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.

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.

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.

Acute exercise is not cardioprotective and may induce apoptotic signalling in heart surgery: a randomized controlled trial.

OBJECTIVES: During open-heart surgery, the myocardium experiences ischaemia-reperfusion injury. A single bout of moderate, 30-min exercise induces preconditioning and protects the heart from ischaemia-reperfusion injury in rats, but this has never been investigated in humans. We aimed to investigate whether 1 bout of moderate exercise 24 h prior to surgery protects against mitochondrial and cardiac damage. METHODS: Patients scheduled for elective coronary artery bypass were eligible for this pilot study. Twenty were included and randomized to the treadmill exercise group (the EX group, n = 10) 24 h preoperatively or to standard presurgical procedures (control n = 10). Right atrial (RA) and left ventricular (LV) biopsies were collected immediately before and as long as possible after aortic cross-clamping to assess the primary outcome of mitochondrial respiration by respirometry, in addition to reactive oxygen species production by fluorometry and apoptotic transcripts. Cardiac troponin T and creatine kinase myocardial brain were measured in plasma at arrival, before surgery and 6 and 24 h postoperatively. RESULTS: Mitochondrial respiration was lower in the EX group after surgery in the LV (Complex I -22%, P < 0.05 and maximal -23%, P < 0.05) and the right atrium (Complex I -25%, P < 0.05). Transcript level of the apoptosis-related marker caspase 3 was increased 1.5-fold in the LV prior to surgery in the EX group when compared with the control group, P < 0.05. Cardiac troponin T was 45% higher in the EX group than in the control group 6 h postoperatively (P = 0.03), although not significant when corrected for aortic cross-clamping time. CONCLUSIONS: Results indicate that exercise did not precondition the heart against surgery-related damage. Exercise may render the myocardium and mitochondria more vulnerable to perioperative damage. Clinical trials registration number: NCT00218985 (https://clinicaltrials.gov/ct2/show/NCT00218985).

Cardiorespiratory Reference Data in Older Adults: The Generation 100 Study.

PURPOSE: Cardiorespiratory fitness (CRF) is regarded a clinical vital sign, and accurate reference values for all age groups are essential. Little data exist on CRF and cardiorespiratory function in older adults. The aim of this study was to provide normative values for CRF and cardiorespiratory function in older adults, including people with history of cardiovascular diseases (CVD). METHODS: In total, 1537 (769 women) participants age 70 to 77 yr underwent clinical examinations and cardiopulmonary exercise tests. Peak oxygen uptake (V˙O2peak), ventilation (V˙Epeak), expiration of carbon dioxide (VV˙CO2peak), breathing frequency (BFpeak), tidal volume (VTpeak), oxygen pulse (O2 pulsepeak), ventilatory efficiency (EqV˙O2peak and EqV˙CO2peak), and 1-min HR recovery were assessed. RESULTS: Men compared with women had higher V˙O2peak (31.3 ± 6.7 vs 26.2 ± 5.0 mL·min·kg), BFpeak (41.8 ± 8.0 vs 39.7 ± 7.1 breaths per minute), VTpeak (2.3 ± 0.5 vs 1.6 ± 0.3), O2 pulsepeak (16.4 ± 3.2 vs 11.3 ± 2.0), V˙CO2peak (2.9 ± 0.2 and 1.9 ± 0.1 L·min), V˙Epeak (96.2 ± 21.7 vs 61.1 ± 21.6 L·min), EqV˙O2peak (38.0 ± 6.9 vs 35.1 ± 5.6), and EqV˙CO2peak (33.5 ± 5.7 vs 31.9 ± 4.5). Women and men with CVD had lower V˙O2peak (14% and 19%), peak HR (5% and 6%), V˙Epeak (8% and 10%), VTpeak (7% and 4%), and lower EqV˙CO2peak (4% and 6%) compared with their healthy counterparts, respectively. Compared with healthy women and men, 1-min HR recovery was 12% and 16% lower for women and men with CVD. CONCLUSIONS: This study represents the largest reference material on directly measured CRF and cardiorespiratory function in older men and women, with and without CVD. This novel information will help researchers and clinicians to interpret data form cardiopulmonary testing in older adults.

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.

High Intensity Interval Training for Maximizing Health Outcomes.

Regular physical activity and exercise training are important actions to improve cardiorespiratory fitness and maintain health throughout life. There is solid evidence that exercise is an effective preventative strategy against at least 25 medical conditions, including cardiovascular disease, stroke, hypertension, colon and breast cancer, and type 2 diabetes. Traditionally, endurance exercise training (ET) to improve health related outcomes has consisted of low- to moderate ET intensity. However, a growing body of evidence suggests that higher exercise intensities may be superior to moderate intensity for maximizing health outcomes. The primary objective of this review is to discuss how aerobic high-intensity interval training (HIIT) as compared to moderate continuous training may maximize outcomes, and to provide practical advices for successful clinical and home-based HIIT.

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.

Mitochondrial Respiration after One Session of Calf Raise Exercise in Patients with Peripheral Vascular Disease and Healthy Older Adults.

PURPOSE: Mitochondria are essential for energy production in the muscle cell and for this they are dependent upon a sufficient supply of oxygen by the circulation. Exercise training has shown to be a potent stimulus for physiological adaptations and mitochondria play a central role. Whether changes in mitochondrial respiration are seen after exercise in patients with a reduced circulation is unknown. The aim of the study was to evaluate the time course and whether one session of calf raise exercise stimulates mitochondrial respiration in the calf muscle of patients with peripheral vascular disease. METHODS: One group of patients with peripheral vascular disease (n = 11) and one group of healthy older adults (n = 11) were included. Patients performed one session of continuous calf raises followed by 5 extra repetitions after initiation of pain. Healthy older adults performed 100 continuous calf raises. Gastrocnemius muscle biopsies were collected at baseline and 15 minutes, one hour, three hours and 24 hours after one session of calf raise exercise. A multi substrate (octanoylcarnitine, malate, adp, glutamate, succinate, FCCP, rotenone) approach was used to analyze mitochondrial respiration in permeabilized fibers. Mixed-linear model for repeated measures was used for statistical analyses. RESULTS: Patients with peripheral vascular disease have a lower baseline respiration supported by complex I and they increase respiration supported by complex II at one hour post-exercise. Healthy older adults increase respiration supported by electron transfer flavoprotein and complex I at one hour and 24 hours post-exercise. CONCLUSION: Our results indicate a shift towards mitochondrial respiration supported by complex II as being a pathophysiological component of peripheral vascular disease. Furthermore exercise stimulates mitochondrial respiration already after one session of calf raise exercise in patients with peripheral vascular disease and healthy older adults. TRIAL REGISTRATION: ClinicalTrials.gov NCT01842412.

Comparison of Three Popular Exercise Modalities on V˙O2max in Overweight and Obese.

INTRODUCTION: In this prospective randomized trial, we examined the effect of three popular exercise training modalities on maximal oxygen uptake (V˙O2max) in overweight and obese individuals. In addition, we examined possible concomitant adaptations in endurance exercise performance (time to exhaustion (TTE)), citrate synthase (CS) activity, venous and arterial function, blood volume, and calculated stroke volume (SV). METHODS: Thirty subjects were recruited (age, 41 ± 9 yr; weight, 91 ± 14 kg; height, 173 ± 8 cm; body mass index, 30 ± 4 kg·m(-2)) and randomized to either 6 wk of 4 × 4-min high-intensity interval training (4HIIT) at 85%-95% of HRmax, 10 × 1-min HIIT (1HIIT) at V˙O2max load, or 45-min moderate-intensity continuous training (MICT) at 70% of HRmax. V˙O2max, TTE, CS activity, venous and arterial function, as well as blood volume were measured before and after the training period. O2 pulse was calculated and used to estimate SV. Analysis was conducted per protocol. RESULTS: Only 4HIIT increased V˙O2max (P < 0.01) and significantly more compared with 1HIIT (P = 0.04) and MICT (P = 0.03) (4HIIT, 10%; 1HIIT, 3.3%; and MICT, 3.1%). All groups increased TTE (4HIIT, 198%; 1HIIT, 116%; MICT, 52%), with a higher increase after 4HIIT compared with that after MICT (P = 0.02). Calculated SV increased only after 4HIIT (14.4%). Plasma volume and hemoglobin mass increased after 1HIIT only (5.6% and 6.5%); however, no group differences were found. All groups increased CS activity (4HIIT, 35%; 1HIIT, 35%; MICT, 56%), with no group differences. Arterial inflow (15.7%) and venous outflow (22.7%) decreased after MICT, but there were no group differences. CONCLUSIONS: 4HIIT was superior to 1HIIT and MICT in improving V˙O2max likely because of an increased SV.

Effect of Change in VO2max on Daily Total Energy Expenditure in a Cohort of Norwegian Men: A Randomized Pilot Study.

OBJECTIVE: To investigate how a change in VO2max induced through 6 weeks of high intensity aerobic interval training affects daily total energy expenditure (TEE), active energy expenditure (AEE) and mitochondrial function in people not previously exposed to structured high intensity aerobic interval training (AIT). METHODS: Thirty healthy males (39±6 yrs) not exposed to structured exercise training were randomized to either 1x4 min AIT (1-AIT), 4x4 min AIT (4-AIT), both at 90-95% maximum heart rate (HRmax) or 47 min of MCT at 70% HRmax. TEE, AEE, number of steps, active time, sedentary time, VO2max and mitochondrial function in m. vastus lateralis were measured before and after intervention. RESULTS: TEE increased 14% (p=0.014) and AEE increased 43% (p= 0.004) after MCT. There was no change in TEE or AEE after 1-AIT or 4-AIT, but 1-AIT had significantly lower TEE (p=0.033) and step-count (p=0.011) compared to MCT post intervention. VO2max increased 7% after 1-AIT (p= 0.004) and 9% after 4-AIT (p=0.004), with no change after MCT. No change was observed in maximal mitochondrial respiration (VMAX) or Citrate Synthase (CS) activity within or between interventions. Basal respiration (V0) increased after 1-AIT (p=0.029) and 4-AIT (p=0.022), with no significant change after MCT. CONCLUSION: AIT interventions that increase VO2max, do not stimulate subjects to increase TEE or AEE. The intensity of exercise seems to play apart, as MCT increased TEE and AEE and AIT did not. Emphasis should be placed on the importance of maintaining everyday activities when introducing structured exercise training to untrained individuals.

How to Be 80 Year Old and Have a VO2max of a 35 Year Old.

UNLABELLED: Background. To discuss the cardiovascular and pulmonary physiology and common risk factors of an 80-year-old man with a world record maximal oxygen uptake of 50 mL·kg(-1)·min(-1). Methods. CASE REPORT: Results. His maximal oxygen uptake of 3.31 L·min(-1), maximal heart rate of 175 beats·min(-1), and maximal oxygen pulse of 19 mL·beats(-1) are high. He is lean (66.6 kg) and muscular (49% skeletal muscle mass). His echo parameters of mitral flow (left ventricular filling, E = 82 cm·s(-1) and E/A = 1.2) were normal for 40- to 60-year-old men. Systolic and diastolic function increased adequately during exercise, with no increase in left ventricular filling pressure. He has excellent pulmonary function (FVC = 4.31 L, FEV1 = 3.41, FEV1/FVC = 0.79, and DLCO = 12.0 Si(1)) and normal FMD and blood volumes (5.8 L). He has a high level of daily activity (10,900 steps·day(-1) and 2:51 hours·day(-1) of physical activity) and a lifelong history of physical activity. Conclusion. The man is in excellent cardiopulmonary fitness and is highly physically active. His cardiac and pulmonary functions are above expectations for his age, and his VO2max is comparable to that of an inactive 25-year-old and of a normal, active 35-year-old Norwegian man.

Heart failure with preserved ejection fraction induces molecular, mitochondrial, histological, and functional alterations in rat respiratory and limb skeletal muscle.

AIMS: Peripheral muscle dysfunction is a key mechanism contributing to exercise intolerance (i.e. breathlessness and fatigue) in heart failure patients with preserved ejection fraction (HFpEF); however, the underlying molecular and cellular mechanisms remain unknown. We therefore used an animal model to elucidate potential molecular, mitochondrial, histological, and functional alterations induced by HFpEF in the diaphragm and soleus, while also determining the possible benefits associated with exercise training. METHODS AND RESULTS: Female Dahl salt-sensitive rats were fed a low (CON; n = 10) or high salt (HFpEF; n = 11) diet of 0.3% or 8% NaCl, respectively, or a high salt diet in combination with treadmill exercise training (n = 11). Compared with low-salt rats, high-salt rats developed (P < 0.05) HFpEF. Compared with CON, the diaphragm of HFpEF rats demonstrated (P < 0.05): a fibre type shift from fast-to-slow twitch; fibre atrophy; a decreased pro-oxidative but increased anti-oxidant capacity; reduced proteasome activation; impaired in situ mitochondrial respiration; and in vitro muscle weakness and increased fatigability. The soleus also demonstrated numerous alterations (P < 0.05), including fibre atrophy, decreased anti-oxidant capacity, reduced mitochondrial density, and increased fatigability. Exercise training, however, prevented mitochondrial and functional impairments in both the diaphragm and soleus (P < 0.05). CONCLUSION: Our findings are the first to demonstrate that HFpEF induces significant molecular, mitochondrial, histological, and functional alterations in the diaphragm and soleus, which were attenuated by exercise training. These data therefore reveal novel mechanisms and potential therapeutic treatments of exercise intolerance in HFpEF.

A randomised controlled study of the long-term effects of exercise training on mortality in elderly people: study protocol for the Generation 100 study.

INTRODUCTION: Epidemiological studies suggest that exercise has a tremendous preventative effect on morbidity and premature death, but these findings need to be confirmed by randomised trials. Generation 100 is a randomised, controlled study where the primary aim is to evaluate the effects of 5 years of exercise training on mortality in an elderly population. METHODS AND ANALYSIS: All men and women born in the years 1936-1942 (n=6966), who were residents of Trondheim, Norway, were invited to participate. Between August 2012 and June 2013, a total of 1567 individuals (790 women) were included and randomised to either 5 years of two weekly sessions of high-intensity training (10 min warm-up followed by 4×4 min intervals at ∼90% of peak heart rate) or, moderate-intensity training (50 min of continuous work at ∼70% of peak heart rate), or to a control group that followed physical activity advice according to national recommendations. Clinical examinations, physical tests and questionnaires will be administered to all participants at baseline, and after 1, 3 and 5 years. Participants will also be followed up by linking to health registries until year 2035. ETHICS AND DISSEMINATION: The study has been conducted according to the SPIRIT statement. All participants signed a written consent form, and the study has been approved by the Regional Committee for Medical Research Ethics, Norway. Projects such as this are warranted in the literature, and we expect that data from this study will result in numerous papers published in world-leading clinical journals; we will also present the results at international and national conferences. TRIAL REGISTRATION NUMBER: Clinicaltrials.gov NCT01666340.

Remote ischemic preconditioning preserves mitochondrial function and activates pro-survival protein kinase Akt in the left ventricle during cardiac surgery: a randomized trial.

BACKGROUND: Understanding the intracellular mechanisms induced by remote ischemic preconditioning (RIPC) in the human left ventricle opens new possibilities for development of pharmacological cardioprotection against ischemia and reperfusion injury. In this study we investigated the effects of RIPC on mitochondrial function, activation of pro-survival protein kinase Akt and microRNA expression in left ventricular biopsies from patients undergoing coronary artery bypass surgery (CABG). METHODS: Sixty patients were randomized to control (n=30) or RIPC (n=30). A blood pressure cuff was applied to the arm of all patients preoperatively. The cuff remained deflated in control group, whereas RIPC was performed by 3 cycles of cuff inflation to 200 mm Hg for 5 min, separated by 5 min deflation intervals. Left ventricular biopsies were obtained before and 15 min after aortic declamping. The primary outcome was mitochondrial respiration measured in situ. Secondary outcomes were activation of protein kinase Akt, assessed by western immunoblotting, and expression of microRNAs assessed by array and real-time polymerase chain reaction. RESULTS: Mitochondrial respiration was preserved during surgery in patients receiving RIPC (+0.2 µmol O2/min/g, p=0.69), and reduced by 15% in controls (-1.5 µmol O2/min/g, p=0.02). Furthermore, RIPC activated protein kinase Akt before aortic clamping (difference from control +43.3%, p=0.04), followed by increased phosphorylation of Akt substrates at reperfusion (+26.8%, p<0.01). No differences were observed in microRNA expression. CONCLUSIONS: RIPC preserves mitochondrial function and activates pro-survival protein kinase Akt in left ventricle of patients undergoing CABG. Modulation of mitochondrial function and Akt activation should be further explored as cardioprotective drug targets. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov, unique identifier: NCT01308138.