Exploring shared genetics between maximal oxygen uptake and disease: the HUNT study.

Low cardiorespiratory fitness, measured as maximal oxygen uptake (V̇o2max), is associated with all-cause mortality and disease-specific morbidity and mortality and is estimated to have a large genetic component (∼60%). However, the underlying mechanisms explaining the associations are not known, and no association study has assessed shared genetics between directly measured V̇o2max and disease. We believe that identifying the mechanisms explaining how low V̇o2max is related to increased disease risk can contribute to prevention and therapy. We used a phenome-wide association study approach to test for shared genetics. A total of 64,479 participants from the Trøndelag Health Study (HUNT) were included. Genetic variants previously linked to V̇o2max were tested for association with diseases related to the cardiovascular system, diabetes, dementia, mental disorders, and cancer as well as clinical measurements and biomarkers from HUNT. In the total population, three single-nucleotide polymorphisms (SNPs) in and near the follicle-stimulating hormone receptor gene (FSHR) were found to be associated (false discovery rate < 0.05) with serum creatinine levels and one intronic SNP in the Rap-associating DIL domain gene (RADIL) with diabetes type 1 with neurological manifestations. In males, four intronic SNPs in the PBX/knotted homeobox 2 gene (PKNOX2) were found to be associated with endocarditis. None of the association tests in the female population reached overall statistical significance; the associations with the lowest P values included other cardiac conduction disorders, subdural hemorrhage, and myocarditis. The results might suggest shared genetics between V̇o2max and disease. However, further effort should be put into investigating the potential shared genetics between inborn V̇o2max and disease in larger cohorts to increase statistical power.NEW & NOTEWORTHY To our knowledge, this is the first genetic association study exploring how genes linked to cardiorespiratory fitness (CRF) relate to disease risk. By investigating shared genetics, we found indications that genetic variants linked to directly measured CRF also affect the level of blood creatinine, risk of diabetes, and endocarditis. Less certain findings showed that genetic variants of high CRF might cause lower body mass index, healthier HDL cholesterol, and lower resting heart rate.

Diastolic function and cardiovascular risk among patients with severe obesity referred to a lifestyle-program - a pilot study.

Objectives. Severe obesity is associated with a high risk of comorbidities and alterations of cardiac structure and function. The primary aim of the study was to investigate the proportion of diastolic dysfunction (DD) at baseline, and changes in cardiac function from baseline (T1) to 6 months follow-up (T2) among participants with severe obesity attending a lifestyle-intervention. The secondary aim was to explore changes in body mass index (BMI), physical fitness (VO2peak) and cardiovascular risk from T1 to T2 and 12 months follow-up (T3).Design. This was an open single-site prospective observational study. Patients were recruited from an obesity clinic to a lifestyle-intervention consisting of three 3-weeks intermittent stays over 12-months period. Echocardiography was performed at T1 and T2 and BMI, VO2peak and cardiovascular risk measured at T1, T2 and T3.Results. Fifty-six patients were included (mean age 45.1 years; BMI 41.9). Six of 52 patients (12%) had grade 1 DD at T1, while five subjects had DD at T2. E/A ratio (11%, p = .005) and mitral deceleration time (9%, p = .014) were improved at T2. A reduction in BMI (-1.8, p < .001) and improvement in VO2peak (1.6 mL/kg min, p = .026) were assessed at T2 and this improvement persisted at T3. The total cardiovascular risk score was not significantly changed.Conclusion. The patients with severe obesity had low prevalence of DD. For all participants, an improvement in diastolic parameters, and an important initial weight loss was observed.Clinical Trial number: NCT02826122.

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.

Longitudinal study of the effect of a 5-year exercise intervention on structural brain complexity in older adults. A Generation 100 substudy.

Physical inactivity has been identified as an important risk factor for dementia. High levels of cardiorespiratory fitness (CRF) have been shown to reduce the risk of dementia. However, the mechanism by which exercise affects brain health is still debated. Fractal dimension (FD) is an index that quantifies the structural complexity of the brain. The purpose of this study was to investigate the effects of a 5-year exercise intervention on the structural complexity of the brain, measured through the FD, in a subset of 105 healthy older adults participating in the randomized controlled trial Generation 100 Study. The subjects were randomized into control, moderate intensity continuous training, and high intensity interval training groups. Both brain MRI and CRF were acquired at baseline and at 1-, 3- and 5-years follow-ups. Cortical thickness and volume data were extracted with FreeSurfer, and FD of the cortical lobes, cerebral and cerebellar gray and white matter were computed. CRF was measured as peak oxygen uptake (VO2peak) using ergospirometry during graded maximal exercise testing. Linear mixed models were used to investigate exercise group differences and possible CRF effects on the brain's structural complexity. Associations between change over time in CRF and FD were performed if there was a significant association between CRF and FD. There were no effects of group membership on the structural complexity. However, we found a positive association between CRF and the cerebral gray matter FD (p < 0.001) and the temporal lobe gray matter FD (p < 0.001). This effect was not present for cortical thickness, suggesting that FD is a more sensitive index of structural changes. The change over time in CRF was associated with the change in temporal lobe gray matter FD from baseline to 5-year follow-up (p < 0.05). No association of the change was found between CRF and cerebral gray matter FD. These results demonstrated that entering old age with high and preserved CRF levels protected against loss of structural complexity in areas sensitive to aging and age-related pathology.

The association of change in peak oxygen uptake with use of psychotropics in community-dwelling older adults - The Generation 100 study.

BACKGROUND: The use of psychotropics is high among the older population and may have detrimental effects on their physical and mental health. Cardiorespiratory fitness (CRF) is a strong and modifiable measure of health and declines with age. We aimed to study the association of change in CRF with use of psychotropics in community-dwelling older adults. METHODS: We analyzed longitudinal data from 1531 older adults from the Generation 100 study, aged 70-77 years at inclusion, and with a permanent address in Trondheim, Norway. Data on objectively measured peak oxygen uptake (VO2peak) were linked with register data from the Norwegian Prescription Database on prescribed psychotropics. The included psychotropics were antidepressants (N06A), antipsychotics (N05A), anxiolytics (N05B), hypnotics and sedatives (N05C), and N03AE (benzodiazepine derivatives). Analyses were done on any psychotropics as one group, and on the following separate groups: antidepressants (N06A), benzodiazepines (N05BA, N05CD, and N03AE), and z-hypnotics (N05CF). Peak oxygen uptake was measured four times over a five-year period and corresponding medication use was measured as defined daily doses (DDD). A random effects estimator was applied to investigate the association of change in VO2peak with the use of psychotropics. RESULTS: We found a statistically significant curvilinear association of change in VO2peak with use of any psychotropics and antidepressants. For VO2peak up to ~ 40 ml/kg/min, each 1 ml/kg/min increase was associated by a 3.3 DDD and 2.5 DDD decrease in use of any psychotropics and antidepressants, respectively. A bottoming-out effect was found and increases in VO2peak above ~ 40 ml/kg/min showed increased use of any psychotropics and antidepressants. However, the association of change in VO2peak with use was stronger for changes in the lower continuum of VO2peak levels and decreased with increasing VO2peak. No statistically significant association of change in VO2peak with use of benzodiazepines and z-hypnotics were found. However, because of a non-randomized design, we cannot rule out the possibility of confounding by indication. CONCLUSIONS: The results of this study show a curvilinear association of change in VO2peak with use of any psychotropics and antidepressants in older adults. This relationship adds a new viewpoint on the adverse effects of psychotropic use and should be considered in interventions and policies aimed at reducing psychotropic medication use among the older population.

Circulating MicroRNA-210 Concentrations in Patients with Acute Heart Failure: Data from the Akershus Cardiac Examination 2 Study.

BACKGROUND: MicroRNA (miR)-210 expression is induced by acute and chronic hypoxia and provides prognostic information in patients with aortic stenosis and acute coronary syndrome. We hypothesized that circulating miR-210 concentrations could provide diagnostic and prognostic information in patients with acute heart failure (HF). METHODS: We measured miR-210 concentrations in serum samples on admission from 314 patients hospitalized for acute dyspnea and 9 healthy control subjects. The diagnostic and prognostic properties of miR-210 were tested in patients after adjudication of all diagnoses and with median follow-up of 464 days. RESULTS: All patients and control subjects had miR-210 concentrations within the range of detection, and the analytical variation was low as the coefficient of variation of synthetic spike-in RNA was 4%. Circulating miR-210 concentrations were increased in patients with HF compared to healthy control subjects, but miR-210 concentrations did not separate patients with acute HF (n = 143) from patients with non-HF-related dyspnea (n = 171): the area under the curve was 0.50 (95% CI 0.43-0.57). Circulating miR-210 concentrations were associated with mortality (n = 114) after adjustment for clinical risk factors (hazard ratio 1.65 [95% CI 1.03-2.62] per unit miR-210 increase), but this association was attenuated and not significant after adjustment for established cardiac protein biomarkers. CONCLUSIONS: Circulating miR-210 concentrations are associated with mortality, but do not add to established protein biomarkers for diagnosis or prognosis in patients with acute dyspnea.

Genome wide association study of response to interval and continuous exercise training: the Predict-HIIT study.

BACKGROUND: Low cardiorespiratory fitness (V̇O2peak) is highly associated with chronic disease and mortality from all causes. Whilst exercise training is recommended in health guidelines to improve V̇O2peak, there is considerable inter-individual variability in the V̇O2peak response to the same dose of exercise. Understanding how genetic factors contribute to V̇O2peak training response may improve personalisation of exercise programs. The aim of this study was to identify genetic variants that are associated with the magnitude of V̇O2peak response following exercise training. METHODS: Participant change in objectively measured V̇O2peak from 18 different interventions was obtained from a multi-centre study (Predict-HIIT). A genome-wide association study was completed (n = 507), and a polygenic predictor score (PPS) was developed using alleles from single nucleotide polymorphisms (SNPs) significantly associated (P < 1 × 10-5) with the magnitude of V̇O2peak response. Findings were tested in an independent validation study (n = 39) and compared to previous research. RESULTS: No variants at the genome-wide significance level were found after adjusting for key covariates (baseline V̇O2peak, individual study, principal components which were significantly associated with the trait). A Quantile-Quantile plot indicates there was minor inflation in the study. Twelve novel loci showed a trend of association with V̇O2peak response that reached suggestive significance (P < 1 × 10-5). The strongest association was found near the membrane associated guanylate kinase, WW and PDZ domain containing 2 (MAGI2) gene (rs6959961, P = 2.61 × 10-7). A PPS created from the 12 lead SNPs was unable to predict V̇O2peak response in a tenfold cross validation, or in an independent (n = 39) validation study (P > 0.1). Significant correlations were found for beta coefficients of variants in the Predict-HIIT (P < 1 × 10-4) and the validation study (P < × 10-6), indicating that general effects of the loci exist, and that with a higher statistical power, more significant genetic associations may become apparent. CONCLUSIONS: Ongoing research and validation of current and previous findings is needed to determine if genetics does play a large role in V̇O2peak response variance, and whether genomic predictors for V̇O2peak response trainability can inform evidence-based clinical practice. Trial registration Australian New Zealand Clinical Trials Registry (ANZCTR), Trial Id: ACTRN12618000501246, Date Registered: 06/04/2018, http://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=374601&isReview=true .

Faster age-related decline in cardiorespiratory fitness in rheumatoid arthritis patients: an observational study in the Trøndelag Health Study.

Primary aim: Compare change in estimated cardiorespiratory fitness (eCRF change) in rheumatoid arthritis (RA) patients with population-based age- and sex-matched controls during ~ 11-year follow-up and identify variables associated with eCRF change. Secondary aim: Compare eCRF level in RA patients and controls. eCRF change from the second (HUNT2 1995-1997) to the third (HUNT3 2006-2008) surveys of the Norwegian Trøndelag Health Study was compared between RA patients (n = 188) and controls (n = 26,202) attending both surveys. Predictors of eCRF change were identified by Lasso regression followed by multiple linear regression. Mean eCRF level in RA patients (n = 436) and controls (n = 67,910) was compared using age-adjusted linear regression stratified on sex, as well as two-sample t tests including RA patients (n = 432) and controls (n = 59,124) who attended either HUNT2, HUNT3 or both HUNT2 and HUNT3. The mean eCRF decline from HUNT2 to HUNT3 in RA patients was 8.3 mL min-1 kg-1 versus 6.7 mL min-1 kg-1 in controls (p < 0.001). The decline was faster in RA patients and larger with higher baseline age (standardized regression coefficient for RA patients: (- 0.482 × age + 0.044); controls: (- 0.367 × age, p < 0.001). The decline was also associated with smoking, cardiovascular disease, increasing body mass index, asthma, and hypertension. Mean differences in age-adjusted eCRF level for RA patients versus controls (p < 0.001): women HUNT2: - 3.2 mL min-1 kg-1; HUNT3: - 5.0 mL min-1 kg-1; men HUNT2: - 1.8 mL min-1 kg-1; HUNT3: - 4.0 mL min-1 kg-1. Higher age at baseline was associated with faster decline in eCRF. This change was more pronounced in RA patients than controls, indicating a larger negative effect on fitness of aging in RA. RA patients had lower eCRF compared to healthy individuals.

Variability of echocardiographic measures of left ventricular diastolic function. The HUNT study.

OBJECTIVE: Investigate variability related to image acquisition and reading process for echocardiographic measures of left ventricular (LV) diastolic function, and its influence on classification of LV diastolic dysfunction (LVDD). METHODS: Forty participants (19 women) mean age 62 (28-88) years underwent echocardiographic examinations twice by different echocardiographers and blinded analyses by four readers in a cross-sectional design. Measurements included quantification of two- (2D) and three-dimensional (3D) recordings of the left atrium (LA) (maximal) volume (LAVmax ) and spectral Doppler blood flow and tissue velocities for assessment of LV diastolic function. Variability and reproducibility measures were calculated using variance component analyses and Kappa statistics. RESULTS: Image acquisition influenced variability more than image reading (mean 24% and 4% of variance, respectively), but variability from image reading was especially important for 2D LAVmax (16% of variance) compared to 4% for 3D LAVmax , which was reflected in better agreement for 3D measures. The variability of measures used in classification of LVDD had clinical significance, and agreement across the four raters in classification using current recommendations was only fair (Kappa 0.42), but the agreement improved when using 3D LAVmax (Kappa 0.58). Agreement and reliability measures were reported for all measures. CONCLUSION: Performing a new image acquisition influenced variability more than a introducing a new image reader, but there were differences across the different measures. LAVmax by 3D is superior to 2D with respect to lower variability. The variability of diastolic measures influences the reliability of LVDD classification, and this should be taken into account in the everyday clinic.

Physical activity, cardiorespiratory fitness, and cardiovascular outcomes in individuals with atrial fibrillation: the HUNT study.

AIMS: Atrial fibrillation (AF) confers higher risk of mortality and morbidity, but the long-term impact of physical activity (PA) and cardiorespiratory fitness (CRF) on outcomes in AF patients is unknown. We, therefore, examined the prospective associations of PA and estimated CRF (eCRF) with all-cause mortality, cardiovascular disease (CVD) mortality, morbidity and stroke in individuals with AF. METHODS AND RESULTS: We followed 1117 AF patients from the HUNT3 study in 2006-08 until first occurrence of the outcomes or end of follow-up in November 2015. We used Cox proportional hazard regression to examine the prospective associations of self-reported PA and eCRF with the outcomes. Atrial fibrillation patients meeting PA guidelines had lower risk of all-cause [hazard ratio (HR) 0.55, 95% confidence interval (CI) 0.41-0.75] and CVD mortality (HR 0.54, 95% CI 0.34-0.86) compared with inactive patients. The respective HRs for CVD morbidity and stroke were 0.78 (95% CI 0.58-1.04) and 0.70 (95% CI 0.42-1.15). Each 1-metabolic equivalent task (MET) higher eCRF was associated with a lower risk of all-cause (HR 0.88, 95% CI 0.81-0.95), CVD mortality (HR 0.85, 95% CI 0.76-0.95), and morbidity (HR 0.88, 95% CI 0.82-0.95). CONCLUSION: Higher PA and CRF are associated with lower long-term risk of CVD and all-cause mortality in individuals with AF. The findings support a role for regular PA and improved CRF in AF patients, in order to combat the elevated risk for mortality and morbidity.

Effect of High-Intensity Interval Training, Moderate Continuous Training, or Guideline-Based Physical Activity Advice on Peak Oxygen Consumption in Patients With Heart Failure With Preserved Ejection Fraction: A Randomized Clinical Trial.

Importance: Endurance exercise is effective in improving peak oxygen consumption (peak V̇o2) in patients with heart failure with preserved ejection fraction (HFpEF). However, it remains unknown whether differing modes of exercise have different effects. Objective: To determine whether high-intensity interval training, moderate continuous training, and guideline-based advice on physical activity have different effects on change in peak V̇o2 in patients with HFpEF. Design, Setting, and Participants: Randomized clinical trial at 5 sites (Berlin, Leipzig, and Munich, Germany; Antwerp, Belgium; and Trondheim, Norway) from July 2014 to September 2018. From 532 screened patients, 180 sedentary patients with chronic, stable HFpEF were enrolled. Outcomes were analyzed by core laboratories blinded to treatment groups; however, the patients and staff conducting the evaluations were not blinded. Interventions: Patients were randomly assigned (1:1:1; n = 60 per group) to high-intensity interval training (3 × 38 minutes/week), moderate continuous training (5 × 40 minutes/week), or guideline control (1-time advice on physical activity according to guidelines) for 12 months (3 months in clinic followed by 9 months telemedically supervised home-based exercise). Main Outcomes and Measures: Primary end point was change in peak V̇o2 after 3 months, with the minimal clinically important difference set at 2.5 mL/kg/min. Secondary end points included changes in metrics of cardiorespiratory fitness, diastolic function, and natriuretic peptides after 3 and 12 months. Results: Among 180 patients who were randomized (mean age, 70 years; 120 women [67%]), 166 (92%) and 154 (86%) completed evaluation at 3 and 12 months, respectively. Change in peak V̇o2 over 3 months for high-intensity interval training vs guideline control was 1.1 vs -0.6 mL/kg/min (difference, 1.5 [95% CI, 0.4 to 2.7]); for moderate continuous training vs guideline control, 1.6 vs -0.6 mL/kg/min (difference, 2.0 [95% CI, 0.9 to 3.1]); and for high-intensity interval training vs moderate continuous training, 1.1 vs 1.6 mL/kg/min (difference, -0.4 [95% CI, -1.4 to 0.6]). No comparisons were statistically significant after 12 months. There were no significant changes in diastolic function or natriuretic peptides. Acute coronary syndrome was recorded in 4 high-intensity interval training patients (7%), 3 moderate continuous training patients (5%), and 5 guideline control patients (8%). Conclusions and Relevance: Among patients with HFpEF, there was no statistically significant difference in change in peak V̇o2 at 3 months between those assigned to high-intensity interval vs moderate continuous training, and neither group met the prespecified minimal clinically important difference compared with the guideline control. These findings do not support either high-intensity interval training or moderate continuous training compared with guideline-based physical activity for patients with HFpEF. Trial Registration: ClinicalTrials.gov Identifier: NCT02078947.

Differences in Acceleration and High-Intensity Activities Between Small-Sided Games and Peak Periods of Official Matches in Elite Soccer Players.

ABSTRACT: Dalen, T, Sandmæl, S, Stevens, TGA, Hjelde, GH, Kjøsnes, TN, and Wisløff, U. Differences in acceleration and high-intensity activities between small-sided games and peak periods of official matches in elite soccer players. J Strength Cond Res 35(7): 2018-2024, 2021-The purpose of this study was to compare whether the physical performance of players during 4 vs. 4 + goalkeeper (4 vs. 4) and 6 vs. 6 + goalkeeper (6 vs. 6) small-sided games (SSGs) is equivalent to those experienced during the most intense 5-minute period of soccer match play. Twenty-six male soccer players from an elite Norwegian league team took part. Players were monitored during 18 matches, 56 SSGs: twenty-eight 4 vs. 4 and twenty-eight 6 vs. 6 games. The ZXY Sport Tracking System was used to measure for each player the total distance covered, high-intensity running distance, sprint distance, number of accelerations, and player load (all expressed per minute). To compare the physical performance variables on players during the SSGs formats and match play, a 1-way analysis of variance with repeated measures was used. Players performed the same number of accelerations and player load in 4 vs. 4 (1.7 and 248, respectively) as in peak match (1.6 and 227, respectively), whereas in 6 vs. 6, there were 63% fewer accelerations and 15% lower player load (1.2 and 198, respectively), than in peak match. High-intensity running and sprint distance were significantly lower than mean match values in both 4 vs. 4 (4.1 and 0.2 m vs. 8.2 and 1.7 m) and 6 vs. 6 games (2.7 and 0.21 m vs. 8.2 and 1.7 m) (p < 0.05). In conclusion, only 4 vs. 4 SSGs are highly valuable, and in that, they elicit player load and accelerations to a level that is (at least) equivalent with peak periods of official match play.

Exercise training reveals micro-RNAs associated with improved cardiac function and electrophysiology in rats with heart failure after myocardial infarction.

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 Ca2+ handling and electrophysiology with micro-RNA (miRNA) profile in exercise trained heart failure rats to establish which miRNAs induce heart failure-like effects in Ca2+ 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, Ca2+ 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 Ca2+ release whereas miR-214-3p and miR-31a-5p prolonged Ca2+ 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 Ca2+ handling and electrophysiology and could be potential treatment targets.

HIITing the brain with exercise: mechanisms, consequences and practical recommendations.

The increasing number of older adults has seen a corresponding growth in those affected by neurovascular diseases, including stroke and dementia. Since cures are currently unavailable, major efforts in improving brain health need to focus on prevention, with emphasis on modifiable risk factors such as promoting physical activity. Moderate-intensity continuous training (MICT) paradigms have been shown to confer vascular benefits translating into improved musculoskeletal, cardiopulmonary and cerebrovascular function. However, the time commitment associated with MICT is a potential barrier to participation, and high-intensity interval training (HIIT) has since emerged as a more time-efficient mode of exercise that can promote similar if not indeed superior improvements in cardiorespiratory fitness for a given training volume and further promote vascular adaptation. However, randomised controlled trials (RCTs) investigating the impact of HIIT on the brain are surprisingly limited. The present review outlines how the HIIT paradigm has evolved from a historical perspective and describes the established physiological changes including its mechanistic bases. Given the dearth of RCTs, the vascular benefits of MICT are discussed with a focus on the translational neuroprotective benefits including their mechanistic bases that could be further potentiated through HIIT. Safety implications are highlighted and components of an optimal HIIT intervention are discussed including practical recommendations. Finally, statistical effect sizes have been calculated to allow prospective research to be appropriately powered and optimise the potential for detecting treatment effects. Future RCTs that focus on the potential clinical benefits of HIIT are encouraged given the prevalence of cognitive decline in an ever-ageing population.

Peak oxygen uptake and incident coronary heart disease in a healthy population: the HUNT Fitness Study.

AIMS: The majority of previous research on the association between cardiorespiratory fitness (CRF) and cardiovascular disease (CVD) is based on indirect assessment of CRF in clinically referred predominantly male populations. Therefore, our aim was to examine the associations between VO2peak measured by the gold-standard method of cardiopulmonary exercise testing and fatal and non-fatal coronary heart disease (CHD) in a healthy and fit population. METHODS AND RESULTS: Data on VO2peak from 4527 adults (51% women) with no previous history of cardiovascular or lung disease, cancer, and hypertension or use of antihypertensive medications participating in a large population-based health-study (The HUNT3 Study), were linked to hospital registries and the cause of death registry. Average VO2peak was 36.0 mL/kg/min and 44.4 mL/kg/min among women and men, and 83.5% had low 10-year risk of CVD at baseline. Average follow-up was 8.8 years, and 147 participants reached the primary endpoint. Multi-adjusted Cox-regression showed 15% lower risk for the primary endpoint per one-MET (metabolic equivalent task) higher VO2peak [hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.77-0.93], with similar results across sex. The highest quartile of VO2peak had 48% lower risk of event compared with the lowest quartile (multi-adjusted HR 0.52, 95% CI 0.33-0.82). Oxygen pulse and ventilatory equivalents of oxygen and carbon dioxide also showed significant predictive value for the primary endpoint. CONCLUSION: VO2peak was strongly and inversely associated with CHD across the whole fitness continuum in a low-risk population sample. Increasing VO2peak may have substantial benefits in reducing the burden of CHD.

The role of fibroblast - Cardiomyocyte interaction for atrial dysfunction in HFpEF and hypertensive heart disease.

AIMS: Atrial contractile dysfunction is associated with increased mortality in heart failure (HF). We have shown previously that a metabolic syndrome-based model of HFpEF and a model of hypertensive heart disease (HHD) have impaired left atrial (LA) function in vivo (rat). In this study we postulate, that left atrial cardiomyocyte (CM) and cardiac fibroblast (CF) paracrine interaction related to the inositol 1,4,5-trisphosphate signalling cascade is pivotal for the manifestation of atrial mechanical dysfunction in HF and that quantitative atrial remodeling is highly disease-dependent. METHODS AND RESULTS: Differential remodeling was observed in HHD and HFpEF as indicated by an increase of atrial size in vivo (HFpEF), unchanged fibrosis (HHD and HFpEF) and a decrease of CM size (HHD). Baseline contractile performance of rat CM in vitro was enhanced in HFpEF. Upon treatment with conditioned medium from their respective stretched CF (CM-SF), CM (at 21 weeks) of WT showed increased Ca2+ transient (CaT) amplitudes related to the paracrine activity of the inotrope endothelin (ET-1) and inositol 1,4,5-trisphosphate induced Ca2+ release. Concentration of ET-1 was increased in CM-SF and atrial tissue from WT as compared to HHD and HFpEF. In HHD, CM-SF had no relevant effect on CaT kinetics. However, in HFpEF, CM-SF increased diastolic Ca2+ and slowed Ca2+ removal, potentially contributing to an in-vivo decompensation. During disease progression (i.e. at 27 weeks), HFpEF displayed dysfunctional excitation-contraction-coupling (ECC) due to lower sarcoplasmic-reticulum Ca2+ content unrelated to CF-CM interaction or ET-1, but associated with enhanced nuclear [Ca2+]. In human patients, tissue ET-1 was not related to the presence of arterial hypertension or obesity. CONCLUSIONS: Atrial remodeling is a complex entity that is highly disease and stage dependent. The activity of fibrosis related to paracrine interaction (e.g. ET-1) might contribute to in vitro and in vivo atrial dysfunction. However, during later stages of disease, ECC is impaired unrelated to CF.

Targeting miR-423-5p Reverses Exercise Training-Induced HCN4 Channel Remodeling and Sinus Bradycardia.

RATIONALE: Downregulation of the pacemaking ion channel, HCN4 (hyperpolarization-activated cyclic nucleotide gated channel 4), and the corresponding ionic current, If, underlies exercise training-induced sinus bradycardia in rodents. If this occurs in humans, it could explain the increased incidence of bradyarrhythmias in veteran athletes, and it will be important to understand the underlying processes. OBJECTIVE: To test the role of HCN4 in the training-induced bradycardia in human athletes and investigate the role of microRNAs (miRs) in the repression of HCN4. METHODS AND RESULTS: As in rodents, the intrinsic heart rate was significantly lower in human athletes than in nonathletes, and in all subjects, the rate-lowering effect of the HCN selective blocker, ivabradine, was significantly correlated with the intrinsic heart rate, consistent with HCN repression in athletes. Next-generation sequencing and quantitative real-time reverse transcription polymerase chain reaction showed remodeling of miRs in the sinus node of swim-trained mice. Computational predictions highlighted a prominent role for miR-423-5p. Interaction between miR-423-5p and HCN4 was confirmed by a dose-dependent reduction in HCN4 3'-untranslated region luciferase reporter activity on cotransfection with precursor miR-423-5p (abolished by mutation of predicted recognition elements). Knockdown of miR-423-5p with anti-miR-423-5p reversed training-induced bradycardia via rescue of HCN4 and If. Further experiments showed that in the sinus node of swim-trained mice, upregulation of miR-423-5p (intronic miR) and its host gene, NSRP1, is driven by an upregulation of the transcription factor Nkx2.5. CONCLUSIONS: HCN remodeling likely occurs in human athletes, as well as in rodent models. miR-423-5p contributes to training-induced bradycardia by targeting HCN4. This work presents the first evidence of miR control of HCN4 and heart rate. miR-423-5p could be a therapeutic target for pathological sinus node dysfunction in veteran athletes.

Effects of Endurance Training on Detrimental Structural, Cellular, and Functional Alterations in Skeletal Muscles of Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is underpinned by detrimental skeletal muscle alterations that contribute to disease severity, yet underlying mechanisms and therapeutic treatments remain poorly established. This study used a nonhuman animal model of HFpEF to better understand whether skeletal muscle abnormalities were (1) fiber-type specific and (2) reversible by various exercise training regimes. METHODS AND RESULTS: Lean control rats were compared with obese ZSF1 rats at 20 weeks and then 8 weeks after sedentary, high-intensity interval training, or moderate continuous treadmill exercise. Oxidative soleus and glycolytic extensor digitorum longus (EDL) muscles were assessed for fiber size, capillarity, glycolytic metabolism, autophagy, and contractile function. HFpEF reduced fiber size and capillarity by 20%-50% (P < .05) in both soleus and EDL, but these effects were not reversed by endurance training. In contrast, both endurance training regimes in HFpEF attenuated the elevated lactate dehydrogenase activity observed in the soleus. Autophagy was down-regulated in EDL and up-regulated in soleus (P < .05), with no influence of endurance training. HFpEF impaired contractile forces of both muscles by ∼20% (P < .05), and these were not reversed by training. CONCLUSIONS: Obesity-related HFpEF was associated with detrimental structural, cellular, and functional alterations to both slow-oxidative and fast-glycolytic skeletal muscles that could not be reversed by endurance training.

Powerful extreme phenotype sampling designs and score tests for genetic association studies.

We consider cross-sectional genetic association studies (common and rare variants) where non-genetic information is available or feasible to obtain for N individuals, but where it is infeasible to genotype all N individuals. We consider continuously measurable Gaussian traits (phenotypes). Genotyping n < N extreme phenotype individuals can yield better power to detect phenotype-genotype associations, as compared to randomly selecting n individuals. We define a person as having an extreme phenotype if the observed phenotype is above a specified threshold or below a specified threshold. We consider a model where these thresholds can be tailored to each individual. The classical extreme sampling design is to set equal thresholds for all individuals. We introduce a design (z-extreme sampling) where personalized thresholds are defined based on the residuals of a regression model including only non-genetic (fully available) information. We derive score tests for the situation where only n extremes are analyzed (complete case analysis) and for the situation where the non-genetic information on N - n non-extremes is included in the analysis (all case analysis). For the classical design, all case analysis is generally more powerful than complete case analysis. For the z-extreme sample, we show that all case and complete case tests are equally powerful. Simulations and data analysis also show that z-extreme sampling is at least as powerful as the classical extreme sampling design and the classical design is shown to be at times less powerful than random sampling. The method of dichotomizing extreme phenotypes is also discussed.

Exercise patterns in older adults instructed to follow moderate- or high-intensity exercise protocol - the generation 100 study.

BACKGROUND: Making older adults exercise and keeping them in exercise programs is a major challenge. Understanding how older adults prefer to exercise may help developing tailored exercise programs and increase sustained exercise participation in ageing populations. We aimed to describe exercise patterns, including frequency, intensity, type, location and social setting of exercise, in older adults instructed to follow continuous moderate-intensity training (MCT) or high-intensity interval training (HIIT) over a one-year period. METHODS: Frequency, intensity, type, location and social setting (alone vs. together with others) of exercise were assessed using exercise logs from 618 older adults (aged 70-77 years) randomized to MCT or HIIT. All participants completed exercise logs after each exercise session they performed during one year. Pearson Chi-square tests were run to assess the association between intensity, type, location and social setting of exercise with training group. RESULTS: Both groups performed 2.2 ± 1.3 exercise sessions per week during the year. Walking was the most common exercise type in both groups, but MCT had a higher proportion of walking sessions than HIIT (54.2% vs. 41.1%, p < 0.01). Compared to MCT, HIIT had a higher proportion of sessions with cycling (14.2% vs. 9.8%, p < 0.01), combined endurance and resistance training (10.3% vs. 7.5%, p < 0.01), jogging (6.5% vs. 3.2%, p < 0.01) and swimming (2.6% vs. 1.7%, p < 0.01). Outdoors was the most common exercise location in both training groups (67.8 and 59.1% of all sessions in MCT and HIIT, respectively). Compared to MCT, HIIT had a higher proportion of sessions at a gym (21.4% vs. 17.5%, p < 0.01) and sports facility (9.8% vs. 7.6%, p < 0.01). Both groups performed an equal amount of sessions alone and together with others, but women had a higher proportion of sessions together with others compared to men (56% vs. 44%, p < 0.01). CONCLUSION: This is the first study that has followed older adults instructed to perform MCT or HIIT over a one-year period, collected data from each exercise session they performed and provided important knowledge about their exercise patterns. This novel information may help researchers and clinicians to develop tailored exercise programs in an ageing population.