The influence of aortoseptal angulation on provocable left ventricular outflow tract obstruction in hypertrophic cardiomyopathy.

OBJECTIVES: Aortoseptal angulation (AoSA) can predict provocable left ventricular outflow tract obstruction (LVOTO) in patients with symptomatic hypertrophic cardiomyopathy (HCM). Lack of a standardised measurement technique in HCM without the need for complex three-dimensional (3D) imaging limits its usefulness in routine clinical practice. This study aimed to validate a simple measurement of AoSA using 2D echocardiography and cardiac MR (CMR) imaging as a predictor of LVOTO. METHODS: We retrospectively assessed 160 patients with non-obstructive HCM, referred for exercise stress echocardiography. AoSA was measured using resting 2D echocardiography in all patients, and CMR in 29. Twenty-five controls with normal echocardiograms were used for comparison. RESULTS: Patients with HCM had a reduced AoSA compared with controls (113°±12 vs 126°±6), p<0.0001. Sixty (38%) patients had provocable LVOTO, with smaller angles than non-obstructive patients (108°±12 vs 116°±12, p<0.0001). AoSA, degree of mitral valvular regurgitation and incomplete systolic anterior motion (SAM) were associated with peak left ventricular outflow tract gradient (r=0.508, p<0.0001). An angle ≤100° had 27% sensitivity, 91% specificity and 59% positive predictive value for predicting provocable LVOTO. When combined with SAM, specificity was 99% and positive predictive value 88%. Intraclass correlation coefficient of AoSA measured by two observers was 0.901 (p<0.0001). Bland-Altman analysis of echocardiographic AoSA showed good agreement with the CMR-derived angle. CONCLUSIONS: Measurement of AoSA using echocardiography in HCM is easy, reproducible and comparable to CMR. Patients with provocable LVOTO have reduced angles compared with non-obstructive patients. AoSA is highly specific for provocable LVOTO and should prompt further evaluation in symptomatic patients without resting obstruction

Prediction of sarcomere mutations in subclinical hypertrophic cardiomyopathy.

BACKGROUND: Sarcomere protein mutations in hypertrophic cardiomyopathy induce subtle cardiac structural changes before the development of left ventricular hypertrophy (LVH). We have proposed that myocardial crypts are part of this phenotype and independently associated with the presence of sarcomere gene mutations. We tested this hypothesis in genetic hypertrophic cardiomyopathy pre-LVH (genotype positive, LVH negative [G+LVH-]). METHODS AND RESULTS: A multicenter case-control study investigated crypts and 22 other cardiovascular magnetic resonance parameters in subclinical hypertrophic cardiomyopathy to determine their strength of association with sarcomere gene mutation carriage. The G+LVH- sample (n=73) was 29 ± 13 years old and 51% were men. Crypts were related to the presence of sarcomere mutations (for ≥1 crypt, β=2.5; 95% confidence interval [CI], 0.5-4.4; P=0.014 and for ≥2 crypts, β=3.0; 95% CI, 0.8-7.9; P=0.004). In combination with 3 other parameters: anterior mitral valve leaflet elongation (β=2.1; 95% CI, 1.7-3.1; P<0.001), abnormal LV apical trabeculae (β=1.6; 95% CI, 0.8-2.5; P<0.001), and smaller LV end-systolic volumes (β=1.4; 95% CI, 0.5-2.3; P=0.001), multiple crypts indicated the presence of sarcomere gene mutations with 80% accuracy and an area under the curve of 0.85 (95% CI, 0.8-0.9). In this G+LVH- population, cardiac myosin-binding protein C mutation carriers had twice the prevalence of crypts when compared with the other combined mutations (47 versus 23%; odds ratio, 2.9; 95% CI, 1.1-7.9; P=0.045). CONCLUSIONS: The subclinical hypertrophic cardiomyopathy phenotype measured by cardiovascular magnetic resonance in a multicenter environment and consisting of crypts (particularly multiple), anterior mitral valve leaflet elongation, abnormal trabeculae, and smaller LV systolic cavity is indicative of the presence of sarcomere gene mutations and highlights the need for further study

Arrhythmogenic right ventricular cardiomyopathy mimics: role of cardiovascular magnetic resonance.

BACKGROUND: Cardiovascular magnetic resonance (CMR) is commonly used in patients with suspected arrhythmogenic right ventricular cardiomyopathy (ARVC) based on ECG, echocardiogram and Holter. However, various diseases may present with clinical characteristics resembling ARVC causing diagnostic dilemmas. The aim of this study was to explore the role of CMR in the differential diagnosis of patients with suspected ARVC. METHODS: 657 CMR referrals suspicious for ARVC in a single tertiary referral centre were analysed. Standardized CMR imaging protocols for ARVC were performed. Potential ARVC mimics were grouped into: 1) displacement of the heart, 2) right ventricular overload, and 3) non ARVC-like cardiac scarring. For each, a judgment of clinical impact was made. RESULTS: Twenty patients (3.0%) fulfilled imaging ARVC criteria. Thirty (4.6%) had a potential ARVC mimic, of which 25 (3.8%) were considered clinically important: cardiac displacement (n=17), RV overload (n=7) and non-ARVC like myocardial scarring (n=4). One patient had two mimics; one patient had dual pathology with important mimic and ARVC. RV overload and scarring conditions were always thought clinically important whilst the importance of cardiac displacement depended on the degree of displacement from severe (partial absence of pericardium) to epiphenomenon (minor kyphoscoliosis). CONCLUSIONS: Some patients referred for CMR with suspected ARVC fulfil ARVC imaging criteria (3%) but more have otherwise unrecognised diseases (4.6%) mimicking potentially ARVC. Clinical assessment should reflect this, emphasising the assessment and/or exclusion of potential mimics in parallel with the detection of ARVC major and minor criteria

Cardiopulmonary Exercise Test in Patients with Hypertrophic Cardiomyopathy: A Systematic Review and Meta-Analysis.

BACKGROUND: Patients with chronic diseases frequently adapt their lifestyles to their functional limitations. Functional capacity in Hypertrophic Cardiomyopathy (HCM) can be assessed by stress testing. We aim to review and analyze the available data from the literature on the value of Cardiopulmonary Exercise Test (CPET) in HCM. Objective measurements from CPET are used for evaluation of patient response to traditional and new developing therapeutic measurements. METHODS: A systematic review of the literature was conducted in PubMed, Web of Science and Cochrane in Mar-20. The original search yielded 2628 results. One hundred and two full texts were read after the first screening, of which, 69 were included for qualitative synthesis. Relevant variables to be included in the review were set and 17 were selected, including comorbidities, body mass index (BMI), cardiac-related symptoms, echocardiographic variables, medications and outcomes. RESULTS: Study sample consisted of 69 research articles, including 11,672 patients (48 ± 14 years old, 65.9%/34.1% men/women). Treadmill was the most common instrument employed (n = 37 studies), followed by upright cycle-ergometer (n = 16 studies). Mean maximal oxygen consumption (VO2max) was 22.3 ± 3.8 mL·kg-1·min-1. The highest average values were observed in supine and upright cycle-ergometer (25.3 ± 6.5 and 24.8 ± 9.1 mL·kg-1·min-1; respectively). Oxygen consumption in the anaerobic threshold (ATVO2) was reported in 18 publications. Left ventricular outflow tract gradient (LVOT) > 30 mmHg was present at baseline in 31.4% of cases. It increased to 49% during exercise. Proportion of abnormal blood pressure response (ABPRE) was higher in severe (>20 mm) vs. mild hypertrophy groups (17.9% vs. 13.6%, p < 0.001). Mean VO2max was not significantly different between severe vs. milder hypertrophy, or for obstructive vs. non-obstructive groups. Occurrence of arrhythmias during functional assessment was higher among younger adults (5.42% vs. 1.69% in older adults, p < 0.001). Twenty-three publications (9145 patients) evaluated the prognostic value of exercise capacity. There were 8.5% total deaths, 6.7% cardiovascular deaths, 3.0% sudden cardiac deaths (SCD), 1.2% heart failure death, 0.6% resuscitated cardiac arrests, 1.1% transplants, 2.6% implantable cardioverter defibrillator (ICD) therapies and 1.2 strokes (mean follow-up: 3.81 ± 2.77 years). VO2max, ATVO2, METs, % of age-gender predicted VO2max, % of age-gender predicted METs, ABPRE and ventricular arrhythmias were significantly associated with major outcomes individually. Mean VO2max was reduced in patients who reached the combined cardiovascular death outcome compared to those who survived (-6.20 mL·kg-1·min-1; CI 95%: -7.95, -4.46; p < 0.01). CONCLUSIONS: CPET is a valuable tool and can safely perform for assessment of physical functional capacity in patients with HCM. VO2max is the most common performance measurement evaluated in functional studies, showing higher values in those based on cycle-ergometer compared to treadmill. Subgroup analysis shows that exercise intolerance seems to be more related to age, medication and comorbidities than HCM phenotype itself. Lower VO2max is consistently seen in HCM patients at major cardiovascular risk

Life-saving automated external defibrillation in a teenager: a case report

<p>Abstract</p> <p>Background</p> <p>Adolescent sudden death during sport participation is commonly due to cardiac causes. Survival is more likely when an automated external defibrillator (AED) is used soon after collapse.</p> <p>Case presentation</p> <p>We describe a case of sudden death in a 14 year old boy with two remarkable points, successful resuscitation at school using an AED and diagnosis of arrhythmogenic right ventricular cardiomyopathy (ARVC). Bystander cardiopulmonary resuscitation (CPR) was immediately started by a witness and 5 minutes after the event the child was placed on an AED monitor that determined he was in a non shockable rhythm, therefore CPR was continued. Two minutes later, the AED monitor detected a shockable rhythm and recommended a shock, which was then administered. One minute after the shock, a palpable pulse was detected and the child began to breathe by himself. Four days after cardiac arrest, the boy was conversing and self-caring. Cardiac magnetic resonance imaging was suggestive of ARVC.</p> <p>Conclusion</p> <p>Ventricular fibrillation secondary to ARVC may be a devastating event and places young patients and athletes at high risk of sudden death. Immediate CPR and AED have been demonstrated to be lifesaving in such events. Therefore, we suggest that schools should have teachers skilled in CPR and accessible AEDs.</p

Cost of the Diet: a method and software to calculate the lowest cost of meeting recommended intakes of energy and nutrients from local foods

Background When food is available, the main obstacle to access is usually economic: people may not be able to afford a nutritious diet, even if they know what foods to eat. The Cost of the Diet method and software was developed to apply linear programming to better understand the extent to which poverty may affect people’s ability to meet their nutritional specifications. This paper describes the principles of the method; the mathematics underlying the linear programming; the parameters and assumptions on which the calculations are based; and then illustrates the output of the software using examples taken from assessments. Results The software contains five databases: the energy and nutrient content of foods; the energy and nutrient specifications of individuals; predefined groups of individuals in typical households; the portion sizes of foods; and currency conversion factors. Data are collected during a market survey to calculate the average cost of foods per 100 g while focus group discussions are used to assess local dietary habits and preferences. These data are presented to a linear programming solver within the software which selects the least expensive combination of local foods for four standard diets that meet specifications for: energy only; energy and macronutrients; energy, macronutrients and micronutrients; and energy, macronutrients and micronutrients but with constraints on the amounts per meal that are consistent with typical dietary habits. Most parameters in the software can be modified by users to examine the potential impact of a wide range of theoretical interventions. The output summarises for each diet the costs, quantity and proportion of energy and nutrient specifications provided by all the foods selected for a given individual or household by day, week, season and year. When the cost is expressed as a percentage of income, the affordability of the diet can be estimated. Conclusions The Cost of the Diet method and software could be used to inform programme design and behaviour change communication in the fields of nutrition, food security, livelihoods and social protection as well as to influence policies and advocacy debates on the financial cost of meeting energy and nutrient specifications

Fractal Dimension Analysis of Transient Visual Evoked Potentials: Optimisation and Applications

Purpose The visual evoked potential (VEP) provides a time series signal response to an external visual stimulus at the location of the visual cortex. The major VEP signal components, peak latency and amplitude, may be affected by disease processes. Additionally, the VEP contains fine detailed and non-periodic structure, of presently unclear relevance to normal function, which may be quantified using the fractal dimension. The purpose of this study is to provide a systematic investigation of the key parameters in the measurement of the fractal dimension of VEPs, to develop an optimal analysis protocol for application. Methods VEP time series were mathematically transformed using delay time, τ, and embedding dimension, m, parameters. The fractal dimension of the transformed data was obtained from a scaling analysis based on straight line fits to the numbers of pairs of points with separation less than r versus log(r) in the transformed space. Optimal τ, m, and scaling analysis were obtained by comparing the consistency of results using different sampling frequencies. The optimised method was then piloted on samples of normal and abnormal VEPs. Results Consistent fractal dimension estimates were obtained using τ = 4 ms, designating the fractal dimension = D2 of the time series based on embedding dimension m = 7 (for 3606 Hz and 5000 Hz), m = 6 (for 1803 Hz) and m = 5 (for 1000Hz), and estimating D2 for each embedding dimension as the steepest slope of the linear scaling region in the plot of log(C(r)) vs log(r) provided the scaling region occurred within the middle third of the plot. Piloting revealed that fractal dimensions were higher from the sampled abnormal than normal achromatic VEPs in adults (p = 0.02). Variances of fractal dimension were higher from the abnormal than normal chromatic VEPs in children (p = 0.01). Conclusions A useful analysis protocol to assess the fractal dimension of transformed VEPs has been developed

Ancestral bias in the Hras1 gene and distal Chromosome 7 among inbred mice

Inbred strains of mice vary in their frequency of liver tumors initiated by a mutation in the Hras1 (H-ras) proto-oncogene. We sequenced 4.5 kb of the Hras1 gene on distal Chr 7 in a diverse set of 12 commonly used laboratory inbred strains of mice and detected no sequence variation to account for strain-specific differences in Hras1 mutation prevalence. Furthermore, the Hras1 sequence is essentially monoallelic for an ancestral gene derived from the M. m. domesticus species. To determine if the monoallelism and associated low rate of polymorphism are unique to Hras1 or representative of the general chromosomal locale, we extended the sequence analysis to 12 genes in the final 8 Mb of distal Chr 7. A region of at least 2.5 Mb that encompasses several genes, including Hras1 and the H19/Igf2 loci, demonstrates virtually no sequence variation. The 12 inbred strains share one dominant haplotype derived from the M. m. domesticus allele. Chromosomal regions flanking the monoallelic segment exhibit a significantly higher rate of variation and multiple haplotypes, a majority of which are attributed to M. m. domesticus or M. m. musculus ancestry

The Gaia-ESO Survey: a kinematical and dynamical study of four young open clusters

Context. The origin and dynamical evolution of star clusters is an important topic in stellar astrophysics. Several models have been proposed to understand the formation of bound and unbound clusters and their evolution, and these can be tested by examining the kinematical and dynamical properties of clusters over a wide range of ages and masses. Aims. We use the Gaia -ESO Survey products to study four open clusters (IC 2602, IC 2391, IC 4665, and NGC 2547) that lie in the age range between 20 and 50 Myr. Methods. We employ the gravity index γ and the equivalent width of the lithium line at 6708 Å, together with e ff ective temperature T e ff , and the metallicity of the stars in order to discard observed contaminant stars. Then, we derive the cluster radial velocity disper- sions σ c , the total cluster mass M tot , and the half mass radius r hm . Using the Gaia -DR1 TGAS catalogue, we independently derive the intrinsic velocity dispersion of the clusters from the astrometric parameters of cluster members. Results. The intrinsic radial velocity dispersions derived by the spectroscopic data are larger than those derived from the TGAS data, possibly due to the di ff erent masses of the considered stars. Using M tot and r hm we derive the virial velocity dispersion σ v ir and we find that three out of four clusters are supervirial. This result is in agreement with the hypothesis that these clusters are dispersing, as predicted by the "residual gas expulsion" scenario. However, recent simulations show that the virial ratio of young star clusters may be overestimated if it is determined using the global velocity dispersion, since the clusters are not fully relaxed

Overexpression of miR-128 specifically inhibits the truncated isoform of NTRK3 and upregulates BCL2 in SH-SY5Y neuroblastoma cells

<p>Abstract</p> <p>Background</p> <p>Neurotrophins and their receptors are key molecules in the regulation of neuronal differentiation and survival. They mediate the survival of neurons during development and adulthood and are implicated in synaptic plasticity. The human neurotrophin-3 receptor gene <it>NTRK3 </it>yields two major isoforms, a full-length kinase-active form and a truncated non-catalytic form, which activates a specific pathway affecting membrane remodeling and cytoskeletal reorganization. The two variants present non-overlapping 3'UTRs, indicating that they might be differentially regulated at the post-transcriptional level. Here, we provide evidence that the two isoforms of <it>NTRK3 </it>are targeted by different sets of microRNAs, small non-coding RNAs that play an important regulatory role in the nervous system.</p> <p>Results</p> <p>We identify one microRNA (miR-151-3p) that represses the full-length isoform of <it>NTRK3 </it>and four microRNAs (miR-128, miR-485-3p, miR-765 and miR-768-5p) that repress the truncated isoform. In particular, we show that the overexpression of miR-128 - a brain enriched miRNA - causes morphological changes in SH-SY5Y neuroblastoma cells similar to those observed using an siRNA specifically directed against truncated <it>NTRK3</it>, as well as a significant increase in cell number. Accordingly, transcriptome analysis of cells transfected with miR-128 revealed an alteration of the expression of genes implicated in cytoskeletal organization as well as genes involved in apoptosis, cell survival and proliferation, including the anti-apoptotic factor <it>BCL2</it>.</p> <p>Conclusions</p> <p>Our results show that the regulation of <it>NTRK3 </it>by microRNAs is isoform-specific and suggest that neurotrophin-mediated processes are strongly linked to microRNA-dependent mechanisms. In addition, these findings open new perspectives for the study of the physiological role of miR-128 and its possible involvement in cell death/survival processes.</p