Right ventricular diastolic adaptation to pressure overload in different rat strains.

Different rat strains are used in various animal models of pulmonary hypertension and right ventricular (RV) failure. No systematic assessment has been made to test differences in RV response to pressure overload between rat strains. We compared RV adaptation to pulmonary trunk banding (PTB) in Wistar (W), Sprague Dawley (SD), and Fischer344 (F) rats by hemodynamic profiling focusing on diastolic function. Age-matched male rat weanlings were randomized to sham surgery (W-sham, n = 5; SD-sham, n = 4; F-sham, n = 4) or PTB (W-PTB, n = 8; SD-PTB, n = 8; F-PTB, n = 8). RV function was evaluated after 5 weeks by echocardiography, cardiac MRI, and invasive pressure-volume measurements. PTB caused RV failure and increased RV systolic pressures four-fold in all three PTB groups compared with sham. W- and SD-PTB had a 2.4-fold increase in RV end-systolic volume index compared with sham, while F-PTB rats were less affected. Diastolic and right atrial impairment were evident by increased RV end-diastolic elastance, filling pressure, and E/e' in PTB rats compared with sham, again F-PTB the least affected. In conclusions, PTB caused RV failure with signs of diastolic dysfunction. Despite a similar increase in RV systolic pressure, F-PTB rats showed less RV dilatation and a more preserved diastolic function compared with W- and SD-PTB.

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.

An Innovative Plate Concept for Rotational Guided Growth: A Porcine Pilot Study.

Background Rotational deformities in children are currently treated with an osteotomy, acute de-rotation, and surgical fixation. Meanwhile, guided growth is now the gold standard in pediatric coronal deformity correction. This study aimed to evaluate the feasibility of a novel implant intended for rotational guided growth (RotOs Plate) in a large porcine animal model. Methodology A submuscular plate was inserted on the medial and lateral aspect of the distal femoral physis of the left femur in 6 pigs. Each plate was anchored with a screw in the metaphysis and epiphysis respectively. The plates were expected to rotate the femur externally. The right femur acted as a control in a paired design. The animals were housed for 12 weeks after surgery. MRI scanning of both femora was performed before euthanasia after 12 weeks. Rotation was determined as the difference in the femoral version on MRI between the operated and non-operated femur after 12 weeks. Results External rotation in all operated femurs was observed. The mean difference in the femoral version on MRI between operated and non-operated femurs was 12.5° (range 9°-16°). No significant changes in axial growth were detected. Conclusions This study shows encouraging results regarding rotational guided growth, which may replace current invasive surgical treatment options for malrotation in children. However, further studies addressing potential secondary deformities are paramount and should be carried out.

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.

Effects of power training in older patients with multiple sclerosis on neurodegeneration, neuromuscular function, and physical function. A study protocol for the "power training in older multiple sclerosis patients (PoTOMS) randomized control trial.

Introduction: Approximately one-third of all persons with multiple sclerosis (pwMS) are older, i.e., having an age ≥60 years. Whilst ageing and MS separately elicit deteriorating effects on brain morphology, neuromuscular function, and physical function, the combination of ageing and MS may pose a particular challenge. To counteract such detrimental changes, power training (i.e., a type of resistance exercise focusing on moderate-to-high loading at maximal intended movement velocity) presents itself as a viable and highly effective solution. Power training is known to positively impact physical function, neuromuscular function, as well as brain morphology. Existing evidence is promising but limited to young and middle-aged pwMS, with the effects of power training remaining to be elucidated in older pwMS. Methods: The presented 'Power Training in Older MS patients (PoTOMS)' trial is a national, multi-center, parallel-group, randomized controlled trial. The trial compares 24 weeks of usual care(n = 30) to 24 weeks of usual care and power training (n = 30). The primary outcome is whole brain atrophy rate. The secondary outcomes include changes in brain micro and macro structures, neuromuscular function, physical function, cognitive function, bone health, and patient-reported outcomes. Ethics and dissemination: The presented study is approved by The Regional Ethics Committee (reference number 1-10-72-222-20) and registered at the Danish Data Protection Agency (reference number 2016-051-000001). All study findings will be published in scientific peer-reviewed journals and presented at relevant scientific conferences independent of the results. The www.clinicaltrials.gov identifier is NCT04762342.

Investigating the importance of left atrial compliance on fluid dynamics in a novel mock circulatory loop.

The left atrium (LA) hemodynamic indices hold prognostic value in various cardiac diseases and disorders. To understand the mechanisms of these conditions and to assess the performance of cardiac devices and interventions, in vitro models can be used to replicate the complex physiological interplay between the pulmonary veins, LA, and left ventricle. In this study, a comprehensive and adaptable in vitro model was created. The model includes a flexible LA made from silicone and allows distinct control over the systolic and diastolic functions of both the LA and left ventricle. The LA was mechanically matched with porcine LAs through expansion tests. Fluid dynamic measures were validated against the literature and pulmonary venous flows recorded on five healthy individuals using magnetic resonance flow imaging. Furthermore, the fluid dynamic measures were also used to construct LA pressure-volume loops. The in vitro pressure and flow recordings expressed a high resemblance to physiological waveforms. By decreasing the compliance of the LA, the model behaved realistically, elevating the a- and v-wave peaks of the LA pressure from 12 to 19 mmHg and 22 to 26 mmHg, respectively, while reducing the S/D ratio of the pulmonary venous flowrate from 1.5 to 0.3. This model provides a realistic platform and framework for developing and evaluating left heart procedures and interventions.

The effects of semaglutide, empagliflozin and their combination on the kidney sodium signal from magnetic resonance imaging: A prespecified, secondary analysis from a randomized, clinical trial.

AIMS: To evaluate the effect of treatment with semaglutide and empagliflozin on the cortico-medullary sodium gradient (MCR; medulla/cortex ratio), urine sodium/creatinine ratio (UNACR), and estimated plasma volume (ePV) and to compare the MCR between persons with and without type 2 diabetes. METHODS: Using the 23Na magnetic resonance imaging (23Na-MRI) technique, we investigated the effects of 32 weeks of treatment with semaglutide, empagliflozin or their combination on MCR in 65 participants with type 2 diabetes and high risk of cardiovascular disease. The participants were recruited from a randomized, controlled interventional trial and further characterized by UNACR and ePV. In addition, in a cross-sectional design, we compared MCR by 23Na-MRI in 12 persons with type 2 diabetes and 17 matched controls. Data from the interventional trial were analyzed using a single, multivariate linear mixed model strategy for repeated measurements. Data from the cross-sectional study were analyzed by fitting a linear regression model adjusted for age and sex. RESULTS: Compared to placebo, semaglutide, but not empagliflozin, significantly decreased the MCR (-9 %, 95%CI (-18, -0.06)%, p = 0.035 and -0.05 %, 95%CI(-0.15, 0.05)%, p = 0.319, respectively). The UNACR decreased in the semaglutide group(-35 %, 95 % CI(-52, -14) %, p = 0.003) but not in the empagliflozin group (7 %, 95 % CI(-21, 44)%, p = 0.657), whereas the ePV decreased in the combination group. The MCR was not different between persons with and without type 2 diabetes. CONCLUSION: 23Na magnetic resonance imaging can identify drug induced changes in the MCR in persons with type 2 diabetes, and 32 weeks of semaglutide decreases the MCR in such persons. There is no difference in the MCR between persons with and without type 2 diabetes. TRIAL NUMBER AND REGISTRY: EUDRACT 2019-000781-38, clinicaltrialsregister.eu.

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.

No neuroprotective effect of therapeutic hypothermia following lipopolysaccharide-sensitized hypoxia-ischemia: a newborn piglet study.

Introduction: Therapeutic hypothermia is the only proven neuroprotective treatment for hypoxic-ischemic encephalopathy. However, studies have questioned whether therapeutic hypothermia may benefit newborns subjected to infection or inflammation before a hypoxic-ischemic insult. We aimed to compare newborn piglets with lipopolysaccharide-sensitized hypoxia-ischemia treated with and without therapeutic hypothermia with regards to measures of neuroprotection. Methods: A total of 32 male and female piglets were included in this randomized experimental study. Lipopolysaccharides from Escherichia coli were infused intravenously before initiation of a standardized global hypoxic-ischemic insult. The piglets were then randomized to either normothermia or therapeutic hypothermia. After 14 h, the piglets were evaluated. Our primary outcome was brain lactate/N-acetylaspartate ratio assessed by magnetic resonance spectroscopy. Secondary outcomes included measures of magnetic resonance imaging, amplitude-integrated electroencephalography, immunohistochemistry, and concentration of blood cells and cytokines. Results: Piglets treated with and without therapeutic hypothermia were subjected to comparable global hypoxic-ischemic insults. We found no difference between the two groups with regards to measures of magnetic resonance spectroscopy and imaging, amplitude-integrated electroencephalography, immunohistochemistry, and concentration of blood cells and cytokines. Conclusion: We found no indication of neuroprotection by therapeutic hypothermia in newborn piglets following lipopolysaccharide-sensitized hypoxia-ischemia. However, interpretation of the results is limited by the short observation period. Further studies are required to determine the potential clinical implications of these findings.

Exercise increases myocardial free fatty acid oxidation in subjects with metabolic dysfunction-associated fatty liver disease.

BACKGROUND AND AIMS: Metabolic dysfunction-associated fatty liver disease (MAFLD) is associated with dyslipidemia and may promote cardiac lipotoxicity. Myocardial free fatty acids (FFA) oxidation (MOFFA) is normal in pre-diabetes, but reduced in heart failure. We hypothesized that during exercise MOFFA, very low-density lipoprotein triglycerides (VLDL-TG) secretion, hepatic FFA utilization, and lactate production differ among obese subjects with and without MAFLD. METHODS: Nine obese subjects with MAFLD and 8 matched subjects without MAFLD (Control) without a history of heart failure and cardiovascular disease were compared before and after 90-min exercise at 50% Peak oxygen consumption. Basal and exercise induced cardiac and hepatic FFA oxidation, uptake and re-esterification and VLDL-TG secretion were measured using [11C]palmitate positron-emission tomography and [1-14C]VLDL-TG. RESULTS: In the heart, increased MOFFA was observed after exercise in MAFLD, whereas MOFFA decreased in Control (basal vs exercise, MAFLD: 4.1 (0.8) vs 4.8 (0.8) µmol·100 ml-1 min-1; Control: 4.9 (1.8) vs 4.0 (1.1); µmol·100 ml-1 min-1, mean (SD), p < 0.048). Hepatic FFA fluxes were significantly lower in MAFLD than Control and increased ≈ two-fold in both groups. VLDL-TG secretion was 50% greater in MAFLD at rest and similarly suppressed during exercise. Plasma lactate increased significantly less in MAFLD than Control during exercise. CONCLUSIONS: Using robust tracer-techniques we found that obese subjects with MAFLD do not downregulate MOFFA during exercise compared to Control, possibly due to diminished lactate supply. Hepatic FFA fluxes are significantly lower in MAFLD than Control, but increase similarly with exercise. VLDL-TG export remains greater in MAFLD compared to Control. Basal and post-exercise myocardial and hepatic FFA, VLDL-TG and lactate metabolism is abnormal in subjects with MAFLD compared to Control.

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.

Ectopic lipid deposition and insulin resistance in patients with GH disorders before and after treatment.

OBJECTIVES: Insulin resistance is associated with ectopic lipid deposition. Growth hormone (GH) status also modulates ectopic lipid accumulation, but how this associates with insulin resistance in patients with GH disorders is not well established. DESIGN AND METHODS: Twenty-one patients diagnosed with acromegaly and 12 patients with adult GH deficiency (GHD) were studied at diagnosis and after treatment. A reference group of 12 subjects was included. Each study day comprised assessment of body composition with dual-energy X-ray absorptiometry, ectopic lipid deposition in the liver by MR spectroscopy, and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR). RESULTS: Disease control of acromegaly decreased lean body mass (LBM) (P < .000) and increased the percentage of total body fat (TBF) (P < .000). GH replacement increased LBM in the GHD patients (P = .007) and decreased the percentage of TBF (P = .010). The intrahepatic lipid (IHL) content increased after disease control in acromegaly (P = .004), whereas IHL did not change significantly after GH replacement in GHD (P = .34). Insulin resistance (HOMA-IR) improved after disease control of acromegaly (P < .000) and remained unaltered after GH replacement in the GHD patients (P = .829). CONCLUSIONS: GH status is a significant modulator of body composition and insulin sensitivity.GH excess reduces total fat mass and intrahepatic lipid content together with induction of insulin resistance.The data support the notion that GH-induced insulin resistance is unassociated with hepatic lipid accumulation.

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.

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.

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.

Effects of empagliflozin on right ventricular adaptation to pressure overload.

Background: Right ventricular (RV) failure is the prime cause of death in patients with pulmonary arterial hypertension. Novel treatment strategies that protect the RV are needed. Empagliflozin, a sodium-glucose co-transporter-2 inhibitor, shows cardioprotective effects on the left ventricle in clinical and preclinical studies, but its direct effects on RV remain elusive. We investigated the effects of empagliflozin on RV dysfunction induced by pulmonary trunk banding (PTB). Methods: Male Wistar rats (116 ± 10 g) were randomized to PTB or sham surgery. One week after surgery, PTB animals received empagliflozin mixed into the chow (300 mg empagliflozin/kg chow; PTB-empa, n = 10) or standard chow (PTB-control, n = 10). Sham rats (Sham, n = 6) received standard chow. After five weeks, RV function was evaluated by echocardiography, cardiac MRI, and invasive pressure-volume measurements. Results: PTB caused RV failure evident by decreased cardiac output compared with sham. PTB-empa rats had a 49% increase in water intake compared with PTB-control yet no differences in hematocrit or blood glucose. Treatment with empagliflozin decreased RV end-systolic pressures without any changes in RV cardiac output or ventricular-arterial coupling (Ees/Ea). The decrease in RV end-systolic pressure was complemented by a slight reduction in RV cross sectional area as a sign of reduced hypertrophy. Load-independent measures of RV systolic and diastolic function were not affected in PTB-empa rats compared with PTB-control. Conclusion: Empagliflozin treatment reduced RV end-systolic pressure in RV failure induced by pressure overload. Further studies are needed to elucidate whether this simply relates to a diuretic effect and/or additional independent beneficial RV effects.

Heterochronic maturation of anatomical plugs for protecting the airway in rorqual whales (Balaenopteridae).

Recently, a unique mechanism for protecting the airway during lunge feeding was discovered in rorqual whales (Balaenopteridae). This mechanism is based on an oral plug structure in the soft palate with similarities in musculo-fatty composition to the nasal plugs protecting the respiratory tract of rorquals from water entry and barotrauma during diving. As a follow-up, we present here a developmental series on fetal, prenatal, juvenile and adult specimens across five species of rorquals, showing differential maturation of the nasal and oral respiratory protection plugs. Nasal plugs are fully formed to serve an immediate crucial function at birth. By contrast, the soft palate remains muscular until the onset of solid food intake, where a musculo-fatty oral plug is developed.

Cerebral monitoring in a pig model of cardiac arrest with 48 h of intensive care.

BACKGROUND: Neurological injury is the primary cause of death after out-of-hospital cardiac arrest. There is a lack of studies investigating cerebral injury beyond the immediate post-resuscitation phase in a controlled cardiac arrest experimental setting. METHODS: The aim of this study was to investigate temporal changes in measures of cerebral injury and metabolism in a cardiac arrest pig model with clinically relevant post-cardiac arrest intensive care. A cardiac arrest group (n = 11) underwent 7 min of no-flow and was compared with a sham group (n = 6). Pigs underwent intensive care with 24 h of hypothermia at 33 °C. Blood markers of cerebral injury, cerebral microdialysis, and intracranial pressure (ICP) were measured. After 48 h, pigs underwent a cerebral MRI scan. Data are presented as median [25th; 75th percentiles]. RESULTS: Return of spontaneous circulation was achieved in 7/11 pigs. Time to ROSC was 4.4 min [4.2; 10.9]. Both NSE and NfL increased over time (p < 0.001), and were higher in the cardiac arrest group at 48 h (NSE 4.2 µg/L [2.4; 6.1] vs 0.9 [0.7; 0.9], p < 0.001; NfL 63 ng/L [35; 232] vs 29 [21; 34], p = 0.02). There was no difference in ICP at 48 h (17 mmHg [14; 24] vs 18 [13; 20], p = 0.44). The cerebral lactate/pyruvate ratio had secondary surges in 3/7 cardiac arrest pigs after successful resuscitation. Apparent diffusion coefficient was lower in the cardiac arrest group in white matter cortex (689 × 10-6 mm2/s [524; 765] vs 800 [799; 815], p = 0.04) and hippocampus (854 [834; 910] vs 1049 [964; 1180], p = 0.03). N-Acetylaspartate was lower on MR spectroscopy in the cardiac arrest group (- 17.2 log [- 17.4; - 17.0] vs - 16.9 [- 16.9; - 16.9], p = 0.03). CONCLUSIONS: We have developed a clinically relevant cardiac arrest pig model that displays cerebral injury as marked by NSE and NfL elevations, signs of cerebral oedema, and reduced neuron viability. Overall, the burden of elevated ICP was low in the cardiac arrest group. A subset of pigs undergoing cardiac arrest had persisting metabolic disturbances after successful resuscitation.

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.