The Role of Immune Cells Driving Electropathology and Atrial Fibrillation.

Atrial fibrillation (AF) is the most common progressive cardiac arrhythmia worldwide and entails serious complications including stroke and heart failure. Despite decades of clinical research, the current treatment of AF is suboptimal. This is due to a lack of knowledge on the mechanistic root causes of AF. Prevailing theories indicate a key role for molecular and structural changes in driving electrical conduction abnormalities in the atria and as such triggering AF. Emerging evidence indicates the role of the altered atrial and systemic immune landscape in driving this so-called electropathology. Immune cells and immune markers play a central role in immune remodeling by exhibiting dual facets. While the activation and recruitment of immune cells contribute to maintaining atrial stability, the excessive activation and pronounced expression of immune markers can foster AF. This review delineates shifts in cardiac composition and the distribution of immune cells in the context of cardiac health and disease, especially AF. A comprehensive exploration of the functions of diverse immune cell types in AF and other cardiac diseases is essential to unravel the intricacies of immune remodeling. Usltimately, we delve into clinical evidence showcasing immune modifications in both the atrial and systemic domains among AF patients, aiming to elucidate immune markers for therapy and diagnostics.

Biatrial arrhythmogenic substrate in patients with hypertrophic obstructive cardiomyopathy.

BACKGROUND: Atrial fibrillation (AF) in patients with hypertrophic obstructive cardiomyopathy (HOCM) may be caused by a primary atrial myopathy. Whether HOCM-related atrial myopathy affects mainly electrophysiological properties of the left atrium (LA) or also the right atrium (RA) has never been investigated. OBJECTIVE: The purpose of this study was to characterize atrial conduction and explore differences in the prevalence of conduction disorders, potential fractionation, and low-voltage areas (LVAs) between the RA and LA during sinus rhythm (SR) as indicators of potential arrhythmogenic areas. METHODS: Intraoperative epicardial mapping of both atria during SR was performed in 15 HOCM patients (age 50 ± 12 years). Conduction delay (CD) and conductin block (CB), unipolar potential characteristics (voltages, fractionation), and LVA were quantified. RESULTS: Conduction disorders and LVA were found scattered throughout both atria in all patients and did not differ between the RA and LA (CD: 2.9% [1.9%-3.6%] vs 2.6% [2.1%-6.4%], P = .541; CB: 1.7% [0.9%-3.1%] vs 1.5% [0.5%-2.8%], P = .600; LVA: 4.7% [1.6%-7.7%] vs 2.9% [2.1%-7.1%], P = .793). Compared to the RA, unipolar voltages of single potentials (SPs) and fractionated potentials (FPs) were higher in the LA (SP: P75 7.3 mV vs 10.9 mV; FP: P75 2.0 mV vs 3.7 mV). FP contained low-voltage components in only 18% of all LA sites compared to 36% of all RA sites. CONCLUSION: In patients with HOCM, conduction disorders, LVA, and FP are equally present in both atria, supporting the hypothesis of a primary atrial myopathy. Conceptually, the presence of a biatrial substrate and high-voltage FP may contribute to failure of ablative therapy of atrial tachyarrhythmias in this population.

Characterization of unipolar electrogram morphology: a novel tool for quantifying conduction inhomogeneity.

AIMS: Areas of conduction inhomogeneity (CI) during sinus rhythm may facilitate the initiation and perpetuation of atrial fibrillation (AF). Currently, no tool is available to quantify the severity of CI. Our aim is to develop and validate a novel tool using unipolar electrograms (EGMs) only to quantify the severity of CI in the atria. METHODS AND RESULTS: Epicardial mapping of the right atrium (RA) and left atrium, including Bachmann's bundle, was performed in 235 patients undergoing coronary artery bypass grafting surgery. Conduction inhomogeneity was defined as the amount of conduction block. Electrograms were classified as single, short, long double (LDP), and fractionated potentials (FPs), and the fractionation duration of non-single potentials was measured. The proportion of low-voltage areas (LVAs, <1 mV) was calculated. Increased CI was associated with decreased potential voltages and increased LVAs, LDPs, and FPs. The Electrical Fingerprint Score consisting of RA EGM features, including LVAs and LDPs, was most accurate in predicting CI severity. The RA Electrical Fingerprint Score demonstrated the highest correlation with the amount of CI in both atria (r = 0.70, P < 0.001). CONCLUSION: The Electrical Fingerprint Score is a novel tool to quantify the severity of CI using only unipolar EGM characteristics recorded. This tool can be used to stage the degree of conduction abnormalities without constructing spatial activation patterns, potentially enabling early identification of patients at high risk of post-operative AF or selection of the appropriate ablation approach in addition to pulmonary vein isolation at the electrophysiology laboratory.

Dissecting the Molecular Mechanisms Driving Electropathology in Atrial Fibrillation: Deployment of RNA Sequencing and Transcriptomic Analyses.

Despite many efforts to treat atrial fibrillation (AF), the most common progressive and age-related cardiac tachyarrhythmia in the Western world, the efficacy is still suboptimal. A plausible reason for this is that current treatments are not directed at underlying molecular root causes that drive electrical conduction disorders and AF (i.e., electropathology). Insights into AF-induced transcriptomic alterations may aid in a deeper understanding of electropathology. Specifically, RNA sequencing (RNA-seq) facilitates transcriptomic analyses and discovery of differences in gene expression profiles between patient groups. In the last decade, various RNA-seq studies have been conducted in atrial tissue samples of patients with AF versus controls in sinus rhythm. Identified differentially expressed molecular pathways so far include pathways related to mechanotransduction, ECM remodeling, ion channel signaling, and structural tissue organization through developmental and inflammatory signaling pathways. In this review, we provide an overview of the available human AF RNA-seq studies and highlight the molecular pathways identified. Additionally, a comparison is made between human RNA-seq findings with findings from experimental AF model systems and we discuss contrasting findings. Finally, we elaborate on new exciting RNA-seq approaches, including single-nucleotide variants, spatial transcriptomics and profiling of different populations of total RNA, small RNA and long non-coding RNA.

Prevention of Atrial Fibrillation: Putting Proteostasis Derailment Back on Track.

Despite the many attempts to treat atrial fibrillation (AF), the most common cardiac tachyarrhythmia in the Western world, the treatment efficacy of AF is still suboptimal. A plausible reason for the suboptimal efficacy is that the current treatments are not directed at the underlying molecular mechanisms that drive AF. Recent discoveries revealed that the derailment of specific molecular proteostasis pathways drive electrical conduction disorders, contractile dysfunction and AF. The degree of this so-called 'electropathology' corresponds to the response to anti-AF treatment. Hence, to develop effective therapies to prevent AF, understanding the molecular mechanisms is of key importance. In this review, we highlight the key modulators of proteostasis derailment and describe the mechanisms that explain how they affect electrical and contractile function in atrial cardiomyocytes and AF. The key modulators of proteostasis derailment include (1) exhaustion of cardioprotective heat shock proteins (HSPs), (2) excessive endoplasmic reticulum (ER) stress and downstream autophagic protein degradation, (3) histone deacetylase 6 (HDAC6)-induced microtubule disruption, (4) activation of DNA damage-PARP1 activation and NAD+ axis and (5) mitochondrial dysfunction. Furthermore, we discuss druggable targets within these pathways that are involved in the prevention of proteostasis derailment, as well as the targets that aid in the recovery from AF. Finally, we will elaborate on the most favorable druggable targets for (future) testing in patients with AF, as well as drugs with potential benefits for AF recovery.

Long Noncoding RNA UCA1 Correlates With Electropathology in Patients With Atrial Fibrillation.

BACKGROUND: Perpetuation of atrial fibrillation (AF) is rooted in derailment of molecular proteostasis pathways that cause electrical conduction disorders that drive AF. Emerging evidence indicates a role for long noncoding RNAs (lncRNAs) in the pathophysiology of cardiac diseases, including AF. OBJECTIVES: In the present study, the authors explored the association between 3 cardiac lncRNAs and the degree of electropathology. METHODS: Patients had paroxysmal AF (ParAF) (n = 59), persistent AF (PerAF) (n = 56), or normal sinus rhythm without a history of AF (SR) (n = 70). The relative expression levels of urothelial carcinoma-associated 1 (UCA1), OXCT1-AS1 (SARRAH), and the mitochondrial lncRNA uc022bqs.q (LIPCAR) were measured by means of quantitative reverse-transcription polymerase chain reaction in the right atrial appendage (RAA) or serum (or both). A selection of the patients was subjected to high-resolution epicardial mapping to evaluate electrophysiologic features during SR. RESULTS: The expression levels of SARRAH and LIPCAR were decreased in RAAs of all AF patients compared with SR. Also, in RAAs, UCA1 levels significantly correlated with the percentage of conduction block and delay, and inversely with conduction velocity, indicating that UCA1 levels in RAA reflect the degree of electrophysiologic disorders. Moreover, in serum samples, SARRAH and UCA1 levels were increased in the total AF group and ParAF patients compared with SR. CONCLUSIONS: LncRNAs SARRAH and LIPCAR are reduced in RAA of AF patients, and UCA1 levels correlate with electrophysiologic conduction abnormalities. Thus, RAA UCA1 levels may aid staging of electropathology severity and act as a patient-tailored bioelectrical fingerprint.

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.

Long COVID and the cardiovascular system-elucidating causes and cellular mechanisms in order to develop targeted diagnostic and therapeutic strategies: a joint Scientific Statement of the ESC Working Groups on Cellular Biology of the Heart and Myocardial and Pericardial Diseases.

Long COVID has become a world-wide, non-communicable epidemic, caused by long-lasting multiorgan symptoms that endure for weeks or months after SARS-CoV-2 infection has already subsided. This scientific document aims to provide insight into the possible causes and therapeutic options available for the cardiovascular manifestations of long COVID. In addition to chronic fatigue, which is a common symptom of long COVID, patients may present with chest pain, ECG abnormalities, postural orthostatic tachycardia, or newly developed supraventricular or ventricular arrhythmias. Imaging of the heart and vessels has provided evidence of chronic, post-infectious perimyocarditis with consequent left or right ventricular failure, arterial wall inflammation, or microthrombosis in certain patient populations. Better understanding of the underlying cellular and molecular mechanisms of long COVID will aid in the development of effective treatment strategies for its cardiovascular manifestations. A number of mechanisms have been proposed, including those involving direct effects on the myocardium, microthrombotic damage to vessels or endothelium, or persistent inflammation. Unfortunately, existing circulating biomarkers, coagulation, and inflammatory markers, are not highly predictive for either the presence or outcome of long COVID when measured 3 months after SARS-CoV-2 infection. Further studies are needed to understand underlying mechanisms, identify specific biomarkers, and guide future preventive strategies or treatments to address long COVID and its cardiovascular sequelae.

Desmin variants: Trigger for cardiac arrhythmias?

Desmin (DES) is a classical type III intermediate filament protein encoded by the DES gene. Desmin is abundantly expressed in cardiac, skeletal, and smooth muscle cells. In these cells, desmin interconnects several protein-protein complexes that cover cell-cell contact, intracellular organelles such as mitochondria and the nucleus, and the cytoskeletal network. The extra- and intracellular localization of the desmin network reveals its crucial role in maintaining the structural and mechanical integrity of cells. In the heart, desmin is present in specific structures of the cardiac conduction system including the sinoatrial node, atrioventricular node, and His-Purkinje system. Genetic variations and loss of desmin drive a variety of conditions, so-called desminopathies, which include desmin-related cardiomyopathy, conduction system-related atrial and ventricular arrhythmias, and sudden cardiac death. The severe cardiac disease outcomes emphasize the clinical need to understand the molecular and cellular role of desmin driving desminopathies. As the role of desmin in cardiomyopathies has been discussed thoroughly, the current review is focused on the role of desmin impairment as a trigger for cardiac arrhythmias. Here, the molecular and cellular mechanisms of desmin to underlie a healthy cardiac conduction system and how impaired desmin triggers cardiac arrhythmias, including atrial fibrillation, are discussed. Furthermore, an overview of available (genetic) desmin model systems for experimental cardiac arrhythmia studies is provided. Finally, potential implications for future clinical treatments of cardiac arrhythmias directed at desmin are highlighted.

Atrial fibrillation.

Atrial fibrillation (AF) is the most common cardiac arrhythmia despite substantial efforts to understand the pathophysiology of the condition and develop improved treatments. Identifying the underlying causative mechanisms of AF in individual patients is difficult and the efficacy of current therapies is suboptimal. Consequently, the incidence of AF is steadily rising and there is a pressing need for novel therapies. Research has revealed that defects in specific molecular pathways underlie AF pathogenesis, resulting in electrical conduction disorders that drive AF. The severity of this so-called electropathology correlates with the stage of AF disease progression and determines the response to AF treatment. Therefore, unravelling the molecular mechanisms underlying electropathology is expected to fuel the development of innovative personalized diagnostic tools and mechanism-based therapies. Moreover, the co-creation of AF studies with patients to implement novel diagnostic tools and therapies is a prerequisite for successful personalized AF management. Currently, various treatment modalities targeting AF-related electropathology, including lifestyle changes, pharmaceutical and nutraceutical therapy, substrate-based ablative therapy, and neuromodulation, are available to maintain sinus rhythm and might offer a novel holistic strategy to treat AF.

Cytoskeletal Protein Variants Driving Atrial Fibrillation: Potential Mechanisms of Action.

The most common clinical tachyarrhythmia, atrial fibrillation (AF), is present in 1-2% of the population. Although common risk factors, including hypertension, diabetes, and obesity, frequently underlie AF onset, it has been recognized that in 15% of the AF population, AF is familial. In these families, genome and exome sequencing techniques identified variants in the non-coding genome (i.e., variant regulatory elements), genes encoding ion channels, as well as genes encoding cytoskeletal (-associated) proteins. Cytoskeletal protein variants include variants in desmin, lamin A/C, titin, myosin heavy and light chain, junctophilin, nucleoporin, nesprin, and filamin C. These cytoskeletal protein variants have a strong association with the development of cardiomyopathy. Interestingly, AF onset is often represented as the initial manifestation of cardiac disease, sometimes even preceding cardiomyopathy by several years. Although emerging research findings reveal cytoskeletal protein variants to disrupt the cardiomyocyte structure and trigger DNA damage, exploration of the pathophysiological mechanisms of genetic AF is still in its infancy. In this review, we provide an overview of cytoskeletal (-associated) gene variants that relate to genetic AF and highlight potential pathophysiological pathways that drive this arrhythmia.

Degree of Fibrosis in Human Atrial Tissue Is Not the Hallmark Driving AF.

BACKGROUND: The current paradigm is that fibrosis promotes electrophysiological disorders and drives atrial fibrillation (AF). In this current study, we investigated the relation between the degree of fibrosis in human atrial tissue samples of controls and patients in various stages of AF and the degree of electrophysiological abnormalities. METHODS: The degree of fibrosis was measured in the atrial tissue and serum of patients in various stages of AF and the controls. Hereto, picrosirius and H&E staining were performed to quantify degree of total, endo-perimysial fibrosis, and cardiomyocyte diameter. Western blot quantified fibrosis markers: neural cell adhesion molecule, tissue inhibitor of metalloproteinase, lysyl oxidase, and α-smooth muscle actin. In serum, the ratio carboxyl-terminal telopeptide of collagen/matrix-metalloproteinase1 was determined. High-resolution epicardial mapping evaluated low-voltage areas and conduction abnormalities. RESULTS: No significant differences were observed in the degree of fibrosis between the groups. Finally, no significant correlation-absolute nor spatial-was observed between all electrophysiological parameters and histological fibrosis markers. CONCLUSIONS: No differences in the degree of fibrosis were observed in patients from various stages of AF compared to the controls. Moreover, electrophysiological abnormalities did not correlate with any of the fibrosis markers. The findings indicate that fibrosis is not the hallmark of structural remodeling in AF.

Animal models and animal-free innovations for cardiovascular research: current status and routes to be explored. Consensus document of the ESC Working Group on Myocardial Function and the ESC Working Group on Cellular Biology of the Heart.

Cardiovascular diseases represent a major cause of morbidity and mortality, necessitating research to improve diagnostics, and to discover and test novel preventive and curative therapies, all of which warrant experimental models that recapitulate human disease. The translation of basic science results to clinical practice is a challenging task, in particular for complex conditions such as cardiovascular diseases, which often result from multiple risk factors and comorbidities. This difficulty might lead some individuals to question the value of animal research, citing the translational 'valley of death', which largely reflects the fact that studies in rodents are difficult to translate to humans. This is also influenced by the fact that new, human-derived in vitro models can recapitulate aspects of disease processes. However, it would be a mistake to think that animal models do not represent a vital step in the translational pathway as they do provide important pathophysiological insights into disease mechanisms particularly on an organ and systemic level. While stem cell-derived human models have the potential to become key in testing toxicity and effectiveness of new drugs, we need to be realistic, and carefully validate all new human-like disease models. In this position paper, we highlight recent advances in trying to reduce the number of animals for cardiovascular research ranging from stem cell-derived models to in situ modelling of heart properties, bioinformatic models based on large datasets, and state-of-the-art animal models, which show clinically relevant characteristics observed in patients with a cardiovascular disease. We aim to provide a guide to help researchers in their experimental design to translate bench findings to clinical routine taking the replacement, reduction, and refinement (3R) as a guiding concept.

Circadian rhythms in ischaemic heart disease: key aspects for preclinical and translational research: position paper of the ESC working group on cellular biology of the heart.

Circadian rhythms are internal regulatory processes controlled by molecular clocks present in essentially every mammalian organ that temporally regulate major physiological functions. In the cardiovascular system, the circadian clock governs heart rate, blood pressure, cardiac metabolism, contractility, and coagulation. Recent experimental and clinical studies highlight the possible importance of circadian rhythms in the pathophysiology, outcome, or treatment success of cardiovascular disease, including ischaemic heart disease. Disturbances in circadian rhythms are associated with increased cardiovascular risk and worsen outcome. Therefore, it is important to consider circadian rhythms as a key research parameter to better understand cardiac physiology/pathology, and to improve the chances of translation and efficacy of cardiac therapies, including those for ischaemic heart disease. The aim of this Position Paper by the European Society of Cardiology Working Group Cellular Biology of the Heart is to highlight key aspects of circadian rhythms to consider for improvement of preclinical and translational studies related to ischaemic heart disease and cardioprotection. Applying these considerations to future studies may increase the potential for better translation of new treatments into successful clinical outcomes.

The Role of Mitochondrial Dysfunction in Atrial Fibrillation: Translation to Druggable Target and Biomarker Discovery.

Atrial fibrillation (AF) is the most prevalent and progressive cardiac arrhythmia worldwide and is associated with serious complications such as heart failure and ischemic stroke. Current treatment modalities attenuate AF symptoms and are only moderately effective in halting the arrhythmia. Therefore, there is an urgent need to dissect molecular mechanisms that drive AF. As AF is characterized by a rapid atrial activation rate, which requires a high energy metabolism, a role of mitochondrial dysfunction in AF pathophysiology is plausible. It is well known that mitochondria play a central role in cardiomyocyte function, as they produce energy to support the mechanical and electrical function of the heart. Details on the molecular mechanisms underlying mitochondrial dysfunction are increasingly being uncovered as a contributing factor in the loss of cardiomyocyte function and AF. Considering the high prevalence of AF, investigating the role of mitochondrial impairment in AF may guide the path towards new therapeutic and diagnostic targets. In this review, the latest evidence on the role of mitochondria dysfunction in AF is presented. We highlight the key modulators of mitochondrial dysfunction that drive AF and discuss whether they represent potential targets for therapeutic interventions and diagnostics in clinical AF.

Atrial heat shock protein levels are associated with early postoperative and persistence of atrial fibrillation.

BACKGROUND: Early detection and staging of atrial fibrillation (AF) is of importance for clinical management. Serum (bio)markers, such as heat shock proteins (HSP), may enable AF staging and identify patients at risk for AF recurrence and postoperative AF (PoAF). OBJECTIVE: This study evaluates the relation between serum and atrial tissue HSP levels, stages of AF, AF recurrence after treatment, and PoAF from patients undergoing cardiothoracic surgery. METHODS: Patients without (control) and with paroxysmal, persistent (PerAF), or longstanding persistent (LSPerAF) AF were included. HSPB1, HSPA1, HSPB7, and HSPD1 levels were measured in serum obtained prior to and post intervention. HSPB1, HSPA1, HSPA5, HSPD1, HSPB5, and pHSF1 levels were measured in left and/or right atrial appendages (respectively, LAA and RAA). RESULTS: In RAA, HSPA5 levels were significantly lower in LSPerAF and HSPD1 levels significantly higher in PerAF patients compared to controls. In RAA of controls who developed PoAF, HSPA1 and HSPA5 levels were significantly higher compared to those without PoAF. Also, HSPB1 RAA levels were lower and HSPA5 LAA levels higher in patients undergoing arrhythmia surgery who developed AF recurrence within 1 week after surgery compared to patients who did not. CONCLUSION: HSPA5 RAA and HSPD1 RAA and LAA levels are altered in persistent stages of AF. RAA HSPA1 and HSPA5 levels associate with development of PoAF. Additionally, HSPB1 RAA and HSPA5 LAA levels can predict AF recurrence in patients who underwent arrhythmia surgery. Nevertheless, HSP levels in serum cannot discriminate AF stages from controls, nor predict PoAF or AF recurrence after treatment.

The Antibiotic Doxycycline Impairs Cardiac Mitochondrial and Contractile Function.

Tetracycline antibiotics act by inhibiting bacterial protein translation. Given the bacterial ancestry of mitochondria, we tested the hypothesis that doxycycline-which belongs to the tetracycline class-reduces mitochondrial function, and results in cardiac contractile dysfunction in cultured H9C2 cardiomyoblasts, adult rat cardiomyocytes, in Drosophila and in mice. Ampicillin and carbenicillin were used as control antibiotics since these do not interfere with mitochondrial translation. In line with its specific inhibitory effect on mitochondrial translation, doxycycline caused a mitonuclear protein imbalance in doxycycline-treated H9C2 cells, reduced maximal mitochondrial respiration, particularly with complex I substrates, and mitochondria appeared fragmented. Flux measurements using stable isotope tracers showed a shift away from OXPHOS towards glycolysis after doxycycline exposure. Cardiac contractility measurements in adult cardiomyocytes and Drosophila melanogaster hearts showed an increased diastolic calcium concentration, and a higher arrhythmicity index. Systolic and diastolic dysfunction were observed after exposure to doxycycline. Mice treated with doxycycline showed mitochondrial complex I dysfunction, reduced OXPHOS capacity and impaired diastolic function. Doxycycline exacerbated diastolic dysfunction and reduced ejection fraction in a diabetes mouse model vulnerable for metabolic derangements. We therefore conclude that doxycycline impairs mitochondrial function and causes cardiac dysfunction.

Cardioprotective Role of Heat Shock Proteins in Atrial Fibrillation: From Mechanism of Action to Therapeutic and Diagnostic Target.

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.