investigated the effects of BFR-NMES on vascular function in which the authors (Gorgey et al., 2016) demonstrated acute increases in brachial artery flow mediated dilation following BFR-NMES when compared BFR alone. These preliminary data suggest vascular benefits with the addition of NMES, however, more work is needed to characterize the effects of BFR-NMES.

Low aerobic capacity in COVID-19 survivors, as assessed through an incremental exercise test for determination of VO_2peak, has been attributed to both central and peripheral factors (Aparisi et al., 2022). Thus, impairments throughout the oxygen transport pathway are likely present. In addition to potentially enhancing oxygen delivery via improved peripheral vascular function, BFR-P could attenuate reductions in aerobic capacity during critical COVID-19 illness by reducing cardiac deconditioning and improving oxygen kinetics in skeletal muscle. Nakajima and colleagues (Nakajima et al., 2008) reported similar hemodynamic responses to that of upright standing when BFR-P was applied to the proximal thighs of participants placed in a 6-degrees head-down tilt position. These data let us speculate that BFR-P could approximate the cardiac demands of standing and attenuate cardiac deconditioning and orthostatic intolerance occurring during prolonged bedrest. Additionally, some authors (Saito et al., 2004; Patterson et al., 2015) have reported that repeated ischemic preconditioning exposure improves local skeletal muscle oxygen dynamics during exercise. Data from Jeffries and colleagues (Jeffries et al., 2018) demonstrated that 7 consecutive days of lower-body ischemic preconditioning increased local skeletal muscle oxidative capacity. Together, BFR-P protocols could help to preserve skeletal muscle mass and strength during critical illness and offer a systemic strategy that can provide benefits to the musculoskeletal system and possibly other organ systems, some of which are affected during COVID-19 infection (Figure 2; bottom left).

The combination of aerobic exercise, such as walking or cycling, with BFR increases muscle size and strength in younger (Slysz et al., 2016) and older adults (Centner et al., 2019). Importantly, these adaptations are achieved at low exercise intensities (e.g., 45% heart rate reserve or 40% VO_2peak) and occur as early as 3 weeks, sooner than that observed with high-intensity resistance training without BFR. In addition to increases in muscle size and strength, BFR-AE also facilitates increases in aerobic capacity in young adults (Bennett and Slattery, 2019; Formiga et al., 2020). Thus, BFR-AE provides an efficient exercise mode that improves both muscle size and strength as well as aerobic capacity simultaneously. Importantly, a systematic review by Clarkson and colleagues (Clarkson et al., 2019) indicated that adaptations to BFR-AE translate to improvements in objective measures of physical function, including the 30-s sit-to-stand, timed up and go, and 6-min walk test. This modality has been safely applied in individuals living with a variety of diseases including hypertension (Barili et al., 2018), end-stage kidney disease (Clarkson et al., 2020), chronic heart failure (Tanaka and Takarada, 2018), and obesity (Karabulut and Garcia, 2017).

Increases in muscle size and strength with the performance of resistance exercise in combination with BFR have been reported in reviews of healthy young (Loenneke et al., 2012b; Slysz et al., 2016; Grønfeldt et al., 2020) and older populations (Centner et al., 2019; Grønfeldt et al., 2020), as well as those individuals with orthopedic limitations (Hughes et al., 2017). Adaptations from BFR-RE are achieved with lower exercise intensities (20%–40% 1RM) and are greater than those attained with low-intensity resistance exercise performed without BFR. Relative to BFR-AE, the magnitude of muscle size and strength improvements with BFR-RE are greater (Slysz et al., 2016) and also translate to improvements in objective measures of physical function (Clarkson et al., 2019; Baker et al., 2020). Few studies have investigated the effects of BFR-RE on aerobic capacity, however, one report (Nakajima et al., 2010) noted increases in aerobic capacity when BFR-RE was performed for 3 months in individuals living with ischemic heart disease. Thus, BFR-RE may have the potential to promote cardiovascular adaptations in diseased and less trained populations. This modality has been applied in individuals living with hypertension (Wong et al., 2018), diabetes (Fini et al., 2021; Malekyian Fini et al., 2021), chronic kidney disease (Corrêa et al., 2021a; Corrêa et al., 2021b), and cardiovascular disease (Nakajima et al., 2010; Fukuda et al., 2013; Madarame et al., 2013; Ishizaka et al., 2019; Kambič et al., 2019; Ogawa et al., 2021).

Elevated levels of inflammation and oxidative stress have been suggested (Del Turco et al., 2020) to play important roles contributing to organ dysfunction with COVID-19. Furthermore, evidence indicates that oxidative stress (Ratchford et al., 2021) and inflammation (Montefusco et al., 2021) remain elevated beyond acute infection and likely contribute to long-term symptoms. Accordingly, it is important that interventions aimed at restoring muscle mass, muscle strength, and aerobic capacity in COVID-19 survivors do not exacerbate the underlying pathological mechanisms of the disease. Traditional high-intensity exercise without BFR can result in acute elevations in oxidative stress, muscle damage, and inflammation (Cerqueira et al., 2019). These responses are greatest in individuals that are deconditioned and unaccustomed to exercise. Given the combination of prolonged immobilization, deconditioning, and pre-existing inflammatory and oxidant-antioxidant imbalances, the acute physiological perturbations associated with high-intensity exercise could be deleterious in those recovering from severe COVID-19. Additionally, meta-analyses (Li et al., 2020; Wu et al., 2020; Bansal et al., 2021) have reported elevated makers of skeletal muscle damage (i.e., creatine kinase, lactate dehydrogenase, myoglobin) associated with COVID-19 infection and case studies (Husain et al., 2020; Jin and Tong, 2020; Mukherjee et al., 2020) have documented rhabdomyolysis in patients. Exercise resulting in muscle damage and a subsequent inflammatory response could further deteriorate physical function, suppress the immune system, and worsen symptoms.

A recent systematic review and meta-analysis (Ferlito et al., 2023) indicates that low-intensity exercise with BFR results in lower acute elevations in biomarkers of oxidative stress when compared to high-intensity exercise without BFR. Additionally, Petrick and colleagues (Petrick et al., 2019) demonstrated that skeletal muscle mitochondrial reactive oxygen species emission rates were acutely decreased 2 h following low-intensity BFR-RE but not after the same exercise protocol performed without BFR. Evidence (Loenneke et al., 2014; Nielsen et al., 2017) also suggests that low-intensity BFR-RE results in minimal muscle damage based on direct (integrity of muscle fibers) and indirect (alterations in muscle strength, range of motion, blood markers) assessments. Accordingly, exercise with BFR provides a novel method to increase muscle size, muscle strength, and aerobic capacity which elicits relatively smaller acute elevations in oxidative stress and muscle damage compared to high-intensity exercise without BFR. Thus, this modality provides an alternative way to restore physical function that may be less likely to exacerbate pathophysiological mechanisms of COVID-19.

A potential mechanism by which COVID-19 promotes systemic pathology, particularly endothelial dysfunction, is interaction of SARS-CoV-2 with the renin angiotensin system (RAS). The principal target of SARS-CoV-2 binding is angiotensin-converting enzyme 2 (ACE2), a membrane bound protein found in numerous tissues throughout the body. The active form of ACE2 opposes the action of the RAS. Specifically, ACE2 degrades Angiotensin I (Ang I) and converts Angiotensin II (Ang II) into Ang (1,7), which exerts vasodilatory and anti-inflammatory effects. With COVID-19 infection, the consumption and downregulation of ACE2 via SARS-CoV-2 binding leaves RAS unopposed, increasing the ratio of ANG II to ANG (1,7) and drives excessive vasoconstriction, inflammation, and oxidative stress. Joshi and colleagues (Joshi et al., 2020) reported that BFR-RE performed in the lower-body substantially increased ACE2 activity and enhanced the ACE2-to-ACE ratio following exercise. Additionally, these authors reported increases in circulating hematopoietic stem/progenitor cells which were associated with three-fold increases in vascular endothelial growth factor receptors. Further, a recent meta-analysis (Li et al., 2022) demonstrated that exercise with BFR facilitates greater expression of angiogenesis related factors than exercise performed without BFR. Collectively, this evidence suggests that exercise with BFR may combat RAS dysregulation in COVID-19 and enhance the adaptive and regenerative capacity of the vascular system. Other data have reported direct benefits of exercise with BFR throughout the vascular tree. In a recent meta-analysis, Pereira-Neto and colleagues (Pereira-Neto et al., 2021) reported that 4 or more weeks of BFR-RE improves endothelial function (i.e., flow mediated dilation, reactive hyperemia blood flow, and reactive hyperemia index) and some data (Evans et al., 2010; Hunt et al., 2013) report enhanced capillary growth.

Among the benefits of exercise is its positive impact on hemostasis. High-intensity resistance training without BFR acutely enhances fibrinolytic activity (deJong et al., 2006), increasing tissue plasminogen activator (tPA) and decreasing plasminogen activator inhibitor-1 (PAI-1), without elevating activity in the coagulation system. Evidence indicates similar responses in the fibrinolytic system with the performance of low-intensity exercise with BFR. Nakajima and colleagues (Nakajima et al., 2007) reported significant increases in tPA antigen and unchanged PAI-1 activity during low-intensity BFR-RE (30% 1RM) performed after 24 h of bedrest. Similarly, Clark and colleagues (Clark et al., 2021) reported a 33% increase in tPA antigen immediately following acute bouts of BFR-RE with no alterations in markers of coagulation. Responses were similar to those observed with high-intensity resistance exercise without BFR. Furthermore, studies (Shimizu et al., 2016; Rapanut et al., 2019) implementing the chronic performance of BFR-RE have demonstrated decreases in von Willebrand factor (vWF) after 4 weeks. Taken together, these data demonstrate that exercise with BFR provides similar fibrinolytic effects as high-intensity exercise without BFR, albeit at lower exercise intensities, and could protect against short and long-term thrombotic complications associated with COVID-19. Exercise with BFR appears to promote a variety of positive adaptations in the vascular system and may confer several unique benefits to COVID-19 survivors that are not achieved with traditional higher intensity exercise (Figure 2; bottom right).