Atrial fibrillation

Abstract

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.

Fig. 1 |. Global prevalence of AF.

Regional prevalence (cases per 100,000 individuals) of atrial fibrillation (AF). The map shows the regions of high prevalence (Western Europe and North America) and the generally lower prevalence in South Asia, Oceania and the Middle East. Data are from the Global Burden of Disease (GBD) Collaborative Network’s GBD 2019 results (obtained using the GBD 2019 results tool).

Fig. 2 |. Combinatorial effects of lifestyle factors on risk of AF.

Unhealthy Lifestyle factors, such as Lack of regular exercise, smoking and excessive alcohol consumption, individually show no to moderate association with risk of new-onset atrial fibrillation (AF), with a lack of regular exercise having the strongest association with increased risk of AF (adjusted hazard ratio (HR) 1.11). However, the combined presence of smoking and lack of regular exercise markedly increases AF risk (HR 1.21), which is similar to the increase in risk of AF in individuals with all three risk factors (HR 1.22). Data are from a nationwide population-based study of 1,719,401 Korean individuals of 66 years of age. Adapted from REF., CC BY 4.0.

Fig. 3 |. Overview of electrical conduction abnormalities in AF.

Electrical conduction is observed by high-resolution mapping of the atria during cardiac surgery. a | Simultaneously acquired endocardial and epicardial activation maps of the right atrial free wall obtained from two different patients with coronary artery disease undergoing cardiac surgery during sinus rhythm, demonstrating synchronous and asynchronous activation. Thus, asynchronous activation of the atrial wall might already be present during normal heart rhythms. Colours indicate the timing of activation (colour bar) in different parts of the mapping area. b | Asynchronous activation of the atrial wall is a prerequisite for the occurrence of transmural propagation of fibrillation waves, giving rise to focal waves. The focal wave maps demonstrate the incidence of focal fibrillation waves (red stars) emerging at each recording site (squares) during 8 s of acute atrial fibrillation (AF) (left) and long-standing persistent AF (centre) at the right atrial wall. Each square represents a recording site. During long-standing persistent AF, focal fibrillation waves (epicardial breakthroughs (EBs)) occur not only more frequently at the same site (although not repetitively) but also occur at more recording sites. The occurrence of focal waves in the patient with long-standing persistent AF was 0.57 per median AF cycle length per squared centimetre compared with only 0.05 during acute AF. The schematic (right) shows a wave map depicting each individual fibrillation wave containing 16 fibrillation waves within an area as small as 16 cm².

Fig. 4 |. Overview of molecular pathways driving electropathology and AF.

Atrial fibrillation (AF) causes loss of protein quality control via downregulation of the heat shock protein (HSP)-mediated heat shock response (HSR) and subsequent reduction in HSP expression levels and loss of chaperone activity. As HSPs represent the cell’s first line of defence against stress, the loss of stress response induces further endoplasmic reticulum stress and downstream excessive activation of the macroautophagy protein degradation pathway. AF also increases the activity of the histone deacetylase HDAC6, resulting in deacetylation of microtubules and destabilization of the microtubule network, Ca²⁺ handling alterations, and loss of cardiomyocyte contractile function (BOX 1). AF triggers DNA damage, poly(ADP-ribose) polymerase 1 (PARP1) activation and depletion of mitochondrial NAD⁺ levels, thereby causing electrophysiological and contractile impairment. Pharmacological treatments (in bold) that boost the HSR (for example, geranylgeranylacetone (GGA)), prevent endoplasmic reticulum stress (for example, 4-phenylbutyrate (4PBA)), inhibit HDAC6 (for example, tubastatin A and tubacin) or PARP1 (for example, olaparib) activity, or supplement NAD⁺ (for example, nicotinamide) protect against proteostasis dysfunction and AF progression in experimental model systems. As several of the proteoceutical compounds are marketed and off-patent, drug repurposing approaches might be within reach. The increased Ca²⁺ release from the sarcoplasmic reticulum (sarcoplasmic reticulum Ca²⁺ leak) in cardiomyocytes might directly activate the NLRP3 inflammasome by facilitating interactions between inflammasome components or might have indirect effects by promoting mitochondrial reactive oxygen species (ROS) production. In addition, increased levels of ROS can activate JUN N-terminal kinase 2 (JNK2) and Ca²⁺/calmodulin-dependent protein kinase IIδ (CaMKIIδ), resulting in excessive abnormal Ca²⁺ signalling. DUB, deubiquitylase; ETC, electron transport chain; MFN2, mitofusin 2; PARPi, PARP inhibitor; RyR2, ryanodine receptor 2; UPS, ubiquitin–proteasome system.