Enhanced efficiency of genetic programming toward cardiomyocyte creation through topographical cues

AbstractGeneration of de novo cardiomyocytes through viral over-expression of key transcription factors represents a highly promising strategy for cardiac muscle tissue regeneration. Although the feasibility of cell reprogramming has been proven possible both in vitro and in vivo, the efficiency of the process remains extremely low. Here, we report a chemical-free technique in which topographical cues, more specifically parallel microgrooves, enhance the directed differentiation of cardiac progenitors into cardiomyocyte-like cells. Using a lentivirus-mediated direct reprogramming strategy for expression of Myocardin, Tbx5, and Mef2c, we showed that the microgrooved substrate provokes an increase in histone H3 acetylation (AcH3), known to be a permissive environment for reprogramming by “stemness” factors, as well as stimulation of myocardin sumoylation, a post-translational modification essential to the transcriptional function of this key co-activator. These biochemical effects mimicked those of a pharmacological histone deacetylase inhibitor, valproic acid (VPA), and like VPA markedly augmented the expression of cardiomyocyte-specific proteins by the genetically engineered cells. No instructive effect was seen in cells unresponsive to VPA. In addition, the anisotropy resulting from parallel microgrooves induced cellular alignment, mimicking the native ventricular myocardium and augmenting sarcomere organization

Multi-modal hydrogel-based platform to deliver and monitor cardiac progenitor/stem cell engraftment

Retention and survival of transplanted cells are major limitations to the efficacy of regenerative medicine, with short-term paracrine signals being the principal mechanism underlying current cell therapies for heart repair. Consequently, even improvements in short-term durability may have a potential impact on cardiac cell grafting. We have developed a multimodal hydrogel-based platform comprised of a poly(ethylene glycol) network cross-linked with bioactive peptides functionalized with Gd(III) in order to monitor the localization and retention of the hydrogel in vivo by magnetic resonance imaging. In this study, we have tailored the material for cardiac applications through the inclusion of a heparin-binding peptide (HBP) sequence in the cross-linker design and formulated the gel to display mechanical properties resembling those of cardiac tissue. Luciferase-expressing cardiac stem cells (CSC-Luc2) encapsulated within these gels maintained their metabolic activity for up to 14 days in vitro. Encapsulation in the HBP hydrogels improved CSC-Luc2 retention in the mouse myocardium and hind limbs at 3 days by 6.5- and 12- fold, respectively. Thus, this novel heparin-binding based, Gd(III)-tagged hydrogel and CSC-Luc2 platform system demonstrates a tailored, in vivo detectable theranostic cell delivery system that can be implemented to monitor and assess the transplanted material and cell retention

A Post Hoc Analysis on Rhythm and High Intensity Interval Training in Cardiac Resynchronization Therapy

Objectives. Evaluate the effects of a 6-month High Intensity Interval Training (HIIT) program on (1) functional capacity and health-related quality of life, (2) multiple blood biomarkers, (3) echocardiographic parameters, and (4) exercise performance, in patients in cardiac resynchronization therapy (CRT) stratified by the presence of atrial fibrillation (AF), targeting the following questions: (1) Does CRT provide similar benefits in patients in AF and sinus rhythm (SR)?; and (2) Does HIIT provides similar benefits in patients in AF and SR? Design. Estimates were available at baseline and 6 months after CRT implantation in 37 patients with heart failure. Patients were randomized after CRT to a 24-week HIIT group or to a usual care group (CON). In this sub-analysis, HIIT (AF = 7; SR = 11) and CON (AF = 9; SR = 10) were stratified by the presence of AF. Results. Patients in AF benefitted to a lesser degree from CRT in functional status than patients in SR (23.8-46.0%). However, HIIT induced superior improvements in patients in AF compared to CON (23.9-61.0%). Decreases in TNF-α (8.5-42.9%), BNP (15.3-34.6%) and left ventricular mass (9.6-26.2%) were only observed in patients in SR, whereas increases in peak oxygen uptake were only observed in patients in AF (19.5-23.2%). HIIT improved exercise capacity (8.8-59.4%) in patients in SR. Conclusions. Patients in AF or SR undergoing CRT demonstrated distinct benefits from device implantation and from HIIT as an adjunctive therapeutic strategy. This suggests that both mainstay and adjunctive therapeutics may need to be managed differently in patients in AF and SR.info:eu-repo/semantics/publishedVersio

High-Intensity Interval Training in Cardiac Resynchronization Therapy: a Randomized Control Trial

AIMS: To determine the effects of high-intensity interval training (HIIT) following cardiac resynchronization therapy (CRT) implantation in patients with chronic heart failure (CHF), on noninvasive estimates of systolic ventricular function, exercise performance, severity of symptoms and quality of life. METHODS: Cardiopulmonary exercise testing, resting transthoracic echocardiogram and health-related quality of life assessment were obtained before and at 6 months after CRT implantation in 37 patients with moderate-to-severe CHF. Patients were randomized after CRT to either a 24-week HIIT group (90-95% peak heart rate, 2 days per week) or to a usual care group (CON). Mixed design 2 × 2 repeated measures ANOVA were used to test for differences within and in-between groups. RESULTS: Improvements in health-related quality of life (HIIT = 98.54%, CON = 123.47%), NYHA class (HIIT = 43.44%, CON = 38.30%) HR recovery at minute 1 (HIIT = 32.32%, CON = 42.94%), pulse pressure at peak effort (HIIT = 14.06%, CON = 9.52%, LVEF (HIIT = 42.17%, CON = 51.10%) and LV Mass (HIIT = 13.26%, CON = 11.88%) were similar in both groups (p > 0.05). Significant increases in CPET duration in the HIIT group (25.94%), and increases in peak VO2 (HIIT = 8.64%, CON = 4.85%) and percent-predicted VO2 (HIIT = 10.57%, CON = 4.26%) in both groups, were observed in the intention-to-treat analysis. CONCLUSION: Six months of HIIT in patients in CRT did not further improved indices of functional capacity and health-related quality of life, and LV structure and function, compared to CRT alone. However, HIIT led to further improvements in exercise performance. It remains unclear whether HIIT benefits patients in CRT to a similar degree as more conventional forms of exercise training previously shown to maximize benefits in CRT.info:eu-repo/semantics/publishedVersio

Noncompaction Cardiomyopathy. A Review of Eight Cases

A miocardiopatia não compactada isolada é uma doença geneticamente determinada cuja patogénese parece envolver uma paragem no desenvolvimento do endomiocárdio. Morfologicamente caracteriza-se pela presença de trabeculações proeminentes separadas por profundos recessos preenchidos por fluxo e como tal por Doppler a cor no estudo ecocardiográfico. No sentido de melhor caracterizar esta entidade recentemente descrita, de prognóstico pouco esclarecido, fazemos uma revisão dos casos diagnosticados no nosso hospital, descrevendo as características clínicas, electrocardiográficas e ecocardiográficas, bem como a terapêutica instituída e seguimento clínico. A propósito da revisão dos casos, é feita uma exposição e discussão da literatura mais relevante relativamente a etiopatogenia, clínica, critérios de diagnóstico, terapêutica e prognóstico

Natural Growth Promoters Replacing Traditional Growth Promoters in Diets for Light Replacement Pullets: A Systematic Approach

ABSTRACT The effect of using natural growth promoters (NGP) to replace traditional antimicrobials on performance, biometry of digestive and reproductive organs, sexual maturity and bone characteristics of replacement pullets was evaluated; and the relationship between these variables according to the diets was verified. Eight-week-old birds were randomly assigned to a completely randomized design and fed different diets: negative control (without growth promoters); positive control - conventional growth promoter; organic acids (OA); symbiotic (S); essential oil (EO); OA + S; and EO + S. The performance, relative weight of digestive and reproductive organs and length intestines, height and crest length, sternum length, bone quality and sexual maturity of birds were similar (p>0.05) between treatments. The heat map combined with cluster analysis showed a uniform static pattern with the formation of three horizontal groups formed by the treatments: 1) negative control, S and OA + S; 2) positive control and OE and 3) OA and OE + S. A null relationship between the treatments and the variables under study was observed. The principal components analysis revealed an association of variables in three components with 60.55% of variation. NGP can replace traditional promoters, as they do not interfere with performance, biometrics or sexual maturity. Height and length are predictive variables for the development of reproductive organs, especially the oviduct. A similarity was identified through multivariate techniques between symbiotic and organic + symbiotic acids; positive control and essential oils; and organic and symbiotic acids + essential oils

Relationship of Left Ventricular Global Longitudinal Strain with Cardiac Autonomic Denervation As Assessed by 123I-mIBG Scintigraphy in Patients with Heart Failure with Reduced Ejection Fraction Submitted to Cardiac Resynchronization Therapy: Assessment of Cardiac Autonomic Denervation by GLS in Patients with Heart Failure with Reduced Ejection Fraction Submitted to CRT

BACKGROUND: Heart failure (HF) is associated with cardiac autonomic denervation (AD), which can be non-invasively assessed by 123I-metaiodobenzylguanidine (123I-mIBG) scintigraphy and has prognostic implications. We aimed to study the relationship between myocardial contractility assessed by global longitudinal strain (GLS) and AD assessed by 123I-mIBG scintigraphy in advanced HF. METHODS/RESULTS: BETTER-HF is a prospective randomized clinical trial including HF patients (pts) submitted to cardiac resynchronization therapy (CRT) who are submitted to a clinical, echocardiographic, and scintigraphic assessment before and 6 months after CRT. 81 pts were included. An echocardiographic response (absolute increase in left ventricular ejection fraction ≥ 10%) was observed in 73.7% of pts. A higher baseline late heart-to-mediastinum ratio (HMR) was associated with a better echocardiographic response. There was a significant association between late HMR and GLS at baseline and 6 months. At baseline, GLS had an AUC of 0.715 for discrimination for a late HMR < 1.6. A GLS cut-off of - 9% maximized the likelihood of correctly classifying a pt as having severe AD (HMR < 1.6). CONCLUSION: Myocardial contractility as assessed by GLS is moderately correlated with AD as assessed by 123I-mIBG scintigraphy and has a good discrimination for the identification of severe cardiac denervation. GLS may allow for a more readily accessible estimation of the degree of AD in advanced HF pts.info:eu-repo/semantics/publishedVersio

Benefits of Cardiac Resynchronization Therapy in "Very Dilated Cardiomyopathy"

INTRODUCTION: Recent clinical trials have studied parameters that could predict response to cardiac resynchronization therapy (CRT) in patients with advanced heart failure. Left ventricular end-diastolic dimension (LVEDD) is regarded as a possible predictor of response to CRT. OBJECTIVE: To study the response to CRT in patients with very dilated cardiomyopathy, i.e. those at a more advanced stage of the pathology, analyzing both the responder rate and reverse remodeling in two groups of patients classified according to LVEDD. METHODS: We performed a retrospective analysis of 71 patients who underwent CRT (aged 62 +/- 11 years; 65% male; 93% in NYHA functional class > or = III; 31% with ischemic cardiomyopathy; left ventricular ejection fraction [LVEF] 25.6 +/- 6.8%; 32% in atrial fibrillation; QRS 176 +/- 31 ms). Twenty-two (31%) patients with LVEDD > or = 45 mm/m2 (49.2 +/- 3.5 mm/m2) were considered to have very dilated cardiomyopathy (Group A) and 49 patients had LVEDD > 37 mm/m2 and or = 1 NYHA class) and by echocardiography, with a minimum 15% increase over baseline LVEF combined with a reduction in LVEDD (reverse remodeling). RESULTS: There were no significant differences in baseline demographic characteristics between the two groups. At six-month followup, we observed an improvement in LVEF (delta 8.5 +/- 11.8%) and a reduction in LVEDD (delta 3.7 +/- 6.8 mm/m2), with fifty-seven (79%) patients being classified as clinical responders. The percentage of patients with reverse remodeling was similar in both groups (64% vs. 73%, p = NS), as were percentages of improved LVEF (delta 6.3 +/- 11% vs. delta 9.6 +/- 12%; p = NS) and decreased LVEDD (delta 3.7 +/- 5.5 mm/m2 vs. delta 3.7 +/- 7.4 mm/m2; p = NS). We found a higher percentage of clinical responders in patients with very dilated cardiomyopathy (96% vs. 72%, p < 0.05). CONCLUSION: In this study, a significant number of responders showed reverse remodeling after CRT. Although a higher percentage of patients with very dilated cardiomyopathy showed improvement in functional class, the extent of reverse remodeling was similar in both groups