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Abstract: Purpose: Cardiac rehabilitation participation rates are low despite strong recommendations, and many chronic heart failure patients remain physically inactive. Rural living, long travel distance, costs, age, and frailty might be factors explaining this. To increase cardiac rehabilitation uptake, we designed an exercise-based randomized controlled telerehabilitation trial enabling chronic heart failure patients unable or unwilling to participate in outpatient cardiac rehabilitation to exercise at home. Aim was to evaluate the long-term effects of telerehabilitation on physical activity levels.Methods and results: CHF patients (n = 61) with reduced (≤40%), mildly reduced (41-49%), or preserved ejection fraction (≥50%) were randomized (1:1) to telerehabilitation (n = 31) with an initial 3-month group-based high-intensity exercise telerehabilitation program or control (n = 30), with regular follow-up visits over a 2-year period. All participants attended a "Living with heart failure" course. Outcomes were measures of physical activity, peak oxygen uptake, 6-minute walk test distance, quality of life, morbidity, and mortality. We found no significant differences between groups for long-term changes in moderate to vigorous activity (MVPA) or peak oxygen uptake from baseline to the 2-year follow-up. Nor quality of life differed between groups, but both groups had significant within-group improvements in score on the Minnesota living with heart failure questionnaire (p = 0.000) and improvement in EQ-5D VAS score was significant (p = 0.05) in the telerehabilitation group.Conclusions: Telerehabilitation performed as home-based real-time high-intensity exercise sessions provided by videoconferencing for participants unable or unwilling to participate in standard outpatient cardiac rehabilitation did not affect long-term physical activity levels or physical capacity as expected. Still, a positive effect on health-related quality of life was seen in both groups., Competing Interests: Conflict of Interest and Funding Source: The work was supported by funds from the Liaison Committee of Central Norway Regional Health Authority and the Norwegian University of Science and Technology and the National Association for Heart and Lung Diseases. The authors declare no conflicts of interest., (Copyright © 2024 by the American College of Sports Medicine.)

Aims: The aims of this sub-study of the SMARTEX trial were (1) to evaluate the effects of a 12-week exercise training programme on serum levels of high sensitivity cardiac troponin I (hs-cTnI) in patients with moderate chronic heart failure (CHF), in New York Heart Association class II-III with reduced ejection fraction (HFrEF) and (2) to explore the associations with left ventricular remodelling, functional capacity and filling pressures measured with N-terminal pro brain natriuretic peptide (NT-proBNP)., Methods and Results: In this sub-study, 196 patients were randomly assigned to high intensity interval training (HIIT, n = 70), moderate continuous training (MCT, n = 59) or recommendation of regular exercise (RRE), (n = 67) for 12 weeks. To reveal potential difference between structured intervention and control, HIIT and MCT groups were merged and named supervised exercise training (SET) group. The RRE group constituted the control group (CG). To avoid contributing factors to myocardial injury, we also evaluated changes in patients without additional co-morbidities (atrial fibrillation, hypertension, diabetes mellitus, and chronic obstructive pulmonary disease). The relationship between hs-cTnI and left ventricular end-diastolic diameter (LVEDD), VO 2peak , and NT-proBNP was analysed by linear mixed models. At 12 weeks, Hs-cTnI levels were modestly but significantly reduced in the SET group from median 11.9 ng/L (interquartile ratio, IQR 7.1-21.8) to 11.5 ng/L (IQR 7.0-20.7), P = 0.030. There was no between-group difference (SET vs. CG, P = 0.116). There was a numerical but not significant reduction in hs-cTnI for the whole population (P = 0.067) after 12 weeks. For the sub-group of patients without additional co-morbidities, there was a significant between-group difference: SET group (delta -1.2 ng/L, IQR -2.7 to 0.1) versus CG (delta -0.1 ng/L, IQR -0.4 to 0.7), P = 0.007. In the SET group, hs-cTnI changed from 10.9 ng/L (IQR 6.0-22.7) to 9.2 ng/L (IQR 5.2-20.5) (P = 0.002), whereas there was no change in the CG (6.4 to 5.8 ng/L, P = 0.64). Changes in hs-cTnI (all patients) were significantly associated with changes in; LVEDD, VO 2peak , and NT-proBNP, respectively., Conclusions: In patients with stable HFrEF, 12 weeks of structured exercise intervention was associated with a modest, but significant reduction of hs-cTnI. There was no significant difference between intervention group and control group. In the sub-group of patients without additional co-morbidities, this difference was highly significant. The alterations in hs-cTnI were associated with reduction of LVEDD and natriuretic peptide concentrations as well as improved functional capacity., (© 2024 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Exercise is an important component of rehabilitation care for patients with heart failure with preserved ejection fraction (HFpEF). However, it is unclear which type of physical rehabilitation exercise is most effective. Thus, the aim of this study was to determine the relative effects of different types of exercise interventions on aerobic capacity measured by peak oxygen consumption (VO 2 peak; in mL/kg·min) in patients with HFpEF. We searched different electronic databases until December 2020 for randomized controlled trials that evaluated the effects of different types of exercise interventions on VO 2 peak of patients with HFpEF. Mean difference, standardized mean difference (SMD), and 95% confidence intervals (CIs) were calculated. Fixed and random-effects Bayesian network meta-analysis was used to compare the relative effectiveness of the different exercise interventions. Nineteen studies met the study criteria, including 720 patients. Comparing the physical rehabilitation interventions with usual care (control group), inspiratory muscle training was the highest ranked exercise intervention with an SMD of 3.6 mL/kg·min (95% CI, 2.3-4.8), followed by the group undergoing high-intensity interval training with a significant pooled improvement in VO 2 peak 3.5 (95% CI, 2.6-4.4) and combined aerobic and resistance exercise with an SMD of 3.2 (95% CI, 1.4-5.0). The inspiratory muscle training, high-intensity interval training, and combined aerobic and resistance exercise were the highest ranked physical rehabilitation intervention to improve VO 2 peak. These interventions should be considered as a component in the care of patients with HFpEF. Registration: https://www.crd.york.ac.uk/PROSPERO/ ; Unique identifier: CRD42021256442., Competing Interests: Disclosure: The authors declare no conflict of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Plasma concentrations of cardiac troponins increase in healthy individuals after strenuous training, but the response to lower exercise intensities has not been characterized., Aim: To determine whether exercise at moderate intensity significantly increases plasma cardiac troponins measured with different assays in healthy recreational athletes., Methods: Twenty-four self-reported healthy volunteers were instructed to complete three 60-min bouts of treadmill running at variable intensities: High-intensity training (HIT) including a maximal exercise test and an anaerobic threshold test followed by training at 80%-95% of maximum heart rate (HR max ), Moderate-intensity training (MIT) at 60%-75% of HR max , and Low-intensity training (LIT) at 45%-55% of HR max . Blood samples were collected before and at 2, 4, and 6 h after HIT and 4 h after MIT and LIT. Troponin I and T were measured in plasma samples with assays from Abbot, Siemens, and Roche., Results: Plasma troponins measured with all assays were significantly increased compared to baseline after HIT but not after LIT. After HIT, the fraction of all participants with one or more values above the assay-specific 99th percentiles ranged from 13% to 61%. The biomarker criteria for acute myocardial injury were met after HIT for troponin T in 75% of female participants having no clinical evidence of coronary artery disease., Conclusion: High-intensity, but not moderate- or low-intensity, training for 60 min induced a potentially clinically significant increase in plasma cardiac troponins in healthy volunteers. Results exceeding the population 99th percentiles were most frequent with the troponin T assay., (© 2023 The Authors. Scandinavian Journal of Medicine & Science In Sports published by John Wiley & Sons Ltd.)

Aims: Despite strong recommendations, outpatient cardiac rehabilitation is underused in chronic heart failure (CHF) patients. Possible barriers are frailty, accessibility, and rural living, which may be overcome by telerehabilitation. We designed a randomized, controlled trial to evaluate the feasibility of a 3-month real-time, home-based telerehabilitation, high-intensity exercise programme for CHF patients who are either unable or unwilling to participate in standard outpatient cardiac rehabilitation and to explore outcomes of self-efficacy and physical fitness at 3 months post-intervention., Methods and Results: CHF patients with reduced (≤40%), mildly reduced (41-49%), or preserved ejection fraction (≥50%) (n = 61) were randomized 1:1 to telerehabilitation or control in a prospective controlled trial. The telerehabilitation group (n = 31) received real-time, home-based, high-intensity exercise for 3 months. Inclusion criteria were (i) ≥18 years, (ii) New York Heart Association class II-III, stable on optimized medical therapy for >4 weeks, and (iii) N-terminal pro-brain natriuretic peptide >300 ng/L. All participants participated in a 2-day 'Living with heart failure' course. No other intervention beyond standard care was provided for controls. Outcome measures were adherence, adverse events, self-reported outcome measures, the general perceived self-efficacy scale, peak oxygen uptake (VO 2peak ) and a 6-min walk test (6MWT). The mean age was 67.6 (11.3) years, and 18% were women. Most of the telerehabilitation group (80%) was adherent or partly adherent. No adverse events were reported during supervised exercise. Ninety-six per cent (26/27) reported that they felt safe during real-time, home-based telerehabilitation, high-intensity exercise, and 96% (24/25) reported that, after the home-based supervised telerehabilitation, they were motivated to participate in further exercise training. More than half the population (15/26) reported minor technical issues with the videoconferencing software. 6MWT distance increased significantly in the telerehabilitation group (19 m, P = 0.02), whereas a significant decrease in VO 2peak (-0.72 mL/kg/min, P = 0.03) was observed in the control group. There were no significant differences between the groups in general perceived self-efficacy scale, VO 2peak , and 6MWT distance after intervention or at 3 months post-intervention., Conclusions: Home-based telerehabilitation was feasible in chronic heart failure patients inaccessible for outpatient cardiac rehabilitation. Most participants were adherent when given more time and felt safe exercising at home under supervision, and no adverse events occurred. The trial suggests that telerehabilitation can increase the use of cardiac rehabilitation, but the clinical benefit of telerehabilitation must be evaluated in larger trials., (© 2023 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Exercise for heart failure (HF) with reduced ejection fraction (HFrEF) is recommended by guidelines, but exercise mode and intensities are not differentiated between HF etiologies. We, therefore, investigated the effect of moderate or high intensity exercise on left ventricular end-diastolic diameter (LVEDD), left ventricular ejection fraction (LVEF) and maximal exercise capacity (peak VO 2 ) in patients with ischemic cardiomyopathy (ICM) and non-ischemic cardiomyopathy (NICM)., Methods: The Study of Myocardial Recovery after Exercise Training in Heart Failure (SMARTEX-HF) consecutively enrolled 231 patients with HFrEF (LVEF ≤ 35 %, NYHA II-III) in a 12-weeks supervised exercise program. Patients were stratified for HFrEF etiology (ICM versus NICM) and randomly assigned (1:1:1) to supervised exercise thrice weekly: a) moderate continuous training (MCT) at 60-70 % of peak heart rate (HR), b) high intensity interval training (HIIIT) at 90-95 % peak HR, or c) recommendation of regular exercise (RRE) according to guidelines. LVEDD, LVEF and peak VO 2 were assessed at baseline, after 12 and 52 weeks., Results: 215 patients completed the intervention. ICM (59 %; n = 126) compared to NICM patients (41 %; n = 89) had significantly lower peak VO 2 values at baseline and after 12 weeks (difference in peak VO 2 2.2 mL/(kg*min); p < 0.0005) without differences between time points (p = 0.11) or training groups (p = 0.15). Etiology did not influence changes of LVEDD or LVEF (p = 0.30; p = 0.12), even when adjusting for sex, age and smoking status (p = 0.54; p = 0.12). Similar findings were observed after 52 weeks., Conclusions: Etiology of HFrEF did not influence the effects of moderate or high intensity exercise on cardiac dimensions, systolic function or exercise capacity., Clinical Trial Registration–url: http://www.clinicaltrials.gov. Unique identifier: NCT00917046., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 Published by Elsevier Inc.)

Aims: To investigate the associations of cardiorespiratory fitness with cardiac, vascular, renal and cardiorenal characteristics in chronic heart failure in a telerehabilitation randomized clinical trial. Secondly, to evaluate the associations of cardiorenal syndrome with the effects of exercise., Methods and Results: Sixty-nine heart failure patients attended baseline examination, and 61 patients were randomly assigned 1:1 to 3-month telerehabilitation or control. Data were collected at baseline and 3-month post-intervention, including echocardiography and vascular ultrasound, laboratory tests, exercise test with peak oxygen consumption (VO 2peak ) measurement and 6-min walk test (6MWT). Baseline VO 2peak and 6MWT distance was 0.85 mL*min -1 *kg -1 lower and 20 m shorter per 10 mL/min/1.73m 2 lower estimated glomerular filtration rate (both P < 0.001). Heart failure patients with cardiorenal syndrome had 3.5 (1.1) mL*min -1 *kg -1 lower VO 2peak and diastolic dysfunction grade 2-3, and elevated filling pressure was >50% more common compared with those without (all P < 0.05). At the 3-month post-intervention follow-up, only the non-CRS patients in the intervention group increased VO 2peak (0.73 (0.51) mL*min -1 *kg -1 ), whereas VO 2peak in the CRS subpopulation of controls decreased (-1.34 (0.43) mL*min -1 *kg -1 ). Cardiorenal syndrome was associated with a decrease in VO 2peak in CRS patients compared with non-CRS patients, -0.91 (0.31) vs. 0.39 (0.35) mL*min -1 *kg -1 respectively, P = 0.013., Conclusions: Cardiorenal syndrome was negatively associated with VO 2peak and 6MWT distance in chronic HF, and the associations were stronger than for heart failure phenotypes and other characteristics. The effect of exercise was negatively associated with cardiorenal syndrome. Exercise seems to be as important in heart failure patients with cardiorenal syndrome, and future studies should include CRS patients to reveal the most beneficial type of exercise., (© 2022 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Skeletal muscle (SM) alterations contribute to exercise intolerance in heart failure patients with preserved (HFpEF) or reduced (HFrEF) left ventricular ejection fraction (LVEF). Protein degradation via the ubiquitin-proteasome-system (UPS), nuclear apoptosis, and reduced mitochondrial energy supply is associated with SM weakness in HFrEF. These mechanisms are incompletely studied in HFpEF, and a direct comparison between these groups is missing., Methods and Results: Patients with HFpEF (LVEF ≥ 50%, septal E/e' > 15 or >8 and NT-proBNP > 220 pg/mL, n = 20), HFrEF (LVEF ≤ 35%, n = 20) and sedentary control subjects (Con, n = 12) were studied. Inflammatory markers were measured in serum, and markers of the UPS, nuclear apoptosis, and energy metabolism were determined in percutaneous SM biopsies. Both HFpEF and HFrEF showed increased proteolysis (MuRF-1 protein expression, ubiquitination, and proteasome activity) with proteasome activity significantly related to interleukin-6. Proteolysis was more pronounced in patients with lower exercise capacity as indicated by peak oxygen uptake in per cent predicted below the median. Markers of apoptosis did not differ between groups. Mitochondrial energy supply was reduced in HFpEF and HFrEF (complex-I activity: -31% and -53%; malate dehydrogenase activity: -20% and -29%; both P < 0.05 vs. Con). In contrast, short-term energy supply via creatine kinase was increased in HFpEF but decreased in HFrEF (47% and -45%; P < 0.05 vs. Con)., Conclusions: Similarly to HFrEF, skeletal muscle in HFpEF is characterized by increased proteolysis linked to systemic inflammation and reduced exercise capacity. Energy metabolism is disturbed in both groups; however, its regulation seems to be severity-dependent., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: Whether an exercise training intervention is associated with reduction in long-term high-sensitivity cardiac troponin T (hs-cTnT) concentration (a biomarker of subclinical myocardial injury) in patients with heart failure with reduced ejection fraction (HFrEF) is unknown. The aims were to determine (i) the effect of a 12 week endurance exercise training intervention with different training intensities on hs-cTnT in stable patients with HFrEF (left ventricular ejection fraction ≤ 35%) and (ii) associations between hs-cTnT and peak oxygen uptake (VO 2peak )., Methods and Results: In this sub-study of the SMARTEX-HF trial originally including 261 patients from nine European centres, 213 eligible patients were included after withdrawals and appropriate exclusions [19% women, mean age 61.2 years (standard deviation: 11.9)], randomized to high-intensity interval training (HIIT; n = 77), moderate continuous training (MCT; n = 63), or a recommendation of regular exercise (RRE; n = 73). Hs-cTnT measurements and clinical data acquired before (BL) and after a 12 week exercise training intervention (12 weeks) and at 1 year follow-up (1 year) were analysed using multivariable mixed models. Baseline hs-cTnT was above the 99th percentile upper reference limit of 14 ng/L in 35 (48%), 35 (56%), and 49 (64%) patients in the RRE, MCT, and HIIT groups, respectively. Median hs-cTnT was 16 ng/L at BL, 14 ng/L at 12 weeks, and 14 ng/L at 1 year. Hs-cTnT was statistically significantly reduced at 12 weeks in a model adjusted for randomization group, centre and VO 2peak , and after further adjustment in the final model that also included age, sex, creatinine concentrations, N-terminal pro-brain natriuretic peptide, smoking, and heart failure treatment. The mean reduction from BL to 12 weeks in the final model was 1.1 ng/L (95% confidence interval: 1.0-1.2 ng/L, P < 0.001), and the reduction was maintained at 1 year with a mean reduction from BL to 1 year of 1.1 ng/L (95% confidence interval: 1.0-1.1 ng/L, P = 0.025). Randomization group was not associated with hs-cTnT at any time point (overall test: P = 0.20, MCT vs. RRE: P = 0.81, HIIT vs. RRE: P = 0.095, interaction time × randomization group: P = 0.88). Independent of time point, higher VO 2peak correlated with lower hs-cTnT (mean reduction over all time points: 0.2 ng/L per increasing mL·kg -1 ·min -1 , P = 0.002), without between-group differences (P = 0.19)., Conclusions: In patients with stable HFrEF, a 12 week exercise intervention was associated with reduced hs-cTnT in all groups when adjusted for clinical variables. Higher VO 2peak correlated with lower hs-cTnT, suggesting a positive long-term effect of increasing VO 2peak on subclinical myocardial injury in HFrEF, independent of training programme., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: Endurance training improves aerobic fitness and cardiac function in individuals with heart failure. However, the underlying mechanisms are not well characterized. Exercise training could therefore act as a tool to discover novel targets for heart failure treatment. We aimed to associate changes in Ca 2+ handling and electrophysiology with micro-RNA (miRNA) profile in exercise trained heart failure rats to establish which miRNAs induce heart failure-like effects in Ca 2+ handling and electrophysiology., Methods and Results: Post-myocardial infarction (MI) heart failure was induced in Sprague Dawley rats. Rats with MI were randomized to sedentary control (sed), moderate (mod)- or high-intensity (high) endurance training for 8 weeks. Exercise training improved cardiac function, Ca 2+ handling and electrophysiology including reduced susceptibility to arrhythmia in an exercise intensity-dependent manner where high intensity gave a larger effect. Fifty-five miRNAs were significantly regulated (up or down) in MI-sed, of which 18 and 3 were changed towards Sham-sed in MI-high and MI-mod, respectively. Thereafter we experimentally altered expression of these "exercise-miRNAs" individually in human induced pluripotent stem cell-derived cardiomyocytes (hIPSC-CM) in the same direction as they were changed in MI. Of the "exercise-miRNAs", miR-214-3p prolonged AP duration, whereas miR-140 and miR-208a shortened AP duration. miR-497-5p prolonged Ca 2+ release whereas miR-214-3p and miR-31a-5p prolonged Ca 2+ decay., Conclusion: Using exercise training as a tool, we discovered that miR-214-3p, miR-497-5p, miR-31a-5p contribute to heart-failure like behaviour in Ca 2+ handling and electrophysiology and could be potential treatment targets., (Copyright © 2020. Published by Elsevier Ltd.)

Objectives. Heart failure (HF) impairs resting myocardial energetics, myocardial mitochondrial performance, and maximal oxygen uptake (VO 2max ). Exercise training is included in most rehabilitation programs and benefits HF patients. However, the effect of exercise intensity on cardiac mitochondrial respiration and concentrations of the key bioenergetic metabolites phosphocreatine (PCr), adenosine triphosphate (ATP), and inorganic phosphate (Pi) is unclear. This study aimed to investigate the effects of exercise training at different intensities in rats with HF. Methods. Rats underwent myocardial infarction or sham operations and were divided into three subgroups: sedentary, moderate intensity, or high intensity. The impact of HF and 6 weeks of exercise training on energy metabolism was evaluated by 31 P magnetic resonance spectroscopy and mitochondrial respirometry. The concentrations of PCr, ATP, and Pi were quantified by magnetic resonance spectroscopy. VO 2max was measured by treadmill respirometry. Results. Exercise training increased VO 2max in sham and HF. PCr/ATP ratio was reduced in HF ( p  < .01) and remained unchanged by exercise training. PCr concentration was significantly lower in HF compared to sham ( p  < .01). Moderate and high-intensity exercise training increased ATP in HF and sham. HF impaired complex I (CI) and complex II ( p  = .034) respiration. High-intensity exercise training recovered CI respiration in HF rats compared to HF sedentary ( p  = .014). Conclusions. Exercise training improved cardiac performance, as indicated by increased VO 2max and higher exercise capacity, without changing the myocardial PCr/ATP ratio. These observations suggest that the PCr/ATP biomarker is not suited to evaluate the beneficial effects of exercise training in the heart. The exact mechanisms require further investigations, as exercise training did increase ATP levels and CI respiration.

Purpose: This study aimed to investigate baseline, exercise testing, and exercise training-mediated predictors of change in peak oxygen uptake (V˙O2peak) from baseline to 12-wk follow-up (ΔV˙O2peak) in a post hoc analysis from the SMARTEX Heart Failure trial., Methods: We studied 215 patients with heart failure with left ventricular ejection fraction (LVEF) ≤35%, and New York Heart Association (NYHA) classes II-III who were randomized to either supervised high-intensity interval training with exercise target intensity of 90%-95% of peak heart rate (HRpeak) or supervised moderate continuous training (MCT) with target intensity of 60%-70% of HRpeak, or who received a recommendation of regular exercise on their own. Predictors of ΔV˙O2peak were assessed in two models: a logistic regression model comparing highest and lowest tertiles (baseline parameters) and a multivariate linear regression model (test/training/clinical parameters)., Results: The change in V˙O2peak in response to the interventions (ΔV˙O2peak) varied substantially, from -8.50 to +11.30 mL·kg·min. Baseline NYHA (class II gave higher odds vs III; odds ratio (OR), 7.1 (2.0-24.9); P = 0.002), LVEF (OR per percent, 1.1 (1.0-1.2); P = 0.005), and age (OR per 10 yr, 0.5 (0.3-0.8); P = 0.003) were associated with ΔV˙O2peak.In the multivariate linear regression, 34% of the variability in ΔV˙O2peak was explained by the increase in exercise training workload, ΔHRpeak between baseline and 12-wk posttesting, age, and ever having smoked., Conclusion: Exercise training response (ΔV˙O2peak) correlated negatively with age, LVEF, and NYHA class. The ability to increase workload during the training period and increased ΔHRpeak between baseline and the 12-wk test were associated with a positive outcome.

Purpose of Review: The aim of this study was to determine the effects of aerobic exercise on peak oxygen uptake (peak VO 2 ), minute ventilation/carbon dioxide production (VE/VCO 2 slope), and health-related quality of life (HRQoL) among patients with heart failure (HF) and preserved ejection fraction (HFpEF)., Recent Findings: We conducted a Cochrane Library, MEDLINE/PubMed, Physiotherapy Evidence Database, and SciELO search (from 1985 to May 2019) for randomized controlled trials that evaluated the effects of aerobic exercise in HFpEF patients. We calculated the mean differences (MD) and 95% confidence interval (CI). Ten intervention studies were included providing a total of 399 patients. Compared with control, aerobic exercise resulted in improvement in peak VO 2 MD 1.9 mL kg -1  min -1 (95% CI 1.3 to 2.5; N = 314) and HRQoL measured by Minnesota Living with Heart Failure MD 5.4 (95% CI - 10.5 to - 0.2; N = 256). No significant difference in VE/VCO 2 slope was found between participants in the aerobic exercise group and the control group. The quality of evidence for peak VO 2 and HRQoL was assessed as being moderate. Aerobic exercise moderately improves peak VO 2 and HRQoL and should be considered a strategy of rehabilitation of HFpEF individuals.

Objective: The aim of this study was to investigate the effects of combined aerobic and resistance training on peak oxygen consumption (peak VO 2 ), minute ventilation/carbon dioxide production (VE/VCO 2 slope), muscle strength and health-related quality of life (HRQoL) in heart failure patients with reduced left ventricular ejection fraction (HFrEF)., Methods: We searched Cochrane, Pubmed, and PEDro (from the earliest date available to September 2018) for RCTs that evaluated the effects of combined aerobic and resistance training in HFrEF patients. Weighted mean differences (WMD), standardized mean difference (SMD), and 95% confidence interval (CI) were calculated., Results: 39 studies met the study criteria, including 2008 patients, 14 compared combined aerobic and resistance training versus aerobic training, and 25 compared combined aerobic and resistance training versus control. Compared to aerobic training, combined aerobic and resistance training resulted in improvement in muscle strength SMD 0.7 (95% CI: 0.3 to 1.0 N = 167) and, HRQoL WMD -2.6 (95% CI: -5.0 to -0.1 N = 138). A nonsignificant difference in peak VO 2 and VE/VCO 2 slope was found for participants in the combined aerobic and resistance training group compared with aerobic training group. Compared to control, combined aerobic and resistance training resulted in improvement in peak VO 2 WMD 2.9 (95% CI: 1.6 to 4.4 N = 638), muscle strength SMD 0.64 (95% CI: 0.4 to 0.9 N = 315) and, HRQoL WMD -9.8 (95% CI: -15.2 to -4.5 N = 524)., Conclusions: Combined aerobic and resistance training improves peak VO 2 , muscle strength and HRQoL and should be considered as a component of care of HFrEF patients., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objective: To investigate whether C-reactive protein (CRP, a general marker of inflammation), neopterin (activated macrophages), lactoferrin (activated neutrophils), and endothelial function (flow-mediated vasodilation [FMD]) are associated with cardiorespiratory fitness (peak oxygen uptake [VO 2peak ]), sex, body mass index (BMI), and the metabolic syndrome (MetSyn) in a healthy adult population., Patients and Methods: This was a cross-sectional association study based on the population-based HUNT3 Fitness Study performed from May 15, 2007, through June 23, 2008. Seven hundred forty self-reported healthy respondents (327 women) identified as having the MetSyn were age- and sex-matched with 692 controls (307 women) from the same cohort. Associations between the inflammatory biomarkers and VO 2peak , FMD, and the MetSyn were analyzed by multivariate linear regression., Results: The CRP level was negatively associated with VO 2peak (P<.001), positively associated with the MetSyn (with a stronger effect in men) (P<.001) and BMI (with a stronger effect in women) (P<.01), but not with FMD (P=.34). Lactoferrin was positively associated with the MetSyn (P<.001), but neither neopterin nor lactoferrin were associated with VO 2peak or FMD., Conclusion: The CRP level was strongly associated with VO 2peak and the MetSyn, but not with FMD. The associations among inflammation, VO 2peak , and the MetSyn were strongly influenced by sex and BMI. These data support that low cardiorespiratory fitness should be considered an etiologic factor contributing to systemic inflammation and that reducing body weight and improving VO 2peak are methods that may positively affect CRP levels., (Copyright © 2018 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

The metabolism and performance of myocardial and skeletal muscle are impaired in heart failure (HF) patients. Exercise training improves the performance and benefits the quality of life in HF patients. The purpose of the present study was to determine the metabolic profiles in myocardial and skeletal muscle in HF and exercise training using MRS, and thus to identify targets for clinical MRS in vivo. After surgically establishing HF in rats, we randomized the rats to exercise training programs of different intensities. After the final training session, rats were sacrificed and tissues from the myocardial and skeletal muscle were extracted. Magnetic resonance spectra were acquired from these extracts, and principal component and metabolic enrichment analysis were used to assess the differences in metabolic profiles. The results indicated that HF affected myocardial metabolism by changing multiple metabolites, whereas it had a limited effect on skeletal muscle metabolism. Moreover, exercise training mainly altered the metabolite distribution in skeletal muscle, indicating regulation of metabolic pathways of taurine and hypotaurine metabolism and carnitine synthesis.

The importance of cardiorespiratory fitness (CRF) is now well established and it is increasingly being recognized as an essential variable which should be assessed in health screenings. The key findings that have established the clinical significance of CRF are reviewed in this report, along with an overview of the current relevance of exercise as a form of medicine that can provide a number of positive health outcomes, including increasing CRF. Current assessment options for assessing CRF are also reviewed, including the direct measurement via cardiopulmonary exercise testing which now can be interpreted with age and sex-specific reference values. Future directions for the use of CRF and related measures are presented., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: Exercise training increases aerobic capacity and is beneficial for health, whereas low aerobic exercise capacity is a strong independent predictor of cardiovascular disease and premature death. The purpose of the present study was to determine the metabolic profiles in a rat model of inborn low versus high capacity runners (LCR/HCR) and to determine the effect of inborn aerobic capacity, aging, and exercise training on skeletal muscle metabolic profile., Methods: LCR/HCR rats were randomized to high intensity low volume interval treadmill training twice a week or sedentary control for 3 or 11 months before they were sacrificed, at 9 and 18 months of age, respectively. Magnetic resonance spectra were acquired from soleus muscle extracts, and partial least square discriminative analysis was used to determine the differences in metabolic profile., Results: Sedentary HCR rats had 54% and 30% higher VO2max compared to sedentary LCR rats at 9 months and 18 months, respectively. In HCR, exercise increased running speed significantly, and VO2max was higher at age of 9 months, compared to sedentary counterparts. In LCR, changes were small and did not reach the level of significance. The metabolic profile was significantly different in the LCR sedentary group compared to the HCR sedentary group at the age of 9 and 18 months, with higher glutamine and glutamate levels (9 months) and lower lactate level (18 months) in HCR. Irrespective of fitness level, aging was associated with increased soleus muscle concentrations of glycerophosphocholine and glucose. Interval training did not influence metabolic profiles in LCR or HCR rats at any age., Conclusion: Differences in inborn aerobic capacity gave the most marked contrasts in metabolic profile, there were also some changes with ageing. Low volume high intensity interval training twice a week had no detectable effect on metabolic profile., Competing Interests: The authors have declared that no competing interests exist.

Objective: The aim of this study was to investigate the effects of high intensity interval training (HIIT) versus moderate intensity continuous training (MICT) in heart failure patients with reduced ejection fraction (HFrEF)., Background: Despite the well-known positive effects of exercise in heart failure patients, the best mode of exercise is still under discussion., Methods: We searched Pubmed/MEDLINE, Cochrane Central Register of Controlled Trials, PEDro data base, and SciELO (from the earliest date available to October 2017) for randomized controlled trials that evaluated the effects of HIIT versus MICT in HFrEF patients. Weighted mean differences (WMD) with 95% confidence interval (CI) were calculated, and heterogeneity was assessed using the I 2 test., Results: 13 studies met the study criteria, including 411 patients. Compared to MICT, HIIT resulted in improvement in Peak VO 2 WMD (1.35 mL·kg -1 ·min -1 95% CI: 0.03 to 2.64 N = 411). HIIT resulted in no difference in VE/VCO 2 slope WMD (-1.21 95% CI: -3.0 to 0.58 N = 135), and quality of life measured by Minnesota Living with Heart Failure questionnaire WMD (1.19 95% CI: -5.81 to 8.19 N = 79). Sub-group analyses comparing studies with and without isocaloric exercise training protocol also showed a nonsignificant difference in peak VO 2 for participants in the HIIT group compared with MICT group., Conclusions: HIIT improves peak VO 2 and should be considered as a component of care of HFrEF patients. However, its superiority versus MICT disappears when isocaloric protocols are compared. An important caveat is uncertainty and variation of actual training intensities compared to program targets., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Aims: Cellular processes in the heart rely mainly on studies from experimental animal models or explanted hearts from patients with terminal end-stage heart failure (HF). To address this limitation, we provide data on excitation contraction coupling, cardiomyocyte contraction and relaxation, and Ca 2+ handling in post-myocardial-infarction (MI) patients at mid-stage of HF., Methods and Results: Nine MI patients and eight control patients without MI (non-MI) were included. Biopsies were taken from the left ventricular myocardium and processed for further measurements with epifluorescence and confocal microscopy. Cardiomyocyte function was progressively impaired in MI cardiomyocytes compared with non-MI cardiomyocytes when increasing electrical stimulation towards frequencies that simulate heart rates during physical activity (2 Hz); at 3 Hz, we observed almost total breakdown of function in MI. Concurrently, we observed impaired Ca 2+ handling with more spontaneous Ca 2+ release events, increased diastolic Ca 2+ , lower Ca 2+ amplitude, and prolonged time to diastolic Ca 2+ removal in MI (P < 0.01). Significantly reduced transverse-tubule density (-35%, P < 0.01) and sarcoplasmic reticulum Ca 2+ adenosine triphosphatase 2a (SERCA2a) function (-26%, P < 0.01) in MI cardiomyocytes may explain the findings. Reduced protein phosphorylation of phospholamban (PLB) serine-16 and threonine-17 in MI provides further mechanisms to the reduced function., Conclusions: Depressed cardiomyocyte contraction and relaxation were associated with impaired intracellular Ca 2+ handling due to impaired SERCA2a activity caused by a combination of alteration in the PLB/SERCA2a ratio and chronic dephosphorylation of PLB as well as loss of transverse tubules, which disrupts normal intracellular Ca 2+ homeostasis and handling. This is the first study that presents these mechanisms from viable and intact cardiomyocytes isolated from the left ventricle of human hearts at mid-stage of post-MI HF., (© 2018 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)

Background: Small studies have suggested that high-intensity interval training (HIIT) is superior to moderate continuous training (MCT) in reversing cardiac remodeling and increasing aerobic capacity in patients with heart failure with reduced ejection fraction. The present multicenter trial compared 12 weeks of supervised interventions of HIIT, MCT, or a recommendation of regular exercise (RRE)., Methods: Two hundred sixty-one patients with left ventricular ejection fraction ≤35% and New York Heart Association class II to III were randomly assigned to HIIT at 90% to 95% of maximal heart rate, MCT at 60% to 70% of maximal heart rate, or RRE. Thereafter, patients were encouraged to continue exercising on their own. Clinical assessments were performed at baseline, after the intervention, and at follow-up after 52 weeks. Primary end point was a between-group comparison of change in left ventricular end-diastolic diameter from baseline to 12 weeks., Results: Groups did not differ in age (median, 60 years), sex (19% women), ischemic pathogenesis (59%), or medication. Change in left ventricular end-diastolic diameter from baseline to 12 weeks was not different between HIIT and MCT ( P =0.45); left ventricular end-diastolic diameter changes compared with RRE were -2.8 mm (-5.2 to -0.4 mm; P =0.02) in HIIT and -1.2 mm (-3.6 to 1.2 mm; P =0.34) in MCT. There was also no difference between HIIT and MCT in peak oxygen uptake ( P =0.70), but both were superior to RRE. However, none of these changes was maintained at follow-up after 52 weeks. Serious adverse events were not statistically different during supervised intervention or at follow-up at 52 weeks (HIIT, 39%; MCT, 25%; RRE, 34%; P =0.16). Training records showed that 51% of patients exercised below prescribed target during supervised HIIT and 80% above target in MCT., Conclusions: HIIT was not superior to MCT in changing left ventricular remodeling or aerobic capacity, and its feasibility remains unresolved in patients with heart failure., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00917046., (© 2017 The Authors.)

Background: Reduced endothelial function is associated with elevated risk of cardiovascular disease, but evidence on the association between migraine and endothelial function is conflicting. The aim of this population-based study was to examine the relationship between flow-mediated dilatation (FMD) and migraine with aura, migraine without aura and tension-type headache., Methods: In the third Nord-Trøndelag Healthy Study (HUNT3) FMD was measured by ultrasound during reactive hyperaemia of the brachial artery in a sample of 4739 healthy adult participants, 3929 of whom answered headache questions. The cross-sectional association between different headache diagnoses and FMD was evaluated by logistic regression, using a categorical approach., Results: Mean FMD did not differ between the headache groups and headache-free controls. In multi-adjusted analyses, no consistent association was found between FMD quintiles and headache groups., Conclusions: There was no relationship between FMD and migraine or other headache diagnoses in this large cross-sectional study of otherwise healthy respondents including freedom from pulmonary and cardiovascular diseases., (© International Headache Society 2016.)

Background: Oral tobacco (snuff) is taking a large market share in Scandinavia, especially with young users. However, long-term health effects are unknown. Small studies show association between snuff and reduced endothelial function, representing an early stage of vascular injury that often precedes manifest cardiovascular disease by several years. We therefore determined the associations between snuff and endothelial function in a large sample of healthy Norwegian men., Methods and Design: In the Fitness substudy of the Nord-Trøndelag Health Study (HUNT3), endothelial function was measured by flow-mediated dilation (FMD). Aerobic fitness was measured by peak oxygen uptake (VO2peak). A cross-sectional design including 1 592 self-reported healthy men compared these observations with records of present tobacco use, standard cardiovascular risk factors, and socioeconomic status, using general linear models., Results: FMD was lower in snuff users (FMD: 4.12%, 3.63, 4.61) compared to non-users (FMD: 4.52%, 4.27, 4.78) after adjustment for age (difference: -0.57%, -1.12, -0.01). After further adjustment for potential confounders, FMD still tended to be lower in snuff users than in non-users (difference: -0.53%, -1.09, 0.02). This difference was even more pronounced in the inactive snuff users (-0.83%, -1.59, -0.06) and in the low fit snuff users (-0.74%, CI -0.55, 0.079)., Conclusions: Oral tobacco is associated with a tendency towards reduced endothelial function, indicating vascular changes that precede cardiovascular disease. The strongest associations were found in men with low physical activity or reduced aerobic fitness.

Background: Evidence on the association between headache and physical fitness is conflicting. The aim of this population-based study was to examine the relationship between peak oxygen uptake (VO2peak) and headache, including migraine and tension-type headache (TTH)., Methods: In the third Nord-Trøndelag Health study (HUNT3), VO2peak was measured by ergospirometry in a sample of 4631 healthy adult participants. Of these, 3899 (54% women) also answered headache questions. The cross-sectional association between headache and VO2peak was evaluated by logistic regression using a categorical approach based on quintiles. Scores in the upper quintile were used as reference., Results: Participants age 20-50 years had significant trends of increasing prevalence of any headache ( ITALIC! p < 0.001), migraine ( ITALIC! p < 0.001), TTH ( ITALIC! p = 0.002) and unclassified headache ( ITALIC! p = 0.027) with lower VO2peak. The highest prevalence odds ratios (ORs) were found in those with VO2peak in the lower quintile: For any headache the OR was 2.3 (95% confidence interval (1.6-3.3), for TTH 1.8 (1.2-2.8), for unclassified headache 1.9 (1.1-3.8), and for migraine 3.7 (2.1-6.6). Similar results were also found among those who reported physical activity levels in accordance with current recommendations of the American College of Sports Medicine but nevertheless had low VO2peak. Being in the lowest VO2peak quintile was also strongly associated with migraine aggravated by physical activity (OR 4.1, 2.1-8.1). No significant association was found between VO2peak and headache for those 50 years or older., Conclusions: In this large cross-sectional study, an inverse relationship was found between VO2peak and headache for adults younger than 50 years of age., (© International Headache Society 2015.)