Molecular adaptations in human atrial fibrillation:mechanisms of protein remodeling

The main goal was to study the molecular remodeling in human atrial fibrillation. We focussed on gene expression of proteins wich influence the calcium homeostasis and action potential duration in human AF. The impact of modulation sysems like the natriuretic peptide system and the endothelin system were also studied

The future of atrial fibrillation therapy: Intervention on heat shock proteins influencing electropathology is the next in line

Atrial fibrillation (AF) is the most common agerelated cardiac arrhythmia accounting for one-third of hospitalisations. Treatment of AF is difficult, which is rooted in the progressive nature of electrical and structural remodelling, called electropathology, which makes the atria more vulnerable for AF. Importantly, structural damage of the myocardium is already present when AF is diagnosed for the first time. Currently, no effective therapy is known that can resolve this damage. Previously, we observed that exhaustion of cardioprotective heat shock proteins (HSPs) contributes to structural damage in AF patients. Also, boosting of HSPs, by the heat shock factor-1 activator geranylgeranylacetone, halted AF initiation and progression in experimental cardiomyocyte and dog models for AF. However, it is still unclear whether induction of HSPs also prolongs the arrhythmia-free interval after, for example, cardioversion of AF. In this review, we discuss the role of HSPs in the pathophysiology of AF and give an outline of the HALT&REVERSE project, initiated by the HALT&REVERSE Consortium and the AF Innovation Platform. This project will elucidate whether HSPs (1) reverse cardiomyocyte electropathology and thereby halt AF initiation and progression and (2) represent novel biomarkers that predict the outcome of AF conversion and/or occurrence of post-surgery AF

Cardioprotective role of heat shock proteins in atrial fibrillation: From mechanism of action to therapeutic and diagnostic t

Atrial fibrillation (AF) is the most common age-related cardiac arrhythmia worldwide and is associated with ischemic stroke, heart failure, and substantial morbidity and mortality. Unfortunately, current AF therapy is only moderately effective and does not prevent AF progression from recurrent intermittent episodes (paroxysmal) to persistent and finally permanent AF. It has been recognized that AF persistence is related to the presence of electropathology. Electropathology is defined as structural damage, including degradation of sarcomere structures, in the atrial tissue which, in turn, impairs electrical conduction and subsequently the contractile function of atrial cardiomyocytes. Recent research findings indicate that derailed proteostasis underlies structural damage and, consequently, electrical conduction impairment. A healthy proteostasis is of vital importance for proper function of cells, including cardiomyocytes. Cells respond to a loss of proteostatic control by inducing a heat shock response (HSR), which results in heat shock protein (HSP) expression. Emerging clinical evidence indicates that AF-induced proteostasis derailment is rooted in exhaustion of HSPs. Cardiomyocytes lose defense against structural damage-inducing pathways, which drives progression of AF and induction of HSP expression. In particular, small HSPB1 conserves sarcomere structures by preventing their degradation by proteases, and overexpression of HSPB1 accelerates recovery from structural damage in experimental AF model systems. In this review, we provide an overview of the mechanisms of action of HSPs in preventing AF and discuss the therapeutic potential of HSP-inducing compounds in clinical AF, as well as the potential of HSPs as biomarkers to discriminate between the various stages of AF and recurrence of AF after treatment

The HF-AF ENERGY Trial:Nicotinamide Riboside for the Treatment of Atrial Fibrillation in Heart Failure Patients

Background: The presence of atrial fibrillation (AF) in heart failure (HF) patients with reduced ejection fraction is common and associated with an increased risk of stroke, hospitalization and mortality. Recent research findings indicate that a reduction in nicotinamide adenine dinucleotide (NAD+) levels results in mitochondrial dysfunction, DNA damage and consequently cardiomyocyte impairment in experimental and clinical HF and AF. The HF-AF ENERGY trial aims to investigate the cardioprotective effects of the NAD+ precursor nicotinamide riboside (NR) treatment in ischemic heart disease patients diagnosed with AF. Study design: The HF-AF ENERGY trial is a prospective intervention study. The study consists of a (retrospective) 4 months observation period and a 4 months intervention period. The cardioprotective effect of NR on AF burden is investigated by remote monitoring software of implantable cardiac defibrillators (ICDs), which enables continuous atrial rhythm monitoring detection. Cardiac dimension and function are examined by echocardiography. Laboratory blood analysis is performed to determine mitochondrial function markers and energy metabolism. All the study parameters are assessed at two fixed time points (pre- and post-treatment). Pre- and post-treatment outcomes are compared to determine the effects of NR treatment on AF burden, mitochondrial function markers and energy metabolism. Conclusion: The HF-AF ENERGY trial investigates the cardioprotective effects of NR on AF burden and whether NR normalizes blood-based mitochondrial function markers and energy metabolites of the NAD metabolome in ischemic heart disease patients diagnosed with AF. The study outcomes elucidate whether NAD+ metabolism can be used as a future therapy for HF patients with AF.</p

Atrial fibrillation fingerprinting; spotting bio-electrical markers to early recognize atrial fibrillation by the use of a bottom-up approach (AFFIP): Rationale and design

Background: The exact pathophysiology of atrial fibrillation (AF) remains incompletely understood and treatment of AF is associated with high recurrence rates. Persistence of AF is rooted in the presence of electropathology, defined as complex electrical conduction disorders caused by structural damage of atrial tissue. The atrial fibrillation fingerprinting (AFFIP) study aims to characterize electropathology, enabling development of a novel diagnostic instrument to predict AF onset and early progression. Hypotheses: History of AF, development of post-operative AF, age, gender, underlying heart disease, and other clinical characteristics impact the degree of electropathology. Methods: This study is a prospective observational study with a planned duration of 48 months. Three study groups are defined: (1) patients with (longstanding) persistent AF, (2) patients with paroxysmal AF, and (3) patients without a history of AF, all undergoing open-chest cardiac surgery. Intra-operative high-resolution epicardial mapping is performed to identify the patient-specific electrical profile, whereas the patient-specific biological profile is assessed by evaluating proteostasis markers in blood samples and atrial appendage tissue samples. Post-operative continuous rhythm monitoring is perfo

The Impact of Filter Settings on Morphology of Unipolar Fibrillation Potentials

Using unipolar atrial electrogram morphology as guidance for ablative therapy is regaining interest. Although standardly used in clinical practice during ablative therapy, the impact of filter settings on morphology of unipolar AF potentials is unknown. Thirty different filters were applied to 2,557,045 high-resolution epicardial AF potentials recorded from ten patients. Deflections with slope ≤ − 0.05 mV/ms and amplitude ≥ 0.3 mV were marked. High-pass filtering decreased the number of detected potentials, deflection amplitude, and percentage of fractionated potentials (≥ 2 deflections) as well as fractionation delay time (FDT) and increased percentage of single potentials. Low-pass filtering decreased the number of potentials, percentage of fractionated potentials, whereas deflection amplitude, percentage of single potentials, and FDT increased. Notch filtering (50 Hz) decreased the number of potentials and deflection amplitude, whereas the percentage of complex fractionated potentials (≥ 3 deflections) increased. Filtering significantly impacted morphology of unipolar fibrillation potentials, becoming a potential source of error in identification of ablative targets.