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.

Impact of High-Intensity Interval Training on Disease Activity and Disease in Patients With Psoriatic Arthritis: A Randomized Controlled Trial.

OBJECTIVE: To evaluate the impact of high-intensity interval training (HIIT) on disease activity and disease perception in patients with psoriatic arthritis (PsA) and to evaluate whether a potential effect could be sustained for a longer period of time. METHODS: We randomly assigned 67 patients with PsA (43 women and 24 men) to an intervention group in which patients performed HIIT for 11 weeks or a control group of patients who were instructed not to change their physical exercise habits. Outcomes were assessed at 3 months and 9 months with the patient's global assessment (PGA), fatigue, and pain scores measured on a 100-mm visual analog scale (VAS), and the composite Disease Activity Score in 44 joints (DAS44) was calculated. We used linear mixed models to calculate the mean difference (95% confidence interval [95% CI]) between groups according to the intent-to-treat principle. RESULTS: At 3 months, there was no clear difference in the PGA score (-0.49 [95% CI -10.91, 9.94]), DAS44 (-0.08 [95% CI -0.36, 0.20]), or pain intensity (5.45 [95% CI -4.36, 15.26]) between the groups. However, patients in the intervention group reported less fatigue (-12.83 [95% CI -25.88, 0.23]) than those in the control group. There was no evidence of long-term effects of HIIT on outcomes measured at 9 months. CONCLUSION: HIIT showed no clear effects on disease activity markers in patients with PsA, but the intervention (exercise) group reported meaningfully less fatigue after the intervention period. The results of this study suggest that patients with PsA tolerate HIIT without deterioration of disease activity and with improvement in fatigue.

Effect of high-intensity interval training on cardiovascular disease risk factors and body composition in psoriatic arthritis: a randomised controlled trial.

BACKGROUND: Psoriatic arthritis (PsA) is associated with an accumulation of cardiovascular disease (CVD) risk factors. The aim of this study was to evaluate the effect of high-intensity interval training (HIIT) on CVD risk factors in patients with PsA. METHODS: We randomly assigned 61 patients with PsA (41 women and 20 men) to an intervention group performing HIIT for 11 weeks or a control group who were instructed to not change their physical exercise habits. Outcomes were assessed at 3 and 9 months with measures on maximal oxygen uptake (VO2max), fat percentage and Body Mass Index (BMI). We used linear mixed models to calculate mean difference with 95% CI between the groups according to the intention-to-treat principle. RESULTS: At 3 months, the HIIT group had a 3.72 mL/kg/min (95% CI 2.38 to 5.06) higher VO2max and a 1.28 (95% CI -2.51 to -0.05) lower truncal fat percentage than controls. There was also some evidence that the HIIT group had lower total fat percentage (-0.80; 95% CI -1.71 to 0.10) and slightly lower BMI (-0.31; 95% CI -0.78 to 0.17) than the control group. At 9 months, the HIIT group had still a higher VO2max (3.08; 95% CI 1.63 to 4.53) than the control group, whereas the difference in other factors were small. CONCLUSION: In patients with PsA, 3 months with HIIT was associated with a substantial increase in VO2max and a reduction in truncal fat percentage compared with controls. The beneficial effect on VO2max was also sustained through 9 months. TRIAL REGISTRATION NUMBER: NCT02995460.

MicroRNAs as Important Regulators of Exercise Adaptation.

A significant body of evidence supports the protective role of exercise training (ET) in cardiovascular diseases, skeletal muscle dystrophies, several types of cancer, Alzheimer disease or even in the recovery of spinal cord injury. In spite of this, the molecular mechanisms underlying the beneficial effects of exercise training are not well understood and remain elusive. Several mechanisms have been proposed in the past, but more recently microRNAs (miRNAs), small non-coding RNA molecules involved in a variety of basic biological processes that negatively modulate gene expression, recognized as important regulatory molecules. In this review, we highlight recent advances on the miRNA involvement in the benefits of ET. Here, we assess the role of microRNAs expressed in the heart, in the skeletal muscle, detected in the circulation (serum and plasma), and in other conditions (e.g., spinal cord injury). Additionally, the long-term effects of diverse ET modalities (e.g., running, cycling, resistance training) in the cardiac miRNA profile are properly addressed.

A small molecule activator of AKT does not reduce ischemic injury of the rat heart.

BACKGROUND: Activation of protein kinase AKT is required for cardioprotection by ischemic preconditioning, and transgenic overexpression of AKT protects the heart against ischemia. However, it is unknown whether acute pharmacological activation of AKT alone, using a therapeutically relevant strategy, induces cardioprotection. In this study we provide the first evidence to clarify this question. METHODS: We used a recently described specific activator of AKT, the small molecule SC79, to treat rat hearts submitted to ischemia and reperfusion. Initially, isolated rat hearts were perfused with increasing doses of SC79 to verify the magnitude of AKT activation. Low and high doses were determined and used to treat hearts submitted to ischemia (35 minutes) and reperfusion (60 minutes), in a randomized and blinded design. AKT activation was verified by western immunobloting. Metabolic profile was determined by cardiac ATP content and mitochondrial enzyme activity, while cytosolic levels of cytochrome C and caspase-3 activity were used as markers of apoptosis. Ischemic injury was assessed by quantification of infarct size and cardiac release of creatine kinase and lactate dehydrogenase. RESULTS: SC79 activated cardiac AKT within 30 minutes in a dose-dependent fashion. ATP content was largely reduced by ischemia, but was not rescued by SC79. Similarly, mitochondrial enzyme activity was not affected by SC79. SC79 administered before ischemia or at reperfusion did not prevent cytosolic accumulation of cytochrome C and overactivation of caspase-3. Finally, SC79 failed to reduce infarct size or release of cardiac injury biomarkers at reperfusion. CONCLUSION: We conclude that selective AKT activation by the synthetic molecule SC79 does not protect the rat heart against ischemic injury, indicating that acute pharmacological activation of AKT is not sufficient for cardioprotection.

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.

Circulating microRNAs and aerobic fitness--the HUNT-Study.

Aerobic fitness, measured as maximal oxygen uptake (VO2max), is a good indicator of cardiovascular health, and a strong predictor of cardiovascular mortality. Biomarkers associated with low VO2max may therefore represent potential early markers of future cardiovascular disease (CVD). The aim of this study was to assess whether circulating microRNAs (miRs) are associated with VO2max-level in healthy individuals. In a screening study, 720 miRs were measured in serum samples from healthy individuals (40-45 yrs) with high (n = 12) or low (n = 12) VO2max matched for gender, age and physical activity. Candiate miRs were validated in a second cohort of subjects with high (n = 38) or low (n = 38) VO2max. miR-210 and miR-222 were found to be higher in the low VO2max-group (p<0.05). In addition, miR-21 was increased in male participants with low VO2max (p<0.05). There were no correlations between traditional risk factors for CVD (blood pressure, cholesterol, smoking habit, or obesity) and miR-21, miR-210 and miR-222. DIANA-mirPath identified 611 potential gene-targets of miR-21, miR-210 and miR-222, and pathway analysis indicated alterations in several important signaling systems in subjects with low VO2max. Potential bias involve that blood was collected from non-fasting individuals, and that 8 performed exercise within 24 h before sampling. In conclusion, we found that miR-210, miR-21, and miR-222 were increased in healthy subjects with low VO2max. The lack of association between these three miRs, and other fitness related variables as well as traditional CVD risk factors, suggests that these miRs may have a potential as new independent biomarkers of fitness level and future CVD.

Aerobic interval training versus continuous moderate exercise after coronary artery bypass surgery: a randomized study of cardiovascular effects and quality of life.

BACKGROUND: Peak oxygen uptake (Vo(2peak)) strongly predicts mortality in cardiac patients. We compared the effects of aerobic interval training (AIT) versus moderate continuous training (MCT) on Vo(2peak) and quality of life after coronary artery bypass grafting (CABG). METHODS: Fifty-nine CABG patients were randomized to either AIT at 90% of maximum heart rate or MCT at 70% of maximum heart rate, 5 d/wk, for 4 weeks at a rehabilitation center. Primary outcome was Vo(2peak), at baseline, after rehabilitation (4 weeks), and after 6 months of home-based exercise (6 months). RESULTS: Vo(2peak) increased between baseline and 4 weeks in AIT (27.1 +/- 4.5 vs 30.4 +/- 5.5 mL.kg(-1).min(-1), P < .001) and MCT (26.2 +/- 5.2 vs 28.5 +/- 5.6 mL.kg(-1).min(-1), P < .001; group difference, not significant). Aerobic interval training increased Vo(2peak) between 4 weeks and 6 months (30.4 +/- 5.5 vs 32.2 +/- 7.0 mL.kg(-1).min(-1), P < .001), with no significant change in MCT (28.5 +/- 5.6 vs 29.5 +/- 5.7 mL.kg(-1).min(-1)). Quality of life improved in both groups from baseline to 4 weeks, remaining improved at 6 months. There were no changes in echocardiographic systolic and diastolic left ventricular function. Adiponectin increased between 4 weeks and 6 months in both groups (group differences, not significant). CONCLUSIONS: Four weeks of intense training increased Vo(2peak) significantly after both AIT and MCT. Six months later, the AIT group had a significantly higher Vo(2peak) than MCT. The results indicate that AIT and MCT increase Vo(2peak) similarly in the short term, but with better long-term effect of AIT after CABG.

Carbon monoxide levels experienced by heavy smokers impair aerobic capacity and cardiac contractility and induce pathological hypertrophy.

Cigarette smoke contains hundreds of potentially toxic compounds and is an important risk factor for cardiovascular disease. However, the key components responsible for endothelial and myocardial dysfunction have not been fully identified. The objective of the present study was to determine the cardiovascular effects of long-term inhalation of carbon monoxide (CO) administrated to give concentrations in the blood similar to those observed in heavy smokers. Female rats were exposed to either CO or air (control group) (n = 12). The CO group was exposed to 200 ppm CO (100 h/wk) for 18 mo. Rats exposed to CO had 24% lower maximal oxygen uptake, longer (145 vs. 123 microm) and wider (47 vs. 25 microm) cardiomyocytes, reduced cardiomyocyte fractional shortening (12 vs. 7%), and 26% longer time to 50% re-lengthening than controls. In addition, cardiomyocytes from CO-exposed rats had 48% lower intracellular calcium (Ca2 +) amplitude, 22% longer time to Ca2 + decay, 34% lower capacity of sarcoplasmic reticulum Ca2 +-ATPase (SERCA2a), and 37% less t-tubule area compared to controls. Phosphorylation levels of phospholamban at Ser16 and Thr17 were significantly reduced in the CO group, whereas total concentration of phospholamban and SERCA2a were unchanged. Cardiac atrial natriuretic peptide, vascular endothelial growth factor, cyclic guanosine monophosphate, calcineurin, calmodulin, pERK, and pS6 increased, whereas pAkt and pCaMKII delta remained unchanged by CO. Endothelial function and systemic blood pressure were not affected by CO exposure. Long-term CO exposure reduces aerobe capacity and contractile function and leads to pathological hypertrophy. Impaired Ca2 + handling and increased growth factor signaling seem to be responsible for these pathological changes.