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Background: Treatment with lower extremity intermittent negative pressure (INP) of -40 mm Hg for one hour twice daily for 12 weeks, increases walking capacity in patients with intermittent claudication (IC). However, the effects of INP treatment beyond 12 weeks have not been elucidated. The aim of the present study was to investigate the clinical effects of INP treatment after 24 weeks in patients with IC., Methods: This was a follow-up study after a randomized sham-controlled trial, where patients randomized to the active treatment group were offered to continue treatment for 12 additional weeks (24 weeks in total). Treatment with -40 mm Hg INP was applied in a pressure chamber sealed around the lower leg, and the patients were instructed to treat themselves at home one hour in the morning and one hour in the evening. Pain free walking distance (PWD), maximal walking distance (MWD), resting ankle-brachial index (ABI) and post exercise ABI were measured at baseline, after 12 and 24 weeks., Results: Ten out of 32 patients (31%) from the active treatment group in the initial trial were included in this follow-up study. At baseline, PWD was (mean ±SD) 151 ± 91 m and MWD was 362 ±159 m. There was a significant increase in both PWD and MWD after 24 weeks of treatment, compared to baseline (ANOVA; P= 0.006 and P= 0.012, respectively). Post hoc tests revealed that PWD increased significantly from baseline to 12 weeks (mean 81 m; 95% CI [6, 156]; P = 0.032), and that MWD increased significantly from 12 to 24 weeks (mean 145 m; 95% CI [22, 268]; P = 0.018). There were no significant changes in resting ABI or post exercise ABI during the 24-week treatment period (ANOVA; P= 0.157 and P= 0.450, respectively)., Conclusion: Both PWD and MWD improved after treatment with - 40 mm Hg INP for one hour twice daily for 24 weeks, compared to baseline. The main improvement in PWD occurred during the first 12 weeks of treatment, whereas the main improvement in MWD occurred between 12 and 24 weeks of treatment., (Copyright © 2021. Published by Elsevier Inc.)

Triathlon and other endurance races have grown in popularity. Although participants are generally fit and presumably healthy, there is measurable morbidity and mortality associated with participation. In triathlon, most deaths occur during the swim leg, and more insight into risk factors, such as hypothermia, is warranted. In this study, we measured the core temperature of 51 participants who ingested temperature sensor capsules before the swim leg of a full-distance triathlon. The water temperature was 14.4-16.4 °C, and the subjects wore wetsuits. One subject with a low body mass index and a long swim time experienced hypothermia (<35 °C). Among the remaining subjects, we found no association between core temperature and swim time, body mass index, or sex. To conclude, the present study indicates that during the swim leg of a full-distance triathlon in water temperatures ≈ 15-16 °C, subjects with a low body mass index and long swim times may be at risk of hypothermia even when wearing wetsuits.

We assessed endothelial function by flow-mediated dilatation (FMD), levels of the NO-precursor L-arginine, and markers of endothelial inflammation before, at the finish line, and one week after the Norseman Xtreme triathlon. The race is an Ironman distance triathlon with a total elevation of 5200 m. Nine male participants were included. They completed the race in 14.5 (13.4-15.3) h. FMD was significantly reduced to 3.1 (2.1-5.0)% dilatation compared to 8.7 (8.2-9.3)% dilatation before the race ( p < 0.05) and was normalized one week after the race. L-arginine showed significantly reduced levels at the finish line ( p < 0.05) but was normalized one week after the race. Markers of endothelial inflammation E-Selectin, VCAM-1, and ICAM-1 all showed a pattern with increased values at the finish line compared to before the race (all p < 0.05), with normalization one week after the race. In conclusion, we found acutely reduced FMD with reduced L-arginine levels and increased E-Selectin, VCAM-1, and ICAM-1 immediately after the Norseman Xtreme triathlon. Our findings indicate a transient reduced endothelial function, measured by the FMD-response, after prolonged strenuous exercise that could be explained by reduced NO-precursor L-arginine levels and increased endothelial inflammation.

Objective: We investigated the effects of lower extremity intermittent negative pressure (INP) treatment for 1 hour two times daily for 12 weeks on the walking distance of patients with intermittent claudication (IC)., Methods: Patients with IC were randomized to treatment with -40 mm Hg INP (treatment group) or -10 mm Hg INP (sham control group). Pain-free walking distance (PWD) and maximal walking distance (MWD) on a treadmill, resting and postexercise ankle-brachial index, resting and postischemic blood flow (plethysmography), and quality of life (EQ-5D-5L and Vascuqol-6) were measured at baseline and after 12 weeks of treatment., Results: A total of 72 patients were randomized, and 63 had data available for the intention-to-treat analyses. The between-group comparisons showed a significant change in the PWD, favoring the treatment group over the sham control group (estimated treatment effect, 50 m; 95% confidence interval [CI], 11-89; P = .014). The PWD had increased by 68 m (P < .001) in the treatment group and 18 m (P = .064) in the sham control group. No significant difference was found in the change in the MWD between the two groups (estimated treatment effect, 42 m; 95% CI, -14 to 97; P = .139). The MWD had increased by 62 m (P = .006) in the treatment group and 20 m (P = .265) in the sham control group. For patients with a baseline PWD of <200 m (n = 56), significant changes had occurred in both PWD and MWD between the two groups, favoring the treatment group (estimated treatment effect, 42 m; 95% CI, 2-83; P = .042; and estimated treatment effect, 62 m; 95% CI, 5-118; P = .032; respectively). Both overall and for the group of patients with a PWD <200 m, no significant differences were found in the changes in the resting and postexercise ankle-brachial index, resting and postischemic blood flow, or quality of life parameters between the two groups., Conclusions: Treatment with -40 mm Hg INP increased the PWD compared with sham treatment in patients with IC. For the patients with a baseline PWD of <200 m, an increase was found in both PWD and MWD compared with sham treatment., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

The acute effects of cold-water endurance swimming on the respiratory system have received little attention. We investigated pulmonary responses to cold-water endurance swimming in healthy recreational triathletes. Pulmonary function, alveolar diffusing capacity ( D L CO ), fractional exhaled nitric oxide (FE NO ) and arterial oxygen saturation by pulse oximetry (SpO 2 ) were assessed in 19 healthy adults one hour before and 2.5 h after a cold-water (mean ± SD, 10 ± 0.9 °C) swim trial (62 ± 27 min). In addition, 12 out of the 19 participants measured pulmonary function, forced vital capacity (FVC) and forced expiratory volume in one second (FEV 1 ) 3, 10, 20 and 45 min post-swim by maximal expiratory flow volume loops and D L CO by the single breath technique. FVC and FEV 1 were significantly reduced 3 min post-swim ( p = 0.02) ( p = 0.04), respectively, and five of 12 participants (42%) experienced exercise-induced bronchoconstriction (EIB), defined as a ≥ 10% drop in FEV 1 . No significant changes were observed in pulmonary function 2.5 h post-swim. However, mean FE NO and D L CO were significantly reduced by 7.1% and 8.1% ( p = 0.01) and ( p < 0.001), respectively, 2.5 h post-swim, accompanied by a 2.5% drop ( p < 0.001) in SpO 2 . The absolute change in D L CO correlated significantly with the absolute decline in core temperature ( r = 0.52; p = 0.02). Conclusion: Cold-water endurance swimming may affect the lungs in healthy recreational triathletes lasting up to 2.5 h post-swim. Some individuals appear to be more susceptible to pulmonary impairments than others, although these mechanisms need to be studied further.

Introduction: Subintimal angioplasty (SIA) was introduced in the late 1980s and is a supplement to bypass surgery. Adaptation of the technique has been hampered by high rates of early intervention to maintain patency, but the long term assisted patency is good., Report: The superficial femoral and popliteal artery containing a patent subintimal canal were explanted from a patient who died in the authors' ward. Histological analysis indicated that the lumen was created in the medial layer of the vessel wall. A collagen rich neointima and fragmented internal elastic lamina were observed, presumably as a result of activated smooth muscle cells. The luminal surface was partly covered by a single layer of CD31, von Willebrand factor, and partly CD144 positive cells. An early atherosclerotic lesion was observed distally in the subintimal canal., Discussion: Remodelling and neo-cellularisation of the vascular wall after SIA are described. Notably, hallmarks of early and late stage atherosclerotic disease were evident throughout the subintimal canal. These observations require confirmation in a larger number of specimens but underscore the need for surveillance after SIA., (© 2020 The Authors.)

Whilst both cardiac output (CO) and total peripheral resistance (TPR) determine mean arterial blood pressure (MAP), their relative importance in the pressor response to isometric exercise remains unclear. This study aimed to elucidate the relative importance of these two different factors by examining pressor responses during cardiopulmonary unloading leading to step-wise reductions in CO. Hemodynamics were investigated in 11 healthy individuals before, during and after two-minute isometric exercise during lower body negative pressure (LBNP; -20mmHg and -40mmHg). The blood pressure response to isometric exercise was similar during normal and reduced preload, despite a step-wise reduction in CO during LBNP (-20mmHg and -40mmHg). During -20mmHg LBNP, the decreased stroke volume, and consequently CO, was counteracted by an increased TPR, while heart rate (HR) was unaffected. HR was increased during -40 mmHg LBNP, although insufficient to maintain CO; the drop in CO was perfectly compensated by an increased TPR to maintain MAP. Likewise, transient application of LBNP (-20mmHg and -40mmHg) resulted in a short transient drop in MAP, caused by a decrease in CO, which was compensated by an increase in TPR. This study suggests that, in case of reductions of CO, changes in TPR are primarily responsible for maintaining the pressor response during isometric exercise. This highlights the relative importance of TPR compared to CO in mediating the pressor response during isometric exercise., Competing Interests: The authors have declared that no competing interests exist.

Objective: Repeated computed tomography angiography (CTA) can be used during follow-up visits for endovascular aneurysm repair (EVAR) but leads to accumulated radiation exposure and may cause renal impairment. Therefore, the use of contrast-enhanced ultrasound (CEUS) has increased, and its ability to detect endoleaks has been promising. The aim of this study was to investigate the diagnostic accuracy of CEUS vs CTA for endoleak detection during EVAR follow-up., Methods: Ninety-two patients with planned EVAR for abdominal aortic aneurysm were prospectively, consecutively enrolled. In total, 233 paired CTA and CEUS procedures were performed within the same day. Follow-up visits occurred 1 month, 6 months, 12 months, and 24 months postoperatively., Results: Of 48 endoleaks discovered by CTA, 39 were also detected on CEUS, giving an overall sensitivity of 81.3% and specificity of 98.9%. All undetected endoleaks were minor, without clinical importance, and occurred in patients with high body mass index., Conclusions: In this study, CEUS was accurate for detecting type II endoleaks during follow-up visits for EVAR. Sensitivity was lower in obese patients. Doppler ultrasound has low sensitivity and seems to be unsuitable for the detection of endoleaks., (Copyright © 2020 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Universities around the world are facing an epidemic of mental distress among their students. The problem is truly a public health issue, affecting many and with serious consequences. The global burden of disease-agenda calls for effective interventions with lasting effects that have the potential to improve the mental health of young adults. In this study we aimed to determine whether yoga, a popular and widely available mind-body practice, can improve student mental health., Methods: We performed a randomised controlled trial with 202 healthy university students in the Oslo area. The participants were assigned to a yoga group or waitlist control group in a 1:1 ratio by a simple online randomisation program. The intervention group was offered 24 yoga sessions over 12 weeks. Measurements were taken at week 0 (baseline), week 12 (post-intervention), and week 24 (follow-up). The primary outcome was psychological distress assessed by the HSCL-25 questionnaire. Analysis was performed based on the intention to treat-principle., Results: Between 24 January 2017, and 27 August 2017, we randomly assigned 202 students to a yoga intervention group ( n  = 100), or waitlist control group ( n  = 102). Compared with the control group, the yoga participants demonstrated a significant reduction in distress symptoms both at post-intervention (adjusted difference in the mean change -0.15, 95% CI -0.26 to -0.03, p  = 0.0110) and follow-up (adjusted difference in the mean change -0.18, 95% CI -0.29 to -0.06, p  = 0.0025). Sleep quality also improved at post-intervention and follow-up. No adverse events were reported., Conclusions: Our findings suggest that yoga has a moderately large and lasting effect, at least for some months, reducing symptoms of distress and improving sleep quality among students. Further research should seek ways to enhance the effect, assess an even longer follow-up period, include active control groups, and consider performing similar studies in other cultural settings. Trial registration: ClinicalTrials.gov identifier: NCT04258540., Competing Interests: The study was approved by the Regional Committee for Medical Research Ethics in South-East Norway in November 2016.TE has been an instructor at HiYoga. She did not teach any yoga classes during the study and owns no part of HiYoga. She declares no other conflict of interest, nor does anyone else in the author group., (© 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

Prolonged exercise is known to cause changes in common biomarkers. Occasionally, competition athletes need medical assistance and hospitalisation during prolonged exercise events. To aid clinicians treating patients and medical teams in such events we have studied common biomarkers after at The Norseman Xtreme Triathlon (Norseman), an Ironman distance triathlon with an accumulated climb of 5200 m, and an Olympic triathlon for comparison. Blood samples were collected before, immediately after, and the day following the Norseman Xtreme Triatlon (n = 98) and Oslo Olympic Triathlon (n = 15). Increased levels of clinical significance were seen at the finish line of the Norseman in white blood cells count (WBC) (14.2 [13.5-14.9] 109/L, p < 0.001), creatinine kinase (CK) (2450 [1620-3950] U/L, p < 0.001) and NT-proBNP (576 [331-856] ng/L, p < 0.001). The following day there were clinically significant changes in CRP (39 [27-56] mg/L, p < 0.001) and Aspartate Aminotransferase (AST) (142 [99-191] U/L, p < 0.001). In comparison, after the Olympic triathlon distance, there were statistically significant, but less clinically important, changes in WBC (7.8 [6.7-9.6] 109/L, p < 0.001), CK (303 [182-393] U/L, p < 0.001) and NT-proBNP (77 [49-88] ng/L, p < 0.01) immediately after the race, and in CRP (2 [1-3] mg/L, p < 0.001) and AST (31 [26-41] U/L, p < 0.01) the following day. Subclinical changes were also observed in Hemoglobin, Thrombocytes, K+, Ca2+, Mg2+, Creatinine, Alanine Aminotransferase and Thyroxine after the Norseman. In conclusion, there were significant changes in biomarkers used in a clinical setting after the Norseman. Of largest clinical importance were clinically significant increased WBC, CRP, AST, CK and NT-proBNP after the Norseman. This is important to be aware of when athletes engaging in prolonged exercise events receive medical assistance or are hospitalised., Competing Interests: The funder provided support in the form of research materials and salaries for author ABS but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Choline is an essential nutrient that has been implicated in athletic performance due to its role in maintaining normal muscle function. The concentration of free choline in serum may decrease during long-distance high-intensity exercise, yet few nutritional strategies to counteract this potentially performance-depleting loss in choline have been investigated outside the laboratory. This exploratory field study was performed to investigate if pre-race supplementation with phosphatidylcholine from krill oil can counteract the expected drop in choline and some of its metabolites during triathlon competitions. Forty-seven triathletes, 12 females and 35 males ranging in age from 25 to 61 years, were recruited from participants in the Ironman-distance Norseman Xtreme triathlon and the Sprint/Olympic-distance Oslo Triathlon. Twenty-four athletes were randomly allocated to the krill oil group, receiving 4 g of Superba Boost ™ krill oil daily for 5 weeks prior to the race, and 23 athletes were randomly allocated to the placebo group, receiving 4 g of mixed vegetable oil daily. Blood samples were obtained before the race, immediately after completion of the race, and the day after the race for analysis of choline and its metabolites. The results showed that serum choline concentrations significantly decreased from pre-race to race finish in all races, with a more pronounced decrease observed in the Ironman-distance Norseman Xtreme triathlon (34% decrease) relative to the Sprint/Olympic-distance Oslo Triathlon (15% decrease). A reduction in betaine was also observed, while dimethylglycine (DMG) concentrations remained stable across all time points. Significantly higher concentrations of choline (9.4% on average) and DMG (21.4% on average) were observed in the krill oil compared to the placebo group, and the krill oil group showed a significantly greater increase in serum choline following race completion. In conclusion, krill oil may help to prevent that circulating choline concentrations become limiting during endurance competitions., (Copyright © 2020 Storsve, Johnsen, Nyborg, Melau, Hisdal and Burri.)

Objectives: We aimed to assess prevalence of left ventricular (LV) systolic and diastolic function in stable cohort of COPD patients, where LV disease had been thoroughly excluded in advance., Methods: 100 COPD outpatients in GOLD II-IV and 34 controls were included. Patients were divided by invasive mean pulmonary artery pressure (mPAP) in COPD-PH (≥25 mmHg) and COPD-non-PH (<25 mmHg), which was subdivided in mPAP ≤20 mmHg and 21-24 mmHg. LV myocardial performance index (LV MPI) and strain by tissue Doppler imaging (TDI) were used for evaluation of LV global and systolic function, respectively. LV MPI ≥0.51 and strain ≤-15.8% were considered abnormal. LV diastolic function was assessed by the ratio between peak early (E) and late (A) velocity, early TDI E´, E/E´, isovolumic relaxation time, and left atrium volume., Results: LV MPI ≥0.51 was found in 64.9% and 88.5% and LV strain ≤-15.8% in 62.2.% and 76.9% in the COPD-non-PH and COPD-PH patients, respectively. Similarly, LV MPI and LV strain were impaired even in patients with mPAP <20 mmHg. In multiple regression analyses, residual volume and stroke volume were best associated to LV MPI and LV strain, respectively. Except for isovolumic relaxation time, standard diastolic echo indices as E/A, E´, E/E´ and left atrium volume did not change from normal individuals to COPD-non-PH., Conclusions: Subclinical LV systolic dysfunction was a frequent finding in this cohort of COPD patients, even in those with normal pulmonary artery pressure. Evidence of LV diastolic dysfunction was hardly present as measured by conventional echo indices., Competing Interests: The authors have declared that no competing interests exist.

Objectives: To examine evidence of exercise-induced bronchoconstriction (EIB) defined as ≥10% reduction in forced expiratory volume in one second (FEV 1 ) and exercise-induced arterial hypoxemia (EIAH) defined as ≥4% reduction in oxygen saturation (SpO 2 ) from before to after participation in the Norseman Xtreme Triathlon. Secondarily, to assess whether changes in FEV 1 and SpO 2 are related to respiratory symptoms, training volume, and race time., Methods: In this quasi-experimental non-controlled study, we included 63 triathletes (50♂/13♀) aged 40.3 (±9.0) years (mean ± SD). Fifty-seven (46♂/11♀) measured lung function and 54 (44♂/10♀) measured SpO 2 before the race, 8-10 minutes after the race (post-test 1) and the day after the race (post-test 2). Respiratory symptoms and training volume were recorded with modified AQUA questionnaire. ANOVA for repeated measures was used to detect differences in lung function and SpO 2 . Statistical significance was accepted at 0.05 level., Results: Twenty-six participants (46%) presented with EIB at post-test 1 and 16 (28%) at post-test 2. Lung function variables were significantly reduced from baseline to post-test 1 and 2. Thirty-five participants (65%) showed evidence of mild to moderate EIAH. No significant correlations were observed except a weak correlation between maximal reduction in FEV 1 and respiratory symptoms (r = 0.35, P = .016)., Conclusion: Our results demonstrated that 46% of the participants presented with EIB and 65% showed evidence of EIAH after the Norseman Xtreme Triathlon. Changes in FEV 1 and SpO 2 were not correlated to weekly training hours or race time. We observed a weak correlation between maximal reduction in FEV 1 and respiratory symptoms., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Purpose: To determine the impact of interval training frequency in elite endurance athletes. It was hypothesized that two longer sessions would elicit greater performance improvements and physiological adaptation than four shorter sessions at the same intensity., Methods: Elite cross-country skiers and biathletes were randomly assigned to either a high-frequency group (HF group) (5 M, 1 F, age 22 (19-26), VO 2max 67.8 (65.5-70.2) mL/kg/min) doing four short interval sessions per week or a low-frequency group (LF group) (8 M, 1 F, age 22 (18-23), VO 2max 70.7 (67.0-73.9) mL/kg/min) doing two longer interval sessions. All interval sessions were performed at ~85% of maximum heart rate, and groups were matched for total weekly training volume. Pre- and post-intervention, athletes completed an 8 km rollerski time-trial, maximal oxygen uptake (VO 2max ) test, and an incremental, submaximal exercise test., Results: The LF group had a statistically significant improved time-trial performance following the intervention ( p = 0.04), with no statistically significant changes in the HF group. Similarly, percentage utilization of VO 2max at anaerobic threshold ( p = 0.04) and exercise economy ( p = 0.01) were statistically significantly improved following the intervention in the LF group only. No statistically significant changes in VO 2max were observed in either group., Conclusions: Two longer interval sessions appear superior to four shorter sessions per week in promoting endurance adaptations and performance improvements in elite endurance athletes. Despite matched training volume and exercise intensity, the larger, more concentrated exercise stimulus in the LF group appears to induce more favorable adaptations. The longer time between training sessions in the LF group may also have allowed athletes to recover more effectively and better "absorb" the training. These findings are in line with the "best practice" observed by many of the world's best endurance athletes.

Objective: In this proof-of-concept study we aim to validate a novel ultrasound Doppler monitoring device for evaluating microcirculation (earlybird) against LDF and pulsed Doppler., Methods: In ten healthy subjects, we measured microcirculatory function at rest and during different autonomic tests (forced respiration, isometric exercise, Valsalva maneuver and cold pressor). Earlybird, LDF and pulsed Doppler were recorded simultaneously. We performed a ZNCC to determine correlation., Results: The curves for earlybird and LDF or pulsed Doppler correlates visually well. Overall median ZNCC 0.87 (interquartile range 0.77 -0.91) between the LDF and earlybird measurements, and 0.90 (0.82 - 0.95) for pulsed Doppler and earlybird. Median ZNCC for baseline and each provocation test for earlybird against LDF and pulsed Doppler were calculated; baseline: LDF 0.87 (0.73 - 0.97) pulsed Doppler 0.91 (0.81 - 0.94), forced respiration: LDF 0.87 (0.28 - 0.90) pulsed Doppler 0.90 (0.85 - 0.96), isometric exercise: LDF 0.82 (0.59 - 0.90) pulsed Doppler 0.87 (0.68 - 0.94), Valsalva maneuver: LDF 0.88 (0.82 - 0.91) pulsed Doppler 0.94 (0.92 - 0.97) and cold pressor: LDF 0.90 (0.85 - 0.95) pulsed Doppler 0.89 (0.65 - 0.94)., Conclusion: Earlybird records vasoconstrictions in healthy subjects as well as LDF and pulsed Doppler.

Low-carbohydrate-high-fat (LCHF) diets are efficient for weight loss, and are also used by healthy people to maintain bodyweight. The main aim of this study was to investigate the effect of 3-week energy-balanced LCHF-diet, with >75 percentage energy (E%) from fat, on glucose tolerance and lipid profile in normal weight, young, healthy women. The second aim of the study was to investigate if a bout of exercise would prevent any negative effect of LCHF-diet on glucose tolerance. Seventeen females participated, age 23.5 ± 0.5 years; body mass index 21.0 ± 0.4 kg/m 2 , with a mean dietary intake of 78 ± 1 E% fat, 19 ± 1 E% protein and 3 ± 0 E% carbohydrates. Measurements were performed at baseline and post-intervention. Fasting glucose decreased from 4.7 ± 0.1 to 4.4 mmol/L ( p < 0.001) during the dietary intervention whereas fasting insulin was unaffected. Glucose area under the curve (AUC) and insulin AUC did not change during an OGTT after the intervention. Before the intervention, a bout of aerobic exercise reduced fasting glucose (4.4 ± 0.1 mmol/L, p < 0.001) and glucose AUC (739 ± 41 to 661 ± 25, p = 0.008) during OGTT the following morning. After the intervention, exercise did not reduce fasting glucose the following morning, and glucose AUC during an OGTT increased compared to the day before (789 ± 43 to 889 ± 40 mmol/L∙120min -1 , p = 0.001). AUC for insulin was unaffected. The dietary intervention increased total cholesterol ( p < 0.001), low-density lipoprotein ( p ≤ 0.001), high-density lipoprotein ( p = 0.011), triglycerides ( p = 0.035), and free fatty acids ( p = 0.021). In conclusion, 3-week LCHF-diet reduced fasting glucose, while glucose tolerance was unaffected. A bout of exercise post-intervention did not decrease AUC glucose as it did at baseline. Total cholesterol increased, mainly due to increments in low-density lipoprotein. LCHF-diets should be further evaluated and carefully considered for healthy individuals., (Copyright © 2019 Valsdottir, Henriksen, Odden, Nellemann, Jeppesen, Hisdal, Westerberg and Jensen.)

Background: The effect of statins over time on coronary atherosclerosis in patients with inflammatory joint diseases (IJD) is unknown. Our aim was to evaluate the change in coronary plaque morphology and volume in long-term statin-treated patients with IJD., Methods: Sixty-eight patients with IJD and carotid artery plaque(s) underwent coronary computed tomography angiography before and after a mean of 4.7 (range 4.0-6.0) years of statin treatment. The treatment target for low density lipoprotein cholesterol (LDL-c) was ≤1.8 mmol/L. Changes in plaque volume (calcified, mixed/soft and total) and coronary artery calcification (CAC) from baseline to follow-up were assessed using the 17-segment American Heart Association-model., Results: Median (IQR) increase in CAC after statin treatment was 38 (5-236) Agatston units (p<0.001). Calcified and total plaque volume increased with 5.6 (0.0-49.1) and 2.9 (0.0-23.5) mm3, respectively (p<0.001 for both). The median (IQR) change in soft/mixed plaque volume was -10 (-7.1-0.0), p = <0.001. Patients who had obtained the LDL-c treatment target at follow-up, experienced reduced progression of both CAC and total plaque volume compared to patients with LDL-c >1.8mmol/L (21 [2-143] vs. 69 [16-423], p = 0.006 and 0.65 [-1.0-13.9] vs. 13.0 [0.0-60.8] mm3, p = 0.019, respectively)., Conclusions: A progression of total atherosclerotic plaque volume in statin-treated patients with IJD was observed. However, soft/mixed plaque volume was reduced, suggesting an alteration in plaque composition. Patients with recommended LDL-c levels at follow-up had reduced atherosclerotic progression compared to patients with LDL-c levels above the treatment target, suggesting a beneficial effect of treatment to guideline-recommended lipid targets in IJD patients., Competing Interests: The authors have declared that no competing interests exist.

Mucosal pathology due to chronic mesenteric ischemia (CMI) is rarely seen during upper endoscopy. Combining Laser Doppler Flowmetry (LDF) and Visible Light Spectroscopy (VLS) may aid in detection of CMI at an early stage. We aimed to investigate the utility of LDF and VLS in detecting microcirculatory changes in patients with CMI during upper endoscopy. In a single center, prospective study, 104 patients were evaluated for mesenteric ischemia during a 24 months period. Patients with a consensus diagnosis of CMI ( n  = 40) were examined with LDF and VLS. Thirty-two were successfully treated and had a definitive diagnosis of CMI. Results were compared with controls ( n  = 38) with normal intestinal circulation evaluated with duplex ultrasonography (DUS). Treatment response was evaluated clinically and with DUS at 1 month and with VLS and LDF at 3 months. A significant reduction in mucosal capillary hemoglobin oxygen saturation (SO 2 ) was found in CMI patients compared to controls before treatment: mean ± SD: 67 ± 9%, 81 ± 4%, respectively ( p  < .001). A significant reduction was also seen for the relative hemoglobin (rHb) amount, flow and velocity ( p  < .001). The sensitivity of SO 2 measured by VLS for diagnosing CMI was 94% and the specificity 72% (cut-off 78%), calculated with ROC curve analysis. A combination of SO 2 and rHb increased the test sensitivity and specificity to 97% and 79%, respectively. Conclusion: CMI patients have significantly reduced microcirculation in the stomach and duodenum compared to controls. The results suggest that VLS should be included when performing an upper endoscopy in patients with suspected CMI.

Intermittent negative pressure (INP) applied to the lower leg induces acute increase in arterial and skin blood flow. The aim of this study was to identify the optimal level of INP to increase blood flow in patients with lower extremity peripheral artery disease (PAD). We investigated the acute effects of different levels of INP in 16 subjects (7 women and 9 men, mean (SD) age 71(8) years) diagnosed with PAD. During application of INP in a pressure chamber sealed below the knee, arterial blood flow was continuously recorded in the dorsalis pedis artery or tibialis posterior artery (ultrasound Doppler), and skin blood flow was continuously recorded at the pulp of the first toe (laser Doppler). Different pressure levels (0, -10, -20, -40, and -60 mmHg) were tested in randomized order. Maximal arterial blood flow relative to baseline (median [25th, 75th percentiles]) was: 0 mmHg; 1.08 (1.02, 1.13), -10 mmHg; 1.11 (1.07, 1.17), -20 mmHg; 1.18 (1.11, 1.32), -40 mmHg; 1.39 (1.27, 1.91) and -60 mmHg; 1.48 (1.37, 1.78). Maximal laser Doppler flux (LDF) relative to baseline was: 0 mmHg; 1.06 (1.02, 1.12), -10 mmHg; 1.08 (1.05, 1.16) -20 mmHg; 1.12 (1.06, 1.27), -40 mmHg; 1.24 (1.14, 1.50) and -60 mmHg; 1.35 (1.10, 1.70). There were significantly higher maximal arterial blood flow and maximal LDF at -40 mmHg compared with -10 mmHg (P = 0.001 and P = 0.025, respectively). There were no significant differences in maximal arterial blood flow and maximal LDF between 0 and -10 mmHg (both P = 1.0), or between -40 and -60 mmHg (both P = 1.0). INP of -40 mmHg was the lowest negative pressure level that increased blood flow., (© 2019 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

Purpose: Respiratory variations in pulse pressure (dPP) and photoplethysmographic waveform amplitude (dPOP) are used for evaluation of volume status in mechanically ventilated patients. Amplification of intrathoracic pressure changes may enable their use also during spontaneous breathing. We investigated the association between the degree of hypovolemia and dPP and dPOP at different levels of two commonly applied clinical interventions; positive expiratory pressure (PEP) and continuous positive airway pressure (CPAP)., Methods: 20 healthy volunteers were exposed to progressive hypovolemia by lower body negative pressure (LBNP). PEP of 0 (baseline), 5 and 10 cmH2O was applied by an expiratory resistor and CPAP of 0 (baseline), 5 and 10 cmH2O by a facemask. dPP was obtained non-invasively with the volume clamp method and dPOP from a pulse oximeter. Central venous pressure was measured in 10 subjects. Associations between changes were examined using linear mixed-effects regression models., Results: dPP increased with progressive LBNP at all levels of PEP and CPAP. The LBNP-induced increase in dPP was amplified by PEP 10 cmH20. dPOP increased with progressive LBNP during PEP 5 and PEP 10, and during all levels of CPAP. There was no additional effect of the level of PEP or CPAP on dPOP. Progressive hypovolemia and increasing levels of PEP were reflected by increasing respiratory variations in CVP., Conclusion: dPP and dPOP reflected progressive hypovolemia in spontaneously breathing healthy volunteers during PEP and CPAP. An increase in PEP from baseline to 10 cmH2O augmented the increase in dPP, but not in dPOP., Competing Interests: The authors have declared that no competing interests exist.

Objective: To investigate the association between sympathetic activity, reactive hyperemia and brachial artery flow-mediated dilation (FMD)., Background: It is claimed that major surgery has an impact on endothelial function, as observed by post-operative reduced brachial artery FMD response. However, another explanation for the observed reduced FMD response post-operatively may be sympathetic stress-induced reduction in blood flow., Methods: Seventeen healthy volunteers with a median age (25th-75th percentiles) of 23.5 (23-24.8) years were recruited. Participants' brachial blood flow and FMD response were measured (i) during normal non-stress conditions (Normal1); (ii) during exposure to ice water; and (iii) afterwards, under normal non-stress conditions (Normal2). We continuously measured arterial blood pressure (Finometer), heart rate (ECG), skin blood flow of the index finger (laser Doppler), and brachial artery blood flow and diameter (Ultrasound Doppler). Measurements were taken at baseline; before a 5-min suprasystolic forearm occlusion; and following a 3-min post-occlusion, to measure reactive hyperemia and FMD., Results: Median (25th-75th percentiles) FMD response after exposure to ice water was reduced compared to non-stress conditions [4.9 (2.9-8.4) % during ice water vs. 9.7 (7.6-12.2) % Normal1 and 9.7 (6.4-10.3) % Normal2, P < 0.001]. Blood flow 60 s after cuff-deflation during ice water exposure was significantly reduced to 328 (289-421) mL compared to non-stress conditions (both P < 0.05). No differences were observed between Normal1 [446 (359-506) mL] and Normal2 [455 (365-515) mL] (both P > 0.05). Heart rate significantly increased during ice water exposure [67 (59-69) beats/min)] compared to 55 (49-60) beats/min during Normal1 and 54 (47-60) beats/min during Normal2 (both P < 0.05). MAP did not change during Normal1 [72 (64-84)] or during Normal2 [71 (65-81) mm Hg] (both P > 0.05), but increased to 86 (75-98) mm Hg during ice water exposure (P < 0.05)., Conclusions: Increased sympathetic activity resulted in decreased blood flow and brachial artery FMD response in healthy volunteers, independent of endothelial dysfunction. Future studies should adjust for blood flow when interpreting the FMD response., Competing Interests: The authors have declared that no competing interests exist.

Reductions in cerebral oxygen saturation (ScO2) measured by near infra-red spectroscopy have been found during compensated hypovolemia in the lower body negative pressure (LBNP)-model, which may reflect reduced cerebral blood flow. However, ScO2 may also be contaminated from extracranial (scalp) tissues, mainly supplied by the external carotid artery (ECA), and it is possible that a ScO2 reduction during hypovolemia is caused by reduced scalp, and not cerebral, blood flow. The aim of the present study was to explore the associations between blood flow in precerebral arteries and ScO2 during LBNP-induced hypovolemia. Twenty healthy volunteers were exposed to LBNP 20, 40, 60 and 80 mmHg. Blood flow in the internal carotid artery (ICA), ECA and vertebral artery (VA) was measured by Doppler ultrasound. Stroke volume for calculating cardiac output was measured by suprasternal Doppler. Associations of changes within subjects were examined using linear mixed-effects regression models. LBNP reduced cardiac output, ScO2 and ICA and ECA blood flow. Changes in flow in both ICA and ECA were associated with changes in ScO2 and cardiac output. Flow in the VA did not change during LBNP and changes in VA flow were not associated with changes in ScO2 or cardiac output. During experimental compensated hypovolemia in healthy, conscious subjects, a reduced ScO2 may thus reflect a reduction in both cerebral and extracranial blood flow., Competing Interests: The authors have declared that no competing interests exist.

Swimming-induced pulmonary edema (SIPE) may develop during strenuous physical exertion in water. This case series reports on three cases of suspected late-presenting SIPE during the Norseman Xtreme Triathlon. A 30-year-old male professional (PRO) triathlete, a 40-year-old female AGE GROUP triathlete and a 34-year-old male AGE GROUP triathlete presented with shortness of breath, chest tightness and coughing up pink sputum during the last part of the bike phase. All three athletes reported an improvement in breathing during the first major uphill of the bike phase and increasing symptoms during the downhill. The PRO athlete had a thoracic computed tomography, and the scan showed bilateral ground glass opacity in the peripheral lungs. The male AGE GROUP athlete had a normal chest x-ray. Both athletes were admitted for further observation and discharged from hospital the following day, with complete regression of symptoms. The female athlete recovered quickly following pre-hospital oxygen treatment. Non-cardiogenic pulmonary edema associated with endurance sports is rare but potentially very dangerous. Knowledge and awareness of possible risk factors and symptoms are essential, and the results presented in this report emphasize the importance of being aware of the possible delayed development of symptoms. To determine the presence of pulmonary edema elicited by strenuous exercise, equipment for measuring oxygen saturation should be available for the medical staff on site.

Increase in mean shear stress represents an important and potent hemodynamic stimulus to improve conduit artery endothelial function in humans. No previous study has examined whether fluctuations in shear rate patterns, without altering mean shear stress, impacts conduit artery endothelial function. This study examined the hypothesis that 30-min exposure to fluctuations in shear rate patterns, in the presence of unaltered mean shear rate, improves brachial artery flow-mediated dilation. Fifteen healthy men (27.3 ± 5.0 yr) completed the study. Bilateral brachial artery flow-mediated dilation was assessed before and after unilateral exposure to 30 min of intermittent negative pressure (10 s, -40mmHg; 7 s, 0 mmHg) to induce fluctuation in shear rate, while the contralateral arm was exposed to a resting period. Negative pressure significantly increased shear rate, followed by a decrease in shear rate upon pressure release (both P < 0.001). Across the 30-min intervention, mean shear rate was not different compared with baseline ( P = 0.458). A linear mixed model revealed a significant effect of time observed for flow-mediated dilation ( P = 0.029), with exploratory post hoc analysis showing an increase in the intervention arm (∆FMD +2.0%, P = 0.008), but not in the contralateral control arm (∆FMD +0.5%, P = 0.664). However, there was no effect for arm ( P = 0.619) or interaction effect ( P = 0.096). In conclusion, we found that fluctuations in shear patterns, with unaltered mean shear, improves brachial artery flow-mediated dilation. These novel data suggest that fluctuations in shear pattern, even in the absence of altered mean shear, represent a stimulus to acute change in endothelial function in healthy individuals. NEW & NOTEWORTHY Intermittent negative pressure applied to the forearm induced significant fluctuations in antegrade and retrograde shear rate, while mean shear was preserved relative to baseline. Our exploratory study revealed that brachial artery flow-mediated dilation was significantly improved following 30-min exposure to intermittent negative pressure. Fluctuations in blood flow or shear rate, with unaltered mean shear, may have important implications for vascular health; however, further research is required to identify the underlying mechanisms and potential long-term health benefits.

Objectives: This study sought to investigate the hypothesis that patients with left bundle branch block (LBBB) are hypersensitive to elevated afterload., Background: Epidemiological data suggest that LBBB can provoke heart failure in patients with hypertension., Methods: In 11 asymptomatic patients with isolated LBBB and 11 age-matched control subjects, left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS) were measured by echocardiography. Systolic arterial pressure was increased by combining pneumatic extremity constrictors and handgrip exercise. To obtain more insight into mechanisms of afterload response, 8 anesthetized dogs with left ventricular (LV) micromanometer and dimension crystals were studied during acutely induced LBBB and aortic constriction. Regional myocardial work was assessed by LV pressure-dimension analysis., Results: Consistent with normal afterload dependency, elevation of systolic arterial pressure by 38 ± 12 mm Hg moderately reduced LVEF from 60 ± 4% to 54 ± 6% (p < 0.01) in control subjects. In LBBB patients, however, a similar blood pressure increase caused substantially larger reduction in LVEF (p < 0.01), from 56 ± 6% to 42 ± 7% (p < 0.01). There were similar findings for GLS. In the dog model, aortic constriction abolished septal shortening (p < 0.02), and septal work decreased to negative values (p < 0.01). Therefore, during elevated systolic pressure, the septum made no contribution to global LV work, as indicated by net negative work, and instead absorbed energy from work done by the LV lateral wall., Conclusions: Moderate elevation of arterial pressure caused marked reductions in LVEF and GLS in patients with LBBB. This reflects a cardiodepressive effect of elevated afterload in the dyssynchronous ventricle and was attributed to loss of septal function., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Low water temperature (<15 °C) has been faced by many organizers of triathlons and swim-runs in the northern part of Europe during recent years. More knowledge about how cold water affects athletes swimming in wetsuits in cold water is warranted. The aim of the present study was therefore to investigate the physiological response when swimming a full Ironman distance (3800 m) in a wetsuit in 10 °C water. Twenty triathletes, 37.6 ± 9 years (12 males and 8 females) were recruited to perform open water swimming in 10 °C seawater; while rectal temperature (Tre) and skin temperature (Tskin) were recorded. The results showed that for all participants, Tre was maintained for the first 10-15 min of the swim; and no participants dropped more than 2 °C in Tre during the first 30 min of swimming in 10 °C water. However; according to extrapolations of the results, during a swim time above 135 min; 47% (8/17) of the participants in the present study would fall more than 2 °C in Tre during the swim. The results show that the temperature response to swimming in a wetsuit in 10 °C water is highly individual. However, no participant in the present study dropped more than 2 °C in Tre during the first 30 min of the swim in 10 °C water., Competing Interests: The authors declare no conflict of interest

The purpose of the present study was to investigate muscle hypertrophy, strength, and myonuclear and satellite cell (SC) responses to high-frequency blood flow-restricted resistance exercise (BFRRE). Thirteen individuals [24 ± 2 yr (mean ± SD), 9 men] completed two 5-day blocks of 7 BFRRE sessions, separated by a 10-day rest period. Four sets of unilateral knee extensions to voluntary failure at 20% of one repetition maximum (1RM) were conducted with partial blood flow restriction (90-100 mmHg). Muscle samples obtained before, during, 3 days, and 10 days after training were analyzed for muscle fiber area (MFA), myonuclei, SC, and mRNA and miRNA expression. Muscle size was measured by ultrasonography and magnetic resonance imaging and strength with 1RM knee extension. With the first block of BFRRE, SC number increased in both fiber types (70%-80%, P < 0.05), whereas type I and II MFA decreased by 6 ± 7% and 15 ± 11% ( P < 0.05), respectively. With the second block of training, muscle size increased by 6%-8%, whereas the number of SCs (type I: 80 ± 63%, type II: 147 ± 95%), myonuclei (type I: 30 ± 24%, type II: 31 ± 28%), and MFA (type I: 19 ± 19%, type II: 11 ± 19%) peaked 10 days after the second block of BFRRE, whereas strength peaked after 20 days of detraining (6 ± 6%, P < 0.05). Pax7- and p21 mRNA expression were elevated during the intervention, whereas myostatin, IGF1R, MyoD, myogenin, cyclinD1 and -D2 mRNA did not change until 3-10 days postintervention. High-frequency low-load BFRRE induced robust increases in SC, myonuclei, and muscle size but modest strength gains. Intriguingly, the responses were delayed and peaked 10-20 days after the training intervention, indicating overreaching. NEW & NOTEWORTHY In line with previous studies, we demonstrate that high-frequency low-load blood flow-restricted resistance exercise (HF-BFRRE) can elicit robust increases in satellite cell and myonuclei numbers, along with gains in muscle size and strength. However, our results also suggest that these processes can be delayed and that with very strenuous HF-BFRRE, there may even be transient muscle fiber atrophy, presumably because of accumulated stress responses. Our findings have implications for the prescription of BFR exercise.

Vascular disease is a major cause of death worldwide, and the growing need for replacement vessels is not fully met by autologous grafts or completely synthetic alternatives. Tissue engineering has emerged as a compelling strategy for the creation of blood vessels for reconstructive surgeries. One promising method to obtain a suitable vessel scaffold is decellularization of donor vascular tissue followed by recellularization with autologous cells. To prevent thrombosis of vascular grafts, a confluent and functional autologous endothelium is required, and researchers are still looking for the optimal cell source and recellularization procedure. Recellularization of a decellularized scaffold with only a small volume of whole blood was recently put forward as a feasible option. Here we show that, in contrast to the published results, this method fails to re-endothelialize decellularized veins. Only occasional nucleated cells were seen on the luminal surface of the scaffolds. Instead, we saw fibrin threads, platelets and scattered erythrocytes. Molecular remnants of the endothelial cells were still attached to the scaffold, which explains in part why earlier results were misinterpreted. Decellularized vascular tissues may still be the best scaffolds available for vascular tissue engineering. However, for the establishment of an adequate autologous endothelial lining, methods other than exposure to autologous whole blood need to be developed., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Study Design: Experimental prestudy and poststudy., Objectives: Examine the acute effects of intermittent negative pressure (INP) applied to the lower limb on foot circulation in people with spinal cord injuries (SCIs)., Setting: Vascular laboratory, Oslo University Hospital., Methods: Twenty-four people with SCI (median age 59 years, range 29-74) were exposed to lower leg INP (-40 mm Hg) using an air-tight pressure chamber connected to an INP generator. The contralateral leg was placed outside the pressure chamber. We continuously measured arterial blood flow velocity (ultrasound Doppler), skin blood flow (laser Doppler), skin temperature of the dorsum of the foot, heart rate (ECG) and systemic blood pressure (Finometer) during 5-min baseline (atmospheric pressure), followed by 10-min INP (alternating 10 s -40 mm Hg and 7 s atmospheric pressure), and 5-min post-INP (atmospheric pressure). Skin blood flow was measured on the foot placed outside the pressure chamber. A mixed effects regression model was applied to estimate the effect of INP on blood flow. To quantify flow fluctuations, we calculated cumulative up-and-down changes in arterial blood flow velocity per minute., Results: Flow fluctuations increased during INP compared to baseline [32.3 cm/s/min (95% CI 26.9 to 37.7) vs. 15.2 cm/s/min (95% CI 9.8 to 20.6), P < 0.001]. Peak blood flow velocity and skin blood flow was reached 2-3 s after the onset of negative pressure and increased 33% (95% CI 16 to 46, P < 0.001) and 11% (95% CI -4.1 to 60, P = 0.14) above baseline, respectively., Conclusions: INP induced increased foot arterial blood flow fluctuations compared to baseline., Sponsorships: The Norwegian Research Council provided funding to Otivio (grant: 241589).

Study Design: Randomized, assessor-blinded crossover pilot study., Objectives: To explore the use of an intermittent negative pressure (INP) device for home use in addition to standard wound care (SWC) for patients with spinal cord injury (SCI) and chronic leg and foot ulcers before conducting a superiority trial., Setting: Patient homes and outpatient clinic., Methods: A 16-week crossover trial on 9 SCI patients (median age: 57 years, interquartile range [IQR] 52-66), with leg ulcers for 52 of weeks (IQR: 12-82) duration. At baseline, patients were allocated to treatment with INP + SWC or SWC alone. After 8 weeks, the ulcers were evaluated. To assess protocol adherence, the patients were then crossed over to the other group and were evaluated again after another 8 weeks. Lower limb INP treatment consisted of an airtight pressure chamber connected to an INP generator (alternating 10 s -40mmHg/7 s atmospheric pressure) used 2 h/day at home. Ulcer healing was assessed using a photographic wound assessment tool (PWAT) and by measuring changes in wound surface area (WSA)., Results: Seven of nine recruited patients adhered to a median of 90% (IQR: 80-96) of the prescribed 8-week INP-protocol, and completed the study without side effects. PWAT improvement was observed in 4/4 patients for INP + SWC vs. 2/5 patients for SWC alone (P = 0.13). WSA improved in 3/4 patients allocated to INP + SWC vs. 3/5 patients in SWC alone (P = 0.72)., Conclusions: INP can be used as a home-based treatment for patients with SCI, and its efficacy should be tested in an adequately sized, preferably multicenter randomized trial.

Background: Exercise tolerance decreases as COPD progresses. Pulmonary hypertension (PH) is common in COPD and may reduce performance further. COPD patients with and without PH could potentially be identified by cardiopulmonary exercise test (CPET). However, results from previous studies are diverging, and a unified conclusion is missing. We hypothesized that CPET combined with arterial blood gases is useful to discriminate between COPD outpatients with and without PH., Methods: In total, 93 COPD patients were prospectively included. Pulmonary function tests, right heart catheterization, and CPET with blood gases were performed. The patients were divided, by mean pulmonary artery pressure, into COPD-noPH (<25 mmHg) and COPD-PH (≥25 mmHg) groups. Linear mixed models (LMMs) were fitted to estimate differences when repeated measurements during the course of exercise were considered and adjusted for gender, age, and airway obstruction., Results: Ventilatory and/or hypoxemic limitation was the dominant cause of exercise termination. In LMM analyses, significant differences between COPD-noPH and COPD-PH were observed for PaO 2 , SaO 2 , PaCO 2 , ventilation, respiratory frequency, and heart rate. PaO 2 <61 mmHg (8.1 kPa) during unloaded pedaling, the only load level achieved by all the patients, predicted PH with a sensitivity of 86% and a specificity of 78%., Conclusion: During CPET, low exercise performance and PaO 2 strongly indicated PH in COPD patients., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Objective: Low association between cardiac symptoms and coronary artery disease (CAD) in patients with inflammatory joint diseases (IJD) demands for objective markers to improve cardiovascular risk stratification. Our main aim was to evaluate the prevalence and characteristics of CAD in patients with IJD with carotid artery plaques. Furthermore, we aimed to assess associations of carotid ultrasonographic findings and coronary plaques., Methods: Eighty-six patients (61% female) with IJD (55 with rheumatoid arthritis, 21 with ankylosing spondylitis and 10 with psoriatic arthritis) and carotid artery plaque were referred to coronary CT angiography (CCTA). CAD was evaluated using the modified 17-segment American Heart Association model. Calcium score, plaque composition, segment involvement score and segment stenosis score were assessed and correlated to the carotid artery plaques and cardiovascular disease risk factors in logistic and linear regression analyses. Risk prediction models were tested with various cut-off values for associating variables., Results: Fifty-five patients (66%) had CAD assessed by CCTA and 36 (43%) of these had coronary plaques defined as either mixed or soft. Eleven patients (13%) had obstructive CAD. The best risk prediction model (area under the curve: 0.832, 95% CI 0.730 to 0.935) included the combination of variables with cut-off values: age ≥55 years (OR: 12.18, 95% CI 2.80 to 53.05), the carotid-intima media thickness ≥0.7 mm (OR: 4.08, 95% CI 1.20 to 13.89) and carotid plaque height ≥1.5 mm (OR: 8.96, 95% CI 1.68 to 47.91), p<0.05., Conclusion: Presence of carotid plaque is alone not sufficient to identify patients at risk for CAD, and a combination of ultrasonographic measurements may be useful in risk stratification of patients with IJD., Trial Registration Number: NCT01389388, Results., Competing Interests: Competing interests: None declared.

Background: Intermittent negative pressure (INP) applied to the lower leg and foot increases foot perfusion in healthy volunteers. The aim of the present study was to describe the effects of INP to the lower leg and foot on foot macro- and microcirculation in patients with lower extremity peripheral arterial disease (PAD)., Methods: In this experimental study, we analyzed foot circulation during INP in 20 patients [median (range): 75 (63-84yrs)] with PAD. One leg was placed inside an air-tight vacuum chamber connected to an INP-generator. During application of INP (alternating 10s of -40mmHg/7s of atmospheric pressure), we continuously recorded blood flow velocity in a distal foot artery (ultrasound Doppler), skin blood flow on the pulp of the first toes (laser Doppler), heart rate (ECG), and systemic blood pressure (Finometer). After a 5-min baseline sequence (no pressure), a 10-min INP sequence was applied, followed by 5-min post-INP (no pressure). To compare and quantify blood flow fluctuations between sequences, we calculated cumulative up-and-down fluctuations in arterial blood flow velocity per minute., Results: Onset of INP induced an increase in arterial flow velocity and skin blood flow. Peak blood flow velocity was reached 3s after the onset of negative pressure, and increased 46% [(95% CI 36-57), P<0.001] above baseline. Peak skin blood flow was reached 2s after the onset of negative pressure, and increased 89% (95% CI 48-130), P<0.001) above baseline. Cumulative fluctuations per minute were significantly higher during INP-sequences compared to baseline [21 (95% CI 12-30)cm/s/min to 41 (95% CI 32-51)cm/s/min, P<0.001]. Mean INP blood flow velocity increased significantly ~12% above mean baseline blood flow velocity [(6.7 (95% CI 5.2-8.3)cm/s to 7.5 (95% CI 5.9-9.1)cm/s, P = 0.03)]., Conclusion: INP increases foot macro- and microcirculatory flow pulsatility in patients with PAD. Additionally, application of INP resulted in increased mean arterial blood flow velocity.

In previous studies, Flow Mediated Dilation (FMD) was used to study the effect of cardiac surgery on endothelial function. This study investigated the effect of on-pump cardiac surgery on FMD and reactive hyperemia. The FMD-response and reactive hyperemia were measured in 25 patients the morning before- and the first morning after cardiac surgery. Brachial artery diameter and blood flow were measured with ultrasound at baseline before 5 min occlusion of the blood flow to the forearm, and continuously for 3 min after release of the occlusion. An exponential wash-out model was fitted to the blood flow over time. Nineteen patients remained for final data analysis. Data are mean ± SEM The FMD response was reduced after surgery from 3.3 ± 0.5% to 1.4 ± 0.6% ( P  = 0.02). Max blood flow after cuff release was reduced from 342 ± 30 mL preoperatively to 305 ± 30 mL postoperatively ( P  < 0.00) and fell toward baseline significantly quicker; preoperative half-life was 36 ± 2.4 sec. versus 29 ± 1.9 sec postoperatively ( P  < 0.00). Resting blood flow was reduced from 84 ± 9 mL/min to 66 ± 9 mL/min, ( P  < 0.00). Brachial artery baseline diameter was unaffected by coronary artery bypass surgery ( P  = 0.3). The observed reduction in brachial artery FMD after surgery, by previous authors taken to represent endothelial dysfunction, may at least partly be due to reduced hyperemic flow postoperatively. In studies where FMD is measured on multiple occasions, flow data should also be included. Reduced postoperative blood flow to the arm may indicate regional differences in vascular resistance after cardiac surgery., (© 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

Background: The role of speckle-tracking echocardiography in the assessment of chronic aortic regurgitation (AR) is not established. Load dependency may encumber the interpretation of strain measurements in the chronically overloaded left ventricle. The aim of this study was to investigate the mechanisms of left ventricular (LV) contraction patterns in asymptomatic patients with moderate to severe AR and preserved ejection fractions., Methods: In this prospective, cross-sectional study, 31 patients with moderate to severe AR, 15 elite endurance athletes, and 17 healthy control subjects were examined using three-dimensional speckle-tracking echocardiography. Global circumferential strain (GCS), global longitudinal strain (GLS), end-systolic circumferential wall stress (ESSc), end-systolic meridional wall stress (ESSm), and the wall stress ratio (ESSc/ESSm) were measured., Results: LV end-diastolic volumes were similar in athletes and patients with AR and significantly larger than in healthy control subjects. Values of GLS in control subjects, athletes, and patients with AR were -18.8 ± 1.9%, -17.3 ± 2.0%, and -16.4± 2.0%, respectively (control subjects vs athletes and patients, P < .05), whereas values of GCS were -16.9 ± 2.0%, -15.5 ± 1.9%, and -17.9 ± 2.6%, respectively (athletes vs control subjects and patients, P < .01). The ESSc/ESSm ratio was lower in patients with AR (P < .01). When adjusted for ESSm, GLS remained impaired in patients compared with control subjects and athletes (P = .015). On the other hand, GCS was better in patients with AR when adjusted for ESSc (P = .003)., Conclusions: In compensated AR, relatively high GCS compensates for reduced GLS in a manner consistent with the preserved ejection fractions observed in these patients., (Copyright © 2016 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved.)

Peripheral circulation is severely compromised in the advanced stages of peripheral arterial disease. Recently, it was shown that the application of -40 mmHg intermittent negative pressure (INP) to the lower leg and foot enhances macro- and microcirculation in healthy volunteers. In this case report, we describe the effects of INP treatment on four patients with lower limb ischemia and hard-to-heal leg and foot ulcers. We hypothesized that INP therapy may have beneficial hemodynamic and clinical effects in the patients. Four patients (age range: 61-79 years) with hard-to-heal leg and foot ulcers (6-24 months) and ankle-brachial pressure indices of ≤0.60 on the affected side were included. They were treated with an 8-week intervention period of -40 mmHg INP (10 sec negative pressure and 7 sec atmospheric pressure) on the lower limbs. A custom-made vacuum chamber was used to apply INP to the affected lower leg and foot for 2 h per day. After 8 weeks of INP therapy, one ulcer healed completely, while the other three ulcers were almost completely healed. These cases suggest that INP may facilitate wound healing. The theoretical foundation is that INP assists wound healing by improving blood flow to the small blood vessels in the affected limb, increasing the flow of oxygen and nutrients to the cells., (© 2016 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.)

Objective: We evaluated the predictive value of these vascular biomarkers for cardiovascular disease (CVD) events in patients with rheumatoid arthritis (RA): aortic pulse wave velocity (aPWV), augmentation index (AIx), carotid intima-media thickness (cIMT), and carotid plaques (CP). They are often used as risk markers for CVD., Methods: In 2007, 138 patients with RA underwent clinical examination, laboratory tests, blood pressure testing, and vascular biomarker measurements. Occurrence of CVD events was recorded in 2013. Predictive values were assessed in Kaplan-Meier plots, log-rank, and crude and adjusted Cox proportional hazard (PH) regression analyses., Results: Baseline median age and disease duration was 59.0 years and 17.0 years, respectively, and 76.1% were women. CVD events occurred in 10 patients (7.2%) during a mean followup of 5.4 years. Compared with patients with low aPWV, AIx, cIMT, and without CP, patients with high aPWV (p < 0.001), high AIx (p = 0.04), high cIMT (p = 0.01), and CP (p < 0.005) at baseline experienced more CVD events. In crude Cox PH regression analyses, aPWV (p < 0.001), cIMT (p < 0.001), age (p = 0.01), statin (p = 0.01), and corticosteroid use (p = 0.01) were predictive of CVD events, while AIx was nonsignificant (p = 0.19). The Cox PH regression estimates for vascular biomarkers were not significantly altered when adjusting individually for demographic variables, traditional CVD risk factors, RA disease-related variables, or medication. All patients who developed CVD had CP at baseline., Conclusion: CP, aPWV, and cIMT were predictive of CVD events in this cohort of patients with RA. Future studies are warranted to examine the additive value of arterial stiffness and carotid atherosclerosis markers in CVD risk algorithms. Regional Ethical Committee approval numbers 2009/1582 and 2009/1583.

Intermittent negative pressure (INP) applied to the lower leg and foot may increase peripheral circulation. However, it is not clear how different patterns of INP affect macro- and microcirculation in the foot. The aim of this study was therefore to determine the effect of different patterns of negative pressure on foot perfusion in healthy volunteers. We hypothesized that short periods with INP would elicit an increase in foot perfusion compared to no negative pressure. In 23 healthy volunteers, we continuously recorded blood flow velocity in a distal foot artery, skin blood flow, heart rate, and blood pressure during application of different patterns of negative pressure (-40 mmHg) to the lower leg. Each participant had their right leg inside an airtight chamber connected to an INP generator. After a baseline period at atmospheric pressure, we applied four different 120 sec sequences with either constant negative pressure or different INP patterns, in a randomized order. The results showed corresponding fluctuations in blood flow velocity and skin blood flow throughout the INP sequences. Blood flow velocity reached a maximum at 4 sec after the onset of negative pressure (average 44% increase above baseline, P < 0.001). Skin blood flow and skin temperature increased during all INP sequences (P < 0.001). During constant negative pressure, average blood flow velocity, skin blood flow, and skin temperature decreased (P < 0.001). In conclusion, we observed increased foot perfusion in healthy volunteers after the application of INP on the lower limb., (© 2016 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.)

Cardiac surgery patients are urged to resume light physical activity on the first postoperative day, even if cardiac function may not have recovered fully after the operation. To elucidate the postoperative recovery process, we examined cardiac surgery patients with exercise echocardiography before and on the first day after the operation. Patients undergoing on-pump coronary artery bypass grafting were examined with echocardiography during semirecumbent cycle exercise. Patients exercised for five minutes at 10 W intensity and five minutes at 30 W intensity in bed with the upper body supported to approximately 30°. Fourteen patients were studied. Mitral annulus excursion and pulsed wave Doppler from the left ventricular outflow tract indicated postoperatively reduced cardiac stroke volume. Early diastolic tissue velocities of the mitral annulus were reduced, and early trans-mitral flow velocity was increased. The ratio between early mitral flow velocity and early diastolic mitral tissue velocity was increased postoperatively, indicating impaired left ventricular relaxation and increased left atrial pressure. Postoperative systolic mitral annulus tissue velocities were similar to preoperative velocities, indicating maintained systolic function. Postoperative exercise was associated with improvements in myocardial function indices and cardiac stroke volume similar to preoperative improvements. There were no signs of further deterioration in myocardial function during 30 W exercise. In summary, reduced left ventricular diastolic function after surgery resulted in reduced cardiac stroke volume, increased left atrial pressure and a higher rate of perceived exertion on the first postoperative day., (© 2014 Scandinavian Society of Clinical Physiology and Nuclear Medicine. Published by John Wiley & Sons Ltd.)

Background: Changes in cardiac power parameters incorporate changes in both aortic flow and blood pressure. We hypothesized that dynamic and non-dynamic cardiac power parameters would track hypovolemia better than equivalent flow- and pressure parameters, both during spontaneous breathing and non-invasive positive pressure ventilation (NPPV)., Methods: Fourteen healthy volunteers underwent lower body negative pressure (LBNP) of 0, -20, -40, -60 and -80 mmHg to simulate hypovolemia, both during spontaneous breathing and during NPPV. We recorded aortic flow using suprasternal ultrasound Doppler and blood pressure using Finometer, and calculated dynamic and non-dynamic parameters of cardiac power, flow and blood pressure. These were assessed on their association with LBNP-levels., Results: Respiratory variation in peak aortic flow was the dynamic parameter most affected during spontaneous breathing increasing 103 % (p < 0.001) from baseline to LBNP -80 mmHg. Respiratory variation in pulse pressure was the most affected dynamic parameter during NPPV, increasing 119 % (p < 0.001) from baseline to LBNP -80 mmHg. The cardiac power integral was the most affected non-dynamic parameter falling 59 % (p < 0.001) from baseline to LBNP -80 mmHg during spontaneous breathing, and 68 % (p < 0.001) during NPPV., Conclusions: Dynamic cardiac power parameters were not better than dynamic flow- and pressure parameters at tracking hypovolemia, seemingly due to previously unknown variation in peripheral vascular resistance matching respiratory changes in hemodynamics. Of non-dynamic parameters, the power parameters track hypovolemia slightly better than equivalent flow parameters, and far better than equivalent pressure parameters.

Introduction: Hypoxia caused by high altitude exposure can impair cerebral and mental functions. Blood flow and oxygenation of the buccal tissue can be reliable markers to detect hypoxia. In this study, near infrared spectroscopy was used in combination with a novel optical probe to evaluate the applicability of the novel probe in measuring hypoxia markers in buccal tissue under a hypoxic condition., Methods: Six healthy participants were tested at altitudes from 2000 to 16,000 ft inside a hypobaric chamber. The buccal reference measurements of blood flow and oxygen saturation were synchronized with the spectral measurements of the novel near infrared probe and the relationship between the reference measurements and spectral data were evaluated by multivariate partial least square method. In addition, finger oxygen saturation was measured during the experiment and the recordings were compared with buccal oxygen saturation., Results: The spectral analysis illustrated that the spectral data from the near infrared probe correlated strongly with the absorption features of both buccal flow and oxygenation measured by the reflectance sensors (average R(2) = 0.89). The results showed probably overestimated values for buccal oxygen saturation recorded by the reference pulse oximeter in comparison with finger oxygen saturation, with the mean difference increasing from 1.8% at 2000 ft to 11.4% at 16,000 ft., Conclusion: The novel near infrared probe showed promising results for simultaneous measurement of blood flow and oxygen saturation in the buccal tissue. The suggested method can be used as a new technique for early indication of hypoxia in future clinical applications.

Objective: Patients with inflammatory joint diseases (IJD) have a high prevalence of hypertension and increased arterial stiffness. The aim of the present study was to evaluate the effect of long-term rosuvastatin treatment on arterial stiffness, measured by augmentation index (AIx) and aortic pulse wave velocity (aPWV), and blood pressure (BP) in IJD patients with established atherosclerosis., Methods: Eighty-nine statin naïve IJD patients with carotid atherosclerotic plaque(s) (rheumatoid arthritis n = 55, ankylosing spondylitis n = 23, psoriatic arthritis n = 11) received rosuvastatin for 18 months to achieve low-density lipoprotein cholesterol goal ≤1.8 mmol/L. Change in AIx (ΔAIx), aPWV (ΔaPWV), systolic BP (ΔsBP) and diastolic BP (ΔdBP) from baseline to study end was assessed by paired samples t-tests. Linear regression was applied to evaluate associations between cardiovascular disease (CVD) risk factors, rheumatic disease specific variables and medication, and ΔAIx, ΔaPWV, ΔsBP and ΔdBP., Results: AIx, aPWV, sBP and dBP were significantly reduced from baseline to study end. The mean (95%CI) changes were: ΔAIx: -0.34 (-0.03, -0.65)% (p = 0.03), ΔaPWV: -1.69 (-0.21, -3.17) m/s2 (p = 0.03), ΔsBP: -5.27 (-1.61, -8.93) mmHg (p = 0.004) and ΔdBP -2.93 (-0.86, -5.00) mmHg (p = 0.01). In linear regression models, ∆aPWV was significantly correlated with ΔsBP and ΔdBP (for all: p<0.001)., Conclusions: There is an unmet need of studies evaluating CVD prevention in IJD patients. We have shown for the first time that long-term intensive lipid lowering with rosuvastatin improved arterial stiffness and induced a clinically significant BP reduction in patients with IJD. These improvements were linearly correlated and may represent novel insight into the pleiotropic effects by statins., Trial Registration: ClinicalTrials.gov NCT01389388.

Purpose: Investigate hemodynamic responses of resistance exercise (RE) with moderate load (i.e., international guidelines for RE of patients) versus RE with high load in patients with coronary artery disease (CAD)., Methods: Medically stable male (n = 11) and female patients (n = 4) treated with PCI or percutaneous coronary intervention, or coronary artery bypass surgery a minimum of 6 months before this study, performed three sets of 15RM and 4RM RE in a randomized order on separate days. Beat-to-beat systolic (SBP), diastolic (DBP) blood pressure, heart rate (HR), stroke volume (SV), cardiac output (CO), and systemic vascular resistance (SVR) were monitored at preexercise, and continuously during RE., Results: Compared with preexercise, SBP and DBP (mean of three sets) increased by 12% to 13% (both; P < 0.001) and 35% to 40% after 15RM RE (both; P < 0.001). 15RM SBP and DBP were higher than 4RM SBP and DBP (both; P < 0.001). The SBP of the fourth repetition of 15 RM RE was similar to the SBP of the fourth repetition of 4RM RE. Compared with preexercise, SV increased moderately after 4RM and 15 RM RE, respectively (both, P < 0.001). HR increased more after 15RM compared with 4RM RE (P < 0.05); thus, higher CO after 15RM (compared with 4RM RE; P < 0.05) was mainly caused by higher HR. SVR decreased by 15% (P < 0.001) and 50% (P < 0.01) after 4RM and 15RM RE., Conclusions: SBP and DBP increased significantly more during moderate load RE; thus, the magnitude of the external load is not the prime determinant of the pressure response during RE. If management of blood pressure is of concern, high load/low rep RE is preferable to medium load/high rep RE.

Background: We aimed to study whether pulmonary hypertension (PH) and elevated pulmonary vascular resistance (PVR) could be predicted by conventional echo Doppler and novel tissue Doppler imaging (TDI) in a population of chronic obstructive pulmonary disease (COPD) free of LV disease and co-morbidities., Methods: Echocardiography and right heart catheterization was performed in 100 outpatients with COPD. By echocardiography the time-integral of the TDI index, right ventricular systolic velocity (RVSmVTI) and pulmonary acceleration-time (PAAcT) were measured and adjusted for heart rate. The COPD patients were randomly divided in a derivation (n = 50) and a validation cohort (n = 50)., Results: PH (mean pulmonary artery pressure (mPAP) ≥ 25mmHg) and elevated PVR ≥ 2Wood unit (WU) were predicted by satisfactory area under the curve for RVSmVTI of 0.93 and 0.93 and for PAAcT of 0.96 and 0.96, respectively. Both echo indices were 100% feasible, contrasting 84% feasibility for parameters relying on contrast enhanced tricuspid-regurgitation. RVSmVTI and PAAcT showed best correlations to invasive measured mPAP, but less so to PVR. PAAcT was accurate in 90- and 78% and RVSmVTI in 90- and 84% in the calculation of mPAP and PVR, respectively., Conclusions: Heart rate adjusted-PAAcT and RVSmVTI are simple and reproducible methods that correlate well with pulmonary artery pressure and PVR and showed high accuracy in detecting PH and increased PVR in patients with COPD. Taken into account the high feasibility of these two echo indices, they should be considered in the echocardiographic assessment of COPD patients.

Objectives: The relation between chest pain and coronary atherosclerosis (CA) in patients with inflammatory joint diseases (IJD) has not been explored previously. Our aim was to evaluate the associations of the presence of chest pain and the predicted 10-year risk of cardiovascular disease (CVD) by use of several CVD risk algorithms, with CA verified by multidetector computed tomography (MDCT) coronary angiography., Methods: Detailed information concerning chest pain and CVD risk factors was obtained in 335 patients with rheumatoid arthritis and ankylosing spondylitis. In addition, 119 of these patients underwent MDCT coronary angiography., Results: Thirty-one percent of the patients (104/335) reported chest pain. Only six patients (1.8%) had atypical angina pectoris (pricking pain at rest). In 69 patients without chest pain, two thirds had CA, while in those who reported chest pain (n = 50), CA was present in 48.0%. In a logistic regression analysis, chest pain was not associated with CA (dependent variable) (p = 0.43). About 30% (Nagelkerke R (2)) of CA was explained by any of the CVD risk calculators: Systematic Coronary Risk Evaluation, Framingham Risk Score, or Reynolds Risk Score., Conclusion: The presence of chest pain was surprisingly infrequently reported in patients with IJD who were referred for a CVD risk evaluation. However, when present, chest pain was weakly associated with CA, in contrast to the predicted CVD risk by several risk calculators which was highly associated with the presence of CA. These findings suggest that clinicians treating patients with IJD should be alert of coronary atherosclerotic disease also in the absence of chest pain symptoms.

Introduction: Endothelial dysfunction is an early step in the atherosclerotic process and can be quantified by flow-mediated vasodilation (FMD). Our aim was to investigate the effect of long-term rosuvastatin therapy on endothelial function in patients with inflammatory joint diseases (IJD) with established atherosclerosis. Furthermore, to evaluate correlations between change in FMD (ΔFMD) and change in carotid plaque (CP) height, arterial stiffness [aortic pulse wave velocity (aPWV) and augmentation index (AIx)], lipids, disease activity and inflammation., Methods: Eighty-five statin-naïve patients with IJD and ultrasound-verified CP (rheumatoid arthritis: n = 53, ankylosing spondylitis: n = 24, psoriatic arthritis: n = 8) received rosuvastatin treatment for 18 months. Paired-samples t tests were used to assess ΔFMD from baseline to study end. Linear regression models were applied to evaluate correlations between ∆FMD and cardiovascular risk factors, rheumatic disease variables and medication., Results: The mean ± SD FMD was significantly improved from 7.10 ± 3.14 % at baseline to 8.70 ± 2.98 % at study end (p < 0.001). Improvement in AIx (p < 0.05) and CP height reduction (p = 0.001) were significantly associated with ΔFMD (dependent variable)., Conclusions: Long-term lipid lowering with rosuvastatin improved endothelial function in IJD patients with established atherosclerotic disease. Reduced arterial stiffness and CP regression were longitudinally correlated with the improvement in endothelial function measured by FMD., Trial Registration: ClinicalTrials.gov NCT01389388 . Registered 16 April 2010.