The favorable effects of systematic physical exercise on the subclinical inflammation and the underlying CV risk in the long-term have been well documented. These appear to be mediated through reduced cytokine production in skeletal muscle, adipose tissue, mononuclear and endothelial cells; improved endothelial function; decreased insulin resistance; and an antioxidant effect [13, 32].
On the other hand, the exercise-induced APR and the factors involved are more difficult to be examined and thus they are still only poorly clarified. Data have mainly been derived from professional athletes after strenuous prolonged exercise (for example, a marathon race) [13–18]. The present study was undertaken in non-CAD individuals undergoing short-term vigorous aerobic exercise (that is, treadmill ET). According to this study, serum levels of most of the acute phase inflammatory markers (hsCRP, SAA and WBC), cytokines (IL-6) and prothrombotic factors (TF) acutely increase shortly after exercise initiation (within few minutes), whereas, at the same time, PAI-1 activity decreases. Therefore, the acute thrombotic reaction is accompanied by a concomitant “protective” anti-thrombotic counter-regulation that is also part of the exercise-induced APR. Whether the systemic inflammatory stress is also counter-regulated by “protective” anti-inflammatory cytokines released into the circulation was not examined in this study. The exercise-induced APR described above seems to be a “normal” human reaction as it is present in the apparently healthy group of our study, as well. However, the present study interestingly indicates that this “normal” exercise-induced APR is more intense in hypertensive patients as compared to apparently healthy individuals (normotensive controls).
The main findings of the present study seem to be in line with the limited previously published data. A study by Mendham et al. sought to compare the respective effects of resistance or aerobic exercise of higher or lower intensities on the acute plasma IL-6, CRP and WBC response in a population of 12 sedentary, overweight, middle-aged, disease-free participants. They found an acute, exercise-induced elevation in all 3 inflammatory biomarkers and also that the exercise modality did not seem to influence the APR. The main determinant of the IL-6 response was exercise intensity (the highest IL-6 response was evident in the moderate-vigorous intensity protocol immediately post-exercise) [19]. Similarly, Dorneles et al. compared the effects of two interval exercises with different intensities on acute inflammatory response in 10 lean and 12 overweight-obese males concluding that the acute inflammatory response (IL-6 increase) to interval exercise is intensity-dependent [20]. Moreover, Tartibian et al. showed that plasma inflammatory biomarkers (IL-6, CRP and WBC) increased in 18 young untrained males 30 min after treadmill running. However, according to this study, exercise intensity cannot be considered as the main factor that determines the inflammatory responses [21]. Regarding the thrombotic / fibrinolytic response to acute exercise, Desouza et al. found that PAI-1 activity significantly decreased immediately after exercise in 12 hypertensive and 11 normotensive older men (by 25% and 22%, respectively) and remained lower for at least 1 h in both groups. They also concluded that the acute exercise-induced fibrinolytic response is not impaired in sedentary, older, hypertensive men [24]. More recently, Gavriilaki et al. also aimed to determine thrombotic and fibrinolytic activity during exercise in 30 patients with AH (pre- and post-treatment with an angiotensin II receptor blocker) as well as in 15 normotensive individuals [25]. By contrast to Desouza et al, they found that in untreated hypertensive patients PAI-1 levels were significantly increased immediately after peak exercise and decreased 30 min later, as compared with baseline levels. At all time points, untreated hypertensives exhibited significantly higher PAI-1 levels compared with normotensives. No significant changes of PAI-1 levels were observed in normotensives and in patients post-treatment. They concluded that acute high-intensity exercise results in impaired thrombotic and fibrinolytic response in untreated patients with AH [25]. Previous studies also suggest that anti-inflammatory cytokines (for example, the immunomodulatory cytokine IL-10) and cytokine inhibitors (for example, IL-1 receptor antagonist) are mobilized during strenuous exercise and downgrade the acute inflammatory response to exercise [13, 15, 20].
The effect of AH on the exercise-induced acute response of thrombotic mediators has also been reviewed by Braschi A [33]. The author highlights the analogies, similarities, and differences between normotensive and hypertensive subjects regarding the acute exercise-induced changes to the hemostatic and fibrinolytic properties, showing what differentiates essential AH from physiological status [33]. In accordance to our results, this review concludes that following acute exercise, normotensive and hypertensive subjects both undergo changes in hemostatic and fibrinolytic properties, but the hypertensive patients’ response to exercise is exaggerated and prolonged, exposing them to increased CV risk during or immediately after vigorous exercise [33]. The activation of the autonomic sympathetic nervous system is more aggressive in hypertensive patients in a pathological milieu characterized by platelet α2-adrenergic receptors with increased responsiveness to circulating catecholamines, altered platelet profile and function, abnormal hemostatic parameters, impaired fibrinolytic potential, endothelial dysfunction and vasoconstriction [33]. The exercise-induced increase in shear stress activates the endothelium and promotes platelet adhesion to endothelial cells, thus affecting the thrombogenic potential of atherosclerotic plaques, even when they are of relatively small dimensions. This pathophysiology probably predisposes to thrombotic complications. The recovery period is particularly dangerous for triggering adverse cardiovascular events, even in healthy subjects, because the balance between the thrombotic and fibrinolytic systems is temporarily shifted toward increased pro-coagulative activity [33].
The underlying mechanisms for this rapid change in circulating levels of the inflammatory cytokines and the thrombotic factors shortly after physical exercise are not clear [15]. They probably involve mobilization, systemic release, functional augmentation and hemoconcentration (concerning the macromolecules), rather than de novo synthesis of neutrophils, cytokines and hemostatic biomolecules.
Regarding the total duration of the exercise-related APR, preliminary data from the present study indicate that approximately 3 hours post-exercise, all of the studied biomarkers almost returned to baseline levels. Our data are in line with them reported by Cipryan et al. who investigated the recovery pattern of the plasma inflammatory markers IL-6 and CRP after a single-bout maximal exercise in 30 males. They concluded that a relatively short duration exercise, no matter what intensity and type, does not elicit a significant change in IL-6 and CRP for the 1 hour to 5 hour period of rest following the exercise [34]. Moreover, PAI-1 activity has been found to remain lower at 60 minutes post-exercise (than pre-exercise levels) in both hypertensive and normotensive individuals [24].
There is some evidence for the possible effects of BP-lowering treatment on the acute exercise-induced inflammatory and thrombotic response. In the NOAAH study, nebivolol has shown to have beneficial effects on inflammation indicators in obese hypertensive patients exposed to exercise-induced stress [35]. Similar favorable effects on vascular markers of inflammation have been reported for perindopril during exercise in patients with metabolic syndrome [36]. A head-to-head comparison trial of our team, compared the effect of different antihypertensive drugs on the exercise-induced APR and found that irbesartan is most likely more effective than diltiazem at suppressing the inflammatory and coagulative reaction during exercise (the percentage increase in hsCRP, SAA, WBC, TNF-a and TF levels was lower in the irbesartan group) [37].
Limitations
The findings of this study have to be seen in light of some limitations. The first is the relatively limited number of participants. However, as already reported, previous studies on this topic had even smaller sample size. We consider that this limitation is partially bypassed by the high homogeneity among the participants of the 2 groups (Table 1). In any case, the results of this study are only suggestive (and not definitive) for the greater exercise-induced APR in hypertensives vs. normotensives. The second limitation is that only patients with grade 1 or 2 hypertension were eligible for enrollment, considering that performing an ET in untreated grade 3 hypertensive patients is relatively contra-indicated. Another limitation is that the exclusion of CAD was mainly based on non-invasive methods, whereas coronary angiography, which remains the gold standard for the diagnosis of CAD, was not performed in the majority of the study population. Nevertheless, angiography is not indicated in subjects without ischemic ST-segment response at the ET, wall motion abnormalities at the stress echocardiogram or perfusion defects at the thallium-201 scintigraphy.