Exercise transiently increases the density of incipient blood clots in antiplatelet-treated lacunar stroke patients.

INTRODUCTION: Older individuals and, in particular, individuals at risk of recurrent stroke, may be susceptible to thrombosis when participating in exercise, however, this aspect has not been well investigated. METHODS: Clot microstructure and conventional markers of thrombotic risk were determined in twenty lacunar stroke patients and fifteen healthy age-matched controls before, immediately after and 1 h after a bout of moderate intensity cycling exercise. Data were analyzed using a linear mixed model approach. RESULTS: At rest, clot microstructure (1.69 ± 0.07 vs. 1.64 ± 0.05, corresponding to a difference of ~ 50% in normalized clot mass; p = 0.009) and thrombocyte count (73%; p < 0.0001) were higher, and activated partial thromboplastin time was lower (18%; p = 0.0001) in stroke patients compared to age-matched controls. Acute exercise increased thrombogenic markers similarly in the two groups: incipient clot microstructure (1.69 ± 0.07 vs. 1.74 ± 0.05; p = 0.0004 and 1.64 ± 0.05 vs. 1.71 ± 0.04; p < 0.0001, for stroke and controls respectively), plasma fibrinogen (12%; p < 0.0001 and 18%; p < 0.0001, for stroke and controls respectively) and the combined coagulation factors II, VII and X (p = 0.0001 and p < 0.0001, for stroke and controls respectively). CONCLUSION: The results show that exercise transiently increases the risk of blood clot formation in both stroke patients and controls, however, due to the higher baseline thrombogenicity in stroke patients, the post exercise risk of forming blood clots may be higher in this group. TRIAL REGISTRATION: Registered at ClinicalTrials.gov (NCT03635177).

Hormetic modulation of angiogenic factors by exercise-induced mechanical and metabolic stress in human skeletal muscle.

This study used an integrative experimental model in humans to investigate whether muscle angiogenic factors are differentially modulated by exercise stimuli eliciting different degrees of mechanical and metabolic stress. In a randomized crossover design, 12 men performed two low-volume high-intensity exercise regimens, including short sprint intervals (SSI) or long sprint intervals (LSI) inducing pronounced mechanical/metabolic stress, and a high-volume moderate-intensity continuous exercise protocol (MIC) inducing mild but prolonged mechanical/metabolic stress. Gene and protein expression of angiogenic factors was determined in vastus lateralis muscle samples obtained before and after exercise. Exercise upregulated muscle VEGF mRNA to a greater extent in LSI and MIC compared with SSI. Analysis of angiogenic factors sensitive to shear stress revealed more marked exercise-induced VEGF receptor 2 (VEGF-R2) mRNA responses in MIC than SSI, as well as greater platelet endothelial cell adhesion molecule (PECAM-1) and endothelial nitric oxide synthase (eNOS) mRNA responses in LSI than SSI. No apparent exercise-induced phosphorylation of shear stress-sensory proteins VEGF-R2Tyr1175, PECAM-1Tyr713, and eNOSSer1177 was observed despite robust elevations in femoral artery shear stress. Exercise evoked greater mRNA responses of the mechanical stretch sensor matrix metalloproteinase-9 (MMP9) in SSI than MIC. Exercise-induced mRNA responses of the metabolic stress sensor hypoxia-inducible factor-1α (HIF-1α) were more profound in LSI than SSI. These results suggest that low-volume high-intensity exercise transcriptionally activates angiogenic factors in a mechanical/metabolic stress-dependent manner. Furthermore, the angiogenic potency of low-volume high-intensity exercise appears similar to that of high-volume moderate-intensity exercise, but only on condition of eliciting severe mechanical/metabolic stress. We conclude that the angiogenic stimulus produced by exercise depends on both magnitude and protraction of myocellular homeostatic perturbations.NEW & NOTEWORTHY Skeletal muscle capillary growth is orchestrated by angiogenic factors sensitive to mechanical and metabolic signals. In this study, we employed an integrative exercise model to synergistically target, yet to different extents and for different durations, the mechanical and metabolic components of muscle activity that promote angiogenesis. Our results suggest that the magnitude of the myocellular perturbations incurred during exercise determines the amplitude of the angiogenic molecular signals, implying hormetic modulation of skeletal muscle angiogenesis by exercise-induced mechanical and metabolic stress.

The exercise timing hypothesis: can exercise training compensate for the reduction in blood vessel function after menopause if timed right?

As women enter menopause at mid-life, oestrogen production ceases and its many beneficial effects on cardiovascular health are lost whereby the age-related risk of cardiovascular disease is accelerated. Oestrogen acts via oestrogen receptors and can activate the oestrogen response element leading to upregulation of a number of proteins of importance for vascular health, including the vasodilator and anti-atherogenic enzyme endothelial nitric oxide synthase and angiogenic factors. Hormone replacement therapy can to some extent counteract the loss of oestrogen although studies have shown that such treatment may only be effective if initiated soon after menopause, the so-called timing hypothesis. An attractive alternative to hormone therapy is regular physical activity, as it is known that exercise induces many of the same cardiovascular health protective effects as oestrogen. Nevertheless, results from studies on the effect of physical activity on vascular function and cardiovascular health are inconsistent, with some studies showing a lack of effect of a physical activity programme and others showing a beneficial effect. The reason for this divergence is unclear but here we explore whether there may be a timing aspect also for exercise training, the exercise timing hypothesis, in which initiation of exercise interventions soon after menopause may be more effective than initiation many years after. The possibility that oestrogen-related receptor-α and oxidative stress may play a role in such a timing effect is discussed.

Cardiovascular, muscular, and skeletal adaptations to recreational team handball training: a randomized controlled trial with young adult untrained men.

PURPOSE: The prevalence of lifestyle diseases has escalated, and effective exercise training programmes are warranted. This study tested the hypothesis that regular participation in small-sided team handball training could provide beneficial health effects on cardiovascular, skeletal, and muscular parameters in young adult untrained men. METHOD: Twenty-six untrained 20-30-year-old men were randomly allocated to either a team handball training group (HG; n = 14), which completed 1.9 ± 0.3 training sessions per week over 12 weeks, or an inactive control group (CG; n = 12). Physiological training adaptations were assessed pre- and post interventions by DXA scans, blood samples, muscle biopsies, and physical tests. RESULTS: The average heart rate during training was equivalent to 84 ± 4% of maximal heart rate. Compared to CG, HG displayed significant increases in VO2max (11 ± 6%), proximal femur bone mineral density (2 ± 1%), whole-body bone mineral content (2 ± 1%), intermittent endurance performance (32 ± 16%), incremental treadmill test performance (16 ± 7%) and muscle citrate synthase activity (22 ± 28%) as well as decreases in total fat mass (7 ± 7%) and total fat percentage (6 ± 7%) (all p < 0.05). There were no significant changes in muscle mass, blood pressure, resting heart rate, muscle hydroxyl-acyl-dehydrogenase activity, or blood lipids (all p > 0.05). CONCLUSION: Participation in regular recreational team handball training was associated with positive cardiovascular, skeletal, and muscular adaptations, including increased maximal oxygen uptake, increased muscle enzymatic activity, and improved bone mineralization as well as lower fat percentage. These findings suggest that recreational team handball training may be an effective health-promoting activity for young adult men.

Correction to: Cardiovascular, muscular, and skeletal adaptations to recreational team handball training: a randomized controlled trial with young adult untrained men.

The author would like to correct the errors in the publication of the original article. The corrected details are given below for your reading.

Platelet responses to pharmacological and physiological interventions in middle-aged men with different habitual physical activity levels.

The current guidelines following an acute coronary syndrome recommend dual-antiplatelet therapy (DAPT) (aspirin plus a P2Y12 antagonist) alongside lifestyle modifications, including more regular physical activity. It is currently unknown whether regular exercise affects the pharmacology of DAPT. AIM: To explore how exercise-induced improvements in vascular and platelet function affect the efficacy of DAPT, in a cross-sectional study of men with different physical activity levels (training status). METHODS: A total of 42 healthy, normal-weight, middle-aged men were divided into 3 groups: untrained, moderately trained and well-trained. Their platelet reactivity (agonist-induced % aggregation) was investigated in platelet-rich plasma at rest and after inhibition with aspirin and ticagrelor and/or prostacyclin and nitric oxide added to the blood in vitro, and after physiological tests of vascular function; passive movement of the leg, flow-mediated dilation and one-leg knee-extensor exercise. Vascular function of the femoral artery (changes in arterial blood flow) was assessed by ultrasound Doppler. RESULTS: Platelets from the well-trained subjects had lower basal reactivity, a higher sensitivity to the anti-aggregatory effects of prostacyclin and were more potently inhibited by DAPT compared to the untrained subjects. The moderately trained and well-trained subjects had a superior vascular function compared to untrained subjects, and their platelets were more inhibited by the passive movement, flow-mediated dilation and one-leg knee-extensor exercise. DISCUSSION: A habitually active lifestyle leads to an increased platelet sensitivity to pharmacological and physiological platelet inhibitors. We suggest that physical activity habits (training status) should be considered when personalizing and optimizing antithrombotic treatment strategies.

Vascular function in health, hypertension, and diabetes: effect of physical activity on skeletal muscle microcirculation.

Regulation of skeletal muscle blood flow is a complex process, which involves an integration of multiple mechanisms and a number of vasoactive compounds. Overall, muscle blood flow is regulated through a balance between vasoconstrictor and vasodilator signals. In a healthy cardiovascular system, the increase in muscle blood flow required for oxygen supply during exercise is achieved through a substantial increase in vasodilators locally formed in the active muscle tissue that overcome the vasoconstrictor signals. Most of the vasodilator signals are mediated via endothelial cells, which lead to the formation of vasodilators such as nitric oxide (NO) and prostacyclin. In essential hypertension and type II diabetes, the endothelial function and regulation of vascular tone is impaired with consequent increases in peripheral vascular resistance and inadequate regulation of oxygen supply to the skeletal muscle, which can affect muscle function. Central aspects in the vascular impairments are alterations in the formation of prostacyclin, the bioavailability of NO and an increased formation of vasoconstrictors and reactive oxygen species (ROS). Regular physical activity effectively improves vascular function by enhancing vasodilator formation and reducing the levels of vasoconstrictors and ROS.

Capillary growth, ultrastructure remodelling and exercise training in skeletal muscle of essential hypertensive patients.

AIM: The aim was to elucidate whether essential hypertension is associated with altered capillary morphology and density and to what extent exercise training can normalize these parameters. METHODS: To investigate angiogenesis and capillary morphology in essential hypertension, muscle biopsies were obtained from m. vastus lateralis in subjects with essential hypertension (n = 10) and normotensive controls (n = 11) before and after 8 weeks of aerobic exercise training. Morphometry was performed after transmission electron microscopy, and protein levels of several angioregulatory factors were determined. RESULTS: At baseline, capillary density and capillary-to-fibre ratio were not different between the two groups. However, the hypertensive subjects had 9% lower capillary area (12.7 ± 0.4 vs. 13.9 ± 0.2 µm(2)) and tended to have thicker capillary basement membranes (399 ± 16 vs. 358 ± 13 nm; P = 0.094) than controls. Protein expression of vascular endothelial growth factor (VEGF), VEGF receptor-2 and thrombospondin-1 were similar in normotensive and hypertensive subjects, but tissue inhibitor of matrix metalloproteinase was 69% lower in the hypertensive group. After training, angiogenesis was evident by 15% increased capillary-to-fibre ratio in the hypertensive subjects only. Capillary area and capillary lumen area were increased by 7 and 15% in the hypertensive patients, whereas capillary basement membrane thickness was decreased by 17% (P < 0.05). VEGF expression after training was increased in both groups, whereas VEGF receptor-2 was decreased by 25% in the hypertensive patients(P < 0.05). CONCLUSION: Essential hypertension is associated with decreased lumen area and a tendency for increased basement membrane thickening in capillaries of skeletal muscle. Exercise training may improve the diffusion conditions in essential hypertension by altering capillary structure and capillary number.

Impact of training status on LPS-induced acute inflammation in humans.

The aim of the present study was to examine the impact of training status on the ability to induce a lipopolysaccharide (LPS)-induced inflammatory response systemically as well as in skeletal muscle (SkM) and adipose tissue (AT) in human subjects. Seventeen young (23.8 ± 2.5 yr of age) healthy male subjects were included in the study with eight subjects assigned to a trained (T) group and nine subjects assigned to an untrained (UT) group. On the experimental day, catheters were inserted in the femoral artery and vein of one leg for blood sampling and a bolus of 0.3 ng LPS/kg body wt was injected into an antecubital vein in the forearm. Femoral arterial blood flow was measured by ultrasound Doppler, and arterial and venous blood samples were drawn before (Pre) LPS injection and 30, 60, 90, and 120 min after the LPS injection. Vastus lateralis muscle and abdominal subcutaneous AT biopsies were obtained Pre and 60 and 120 min after the LPS injection. LPS increased the systemic plasma TNFα and IL-6 level as well as the TNFα and IL-6 mRNA content in SkM and AT of both UT and T. However, whereas the LPS-induced inflammatory response in SkM was enhanced in T subjects relative to UT, the inflammatory response systemically and in AT was somewhat delayed in T subjects relative to UT. The present findings highlight that training status affects the ability to induce a LPS-induced acute inflammatory response in a tissue-specific manner.

Health promotion: the impact of beliefs of health benefits, social relations and enjoyment on exercise continuation.

The aim of this study was to explore how and why participants in structured exercise intervention programs continue or stop exercising after the program is finished. We conducted four focus group interviews with four groups of middle-aged and elderly men (total n = 28) who had participated in exercise interventions involving playing either a team sport (football) or a more individually focused activity (spinning and crossfit). Our results show that different social, organizational and material structures inherent in the different activities shape the subjects' enjoyment of exercise participation, as well as their intention and ability to continue being active. In conclusion, team sport activities seem to be intrinsically motivating to the participants through positive social interaction and play. They are therefore more likely to result in exercise continuation than activities that rely primarily on extrinsic motivation such as the expectation of improved health and well-being.

Nitric oxide and reactive oxygen species in limb vascular function: what is the effect of physical activity?

Nitric oxide (NO) is known to be one of the most important regulatory compounds within the cardiovascular system where it is central for functions such as regulation of blood pressure, blood flow, and vascular growth. The bioavailability of NO is determined by a balance between, on one hand, the extent of enzymatic and non-enzymatic formation of NO and on the other hand, removal of NO, which in part is dependent on the reaction of NO with reactive oxygen species (ROS). The presence of ROS is dependent on the extent of ROS formation via mitochondria and/or enzymes such as NAD(P)H oxidase (NOX) and xanthine oxidase (XO) and the degree of ROS removal through the antioxidant defense system or other reactions. The development of cardiovascular disease has been proposed to be closely related to a reduced bioavailability of NO in parallel with an increased presence of ROS. Excessive levels of ROS not only lower the bioavailability of NO but may also cause cellular damage in the cardiovascular system. Physical activity has been shown to greatly improve cardiovascular function, in part through improved bioavailability of NO, enhanced endogenous antioxidant defense and a lowering of the expression of ROS-forming enzymes. Regular physical activity is therefore likely to be a highly useful tool in the treatment of cardiovascular disease. Future studies should focus on which form of exercise may be most optimal for enhancing NO bioavailability and improving cardiovascular health.