scholarly journals Cardiac phenotype and tissue sodium content in adolescents with defects in the melanocortin system

Author(s):  
Lia Puder ◽  
Sophie Roth ◽  
Philipp Krabusch ◽  
Susanna Wiegand ◽  
Robert Opitz ◽  
...  

Abstract CONTEXT Pro-opiomelanocortin (POMC) and the melanocortin-4 receptor (MC4R) play a pivotal role in the leptin-melanocortin pathway. Mutations in these genes lead to monogenic types of obesity due to severe hyperphagia. In addition to dietary-induced obesity, a cardiac phenotype without hypertrophy has been identified in MC4R knockout mice. OBJECTIVE We aimed to characterize cardiac morphology and function as well as tissue Na + content in humans with mutations in POMC and MC4R genes. PARTICIPANTS A cohort of 42 patients (5 patients with bi-allelic POMC mutations, 6 heterozygous MC4R mutation carriers, 19 obese controls without known monogenic cause and 12 normal-weight controls) underwent cardiac magnetic resonance (CMR) imaging and 23Na-MRI. RESULTS Monogenic obese patients with POMC or MC4R mutation respectively had a significantly lower left ventricular mass/body surface area (BSA) compared to non-monogenic obese patients. Left ventricular end-diastolic volume/BSA was significantly lower in POMC- and MC4R-deficient patients than in non-monogenic obese patients. Subcutaneous fat and skin Na + content was significantly higher in POMC- and MC4R-deficient patients compared to non-monogenic obese patients. In these compartments, the water content was significantly higher in patients with POMC and MC4R mutation than in control-groups. CONCLUSIONS Patients with POMC or MC4R mutations carriers had a lack of transition to hypertrophy, significantly lower cardiac muscle mass/BSA and stored more Na + within the subcutaneous fat tissue compared to non-monogenic obese patients. The results point towards the role of the melanocortin pathway for cardiac function, tissue Na + storage and the importance of including cardiologic assessments into the diagnostic work-up of these patients.

2011 ◽  
Vol 109 (suppl_1) ◽  
Author(s):  
Marie Schroeder ◽  
Angus Z Lau ◽  
Albert P Chen ◽  
Jennifer Barry ◽  
Damian J Tyler ◽  
...  

Disordered metabolic substrate utilisation has been implicated in the pathogenesis of heart failure (HF). Hyperpolarised (HYP) 13C magnetic resonance, a technique in which the fate of 13C-labelled metabolites can be followed using MR imaging or spectroscopy, has enabled non-invasive assessment of metabolism. The aim of this study was to monitor carbohydrate metabolism alongside cardiac structure, function, and energetics, throughout HF progression. HF was induced in pigs (n=5) by right ventricular pacing at 188 bpm for 5 weeks. Pigs were examined at weekly time points: cine MRI assessed cardiac structure and function, HYP 13C2-pyruvate was administered intravenously and 13C MRS was used to assess 13C-glutamate production via Krebs cycle, 31P MRS assessed myocardial energetics, and HYP 13C1-pyruvate was administered to enable MRI of H13CO3- production from pyruvate dehydrogenase (PDH). At baseline, pigs had a normal left ventricular (LV) cardiac index (CI) and end diastolic volume (EDVi). The PCr/ATP was 2.3 ± 0.2. The 13C-glutamate/13C2-pyruvate was 4.3 ± 0.9%, and the H13CO3-/13C1-pyruvate ratio was 1.6 ± 0.2%. After 1–2 weeks of pacing, CI decreased to 3.3 ± 0.5 l/min/m2, PCr/ATP decreased to 1.7 ± 0.1, and 13C-glutamate/13C2-pyruvate decreased to 2.1 ± 0.6%. With the onset of HF, EDVi increased to 140.3 ± 14.1 ml/m2 and H13CO3-/13C1-pyruvate decreased to 0.5 ± 0.2%. In conclusion, we observed an early defect in Krebs' cycle that occurred alongside impaired cardiac energetics and function. Carbohydrate oxidation via PDH was maintained until the onset of HF. These results encourage use of metabolic therapies to delay/prevent the onset of heart failure in patients.


2018 ◽  
Vol 115 (3) ◽  
pp. 519-529 ◽  
Author(s):  
Sarah-Lena Puhl ◽  
Kate L Weeks ◽  
Alican Güran ◽  
Antonella Ranieri ◽  
Peter Boknik ◽  
...  

Abstract Aims B56α is a protein phosphatase 2A (PP2A) regulatory subunit that is highly expressed in the heart. We previously reported that cardiomyocyte B56α localizes to myofilaments under resting conditions and translocates to the cytosol in response to acute β-adrenergic receptor (β-AR) stimulation. Given the importance of reversible protein phosphorylation in modulating cardiac function during sympathetic stimulation, we hypothesized that loss of B56α in mice with targeted disruption of the gene encoding B56α (Ppp2r5a) would impact on cardiac responses to β-AR stimulation in vivo. Methods and results Cardiac phenotype of mice heterozygous (HET) or homozygous (HOM) for the disrupted Ppp2r5a allele and wild type (WT) littermates was characterized under basal conditions and following acute β-AR stimulation with dobutamine (DOB; 0.75 mg/kg i.p.) or sustained β-AR stimulation by 2-week infusion of isoproterenol (ISO; 30 mg/kg/day s.c.). Left ventricular (LV) wall thicknesses, chamber dimensions and function were assessed by echocardiography, and heart tissue collected for gravimetric, histological, and biochemical analyses. Western blot analysis revealed partial and complete loss of B56α protein in hearts from HET and HOM mice, respectively, and no changes in the expression of other PP2A regulatory, catalytic or scaffolding subunits. PP2A catalytic activity was reduced in hearts of both HET and HOM mice. There were no differences in the basal cardiac phenotype between genotypes. Acute DOB stimulation induced the expected inotropic response in WT and HET mice, which was attenuated in HOM mice. In contrast, DOB-induced increases in heart rate were unaffected by B56α deficiency. In WT mice, ISO infusion increased LV wall thicknesses, cardiomyocyte area and ventricular mass, without LV dilation, systolic dysfunction, collagen deposition or foetal gene expression. The hypertrophic response to ISO was blunted in mice deficient for B56α. Conclusion These findings identify B56α as a potential regulator of cardiac structure and function during β-AR stimulation.


1985 ◽  
Vol 58 (2) ◽  
pp. 409-415 ◽  
Author(s):  
L. A. Wolfe ◽  
R. P. Martin ◽  
D. D. Watson ◽  
R. D. Lasley ◽  
D. E. Bruns

Twelve healthy well-trained participants in a supervised exercise program (mean age, 41.3 yr) were compared with 12 sedentary control subjects (mean age, 38.9 yr) with physical characteristics similar to the exercised group (EG) before training. Resting echocardiograms revealed significantly lower heart rates (HR) in the EG compared with control group (CG) but no evidence for cardiac structural differences between groups. Radionuclide angiograms performed at rest and during two levels of supine cycling (HR targets: 120 and 140 beats X min-1) resulted in increases in background-corrected end-diastolic counts [EDC(bc)] and confirmed use of the Frank-Starling mechanism in the majority of subjects. Mean values (+/- SD) for ejection fraction (EF) and normalized peak systolic ejection rate (PSER) (P greater than 0.05 between groups) were the following. (Formula: see text) The results suggested that fitness training does not induce significant cardiac enlargement as apparent from measurements at rest or important changes in contractile state during exercise. Increases in exercise stroke volume with such training may be the result of an increased end-diastolic volume.


2018 ◽  
Vol 315 (6) ◽  
pp. R1232-R1241 ◽  
Author(s):  
Loren P. Thompson ◽  
Ling Chen ◽  
Brian M. Polster ◽  
Gerard Pinkas ◽  
Hong Song

Adverse intrauterine conditions cause fetal growth restriction and increase the risk of adult cardiovascular disease. We hypothesize that intrauterine hypoxia impairs fetal heart function, is sustained after birth, and manifests as both cardiac and mitochondrial dysfunction in offspring guinea pigs (GPs). Pregnant GPs were exposed to 10.5% O2 (HPX) at 50 days of gestation (full term = 65 days) or normoxia (NMX) for the duration of the pregnancy. Pups were allowed to deliver vaginally and raised in a NMX environment. At 90 days of age, mean arterial pressure (MAP) was measured in anesthetized GPs. NMX and prenatally HPX offspring underwent echocardiographic imaging for in vivo measurement of left ventricular cardiac morphology and function, and O2 consumption rates and complex IV enzyme activity were measured from isolated cardiomyocytes and mitochondria, respectively. Prenatal HPX increased ( P < 0.01) MAP (52.3 ± 1.3 and 58.4 ± 1.1 mmHg in NMX and HPX, respectively) and decreased ( P < 0.05) stroke volume (439.8 ± 54.5 and 289.4 ± 15.8 μl in NMX and HPX, respectively), cardiac output (94.4 ± 11.2 and 67.3 ± 3.8 ml/min in NMX and HPX, respectively), ejection fraction, and fractional shortening in male, but not female, GPs. HPX had no effect on left ventricular wall thickness or end-diastolic volume in either sex. HPX reduced mitochondrial maximal respiration and respiratory reserve capacity and complex IV activity rates in hearts of male, but not female, GPs. Prenatal HPX is a programming stimulus that increases MAP and decreases cardiac and mitochondrial function in male offspring. Sex-related differences in the contractile and mitochondrial responses suggest that female GPs are protected from cardiovascular programming of prenatal HPX.


2018 ◽  
Vol 9 (1) ◽  
pp. 204589401881978 ◽  
Author(s):  
Anthony C. Chyou ◽  
Barbara E.K. Klein ◽  
Ronald Klein ◽  
R. Graham Barr ◽  
Mary Frances Cotch ◽  
...  

Retinal vessel diameters have been associated with left ventricular morphology and function but their relationship with the right ventricle (RV) has not been studied. We hypothesized that wider retinal venules and narrower retinal arterioles are associated with RV morphology and function. RV end-diastolic mass (RVEDM), end-diastolic volume (RVEDV), end-systolic volume (RVESV), stroke volume (RVSV), and ejection fraction (RVEF) were assessed using cardiac magnetic resonance imaging (MRI) scans of 4204 participants without clinical cardiovascular disease at the baseline examination; retinal photography was obtained at the second examination. Mean diameters of retinal arterioles and venules were measured and summarized as central retinal vein and artery equivalents (“veins” and “arteries,” respectively). After adjusting for covariates, wider veins were associated with greater RVEDM and RVEDV in women ( P = 0.04 and P = 0.02, respectively), whereas there was an inverse association with RVEDV in men ( P = 0.02). In both sexes, narrower arteries were associated with lower RVEDM ( P < 0.001 in women and P = 0.002 in men) and smaller RVEDV ( P < 0.001 in women and P = 0.04 in men) in adjusted models. Narrower arteries were also associated with lower RVEF in men but this was of borderline significance after adjusting for the LVEF ( P = 0.08). Wider retinal venular diameter was associated with sex-specific changes in RVEDM and RVEDV in adults without clinical cardiovascular disease. Narrower retinal arteriolar diameter was associated with significantly lower RVEDM and smaller RVEDV in both sexes.


2019 ◽  
Vol 8 (10) ◽  
pp. 1654
Author(s):  
Radka Kočková ◽  
Hana Línková ◽  
Zuzana Hlubocká ◽  
Alena Pravečková ◽  
Andrea Polednová ◽  
...  

Background: Determining the value of new imaging markers to predict aortic valve (AV) surgery in asymptomatic patients with severe aortic regurgitation (AR) in a prospective, observational, multicenter study. Methods: Consecutive patients with chronic severe AR were enrolled between 2015–2018. Baseline examination included echocardiography (ECHO) with 2- and 3-dimensional (2D and 3D) vena contracta area (VCA), and magnetic resonance imaging (MRI) with regurgitant volume (RV) and fraction (RF) analyzed in CoreLab. Results: The mean follow-up was 587 days (interquartile range (IQR) 296–901) in a total of 104 patients. Twenty patients underwent AV surgery. Baseline clinical and laboratory data did not differ between surgically and medically treated patients. Surgically treated patients had larger left ventricular (LV) dimension, end-diastolic volume (all p < 0.05), and the LV ejection fraction was similar. The surgical group showed higher prevalence of severe AR (70% vs. 40%, p = 0.02). Out of all imaging markers 3D VCA, MRI-derived RV and RF were identified as the strongest independent predictors of AV surgery (all p < 0.001). Conclusions: Parameters related to LV morphology and function showed moderate accuracy to identify patients in need of early AV surgery at the early stage of the disease. 3D ECHO-derived VCA and MRI-derived RV and RF showed high accuracy and excellent sensitivity to identify patients in need of early surgery.


Open Heart ◽  
2018 ◽  
Vol 5 (2) ◽  
pp. e000919
Author(s):  
Rine Bakkestrøm ◽  
Ann Banke ◽  
Redi Pecini ◽  
Akhmadjon Irmukhamedov ◽  
Søren Kristian Nielsen ◽  
...  

ObjectiveTo assess the association between cardiac morphology and function assessed with cardiac MRI (CMRI) and haemodynamics at rest and during exercise in patients with primary mitral regurgitation (MR).MethodsIn an observational study, subjects with significant primary MR (N = 46) with effective regurgitant orifice ≥ 0.30 cm2 and left ventricular (LV) ejection fraction > 60% were examined with right heart catheterisation during rest and exercise and CMRI at rest. End-diastolic pressure volume relationship (EDPVR) was assessed using a single beat method using pulmonary capillary wedge pressure (PCWP) and end-diastolic volume. Patients were divided according to normal PCWP at rest (> 12 mm Hg) and with exercise (> 28 mm Hg). Results: Resting regurgitant volume correlated positively with resting PCWP, (r = 0.42, p = 0.002). However, with exercise no association between PCWP and regurgitant volume was seen (r = 0.09, p = 0.55). At rest left atrial (LA) maximal, minimal and volume index at atrial contraction correlated positively with PCWP (r = 0.60; r = 0.55; r = 0.58, all p < 0.001); in contrast none of these correlated with exercise PCWP (all p > 0.2). EDPVR in patients with high PCWP at rest was shifted towards higher volumes for the same pressures. The opposite was seen for patients with high PCWP during exercise where estimated volumes were smaller for the same pressure than patients with normal exercise PCWP.ConclusionIn patients with significant MR the degree of regurgitation and LA dilatation is associated with resting PCWP. However, with exercise this association disappears. Estimation of EDPVR suggests lower LV compliance in patients where PCWP is increased with exercise.Clinical trial registrationURL: https://clinicaltrials.gov/ct2/show/NCT02961647?term=HEMI&rank=1. ID: NCT02961647


2011 ◽  
Vol 301 (5) ◽  
pp. H2061-H2072 ◽  
Author(s):  
Takayuki Shimazu ◽  
Hajime Otani ◽  
Kei Yoshioka ◽  
Masanori Fujita ◽  
Toru Okazaki ◽  
...  

Uncoupling of nitric oxide synthase (NOS) has been implicated in left ventricular (LV) remodeling and dysfunction after myocardial infarction (MI). We hypothesized that inducible NOS (iNOS) plays a crucial role in LV remodeling after MI, depending on its coupling status. MI was created in wild-type, iNOS-knockout (iNOS−/−), endothelial NOS-knockout (eNOS−/−), and neuronal NOS-knockout (nNOS−/−) mice. iNOS and nNOS expressions were increased after MI associated with an increase in nitrotyrosine formation. The area of myocardial fibrosis and LV end-diastolic volume and ejection fraction were more deteriorated in eNOS−/− mice compared with other genotypes of mice 4 wk after MI. The expression of GTP cyclohydrolase was reduced, and tetrahydrobiopterin (BH4) was depleted in the heart after MI. Oral administration of sepiapterin after MI increased dihydrobiopterin (BH2), BH4, and BH4-to-BH2 ratio in the infarcted but not sham-operated heart. The increase in BH4-to-BH2 ratio was associated with inhibition of nitrotyrosine formation and an increase in nitrite plus nitrate. However, this inhibition of NOS uncoupling was blunted in iNOS−/− mice. Sepiapterin increased capillary density and prevented LV remodeling and dysfunction after MI in wild-type, eNOS−/−, and nNOS−/− but not iNOS−/− mice. Nω-nitro-l-arginine methyl ester abrogated sepiapterin-induced increase in nitrite plus nitrate and angiogenesis and blocked the beneficial effects of sepiapterin on LV remodeling and function. These results suggest that sepiapterin enhances angiogenesis and functional recovery after MI by activating the salvage pathway for BH4 synthesis and increasing bioavailable nitric oxide predominantly derived from iNOS.


2020 ◽  
Author(s):  
Rama J. Wahab ◽  
Vincent W.V. Jaddoe ◽  
Arno A.W. Roest ◽  
Liza Toemen ◽  
Romy Gaillard

<b>OBJECTIVE: </b>Gestational diabetes has been associated with offspring cardiac congenital malformations, ventricular hypertrophy and diastolic dysfunction in large observational cohort studies and experimental animal models. We assessed the associations of maternal random glucose concentrations across the full range with childhood cardiac ventricular structure and function. <p><b>RESEARCH DESIGN AND METHODS: </b>In a population-based prospective cohort among 1,959 women and their offspring, maternal random glucose concentrations were measured at a median 13.1 weeks gestation (95% range 10.5; 16.8 weeks). We obtained offspring cardiac outcomes, relative to body size, through cardiac Magnetic Resonance Imaging at 10 years.</p> <p><b>RESULTS: </b>The mean maternal random glucose concentration was 4.4 mmol/l (Standard Deviation 0.8). The highest quintile of maternal glucose concentrations, compared to the lowest quintile, was associated with a lower childhood left ventricular mass (-0.19 Standard Deviation Score (SDS), 95% Confidence Interval (CI) -0.31; -0.07) and left ventricular end-diastolic-volume (-0.17 SDS, 95% -0.28; -0.05). Also, higher maternal glucose concentrations across the full range per 1 mmol/l increase were associated with a lower childhood left ventricular mass and left ventricular end-diastolic-volume (p-values≤0.05). Adjustment for maternal prepregnancy BMI, gestational age and weight at birth or childhood BMI and blood pressure did not influence the effect estimates. Maternal glucose concentrations were not significantly associated with childhood right ventricular end-diastolic-volume and left and right ventricular ejection fraction.</p> <p><b>CONCLUSIONS: </b><a>Higher maternal random glucose concentrations in the first half of pregnancy are associated with a lower childhood left ventricular mass and left ventricular end-diastolic-volume, with the strongest associations for childhood left ventricular mass. These associations were not explained by maternal, birth or childhood characteristics. Further studies are needed to replicate these findings using repeated maternal glucose measurements throughout pregnancy and offspring cardiac outcomes throughout childhood and adulthood.</a></p>


Author(s):  
А.Е. Копасов ◽  
Е.Н. Волкова ◽  
С.Н. Блохин ◽  
С.Г. Морозов

Цель работы - определение уровня хемокинов, ассоциированных с фибробластами и кератиноцитами, в клетках кожи, выделеных из операционного материала при абдоминопластике у пациенток с нормальной массой тела и ожирением. Методика. Для исследования использовали фрагменты кожи пациенток с нормальной массой тела и ожирением. Степень ожирения оценивали по индексу массы тела (ИМТ) согласно международным критериям. ИМТ, принятый в исследовании за норму, составлял 19,8±1,7 кг/м2, для пациенток с ожирением - 38,3±4,1 кг/м2. Клетки выделяли путем ферментативной обработки коллагеназой II. Проводили иммунотипирование клеток моноклональными антителами меченными флуоресцентными красителями. Использовали антитела к хемокинам семейства CXCL (R&D systems) и CCL (Boeringer Ingelheim, Германия). Меченные флуоресцентными красителями иммунотипированные клетки анализировали на проточном цитометре FACSCalibur (Becton Dickinson, США) по программе SimulSet. Статистический анализ проводили по программе ANOVA. Результаты. Были проанализированы хемокины семейства CCL и CXCL, секретируемые кератиноцитами и фибробластами кожи. Показано, что в коже пациенток с ожирением повышен процент клеток, экспрссирующих рецепторы CXCR3, CXCR4, CCR3, CCR10, регулирующие секрецию хемокинов кератиноцитами и фибробластами кожи. При ожирении в клетках кожи повышен уровень хемокинов CXCL8, CXCL9, CXCL10, CXCL13, CCL24 и CCL27, имеющих отношение к развитию и поддержанию воспалительного процесса в коже, а уровень хемокинов CCL17, CCL22, CCL28 снижен, что указывает на нарушение хемокиновой и цитокиновой регуляции при ожирении и является основой для развития послеоперационных осложнений при абдоминопластике. Заключение. Полученные данные указывают на нарушение хемокиновой регуляции при ожирении, что способствует развитию послеоперационных осложнений при абдоминопластике. The aim of the study was to compare chemokine expression in skin cells obtained from patients with normal body weight and obesity after abdominoplasty. Methods. Obesity was determined by body weight index (normal, 19.8±1.7 kg/m2; obesity, 38.3±4.1 kg/m2). Only skin without subcutaneous fat was isolated from surgical material. The skin cells obtained from surgical material were stained with monoclonal antibodies to chemokines. Fluorescence of proteins and receptors was analyzed by flow cytometry. Statistical analysis was performed with ANOVA. Results. Keratinocyte- and fibroblast-derived chemokines of the CCL and CXCL families were analyzed. Percentage of cells expressing CXCR3, CXCR4, CCR3, and CCR10 receptors (regulators of chemokine secretion by keratinocytes and skin fibroblasts) was increased in the skin of obese patients. Expression of the pro-inflammatory chemokines, CXCL8, CXCL9, CXCL10, CXCL13, CCL24, and CCL27, was increased in skin cells from obese patients. Obesity was associated with reduced expression of the chemokines CCL17, CCL22, and CCL28 in skin cells. Conclusion. Chemokine regulation is disturbed in obesity, which may underlie the development of complications after abdominal surgery.


Sign in / Sign up

Export Citation Format

Share Document