Exercise for healthy flow

The year 2010 marked the 2500th anniversary of the battle of Marathon, in which the army of the Persian King Darius I invaded Greece and fought the Athenians. In the aftermath, the Greek messenger Pheidippides ran non-stop from Marathon to Athen and proclaimed ‘Nenikekamen’ (We were victorious!) (Plutarch, 4–125). This story inspired people for centuries. Today, long-distance running is a popular physical and mental challenges (Parto et al. 2016). Exercise is seen as vital for the well-being and a cornerstone of disease prevention and rehabilitation in ageing western societies. However, the continuous exposure to strenuous exercise may have negative side effects as well, and intensive training is seen as problematic. Pheidippides died upon completion of mankind's first Marathon. Cardiovascular disease (CVD) is the most common cause of death in Western countries, although life expectancy of patients with CVD has significantly increased in last decades (Lozano et al. 2012). Ageing causes subclinical functional and structural alterations within the cardiovascular system; critical factors are progressive heart failure and specific vascular alterations, such as atherosclerosis and arterial stiffness (Vigorito & Giallauria 2014). The benefits of exercise training in patients with cardiovascular disease (CVD) are profound and have been recognized in patient management guidelines. Epidemiologic studies demonstrated an increase in physical activities in the elderly, which is associated with improved health outcomes (Sattelmair et al. 2009). Recently, the WHO published evidence-based recommendations proposing a minimum of 150-min moderate-intensity aerobic training or 75 min of vigorous-intensity aerobic training per week (World Health Organization 2016). Exercise counteracts ageing processes and improves three cornerstones of cardiovascular health: (i) myocardial structure (Budiono et al. 2016), (ii) peripheral hemodynamics (Esposito et al. 2015) and (iii) vascular regeneration (Zietzer et al. 2016) (Fig. 1). The effects of exercise on the myocardial and vascular system depend upon training intensity, frequency, duration and whether subjects are trained or untrained (Wilson et al. 2016). First, regular intensive exercise performed by untrained individuals for more than 6 months resulted in a 5–20 beats lower resting and submaximal exercising heart rates, enhanced myocardial contractility and an increase in stroke volume of approx. 20% (Swedish National Institute of Public Health 2010). Second, exercise-induced haemodynamic alterations enhance blood flow, elevate arterial pressure and increase shear stress on the endothelial layer (Prior et al. 2004). In response, an increased endothelial NO production causes smooth muscle cell relaxation and has anti-atherogenic and antithrombotic properties (Jin & Loscalzo 2010). Exercise improves NO production and endothelial function in general (Buschmann et al. 2016). Third, exercise promotes vascular regeneration through both the arteriogenic outgrowth of pre-existing collateral vessels (Bondke Persson et al. 2011) and an expansion of the capillary network through angiogenesis (Laufs et al. 2004). Interestingly, regenerative exercise effects are not limited to blood vessels (Greiwe et al. 2016) and differ between vascular beds (Kylhammar & Rådegran 2016). The mechanisms through which exercise exerts its beneficial effects remain to be elucidated in detail (Prior et al. 2004). Multiple markers and signalling factors have been proposed, some recent ones including non-coding microRNAs and leucocyte telomeres (Dietze & Patzak 2016, Navickas et al. 2016). Non-coding RNA segments such as short microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) regulate gene expression and function. One initial step of cardiovascular disease is endothelial dysfunction (Vanhoutte et al. 2015), mainly at sites of disturbed laminar blood flow. The miRNA miR-126-5p is critically involved in maintaining a proliferative reserve of ECs in response to shear stress, while low levels of miR-126-5p reduce this proliferative reserve and promote atherosclerotic plaque formation (Schober et al. 2014). Exercise-regulated factors as diverse as the myocyte factor myostatin (Liu et al. 2012, Hjorth et al. 2016), the multi-domain adapter protein Shb (Nikpour et al. 2015), myokine chitinase-3-like protein 1 (Johansen et al. 2009, Görgens et al. 2016), neurotrophic BDNF (Monnier et al. 2016) and insulin-like growth factor 1 (Jacobo & Kazlauskas 2015, Roof et al. 2016) featured recently in Acta Physiologica and have been suggested as potential targets for vascular regeneration. Training-induced PPAR-gamma expression is anti-atherosclerotic and pro-arteriogenic (Szostak et al. 2016), although, in contrast to other pro-arteriogenic factors, PPAR-gamma also exerts anti-inflammatory effects (Liu et al. 2015). All of these exercise-regulated factors have been shown, in different contexts, to interact with the famous pro-angiogenic, HIF-regulated vascular endothelial growth factor VEGF. When Gregg Semenza and Guang Wang, in 1992, discovered the first of the hypoxia-inducible factors (HIFs) (Semenza & Wang 1992), and shortly after the enormous biological potential of their discovery was appreciated, the potential of these signalling molecules for targeted vascular regeneration was celebrated almost euphorically. Neither hypoxic pre-conditioning nor therapeutic administration of VEGF has, however, made it to the bedside of the common patient with CVD. Hypoxia is a powerful stimulus of structural changes in the cardiovascular system (Netzer et al. 2016), and the effects of ischaemic pre-conditioning go well beyond local responses (Heyman et al. 2016). Inhibition of the oxygen-sensing HIF prolyl hydroxylases (PHDs), which control HIFα degradation, increases maximal exercise capacity (Nunomiya et al. 2016) and hypoxic tolerance (Heyman et al. 2016). Regenerative restoration of blood flow needs, however, to take both the regeneration of the microvascular bed (Gliemann et al. 2015, Uchida et al. 2015) and of the feeding conductance vessel (van Royen et al. 2009) into account – think Hagen–Poiseuille's equation. Angiogenic stimulation alone is not sufficient (Egginton et al. 2016). Exercise training stimulates both angiogenic and arteriogenic regeneration processes and thus goes beyond mere hypoxic, VEGF-induced capillary growth (Risau 1997). Angiogenesis and arteriogenesis should, however, not be separated dogmatically, overlaps occur, HIFs are involved in conductance vessel regeneration, and combined therapeutic approaches may hold promise for future therapies. The exercise-induced ‘satiety’ (proteo-) hormon Leptin (Rodríguez et al. 2016) could provide another interesting link between exercise and conductance vessel growth (Schirmer et al. 2004) in both peripheral vascular provinces and the brain (Busch et al. 2011), which calls for further investigation. DNA methylation can stably alter the expression of genes. Exercise-regulated DNA methylation (Voisin et al. 2015) affects white blood cells (Zhang et al. 2011), major players in cardiovascular regeneration: differential promoter methylation of macrophage genes has been shown to be strongly associated with vascular growth (Babu et al. 2015), a solid lead currently further investigated in animal models of health and disease. Exercise-induced cardiovascular regeneration depends on the training regimen, training and health status. No perfectly safe exercise dose and duration have been established. Low doses of casual lifelong exercise (2–3 training units per week) may delay, but do not completely prevent a decreased cardiac compliance or a progressive atherosclerosis in healthy and ageing subjects (Haas et al. 2012). Short-term exercise increases telomerase activity, a surrogate marker of vascular ageing, in peripheral circulating leucocytes of untrained subjects (Zietzer et al. 2016). However, Laye et al., who studied telomerase activity in PBMCs of well-trained subjects exposed to extreme exercise stimuli, found no differences in telomerase activity in a midterm trail analysis (Laye et al. 2012). Likewise, Rassaf et al. enrolled 55 healthy subjects with a mean age of 40 in a clinical trial showing a significant increase in nitrite concentration (NO plasma carrier) after a single ergometric exercise test (Rassaf et al. 2007). In contrast, Cubrilo et al. revealed that different kinds of short-term exercise programmes did not influence nitrite plasma levels in athletes (Cubrilo, 2011). Left ventricle (LV) structural and functional data are different in male endurance-trained, resistance-trained and sedentary control (Utomi et al. 2013). LV stiffening, associated with CVD, increases more in casual exercisers (two–three sessions per week) than intense athletes (four–five exercise sessions per week) (Bhella et al. 2014). In paediatric patients, physical exercise is inversely associated with pro-inflammatory biomarkers and prevents the development of CVD (Thomas & Williams 2008). Physical exercise protects against clinical disorders associated with systemic low-grade inflammation. The effect of regular exercise positively modulates inflammatory biomarkers and circulating macrophages (Petersen & Pedersen 2005, Cayres et al. 2016). In particular, exercise-induced modulation of the innate immune response is a key mechanism preventing chronic inflammation in vascular disease (Woods et al. 2006). Exercise in combination with balanced lifestyle and healthy diet promotes anti-inflammatory and anti-atherosclerotic effects (Szostak & Laurant 2011, Fleg et al. 2015). However, too much exercise induces an overtraining syndrome and may activate harmful effects. Excessive training loads result in fatigue, decreased performance and may reverse a positive effect by increasing the concentration of pro-inflammatory molecules (Nimmo & Ekblom 2007, Lee et al. 2015). Marathon running or prolonged endurance sport is frequently accompanied by an 30% increase in serologic markers of cardiac damage such as troponin T, creatinine kinase-MB and B-type natriuretic peptide (Kim et al. 2012, O'Keefe et al. 2012, Parto et al. 2016). Increased vascular plaque formation and mortality rates in extreme athletes led to the hypothesis that intense and repetitive long-term exercise can induce endothelial dysfunction, increase oxidative stress and the production of atherogenic particles (Goel & Bale 2009, Michaelides et al. 2011). Indeed, long-distance runners are at an elevated risk of atherosclerosis, arterial calcification and subclinical myocardial damage compared to those who engage in less-intense training (Möhlenkamp et al. 2008). A clinical study evaluating long-term marathon revealed increased coronary and peripheral atherosclerotic plaque formation in marathon runners (Kröger et al. 2011). Furthermore, approx. one-third of marathon runners experience acute, but reversible dilatations in cardiac chambers (Patil et al. 2012); however, the continuous exposure to strenuous exercise and the resulting volume overload may lead to irreversible and long-term myocardial scarring within the right ventricle and the right atrium, as well as ventricular septum dysfunction (Maron et al. 1995, Ector et al. 2007). Exercise positively affects the cardiovascular system, in particular the myocardial structure, hemodynamic flow pattern and regenerative vascular remodelling, which might counteract disease and ageing processes. However, bevor starting a regular or intense physical exercise programme, it is important to consider training status, health status, age, gender, functional status of the cardiac or vascular system. Individualized training settings are recommended for patients with CVD. Herewith, we declare that there is no conflict of interest regarding our manuscript ‘Exercise for healthy flow’.