Exploring the influence of smoking and alcohol consumption on clinical severity in patients with facioscapulohumeral muscular dystrophy.

Despite the growing knowledge on the (epi)genetic background of facioscapulohumeral muscular dystrophy (FSHD), the substantial variability in disease severity that exists between FSHD patients is not fully understood. We hypothesized that smoking and alcohol consumption are disease modifiers in FSHD and contribute to the variability in disease severity, because they are both associated with higher levels of oxidative stress in muscle tissue. Oxidative stress is known to influence FSHD muscle tissue. One hundred and ninety-eight genetically confirmed FSHD patients completed a questionnaire from which the number of packyears of smoking and the lifetime cumulative alcohol units consumed were calculated. Disease severity was determined by the FSDH evaluation score. Multiple linear regression analyses showed that both the number of packyears and the amount of alcohol consumption did not influence disease severity (respectively B = 0.025, ΔR2=0.006, p = 0.231; and B = 0.000, ΔR2=0.004, p = 0.406). Although smoking and excessive alcohol consumption are unhealthy habits which should be discouraged, these results show that smoking and alcohol consumption have no clinically meaningful modifying effect on disease severity in FSHD patients. However, prospective data should show whether alcohol consumption and smoking influence disease progression rate.

Reduced specific force in patients with mild and severe facioscapulohumeral muscular dystrophy.

BACKGROUND: Specific force, that is the amount of force generated per unit of muscle tissue, is reduced in patients with facioscapulohumeral muscular dystrophy (FSHD). The causes of reduced specific force and its relation with FSHD disease severity are unknown. METHODS: Quantitative muscle magnetic resonance imaging (MRI), measurement of voluntary maximum force generation and quadriceps force-frequency relationship, and vastus lateralis muscle biopsies were performed in 12 genetically confirmed patients with FSHD and 12 controls. RESULTS: Specific force was reduced by ~33% in all FSHD patients independent of disease severity. Quadriceps force-frequency relationship shifted to the right in severe FSHD compared to controls. Fiber type distribution in vastus lateralis muscle biopsies did not differ between groups. CONCLUSIONS: Reduced quadriceps specific force is present in all FSHD patients regardless of disease severity or fatty infiltration. Early myopathic changes, including fibrosis, and non-muscle factors, such as physical fatigue and musculoskeletal pain, may contribute to reduced specific force.

Muscle ultrasound is a responsive biomarker in facioscapulohumeral dystrophy.

OBJECTIVE: With drug trials starting soon, responsive, relevant, and patient-friendly biomarkers are highly needed in facioscapulohumeral dystrophy (FSHD). Our objective was to assess muscle ultrasound (MUS) as an imaging biomarker in patients with FSHD. METHODS: One-year observational, longitudinal study of both quantitative and qualitative MUS changes in FSHD. RESULTS: Twenty-two patients with symptomatic FSHD1 underwent a clinical examination and MUS at baseline and after 1-year follow-up. The qualitative MUS sum score increased from 18.59 to 20.32 (p = 0.005) and the quantitative MUS sum z scores increased from 19.96 to 24.72 (p = 0.003). The clinical scores did not change over 1 year. Muscle echogenicity correlated with the FSHD clinical score at baseline (r = 0.61, p = 0.002). CONCLUSIONS: MUS shows a significant increase in echogenicity in FSHD over 1 year. Both quantitative and qualitative MUS correlate cross-sectionally with clinical severity in FSHD and identify structural muscle changes in a clinically stable group of patients. MUS thus seems a potentially responsive biomarker that could be standardized between centers. We recommend its use in therapeutic trials. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that in patents with FSHD1, MUS findings correlate with baseline FSHD clinical scores.

Relationship Between Endothelial Function and the Eliciting Shear Stress Stimulus in Women: Changes Across the Lifespan Differ to Men.

Background Premenopausal women have a lower incidence of cardiovascular disease, which may partly be due to a protective effect of estrogen on endothelial function. Animal studies suggest that estrogen may also improve the relationship between shear rate ( SR ) and endothelial function. We aimed to explore the relationship between endothelial function (ie, flow-mediated dilation [ FMD ]) and SR (ie, SR area under the curve [ SRAUC ]) in women versus men, and between pre- versus postmenopausal women. Methods and Results Brachial artery FMD and SRAUC were measured in accordance with expert-consensus guidelines in 932 healthy participants who were stratified into young adults (18-40 years, 389 men, 144 women) and older adults (>40 years, 260 men, 139 women). Second, we compared premenopausal (n=173) and postmenopausal women (n=110). There was evidence of a weak correlation between SRAUC and FMD in all groups but older men, although there was variation in strength of outcomes. Further exploration using interaction terms (age-sex× SRAUC ) in linear regression revealed differential relationships with FMD (young women versus young men [ß=-5.8-4, P=0.017] and older women [ß=-5.9-4, P=0.049]). The correlation between SRAUC and FMD in premenopausal women ( r2=0.097) was not statistically different from that in postmenopausal women ( r2=0.025; Fisher P=0.30). Subgroup analysis using stringent inclusion criteria for health markers (n=505) confirmed a stronger FMD - SRAUC correlation in young women compared with young men and older women. Conclusions Evidence for a stronger relationship between endothelial function and the eliciting SR stimulus is present in young women compared with men. Estrogen may contribute to this finding, but larger healthy cohorts are required for conclusive outcomes.

Haemostatic Profiles are Similar across All Aetiologies of Cirrhosis.

BACKGROUND AND AIM: Patients with cirrhosis may acquire profound changes in haemostasis. Although haemostatic changes in cirrhosis have been extensively studied, most studies were performed in groups of patients with mixed aetiology. As thrombotic events appear more common in some aetiologies of disease, notably non-alcoholic steatohepatitis (NASH) and cholestatic disease, we hypothesized that haemostatic changes might be different across aetiologies. PATIENTS AND METHODS: We studied 109 patients with cirrhosis (31 cholestatic liver disease, 23 NASH, 37 alcoholic liver disease [ALD], 18 viral hepatitis) and 44 healthy controls. Patients with malignancy were excluded. Routine diagnostic tests of haemostasis, thrombin generation assays, fibrin permeability assays and a plasma-based fibrinolytic assay were performed. RESULTS: All patients had comparable severity of disease according to their Model for End-Stage Liver Disease score (9 [7-11]). Plasma levels of von Willebrand factor were substantially elevated across all aetiologies, with a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 levels comparable to controls. Thrombin generation capacity was elevated in all aetiologies, most profoundly in ALD. Fibrin permeability was decreased in all aetiologies, which was accompanied by elevated fibrinogen levels. Clot lysis times were prolonged in NASH and cholestatic disease. Plasma levels of individual proteins were similarly altered in all aetiologies. CONCLUSION: Our in-depth haemostatic profiling of primary, secondary and tertiary haemostasis in a group of patients with Childs-Turcotte-Pugh A/B cirrhosis showed no large differences between aetiologies, and was consistent with a general hypercoagulable profile in patients with mild cirrhosis. These results suggest that patients with cirrhosis have an increased risk of thrombosis, irrespective of their aetiology.

Early onset as a marker for disease severity in facioscapulohumeral muscular dystrophy.

OBJECTIVE: To assess the relation between age at onset and disease severity in facioscapulohumeral muscular dystrophy (FSHD). METHODS: In this prospective cross-sectional study, we matched adult patients with FSHD with an early disease onset with 2 sex-matched FSHD control groups with a classic onset; the first group was age matched, and the second group was disease duration matched. Genetic characteristics, muscle performance, respiratory functioning, hearing loss, vision loss, epilepsy, educational level, and work status were compared with the 2 control groups. RESULTS: Twenty-eight patients with early-onset FSHD were age (n = 28) or duration (n = 27) matched with classic-onset patients. Patients with early-onset FSHD had more severe muscle weakness (mean FSHD clinical score 11 vs 5 in the age-matched and 9 in the duration-matched group, p < 0.05) and a higher frequency of wheelchair dependency (57%, 0%, and 30%, respectively, p < 0.05). In addition, systemic features were more frequent in early-onset FSHD, most important, hearing loss, decreased respiratory function and spinal deformities. There was no difference in work status. Genetically, the shortest D4Z4 repeat arrays (2-3 units) were found exclusively in the early-onset group, and the largest repeat arrays (8-9 units) were found only in the classic-onset groups. De novo mutations were more frequent in early-onset patients (46% vs 4%). CONCLUSIONS: Patients with early-onset FSHD more often have severe muscle weakness and systemic features. The disease severity is greater than in patients with classic-onset FSHD who are matched for disease duration, suggesting that the progression is faster in early-onset patients.

Facioscapulohumeral Dystrophy in Childhood: A Nationwide Natural History Study.

OBJECTIVE: Facioscapulohumeral dystrophy (FSHD) is one of the most frequent heritable muscular dystrophies, with a large variety in age at onset and disease severity. The natural history and molecular characteristics of FSHD in childhood are incompletely understood. Our objective is to clinically and genetically characterize FSHD in childhood. METHODS: We performed a nationwide, single-investigator, natural history study on FSHD in childhood. RESULTS: Multiple-source recruitment resulted in 32 patients with FSHD (0-17 years), leading to an estimated prevalence of 1 in 100,000 children in The Netherlands. This series of 32 children with FSHD revealed a heterogeneous phenotype and genotype in childhood. The phenotypic hallmarks of FSHD in childhood are: facial weakness with normal or only mildly affected motor performance, decreased functional exercise capacity (6-minute walk test), lumbar hyperlordosis, and increased echo intensity on muscle ultrasonography. In addition, pain and fatigue were frequent and patients experienced a lower quality of life compared to healthy peers. In contrast to the literature on early-onset FSHD, systemic features such as hearing loss and retinal and cardiac abnormalities were infrequent and subclinical, and epilepsy and intellectual disability were absent. Genotypically, patients had a mean D4Z4 repeat array of 5 units (range, 2-9), and 14% of the mutations were de novo. INTERPRETATION: FSHD in childhood is more prevalent than previously known and the genotype resembles classic FSHD. Importantly, FSHD mainly affects functional exercise capacity and quality of life in children. As such, these results are paramount for counseling, clinical management, and stratification in clinical research. Ann Neurol 2018;84:635-645.

Lifetime endogenous estrogen exposure and disease severity in female patients with facioscapulohumeral muscular dystrophy.

Facioscapulohumeral muscular dystrophy (FSHD) is characterized by large variability in disease severity, that is only partly explained by (epi)genetic factors. Clinical observations and recent in vitro work suggest a protective effect of estrogens in FSHD. The aims of this study were to assess whether the lifetime endogenous estrogen exposure contributes to the variability in disease severity in female patients, and whether female patients experience changes in disease progression during periods of hormonal changes. We calculated the lifetime endogenous estrogen exposure by subtracting periods with high progesterone levels (in which estrogens are counteracted) from the reproductive life span. Multiple linear regression in 85 patients did not show a contribution of the lifetime endogenous estrogen exposure to disease severity (B = 0.063, P-value = 0.517, ΔR2 = 0.003). The majority of women reported an unchanged rate of disease progression through periods of hormonal changes, like menarche, pregnancy or menopause. Women that noticed differences reported accelerations as well as decelerations. These results indicate that differences in estrogen exposure do not have a clinically relevant modifying effect on disease severity. However, a clinically relevant protective effect of greater differences in estrogen levels, or a protective effect caused by a more complex interplay with other reproductive hormones, cannot be ruled out.

Improvements in fitness are not obligatory for exercise training-induced improvements in CV risk factors.

The purpose of this study was to assess whether changes in physical fitness relate to changes in cardiovascular risk factors following standardized, center-based and supervised exercise training programs in subjects with increased cardiovascular risk. We pooled data from exercise training studies of subjects with increased cardiovascular risk (n = 166) who underwent 8-52 weeks endurance training. We determined fitness (i.e., peak oxygen uptake) and traditional cardiovascular risk factors (body mass index, blood pressure, total cholesterol, high-density lipoprotein cholesterol), before and after training. We divided subjects into quartiles based on improvement in fitness, and examined whether these groups differed in terms of risk factors. Associations between changes in fitness and in cardiovascular risk factors were further tested using Pearson correlations. Significant heterogeneity was apparent in the improvement of fitness and individual risk factors, with nonresponder rates of 17% for fitness, 44% for body mass index, 33% for mean arterial pressure, 49% for total cholesterol, and 49% for high-density lipoprotein cholesterol. Neither the number, nor the magnitude, of change in cardiovascular risk factors differed significantly between quartiles of fitness change. Changes in fitness were not correlated with changes in cardiovascular risk factors (all P > 0.05). Our data suggest that significant heterogeneity exists in changes in peak oxygen uptake after training, while improvement in fitness did not relate to improvement in cardiovascular risk factors. In subjects with increased cardiovascular risk, improvements in fitness are not obligatory for training-induced improvements in cardiovascular risk factors.

Liver transplantation for NASH cirrhosis is not performed at the expense of major post-operative morbidity.

BACKGROUND: Non-alcoholic steatohepatitis (NASH) is an emerging indication for liver transplantation (LT) and coexists with multiple comorbidities. Obese and cirrhotic patients experience more perioperative complications. Limited data exist about short-term complications after LT for NASH cirrhosis. AIM: Investigate short-term complications in patients transplanted for NASH cirrhosis. METHODS: Single center retrospective cohort study including patients >18years who underwent LT between 2009-2015. Exclusion criteria were LT for acute liver failure and non-cirrhotic disease. Post-operative complications and severity within 90-days were classified using the Clavien-Dindo classification of surgical complications and comprehensive complication index (CCI). P<0.05 was significant. RESULTS: Out of 169 eligible patients, 34 patients (20.1%) were transplanted for NASH cirrhosis. These patients were significantly older (59.2 vs. 54.8 years, P=0.01), more obese (61.8% vs. 8.1%, P<0.01), had more diabetes mellitus (73.5% vs. 20%, P<0.01), metabolic syndrome (83.3% vs. 37.8%, P<0.01) and cardiovascular disease (29.4% vs. 11.1%, P<0.01). More grade 1 complications (OR 1.64, 95%CI 1.03-2.63, P=0.04) and more grade 2 urogenital infections (OR 3.4, 95%CI 1.1-10.6, P=0.03) were found. Major complications, CCI, 90-day mortality and graft survival were similar. CONCLUSION: Despite significantly increased comorbidities in patients transplanted for NASH cirrhosis, major morbidity, mortality and graft survival after 90days were comparable to patients transplanted for other indications.

Disturbed Vitamin A Metabolism in Non-Alcoholic Fatty Liver Disease (NAFLD).

Vitamin A is required for important physiological processes, including embryogenesis, vision, cell proliferation and differentiation, immune regulation, and glucose and lipid metabolism. Many of vitamin A's functions are executed through retinoic acids that activate transcriptional networks controlled by retinoic acid receptors (RARs) and retinoid X receptors (RXRs).The liver plays a central role in vitamin A metabolism: (1) it produces bile supporting efficient intestinal absorption of fat-soluble nutrients like vitamin A; (2) it produces retinol binding protein 4 (RBP4) that distributes vitamin A, as retinol, to peripheral tissues; and (3) it harbors the largest body supply of vitamin A, mostly as retinyl esters, in hepatic stellate cells (HSCs). In times of inadequate dietary intake, the liver maintains stable circulating retinol levels of approximately 2 µmol/L, sufficient to provide the body with this vitamin for months. Liver diseases, in particular those leading to fibrosis and cirrhosis, are associated with impaired vitamin A homeostasis and may lead to vitamin A deficiency. Liver injury triggers HSCs to transdifferentiate to myofibroblasts that produce excessive amounts of extracellular matrix, leading to fibrosis. HSCs lose the retinyl ester stores in this process, ultimately leading to vitamin A deficiency. Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome and is a spectrum of conditions ranging from benign hepatic steatosis to non-alcoholic steatohepatitis (NASH); it may progress to cirrhosis and liver cancer. NASH is projected to be the main cause of liver failure in the near future. Retinoic acids are key regulators of glucose and lipid metabolism in the liver and adipose tissue, but it is unknown whether impaired vitamin A homeostasis contributes to or suppresses the development of NAFLD. A genetic variant of patatin-like phospholipase domain-containing 3 (PNPLA3-I148M) is the most prominent heritable factor associated with NAFLD. Interestingly, PNPLA3 harbors retinyl ester hydrolase activity and PNPLA3-I148M is associated with low serum retinol level, but enhanced retinyl esters in the liver of NAFLD patients. Low circulating retinol in NAFLD may therefore not reflect true "vitamin A deficiency", but rather disturbed vitamin A metabolism. Here, we summarize current knowledge about vitamin A metabolism in NAFLD and its putative role in the progression of liver disease, as well as the therapeutic potential of vitamin A metabolites.

Early onset facioscapulohumeral dystrophy - a systematic review using individual patient data.

Infantile or early onset is estimated to occur in around 10% of all facioscapulohumeral dystrophy (FSHD) patients. Although small series of early onset FSHD patients have been reported, comprehensive data on the clinical phenotype is missing. We performed a systematic literature search on the clinical features of early onset FSHD comprising a total of 43 articles with individual data on 227 patients. Additional data from four cohorts was provided by the authors. Mean age at reporting was 18.8 years, and 40% of patients were wheelchair-dependent at that age. Half of the patients had systemic features, including hearing loss (40%), retinal abnormalities (37%) and developmental delay (8%). We found an inverse correlation between repeat size and disease severity, similar to adult-onset FSHD. De novo FSHD1 mutations were more prevalent than in adult-onset FSHD. Compared to adult FSHD, our findings indicate that early onset FSHD is overall characterized by a more severe muscle phenotype and a higher prevalence of systemic features. However, similar as in adults, a significant clinical heterogeneity was observed. Based on this, we consider early onset FSHD to be on the severe end of the FSHD disease spectrum. We found natural history studies and treatment studies to be very scarce in early onset FSHD, therefore longitudinal studies are needed to improve prognostication, clinical management and trial-readiness.

High prevalence of apolipoprotein B dyslipoproteinemias in non-alcoholic fatty liver disease: The lifelines cohort study.

OBJECTIVE: Cardiovascular disease (CVD) is a major adverse consequence of non-alcoholic fatty liver disease (NAFLD). The association of NAFLD with various apolipoprotein B (apoB) dyslipoproteinemias is unclear. We determined the prevalence of specific apoB dyslipoproteinemias in subjects with suspected NAFLD. METHODS: This study was conducted among 22,865 fasting adults living in the northern part of the Netherlands (Lifelines Cohort Study). Six apoB dyslipoproteinemias were defined using an algorithm derived from apoB, total cholesterol and triglycerides. NAFLD was defined as Fatty Liver Index (FLI) ≥60. Advanced hepatic fibrosis was defined as NAFLD fibrosis score (NFS) ≥0.676. RESULTS: 4790 participants (20.9%) had an FLI≥60. NAFLD subjects were older, more likely to be men, more obese and more often had diabetes and metabolic syndrome (P<0.001 for each). Among NAFLD subjects, any apoB dyslipoproteinemia was present in 61.5% vs. 16.5% in subjects without NAFLD (P<0.001). Elevated chylomicrons were not observed in NAFLD. In univariate analysis, NAFLD was associated with a higher prevalence of each apoB dyslipoproteinemia vs. subjects with an FLI<60 (P<0.001), except for low density lipoprotein (LDL) dyslipoproteinemia. Additionally, each apoB dyslipoproteinemia was independently associated with NAFLD in age- and sex-adjusted logistic regression analysis, including the apoB dyslipoproteinemias together (P<0.001). The prevalence of apoB dyslipoproteinemias was not altered in subjects with NFS ≥0.676. CONCLUSIONS: NAFLD rather than advanced hepatic fibrosis is independently associated with increased prevalence of chylomicrons+very low-density lipoproteins (VLDL) remnants, VLDL, LDL and VLDL+LDL dyslipoproteinemias. ApoB dyslipoproteinemias may contribute to increased CVD risk associated with NAFLD.

Prevalence and determinants of non-alcoholic fatty liver disease in lifelines: A large Dutch population cohort.

BACKGROUND & AIMS: Non-alcoholic fatty liver disease is an increasing health issue that develops rather unnoticed with obesity, type 2 diabetes mellitus and metabolic syndrome. We investigated prevalence, determinants and associated metabolic abnormalities of non-alcoholic fatty liver disease in the largest population-based cohort to date. METHODS: Biochemical characteristics, type 2 diabetes mellitus and metabolic syndrome were determined in the Lifelines Cohort Study (N = 167,729), a population-based cohort in the North of the Netherlands. Non-alcoholic fatty liver disease was defined as Fatty Liver Index (FLI)≥60. Exclusion criteria were age <18 years, immigrants, missing data to assess FLI and metabolic syndrome, excessive alcohol use, previous-diagnosed hepatitis or cirrhosis and non-fasting blood sampling. RESULTS: Out of 37,496 included participants (median age 44 years, 62.1% female), 8,259 (22.0%) had a FLI≥60. Individuals with a FLI≥60 were more often male, older, obese, had higher levels of hemoglobinA1c, fasting glucose, liver enzymes, total cholesterol, low-density lipoprotein cholesterol, triglycerides, c-reactive protein and leucocytes and lower high-density lipoprotein cholesterol (all P<0.0001). Participants with a FLI≥60 showed higher prevalence of type 2 diabetes mellitus (9.3% vs. 1.4%), metabolic syndrome (54.2% vs. 6.2%), impaired renal function (20.1% vs. 8.7%) and cardiovascular disease (4.6% vs. 1.6%) (all P<0.0001). Multivariable logistic analysis showed that smoking, hemoglobin, leucocytes, c-reactive protein, platelets, alanine aminotransferase, alkaline phosphatase, albumin, impaired renal function (OR 1.27, 95%CI 1.15-1.41), metabolic syndrome (OR 11.89, 95%CI 11.03-12.82) and its individual components hyperglycemia (OR 2.53, 95%CI 2.34-2.72), hypertension (OR 1.89, 95%CI 1.77-2.01) and reduced high-density lipoprotein cholesterol (OR 3.44, 95%CI 3.22-3.68) were independently associated with suspected non-alcoholic fatty liver disease (all P<0.0001). CONCLUSION: Twenty-two percent (22.0%) of the population in the North of the Netherlands is suspected to suffer from non-alcoholic fatty liver disease, coinciding with a significant increased risk of type 2 diabetes mellitus, metabolic syndrome, cardiovascular disease and impaired renal function.

Higher free triiodothyronine is associated with non-alcoholic fatty liver disease in euthyroid subjects: the Lifelines Cohort Study.

OBJECTIVE: Overt hypothyroidism confers an increased risk of non-alcoholic fatty liver disease (NAFLD). The liver plays a crucial role in the metabolism of cholesterol and triglycerides; thyroid hormones interact on hepatic lipid homeostasis. Thyroid function within the euthyroid range affects a number of health issues, including atherosclerosis development and biochemical markers of increased cardiovascular risk. However, the association of thyroid hormones with NAFLD in euthyroid subjects has not been unequivocally established. We therefore determined associations of thyroid hormone parameters with NAFLD among euthyroid subjects. METHODS: The study was conducted in the Lifelines Cohort Study, a population-based cohort study of participants living in the North of the Netherlands. Only euthyroid subjects (thyroid-stimulating hormone (TSH) 0.5-4.0mU/L, free thyroxine (FT4) 11-19.5pmol/L and free triiodothyronine (FT3) 4.4-6.7pmol/L) older than 18years were included. Exclusion criteria were participants with excessive alcohol use, known hepatitis or cirrhosis, liver functions ≥ three times the upper limit, current cancer, non-white ancestry, previous or current use of thyroid medication and current use of lipid or glucose lowering medication. A priori defined liver biochemistry, thyroid function parameters and metabolic syndrome (MetS) were studied. NAFLD was defined by using the validated Fatty Liver Index (FLI); FLI≥60 was categorized as NAFLD. A P<0.01 was considered significant. RESULTS: FLI≥60 was found in 4274 (21.1%) of 20,289 individuals (62.1% male, median age 46years) with increased prevalence of MetS (P<0.0001). In age- and sex-adjusted analysis FLI≥60 was independently associated with a higher FT3 (OR 1.34, 95% CI 1.29-1.39, per SD increment, P<0.0001) and a lower FT4 (OR 0.73, 95% CI 0.70-0.75, P<0.0001) but not by TSH. The strongest association was found for the FT3/FT4 ratio (OR 1.44, 95% CI 1.39-1.49, P<0.0001). These associations remained similar after additional adjustment for the presence of MetS. In subjects with enlarged waist circumference, TSH and FT4 were lower while FT3 was higher, resulting in an increased FT3/FT4 ratio (P<0.0001). CONCLUSIONS: Euthyroid subjects with suspected NAFLD are characterized by higher FT3, lower FT4 and higher FT3/FT4 ratio, probably consequent to central obesity.

Vascular Function and Structure in Veteran Athletes after Myocardial Infarction.

PURPOSE: Although athletes demonstrate lower cardiovascular risk and superior vascular function compared with sedentary peers, they are not exempted from cardiac events (i.e., myocardial infarction [MI]). The presence of an MI is associated with increased cardiovascular risk and impaired vascular function. We tested the hypothesis that lifelong exercise training in post-MI athletes, similar as in healthy controls, is associated with a superior peripheral vascular function and structure compared with a sedentary lifestyle in post-MI individuals. METHODS: We included 18 veteran athletes (ATH) (>20 yr) and 18 sedentary controls (SED). To understand the effect of lifelong exercise training after MI, we included 20 veteran post-MI athletes (ATH + MI) and 19 sedentary post-MI controls (SED + MI). Participants underwent comprehensive assessment using vascular ultrasound (vascular stiffness, intima-media thickness, and endothelium (in)dependent mediated dilatation). Lifetime risk score was calculated for a 30-yr risk prediction of cardiovascular disease mortality of the participants. RESULTS: ATH demonstrated a lower vascular stiffness and smaller femoral intima-media thickness compared with SED. Vascular function and structure did not differ between ATH + MI and SED + MI. ATH (4.0% ± 5.1%) and ATH + MI (6.1% ± 3.7%) had a significantly better lifetime risk score compared with their sedentary peers (SED: 6.9% ± 3.7% and SED + MI: 9.3% ± 4.8%). ATH + MI had no secondary events versus two recurrent MI and six elective percutaneous coronary interventions within SED + MI (P < 0.05). CONCLUSION: Although veteran post-MI athletes did not have a superior peripheral vascular function and structure compared with their sedentary post-MI peers, benefits of lifelong exercise training in veteran post-MI athletes relate to a better cardiovascular risk profile and lower occurrence of secondary events.

Facioscapulohumeral dystrophy in children: design of a prospective, observational study on natural history, predictors and clinical impact (iFocus FSHD).

BACKGROUND: Facioscapulohumeral muscular dystrophy (FSHD; OMIM 158900 & 158901) is a progressive skeletal muscle dystrophy, characterized by an autosomal dominant inheritance pattern. One of the major unsolved questions in FSHD is the marked clinical heterogeneity, ranging from asymptomatic individuals to severely affected patients with an early onset. An estimated 10% of FSHD patients have an early onset (onset before 10 years of age) and are traditionally classified as infantile FSHD. This subgroup is regarded as severely affected and extra-muscular symptoms, such as hearing loss and retinopathy, are frequently described. However, information on the prevalence, natural history and clinical management of early onset FSHD is currently lacking, thereby hampering adequate patient counselling and management. Therefore, a population-based prospective cohort study on FSHD in children is highly needed. METHODS/DESIGN: This explorative study aims to recruit all children (aged 0-17 years) with a genetically confirmed diagnosis of FSHD in The Netherlands. The children will be assessed at baseline and at 2-year follow-up. The general aim of the study is the description of the clinical features and genetic characteristics of this paediatric cohort. The primary outcome is the motor function as measured by the Motor Function Measure. Secondary outcomes include quantitative and qualitative description of the clinical phenotype, muscle imaging, genotyping and prevalence estimations. The ultimate objective will be a thorough description of the natural history, predictors of disease severity and quality of life in children with FSHD. DISCUSSION: The results of this population-based study are vital for adequate patient management and clinical trial-readiness. Furthermore, this study is expected to provide additional insight in the epigenetic and environmental disease modifying factors. In addition to improve counselling, this could contribute to unravelling the aetiology of FSHD. TRIAL REGISTRATION: clinicaltrials.gov NCT02625662.

Glycemic control during consecutive days with prolonged walking exercise in individuals with type 1 diabetes mellitus.

AIMS: Despite its general benefits for health, exercise complicates the maintenance of stable blood glucose concentrations in individuals with type 1 diabetes. The aim of the current study was to examine changes in food intake, insulin administration, and 24-h glycemic control in response to consecutive days with prolonged walking exercise (∼8h daily) in individuals with type 1 diabetes. METHODS: Ten individuals with type 1 diabetes participating in the worlds' largest walking event were recruited for this observational study. Simultaneous measurements of 24-h glycemic control (continuous glucose monitoring), insulin administration and food intake were performed during a non-walking day (control) and during three subsequent days with prolonged walking exercise (daily distance 40 or 50km). RESULTS: Despite an increase in daily energy (31±18%; p<0.01) and carbohydrate (82±71g; p<0.01) intake during walking days, subjects lowered their insulin administration by 26±16% relative to the control day (p<0.01). Average 24-h blood glucose concentrations, the prevalence of hyperglycemia (blood glucose >10 mmol/L) and hypoglycemia (blood glucose <3.9mmol/L) did not differ between the control day and walking days (p>0.05 for all variables). The prolonged walking exercise was associated with a modest increase in glycemic variability compared with the control day (p<0.05). CONCLUSION: Prolonged walking exercise allows for profound reductions in daily insulin administration in persons with type 1 diabetes, despite large increments in energy and carbohydrate intake. When taking such adjustments into account, prolonged moderate-intensity exercise does not necessarily impair 24-h glycemic control.

Impact of 2-Weeks Continuous Increase in Retrograde Shear Stress on Brachial Artery Vasomotor Function in Young and Older Men.

BACKGROUND: Although acute elevation in retrograde shear rate (SR) impairs endothelial function, no previous study has explored the effect of prolonged elevation of retrograde SR on conduit artery vascular function. We examined the effect of 2-weeks elevation of retrograde SR on brachial artery endothelial function in young and in older men. METHODS AND RESULTS: Thirteen healthy young (23±2 years) and 13 older men (61±5 years) were instructed to continuously wear a compression sleeve around the right forearm to chronically (2 weeks) elevate brachial artery retrograde SR in 1 arm. We assessed SR, diameter, and flow-mediated dilation in both the sleeve and contralateral control arms at baseline and after 30 minutes and 2 weeks of continuous sleeve application. The sleeve intervention increased retrograde SR after 30 minutes and 2 weeks in both young and older men (P=0.03 and 0.001, respectively). In young men, brachial artery flow-mediated dilation % was lower after 30 minutes and 2 weeks (P=0.004), while resting artery diameter was reduced after 2 weeks (P=0.005). The contralateral arm showed no change in retrograde SR or flow-mediated dilation % (P=0.32 and 0.26, respectively), but a decrease in diameter (P=0.035). In older men, flow-mediated dilation % and diameter did not change in either arm (all P>0.05). CONCLUSIONS: Thirty-minute elevation in retrograde SR in young men caused impaired endothelial function, while 2-week exposure to elevated levels of retrograde SR was associated with a comparable decrease in endothelial function. Interestingly, these vascular changes were not present in older men, suggesting age-related vascular changes to elevation in retrograde SR.