Prospective Natural History Study in 24 Adult Patients With LGMDR12 Over 2 Years of Follow-up: Quantitative MRI and Clinical Outcome Measures.

BACKGROUND AND OBJECTIVES: Limb-girdle muscular dystrophy autosomal recessive type 12 (LGMDR12) is a rare hereditary muscular dystrophy for which outcome measures are currently lacking. We evaluated quantitative MRI and clinical outcome measures to track disease progression to determine which tests could be useful in future clinical trials to evaluate potential therapies. METHODS: We prospectively measured the following outcome measures in all participants at baseline and after 1 and 2 years: 6-minute walk distance (6MWD), 10-meter walk test (10MWT), the Medical Research Council (MRC) sum scores, Biodex isometric dynamometry, serum creatine kinase, and 6-point Dixon MRI of the thighs. RESULTS: We included 24 genetically confirmed, adult patients with LGMDR12 and 24 age-matched and sex-matched healthy controls. Patients with intermediate-stage thigh muscle fat replacement at baseline (proton density fat fraction [PDFF] 20%-70%) already showed an increase in PDFF in 8 of the 14 evaluated thigh muscles after 1 year. The standardized response mean demonstrated a high responsiveness to change in PDFF for 6 individual muscles over 2 years in this group. However, in patients with early-stage (<20%) or end-stage (>70%) muscle fat replacement, PDFF did not increase significantly over 2 years of follow-up. Biodex isometric dynamometry showed a significant decrease in muscle strength in all patients in the right and left hamstrings (-6.2 Nm, p < 0.002 and -4.6 Nm, p < 0.009, respectively) and right quadriceps muscles (-9 Nm, p = 0.044) after 1 year of follow-up, whereas the 6MWD, 10MWT, and MRC sum scores were not able to detect a significant decrease in muscle function/strength even after 2 years. There was a moderately strong correlation between total thigh PDFF and clinical outcome measures at baseline. DISCUSSION: Thigh muscle PDFF imaging is a sensitive outcome measure to track progressive muscle fat replacement in selected patients with LGMDR12 even after 1 year of follow-up and correlates with clinical outcome measures. Biodex isometric dynamometry can reliably capture the loss of muscle strength over the course of 1 year in patients with LGMDR12 and should be included as an outcome measure in future clinical trials as well.

Right ventricular and cyclic guanosine monophosphate signalling abnormalities in stages B and C of heart failure with preserved ejection fraction.

AIMS: Identifying early right ventricular (RV) dysfunction and impaired vasodilator reserve is challenging in heart failure with preserved ejection fraction (HFpEF). We hypothesized that cardiac magnetic resonance (CMR)-based exercise imaging and serial cyclic guanosine monophosphate (cGMP) measurements can identify dynamic RV-arterial uncoupling and responsiveness to pulmonary vasodilators at early stages of the HFpEF syndrome. METHODS AND RESULTS: Patients with HFpEF (n = 16), impaired left ventricular relaxation due to concentric remodelling (LVCR, n = 7), and healthy controls (n = 8) underwent CMR at rest and during supine bicycle exercise with simultaneous measurements of central haemodynamics and circulating cGMP levels, before and after oral administration of 50 mg sildenafil. At rest, mean pulmonary artery pressures (mPAP) were higher in HFpEF, compared with LVCR and controls (27 ± 2, 18 ± 1, and 11 ± 1, respectively; P = 0.01), whereas biventricular volumes, heart rate, and stroke volume were similar. During exercise, LVCR and HFpEF had a greater increase in the ratio of mPAP over cardiac output than controls (5.50 ± 0.77 and 6.34 ± 0.86 vs. 2.24 ± 0.55 in controls, P = 0.005). The ratio of peak exercise to rest RV end-systolic pressure-volume, a surrogate of RV contractility, was significantly reduced in LVCR and HFpEF (2.32 ± 0.17 and 1.56 ± 0.08 vs. 3.49 ± 0.35 in controls, P < 0.001) and correlated with peak exercise VO2 (R2  = 0.648, P < 0.001). cGMP levels increased with exercise across the HFpEF spectrum (P < 0.05 vs. baseline), except when postcapillary pulmonary hypertension was present at rest (P = 0.73 vs. baseline). A single sildenafil administration failed to increase circulating cGMP levels and did not improve RV performance. CONCLUSION: Exercise CMR identifies impaired RV-arterial coupling at an early stage of HFpEF. Circulating cGMP levels phenocopy the haemodynamic spectrum in HFpEF but fail to increase after phosphodiesterase type 5 inhibition, endorsing the need for alternative interventions to increase cGMP signalling in HFpEF.

Effect of protein composition of enteral formula on gastric content volume during continuous feeding: A randomized controlled cross-over study in healthy adults.

BACKGROUND & AIMS: Enteral nutrition with polymeric intact protein formula is the preferred medical nutrition strategy in critically ill patients when oral intake is insufficient. Enteral nutrition formulas are often rich in casein protein, which has coagulating properties. Coagulation in the stomach impedes gastric emptying and might result in high gastric residual volumes which are a clinical sign of gastrointestinal intolerance and a major reason to decrease or to discontinue enteral feeding. In this study the impact of protein composition of enteral formula on gastric content volume (GCV) during and after continuous feeding was tested in healthy volunteers in whom gastrointestinal conditions of critically ill patients were mimicked. METHODS: An enteral formula including 4 proteins (P4) with non-coagulating properties was compared to a casein-dominant formula (Cas) with coagulating properties. Esomeprazole and codeine were administered to mimic stress ulcer prophylaxis and induce gastroduodenal motor dysfunction, both being hallmarks of critically ill patients. GCV was measured with magnetic resonance imaging during and after continuous enteral feeding (100 mL/h for 4h) in a randomized single-center cross-over study. Results are provided as mean (SD). Significance level of p < 0.05 was applied. RESULTS: Twenty subjects completed the study (14 women, 6 men, 25.8 (4.6) years old, BMI: 22.5 (1.5) kg/m2). The GCV as change from baseline at T = 240 (primary endpoint) did not differ between study products (P4: 124.3 (83.4) vs. Cas: 137.1 (102.0) mL, 95% CI: -57.4, 27.0, p = 0.457). During feeding and after cessation of feeding, the area under the GCV-curve (AUC0-360 GCV) for P4 and Cas was 44631.1 (15546.1) and 52822.2 (19686.1) mL∗min, respectively (p = 0.061). During feeding the GCV was lower at T = 180 min (175.4 (64.8) vs. 205.2 (75.4) mL, p = 0.038) and after cessation of feeding at T = 300 min (81.3 (71.1) vs. 116.3 (84.3) mL, p = 0.004) and T = 330 min (39.9 (53.9) vs. 73.6 (81.1) mL, p = 0.031). With P4 it took less time to reach half of the GCV at T = 240 min compared to Cas (52.8 (27.6) vs. 65.4 (29.9) min, p = 0.020). CONCLUSIONS: In this study in which healthy volunteers received esomeprazole and codeine to mimic gastrointestinal conditions of critically ill patients, observations of secondary endpoints suggest faster gastric emptying with P4 compared to Cas, and less gastric accumulation, possibly due to the non-coagulating properties of the P4 protein blend. Considering the small effect and the possible clinical relevance of reduced intragastric accumulation of enteral nutrition, the potential impact of protein coagulation should be further investigated in relevant study populations. Registered under Netherlands Trial Register identifier no. NTR6423.

Gastric accumulation of enteral nutrition reduces pressure changes induced by phasic contractility in an isovolumetric intragastric balloon.

BACKGROUND: An isovolumetric intragastric balloon to continuously measure gastric phasic contractility was recently developed by us. We aimed to investigate the readout of this technique in relation to gastric content and gastric emptying. METHODS: In this crossover investigation, the VIPUNTM Gastric Monitoring System, which comprises a double lumen nasogastric feeding tube with integrated intragastric balloon, was used to assess phasic gastric contractility by interpretation of the pressure in an isovolumetric balloon in 10 healthy subjects. Balloon pressure was recorded in fasted state, during a 2-hour intragastric nutrient infusion (1 kcal/ml at 25, 75, or 250 ml/h) and 4 hours post-infusion, and quantified as Gastric Balloon Motility Index (GBMI), ranging from 0 (no contractility) to 1 (maximal contractility). Gastric accumulation was quantified with magnetic resonance imaging and gastric emptying with a13 C-breath test. Results are expressed as mean(SD). KEY RESULTS: GBMI was significantly lower during infusion at 250 ml/h compared to baseline (0.13(0.05) versus 0.46(0.12)) and compared to infusion at 25 (0.54(0.21)) and 75 ml/h (0.43(0.20)), all P < 0.005. Gastric content volume was larger after infusion at 250 versus 75 ml/h (P < 0.001). Half-emptying time and accumulation were both negatively correlated with postprandial contractility. Postprandial GBMI was significantly lower when GCV>0 ml compared to when the stomach was empty. CONCLUSIONS AND INFERENCES: Enteral nutrition dose-dependently decreased the contractility readout. This decrease was linked to gastric accumulation of enteral nutrition.

Right ventricular fatigue developing during endurance exercise: an exercise cardiac magnetic resonance study.

INTRODUCTION: Prolonged intense exercise has often been associated with the impairment of right ventricular (RV) function after activity, whereas this is rare for the left ventricle (LV). The effect of prolonged exercise on the heart has not been adequately measured during exercise itself. METHODS: We performed real-time cardiac magnetic resonance imaging at rest and during incremental exercise in 14 male endurance athletes (mean ± SD; age = 36 ± 6 yr, BMI = 23.1 ± 1.94 kg·m) 1-3 wk before (baseline) and immediately after a 150-km cycling event (end-of-race) to measure LV and RV end-diastolic and end-systolic volumes (EDV and ESV), ejection fraction (EF), and ventricular-arterial coupling (stroke volume [SV]/ESV). RESULTS: End-of-race RV EDV was unchanged from baseline at rest but was significantly increased during near-maximal exercise (235 ± 18 vs 217 ± 24 mL, P < 0.0001). Resting RV ESV was higher end-of-race (100 ± 16 vs 93 ± 15 mL, P = 0.009), which became more appreciable during near-maximal exercise (75 ± 15 vs 60 ± 14 mL, P < 0.0001). RV EF, although unchanged at rest, was significantly decreased during near-maximal exercise (68% ± 5% vs 73% ± 4%, P = 0.001). LV volume measures were similar at baseline and end-of-race. Therefore, the effect of endurance activity on the RV and LV was significantly different (P < 0.0001). Cardiac output increased to similar values at near-maximal exertion before and at the end of the race. However, whereas LV SV/ESV was unchanged, RV SV/ESV was attenuated end-of-race (P = 0.02 for interaction with race setting). CONCLUSIONS: Intense endurance exercise does not affect LV volume or function but results in RV dilatation and reduced RV EF, which becomes even more significant during exercise. Alterations in RV ventricular-arterial coupling suggest that this may be an expression of exercise-induced RV contractile impairment rather than changes in autonomic or loading conditions.