Exercise Rehabilitation in Heart Disease: the real “polypill” for primary and secondary prevention

Our society is currently at war against the ominous enemy of chronic disease. Chronic disease presents a heavy burden to society, in terms of both medical costs and human suffering. It is our perception that: 1) much of the medical community underpractises primary prevention as regards appropriate levels of physical activity for health, and 2) much of the research community undervalues the importance of understanding the physiological, genetic and clinical bases of diseases caused by physical inactivity. For many, exercise is viewed solely as a research or diagnostic tool and not as a true weapon against chronic disease. In reality, however, exercise attacks the roots of chronic disease, i.e. physical inactivity. The first step in a common “battle plan” is to convince the medical community that chronic disease is rooted in physical inactivity. In this review, we focus on the biological evidence to date showing how physical inactivity leads to chronic disease. One purpose of this review is to demonstrate that exercise, such as treadmill testing of humans for cardiac dysfunctions, is more than a diagnostic tool but part of disease management itself

The Walking Test: Use in clinical practice

Exercise Capacity is the expression of the cardiovascular and of metabolic organic efficiency and represents a important prognostic marker. The Six Minute Walking Test is adopted in the practice for exercise capacity evaluation in the normal subject as in pneumologic or cardiac rehabilitation programs, and in both pediatric and elderly ages. The aim of the work is to present a practical summary of the application of the six minutes walking test, according to the American Thoracic Society statement. We reviewed the various experiences of its application, and reported the indications, clinical interpretation parameters, relationship and correlation between functional and clinical parameters (hospitalization, quality of life, therapy and exercise control response and compliance), the basic and advanced protocol, the application modality, the reporting models, and the educational checklist

Summary Statement on Cardiopulmonary Exercise Testing in Chronic Heart Failure due to Left Ventricular Dysfunction Recommendations for Performance and Interpretation

Cardiopulmonary exercise testing (CPET) is a non-invasive tool that provides the physician with relevant information to assess the integrated response to exercise involving pulmonary, cardiovascular, haematopoietic, neuro-psychological, and skeletal muscle systems. Measurement of expiratory gases during exercise allows the best estimate of functional capacity, grade the severity of the impairment, objectively evaluate the response to interventions, objectively track the progression of disease, and assist in differentiating cardiac from pulmonary limitations in exercise tolerance. To achieve optimal use of this test in every day clinical practice, clarification of conceptual issues and standardization of CPET practices are necessary. Recently, a Statement on Cardiopulmonary Exercise Testing in Chronic Heart Failure due to Left Ventricular Dysfunction, by the Gruppo Italiano di Cardiologia Riabilitativa and endorsed by the Working Group on Cardiac Rehabilitation and Exercise Physiology of the European Society of Cardiology, has been published. Here are resumed the cardinal points of the Statement: (1) Definition of Cardiopulmonary Exercise Testing Parameters for Appropriate Use in Chronic Heart Failure, (2) How to Perform Cardiopulmonary Exercise Testing in Chronic Heart Failure, (3) Interpretation of Cardiopulmonary Exercise Testing in Chronic Heart Failure and Future Applications

The cardiopulmonary exercise test in the prognostic evaluation of patients with heart failure and cardiomyopathies: the long history of making a one-size-fits-all suit

Cardiopulmonary exercise test (CPET) has become pivotal in the functional evaluation of patients with chronic heart failure (HF), supplying a holistic evaluation both in terms of exercise impairment degree and possible underlying mechanisms. Conversely, there is growing interest in investigating possible multiparametric approaches in order to improve the overall HF risk stratification. In such a context, in 2013, a group of 13 Italian centres skilled in HF management and CPET analysis built the Metabolic Exercise test data combined with Cardiac and Kidney Indexes (MECKI) score, based on the dynamic assessment of HF patients and on some other instrumental and laboratory parameters. Subsequently, the MECKI score, initially developed on a cohort of 2716 HF patients, has been extensively validated as well as challenged with the other multiparametric scores, achieving optimal results. Meanwhile, the MECKI score research group has grown over time, involving up to now a total of 27 centres with an available database accounting for nearly 8000 HF patients. This exciting joint effort from multiple HF Italian centres allowed to investigate different HF research field in order to deepen the mechanisms underlying HF, to improve the ability to identify patients at the highest risk as well as to analyse particular HF categories. Most recently, some of the participants of the MECKI score group started to join the forces in investigating a possible additive role of CPET assessment in the cardiomyopathy setting too. The present study tells the ten-year history of the MECKI score presenting the most important results achieved as well as those projects in the pipeline, this exciting journey being far to be concluded

Multifaceted enrichment analysis of RNA-RNA crosstalk reveals cooperating micro-societies in human colorectal cancer

Alterations in the balance of mRNA and microRNA (miRNA) expression profiles contribute to the onset and development of colorectal cancer. The regulatory functions of individual miRNA-gene pairs are widely acknowledged, but group effects are largely unexplored. We performed an integrative analysis of mRNA–miRNA and miRNA–miRNA interactions using high-throughput mRNA and miRNA expression profiles obtained from matched specimens of human colorectal cancer tissue and adjacent non- tumorous mucosa. This investigation resulted in a hypernetwork-based model, whose functional back- bone was fulfilled by tight micro-societies of miR- NAs. These proved to modulate several genes that are known to control a set of significantly enriched cancer-enhancer and cancer-protection biological processes, and that an array of upstream regulatory analyses demonstrated to be dependent on miR-145, a cell cycle and MAPK signalling cascade master regulator. In conclusion, we reveal miRNA-gene clusters and gene families with close functional relationships and highlight the role of miR-145 as potent upstream regulator of a complex RNA–RNA crosstalk, which mechanistically modulates several signalling path- ways and regulatory circuits that when deranged are relevant to the changes occurring in colorectal carcinogenesis

Indexed maximal left atrial volume predicts response to cardiac resynchronization therapy

Aims Cardiac resynchronization therapy (CRT) has shown morbidity and mortality benefits in patients with advanced congestive heart failure (HF). Since about one-third of the patients did not appear to respond to CRT, it would seem reasonable to try to identify patients more accurately before implantation. Left atrial (LA) dimension has been proposed as a powerful outcome predictor in patients with heart disease. Accordingly, the aim of this study is to prospectively assess the predictive value of LA for selecting CRT responders. Methods Fifty two consecutive patients with refractory HF, sinus rhythm and left bundle branch block were enrolled in the study and planned for CRT implantation. Clinical and echocardiographic evaluations were performed before CRT implantation and after 6 months. Three LA volumes indexed to body surface area (iLAV) were computed to evaluate the LA complexity: maximal LAV (iLAVmax), LAV just before atrial systole (iLAVpre), and minimal LAV (iLAVpost). CRT responders were defined as those who presented a reduction of > 10% in LVESVi at 6-month follow-up. Results Responders (63%) and nonresponders (37%) had similar baseline clinical characteristics and pre-implantation LV volumes. However, baseline LA volumes were significantly associated with the extent of LV reverse remodeling: in particular, baseline iLAVmax was remarkably lower in responders than in nonresponders (50.2 ± 14.1 ml/m2 vs 65.8 ± 15.7 ml/m2, p = 0.001) resulting predictive for CRT response. Conclusion Patients with small iLAV result as better responders to CRT than larger one. iLAVmax is an independent predictor of LV reverse remodeling and allows to indentify the best candidates for CRT. © 2013 Elsevier Ireland Ltd

Muscle Ergoreceptor Overactivity Reflects Deterioration in Clinical Status and Cardiorespiratory Reflex Control in Chronic Heart Failure

Background In chronic heart failure (CHF), overactivation of ergoreceptors (afferents sensitive to the metabolic effects of muscular work) may be a link between peripheral changes, sympathetic overactivation, and increased hemodynamic and ventilatory responses to exercise. The relationship between ergoreceptors, autonomic changes, and the progression of the syndrome has not yet been studied. Methods and Results Thirty-eight stable CHF patients (age, 57±1 years; ejection fraction, 26±2%) were compared with 12 age-matched normal control subjects. The ergoreflex contribution to the ventilatory and hemodynamic responses to exercise, together with peripheral and central chemoreceptor sensitivity, arterial baroreflex sensitivity, plasma norepinephrine, epinephrine, and heart rate variability, were measured. Enhanced ergoreflex effects on ventilation (78±2% versus 50±8%), peripheral chemosensitivity (0.6±0.4 versus 0.2±0.1 L/min per percent Sa o 2 ), and central chemosensitivity (2.9±0.2 versus 2.0±0.2 L · min −1 · mm Hg −1 ) and an impaired baroreflex function (4.1±0.6 versus 9.1±5.6 ms/mm Hg) were confirmed in CHF compared with control subjects ( P <0.01 in all comparisons). Ergoreceptor overactivity was associated with a worse symptomatic state (NYHA class, P <0.05), lower exercise tolerance (peak V o 2 , P <0.05), and pronounced exercise hyperventilation (V̇ e /V co 2 , P <0.01). It was also a strong predictor of increased central chemosensitivity (independently of clinical parameters), baroreflex impairment, and sympathetic activation (plasma catecholamines and heart rate variability indexes; all P <0.05). In multivariate analysis, among all reflexes studied, the ventilatory component of the ergoreflex was the only independent predictor of peak V o 2 and V̇ e /V co 2 . Conclusions In CHF, overactivation of the ergoreflex is associated with abnormal cardiorespiratory reflex control, independently of clinical severity. Among impaired reflexes, overactivation of the ergoreflex is an important determinant of exercise hyperventilation and reduced exercise tolerance

BEAT: Bioinformatics Exon Array Tool to store, analyze and visualize Affymetrix GeneChip Human Exon Array data from disease experiments

<p>Abstract</p> <p>Background</p> <p>It is known from recent studies that more than 90% of human multi-exon genes are subject to Alternative Splicing (AS), a key molecular mechanism in which multiple transcripts may be generated from a single gene. It is widely recognized that a breakdown in AS mechanisms plays an important role in cellular differentiation and pathologies. Polymerase Chain Reactions, microarrays and sequencing technologies have been applied to the study of transcript diversity arising from alternative expression. Last generation Affymetrix GeneChip Human Exon 1.0 ST Arrays offer a more detailed view of the gene expression profile providing information on the AS patterns. The exon array technology, with more than five million data points, can detect approximately one million exons, and it allows performing analyses at both gene and exon level. In this paper we describe BEAT, an integrated user-friendly bioinformatics framework to store, analyze and visualize exon arrays datasets. It combines a data warehouse approach with some rigorous statistical methods for assessing the AS of genes involved in diseases. Meta statistics are proposed as a novel approach to explore the analysis results. BEAT is available at <url>http://beat.ba.itb.cnr.it</url>.</p> <p>Results</p> <p>BEAT is a web tool which allows uploading and analyzing exon array datasets using standard statistical methods and an easy-to-use graphical web front-end. BEAT has been tested on a dataset with 173 samples and tuned using new datasets of exon array experiments from 28 colorectal cancer and 26 renal cell cancer samples produced at the Medical Genetics Unit of IRCCS Casa Sollievo della Sofferenza.</p> <p>To highlight all possible AS events, alternative names, accession Ids, Gene Ontology terms and biochemical pathways annotations are integrated with exon and gene level expression plots. The user can customize the results choosing custom thresholds for the statistical parameters and exploiting the available clinical data of the samples for a multivariate AS analysis.</p> <p>Conclusions</p> <p>Despite exon array chips being widely used for transcriptomics studies, there is a lack of analysis tools offering advanced statistical features and requiring no programming knowledge. BEAT provides a user-friendly platform for a comprehensive study of AS events in human diseases, displaying the analysis results with easily interpretable and interactive tables and graphics.</p

MicroRNA co-expression networks exhibit increased complexity in pancreatic ductal compared to Vater’s papilla adenocarcinoma

iRNA expression abnormalities in adenocarcinoma arising from pancreatic ductal system (PDAC) and Vater’s papilla (PVAC) could be associated with distinctive pathologic features and clinical cancer behaviours. Our previous miRNA expression profiling data on PDAC (n=9) and PVAC (n=4) were revaluated to define differences/ similarities in miRNA expression patterns. Afterwards, in order to uncover target genes and core signalling pathways regulated by specific miRNAs in these two tumour entities, miRNA interaction networks were wired for each tumour entity, and experimentally validated target genes underwent pathways enrichment analysis. One hundred and one miRNAs were altered, mainly over-expressed, in PDAC samples. Twenty-six miRNAs were deregulated in PVAC samples, where more miRNAs were down-expressed in tumours compared to normal tissues. Four miRNAs were significantly altered in both subgroups of patients, while 27 miRNAs were differentially expressed between PDAC and PVAC. Although miRNA interaction networks were more complex and dense in PDAC than in PVAC, pathways enrichment analysis uncovered a functional overlapping between PDAC and PVAC. However, shared signalling events were influenced by different miRNA and/or genes in the two tumour entities. Overall, specific miRNA expression patterns were involved in the regulation of a limited core signalling pathways in the biology landscape of PDAC and PVAC