Effect of 5 years of exercise training on the cardiovascular risk profile of older adults: the Generation 100 randomized trial.

AIMS: The aim of this study was to compare the effects of 5 years of supervised exercise training (ExComb), and the differential effects of subgroups of high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT), with control on the cardiovascular risk profile in older adults. METHODS AND RESULTS: Older adults aged 70-77 years from Trondheim, Norway (n = 1567, 50% women), able to safely perform exercise training were randomized to 5 years of two weekly sessions of HIIT [∼90% of peak heart rate (HR), n = 400] or MICT (∼70% of peak HR, n = 387), together forming ExComb (n = 787), or control (instructed to follow physical activity recommendations, n = 780). The main outcome was a continuous cardiovascular risk score (CCR), individual cardiovascular risk factors, and peak oxygen uptake (VO2peak). CCR was not significantly lower [-0.19, 99% confidence interval (CI) -0.46 to 0.07] and VO2peak was not significantly higher (0.39 mL/kg/min, 99% CI -0.22 to 1.00) for ExComb vs. control. HIIT showed higher VO2peak (0.76 mL/kg/min, 99% CI 0.02-1.51), but not lower CCR (-0.32, 99% CI -0.64 to 0.01) vs. control. MICT did not show significant differences compared to control or HIIT. Individual risk factors mostly did not show significant between-group differences, with some exceptions for HIIT being better than control. There was no significant effect modification by sex. The number of cardiovascular events was similar across groups. The healthy and fit study sample, and contamination and cross-over between intervention groups, challenged the possibility of detecting between-group differences. CONCLUSIONS: Five years of supervised exercise training in older adults had little effect on cardiovascular risk profile and did not reduce cardiovascular events. REGISTRATION: ClinicalTrials.gov: NCT01666340.

Exercise in claudicants increase or decrease walking ability and the response relates to mitochondrial function.

BACKGROUND: Exercise of patients with intermittent claudication improves walking performance. Exercise does not usually increase blood flow, but seems to increase muscle mitochondrial enzyme activities. Although exercise is beneficial in most patients, it might be harmful in some. The mitochondrial response to exercise might therefore differ between patients. Our hypothesis was that changes in walking performance relate to changes in mitochondrial function after 8 weeks of exercise. At a subgroup level, negative responders decrease and positive responders increase mitochondrial capacity. METHODS: Two types of exercise were studied, calf raising and walking (n = 28). We wanted to see whether there were negative and positive responders, independent of type of exercise. Measurements of walking performance, peripheral hemodynamics, mitochondrial respiration and content (citrate synthase activity) were obtained on each patient before and after the intervention period. Multiple linear regression was used to test whether changes in peak walking time relate to mitochondrial function. Subgroups of negative (n = 8) and positive responders (n = 8) were defined as those that either decreased or increased peak walking time following exercise. Paired t test and analysis of covariance was used to test changes within and between subgroups. RESULTS: Changes in peak walking time were related to changes in mitochondrial respiration supported by electron transferring flavoprotein (ETF + CI)P (p = 0.004), complex I (CI + ETF)P (p = 0.003), complex I + complex II (CI + CII + ETF)P (p = 0.037) and OXPHOS coupling efficiency (p = 0.046) in the whole group. Negative responders had more advanced peripheral arterial disease. Mitochondrial respiration supported by electron transferring flavoprotein (ETF + CI)P (p = 0.0013), complex I (CI + ETF)P (p = 0.0005), complex I + complex II (CI + CII + ETF)P (p = 0.011) and electron transfer system capacity (CI + CII + ETF)E (p = 0.021) and OXPHOS coupling efficiency decreased in negative responders (p = 0.0007) after exercise. Positive responders increased citrate synthase activity (p = 0.010). CONCLUSIONS: Changes in walking performance seem to relate to changes in mitochondrial function after exercise. Negative responders have more advanced peripheral arterial disease and decrease, while positive responders increase mitochondrial capacity. Trial registration ClinicalTrials.gov ID: NCT023110256.

Calf raise exercise increases walking performance in patients with intermittent claudication.

BACKGROUND: Symptoms of intermittent claudication (IC) are improved by exercise. The improvement might be secondary to increased blood perfusion or increased muscle mitochondrial capacity. Ischemia followed by reperfusion, also named preconditioning, is known to stimulate the mitochondria. We focused on a calf raise exercise inducing preconditioning in the calf muscle of patients with IC. We hypothesized that 8 weeks of this exercise would increase walking performance and mitochondrial capacity without a change in blood flow. METHODS: Patients with IC were randomized to either a calf raise exercise group (n = 14) or a traditional walking exercise group (n = 15). The calf raise group was instructed to perform a specific type of calf raise exercise three times a day. The walking group was instructed to walk near the pain threshold at least 30 minutes three times a week. Both interventions lasted 8 weeks and were not supervised. Measurements of walking performance, mitochondrial capacity, peak oxygen uptake, peripheral hemodynamics, and health-related quality of life were obtained on each patient before and after the intervention period. Adherence was measured by a training diary, and an activity monitor was used. RESULTS: The calf raise group improved pain-free walking distance by 44 meters (P = .04) and maximal walking distance by 99 meters (P = .047). Furthermore, claudication onset time increased by 123 seconds (P = .02), and peak walking time increased by 104 seconds (P = .01). The calf raise group increased the enzyme citrate synthase activity, which is a biomarker of mitochondrial volume-density in the muscle tissue (P = .02). The walking group did not increase any of these variables. Maximal blood flow, peak oxygen uptake, and mitochondrial respiration did not change in any group. The calf raise group experienced less disease anxiety (P < .01). Adherence to the instruction of exercise was 100% in the calf raise group and 80% in the walking group. The calf raise group maintained physical activity. A reduction in activity (P < .01) was found in the walking group. CONCLUSIONS: Calf raise exercise improves walking performance and increases mitochondrial volume-density in the gastrocnemius muscle without increasing blood flow in patients with IC.

Remote ischemic preconditioning preserves mitochondrial function and influences myocardial microRNA expression in atrial myocardium during coronary bypass surgery.

RATIONALE: Remote ischemic preconditioning (RIPC) has been suggested to induce cardioprotection during cardiac surgery. Maintaining proper atrial function is imperative in preventing arrhythmia and thrombus formation. Mitochondria have been proposed as key targets in conveying RIPC mechanisms and effects. MicroRNA (miR) is emerging as an important regulator of mitochondrial function, arrhythmia, and protection from ischemia and reperfusion. OBJECTIVE: This study aimed to evaluate the effect of RIPC on mitochondrial respiration and miR expression in human atrial tissue. METHODS AND RESULTS: Sixty patients undergoing coronary artery bypass graft surgery were randomized to RIPC (n=30) or control (n=30). RIPC was performed preoperatively by inflating a blood pressure cuff on the upper arm to 200 mm Hg for 3×5 minutes, with 5 minutes reperfusion intervals. Biopsies were obtained from the right atrial appendage before and after aortic cross-clamping. Mitochondrial respiration was measured in situ and miR assessed by commercial miR array and quantitative reverse transcription polymerase chain reaction. Postoperative atrial fibrillation occurrence was monitored by biotelemetry. Maximal mitochondrial respiration was preserved throughout surgery after RIPC but significantly reduced (-28%; P<0.05) after aortic cross-clamping in control. Incidence of postoperative atrial fibrillation was lower after RIPC versus control (14% versus 50%; P<0.01). Myocardial expression of miR-133a and miR-133b increased after aortic cross-clamping in both RIPC and control, whereas miR-1 was upregulated in control only. MiR-338-3p expression was higher in RIPC versus control after aortic cross-clamping. CONCLUSIONS: RIPC preserves mitochondrial respiration and prevents upregulation of miR-1 in the right atrium during coronary artery bypass graft. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01308138.

Mitochondrial respiration and microRNA expression in right and left atrium of patients with atrial fibrillation.

Atrial fibrillation (AF) is the most common cardiac arrhythmia with a potential to cause serious complications. Mitochondria play central roles in cardiomyocyte function and have been implicated in AF pathophysiology. MicroRNA (miR) are suggested to influence both mitochondrial function and the development of AF. Yet mitochondrial function and miR expression remain largely unexplored in human atrial tissue. This study aims to investigate mitochondrial function and miR expression in the right (RA) and left atria (LA) of patients with AF and sinus rhythm (SR). Myocardial tissue from the RA and LA appendages was investigated in 37 patients with AF (n = 21) or SR (n = 16) undergoing coronary artery bypass surgery and/or heart valve surgery. Mitochondrial respiration was measured in situ after tissue permeabilization by saponin. MiR expression was assessed by miR array and real-time quantitative reverse-transcription polymerase chain reaction. Maximal mitochondrial respiratory rate was increased in both RA and LA tissue of patients with AF vs. SR. Biatrial downregulation of miR-208a and upregulation of miR-106b, -144, and -451 were observed in AF vs. SR. In addition, miR-15b was upregulated in AF within RA only, and miR-106a, -18a, -18b, -19a, -19b, -23a, -25, -30a, -363, -486-5p, -590-5p, and -93 were upregulated in AF within LA only. These findings suggest that mitochondrial function and miR are involved in AF pathophysiology and should be areas of focus in the exploration for potential novel therapeutic targets.

Cardiovascular risk of high- versus moderate-intensity aerobic exercise in coronary heart disease patients.

BACKGROUND: Exercise performed at higher relative intensities has been found to elicit a greater increase in aerobic capacity and greater cardioprotective effects than exercise at moderate intensities. An inverse association has also been detected between the relative intensity of physical activity and the risk of developing coronary heart disease, independent of the total volume of physical activity. Despite that higher levels of physical activity are effective in reducing cardiovascular events, it is also advocated that vigorous exercise could acutely and transiently increase the risk of sudden cardiac death and myocardial infarction in susceptible persons. This issue may affect cardiac rehabilitation. METHODS AND RESULTS: We examined the risk of cardiovascular events during organized high-intensity interval exercise training and moderate-intensity training among 4846 patients with coronary heart disease in 3 Norwegian cardiac rehabilitation centers. In a total of 175 820 exercise training hours during which all patients performed both types of training, we found 1 fatal cardiac arrest during moderate-intensity exercise (129 456 exercise hours) and 2 nonfatal cardiac arrests during high-intensity interval exercise (46 364 exercise hours). There were no myocardial infarctions in the data material. Because the number of high-intensity training hours was 36% of the number of moderate-intensity hours, the rates of complications to the number of patient-exercise hours were 1 per 129 456 hours of moderate-intensity exercise and 1 per 23 182 hours of high-intensity exercise. CONCLUSIONS: The results of the current study indicate that the risk of a cardiovascular event is low after both high-intensity exercise and moderate-intensity exercise in a cardiovascular rehabilitation setting. Considering the significant cardiovascular adaptations associated with high-intensity exercise, such exercise should be considered among patients with coronary heart disease.

Aerobic exercise training improves right- and left ventricular systolic function in patients with COPD.

OBJECTIVE: The aim of this study was to investigate the effects of moderate continuous training (MCT) and high intensity aerobic interval training (AIT) on systolic ventricular function and aerobic capacity in COPD patients. METHODS: Seventeen patients with COPD (64 ± 8 years, 12 men) with FEV1 of 52.8 ± 11% of predicted, were randomly assigned to isocaloric programs of MCT at 70% of max heart rate (HR) for 47 minutes) or AIT (~90% of max HR for 4×4 minutes) three times per week for 10 weeks. Baseline cardiac function was compared with 17 age- and sex-matched healthy individuals. Peak oxygen uptake (VO(2-peak)) and left (LV) and right ventricular (RV) function examined by echocardiography, were measured at baseline and after 10 weeks of training. RESULTS: At baseline, the COPD patients had reduced systolic function compared to healthy controls (p < 0.05). After the training, AIT and MCT increased VO(2-peak) by 8% and 9% and work economy by 7% and 10%, respectively (all p < 0.05). LV and RV systolic function both improved (p < 0.05), with no difference between the groups after the two modes of exercise training. Stroke volume increased by 17% and 20%, LV systolic tissue Doppler velocity (S') by 18% and 17% and RV S' by 15% after AIT and MCT, respectively (p < 0.05). CONCLUSION: Systolic cardiac function is reduced in COPD. Both AIT and MCT improved systolic cardiac function. In contrast to other patient groups studied, higher exercise intensity does not seem to have additional effects on cardiac function or aerobic capacity in COPD patients.

High-intensity knee extensor training restores skeletal muscle function in COPD patients.

Improving reduced skeletal muscle function is important for optimising exercise tolerance and quality of life in chronic obstructive pulmonary disease (COPD) patients. By applying high-intensity training to a small muscle group, we hypothesised a normalisation of muscle function. Seven patients with COPD performed 6 weeks (3 days·week(-1)) of high-intensity interval aerobic knee extensor exercise training. Five age-matched healthy individuals served as a reference group. Muscle oxygen uptake and mitochondrial respiration of the vastus lateralis muscle were measured before and after the 6-week training programme. Initial peak work and maximal mitochondrial respiration were reduced in COPD patients and improved significantly after the training programme. Peak power and maximal mitochondrial respiration in vastus lateralis muscle increased to the level of the control subjects and were mainly mediated via improved complex I respiration. Furthermore, when normalised to citrate synthase activity, no difference in maximal respiration was found either after the intervention or compared to controls, suggesting normal functioning mitochondrial complexes. The present study shows that high-intensity training of a restricted muscle group is highly effective in restoring skeletal muscle function in COPD patients.

One-arm maximal strength training improves work economy and endurance capacity but not skeletal muscle blood flow.

Maximal strength training with a focus on maximal mobilization of force in the concentric phase improves endurance performance that employs a large muscle mass. However, this has not been studied during work with a small muscle mass, which does not challenge convective oxygen supply. We therefore randomized 23 adult females with no arm-training history to either one-arm maximal strength training or a control group. The training group performed five sets of five repetitions of dynamic arm curls against a near-maximal load, 3 days a week for 8 weeks. This training increased maximal strength by 75% and improved rate of force development during both strength and endurance exercise, suggesting that each arm curl became more efficient. This coincided with a 17-18% reduction in oxygen cost at standardized submaximal workloads (work economy), and a 21% higher peak oxygen uptake and 30% higher peak load during maximal arm endurance exercise. Blood flow assessed by Doppler ultrasound in the axillary artery supplying the working biceps brachii and brachialis muscles could not explain the training-induced adaptations. These data suggest that maximal strength training improved work economy and endurance performance in the skeletal muscle, and that these effects are independent of convective oxygen supply.

Time course of endothelial adaptation after acute and chronic exercise in patients with metabolic syndrome.

Clustering of cardiovascular risk factors may lead to endothelial dysfunction. Physical exercise is an important factor in prevention and treatment of endothelial dysfunction. We wanted to determine the time course of adaptation to a single bout of exercise at either high or moderate intensity upon endothelial function both before and after a 16-week fitness program in patients with metabolic syndrome. Twenty-eight patients with metabolic syndrome participated in the study and were randomized and stratified (according to age and sex) into an aerobic interval exercise training group (AIT, n = 11), a continuously moderate-intensity exercise training group (CME, n = 8) or to a control group (n = 9). Flow-mediated dilatation (FMD) was determined at baseline, immediately, 24, 48, and 72 hours after 1 bout of exercise and repeated after 16 weeks of exercise. In the untrained state, FMD improved from 5 to 11% (p = 0.003) immediately after a single bout of aerobic interval training (AIT), an effect lasting 72 hours postexercise. In comparison, continuous moderate exercise (CME) improved FMD immediately after a single bout of exercise from 5 to 8% (p = 0.02), an effect lasting 24 hours postexercise (group difference, p < 0.001). In the trained state, a single bout of AIT resulted in a 2% (p = 0.007) acute increase of FMD lasting 48 hours postexercise. The CME increased FMD by 3% (p < 0.01), an effect lasting 24 hours postexercise (group difference p = 0.0012). Blood glucose level decreased after 1 single bout of AIT in the untrained state (p < 0.05), and the effect lasted at least 72 hours postexercise (p < 0.01). Acute CME decreased blood glucose with normalization of the values 24 hours postexercise (p < 0.01). A single bout of exercise in the trained state reduced fasting blood glucose by 10% (p < 0.05) after both AIT and CME. Exercise training, especially high intensity, thus appears to be highly beneficial in reducing blood glucose and improving endothelial function.

Effect of exercise training for five years on all cause mortality in older adults-the Generation 100 study: randomised controlled trial.

OBJECTIVE: To evaluate the effect of five years of supervised exercise training compared with recommendations for physical activity on mortality in older adults (70-77 years). DESIGN: Randomised controlled trial. SETTING: General population of older adults in Trondheim, Norway. PARTICIPANTS: 1567 of 6966 individuals born between 1936 and 1942. INTERVENTION: Participants were randomised to two sessions weekly of high intensity interval training at about 90% of peak heart rate (HIIT, n=400), moderate intensity continuous training at about 70% of peak heart rate (MICT, n=387), or to follow the national guidelines for physical activity (n=780; control group); all for five years. MAIN OUTCOME MEASURE: All cause mortality. An exploratory hypothesis was that HIIT lowers mortality more than MICT. RESULTS: Mean age of the 1567 participants (790 women) was 72.8 (SD 2.1) years. Overall, 87.5% of participants reported to have overall good health, with 80% reporting medium or high physical activity levels at baseline. All cause mortality did not differ between the control group and combined MICT and HIIT group. When MICT and HIIT were analysed separately, with the control group as reference (observed mortality of 4.7%), an absolute risk reduction of 1.7 percentage points was observed after HIIT (hazard ratio 0.63, 95% confidence interval 0.33 to 1.20) and an absolute increased risk of 1.2 percentage points after MICT (1.24, 0.73 to 2.10). When HIIT was compared with MICT as reference group an absolute risk reduction of 2.9 percentage points was observed (0.51, 0.25 to 1.02) for all cause mortality. Control participants chose to perform more of their physical activity as HIIT than the physical activity undertaken by participants in the MICT group. This meant that the controls achieved an exercise dose at an intensity between the MICT and HIIT groups. CONCLUSION: This study suggests that combined MICT and HIIT has no effect on all cause mortality compared with recommended physical activity levels. However, we observed a lower all cause mortality trend after HIIT compared with controls and MICT. TRIAL REGISTRATION: ClinicalTrials.gov NCT01666340.

Aerobic interval training versus continuous moderate exercise as a treatment for the metabolic syndrome: a pilot study.

BACKGROUND: Individuals with the metabolic syndrome are 3 times more likely to die of heart disease than healthy counterparts. Exercise training reduces several of the symptoms of the syndrome, but the exercise intensity that yields the maximal beneficial adaptations is in dispute. We compared moderate and high exercise intensity with regard to variables associated with cardiovascular function and prognosis in patients with the metabolic syndrome. METHODS AND RESULTS: Thirty-two metabolic syndrome patients (age, 52.3+/-3.7 years; maximal oxygen uptake [o(2)max], 34 mL x kg(-1) x min(-1)) were randomized to equal volumes of either moderate continuous moderate exercise (CME; 70% of highest measured heart rate [Hfmax]) or aerobic interval training (AIT; 90% of Hfmax) 3 times a week for 16 weeks or to a control group. o(2)max increased more after AIT than CME (35% versus 16%; P<0.01) and was associated with removal of more risk factors that constitute the metabolic syndrome (number of factors: AIT, 5.9 before versus 4.0 after; P<0.01; CME, 5.7 before versus 5.0 after; group difference, P<0.05). AIT was superior to CME in enhancing endothelial function (9% versus 5%; P<0.001), insulin signaling in fat and skeletal muscle, skeletal muscle biogenesis, and excitation-contraction coupling and in reducing blood glucose and lipogenesis in adipose tissue. The 2 exercise programs were equally effective at lowering mean arterial blood pressure and reducing body weight (-2.3 and -3.6 kg in AIT and CME, respectively) and fat. CONCLUSIONS: Exercise intensity was an important factor for improving aerobic capacity and reversing the risk factors of the metabolic syndrome. These findings may have important implications for exercise training in rehabilitation programs and future studies.

Global physical activity levels - Need for intervention.

Substantial evidence shows that physical inactivity (PI) and sedentary behavior (SB) increases the risk of many chronic diseases and shortens life expectancy. We describe evidence that certain domains of physical activity (PA) in the United States (US) population have declined substantially over 5 decades. The prevalence of PI is very high worldwide, which has contributed to 6%-10% of the burden of many chronic diseases and premature mortality. Reduction or elimination of PI would likely produce substantial increases in life expectancy of the world's population. Great efforts are needed to reduce PI and SB and increase levels of PA in the US and worldwide.

Superior cardiovascular effect of aerobic interval training versus moderate continuous training in heart failure patients: a randomized study.

BACKGROUND: Exercise training reduces the symptoms of chronic heart failure. Which exercise intensity yields maximal beneficial adaptations is controversial. Furthermore, the incidence of chronic heart failure increases with advanced age; it has been reported that 88% and 49% of patients with a first diagnosis of chronic heart failure are >65 and >80 years old, respectively. Despite this, most previous studies have excluded patients with an age >70 years. Our objective was to compare training programs with moderate versus high exercise intensity with regard to variables associated with cardiovascular function and prognosis in patients with postinfarction heart failure. METHODS AND RESULTS: Twenty-seven patients with stable postinfarction heart failure who were undergoing optimal medical treatment, including beta-blockers and angiotensin-converting enzyme inhibitors (aged 75.5+/-11.1 years; left ventricular [LV] ejection fraction 29%; VO2peak 13 mL x kg(-1) x min(-1)) were randomized to either moderate continuous training (70% of highest measured heart rate, ie, peak heart rate) or aerobic interval training (95% of peak heart rate) 3 times per week for 12 weeks or to a control group that received standard advice regarding physical activity. VO2peak increased more with aerobic interval training than moderate continuous training (46% versus 14%, P<0.001) and was associated with reverse LV remodeling. LV end-diastolic and end-systolic volumes declined with aerobic interval training only, by 18% and 25%, respectively; LV ejection fraction increased 35%, and pro-brain natriuretic peptide decreased 40%. Improvement in brachial artery flow-mediated dilation (endothelial function) was greater with aerobic interval training, and mitochondrial function in lateral vastus muscle increased with aerobic interval training only. The MacNew global score for quality of life in cardiovascular disease increased in both exercise groups. No changes occurred in the control group. CONCLUSIONS: Exercise intensity was an important factor for reversing LV remodeling and improving aerobic capacity, endothelial function, and quality of life in patients with postinfarction heart failure. These findings may have important implications for exercise training in rehabilitation programs and future studies.

Endothelial function in highly endurance-trained men: effects of acute exercise.

Exercise training reverses endothelial dysfunction, but the effect in young, healthy subjects is less clear. We determined the influence of maximal oxygen uptake (VO2max) and a single bout of high-intensity exercise on flow-mediated dilatation (FMD), brachial artery diameter, peak blood flow, nitric oxide (NO) bioavailability, and antioxidant status in highly endurance-trained men and their sedentary counterparts. Ten men athletes (mean +/- SEM age 23.5 +/- 0.9 years, height 182.6 +/- 2.4 cm, weight 72.5 +/- 2.4 kg, VO2max 75.9 +/- 0.8 mL.kg.min) and seven healthy controls (age 25.4 +/- 1.2 years, height 183.9 +/- 3.74 cm, weight 92.8 +/- 3.9 kg, VO2max 47.7 +/- 1.7 mL.kg.min) took part in the study. FMD, brachial artery diameter, and peak blood flow were measured using echo-Doppler before, 1 hour, 24 hours, and 48 hours after a single bout of interval running for 5 x 5 minutes at 90% of maximal heart rate. NO bioavailability and antioxidant status in blood were measured at all time points. Maximal arterial diameter and peak flow were 10-15% (P < 0.02) and 28-35% (P < 0.02) larger, respectively, in athletes vs. controls at all time points, and similar FMD were observed, apart from a transient decay of FMD in athletes 1 hour post exercise. NO bioavailability increased significantly after exercise in both groups and decreased to baseline levels after 24 hours in controls but remained increased 80% and 93% above baseline 24 and 48 hours post exercise in athletes. Antioxidant status was equal in the two groups at baseline and increased by approximately 10% 1 hour post exercise, an effect that lasted for 24 hours. Athletes had larger arterial diameter but similar FMD as untrained subjects, i.e., athletes had larger capacity for blood transport compared with their untrained counterparts. The observed FMD, bioavailability of NO, and antioxidant status in blood were highly dependent on the time elapsed after the exercise session.