Desmin is essential for the structure and function of the sinoatrial node:implications for increased arrhythmogenesis

Our objective was to investigate the effect of desmin depletion on the structure and function of the sinoatrial pacemaker complex (SANcl) and its implication in arrhythmogenesis. Analysis of mice and humans (SANcl) indicated that the sinoatrial node exhibits high amounts of desmin, desmoplakin, N-cadherin, and β-catenin in structures we call “lateral intercalated disks” connecting myocytes side by side. Examination of the SANcl from an arrhythmogenic cardiomyopathy model, desmin-deficient (Des-/-) mouse, by immunofluorescence, ultrastructural, and Western blot analysis showed that the number of these lateral intercalated disks was diminished. Also, electrophysiological recordings of the isolated compact sinoatrial node revealed increased pacemaker systolic potential and higher diastolic depolarization rate compared with wild-type mice. Prolonged interatrial conduction expressed as a longer P wave duration was also observed in Des-/mice. Upregulation of mRNA levels of both T-type Ca2+ current channels, Cav3.1 and Cav3.2, in the Des-/- myocardium (1.8- and 2.3-fold, respectively) and a 1.9-fold reduction of funny hyperpolarization-activated cyclic nucleotide-gated K+ channel 1 could underlie these functional differences. To investigate arrhythmogenicity, electrocardiographic analysis of Des-deficient mice revealed a major increase in supraventricular and ventricular ectopic beats compared with wild-type mice. Heart rate variability analysis indicated a sympathetic predominance in Des-/- mice, which may further contribute to arrhythmogenicity. In conclusion, our results indicate that desmin elimination leads to structural and functional abnormalities of the SANcl. These alterations may be enhanced by the sympathetic component of the cardiac autonomic nervous system, which is predominant in the desmin-deficient heart, thus leading to increased arrhythmogenesis

Exercise-Based Cardiac Rehabilitation in Twelve European Countries Results of the European Cardiac Rehabilitation Registry

AIM: Results from EuroCaReD study should serve as a benchmark to improve guideline adherence and treatment quality of cardiac rehabilitation (CR) in Europe. METHODS AND RESULTS: Data from 2.054 CR patients in 12 European countries were derived from 69 centres. 76% were male. Indication for CR differed between countries being predominantly ACS in Switzerland (79%), Portugal (62%) and Germany (61%), elective PCI in Greece (37%), Austria (36%) and Spain (32%), and CABG in Croatia and Russia (36%). A minority of patients presented with chronic heart failure (4%). At CR start, most patients already were under medication according to current guidelines for the treatment of CV risk factors. A wide range of CR programme designs was found (duration 3 to 24weeks; total number of sessions 30 to 196). Patient programme adherence after admission was high (85%). With reservations that eCRF follow-up data exchange remained incomplete, patient CV risk profiles experienced only small improvements. CR success as defined by an increase of exercise capacity >25W was significantly higher in young patients and those who were employed. Results differed by countries. After CR only 9% of patients were admitted to a structured post-CR programme. CONCLUSIONS: Clinical characteristics of CR patients, indications and programmes in Europe are different. Guideline adherence is poor. Thus, patient selection and CR programme designs should become more evidence-based. Routine eCRF documentation of CR results throughout European countries was not sufficient in its first application because of incomplete data exchange. Therefore better adherence of CR centres to minimal routine clinical standards is requested

Secondary prevention through comprehensive cardiovascular rehabilitation : from knowledge to implementation. 2020 update. A position paper from the Secondary Prevention and Rehabilitation Section of the European Association of Preventive Cardiology

©The European Society of Cardiology 2020. Article reuse guidelines : sagepub.com/journals-permissionsSecondary prevention through comprehensive cardiac rehabilitation has been recognized as the most cost-effective intervention to ensure favourable outcomes across a wide spectrum of cardiovascular disease, reducing cardiovascular mortality, morbidity and disability, and to increase quality of life. The delivery of a comprehensive and ‘modern’ cardiac rehabilitation programme is mandatory both in the residential and the out-patient setting to ensure expected outcomes. The present position paper aims to update the practical recommendations on the core components and goals of cardiac rehabilitation intervention in different cardiovascular conditions, in order to assist the whole cardiac rehabilitation staff in the design and development of the programmes, and to support healthcare providers, insurers, policy makers and patients in the recognition of the positive nature of cardiac rehabilitation. Starting from the previous position paper published in 2010, this updated document maintains a disease-oriented approach, presenting both well-established and more controversial aspects. Particularly for implementation of the exercise programme, advances in different training modalities were added and new challenging populations were considered. A general table applicable to all cardiovascular conditions and specific tables for each clinical condition have been created for routine practice.info:eu-repo/semantics/publishedVersio

British randomised controlled trial of AV and VV optimization ("BRAVO") study:rationale, design, and endpoints

Background Echocardiographic optimization of pacemaker settings is the current standard of care for patients treated with cardiac resynchronization therapy. However, the process requires considerable time of expert staff. The BRAVO study is a non-inferiority trial comparing echocardiographic optimization of atrioventricular (AV) and interventricular (VV) delay with an alternative method using non-invasive blood pressure monitoring that can be automated to consume less staff resources. Methods/Design BRAVO is a multi-centre, randomized, cross-over, non-inferiority trial of 400 patients with a previously implanted cardiac resynchronization device. Patients are randomly allocated to six months in each arm. In the echocardiographic arm, AV delay is optimized using the iterative method and VV delay by maximizing LVOT VTI. In the haemodynamic arm AV and VV delay are optimized using non-invasive blood pressure measured using finger photoplethysmography. At the end of each six month arm, patients undergo the primary outcome measure of objective exercise capacity, quantified as peak oxygen uptake (VO2) on a cardiopulmonary exercise test. Secondary outcome measures are echocardiographic measurement of left ventricular remodelling, quality of life score and N-terminal pro B-type Natriuretic Peptide (NT-pro BNP). The study is scheduled to complete recruitment in December 2013 and to complete follow up in December 2014. Discussion If exercise capacity is non-inferior with haemodynamic optimization compared with echocardiographic optimization, it would be proof of concept that haemodynamic optimization is an acceptable alternative which has the potential to be more easily implemented

Identification of molecular signatures specific for distinct cranial sensory ganglia in the developing chick

Background The cranial sensory ganglia represent populations of neurons with distinct functions, or sensory modalities. The production of individual ganglia from distinct neurogenic placodes with different developmental pathways provides a powerful model to investigate the acquisition of specific sensory modalities. To date there is a limited range of gene markers available to examine the molecular pathways underlying this process. Results Transcriptional profiles were generated for populations of differentiated neurons purified from distinct cranial sensory ganglia using microdissection in embryonic chicken followed by FAC-sorting and RNAseq. Whole transcriptome analysis confirmed the division into somato- versus viscerosensory neurons, with additional evidence for subdivision of the somatic class into general and special somatosensory neurons. Cross-comparison of distinct ganglia transcriptomes identified a total of 134 markers, 113 of which are novel, which can be used to distinguish trigeminal, vestibulo-acoustic and epibranchial neuronal populations. In situ hybridisation analysis provided validation for 20/26 tested markers, and showed related expression in the target region of the hindbrain in many cases. Results One hundred thirty-four high-confidence markers have been identified for placode-derived cranial sensory ganglia which can now be used to address the acquisition of specific cranial sensory modalities.</p

A new class of glycomimetic drugs to prevent free fatty acid-induced endothelial dysfunction

Background: Carbohydrates play a major role in cell signaling in many biological processes. We have developed a set of glycomimetic drugs that mimic the structure of carbohydrates and represent a novel source of therapeutics for endothelial dysfunction, a key initiating factor in cardiovascular complications. Purpose: Our objective was to determine the protective effects of small molecule glycomimetics against free fatty acid­induced endothelial dysfunction, focusing on nitric oxide (NO) and oxidative stress pathways. Methods: Four glycomimetics were synthesized by the stepwise transformation of 2,5­dihydroxybenzoic acid to a range of 2,5­substituted benzoic acid derivatives, incorporating the key sulfate groups to mimic the interactions of heparan sulfate. Endothelial function was assessed using acetylcholine­induced, endotheliumdependent relaxation in mouse thoracic aortic rings using wire myography. Human umbilical vein endothelial cell (HUVEC) behavior was evaluated in the presence or absence of the free fatty acid, palmitate, with or without glycomimetics (1µM). DAF­2 and H2DCF­DA assays were used to determine nitric oxide (NO) and reactive oxygen species (ROS) production, respectively. Lipid peroxidation colorimetric and antioxidant enzyme activity assays were also carried out. RT­PCR and western blotting were utilized to measure Akt, eNOS, Nrf­2, NQO­1 and HO­1 expression. Results: Ex vivo endothelium­dependent relaxation was significantly improved by the glycomimetics under palmitate­induced oxidative stress. In vitro studies showed that the glycomimetics protected HUVECs against the palmitate­induced oxidative stress and enhanced NO production. We demonstrate that the protective effects of pre­incubation with glycomimetics occurred via upregulation of Akt/eNOS signaling, activation of the Nrf2/ARE pathway, and suppression of ROS­induced lipid peroxidation. Conclusion: We have developed a novel set of small molecule glycomimetics that protect against free fatty acidinduced endothelial dysfunction and thus, represent a new category of therapeutic drugs to target endothelial damage, the first line of defense against cardiovascular disease

Prediction of second neurological attack in patients with clinically isolated syndrome using support vector machines

The aim of this study is to predict the conversion from clinically isolated syndrome to clinically definite multiple sclerosis using support vector machines. The two groups of converters and non-converters are classified using features that were calculated from baseline data of 73 patients. The data consists of standard magnetic resonance images, binary lesion masks, and clinical and demographic information. 15 features were calculated and all combinations of them were iteratively tested for their predictive capacity using polynomial kernels and radial basis functions with leave-one-out cross-validation. The accuracy of this prediction is up to 86.4% with a sensitivity and specificity in the same range indicating that this is a feasible approach for the prediction of a second clinical attack in patients with clinically isolated syndromes, and that the chosen features are appropriate. The two features gender and location of onset lesions have been used in all feature combinations leading to a high accuracy suggesting that they are highly predictive. However, it is necessary to add supporting features to maximise the accuracy. © 2013 IEEE

Temporal trends in avalanche activity in the French Alps and subregions: from occurrences and runout altitudes to unsteady return periods.

We present an analysis of temporal trends in ∼55 000 avalanches recorded between 1946 and 2010 in the French Alps and two north/south subregions. First, Bayesian hierarchical modelling is used to isolate low-, intermediate- and high-frequency trends in the mean avalanche occurrence and runout altitude per year/winter. Variables are then combined to investigate their correlation and the recent evolution of large avalanches. Comparisons are also made to climatic and flow regime covariates. The results are important for risk assessment, and the development of new high-altitude climate proxies. At the entire French Alps scale, a major change-point exists in ∼1978 at the heart of a 10 year period of high occurrences and low runout altitudes corresponding to colder and snowier winters. The differences between this change-point and the beginning/end of the study period are 0.1 avalanche occurrences per winter and per path and 55 m in runout altitude. Trends before/after are well correlated, leading to enhanced minimal altitudes for large avalanches at this time. A marked upslope retreat (80 m for the 10 year return period runout altitude) accompanied by a 12% decrease in the proportion of powder snow avalanches has occurred since then, interrupted from about 2000. The snow-depth and temperature control on these patterns seems significant (R = 0.4–0.6), but is stronger at high frequencies for occurrences, and at lower frequencies for runout altitudes. Occurrences between the northern and southern French Alps are partially coupled (R∼0.4, higher at low frequencies). In the north, the main change-point was an earlier shift in ∼1977, and winter snow depth seems to be the main control parameter. In the south, the main change-point occurred later, ∼1979–84, was more gradual, and trends are more strongly correlated with winter temperature