Exercise and cardiovascular diseases

In the United States in 2019, every 40 seconds someone suffers a myocardial infarction and every 37 seconds someone dies of cardiovascular disease (CVD).1 The annual total cost of CVD in the United States was estimated to be $351.2 billion.1 There are many risk factors that can explain high CV mortality in an era of modern therapeutic approaches, but a significant proportion of this mortality might be ascribed to a sedentary lifestyle.2 It has been estimated that a sedentary lifestyle nowadays kills more people worldwide than smoking because of the remarkably high prevalence of physical inactivity, which exceeds one-third of the population.3 In a pooled analysis that included 1.9 million participants, more than one quarter of all subjects showed insufficient physical activity, which was more prevalent among women.4 However, levels of insufficient activity were stable between 2001 and 2016, which confirms a high prevalence of sedentary lifestyle. Its prevalence was twofold higher in high-income than in low-income countries, and showed a trend of significant increment in high-income countries over time. On the other hand, higher recreational and non-recreational physical activities are related to a lower risk of mortality and CVD events.5 Different guidelines recommend a weekly exercise of either 150 minutes of moderate intensity physical activity, 75 minutes of vigorous intensity activity or some combination of moderate or vigorous intensity activity.6-8 Despite the fact that a large body of evidence supports the protective effect of physical activity, it has not yet been established which level of exercise should be recommended to various groups of CV patients. Furthermore, CVD with cardiac failure often leads to exercise intolerance, impeding exercise training programs.9 The large majority of guidelines are based on comprehensive literature reviews and expert consensus, which does not have the highest level of evidence. Additionally, a distinction should be made between ‘physical activity’, which considers any body movement that results in energy loss, and ‘exercise’, which represent a systematic physical activity for a specific purpose.6, 7 Exercise is highly recommended for primary and secondary prevention and the positive effects of physical activity on CV risk factors, such as (a) obesity, (b) hypertension and (c) diabetes, are analysed, validated and reported many times. In 2015, increase in obesity driven by a sedentary lifestyle and the uptake of energy-dense foods reached 603 million adults worldwide with an additional overall prevalence of 5% among children. Elevated body mass index (BMI) higher than >25 decreases quality of life and is known to be the major risk factor for cardiovascular diseases (41% of BMI-related deaths), such as insulin resistance or type 2 diabetes mellitus.10 In 2014, diabetes mellitus globally affected 422 million people with increasing prevalence. The outcome of high-intensity interval training in a cohort of type 2 diabetes patients demonstrated improvement of skeletal muscle insulin sensitivity.11 Recently published data estimated that slight improvement in cardiorespiratory fitness might prevent 4%-21% of new annual cases of type 2 diabetes among individuals between 45 and 64 years.12 Hence, even people currently not suffering from diabetes would benefit from preventive measures or a change in lifestyle. Bescos et al investigated the influence of shift work on healthy adults. Alarmingly, insulin sensitivity decreased by 25% following four nights of shift work with no changes as compared to the day shift group.13 It is known that exercise is associated with a reduction of sympathetic activity, decrease in blood pressure and heart rate in hypertensive and diabetic patients.14 Cornelissen et al included 5223 hypertensive participants in their meta-analysis and found that regular aerobic exercise was responsible for significant reduction of both systolic and diastolic blood pressure.15 Our group has demonstrated that even patients with resistant hypertension benefit from aerobic exercise with a significant reduction of systolic and diastolic daytime blood pressure by 6 mmHg and 3 mmHg on top of that achieved by the existed antihypertensive medication.16 Here, it should be emphasized that physical activity is not only important for the prevention of cardiovascular diseases, but also for strengthening the whole organism. The response to physical activity and exercise may be considered an organic attempt to maintain a physiological state of homeostasis.17 The body responds to physical activity by comprehensive adaptation processes in the (a) respiratory, (b) cognitive and in particular (c) muscular system. Basic research emphasized molecular adaptations such as that exercise reduce lung fibrosis via a modulation of endogenous hydrogen sulfide generation in mice,18 or the enhancement of episodic memory function via an IGF-1-mediated process.19 Exercise-induced muscle adaptations are accompanied by muscle fibre type-dependent regulation of Na+, K+-ATPase isoform expression and improved K+ regulation.20 The change from sedentary lifestyle to one that included five aerobic exercise trainings per week demonstrated an improvement in skeletal muscle mitochondrial volume. Skeletal muscle mitochondrial biogenesis and angiogenesis occur quickly with exercise training, and it was shown that mitochondria itself enhance O2 diffusion from microvessels during physical activity.21 Axelrod and colleagues revealed exercise-induced expression of mitochondrial fusion and fission proteins in human skeletal muscle demonstrating a more fused, tubular network.22 Arribat et al demonstrated distinct patterns of molecular adaptations in human skeletal muscle mitochondria under chronic exercise training and suggest a specific role for the mitochondria membrane protein BCL2L13. In particular, lifelong exercise showed an increase in mitochondrial turnover indicated by strong mitophagy matched with increased mitochondrial fusion and decreased fission.23 PGC-1α, master regulator of mitochondrial biogenesis and apparent key player in the hepatic stress response to bouts of acute exercise,24 may assume a critical role in preventing simvastatin-associated myotoxicity.25 However, exercise-induced physiological adaptations described above might not necessarily be similar for persons who suffer from different CV risk factors, and personalized, supervised exercise programs should target the situation and training status of individual patients.26 Hypertensive individuals demonstrate anomalous muscle mitochondrial turnover and amplified oxidative damage. However, high-intensity exercise training showed that hypertension-related impairments can be partly reversed.27 We need more personalized research on physical activity; however, individualized approaches are often cost-intensive. Interestingly, exercise research in the Drosophila model has been used to carry out exploratory studies to gain insights towards individually tailored exercise regimens.28 Furthermore, for identifying markers of activity and training in individualized precision medicine, the circulatory blood system and the interplay with the vascular endothelial cells constitute a suitable field of research. The immune system is involved in regulating and maintaining the effects of physical activity such as vascular remodelling, muscle development and repair. Many of the beneficial cardiovascular effects of exercise are mediated by the improvement of (a) circulating white blood cell activity, (b) endothelial function and (c) the antioxidant state in blood. Skeletal muscle macrophages are related to insulin sensitivity in response to changes in physical activity in healthy older adults.29 Aerobic exercise is not only able to improve endothelial function but also to ameliorate endothelial dysfunction of patients with coronary artery disease. In a landmark trial, Hambrecht et al30 demonstrated a direct improvement of the endothelial-dependent vasodilation of the coronary vessels in patients with endothelial dysfunction. Analogue results have also been demonstrated in peripheral arteries of patients with peripheral artery disease (PAD). Other positive results of exercise are related to improvement of the lipid status with known beneficial effects on low density lipoprotein (LDL), whole cholesterol, triglycerides and high density lipoprotein (HDL). Even more interesting is the fact that aerobic exercise improves not only the quantity but also the function of HDL and LDL by reducing the oxidized HDL and LDL in serum of patients with cardiovascular diseases. For these beneficial effects, the main mechanism of action is at least the reduction of reactive oxygen species in response to increased shear stress after exercise. In summary, the effects of physical activity are numerous ranging from precisely controlled molecular processes to structural organ adaptations. Furthermore, the effect of training depends on the type and intensity of exercise, as well as on the personal health status of the individual. Exercise in general is highly recommended for primary and secondary prevention, in particular, against cardiovascular diseases. A meta-analysis that involved 14 486 participants who were followed for at least 12 months showed that exercise-based cardiac rehabilitation reduced CV mortality by 26% and the risk of hospital admissions by 18% in patients after myocardial infarction or revascularization (percutaneous or surgical).31 Furthermore, a large study that included 15 486 patients with stable coronary heart disease reported that physical activity was related with reduced all-cause and cardiovascular mortality, but myocardial infarction and stroke were not associated with exercise volume after adjusting for covariates.32 Beneficial effect of exercise was also reported in patients with PAD in whom a home exercise program improved maximum walking distance, claudication distance, walking distance in a 6-min walking test and physical activity.33 These findings encouraged the promotion of regular physical activity among PAD patients.34 If the ability to walk or run is restricted, this affects almost all areas of daily life. Movement determines your health status, enables mobility and often makes social life possible. The WHO has therefore now included physical activity in its Global Action Plan 2020. In order to contribute to the WHO action plan, we recently initiated the WalkInLab (Lauflabor) registry trial. Here, numerous modern aspects which influence mobility, such as the age of the vessels, the elasticity of the vessels, the walking distance (due to PAD) or the limitation of the walking performance (due to open wounds on the foot/leg) are examined and scientifically recorded. None.