Oral geranylgeranylacetone treatment increases heat shock protein expression in human atrial tissue

BACKGROUND Heat shock proteins (HSPs) are important chaperones that regulate the maintenance of healthy protein quality control in the cell. Impairment of HSPs is associated with aging-related neurodegenerative and cardiac diseases. Geranylgeranylacetone (GGA) is a compound well known to increase HSPs through activation of heat shock factor-1 (HSF1). GGA increases HSPs in various tissues, but whether GGA can increase HSP expression in human heart tissue is unknown. OBJECTIVE The purpose of this study was to test whether oral GGA treatment increases HSP expression in the atrial appendages of patients undergoing cardiac surgery. METHODS HSPB1, HSPA1, HSPD1, HSPA5, HSF1, and phosphorylated HSF1 levels were measured by western blot analysis in right and left atrial appendages (RAAs and LAAs, respectively) collected from patients undergoing coronary artery bypass grafting (CABG) who were treated with placebo (n = 13) or GGA 400 mg/da(n = 13) 3 days before surgery. Myofilament fractions were isolated from LAAs to determine the levels of HSPB1 and HSPA1 present in these fractions. RESULTS GGA treatment significantly increased HSPB1 and HSPA1 expression levels in RAA and LAA compared to the placebo group, whereas HSF1, phosphorylated HSF1, HSPD1, and HSPA5 were unchanged. In addition, GGA treatment significantly enhanced HSPB1 levels at the myofilaments compared to placebo. CONCLUSION Three days of GGA treatment is associated with higher HSPB1 and HSPA1 expression levels in RAA and LAA of patients undergoing CABG surgery and higher HSPB1 levels at the myofilaments. These findings pave the way to study the role of GGA as a protective compound against other cardiac diseases, including postoperative atrial fibrillation

Mitochondrial Dysfunction Underlies Cardiomyocyte Remodeling in Experimental and Clinical Atrial Fibrillation

Atrial fibrillation (AF), the most common progressive tachyarrhythmia, results in structural remodeling which impairs electrical activation of the atria, rendering them increasingly permissive to the arrhythmia. Previously, we reported on endoplasmic reticulum stress and NAD+ depletion in AF, suggesting a role for mitochondrial dysfunction in AF progression. Here, we examined mitochondrial function in experimental model systems for AF (tachypaced HL-1 atrial cardiomyocytes and Drosophila melanogaster) and validated findings in clinical AF. Tachypacing of HL-1 cardiomyocytes progressively induces mitochondrial dysfunction, evidenced by impairment of mitochondrial Ca2+-handling, upregulation of mitochondrial stress chaperones and a decrease in the mitochondrial membrane potential, respiration and ATP production. Atrial biopsies from AF patients display mitochondrial dysfunction, evidenced by aberrant ATP levels, upregulation of a mitochondrial stress chaperone and fragmentation of the mitochondrial network. The pathophysiological role of mitochondrial dysfunction is substantiated by the attenuation of AF remodeling by preventing an increased mitochondrial Ca2+-influx through partial blocking or downregulation of the mitochondrial calcium uniporter, and by SS31, a compound that improves bioenergetics in mitochondria. Together, these results show that conservation of the mitochondrial function protects against tachypacing-induced cardiomyocyte remodeling and identify this organelle as a potential novel therapeutic target

Aspects of the ecology of the greater bilby, Macrotis lagotis, in Queensland

AIMS: It has been suggested that in patients with type 2 diabetes mellitus (T2DM), brain atrophy is most pronounced in the hippocampus, but this has not been investigated systematically. The present pooled analysis of three studies examined if hippocampal atrophy is more prominent than global brain atrophy in patients with T2DM relative to controls. METHODS: Data were derived from a cohort study of patients with vascular disease (SMART-Medea (T2DM=120; no T2DM=502)), and from two case-control studies (UDES1 (T2DM=61; controls=30) and UDES2 (T2DM=54; controls=53)). In SMART-Medea and UDES1, hippocampal volume was obtained by manual tracing on 1.5 Tesla (T) MRI scans. Total brain and intracranial volume (ICV) were determined by an automated segmentation method. In UDES2, hippocampal and total brain volume were determined by FreeSurfer and ICV by manual segmentation on 3 T MRI scans. RESULTS: The pooled analyses, adjusted for age and sex, showed a significant negative relation between T2DM and total brain-to-ICV ratio (standardized mean difference=-1.24%, 95% CI: -1.63; -0.86), but not between T2DM and hippocampal-to-ICV ratio (0.00%, 95% CI: -0.01; 0.00) or between T2DM and hippocampal-to-total brain volume ratio (0.01%, 95% CI: -0.01; 0.02). In patients with T2DM no associations were found between brain volume measures and HbA1c or memory. CONCLUSION: Patients with T2DM had greater brain atrophy but not hippocampal atrophy, compared to controls. These findings do not support specific vulnerability of the hippocampus in patients with T2DM

HSPB1, HSPB6, HSPB7 and HSPB8 Protect against RhoA GTPase-Induced Remodeling in Tachypaced Atrial Myocytes

BACKGROUND: We previously demonstrated the small heat shock protein, HSPB1, to prevent tachycardia remodeling in in vitro and in vivo models for Atrial Fibrillation (AF). To gain insight into its mechanism of action, we examined the protective effect of all 10 members of the HSPB family on tachycardia remodeling. Furthermore, modulating effects of HSPB on RhoA GTPase activity and F-actin stress fiber formation were examined, as this pathway was found of prime importance in tachycardia remodeling events and the initiation of AF. METHODS AND RESULTS: Tachypacing (4 Hz) of HL-1 atrial myocytes significantly and progressively reduced the amplitude of Ca²⁺ transients (CaT). In addition to HSPB1, also overexpression of HSPB6, HSPB7 and HSPB8 protected against tachypacing-induced CaT reduction. The protective effect was independent of HSPB1. Moreover, tachypacing induced RhoA GTPase activity and caused F-actin stress fiber formation. The ROCK inhibitor Y27632 significantly prevented tachypacing-induced F-actin formation and CaT reductions, showing that RhoA activation is required for remodeling. Although all protective HSPB members prevented the formation of F-actin stress fibers, their mode of action differs. Whilst HSPB1, HSPB6 and HSPB7 acted via direct prevention of F-actin formation, HSPB8-protection was mediated via inhibition of RhoA GTPase activity. CONCLUSION: Overexpression of HSPB1, as well as HSPB6, HSPB7 and HSPB8 independently protect against tachycardia remodeling by attenuation of the RhoA GTPase pathway at different levels. The cardioprotective role for multiple HSPB members indicate a possible therapeutic benefit of compounds able to boost the expression of single or multiple members of the HSPB family

Tachyarrhythmia in patients with congenital heart disease:inevitable destiny?

Contains fulltext : 171611.pdf (publisher's version ) (Open Access)The prevalence of patients with congenital heart disease (CHD) has increased over the last century. As a result, the number of CHD patients presenting with late, postoperative tachyarrhythmias has increased as well. The aim of this review is to discuss the present knowledge on the mechanisms underlying both atrial and ventricular tachyarrhythmia in patients with CHD and the advantages and disadvantages of the currently available invasive treatment modalities

Atrial arrhythmogenicity in aged Scn5a+/∆KPQ mice modeling long QT type 3 syndrome and its relationship to Na+ channel expression and cardiac conduction

Recent studies have reported that human mutations in Nav1.5 predispose to early age onset atrial arrhythmia. The present experiments accordingly assess atrial arrhythmogenicity in aging Scn5a+/∆KPQ mice modeling long QT3 syndrome in relationship to cardiac Na+ channel, Nav1.5, expression. Atrial electrophysiological properties in isolated Langendorff-perfused hearts from 3- and 12-month-old wild type (WT), and Scn5a+/∆KPQ mice were assessed using programmed electrical stimulation and their Nav1.5 expression assessed by Western blot. Cardiac conduction properties were assessed electrocardiographically in intact anesthetized animals. Monophasic action potential recordings demonstrated increased atrial arrhythmogenicity specifically in aged Scn5a+/ΔKPQ hearts. These showed greater action potential duration/refractory period ratios but lower atrial Nav1.5 expression levels than aged WT mice. Atrial Nav1.5 levels were higher in young Scn5a+/ΔKPQ than young WT. These levels increased with age in WT but not Scn5a+/ΔKPQ. Both young and aged Scn5a+/ΔKPQ mice showed lower heart rates and longer PR intervals than their WT counterparts. Young Scn5a+/ΔKPQ mice showed longer QT and QTc intervals than young WT. Aged Scn5a+/ΔKPQ showed longer QRS durations than aged WT. PR intervals were prolonged and QT intervals were shortened in young relative to aged WT. In contrast, ECG parameters were similar between young and aged Scn5a+/ΔKPQ. Aged murine Scn5a+/ΔKPQ hearts thus exhibit an increased atrial arrhythmogenicity. The differing Nav1.5 expression and electrocardiographic indicators of slowed cardiac conduction between Scn5a+/ΔKPQ and WT, which show further variations associated with aging, may contribute toward atrial arrhythmia in aged Scn5a+/ΔKPQ hearts

Heat shock proteins in stabilization of spontaneously restored sinus rhythm in permanent atrial fibrillation patients after mitral valve surgery

A spontaneously restored sinus rhythm in permanent atrial fibrillation patients has been often observed after mitral valve (MV) surgery, but persisting duration in sinus rhythm varies from patient to patient. Heat shock proteins (Hsps) may be involved in pathogenesis of atrial fibrillation. We hypothesized that stabilization of restored sinus rhythm is associated with expression of Hsps in the atria. To test this hypothesis, clinical data, biopsies of right atrial appendage, and blood samples were collected from 135 atrial fibrillation patients who spontaneously restored sinus rhythm after conventional isolated MV replacement. Comparison was made between patients who had recurrence of atrial fibrillation within 7 days (AF) vs. patients with persisted sinus rhythm for more than 7 days (SR). Results showed that SR patients had higher activity of heat shock transcription factor 1 (HSF1) as well as upregulated expressions of heat shock cognate 70, Hsp70, and Hsp27 in the tissues. The activation of HSF1–Hsps pathway was associated with less-aggressive pathogenesis as reflected by lower rates of myolysis, apoptosis, interstitial fibrosis, and inflammation in SR patients. However, Hsp60 was lower in both tissue and plasma in SR patients, and was positively correlated with apoptosis, interstitial fibrosis, and inflammation. These findings suggest that the Hsps play important roles in stabilization of restored sinus rhythm after MV surgery by inhibiting AF-related atrial remodeling and arrhythmogenic substrates in atrial fibrillation patients. Low circulating Hsp60 levels preoperatively might predict a stable spontaneously restored sinus rhythm postoperatively

Mitochondrial Dysfunction Underlies Cardiomyocyte Remodeling in Experimental and Clinical Atrial Fibrillation

Atrial fibrillation (AF), the most common progressive tachyarrhythmia, results in structural remodeling which impairs electrical activation of the atria, rendering them increasingly permissive to the arrhythmia. Previously, we reported on endoplasmic reticulum stress and NAD+ depletion in AF, suggesting a role for mitochondrial dysfunction in AF progression. Here, we examined mitochondrial function in experimental model systems for AF (tachypaced HL-1 atrial cardiomyocytes and Drosophila melanogaster) and validated findings in clinical AF. Tachypacing of HL-1 cardiomyocytes progressively induces mitochondrial dysfunction, evidenced by impairment of mitochondrial Ca2+-handling, upregulation of mitochondrial stress chaperones and a decrease in the mitochondrial membrane potential, respiration and ATP production. Atrial biopsies from AF patients display mitochondrial dysfunction, evidenced by aberrant ATP levels, upregulation of a mitochondrial stress chaperone and fragmentation of the mitochondrial network. The pathophysiological role of mitochondrial dysfunction is substantiated by the attenuation of AF remodeling by preventing an increased mitochondrial Ca2+-influx through partial blocking or downregulation of the mitochondrial calcium uniporter, and by SS31, a compound that improves bioenergetics in mitochondria. Together, these results show that conservation of the mitochondrial function protects against tachypacing-induced cardiomyocyte remodeling and identify this organelle as a potential novel therapeutic target

Electrophysiological characteristics of permanent atrial fibrillation: insights from research models of cardiac remodeling

[EN] Atrial fibrillation (AF) results in a remodeling of the electrical and structural characteristics of the cardiac tissue which dramatically reduces the efficacy of pharmacological and catheter-based ablation therapies. Recent experimental and clinical results have demonstrated that the complexity of the fibrillatory process significantly differs in paroxysmal versus persistent AF; however, the lack of appropriate research models of remodeled atrial tissue precludes the elucidation of the underlying AF mechanisms and the identification of appropriated therapeutic targets. Here, we summarize the different research models used to date, highlighting the lessons learned from them and pointing to the new doors that should be open for the development of innovative treatments for AF.The authors were supported by grants from the Spanish Ministry of Science and Innovation (PLE2009-0152), the Instituto de Salud Carlos III (Ministry of Economy and Competitiveness, Spain: PI13-01882 and PI13-00903) the Red de Investigacion Cardiovacular (RIC) from Instituto de Salud Carlos III (Ministry of Economy and Competitiveness, Spain). F Atienza served on the advisory board of Medtronic and has received research funding from St. Jude Medical Spain. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.Climent, A.; Guillem Sánchez, MS.; Atienza Fernández, F.; Fernandez-Aviles, F. (2014). Electrophysiological characteristics of permanent atrial fibrillation: insights from research models of cardiac remodeling. Expert Review of Cardiovascular Therapy. 13(1):1-3. https://doi.org/10.1586/14779072.2015.986465S1313