Similar insulin regulation of splanchnic FFA and VLDL-TG in men with nonalcoholic hepatic steatosis and steatohepatitis.

This study aimed to determine whether obese men with nonalcoholic fatty liver disease (NAFLD) display differences between those with simple steatosis versus steatohepatitis (NASH) in splanchnic and hepatic FFA and VLDL-triglycerides (VLDL-TG) balances. The study involved 17 obese men with biopsy-proven NAFLD (9 with NASH and 8 with simple steatosis). We used hepatic vein catheterization in combination with [3H]palmitate and [14C]VLDL-TG tracers to measure splanchnic palmitate and VLDL-TG uptake and release rates during basal and hyperinsulinemic conditions. Indocyanine green was used to measure splanchnic plasma flow. Splanchnic palmitate uptake was similar in the two groups and significantly reduced during hyperinsulinemia (NASH: 62 (48-77) versus 38 (18-58) µmol/min; simple steatosis: 62 (46-78) versus 45 (25-65) µmol/min, mean (95% CI), basal versus clamp periods, respectively, P = 0.02 time-effect). Splanchnic palmitate release was also comparable between groups and nonsignificantly diminished during hyperinsulinemia. The percent palmitate delivered to the liver originating from visceral adipose tissue lipolysis was similar and unchanged by hyperinsulinemia. Splanchnic uptake and release of VLDL-TG were similar between groups. Hyperinsulinemia suppressed VLDL-TG release (P <0.05 time-effect) in both groups. Insulin-mediated glucose disposal was similar in the two groups (P = 0.54). Obese men with NASH and simple steatosis have similar splanchnic uptake and release of FFA and VLDL-TG and a similar proportion of FFA from visceral adipose tissue lipolysis delivered to the liver. These results demonstrate that the splanchnic balances of FFA and VLDL-TG do not differ between obese men with NASH and those with simple steatosis.

Effects of semaglutide, empagliflozin and their combination on renal diffusion-weighted MRI and total kidney volume in patients with type 2 diabetes: a post hoc analysis from a 32 week randomised trial.

AIMS/HYPOTHESIS: The apparent diffusion coefficient (ADC) derived from diffusion-weighted MRI (DWI-MRI) has been proposed as a measure of changes in kidney microstructure, including kidney fibrosis. In advanced kidney disease, the kidneys often become atrophic; however, in the initial phase of type 2 diabetes, there is an increase in renal size. Glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter 2 inhibitors both provide protection against progression of kidney disease in diabetes. However, the mechanisms are incompletely understood. To explore this, we examined the effects of semaglutide, empagliflozin and their combination on renal ADC and total kidney volume (TKV). METHODS: This was a substudy of a randomised clinical trial on the effects of semaglutide and empagliflozin alone or in combination. Eighty patients with type 2 diabetes and high risk of CVD were randomised into four groups (n=20 in each) receiving either tablet placebo, empagliflozin, a combination of semaglutide and tablet placebo (herein referred to as the 'semaglutide' group), or the combination of semaglutide and empagliflozin (referred to as the 'combination-therapy' group). The semaglutide and the combination-therapy group had semaglutide treatment for 16 weeks and then had either tablet placebo or empagliflozin added to the treatment, respectively, for a further 16 weeks; the placebo and empagliflozin groups were treated with the respective monotherapy for 32 weeks. We analysed the effects of treatment on changes in ADC (cortical, medullary and the cortico-medullary difference [ΔADC; medullary ADC subtracted from cortical ADC]), as well as TKV measured by MRI. RESULTS: Both semaglutide and empagliflozin decreased cortical ADC significantly compared with placebo (semaglutide: -0.20×10-3 mm2/s [95% CI -0.30, -0.10], p<0.001; empagliflozin: -0.15×10-3 mm2/s [95% CI -0.26, -0.04], p=0.01). No significant change was observed in the combination-therapy group (-0.05×10-3 mm2/s [95%CI -0.15, 0.05]; p=0.29 vs placebo). The changes in cortical ADC were not associated with changes in GFR, albuminuria, TKV or markers of inflammation. Further, there were no changes in medullary ADC in any of the groups compared with placebo. Only treatment with semaglutide changed ΔADC significantly from placebo, showing a decrease of -0.13×10-3 mm2/s (95% CI -0.22, -0.04; p=0.01). Compared with placebo, TKV decreased by -3% (95% CI -5%, -0.3%; p=0.04), -3% (95% CI -5%, -0.4%; p=0.02) and -5% (95% CI -8%, -2%; p<0.001) in the semaglutide, empagliflozin and combination-therapy group, respectively. The changes in TKV were associated with changes in GFR, albuminuria and HbA1c. CONCLUSIONS/INTERPRETATION: In a population with type 2 diabetes and high risk of CVD, semaglutide and empagliflozin significantly reduced cortical ADC compared with placebo, indicating microstructural changes in the kidneys. These changes were not associated with changes in GFR, albuminuria or inflammation. Further, we found a decrease in TKV in all active treatment groups, which was possibly mediated by a reduction in hyperfiltration. Our findings suggest that DWI-MRI may serve as a promising tool for investigating the underlying mechanisms of medical interventions in individuals with type 2 diabetes but may reflect effects not related to fibrosis. TRIAL REGISTRATION: European Union Drug Regulating Authorities Clinical Trials Database (EudraCT) 2019-000781-38.

Magnetic resonance imaging as a noninvasive adjunct to conventional assessment of functional differences between kidneys in vivo and during ex vivo normothermic machine perfusion.

Normothermic machine perfusion (NMP) is increasingly considered for pretransplant kidney quality assessment. However, fundamental questions about differences between in vivo and ex vivo renal function, as well as the impact of ischemic injury on ex vivo physiology, remain unanswered. This study utilized magnetic resonance imaging (MRI), alongside conventional parameters to explore differences between in vivo and ex vivo renal function and the impact of warm ischemia on a kidney's behavior ex vivo. Renal MRI scans and samples were obtained from living pigs (n = 30) in vivo. Next, kidney pairs were procured and exposed to minimal, or 75 minutes of warm ischemia, followed by 6 hours of hypothermic machine perfusion. Both kidneys simultaneously underwent 6-hour ex vivo perfusion in MRI-compatible NMP circuits to obtain multiparametric MRI data. Ischemically injured ex vivo kidneys showed a significantly altered regional blood flow distribution compared to in vivo and minimally damaged organs. Both ex vivo groups showed diffusion restriction relative to in vivo. Our findings underscore the differences between in vivo and ex vivo MRI-based renal characteristics. Therefore, when assessing organ viability during NMP, it should be considered to incorporate parameters beyond the conventional functional markers that are common in vivo.

Daytime Variation in Kidney Perfusion, Oxygenation, and Sodium Concentration Assessed by Multiparametric MRI in Healthy Volunteers.

BACKGROUND: MRI can provide information on kidney structure, perfusion, and oxygenation. Furthermore, it allows for the assessment of kidney sodium concentrations and handling, allowing multiparametric evaluation of kidney physiology. Multiparametric MRI is promising for establishing prognosis and monitoring treatment responses in kidney diseases, but its intraindividual variation during the day is unresolved. PURPOSE: To investigate the variation in multiparametric MRI measurements from the morning to the evening. STUDY TYPE: Prospective. POPULATION: Ten healthy volunteers, aged 29 ± 5 without history of kidney disease. FIELD STRENGTH/SEQUENCE: 3 T/T1 mapping, blood-oxygen level dependent imaging, arterial spin labeling perfusion imaging, diffusion weighted imaging, and sodium imaging. ASSESSMENT: A multiparametric MRI protocol, yielding T1, R2*, ADC, renal blood flow and renal sodium levels, was acquired in the morning, noon, and evening. The participants were fasting prior to the first examination. Urine biochemical analyses were performed to complement MRI data. The cortex and medulla were analyzed separately in a semi-automatic fashion, and gradients of total sodium concentration (TSC) and R2* gradients were calculated from outer cortex to inner medulla. STATISTICAL TEST: Analyses of variance and mixed-effects models to estimate differences from time of day. Coefficients of variation to assess variability within and between participants. A P-value <0.05 was considered statistically significant. RESULTS: The coefficients of variation varied from 5% to 18% for proton-based parametric sequences, while it was 38% for TSC over a day. DATA CONCLUSION: Multiparametric MRI is stable over the day. The coefficients of variation over a day were lower for proton multiparametric MRI, but higher for sodium MRI. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 2.

Lung volumes are increased in fetuses with transposition of the great arteries on intrauterine MRI.

Fetal brain size is decreased in some children with complex CHDs, and the distribution of blood and accompanying oxygen and nutrients is regionally skewed from early fetal life dependent on the CHD. In transposition of the great arteries, deoxygenated blood preferentially runs to the brain, whereas the more oxygenated blood is directed towards the lungs and the abdomen. Knowledge of whether this impacts intrauterine organ development is limited. We investigated lung, liver, and total intracranial volume in fetuses with transposition of the great arteries using MRI.Eight fetuses with dextro-transposition and without concomitant disease or chromosomal abnormalities and 42 fetuses without CHD or other known diseases were scanned once or twice at gestational age 30 through 39 weeks. The MRI scans were conducted on a 1.5T system, using a 2D balanced steady-state free precession sequence. Slices acquired covered the entire fetus, slice thickness was 10 mm, pixel size 1.5 × 1.5 mm, and scan duration was 30 sec.The mean lung z score was significantly larger in fetuses with transposition compared with those without a CHD; mean difference is 1.24, 95% CI:(0.59;1.89), p < 0.001. The lung size, corrected for estimated fetal weight, was larger than in the fetuses without transposition; mean difference is 8.1 cm3/kg, 95% CI:(2.5;13.7 cm3/kg), p = 0.004.In summary, fetuses with dextro-transposition of the great arteries had both absolute and relatively larger lung volumes than those without CHD. No differences were seen in liver and total intracranial volume. Despite the small number of cases, the results are interesting and warrant further investigation.

Separate and combined effects of semaglutide and empagliflozin on kidney oxygenation and perfusion in people with type 2 diabetes: a randomised trial.

AIMS/HYPOTHESIS: Glucagon-like peptide-1 receptor agonists (GLP-1ras) and sodium-glucose cotransporter 2 inhibitors (SGLT2is) have shown kidney-protective effects. Improved kidney oxygenation and haemodynamic changes are suggested mechanisms; however, human data are scarce. We therefore investigated whether semaglutide (GLP-1ra), empagliflozin (SGLT2i) or their combination improve kidney oxygenation and perfusion. METHODS: The trial was undertaken at Aarhus University Hospital, Denmark. A total of 120 people with type 2 diabetes (HbA1c ≥48 mmol/mol [6.5%]) and at high risk of CVD (age ≥50 years) were randomised into four parallel groups (n=30 in each group) for 32 weeks: 1.0 mg semaglutide (open label); 10 mg empagliflozin (blinded to participants, caregivers, examiners and outcome assessors); their combination (1.0 mg semaglutide open label plus 10 mg empagliflozin blinded to participants, caregivers, examiners and outcome assessors); and placebo tablet (blinded to participants, caregivers, examiners and outcome assessors). Sequentially numbered, sealed envelopes containing computer-generated randomisation codes, provided by Glostrup Pharmacy, Glostrup, Denmark, determined the intervention. The two co-primary outcomes were change in kidney oxygenation and change in arterial stiffness. This paper reports on kidney oxygenation, for which 80 individuals as prespecified, 20 in each group, underwent MRI. We primarily hypothesised that kidney oxygenation would be improved in the active treatment groups compared with placebo after 32 weeks. Secondary outcomes included changes in kidney perfusion, erythropoietin, haematocrit, urine albumin/creatinine ratio (UACR) and GFR (measured using technetium-99m) compared with baseline and between treatment groups at week 32. RESULTS: Our model estimated a common baseline R2* value across all four groups in the cortex and the medulla. At baseline, the value was 24.5 (95% CI 23.9, 24.9) Hz in the medulla. After 32 weeks, the R2* values in the medulla were estimated to be 25.4 (95% CI 24.7, 26.2) Hz in the empagliflozin group and 24.5 (95% CI 23.9, 25.1) Hz in the placebo group (p=0.016) (higher R2* corresponds to a lower oxygenation). Semaglutide decreased perfusion in both the cortex and the medulla. Empagliflozin increased erythropoietin and haematocrit. All three active treatments decreased GFR but not UACR. Ten serious adverse events were reported, among them two occurrences of semaglutide-associated obstipation. CONCLUSIONS/INTERPRETATION: Our hypothesis, that semaglutide, empagliflozin or their combination improve kidney oxygenation, was rejected. On the contrary, empagliflozin induced a reduction in medullary kidney oxygenation. Semaglutide substantially reduced kidney perfusion without affecting oxygenation. TRIAL REGISTRATION: Clinicaltrialsregister.eu EudraCT 2019-000781-38 FUNDING: Novo Nordisk Foundation, Central Denmark Region Research Fund and Danish Medical Associations Research Foundation.

Epinephrine vs placebo in neonatal resuscitation: ROSC and brain MRS/MRI in term piglets.

BACKGROUND: We aimed to investigate the effect of epinephrine vs placebo on return of spontaneous circulation (ROSC) and brain magnetic resonance spectroscopy and imaging (MRS/MRI) in newborn piglets with hypoxic cardiac arrest (CA). METHODS: Twenty-five piglets underwent hypoxia induced by endotracheal tube clamping until CA. The animals were randomized to CPR + intravenous epinephrine or CPR + placebo (normal saline). The primary outcome was ROSC, and secondary outcomes included time-to-ROSC, brain MRS/MRI, and composite endpoint of death or severe brain MRS/MRI abnormality. RESULTS: ROSC was more frequent in animals treated with epinephrine than placebo; 10/13 vs 4/12, RR = 2.31 (95% CI: 1.09-5.77). We found no difference in time-to-ROSC (120 (113-211) vs 153 (116-503) seconds, p = 0.7) or 6-h survival (7/13 vs 3/12, p = 0.2). Among survivors, there was no difference between groups in brain MRS/MRI. We found no difference in the composite endpoint of death or severe brain MRS/MRI abnormality; RR = 0.7 (95% CI: 0.37-1.19). CONCLUSIONS: Resuscitation with epinephrine compared to placebo improved ROSC frequency after hypoxic CA in newborn piglets. We found no difference in time-to-ROSC or the composite endpoint of death or severe brain MRS/MRI abnormality. IMPACT: In a newborn piglet model of hypoxic cardiac arrest, resuscitation with epinephrine compared to placebo improved the rate of return of spontaneous circulation and more than doubled the 6-h survival. Brain MRS/MRI biomarkers were used to evaluate the effect of epinephrine vs placebo. We found no difference between groups in the composite endpoint of death or severe brain MRS/MRI abnormality. This study adds to the limited evidence regarding the effect and safety of epinephrine; the lack of high-quality evidence from randomized clinical trials was highlighted in the latest ILCOR 2020 guidelines, and newborn animal studies were specifically requested.

Evaluation of renal oxygenation by BOLD-MRI in high-risk patients with type 2 diabetes and matched controls.

BACKGROUND: Diabetic kidney disease (DKD) accounts for ∼50% of end-stage kidney disease. Renal hypoxia is suggested as a main driver in the pathophysiology underlying chronic DKD. Blood oxygenation level-dependent magnetic resonance imaging (BOLD-MRI) has made noninvasive investigations of renal oxygenation in humans possible. Whether diabetes per se contributes to measurable changes in renal oxygenation by BOLD-MRI remains to be elucidated. We investigated whether renal oxygenation measured with BOLD-MRI differs between people with type 2 diabetes (T2DM) with normal to moderate chronic kidney disease (CKD) (Stages 1-3A) and matched controls. The repeatability of the BOLD-MRI method was also assessed. METHODS: In this matched cross-sectional study, 20 people with T2DM (age 69.2 ± 4.7 years, duration of diabetes 10.5 ± 6.7 years, male 55.6%) and 20 matched nondiabetic controls (mean age 68.8 ± 5.4 years, male 55.%) underwent BOLD-MRI analysed with the 12-layer concentric object method (TLCO). To investigate the repeatability, seven in the T2DM group and nine in the control group were scanned twice. RESULTS: A significant reduction in renal oxygenation from the cortex to medulla was found in both groups (P < .01) but no intergroup difference was detected [0.71/s (95% confidence interval -0.28-1.7), P = .16]. The median intraindividual coefficient of variation (CV) varied from 1.2% to 7.0%. CONCLUSION: T2DM patients with normal to moderate CKD do not seem to have lower renal oxygenation when measured with BOLD-MRI and TLCO. BOLD-MRI has a low intraindividual CV and seems like a reliable method for investigation of renal oxygenation in T2DM.

Buoyancy and hydrostatic balance in a West Indian Ocean coelacanth Latimeria chalumnae.

BACKGROUND: Buoyancy and balance are important parameters for slow-moving, low-metabolic, aquatic organisms. The extant coelacanths have among the lowest metabolic rates of any living vertebrate and can afford little energy to keep station. Previous observations on living coelacanths support the hypothesis that the coelacanth is neutrally buoyant and in close-to-perfect hydrostatic balance. However, precise measurements of buoyancy and balance at different depths have never been made.  RESULTS: Here we show, using non-invasive imaging, that buoyancy of the coelacanth closely matches its depth distribution. We found that the lipid-filled fatty organ is well suited to support neutral buoyancy, and due to a close-to-perfect hydrostatic balance, simple maneuvers of fins can cause a considerable shift in torque around the pitch axis allowing the coelacanth to assume different body orientations with little physical effort. CONCLUSIONS: Our results demonstrate a close match between tissue composition, depth range and behavior, and our collection-based approach could be used to predict depth range of less well-studied coelacanth life stages as well as of deep sea fishes in general.

Adults with small, unrepaired atrial septal defects have reduced cardiac index during exercise.

OBJECTIVES: Small, unrepaired atrial septal defects are considered a benign lesion with good prognosis. Recently, clinical and register-based studies discovered increased long-term mortality and morbidity. The nature of these findings is not fully understood. Therefore, MRI was performed to evaluate cardiac function at rest and during exercise. METHODS: Adults with open or spontaneously closed atrial septal defects and healthy, matched controls underwent MRI for evaluation of cardiac chamber volume. Quantitative flow scans measured blood flow in the ascending aorta and the proximal pulmonary artery at rest and during increasing supine exercise. RESULTS: In total, 15 open defects (39 ± 11 years) and 15 matched controls (38 ± 12 years) were included, along with 20 spontaneously closed (36 ± 13 years) and 20 controls (36 ± 11 years). Cardiac chamber volumes and flow measurements at rest were comparable between groups, as were heart rates and workloads during exercise. At maximal exercise, open defects reached 31% lower cardiac index and had 38% higher retrograde flow in the pulmonary artery than their controls, p < 0.01. Shunt ratio remained unchanged during exercise, 1.2 ± 0.2. Closed defects reached 18% lower cardiac index, p = 0.02, with comparable pulmonary retrograde flow. Maximal cardiac index was inversely correlated with increasing age for patients only. CONCLUSION: Adults with a small, open or spontaneously closed atrial septal defects exhibit markedly lower exercise capacity compared with healthy peers. Moreover, open defects exhibit higher retrograde flows with increasing exercise. Finally, increasing age is related to poorer results in patients but not healthy controls. Longitudinal studies are necessary in order to determine potential accelerated worsening of physical capacity along with age-related changes in patients.

Remodeling after myocardial infarction and effects of heart failure treatment investigated by hyperpolarized [1-13 C]pyruvate magnetic resonance spectroscopy.

PURPOSE: Hyperpolarized [1-13 C]pyruvate MRS can measure cardiac metabolism in vivo. We investigated whether [1-13 C]pyruvate MRS could predict left ventricular remodeling following myocardial infarction (MI), long-term left ventricular effects of heart failure medication, and could identify responders to treatment. METHODS: Thirty-five rats were scanned with hyperpolarized [1-13 C]pyruvate MRS 3 days after MI or sham surgery. The animals were re-examined after 30 days of therapy with ß-blockers and ACE-inhibitors (active group, n = 12), placebo treatment (placebo group, n = 13) or no treatment (sham group, n = 10). Furthermore, heart tissue mitochondrial respiratory capacity was assessed by high-resolution respirometry. Metabolic results were compared between groups, over time and correlated to functional MR data at each time point. RESULTS: At 30 ± 0.5 days post MI, left ventricular ejection fraction (LVEF) differed between groups (sham, 77% ± 1%; placebo, 52% ± 3%; active, 63% ± 2%, P < .001). Cardiac metabolism, measured by both hyperpolarized [1-13 C]pyruvate MRS and respirometry, neither differed between groups nor between baseline and follow-up. Three days post MI, low bicarbonate + CO2 /pyruvate ratio was associated with low LVEF. At follow-up, in the active group, a poor recovery of LVEF was associated with high bicarbonate + CO2 /pyruvate ratio, as measured by hyperpolarized MRS. CONCLUSION: In a rat model of moderate heart failure, medical treatment improved function, but did not on average influence [1-13 C]pyruvate flux as measured by MRS; however, responders to heart failure medication had reduced capacity for carbohydrate metabolism.

Concentration-dependent effects of dichloroacetate in type 2 diabetic hearts assessed by hyperpolarized [1-13 C]-pyruvate magnetic resonance imaging.

Personalized medicine or individualized therapy promises a paradigm shift in healthcare. This is particularly true in complex and multifactorial diseases such as diabetes and the multitude of related pathophysiological complications. Diabetic cardiomyopathy represents an emerging condition that could be effectively treated if better diagnostic and, in particular, better therapeutic monitoring tools were available. In this study, we investigate the ability to differentiate low and high doses of metabolically targeted therapy in an obese type 2 diabetic rat model. Low-dose dichloroacetate (DCA) treatment was associated with increased lactate production, while no or little change was seen in bicarbonate production. High-dose DCA treatment was associated with a significant metabolic switch towards increased bicarbonate production. These findings support further studies using hyperpolarized [1-13 C]-pyruvate magnetic resonance imaging to differentiate treatment effects and thus allow for personalized titration of therapeutics.

Consensus-Based Technical Recommendations for Clinical Translation of Renal Phase Contrast MRI.

BACKGROUND: Phase-contrast (PC) MRI is a feasible and valid noninvasive technique to measure renal artery blood flow, showing potential to support diagnosis and monitoring of renal diseases. However, the variability in measured renal blood flow values across studies is large, most likely due to differences in PC-MRI acquisition and processing. Standardized acquisition and processing protocols are therefore needed to minimize this variability and maximize the potential of renal PC-MRI as a clinically useful tool. PURPOSE: To build technical recommendations for the acquisition, processing, and analysis of renal 2D PC-MRI data in human subjects to promote standardization of renal blood flow measurements and facilitate the comparability of results across scanners and in multicenter clinical studies. STUDY TYPE: Systematic consensus process using a modified Delphi method. POPULATION: Not applicable. SEQUENCE FIELD/STRENGTH: Renal fast gradient echo-based 2D PC-MRI. ASSESSMENT: An international panel of 27 experts from Europe, the USA, Australia, and Japan with 6 (interquartile range 4-10) years of experience in 2D PC-MRI formulated consensus statements on renal 2D PC-MRI in two rounds of surveys. Starting from a recently published systematic review article, literature-based and data-driven statements regarding patient preparation, hardware, acquisition protocol, analysis steps, and data reporting were formulated. STATISTICAL TESTS: Consensus was defined as ≥75% unanimity in response, and a clear preference was defined as 60-74% agreement among the experts. RESULTS: Among 60 statements, 57 (95%) achieved consensus after the second-round survey, while the remaining three showed a clear preference. Consensus statements resulted in specific recommendations for subject preparation, 2D renal PC-MRI data acquisition, processing, and reporting. DATA CONCLUSION: These recommendations might promote a widespread adoption of renal PC-MRI, and may help foster the set-up of multicenter studies aimed at defining reference values and building larger and more definitive evidence, and will facilitate clinical translation of PC-MRI. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY STAGE: 1.

Investigating the potential disease-modifying and neuroprotective efficacy of exercise therapy early in the disease course of multiple sclerosis: The Early Multiple Sclerosis Exercise Study (EMSES).

BACKGROUND: Potential supplemental disease-modifying and neuroprotective treatment strategies are warranted in multiple sclerosis (MS). Exercise is a promising non-pharmacological approach, and an uninvestigated 'window of opportunity' exists early in the disease course. OBJECTIVE: To investigate the effect of early exercise on relapse rate, global brain atrophy and secondary magnetic resonance imaging (MRI) outcomes. METHODS: This randomized controlled trial (n = 84, disease duration <2 years) included 48 weeks of supervised aerobic exercise or control condition. Population-based control data (Danish MS Registry) was included (n = 850, disease duration <2 years). Relapse rates were obtained from medical records, and patients underwent structural and diffusion-kurtosis MRI at baseline, 24 and 48 weeks. RESULTS: No between-group differences were observed for primary outcomes, relapse rate (incidence-rate-ratio exercise relative to control: (0.49 (0.15; 1.66), p = 0.25) and global brain atrophy rate (-0.04 (-0.48; 0.40)%, p = 0.87), or secondary measures of lesion load. Aerobic fitness increased in favour of the exercise group. Microstructural integrity was higher in four of eight a priori defined motor-related tracts and nuclei in the exercise group compared with the control (thalamus, corticospinal tract, globus pallidus, cingulate gyrus) at 48 weeks. CONCLUSION: Early supervised aerobic exercise did not reduce relapse rate or global brain atrophy, but does positively affect the microstructural integrity of important motor-related tracts and nuclei.

Dosing Limitation for Intra-Renal Arterial Infusion of Mesenchymal Stromal Cells.

The immunomodulatory and regenerative properties of mesenchymal stromal cells (MSCs) make MSC therapy a promising therapeutic strategy in kidney disease. A targeted MSC administration via the renal artery offers an efficient delivery method with limited spillover to other organs. Although local administration alleviates safety issues with MSCs in systemic circulation, it introduces new safety concerns in the kidneys. In a porcine model, we employed intra-renal arterial infusion of ten million allogenic adipose tissue-derived MSCs. In order to trigger any potential adverse events, a higher dose (hundred million MSCs) was also included. The kidney function was studied by magnetic resonance imaging after the MSC infusion and again at two weeks post-treatment. The kidneys were assessed by single kidney glomerular filtration rate (skGFR) measurements, histology and inflammation, and fibrosis-related gene expression. None of the measured parameters were affected immediately after the administration of ten million MSCs, but the administration of one hundred million MSCs induced severe adverse events. Renal perfusion was reduced immediately after MSC administration which coincided with the presence of microthrombi in the glomeruli and signs of an instant blood-mediated inflammatory reaction. At two weeks post-treatment, the kidneys that were treated with one hundred million MSCs showed reduced skGFR, signs of tissue inflammation, and glomerular and tubular damage. In conclusions, the intra-renal administration of ten million MSCs is well-tolerated by the porcine kidney. However, higher concentrations (one hundred million MSCs) caused severe kidney damage, implying that very high doses of intra-renally administered MSCs should be undertaken with caution.

Influence of Second Generation Oral Contraceptive Use on Adaptations to Resistance Training in Young Untrained Women.

ABSTRACT: Dalgaard, LB, Jørgensen, EB, Oxfeldt, M, Dalgaard, EB, Johansen, FT, Karlsson, M, Ringgaard, S, and Hansen, M. Influence of second generation oral contraceptive use on adaptations to resistance training in young untrained women. J Strength Cond Res 36(7): 1801-1809, 2022-The study purpose was to determine effects of using second generation oral contraceptives (OC) on muscle adaptations to resistance training in young untrained women. Twenty users and 18 nonusers of OC completed a 10-week supervised progressive resistance training program. Before and after the intervention, muscle cross-sectional area (mCSA) of the quadriceps was measured using magnetic resonance imaging and muscle fiber CSA (fCSA) was determined by immunohistochemistry. In addition, body composition (DXA, fat mass/fat-free mass), maximal isometric muscle strength (dynamometry), 5 repetition maximum (5RM) leg press strength, counter movement jump (CMJ) height, and average power using a modified Wingate test were determined. Serum hormone analysis ensured OC compliance and 4-day food records documented dietary intake. After the training period, quadriceps mCSA (OC: 11.0 ± 6.0% vs. non-OC: 9.2 ± 5.0%, p = 0.001), type II fCSA (OC: 19.9 ± 7.9% vs. non-OC: 16.6 ± 7.2%, p = 0.05), muscle strength (knee extension, knee flexion and 5RM, p < 0.001), and functional power (CMJ, AP, p < 0.001) were significantly increased with no significant difference between the groups. However, a tendency toward a greater increase in fat-free mass (FFM) in the OC group was observed (OC: 3.7 ± 3.8% vs. non-OC: 2.7 ± 3.5%, p = 0.08). Collectively, use of second generation OCs in young untrained women did not significantly improve adaptations to 10 weeks of resistance training compared with nonusers. The trend toward greater gains in FFM in the OC group warrant future studies.

Development of a human heart-sized perfusion system for metabolic imaging studies using hyperpolarized [1-13 C]pyruvate MRI.

PURPOSE: Increasing worldwide demand for cardiac transplantation has spurred new developments to increase the donor pool. Normothermic preservation of heart grafts for transplantation is an emerging strategy to improve the utilization of marginal grafts. Hyperpolarized MR using metabolic tracers such as [1-13 C]pyruvate, provide a novel means of investigating metabolic status without the use of ionizing radiation. We demonstrate the use of this methodology to examine ex vivo perfused porcine heart grafts. METHODS: Hearts from three 40-kg Danish domestic pigs were harvested and subsequently perfused in Langendorff mode under normothermic conditions, using an MR-compatible perfusion system adapted to the heart. Proton MRI and hyperpolarized [1-13 C]pyruvate were used to investigate and quantify the functional and metabolic status of the grafts. RESULTS: Hearts were perfused with whole blood for 120 min, using a dynamic contrast-enhanced perfusion experiment to verify successful myocardial perfusion. Hyperpolarized [1-13 C]pyruvate MRI was used to assess the metabolic state of the myocardium. Functional assessment was performed using CINE imaging and ventricular pressure data. High lactate and modest alanine levels were observed in the hyperpolarized experiment. The functional assessment produced reduced functional parameters. This suggests an altered functional and metabolic profile compared with corresponding in vivo values. CONCLUSION: We investigated the metabolic and functional status of machine-perfused porcine hearts. Utilizing hyperpolarized methodology to acquire detailed myocardial metabolic information-in combination with already established MR methods for cardiac investigation-provides a powerful tool to aid the progress of donor heart preservation.

Reverse remodeling of tricuspid valve morphology and function in chronic thromboembolic pulmonary hypertension patients following pulmonary thromboendarterectomy: a cardiac magnetic resonance imaging and invasive hemodynamic study.

BACKGROUND: To investigate changes in tricuspid annulus (TA) and tricuspid valve (TV) morphology among chronic thromboembolic pulmonary hypertension (CTEPH) patients before and 12 months after pulmonary thromboendarterectomy (PEA) and compare these findings to normal control subjects. METHODS: 20 CTEPH patients and 20 controls were enrolled in the study. The patients were examined with echocardiography, right heart catherization and cardiac magnetic resonance imaging prior to PEA and 12 months after. RESULTS: Right atrium (RA) volume was significantly reduced from baseline to 12 months after PEA (30 ± 9 vs 23 ± 5 ml/m2, p < 0.005). TA annular area in systole remained unchanged (p = 0.11) and was comparable to controls. The leaflet area, tenting volume and tenting height in systole were significantly increased at baseline but decreased significantly with comparable values to controls after 12 months (p < 0.005). There was correlation between the changes of right ventricular-pulmonary artery coupling and changes of TV tenting height (r = - 0.54, p = 0.02), TV tenting volume (r = - 0.73, p < 0.001) and TV leaflet area (- 0.57, p = 0.01) from baseline to 12 months after PEA. Tricuspid regurgitation jet area/RA area was significantly (p < 0.01) reduced from baseline (30 ± 13%) to 12 months after PEA (9 ± 10%). CONCLUSION: In CTEPH patients selected for PEA, TV tenting height, volume and valve area are significantly increased whereas annulus size and shape are less affected. The alterations in TV morphology are fully reversed after PEA and correlates to improvements of right ventricular-pulmonary arterial coupling.

Nicotinamide riboside does not alter mitochondrial respiration, content or morphology in skeletal muscle from obese and insulin-resistant men.

KEY POINTS: This is the first long-term human clinical trial to report on effects of nicotinamide riboside (NR) on skeletal muscle mitochondrial function, content and morphology. NR supplementation decreases nicotinamide phosphoribosyltransferase (NAMPT) protein abundance in skeletal muscle. NR supplementation does not affect NAD metabolite concentrations in skeletal muscle. Respiration, distribution and quantity of muscle mitochondria are unaffected by NR. NAMPT in skeletal muscle correlates positively with oxidative phosphorylation Complex I, sirtuin 3 and succinate dehydrogenase. ABSTRACT: Preclinical evidence suggests that the nicotinamide adenine dinucleotide (NAD+ ) precursor nicotinamide riboside (NR) boosts NAD+ levels and improves diseases associated with mitochondrial dysfunction. We aimed to determine if dietary NR supplementation in middle-aged, obese, insulin-resistant men affects mitochondrial respiration, content and morphology in skeletal muscle. In a randomized, placebo-controlled clinical trial, 40 participants received 1000 mg NR or placebo twice daily for 12 weeks. Skeletal muscle biopsies were collected before and after the intervention. Mitochondrial respiratory capacity was determined by high-resolution respirometry on single muscle fibres. Protein abundance and mRNA expression were measured by Western blot and quantitative PCR analyses, respectively, and in a subset of the participants (placebo n = 8; NR n = 8) we quantified mitochondrial fractional area and mitochondrial morphology by laser scanning confocal microscopy. Protein levels of nicotinamide phosphoribosyltransferase (NAMPT), an essential NAD+ biosynthetic enzyme in skeletal muscle, decreased by 14% with NR. However, steady-state NAD+ levels as well as gene expression and protein abundance of other NAD+ biosynthetic enzymes remained unchanged. Neither respiratory capacity of skeletal muscle mitochondria nor abundance of mitochondrial associated proteins were affected by NR. Moreover, no changes in mitochondrial fractional area or network morphology were observed. Our data do not support the hypothesis that dietary NR supplementation has significant impact on skeletal muscle mitochondria in obese and insulin-resistant men. Future studies on the effects of NR on human skeletal muscle may include both sexes and potentially provide comparisons between young and older people.

Graft assessment of the ex vivo perfused porcine kidney using hyperpolarized [1-13 C]pyruvate.

PURPOSE: Normothermic perfusion is an emerging strategy for donor organ preservation and therapy, incited by the high worldwide demand for organs for transplantation. Hyperpolarized MRI and MRS using [1-13 C]pyruvate and other 13 C-labeled molecules pose a novel way to acquire highly detailed information about metabolism and function in a noninvasive manner. This study investigates the use of this methodology as a means to study and monitor the state of ex vivo perfused porcine kidneys, in the context of kidney graft preservation research. METHODS: Kidneys from four 40-kg Danish domestic pigs were perfused ex vivo with whole blood under normothermic conditions, using an MR-compatible perfusion system. Kidneys were investigated using 1 H MRI as well as hyperpolarized [1-13 C]pyruvate MRI and MRS. Using the acquired anatomical, functional and metabolic data, the state of the ex vivo perfused porcine kidney could be quantified. RESULTS: Four kidneys were successfully perfused for 120 minutes and verified using a DCE perfusion experiment. Renal metabolism was examined using hyperpolarized [1-13 C]pyruvate MRI and MRS, and displayed an apparent reduction in pyruvate turnover compared with the usual case in vivo. Perfusion and blood gas parameters were in the normal ex vivo range. CONCLUSION: This study demonstrates the ability to monitor ex vivo graft metabolism and function in a large animal model, resembling human renal physiology. The ability of hyperpolarized MRI and MRS to directly compare the metabolic state of an organ in vivo and ex vivo, in combination with the simple MR implementation of normothermic perfusion, renders this methodology a powerful future tool for graft preservation research.