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

Impact of atrial programmed electrical stimulation techniques on unipolar electrogram morphology

Introduction: Intra-atrial conduction abnormalities are associated with the development of atrial fibrillation (AF) and cause morphological changes of the unipolar atrial electrogram (U-AEGM). This study examined the impact of

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

Clinical experience with a novel subcutaneous implantable defibrillator system in a single center

Background: Implantable cardioverter-defibrillators (ICDs) reduce mortality in both primary and secondary prevention, but are associated with substantial short- and long-term morbidity. A totally subcutaneous ICD (S-ICD) system has been developed. We report the initial clinical experience of the first 31 patients implanted at our hospital. Methods: All patients had an ICD indication according to the ACC/AHA/ESC guidelines. The first 11 patients were part of the reported CE trial. The implantation was performed without fluoroscopy. The device was implanted subcutaneously in the anterior axillary line, with a parasternal lead tunneled from the xiphoid to the manubrial-sternal junction. Ventricular fibrillation (VF) was induced to assess detection accuracy and defibrillation efficacy using 65 J shocks. Results: Post-implant, 52 sustained episodes of VF were induced. Sensitivity was 100% and induced conversion efficacy was 100% (with standard polarity in 29 patients). Mean time to therapy was 13.9 ± 2.5 s (range 11-21.6 s). Late procedure-related complications were observed in 2 of the first 11 implantations (lead migration). During follow-up, spontaneous ventricular arrhythmias occurred in four patients, with accurate detection of all episodes. Inappropriate therapy was observed in five patients. Recurrences were prevented with reprogramming. Conclusions: The S-ICD system can be implanted without the use of fluoroscopy by using anatomical landmarks only. Episodes of VF were accurately detected using subcutaneous signals, and all induced and clinical episodes were successfully converted. The S-ICD system is a viable alternative to conventional ICD systems for selected patients

Hemodynamic deterioration precedes onset of ventricular tachyarrhythmia after Heartmate II implantation

Background: Early postoperative ventricular tachyarrhythmia (PoVT) after left ventricular assist device (LVAD) implantation are common and associated with higher mortality-rates. At present, there is no data on initiation of these PoVT and the role of alterations in cardiac hemodynamics. Case Presentation: A LVAD was implanted in a patient with end-stage heart failure due to a ischemic cardiomyopathy. Alterations in cardiac rhythm and hemodynamics preceding PoVT-episodes during the first five postoperative days were examined by using continuous recordings of cardiac rhythm and various hemodynamic parameters. All PoVT (N=120) were monomorphic, most often preceded by short-long-short-sequences or regular SR and initiated by ventricular runs. Prior to PoVT, mean arterial pressure decreased; heart rate and ST-segments deviations increased. Conclusions: PoVT are caused by different underlying electrophysiological mechanisms. Yet, they are all monomorphic and preceded by hemodynamic deterioration due to myocardial ischemia

Dynamics of the QTc interval over a 24-h dose interval after start of intravenous ciprofloxacin or low-dose erythromycin administration in ICU patients

QTc interval prolongation is an adverse effect associated with the use of fluoroquinolones and macrolides. Ciprofloxacin and erythromycin are both frequently prescribed QTc-prolonging drugs in critically ill patients. Critically ill patients may be more vulnerable to developing QTc prolongation, as several risk factors can be present at the same time. Therefore, it is important to know the QTc-prolonging potential of these drugs in the intensive care unit (ICU) population. The aim of this study was to assess the dynamics of the QTc interval over a 24-hour dose interval during intravenous ciprofloxacin and low-dose erythromycin treatment. Therefore, an observational study was performed in ICU patients (>= 18 years) receiving ciprofloxacin 400 mg t.i.d. or erythromycin 100 mg b.i.d. intravenously. Continuous ECG data were collected from 2 h before to 24 h after the first administration. QT-analyses were performed using high-end holter software. The effect was determined with a two-sample t-test for clustered data on all QTc values. A linear mixed model by maximum likelihood was applied, for which QTc values were assessed for the available time intervals and therapy. No evident effect over time on therapy with ciprofloxacin and erythromycin was observed on QTc time. There was no significant difference (p = 0.22) in QTc values between the ciprofloxacin group (mean 393 ms) and ciprofloxacin control group (mean 386 ms). The erythromycin group (mean 405 ms) and erythromycin control group (mean 404 ms) neither showed a significant difference (p = 0.80). In 0.6% of the registrations (1.138 out of 198.270 samples) the duration of the QTc interval was longer than 500 ms. The index groups showed slightly more recorded QTc intervals over 500 ms. To conclude, this study could not identify differences in the QTc interval between the treatments analyzed.Clinical Pharmacy and Toxicolog

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

Converse role of class I and class IIa HDACs in the progression of atrial fibrillation

Atrial fibrillation (AF), the most common persistent clinical tachyarrhythmia, is associated with altered gene transcription which underlies cardiomyocyte dysfunction, AF susceptibility and progression. Recent research showed class I and class Ha histone deacetylases (HDACs) to regulate pathological and fetal gene expression, and thereby induce hypertrophy and cardiac contractile dysfunction. Whether class I and class Ha HDACs are involved in AF promotion is unknown. We aim to elucidate the role of class I and class Ila HDACs in tachypacinginduced contractile dysfunction in experimental model systems for AF and clinical AF. Methods and results: Class I and Ila HDACs were overexpressed in HL-1 cardiomyocytes followed by calcium transient (CaT) measurements. Overexpression of class I HDACs, HDAC1 or HDAC3, significantly reduced CaT amplitude in control normal-paced (1 Hz) cardiomyocytes, which was further reduced by tachypacing (5 Hz) in HDAC3 overexpressing cardiomyocytes. HDAC3 inhibition by shRNA or by the specific inhibitor, RGFP966, prevented contractile dysfunction in both tachypaced HL-1 cardiomyocytes and Drosophila prepupae. Conversely, overexpression of class Ha HDACs (HDAC4, HDAC5, HDAC7 or HDAC9) did not affect CaT in controls, with HDAC5 and HDAC7 overexpression even protecting against tachypacing-induced CaT loss. Notably, the protective effect of HDAC5 and HDAC7 was abolished in cardiomyocytes overexpressing a dominant negative HDAC5 or HDAC7 mutant, bearing a mutation in the binding domain for myosin enhancer factor 2 (MEF2). Furthermore, tachypacing induced phosphorylation of HDAC5 and promoted its translocation from the nucleus to cytoplasm, leading to up-regulation of MEF2-related fetal gene expression (f3-MHC, BNP). In accord, boosting nuclear localization of HDAC5 by MC1568 or Go6983 attenuated CaT loss in tachypaced HL-1 cardiomyocytes and preserved contractile function in Drosophila prepupae. Findings were expanded to clinical AF. Here, patients with AF showed a significant increase in expression levels and activity of HDAC3, phosphorylated HDAC5 and fetal genes (13-MHC, BNP) in atrial tissue compared to controls in sinus rhythm. Conclusion: Class I and class Ha HDACs display converse roles in AF progression. Whereas overexpression of Class I HDAC3 induces cardiomyocyte dysfunction, class Ha HDAC5 overexpression reveals protective properties. Accordingly, HDAC3 inhibitors and HDAC5 nuclear boosters show protection from tachypacing-induced changes and therefore may represent interesting therapeutic options in clinical AF