Metabolic effects of exercise may partly depend on the time-of-day when exercise is performed. We tested the hypothesis that exercise timing affects the adaptations in multi-tissue metabolome and ...skeletal muscle proteome profiles in men with type 2 diabetes.
Men fitting the inclusion (type 2 diabetes, age 45–68 years and body mass index 23–33 kg/m2) and exclusion criteria (insulin treatment, smoking, concurrent systemic disease, and regular exercise training) were included in a randomized crossover trial (n = 15). Participants included in this metabolomics and proteomics analysis fully completed all exercise sessions (n = 8). The trial consisted of two weeks of high-intensity interval training (HIT) (three sessions/week) either in the morning (08:00, n = 5) or afternoon (16:45, n = 3), a two-week wash-out period, and an additional two weeks of HIT at the opposing time. Participants and researchers were not blinded to group allocation. Blood, skeletal muscle and subcutaneous adipose tissue were obtained before the first, and after each training period. Broad-spectrum, untargeted proteomic analysis was performed on skeletal muscle, and metabolomic analysis was performed on all biosamples. Differential content was assessed by linear regression and pathway set enrichment analyses were performed. Coordinated metabolic changes across tissues were identified by Spearman correlation analysis.
Metabolic and proteomic profiles remained stable after two weeks of HIT, and individual metabolites and proteins were not altered, irrespective of the time of day at which the training was performed. However, coordinated changes in relevant metabolic pathways and protein categories were identified. Morning and afternoon HIT similarly increased plasma diacylglycerols, skeletal muscle acyl-carnitines, and subcutaneous adipose tissue sphingomyelins and lysophospholipids. Acyl-carnitines were central to training-induced metabolic cross-talk across tissues. Plasma carbohydrates, via the penthose phosphate pathway, were increased and skeletal muscle lipids were decreased after morning compared to afternoon HIT. Skeletal muscle lipoproteins were higher, and mitochondrial complex III abundance was lower after morning compared to afternoon HIT.
We provide a comprehensive analysis of a multi-tissue metabolomic and skeletal muscle proteomic responses to training at different times of the day in men with type 2 diabetes. Increased circulating lipids and changes in adipose tissue lipid composition were common between morning and afternoon HIT. However, afternoon HIT increased skeletal muscle lipids and mitochondrial content to a greater degree than morning training. Thus, there is a diurnal component in the metabolomic and proteomic response to exercise in men with type 2 diabetes. The clinical relevance of this response warrants further investigation.
•Several distinct responses are apparent between high intensity interval training (HIT) performed in the morning and afternoon•Morning training raised plasma carbohydrates and skeletal muscle lipoproteins more robustly than afternoon HIT•Afternoon HIT increased skeletal muscle lipids and mitochondrial complex III abundance to a greater extent than morning HIT•Exercise timing may be important to consider for the management of type 2 diabetes
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Identification and treatment of abdominal aortic aneurysm (AAA) remain among the most prominent challenges in vascular medicine. MicroRNAs (miRNAs) are crucial regulators of cardiovascular pathology ...and represent intriguing targets to limit AAA expansion. Here we show, by using two established murine models of AAA disease along with human aortic tissue and plasma analysis, that miR-24 is a key regulator of vascular inflammation and AAA pathology. In vivo and in vitro studies reveal chitinase 3-like 1 (Chi3l1) to be a major target and effector under the control of miR-24, regulating cytokine synthesis in macrophages as well as their survival, promoting aortic smooth muscle cell migration and cytokine production, and stimulating adhesion molecule expression in vascular endothelial cells. We further show that modulation of miR-24 alters AAA progression in animal models, and that miR-24 and CHI3L1 represent novel plasma biomarkers of AAA disease progression in humans.
Arterial stiffness is an important cardiovascular risk marker, which can be measured noninvasively with different techniques. To validate such techniques in healthy subjects, we compared the recently ...introduced oscillometric Arteriograph (AG) technique with the tonometric SphygmoCor (SC) method and their associations with carotid ultrasound measures and traditional risk indicators. Sixty-three healthy subjects aged 20-69 (mean 48 ± 15) years were included. We measured aortic pulse wave velocity (PWVao) and augmentation index (AIx) by AG and SC, and with SC also the PWVao standardized to 80% of the direct distance between carotid and femoral sites (St-PWVaoSC). The carotid strain, stiffness index and intima-media thickness (cIMTmean) were evaluated by ultrasound. PWVaoAG (8.00 ± 2.16 m s(-1)) was higher (P<0.001) than PWVaoSC (6.87 ± 1.47 m s(-1)), but did not differ from St-PWVaoSC (7.68 ± 1.58 m s(-1)), and correlated (P<0.001) with both (r = 0.54 and 0.59). St-PWVaoSC was significantly (P < 0.01) higher than PWVaoAG for values below median (7.4 m s(-1)). PWVao by SC and AG differed significantly in females (P<0.001), but not in males (P=0.40). AIxaoAG (27.5 ± 14.5%) was higher (P < 0.001) than AIxaoSC (20.5 ± 17.4%), but related closely (r=0.97, P<0.001). St-PWVaoSC, PWVao and AIxao by SC, and PWVao and AIxao by AG were all related to serum cholesterol and to cIMTmean (P<0.001). Arterial stiffness indices by AG and SC correlate with vascular risk markers in healthy subjects. AIxao results by AG and SC are closely interrelated, but higher values are obtained by AG. In the lower range, PWVao values by AG and SC are similar, but differ for higher values. Our results imply the necessity to apply one and the same technique for repeated studies.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Contrast enhanced ultrasound is a powerful diagnostic tool and ultrasound contrast media are based on microbubbles (MBs). The use of MBs in drug delivery applications and molecular imaging is a ...relatively new field of research which has gained significant interest during the last decade. MBs available for clinical use are fragile with short circulation half-lives due to the use of a thin encapsulating shell for stabilization of the gas core. Thick-shelled MBs can have improved circulation half-lives, incorporate larger amounts of drugs for enhanced drug delivery or facilitate targeting for use in molecular ultrasound imaging. However, methods for robust imaging of thick-shelled MBs are currently not available. We propose a simple multi-pulse imaging technique which is able to visualize thick-shelled polymeric MBs with a superior contrast-to-tissue ratio (CTR) compared to commercially available harmonic techniques. The method is implemented on a high-end ultrasound scanner and in-vitro imaging in a tissue mimicking flow phantom results in a CTR of up to 23 dB. A proof-of-concept study of molecular ultrasound imaging in a soft tissue inflammation model in rabbit is then presented where the new imaging technique showed an enhanced accumulation of targeted MBs in the inflamed tissue region compared to non-targeted MBs and a mean CTR of 13.3 dB for stationary MBs. The presence of fluorescently labelled MBs was verified by confocal microscopy imaging of tissue sections post-mortem.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Arterial stiffening and increased intima-media thickness can be seen as early as childhood and are associated with increased risk of cardiovascular events in adult life. The authors hypothesized that ...exposure to prenatal smokeless tobacco (Swedish snus) without additional nicotine exposure after the breastfeeding period would be associated with increased arterial stiffness and intima-media thickening in preschool children.
This was a longitudinal follow-up cohort study of children aged 5 to 6 years exposed to high doses of nicotine in utero. Women exclusively using snus and unexposed controls were enrolled in early pregnancy (gestational age range, 6-12 weeks). Exposure data were collected during and after pregnancy with questionnaires from both groups. For this study, only children of women using >48 mg nicotine per day during their entire pregnancy were included in the exposure group. Outcomes were determined in 40 healthy children (21 exposed to snus in utero). Ultrasonography of the common carotid artery was used to determine carotid intima-media thickness and calculate arterial stiffness index from the relationship between pulsatile changes in arterial diameter and arterial pressure. Children exposed to snus in fetal life had higher carotid stiffness (median 4.1 interquartile range (IQR), 2.4-5 versus 2.9 IQR, 2.1-3.5;
=0.014) than tobacco-free controls. Carotid strain (relative diameter change) was lower in children exposed to snus (mean 16% SD, 5.7% versus 21% SD, 6.6%) than in controls (
=0.015). Carotid intima-media thickness did not differ significantly between children exposed to snus and controls.
Exposure to snus during fetal life was associated with a stiffer carotid artery in preschool children.
Abstract
The QRS complex has been shown to be a prognostic marker in coronary artery disease. However, the changes in QRS duration over time, and its predictive value for cardiovascular disease in ...the general population is poorly studied. So we aimed to explore if increased QRS duration from the age of 50–60 is associated with increased risk of major cardiovascular events during a further follow-up to age 71. A random population sample of 798 men born in 1943 were examined in 1993 at 50 years of age, and re-examined in 2003 at age 60 and 2014 at age 71. Participants who developed cardiovascular disease before the re-examination in 2003 (n = 86) or missing value of QRS duration in 2003 (n = 127) were excluded. ΔQRS was defined as increase in QRS duration from age 50 to 60. Participants were divided into three groups: group 1: ΔQRS < 4 ms, group 2: 4 ms ≤ ΔQRS < 8 ms, group 3: ΔQRS ≥ 8 ms. Endpoints were major cardiovascular events. And we found compared with men in group 1 (ΔQRS < 4 ms), men with ΔQRS ≥ 8 ms had a 56% increased risk of MACE during follow-up to 71 years of age after adjusted for BMI, systolic blood pressure, smoking, hyperlipidemia, diabetes and heart rate in a multivariable Cox regression analysis (HR 1.56, 95% CI:1.07–2.27, P = 0.022). In conclusion, in this longitudinal follow-up over a decade QRS duration increased in almost two out of three men between age 50 and 60 and the increased QRS duration in middle age is an independent predictor of major cardiovascular events.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The cause of reduced exercise capacity (ExCap) in chronic kidney disease (CKD) is multifactorial. The aim of this study was to investigate determinants of aerobic ExCap in patients with mild to ...severe CKD not undergoing dialysis.
We included 52 individuals with CKD stage 2-3, 47 with stage 4-5, and 54 healthy controls. Peak workload and peak heart rate (HR) were assessed by a maximal cycle exercise test. Cardiac function including stroke volume (SV) and vascular stiffness were evaluated by ultrasound at rest. Handgrip strength, body composition, haemoglobin level and self-reported physical activity were assessed.
Peak workload (221±60, 185±59, 150±54 W for controls, CKD 2-3 and CKD 4-5 respectively), peak HR (177±11, 161±24, 144±31 beats/min) and haemoglobin level (14.2±1.2, 13.5±1.4, 12.2±1.3 g/dL) were all three significantly lower in CKD 2-3 than in controls, (p = 0.001, 0.001 and 0.03 respectively) and were even lower in stages 4-5 CKD than in CKD 2-3 (p = 0.01, 0.001 and <0.001 respectively). Resting SV and lean body mass did not differ between groups and handgrip strength was significantly lower only in CKD 4-5 compared to controls (p = 0.02). Peak workload was strongly associated with the systemic oxygen delivery factors: SV, peak HR and haemoglobin level. These three factors along with age, sex and height2 explained 82% of variation in peak workload. Peak HR contributed most to the variation; the peripheral variables handgrip strength and vascular stiffness did not improve the explanatory value in regression analysis.
In this cross-sectional study of CKD patients not on dialysis, aerobic ExCap decreased gradually with disease severity. ExCap was associated mainly with systemic oxygen delivery factors, in particular peak HR. Neither muscle function and mass, nor vascular stiffness were independent determinants of aerobic ExCap in this group of CKD patients.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Current guidelines recommend the measurement of arterial stiffness in terms of aortic pulse wave velocity (PWV) as an important cardio-vascular risk marker. Both aortic PWV and the aortic ...augmentation index (AIxao) can be measured using different techniques, e.g., the Arteriograph and SphygmoCor. A new version of the software for the Arteriograph (v. 3.0.0.1, TensioMed, Budapest, Hungary; Arteriograph II) is now available. We wanted to determine whether this improved software differs from the previous version (Arteriograph v. 1.9.9.12; Arteriograph I). We compared the estimated aortic PWV (ePWVao) and AIxao measured with both versions of Arteriograph software and analysed the agreement of these values with those measured by SphygmoCor (v. 7.01, AtCor Medical, Sydney, Australia).
Eighty-seven subjects without known cardio-vascular disease (23 men and 64 women) aged 54.2 ± 8.7 years (mean ± standard deviation; range 33-68 years) were included in the study. Estimated PWVao and AIxao were measured by both Arteriograph and SphygmoCor. We compared Arteriograph I and Arteriograph II with each other and with SphygmoCor.
Estimated PWVao measured by Arteriograph II was lower than that measured by Arteriograph I, while the AIxao was higher. Divergence in ePWVao values was especially noted above 9 m/s. Estimated PWVao measured by Arteriograph II (7.2 m/s, 6.6-8.0 median, 25th-75th percentile) did not differ from that measured by SphygmoCor (7.1 m/s, 6.7-7.9 median, 25th-75th percentile). However, the AIao measured by Arteriograph II was significantly higher (P < 0.001).
Regularly upgraded software versions resulting from continuous technical development are needed for quality improvement of methods. However, the changes in software, even if the basic patented operational algorithm has not changed, may influence the measured values as shown in the present study. Therefore, attention should be paid to the software version of the method used when comparing arterial stiffness results in clinical settings or when performing scientific studies.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Patients with myocardial infarction with nonobstructive coronary arteries (MINOCA), including Takotsubo syndrome (TS), are considered to have a better survival compared with those with coronary heart ...disease (CHD). Studies of patients with MINOCA measuring physical and mental function including matched control groups are lacking. The aim of this study was to determine the physical capacity and quality of life in patients with MINOCA. One-hundred patients with MINOCA along with TS (25%) were investigated from 2007 to 2011. A bicycle exercise stress test was performed 6 weeks after hospitalization and QoL was investigated by the Short Form Survey 36 at 3 months' follow-up. Both a healthy and a CHD group that were age and gender matched were used as controls. The MINOCA group had a lower physical capacity (139 ± 42 W) compared with the healthy control group (167 ± 53 W, p <0.001) but better than the CHD control group (124 ± 39 W, p = 0.023). Patients with MINOCA had lower physical and mental component summary scores compared with the healthy controls (p <0.001) and lower mental component summary (p = 0.012), mental health (p = 0.016), and vitality (p = 0.008) scores compared with the CHD controls. In conclusion, the findings of this first study on exercise capacity and QoL in patients with MINOCA showed both physical and mental distress from 6 weeks to 3 months after the acute event similar to CHD controls and in some perspectives even lower scores especially in the mental component of QoL.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
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