Renin‐Angiotensin System Blockade and Exercise‐Induced Increase in Aortic Stiffness

In physiological conditions, the cushioning function of central conduit arteries transforms the cyclic high‐flow and pressure oscillations in the ascending aorta into continuous and low‐pressure blood flow at the level of microcirculation.1, 2 Aging and elevated blood pressure (BP) induces structural and functional changes in arterial wall viscoelastic properties, resulting in arterial stiffening.1, 2 The latter is reflected in progressive impairment of the cushioning function of central arteries and is typically associated with the development of isolated systolic hypertension and left ventricular hypertrophy. Importantly, prospective cohort studies have demonstrated that arterial hardening represents a strong and independent predictor of all‐cause and cardiovascular mortality in various diseased populations,3 including patients with essential hypertension.4

Current guidelines on the management of arterial hypertension recommend regular physical activity as a major nonpharmacologic treatment approach towards BP lowering and cardiovascular risk reduction.5 In contrast, several lines of evidence from clinical studies suggest that acute high‐intensity exercise can transiently elevate the risk of fatal and nonfatal cardiovascular events, mainly in prediposed individuals with substrate of structural cardiovascular disease.6, 7 The mechanistic background of this deleterious impact of acute exercise on the cardiovascular system remains largely unclear. Activation of the sympathetic nervous system, aggravation of oxidative stress, platelet activation,8 impaired coagulation and fibrinolysis,9 and acute deterioration of large artery elasticity10 represent some of the mechanisms that have been proposed to be involved.

It has to be noted that the type, frequency, duration, and intensity of physical exercise, play an important role in the exercise‐induced alterations on the cardiovascular system.6 In this regard, previous clinical studies that investigated the effects of acute exercise on arterial elasticity, provide variable results. Some studies have shown high‐intensity exercise to be associated with an acute increase in stiffness of central conduit arteries in healthy individuals.10, 11 In other clinical studies, maximal aerobic exercise was found not to acutely affect large artery elasticity in young healthy patients.12 In contrast to the above, other investigators observed a sustained and prolonged improvement in compliance of peripheral muscular‐type arteries and no change in elasticity of central conduit arteries after submaximal acute exercise in healthy patients.13

In this issue of The Journal of Clinical Hypertension, Gkaliagkousi and coworkers14 add important information to our knowledge, in this area, by reporting the results of a clinical study that explored acute changes in aortic stiffness after a high‐intensity aerobic exercise test: (1) in untreated hypertensive compared with normotensive individuals, and (2) in hypertensive patients after 3 months of treatment with the angiotensin receptor blocker (ARB), valsartan. The study included 25 young patients with never‐treated, newly diagnosed, stage I hypertension and 15 age‐ and sex‐matched healthy volunteers. The investigators performed a careful workup of patients prior to study enrollment, excluding patients with secondary causes of hypertension and patients with white‐coat or masked hypertension by performing 24‐hour ambulatory BP monitoring. Arterial stiffness was assessed by measuring carotid to femoral pulse wave velocity (cf‐PWV) with the use of the Sphygmocor device (AtCor Medical, West Ryde, Australia) at maximal exercise and at 10, 30, and 60 minutes after the completion of a treadmill exercise test. At baseline exercise test, significant elevations in systolic BP were noted at maximal exercise in both, hypertensive patients and healthy controls, which returned to pre‐exercise levels after 10 and 30 minutes of recovery, respectively. In contrast, diastolic BP was not significantly different during acute high‐intensity exercise, in both study groups. With regards to exercised‐induced changes in aortic stiffness, cf‐PWV was significantly elevated at maximal exercise in the group of hypertensive patients but not in the group of healthy controls. Of importance, despite the post‐exercise reduction in systolic BP levels, the increase in cf‐PWV persisted, even after 30 minutes of recovery in hypertensive patients. As expected, systolic BP and cf‐PWV levels at all 5 timepoints of the baseline exercise test were significantly higher in hypertensive patients than in controls.14

After completion of the baseline test, 15 hypertensive participants who had indications to receive BP‐lowering therapy according to guidelines were included in a subsequent interventional phase of the study to receive treatment with valsartan 160 mg daily for 3 months. Valsartan treatment resulted in significant reductions in both office and ambulatory BP and all treated hypertensive patients achieved adequate BP control at study end. In a repeat acute high‐intensity exercise test at study completion, systolic BP was elevated at maximal exercise and at 10 minutes of recovery, without any change in diastolic BP. Similarly, cf‐PWV was significantly increased at maximal exercise and 10 minutes after the treadmill test. However, the peak post‐exercise elevations in cf‐PWV and systolic BP were significantly lower from the relevant increases that occurred at baseline evaluation. Further, at the 3‐month test, cf‐PWV values returned rapidly to the pre‐exercise levels, without any significant difference between pre‐exercise and post‐exercise cf‐PWV, suggesting that valsartan treatment was associated with attenuation of the acute exercise‐induced deterioration of aortic elasticity.

Until recently, the only available data in hypertensive patients on the effects of acute high‐intensity exercise on aortic stiffness were derived from a small study (9 treated hypertensive individuals) which showed that acute dynamic exercise did not influence distensibility or β stiffness index of carotid and brachial arteries.15 The study by Gkaliagkousi and coworkers14 advances our knowledge in the field of acute cardiovascular effects of high‐intensity exercise, showing that the treadmill aerobic test was associated with a transient deterioration of elastic properties of the aorta in young patients with untreated, newly diagnosed essential hypertension, whereas this harmful effect was not evident in age‐ and sex‐matched healthy individuals. This study further expands previous findings which show that treatment with the ARB valsartan for 3 months can ameliorate this exercise‐induced increase in aortic stiffness. Such an effect is in line with the results of randomized clinical studies showing that agents blocking the renin‐angiotensin system (RAS) can delay the progression of arteriosclerosis in patients with hypertension.16

The findings of this study are limited by some methodological issues that have to be acknowledged. First, the investigators did not report radial artery applanation tonometry measurements concomitantly with cf‐PWV assessment. Therefore, this study cannot provide information on the effect of acute high‐intensity exercise on the reflecting properties of the periphery and on central aortic pressure augmentation, which are also important components of the arterial cushioning function.1 In addition, the interventional second phase of the study did not include an appropriate control group, in order to compare the effect of valsartan with placebo or active‐treatment; thus, whether this effect is attributed to BP‐lowering or to RAS blockade per se, or to other mechanisms involving structural alterations in the aortic wall, cannot be clarified.

Conclusions

Gkaliagkousi and colleagues add new information on the effects of acute exercise on arterial cushioning function, a rather underinvestigated issue. This study showed that high‐intensity exercise results in an acute transient elevation of cf‐PWV in patients with newly diagnosed stage I hypertension, but not in normotensive individuals providing another potential mechanistic explanation for the heightened cardiovascular risk associated with acute exercise in specific patient populations. Further, the present work brought to light promising data, that short‐term antihypertensive treatment with an ARB can ameliorate the exercise‐induced increase in arterial stiffness, providing a possible therapeutic approach. Additional research efforts, including proper randomized controlled trials, are warranted in order to fully elucidate the cardiovascular effects of acute high‐intensity exercise in hypertensive individuals and to investigate the role of different antihypertensive drug classes on this phenomenon.