Introduction
Cardiovascular disease (CVD) represents a significant global health burden, being the leading cause of death worldwide (GBD 2013 Mortality and Causes of Death Collaborators
2015). To exemplify the modifiable nature of CVD risk, known risk factors such as hypertension, dyslipidaemia, smoking, diabetes, abdominal obesity, diet and physical inactivity may all be influenced and have been held accountable for over 90% of the risk of having an acute myocardial infarction (Bonow
2002; Yusuf et al.
2004). A number of these risk factors may be modified using medication, however, they are not without side effects (Finegold et al.
2014; Taylor and Thompson
2015) and compliance remains poor (Peterson and McGhan
2005; Gislason et al.
2006; Newby et al.
2006; Larbizabal and Deedwania
2010). In addition, patients are often unwilling to take medications in the absence of symptoms (Ross et al.
2004; Munger et al.
2007).
Non-pharmacological interventions (i.e., diet and exercise) can also modulate CVD risk (Hellenius et al.
1993; Bassuk and Manson
2005). However, despite these well-publicised benefits, the uptake of physical activity remains low. Indeed, one-third of adults and four-fifths of adolescents worldwide fail to meet physical activity guidelines (Hallal et al.
2012). Exercise referral schemes have long been promoted as a means of increasing physical activity (Fox et al.
1997), but have variable compliance and efficacy (Dugdill et al.
2005; Williams et al.
2007). Key cited barriers to physical activity include financial cost, childcare access and crucially, lack of time (Withall et al.
2011). These barriers make the prospect of an inexpensive, time-efficient form of physical conditioning, which can be performed at home without specialist equipment very attractive.
Repeated remote ischaemic preconditioning (RIPC) (Epps et al.
2016) and isometric handgrip training (IHG) (Inder et al.
2016) are two simple interventions which have been shown to have the potential to modify CVD risk factors. RIPC involves repeatedly alternating periods of ischaemia and reperfusion in a muscle bed in an attempt to precondition the body to withstand future periods of hypoxia. IHG involves sustained repeated contractions of the hand around a dynamometer maintaining a fixed muscle length. Single session RIPC performed immediately prior to exercise has been shown to improve athletic performance in both competitive athletes (Jean-St-Michel et al.
2011) and recreationally active young individuals (Cruz et al.
2015,
2016). However, the few studies of repeated RIPC that exist (over 7 days to 8 weeks) have had mixed effects on cardiorespiratory fitness (CRF) (Jones et al.
2014; Banks et al.
2016; Lindsay et al.
2017), a validated predictor of future CVD risk (Kodama et al.
2009). It must, however, be noted that the majority of these studies were in male volunteers. The potential mechanisms behind how repeated RIPC could mediate improvements in CRF are still unknown, with local effects on the muscle being preconditioned as well as remote effects via both neural pathways and humoral factors being postulated (Sharma et al.
2015). Several studies have reported the effects of repeated RIPC on resting blood pressure (BP), although as yet a consensus on its efficacy has not been reached (Epps et al.
2016). Conversely, IHG has been shown in a number of trials to reduce resting BP in both normotensive and hypertensive individuals (Inder et al.
2016). However, the only two studies to date which measured changes in CRF after a prolonged period of IHG did not show benefit (Blackwell et al.
2017; Goessler et al.
2018), moreover, the larger of these two studies was of unsupervised IHG with a reported adherence as low as 63%.
Another predictor of CVD risk (alongside BP and CRF) is endothelial dysfunction (Bonetti et al.
2002). Reduced endothelial function may precede overt vascular disease by a number of years (Anderson et al.
1995) and can be estimated by brachial artery ultrasound scanning to detect flow mediated dilatation (FMD) in response to shear stress applied to the artery wall (Faulx et al.
2003; Pyke and Tschakovsky
2005; Charakida et al.
2010). This measure of endothelial plasticity is commonly used as a surrogate for cardiovascular health and has been validated as a means of assessing vascular responsiveness (Charakida et al.
2010). IHG has been shown to improve FMD in medicated hypertensive (McGowan et al.
2007b), but not normotensive subjects (McGowan et al.
2007a), over an 8-week period. Similarly, RIPC has shown promise with improvements in FMD demonstrated after 2-week intervention (Jones et al.
2014) in a young normotensive healthy population. However, as with the aforementioned studies assessing the effects of these ‘static’ interventions on CRF and resting BP, almost all of the study subjects were male.
The current paucity of any substantial studies investigating these interventions in premenopausal females means no firm conclusions can yet be drawn as to whether they have any role to play in CVD risk modulation in this population. This is of increasing importance with many traditional CVD risk factors now increasing in this population (Garcia et al.
2016). This study was therefore designed to investigate the efficacy of 4 weeks supervised RIPC or IHG on CRF, BP and endothelial function in inactive but otherwise healthy, premenopausal females. A 4-week intervention was chosen to try to minimise natural variation in physiological parameters within subjects due to phases of their menstrual cycle (Mihm et al.
2011). We hypothesised that both RIPC and IHG would each improve at least one parameter associated with CVD risk.
Discussion
This study is the first to compare the effects of IHG and RIPC on markers of cardiovascular health in inactive otherwise healthy premenopausal females. It demonstrates that IHG and RIPC are both well-tolerated in this group, with 100% compliance and no adverse events. We showed that IHG, conducted over 4 weeks can lead to statistically significant reductions in both SBP and DBP but was unable to elicit any change in CRF. We did not detect changes in any measures of cardiovascular health or fitness from our RIPC protocol, questioning the application of this particular time-efficient RIPC protocol to reduce CVD risk in this specific population.
The significant reduction in SBP in our IHG group mirrors the findings of Gill et al. who observed a 6.9-mmHg reduction in SBP in normotensive females after 3-weeks of isometric exercise training (IET) (Gill et al.
2015). However, Gill et al. employed bilateral leg extensions as their mode of IET, thus recruiting a much larger muscle. We have demonstrated a similar reduction in BP using only a handgrip protocol, which may have greater potential for translation to real-world use. Of note, a previous meta-analysis has demonstrated that IET reduces blood pressure most effectively in hypertensive males (Inder et al.
2016), as the subjects in this study were neither hypertensive nor male the potential for greater improvements in other cohorts with IHG remains.
The absence of a significant change in SBP and DBP in our RIPC group is in keeping with a previous study of RIPC in young adults which also showed no change in BP or exercise capacity in normotensive male and female participants (Banks et al.
2016).
We did not demonstrate significant improvements in any CPET parameter in any group. This mirrors the findings of the only previous study assessing CPET variables before and after a prolonged period of IHG (Blackwell et al.
2017). Similarly, this finding also agrees with two previous studies that have performed a CPET before and after repeated RIPC (Jones et al.
2014; Banks et al.
2016). It is noteworthy that despite a lack of improvement in CPET parameters with repeated RIPC, a single-bout of RIPC performed immediately prior to exercise has been shown to improve athletic performance (Jean-St-Michel et al.
2011; Cruz et al.
2015). This suggests that the mechanisms by which a single-bout of RIPC improve athletic performance [postulated to be either through improved metabolic efficiency or increased limb blood flow (Incognito et al.
2016)] are not retained over the long-term and cannot be further improved and/or maintained by repeated sessions.
This study also failed to demonstrate any significant improvement in FMD in any group. This is in keeping with previous studies that have shown IHG to be effective at increasing FMD in hypertensive subjects only (McGowan et al.
2007a,
b). However, the only previous study investigating the effect of RIPC on FMD (Jones et al.
2014) did demonstrate a significant improvement in healthy normotensive young males, this is contrary to the findings reported herein. The lack of effect of RIPC observed in this study may indicate sexual dimorphism in the effects of RIPC on FMD, a postulation that has also been suggested for other cardiovascular parameters in response to static interventions (Gill et al.
2015).
One limitation of this study was the inability to control for the length of the menstrual cycle of the subjects or their stage of menstrual cycle whilst participating in the study. Stage of menstrual cycle is known to effect physiological parameters and this may have confounded our results (Dunne et al.
1991). However, recruiting a group of subjects with identical menstrual cycles and/or running the testing days on a set-day of the cycle would not have been feasible in our institution.
It must also be acknowledged that our single arm, 3 × 3-min of ischaemia protocol for our RIPC intervention involved less ischaemic time that many other previous studies of RIPC (Banks et al.
2016, Epps et al.
2016). We chose this protocol to limit the time commitment of training sessions, making it comparable to the IHG intervention, however, in doing so we may have not delivered a sufficient ischaemic stimulus. Future studies of RIPC should consider using a longer occlusion time ischaemic occlusion of a larger muscle mass.
Based on the findings of this study and the previous literature in this area, IHG, deliverable through a single-arm handgrip protocol may lead to significant reductions in resting blood pressure in premenopausal women, while repeated RIPC using our single arm, 3-min ischaemia protocol appears to be ineffective in this population. Further work is required to determine the effects of RIPC and IHG on physiological parameters associated with CVD risk in female subgroups in which this risk is elevated (e.g., hypertensives, older females). Given the tolerability of these simple, inexpensive interventions as shown in this study, if proven effective, these interventions may offer large public health benefit as independent or adjuvant [i.e., alongside established exercise and dietary changes (Warburton et al.
2006; Cook et al.
2007)] lifestyle recommendations to improve cardiovascular health in specific groups.
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