Giuliana Durighel

Ghrelin mimics fasting to enhance human hedonic, orbitofrontal cortex, and hippocampal responses to food

BACKGROUND Ghrelin, which is a stomach-derived hormone, increases with fasting and energy restriction and may influence eating behaviors through brain hedonic reward-cognitive systems. Therefore, changes in plasma ghrelin might mediate counter-regulatory responses to a negative energy balance through changes in food hedonics. OBJECTIVE We investigated whether ghrelin administration (exogenous hyperghrelinemia) mimics effects of fasting (endogenous hyperghrelinemia) on the hedonic response and activation of brain-reward systems to food. DESIGN In a crossover design, 22 healthy, nonobese adults (17 men) underwent a functional magnetic resonance imaging (fMRI) food-picture evaluation task after a 16-h overnight fast (Fasted-Saline) or after eating breakfast 95 min before scanning (730 kcal, 14% protein, 31% fat, and 55% carbohydrate) and receiving a saline (Fed-Saline) or acyl ghrelin (Fed-Ghrelin) subcutaneous injection before scanning. One male subject was excluded from the fMRI analysis because of excess head motion, which left 21 subjects with brain-activation data. RESULTS Compared with the Fed-Saline visit, both ghrelin administration to fed subjects (Fed-Ghrelin) and fasting (Fasted-Saline) significantly increased the appeal of high-energy foods and associated orbitofrontal cortex activation. Both fasting and ghrelin administration also increased hippocampus activation to high-energy- and low-energy-food pictures. These similar effects of endogenous and exogenous hyperghrelinemia were not explicable by consistent changes in glucose, insulin, peptide YY, and glucagon-like peptide-1. Neither ghrelin administration nor fasting had any significant effect on nucleus accumbens, caudate, anterior insula, or amygdala activation during the food-evaluation task or on auditory, motor, or visual cortex activation during a control task. CONCLUSIONS Ghrelin administration and fasting have similar acute stimulatory effects on hedonic responses and the activation of corticolimbic reward-cognitive systems during food evaluations. Similar effects of recurrent or chronic hyperghrelinemia on an anticipatory food reward may contribute to the negative impact of skipping breakfast on dietary habits and body weight and the long-term failure of energy restriction for weight loss.

Nutritional Evaluation and Optimisation in Neonates: a randomized, double-blind controlled trial of amino acid regimen and intravenous lipid composition in preterm parenteral nutrition

Background: Parenteral nutrition is central to the care of very immature infants. Current international recommendations favor higher amino acid intakes and fish oil–containing lipid emulsions. Objective: The aim of this trial was to compare 1) the effects of high [immediate recommended daily intake (Imm-RDI)] and low [incremental introduction of amino acids (Inc-AAs)] parenteral amino acid delivery within 24 h of birth on body composition and 2) the effect of a multicomponent lipid emulsion containing 30% soybean oil, 30% medium-chain triglycerides, 25% olive oil, and 15% fish oil (SMOF) with that of soybean oil (SO)-based lipid emulsion on intrahepatocellular lipid (IHCL) content. Design: We conducted a 2-by-2 factorial, double-blind, multicenter randomized controlled trial. Results: We randomly assigned 168 infants born at <31 wk of gestation. We evaluated outcomes at term in 133 infants. There were no significant differences between Imm-RDI and Inc-AA groups for nonadipose mass [adjusted mean difference: 1.0 g (95% CI: −108, 111 g; P = 0.98)] or between SMOF and SO groups for IHCL [adjusted mean SMOF:SO ratio: 1.1 (95% CI: 0.8, 1.6; P = 0.58]. SMOF does not affect IHCL content. There was a significant interaction (P = 0.05) between the 2 interventions for nonadipose mass. There were no significant interactions between group differences for either primary outcome measure after adjusting for additional confounders. Imm-RDI infants were more likely than Inc-AA infants to have blood urea nitrogen concentrations >7 mmol/L or >10 mmol/L, respectively (75% compared with 49%, P < 0.01; 49% compared with 18%, P < 0.01). Head circumference at term was smaller in the Imm-RDI group [mean difference: −0.8 cm (95% CI: −1.5, −0.1 cm; P = 0.02)]. There were no significant differences in any prespecified secondary outcomes, including adiposity, liver function tests, incidence of conjugated hyperbilirubinemia, weight, length, mortality, and brain volumes. Conclusion: Imm-RDI of parenteral amino acids does not benefit body composition or growth to term and may be harmful. This trial was registered at www.isrctn.com as ISRCTN29665319 and at eudract.ema.europa.eu as EudraCT 2009-016731-34.

Population-based studies of myocardial hypertrophy: high resolution cardiovascular magnetic resonance atlases improve statistical power

BackgroundCardiac phenotypes, such as left ventricular (LV) mass, demonstrate high heritability although most genes associated with these complex traits remain unidentified. Genome-wide association studies (GWAS) have relied on conventional 2D cardiovascular magnetic resonance (CMR) as the gold-standard for phenotyping. However this technique is insensitive to the regional variations in wall thickness which are often associated with left ventricular hypertrophy and require large cohorts to reach significance. Here we test whether automated cardiac phenotyping using high spatial resolution CMR atlases can achieve improved precision for mapping wall thickness in healthy populations and whether smaller sample sizes are required compared to conventional methods.MethodsLV short-axis cine images were acquired in 138 healthy volunteers using standard 2D imaging and 3D high spatial resolution CMR. A multi-atlas technique was used to segment and co-register each image. The agreement between methods for end-diastolic volume and mass was made using Bland-Altman analysis in 20 subjects. The 3D and 2D segmentations of the LV were compared to manual labeling by the proportion of concordant voxels (Dice coefficient) and the distances separating corresponding points. Parametric and nonparametric data were analysed with paired t-tests and Wilcoxon signed-rank test respectively. Voxelwise power calculations used the interstudy variances of wall thickness.ResultsThe 3D volumetric measurements showed no bias compared to 2D imaging. The segmented 3D images were more accurate than 2D images for defining the epicardium (Dice: 0.95 vs 0.93, P < 0.001; mean error 1.3 mm vs 2.2 mm, P < 0.001) and endocardium (Dice 0.95 vs 0.93, P < 0.001; mean error 1.1 mm vs 2.0 mm, P < 0.001). The 3D technique resulted in significant differences in wall thickness assessment at the base, septum and apex of the LV compared to 2D (P < 0.001). Fewer subjects were required for 3D imaging to detect a 1 mm difference in wall thickness (72 vs 56, P < 0.001).ConclusionsHigh spatial resolution CMR with automated phenotyping provides greater power for mapping wall thickness than conventional 2D imaging and enables a reduction in the sample size required for studies of environmental and genetic determinants of LV wall thickness.

Precursors of Hypertensive Heart Phenotype Develop in Healthy Adults: A High-Resolution 3D MRI Study

Objectives This study used high-resolution 3-dimensional cardiac magnetic resonance to define the anatomical and functional left ventricular (LV) properties associated with increasing systolic blood pressure (SBP) in a drug-naive cohort.Objectives This study used high-resolution 3-dimensional cardiac magnetic resonance to define the anatomical and functional left ventricular (LV) properties associated with increasing systolic blood pressure (SBP) in a drug-naïve cohort. Background LV hypertrophy and remodeling occur in response to hemodynamic stress but little is known about how these phenotypic changes are initiated in the general population. Methods In this study, 1,258 volunteers (54% women, mean age 40.6 ± 12.8 years) without self-reported cardiovascular disease underwent 3-dimensional cardiac magnetic resonance combined with computational modeling. The relationship between SBP and wall thickness (WT), relative WT, end-systolic wall stress (WS), and fractional wall thickening were analyzed using 3-dimensional regression models adjusted for body surface area, sex, race, age, and multiple testing. Significantly associated points in the LV model (p < 0.05) were identified and the relationship with SBP reported as mean β coefficients. Results There was a continuous relationship between SBP and asymmetric concentric hypertrophic adaptation of the septum and anterior wall that was associated with normalization of wall stress. In the lateral wall an increase in wall stress with rising SBP was not balanced by a commensurate hypertrophic relationship. In normotensives, SBP was positively associated with WT (β = 0.09) and relative WT (β = 0.07) in the septal and anterior walls, and this regional hypertrophic relationship was progressively stronger among pre-hypertensives (β = 0.10) and hypertensives (β = 0.30). Conclusions These findings show that the precursors of the hypertensive heart phenotype can be traced to healthy normotensive adults and that an independent and continuous relationship exists between adverse LV remodeling and SBP in a low-risk population. These adaptations show distinct regional variations with concentric hypertrophy of the septum and eccentric hypertrophy of the lateral wall, which challenge conventional classifications of LV remodeling.

Early nutritional determinants of intrahepatocellular lipid deposition in preterm infants at term age

Background:We have previously shown that by term age, preterm infants have elevated intrahepatocellular lipid (IHCL) content and altered regional adiposity, both of which are risk factors for cardiometabolic illness in adult life. Preterm nutritional intake is a plausible determinant of these aberrant trajectories of development.Objective:We aimed to establish if macronutritional components of the preterm diet were determinants of IHCL deposition measured at term equivalent age, using 1H Magnetic Resonance spectroscopy (MRS).Methods:Prospective observational case–control study in a single UK neonatal unit. 1H MR spectra were acquired from 18 preterm infants (<32 weeks gestational age at birth) at term age and 31 healthy term infants, who acted as a control group. Neonatal nutritional information was collected from birth to 34+6 weeks postmenstrual age.Results:IHCL (median, interquartile range) was significantly higher in preterm-at-term infants compared with term-born infants: 0.735, 0–1.46 versus 0.138, 0–0.58; P=0.003. In preterm infants, IHCL was positively correlated with lipid intake in the first week of life (r=0.52, P=0.04).Conclusions:This study confirms our previous observation of elevated IHCL in preterm infants at term and suggests that early lipid intake may be a determinant. Future work is warranted to establish the clinical relevance and the role of nutritional intervention in attenuating or exacerbating this effect in preterm infants.

Pulmonary Artery Stiffness Is Independently Associated with Right Ventricular Mass and Function: A Cardiac MR Imaging Study

Purpose To determine the relationship between pulmonary artery (PA) stiffness and both right ventricular (RV) mass and function with cardiac magnetic resonance (MR) imaging. Materials and Methods The study was approved by the local research ethics committee, and all participants gave written informed consent. Cardiac MR imaging was performed at 1.5 T in 156 healthy volunteers (63% women; age range, 19-61 years; mean age, 36.1 years). High-temporal-resolution phase-contrast imaging was performed in the main and right PAs. Pulmonary pulse wave velocity (PWV) was determined by the interval between arterial systolic upslopes. RV function was assessed with feature tracking to derive peak systolic strain and strain rate, as well as peak early-diastolic strain rate. RV volumes, ejection fraction (RVEF), and mass were measured from the cine images. The association of pulmonary PWV with RV function and mass was quantified with univariate linear regression. Interstudy repeatability was assessed with intraclass correlation. Results The repeatability coefficient for pulmonary PWV was 0.96. Increases in pulmonary PWV and RVEF were associated with increases in age (r = 0.32, P < .001 and r = 0.18, P = .025, respectively). After adjusting for age (P = .090), body surface area (P = .073), and sex (P = .005), pulmonary PWV demonstrated an independent positive association with RVEF (r = 0.34, P = .026). Significant associations were also seen with RV mass (r = 0.41, P = .004), RV radial strain (r = 0.38, P = .022), and strain rate (r = 0.35, P = .002), and independent negative associations were seen with radial (r = 0.27, P = .003), longitudinal (r = 0.40, P = .007), and circumferential (r = 0.31, P = .005) peak early-diastolic strain rate with the same covariates. Conclusion Pulmonary PWV is reliably assessed with cardiac MR imaging. In subjects with no known cardiovascular disease, increasing PA stiffness is associated with increasing age and is also moderately associated with both RV mass and function after controlling for age, body surface area, and sex. (©) RSNA, 2016 Online supplemental material is available for this article.

Sexual dimorphism in relation to adipose tissue and intrahepatocellular lipid deposition in early infancy

Sexual dimorphism in adiposity is well described in adults, but the age at which differences first manifest is uncertain. Using a prospective cohort, we describe longitudinal changes in directly measured adiposity and intrahepatocellular lipid (IHCL) in relation to sex in healthy term infants. At median ages of 13 and 63 days, infants underwent quantification of adipose tissue depots by whole-body magnetic resonance imaging and measurement of IHCL by in vivo proton magnetic resonance spectroscopy. Longitudinal data were obtained from 70 infants (40 boys and 30 girls). In the neonatal period girls are more adipose in relation to body size than boys. At follow-up (median age 63 days), girls remained significantly more adipose. The greater relative adiposity that characterises girls is explained by more subcutaneous adipose tissue and this becomes increasingly apparent by follow-up. No significant sex differences were seen in IHCL. Sex-specific differences in infant adipose tissue distribution are in keeping with those described in later life, and suggest that sexual dimorphism in adiposity is established in early infancy.

Adverse changes in left ventricular structure begin at normotensive systolic blood pressures: a high resolution MRI study

Background The prevalence of hypertension has doubled over the previous decade and represents a significant public health problem worldwide. Excess cardiovascular risk due to increased blood pressure shows no evidence of a threshold to at least 115/75 mmHg. Left ventricular (LV) hypertrophy has a strong association with essential hypertension and is an independent risk factor for mortality. However, there is little data on whether systolic blood pressure (SBP) influences LV morphology and function in a healthy population. Furthermore it is not clear if any phenotypical changes are part of an adaptive response to increasing afterload or the beginning of a maladaptive process that ultimately leads to cardiomyopathy.

Precursors of the hypertensive heart phenotype develop in normotensive adults: a high resolution 3D MRI study

Objectives This study used high-resolution 3-dimensional cardiac magnetic resonance to define the anatomical and functional left ventricular (LV) properties associated with increasing systolic blood pressure (SBP) in a drug-naive cohort.Objectives This study used high-resolution 3-dimensional cardiac magnetic resonance to define the anatomical and functional left ventricular (LV) properties associated with increasing systolic blood pressure (SBP) in a drug-naïve cohort. Background LV hypertrophy and remodeling occur in response to hemodynamic stress but little is known about how these phenotypic changes are initiated in the general population. Methods In this study, 1,258 volunteers (54% women, mean age 40.6 ± 12.8 years) without self-reported cardiovascular disease underwent 3-dimensional cardiac magnetic resonance combined with computational modeling. The relationship between SBP and wall thickness (WT), relative WT, end-systolic wall stress (WS), and fractional wall thickening were analyzed using 3-dimensional regression models adjusted for body surface area, sex, race, age, and multiple testing. Significantly associated points in the LV model (p < 0.05) were identified and the relationship with SBP reported as mean β coefficients. Results There was a continuous relationship between SBP and asymmetric concentric hypertrophic adaptation of the septum and anterior wall that was associated with normalization of wall stress. In the lateral wall an increase in wall stress with rising SBP was not balanced by a commensurate hypertrophic relationship. In normotensives, SBP was positively associated with WT (β = 0.09) and relative WT (β = 0.07) in the septal and anterior walls, and this regional hypertrophic relationship was progressively stronger among pre-hypertensives (β = 0.10) and hypertensives (β = 0.30). Conclusions These findings show that the precursors of the hypertensive heart phenotype can be traced to healthy normotensive adults and that an independent and continuous relationship exists between adverse LV remodeling and SBP in a low-risk population. These adaptations show distinct regional variations with concentric hypertrophy of the septum and eccentric hypertrophy of the lateral wall, which challenge conventional classifications of LV remodeling.

259 ASYMMETRICAL SEPTAL HYPERTROPHY IS ASSOCIATED WITH MEAN ARTERIAL BLOOD PRESSURE IN HEALTHY ADULTS: DATA FROM HIGH RESOLUTION 3D CARDIAC MRI

Background Left ventricular hypertrophy (LVH) is the result of complex interactions between genes and environmental factors, and an independent risk factor for all-cause mortality. Clinically, it is important to differentiate ‘physiological’ LVH, such as in hypertension, from pathological LVH as found in hypertrophic cardiomyopathy. Standard methods of cardiac phenotyping such as echocardiography or 2D cardiac magnetic resonance (CMR) provide only macroscopic descriptors of LV mass (LVM) and function. These methods are underpowered for population wide study of regional wall thickness variability. Methods and Results 187 healthy multi-ethnic volunteers (105 female, age range 18–72, mean age 40) were recruited into a sub-study of the UK GenScan project. Exclusion criteria included established history of cardiovascular disease, hypertension, diabetes or hypercholesterolemia. Subjects were phenotyped by CMR using a 1.5T Philips Achieva system with a 32 element cardiac phased-array coil. High resolution 3D cine imaging of the LV was obtained with a voxel size of 2x2x4 mm and 20 cardiac phases. Three blood pressure (BP) measurements were taken and averaged (in mmHg): Mean systolic BP 123 (range 90–186), mean diastolic BP 80.4 (range 47–109). The high resolution 3D images were automatically segmented using training data from 10 healthy volunteers in which the myocardium had been manually labelled at end-diastole and end-systole (Figure 1). The 187 3D segmentations were exactly co-registered with each other so that corresponding points within the myocardium could be accurately compared within the cohort. Mean wall thickness was calculated at each point as the distance between the endocardial and epicardial surfaces. Automated measurements were validated against manual readings using standard clinical software (Philips Extended Workspace). LV end-diastolic volumes and LVM measurements were highly correlated (R2=.98 and R2=0.93 respectively). Mass univariate analysis was performed on the co-registered 3D models with wall thickness as the dependent variable. Pooling data from all the subjects, we plotted wall thickness at each 3D coordinate as a linear function of Mean Arterial Pressures (MAP) with gender and age held constant. The 3D models showed that blood pressure associated LVH begins asymmetrically within the mid-septum and progressively extends towards the base and apex with rising MAP (Figure 2). The lateral wall and apex are relatively spared. Figure 1 Figure 2 Conclusions Whole-heart high-resolution 3D CMR provides new opportunities for quantitative phenotyping of the heart and understanding the genetic and environmental determinants of heart disease. In this study we used these techniques to show the pattern of progressive asymmetrical septal hypertrophy that is associated with increasing blood pressure even within the general population.