High-intensive interval training for inducing coronary plaque regression: is it the best choice?

This editorial refers to ‘High-intensity interval training induces beneficial effects on coronary atheromatous plaques: a randomized trial’, by E.K. Vesterbekkmo et al., https://10.1093/eurjpc/zwac309. Cardiovascular diseases are the leading cause of death worldwide, being responsible for ∼30% of total mortality. Coronary artery disease (CAD), in turn, accounts for ∼45% of deaths ascribed to cardiovascular diseases and, therefore, it places a substantial medical and economic burden on society.1 In patients with CAD, the prognosis can be improved through secondary prevention programmes that include lifestyle changes, control of modifiable cardiovascular risk factors, and prevention of blood clot formation with anti-thrombotic therapies. Among non-pharmacological measures, there is clear evidence that exercise training reduces symptoms, improves coronary flow, and, ultimately, reduces the risk for cardiovascular events. The mechanisms by which exercise exerts these favourable effects are not fully understood. The exercise-mediated increase of coronary flow is, at least in part, mediated by the improvements in conventional cardiovascular risk factors such as hypertension, hypercholesterolaemia, and diabetes; nevertheless, the direct effects of exercise on coronary arteries have also been demonstrated. The proposed mechanisms include cardiac preconditioning, increased reactive oxygen species scavenging, coronary collateralization, arteriogenesis, and plaque regression. The first demonstration of exercise-induced plaque regression dates back to the 1990s, when it was observed that 1 year of moderate exercise, associated with a low-fat Mediterranean diet, induced a 3.1% regression in coronary stenosis without the use of lipid-lowering drugs.2 Since then, other authors have tested the hypothesis of exercise-induced coronary plaque regression, and overall, they have showed that exercise can slow the progression or induce modest regressions of coronary lesions (Figure 1). These studies have led to the conclusion that the amount of coronary regression that can be obtained with exercise training is not large enough to explain the significant improvements in myocardial perfusion observed in patients with CAD in response to exercise.3 Two factors that can affect the impact of exercise on coronary lesions are the ‘dose’ and the modality of the exercise training. The current idea is that a critical exercise volume must be achieved in order to induce substantial effects on coronary plaques. It has been observed that an energy expenditure >2200 calories/week, corresponding ∼5–6 h of exercise/week, has to be achieved in order to elicit regression in coronary lesions.4 Regarding exercise modality, while the first studies on plaque regression have used aerobic continuous moderate-intensity exercise, more recently, high-intensity interval training (HIIT) has also been investigated with the hypothesis that this exercise modality, by inducing a higher endothelial shear stress during repeated peaks of exercise at maximal intensity, could be more effective in eliciting plaque regression. However, in a pilot study comparing 3 months of HIIT vs. aerobic continuous training, both exercise modalities determined small, not significant, plaque regression.5 In this issue of European Journal of Preventive Cardiology, Vesterbekkmo et al.6 report the findings of predefined secondary endpoints of the recently published ‘Impact of the Cardiac Exercise Training in Coronary Atheromatous Plaques Evaluated by Near-Infrared Spectroscopy—a Randomized Trial’ (CENIT).7 In this trial, 60 patients with stable CAD were randomized either to a supervised HIIT intervention, consisting of two sessions/week at 85–95% of peak heart rate, or to unsupervised exercise with standard counselling. The trial lasted 6 months. All patients received background statin and antiplatelet therapy. The main objective of the CENIT trial was to measure changes in the lipid content of coronary plaques. Instead, the present study focuses on changes in atheroma volume, from baseline to 6 months, between the two groups. For this purpose, the authors calculated total atheroma volume and per cent atheroma volume by measuring the atheroma lumen membrane cross-sectional area and external elastic membrane cross-sectional area through intravascular ultrasound. They observed that, at 6 months, total atheroma volume was significantly reduced by 9.0 mm3 after HIIT, while it tended to increase in the control group. Moreover, they found a significant reduction in per cent atheroma volume in the HIIT group that was not much less than the reduction observed in previous trials using statins. On a statistical level, when compared with the previous study that tested the effects of HIIT on plaque regression,5 the CENIT trial represents a step forward, with its strengths including a larger sample size, a longer intervention period (6 vs. 3 months), and the inclusion of a control group. However, since the present study shows the results of secondary endpoints of the CENIT trial, they should be seen as hypothesis-generating and need to be confirmed in larger trials directly conceived for assessing changes in plaque dimension. From a conceptual point of view, this is an interesting piece of research, the results of which contribute to the hypothesis that exercise may confer some of its cardiovascular benefits by inducing favourable changes in plaque dimensions. However, at the same time, it raises several questions that need to be answered in the near future. For example, since there were no significant changes in lipid core levels after HIIT, as shown by the first endpoint of the CENIT trial,7 it is natural to wonder what accounts for the atheroma volume change observed in the present study. It is conceivable that improvements in endothelial shear stress are involved in the atheroma remodelling found by the authors. In healthy subjects, it has been previously shown that exercise-induced changes in shear stress provide the principal physiological stimulus to adaptation in flow-mediated endothelial function and vascular remodelling in response to exercise.8 Moreover, a low local endothelial shear stress has been associated with atherosclerotic plaques progression independently from their composition.9 From this point of view, HIIT represents a particularly attractive exercise modality, since it has been proved to be more effective than moderate continuous training in improving exercise tolerance and vascular function of individuals with cardiovascular disease. Moreover, as emerging from a recently published review and meta-analysis of studies investigating the effects of HIIT in post-myocardial infarction patients, no safety issue was reported in these patients.10 However, further research studies are needed to better understand the health benefits, risks, and optimal design of HIIT in CAD patients. At the same time, data on long-term tolerability of HIIT in senior age-group populations with cardiovascular diseases are lacking, because most studies have been done in young and middle-aged adults. Moreover, while short-term interventions have shown good adherence to HIIT protocols also in elderly populations, the long-term adherence, particularly in unsupervised contexts, still remains a challenging task. In this study, the HIIT intervention consisted of two sessions/week, which was lower than in other studies,4 and appeared to correspond to a modest volume of exercise/week; despite this, it was effective in reducing the coronary plaque volume significantly. This is a very interesting result, since a less demanding exercise protocol would be better accepted in the long run by the patients. Meanwhile, it underlines the need to identify what is the optimal volume of exercise to be administered to CAD patients. While available data indicate that a certain volume of exercise is required for inducing coronary plaque regression, other observations suggest the existence of a U-shaped relationship between exercise volume and its effects on coronary plaques, with the highest volumes being related to progression, instead of regression, of atherosclerotic lesions. For example, studies performed on endurance athletes by using coronary computed tomography angiography have found that high-volume, high-intensity exercise protocols may actually increase the prevalence and extent of coronary atherosclerosis.11 Therefore, future research should be aimed to better understand the dose–response curve regulating the effects of exercise training on coronary atherosclerosis. Data derived from this study represent important contributions to the understanding of the effects of exercise on coronary lesions. However, further larger trials are needed in this field in order to clarify what are the mechanisms and clinical implications of the anti-atherosclerotic effects of exercise training. Timeline of studies pursuing the hypothesis of exercise-mediated coronary plaque regression and future prospectives.