Midlife crisis? Keep running against the vascular aging clock!

It is well established that regular physical activity protects against premature cardiovascular death.1 Mechanisms leading to this cardiovascular protection are still being unravelled, with hopes of finding physiological or molecular targets for the treatment of cardiovascular disease.2 Sustained endurance training induces a series of adaptations affecting the structure and function of the heart and its neurohumoral modulation that facilitate appropriate increases of cardiac output during exercise.3 The ‘athlete’s heart’ of an endurance athlete shows an increased biventricular cavity volume and muscle mass with normal or improved atrial, systolic and diastolic function.4 The underlying cardiomyocyte hypertrophy and neoangiogenesis are achieved by activation of the insulin-like growth factor 1 pathway. Cardiomyocyte function is further improved by exercise training through better calcium handling.5 However, the beneficial effects of physical activity are not limited to the heart. The haemodynamic changes during an exercise bout lead to acute functional changes of the vessel wall, and after repeated exercise also to structural vascular adaptations on conduit arteries, resistance arteries and microcirculation.6 Mechanotransduction induced by the increased blood flow, luminal shear stress, arterial pressure and tangential wall stress during exercise leads to activation of intracellular signalling cascades in the endothelial cells and the underlying smooth muscle cells triggering functional and structural changes in the vascular wall. The vascular adaptations to repeated exercise show consecutive time-dependent changes: it starts with an improvement of endothelium-dependent flow-mediated vasodilation followed later on by an eccentric remodelling of the large muscular conduit arteries. Arterial stiffness is not a static property, but the relation between blood pressure and arterial stiffness is highly dynamic and critically dependent on endothelial nitric oxide supply.7 These processes also operate in the large conduit arteries: preparation for a marathon run resulted in increased distensibility of the descending aorta.8 In the microcirculation, exercise training leads to an enhanced vasodilator capacity due to an increase in capillary density and also to augmented endothelium-derived vasodilation. In the coronary microcirculation, the increased production of endothelium-derived nitric oxide has a modulating effect on the cardiac contractile function through endothelium–cardiomyocyte crosstalk.9 Especially diastolic function is influenced: through the cyclic guanosine monophosphate–soluble guanylyl cyclase–protein kinase G pathway, nitric oxide reduces passive myocardial stiffness and blocks development of cardiomyocyte hypertrophy.10 The beneficial effect of physical activity on mortality is considered consistent across age groups.11 However, some studies have shown a trend for an increased benefit of physical activity in older (>45 years) subjects.12 In this issue of the Journal, Torlasco et al. describe age-dependent changes in cardiovascular function and structure in sedentary healthy subjects training for their first marathon.13 Younger subjects (>35 years old; U35) displayed classical ‘athlete’s heart’ remodelling, while older subjects (≥35 years old; O35) had less prominent cardiac remodelling but prominent vascular remodelling. While absolute changes were small, and no linear association between age and remodelling parameters was found, the authors used gold-standard cardiac magnetic resonance imaging to assess remodelling in a large number of subjects, providing credibility to the results. These findings may provide a first clue of why age-specific differences exist in the association between physical activity and mortality. Aging is associated with a progressive impairment of the cushioning effect of the large conduit arteries due to arterial stiffening. Large artery stiffening with increasing age results in the development of isolated systolic hypertension, decreased coronary perfusion pressure, increased left ventricular (LV) afterload and increased pulsatility of the blood flow within the microcirculation.14 Systolic hypertension and the ensuing increased LV afterload promote the development of hypertrophic remodelling. Reduced endothelial nitric oxide release further stimulates cardiomyocyte hypertrophy and passive stiffness, leading to diastolic dysfunction and heart failure.10 The increased pulsatility in the microcirculation provokes organ damage in vital organs such as the kidney and the brain. Through these processes, large artery stiffening is the determining driver of aging-related cardiovascular morbidities. Prevention of aging-related large artery stiffening is, therefore, an essential objective in the prevention of cardiovascular diseases. ‘You are only as old as your arteries’ (Thomas Sydenham, 1624–1689). It is a relief to read that in the study by Torlasco et al.13 exercise training could effectively halt the presumed inevitable vascular aging process. In their study, central systolic blood pressure was reduced by 4 mmHg overall and by 6 mmHg in O35, which is significant with regard to cardiovascular risk reduction.15 However, the effect on aortic pulse wave velocity, representing large artery stiffness, was small. This suggests that exercise training has a functional rather than a structural effect on the vasculature. Also, the more noticeable improvement in vascular parameters in O35 can partly be explained by the fact that central blood pressure and pulse wave velocity were within normal ranges in the U35, and they differed already significantly at baseline. A ‘normal’ vasculature cannot (and does not have to) be improved. The absence of an eccentric left ventricular remodelling in the O35 is at odds with an earlier study in previously sedentary healthy middle-aged adults, in which intensive exercise training during two years improved maximal oxygen uptake by 18% and resulted in a larger more compliant left ventricle.16 Lower intensity and shorter duration of the exercise training may explain the absence of eccentric cardiac remodelling in the present study. The increase of cardiac volumes in the U35 and absence of eccentric remodelling in O35 could also point towards a decreased or slower plasticity in older hearts. Furthermore, increased myocardial stiffness associated with aging, not assessed in this study, may have hampered the ‘necessary’ adaptive LV dilatation in the O35. Studies in elderly obese patients with heart failure with preserved ejection fraction, which is associated with severe myocardial stiffness,10 showed that exercise training did not affect LV volumes (nor improve LV diastolic function).17 As already mentioned, volume and intensity of training are other factors that may influence the physiologic response to training.2 High-intensity interval training confers similar or even superior cardiovascular remodelling compared with standard moderate training on a matched-work basis.18 In the study by Torlasco et al., while the training schedule was unsupervised, comparable changes in cardiorespiratory fitness (peak oxygen uptake; VO2peak) and similar numbers of subjects completing the marathon indicate that there were likely no substantial differences in training volume or intensity. While the population consisted of first-time marathon runners, the effects of training on VO2peak were minimal. This suggests that either the training volume and intensity were rather low, or that the population was already well-trained before enrolment. Higher VO2peak is strongly and independently associated with lower cardiovascular and non-cardiovascular mortality.19 In this light, training-induced effects on VO2peak are likely more important than vascular adaptations when assessing long-term risk. In conclusion, exercise training is beneficial to vascular health, with the potential for long-term cardiovascular risk reduction, especially in middle – aged subjects. Previous studies have already demonstrated that habitual aerobic physical exercise attenuates age-dependent large artery stiffening in normotensive middle-aged adults.20,21 The study by Torlasco et al. crucially contributes to our understanding of age-dependent changes in cardiovascular function in response to exercise training, but uncovers at the same time exciting avenues to be explored. The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. The opinions expressed in this article are not necessarily those of the Editors of the European Journal of Preventive Cardiology or of the European Society of Cardiology. The author(s) received no financial support for the research, authorship, and/or publication of this article.