Atrial Cardiomyopathy and Atrial Fibrillation in Different Heart Failure Substrates

Heart failure (HF) is prevalent, affecting more than 64 million people globally, with a prevalence rate of 1–3% in the adult population of industrialised countries and an incidence estimated at 1–20 cases per 1,000 person-years or per 1,000 individuals.¹ Moreover, with a 1-year mortality risk of 15–30%, HF is a predominant cause of death.¹ In addition to considerable morbidity, HF also presents a substantial health and economic burden worldwide.¹ Historically, HF subtypes have been categorised according to left ventricular (LV) ejection fraction (LVEF), using the designations HF with reduced EF (HFrEF; LVEF ≤40%), HF with mid-range ejection fraction (HFmrEF; LVEF 41–49%), and HF with preserved EF (HFpEF; LVEF ≥50%).^2,3 The diagnosis of HFpEF requires the concomitant presence of indicators of LV diastolic dysfunction, typically shown by elevated LV filling pressure and increased natriuretic peptide biomarkers.^2,3

Over the past two decades, the incidence and mortality rates linked to HFrEF have declined due to improved management of HF risk factors and advances in guideline-directed medical therapy, which encompasses angiotensin receptor–neprilysin inhibitors (ARNI), β-blockers, mineralocorticoid receptor antagonists (MRA), and sodium-glucose cotransporter 2 inhibitors (SGLT2I), the four pillars of HF pharmacotherapy. In contrast, the prevalence of HFpEF has been rising and therapeutic successes have been limited compared with HFrEF.^2,3

Over the past two decades, the incidence of AF has significantly increased globally, with its prevalence rising from 33.5 million to 59 million individuals between 2010 and 2019.^4,5 This trend, together with the significant morbidity and mortality associated with AF, has stimulated a large number of studies on advanced early AF detection, screening approaches, preventative measures, and different sophisticated therapies, including catheter ablation (CA), in the comprehensive management of AF.^5–9

Cardiac arrhythmias, regardless of their clinical nature or severity, are prevalent in all types of HF.¹⁰ Consequently, HF and AF maintain a closely linked symbiotic relationship, wherein ‘AF begets HF’ and ‘HF begets AF’. As many as 45% of patients with HF also present with AF, and in hospitalised patients with HF, new-onset AF is an independent predictor of in-hospital mortality (OR 1.53; 95% CI [1.1–2.0]).^11,12 Data from the Framingham Heart Study demonstrate that HF itself increases the risk of AF by 4.5-fold in men and 5.9-fold in women.¹³ Numerous cardiovascular disorders, including ischaemic heart disease, valvular heart disease, and different forms of cardiomyopathy, promote both HF and AF, with specific risk factors such as hypertension (HTN) and diabetes being prevalent.^14–17 More recently, infiltrative diseases including cardiac sarcoidosis, cardiac amyloidosis, and various malignancies together with their chemotherapeutic agents, have also been identified as contributors to AF and HF.^18–25 These conditions, via diverse mechanisms such as ventricular mechanical dysfunction, cardiac chamber dilatation, altered haemodynamics, and dysregulation of the renin–angiotensin–aldosterone system (RAAS) and autonomic function, may facilitate proarrhythmic atrial remodelling, with variable ventricular involvement, a phenomenon termed atrial cardiomyopathy (ACM), or atriopathy.^26,27

In this review, we discuss some of the basic, translational and clinical science data with possible clinical applications that link some of the substrates of HF and ACM.

Atrial Cardiomyopathy: Definition and Staging

A combined heart rhythm societies working group (EHRAS) produced an expert consensus document delineating that ACM encompasses any combination of structural, architectural, contractile or electrophysiological alterations impacting the atria that may lead to clinically relevant manifestations.²⁶ In the absence of a validated histopathological classification of atrial diseases, EHRAS additionally suggested a descriptive classification to reflect the primary underlying pathology in diverse clinical scenarios: class I, principal cardiomyocyte alterations; class II, predominantly fibrotic modifications; class III, combined cardiomyocyte-pathology and fibrosis; and class IV, primarily non-collagen infiltration (with or without cardiomyocyte alterations). Class IV has been further sub-categorised into IVa, IVf, IVi and IVo according to the type of non-collagen infiltration (a, amyloid; f, fatty; i, inflammatory cells; o, other interstitial changes).²⁶

The EHRAS classification suggests that an atrial biopsy is necessary to ascertain histological alterations; however, this notion can be implemented by surrogate methods of multimodality imaging and corroborative data, such as blood-based biomarkers, to indicate the primary underlying pathology. Cardiac amyloidosis can now be identified without the necessity of an atrial biopsy, and class IVa ACM may possess inherent prognostic significance.²⁰ Recently, the Heart Failure Association (HFA) of the European Society of Cardiology (ESC), in its consensus statement, defined ACM as a graded disorder characterised by electrical dysfunction of the atria, accompanied by evidence of mechanical atrial dysfunction, atrial enlargement, and/or atrial fibrosis.²⁷ The consensus statement also established the term ‘atrial failure’, which represents the terminal stage of ACM, marked by advancing structural, electrophysiological and functional alterations.²⁷

Basic to Translational Science Aspects: Cellular and Molecular Mechanisms of ACM

The formation of ACM is a multifaceted process involving a complex interplay of interconnected molecular pathways. Various processes that modulate fibrosis, inflammation, and ion-channel function and expression, interact to alter the healthy atrial myocardium into a substrate conducive to AF, ultimately resulting in morphological and electrical remodelling in ACM. Augmented fibrosis resulting from the excessive accumulation of extracellular matrix proteins is the histological characteristic of ACM.²⁶ Atrial fibrosis establishes physical barriers that hinder electrical transmission, facilitating micro-reentrant circuits and forming a substrate for AF.²⁸ The Transforming Growth Factor β1/Suppressor of Mothers against Decapentaplegic (TGF-β1/Smad) pathway is the principal pro-fibrotic signalling cascade, the activation of which is recognised to facilitate atrial fibrosis in individuals with AF.^29–31 TGF-β1 signalling is initiated by several stimuli, including angiotensin II, mechanical stretch and inflammatory cytokines, which promote the release and activation of TGF-β1. Activated TGF-β1 binds to its receptor on cardiac fibroblasts, initiating the activation of downstream signalling proteins, primarily Smad2 and Smad3. The phosphorylated Smad complex translocates to the nucleus, functioning as a transcription factor. This facilitates the transformation of quiescent fibroblasts into active myofibroblasts. Myofibroblasts are hypersecretory cells that synthesise substantial quantities of extracellular matrix proteins, particularly collagen type I and type III. This results in both interstitial fibrosis (surrounding myocytes) and replacement fibrosis (replacing necrotic myocytes), which stiffens the atria and disrupts electrical signal propagation.^29–31

Inflammation serves as both a catalyst and an outcome of atrial remodelling, establishing a feed-forward loop that exacerbates fibrosis and myocyte injury.^32–34 This is especially evident in HFpEF, when comorbidities induce a systemic inflammatory condition.^35,36 Recent findings indicate that activation of the NLRP3 (nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3) inflammasome serves as a crucial cellular mediator for both AF and HF.^37–39 The NLRP3 inflammasome consists of three components: NLRP3, the adapter protein ASC and the effector pro-caspase-1. This complex is activated by numerous stimuli, including metabolic stress, uric acid crystals and reactive oxygen species. Upon assembly, the inflammasome activates caspase-1, which cleaves pro-interleukin-1β (pro-IL−1β) and pro-interleukin-18 (pro-IL−18) into their active, highly pro-inflammatory forms. These cytokines can subsequently influence both cardiomyocytes and fibroblasts by enhancing fibroblast activation and causing pyroptosis, thus contributing to cell death.^35,36

Alterations in the electrochemical coupling of cardiomyocytes facilitate the electrical remodelling that results in AF.^40,41 The aberrant handling of intracellular calcium (Ca²⁺) is a fundamental catalyst of AF triggers.^42–44 Aberrant Ca²⁺ release from the sarcoplasmic reticulum through leaky ryanodine receptors (RyR2) has been demonstrated to facilitate AF.^45–47 RyR2 undergoes hyperphosphorylation by CaMKII (calcium/calmodulin-dependent protein kinase II) and PKA (protein kinase A) in the context of both AF and HF, resulting in aberrant Ca²⁺ release that triggers spontaneous Ca²⁺ release events, which activate the sodium–calcium exchanger, producing an inward current that may induce delayed afterdepolarisations (DADs).⁴⁸ Should these DADs attain the threshold potential, they may elicit ectopic beats that precipitate AF.⁴⁸ Likewise, additional Ca²⁺-handling proteins such as the sarco/endoplasmic reticulum Ca²⁺ ATPase 2a and L-type Ca²⁺ channel have been implicated in AF pathophysiology. Dysregulated Ca²⁺ signalling results in a reduction of action potential duration and effective refractory period (ERP) due to diminished L-type calcium currents (I_{CaL) and an increase in repolarising potassium (K⁺) currents, including the basal inward-rectifier K⁺ current and small-conductance Ca²⁺ -activated K⁺ current.^49,50 This reduction in atrial ERP promotes AF characterised by multiple, chaotic re-entrant wavelets existing inside the confined anatomical area of the atria.}

During atrial structural remodelling, considerable overexpression of collagen I, collagen III and ST2, a protein belonging to the interleukin 1 receptor family, occurs.⁵¹ In addition, transient receptor potential channel 6 (TRPC6) and calcineurin/nuclear factor of activated T cells (CaN/NFAT) signalling, which in turn is inhibited by the cyclic guanosine monophosphate (cGMP)/protein kinase G axis, may contribute to atrial remodelling.⁵² Both pathways may represent novel therapeutic strategies. Vericiguat is a soluble guanylate cyclase agonist that functions independently of nitric oxide (NO) to enhance the enzyme’s sensitivity to NO and facilitate cGMP signalling.⁵³ In a rabbit model, vericiguat alleviated atrial structural remodelling by reducing myocardial fibrosis, mediated by reductions in the levels of collagen I, collagen III and ST2. In addition, by modulating TRPC6/CaN/NFAT signalling, vericiguat reduced calcium concentrations and ICaL current density, prevented atrial effective refractory period (AERP) reduction and reduced AF induction.⁵³ Thus, vericiguat represents one potential approach for averting ACM development or progression in humans.

Clinical Science Aspects: Diagnosis of Atrial Cardiomyopathy

ACM is closely linked to the onset of AF due to its electrical and structural remodelling. In addition, the associated atrial mechanical dysfunction may contribute to thromboembolism associated with AF. The accurate diagnosis and classification of ACM, particularly in various HF states, continue to be a significant challenge.

In the absence of atrial tissue biopsy, diagnosing ACM may necessitate ECG, multimodality imaging, including echocardiography with speckle-tracking to evaluate left atrial (LA) mechanical dyssynchrony, cardiac MRI, CT, 3D electroanatomic voltage mapping, biomarkers, or genetic testing (Figure 1 and Table 1 ). These investigations, however, each have important limitations.

ECG

The ECG is fundamental for evaluating cardiac remodelling. A multitude of P wave parameters have been identified as indicators of ACM and predictors of AF, including P wave axis, P wave index (PWI, standard deviation of P wave duration across the 12 leads), P wave dispersion (the difference between maximum and minimum P wave durations), P wave amplitude (the height of P waves in different leads), P wave terminal force (PTFV₁, the duration of the terminal negative portion of the P wave in lead V₁ multiplied by its depth), P wave duration (PWD, duration of P wave measured from the initial vertical deviation from the baseline to its return to baseline), and interatrial block (IAB, classified as ‘partial’ for P wave duration >120 ms, or ‘advanced’ for P wave duration >120 ms accompanied by biphasic inferior P wave morphology in the inferior leads).^54,55 Based on the aforementioned ECG characteristics, an ACM P wave score has been established: score 0, absence of any abnormalities; score 1, prolonged PWD; score 2, advanced IAB and biphasic morphology in more than two inferior leads without atrial arrhythmias; score 3, advanced IAB with paroxysmal atrial arrhythmia; and score 4, persistent atrial arrhythmia.²⁷ Patients with a score of 1 or 2 should undergo preventative risk modification for comorbidities, while those with a score of 3 or higher require an evaluation of thromboembolic risk and treatment with anticoagulation or antiarrhythmic strategies based on clinical practice guidelines.²⁷ However, it should be noted that not all components of ACM-related atrial remodelling may be readily identifiable from a 12-lead ECG.

Echocardiography

Although conventional M-mode and 2D echocardiography can evaluate the anteroposterior diameter and volume of the LA, which are recognised markers of atrial contractile mechanics, they offer little utility in assessing regional atrial mechanical dysfunction.

The limitation of the tissue Doppler technique for evaluating atrial function arises from its reliance on the angle of interrogation and the comparatively thin atrial tissue. Speckle-tracking strain echocardiography uses the tracking of acoustic speckles for real-time, quantitative evaluation of regional myocardial deformation and assessment of the three phases of atrial mechanical function. These phases are: a ‘reservoir’ phase during which the atria are being filled with incoming blood while the ventricles are going through systole and isovolumic relaxation; a ‘conduit’ phase during which the atria passively fill the ventricles through a pressure gradient in the early ventricular diastole; and a ‘contractile’ phase when the atria actively contract and fill the ventricles during late ventricular diastole. In the case of abnormal LV relaxation, as in the case of HFpEF, the contributions of the reservoir and contractile functions increase while that of the conduit function decreases as part of atrial mechanical dysfunction in ACM.²⁷. In a clinical study, the time to peak longitudinal strain in opposing walls of the mid-portion of the LA during peak atrial contraction (an indicator of LA mechanical dyssynchrony), predicted AF recurrence with high sensitivity (89%) and specificity (72%).⁵⁶ Speckle-tracking strain echocardiography offers a viable method to examine ACM across different HF substrates.

High-density endocardial contact mapping and LA haemodynamic parameters obtained during ablation correlated linearly with ECG and echocardiography, as well as speckle-tracking strain parameters, thereby underscoring the diagnostic value of ECG and echocardiography for ACM. Furthermore, elevated recurrence rates of AF following ablation in patients with abnormal parameters strongly indicate their prognostic significance.⁵⁷

Cardiac CT and MRI

The evaluation of atrial fibrosis, a central concern in ACM, can be conducted using cardiac CT, including late iodine enhancement; however, it is less efficient than cardiac MRI (CMR), particularly when using late gadolinium enhancement (LGE), which also provides additional prognostic information.^58–60 However, the limited resolution of LGE-CMR makes accurate assessment of fibrosis in the thin-walled atria challenging. The Utah scoring system categorises stages of atrial fibrosis according to the percentage of LA wall enhancement relative to the total LA wall surface: stage I, defined as <10%; stage II, ≥10–<20%; stage III, ≥20–<30%; and stage IV, ≥30%. This system was used in the DECAAF study involving patients with AF undergoing CA.^59,60 In DECAAF, a progressively elevated occurrence of recurrent arrhythmia after AF ablation was observed with advancing fibrosis staging: 51.1% (95% CI [32.8–72.2%]) for stage 4 compared with 15.3% (95% CI [7.6–29.6%]) for stage 1 fibrosis by day 325.⁶⁰ However, targeting these fibrotic areas using CA did not improve time to atrial arrhythmia recurrence in patients with persistent AF and resulted in more adverse safety events, making their clinical relevance uncertain.⁶⁰

Voltage Mapping

Multiple thresholds of unipolar and bipolar voltages have been used in clinical practice to delineate fibrotic regions based on invasive mapping data. In patients with idiopathic AF, the condition is seen as an arrhythmic expression of ‘fibrotic’ ACM.⁶¹ Traditionally, healthy regions are characterised by voltages over 2.5 mV, while fibrosis or scar is indicated by voltages below 0.5 mV. Severe fibrosis or regions of electric silence can often be defined by the lack of detectable atrial activity at a bipolar voltage of less than 0.1 mV.⁶² Isolated although significant fibrosis devoid of amyloidosis or adipose deposition on histological analysis, alongside sinus node involvement presenting as atrial standstill, represents a variant of ACM, attributed to a mutation in the Natriuretic Peptide Precursor A (NPPA) gene.^62,63 In particular patient cohorts with cardiac implantable electronic devices, a temporal reduction in the amplitudes of atrial electrograms (AEGMs), characterised by a significant fall in AEGM voltage, may signify the onset of subclinical ACM, hence increasing the risk of AF.⁶⁴

Biomarkers

Blood-based biomarkers include the inflammatory marker C-reactive protein (CRP), atrial natriuretic peptide (ANP) primarily synthesised by the atria, as well as brain natriuretic peptide (BNP) and N-terminal proBNP (NT-proBNP), which indicate congestive HF and myocardial injury. Among these biomarkers, NT-proBNP is predominantly used in clinical practice for the diagnosis, monitoring and prognosis of HF and AF. In the large ARCADIA trial involving patients with ACM absent of AF, ACM was characterised by a P wave terminal force >5,000 μV × ms in ECG lead V1, a serum NT-proBNP level >250 pg/ml, or an LA diameter index ≥3 cm/m² on echocardiogram.⁶⁵ This definition of ACM had a moderately predictive c-statistic of 0.82 (95% CI [0.79–0.85]) for subsequent AF development.⁶⁶ A comprehensive meta-analysis of 16 cohorts with 136,089 participants and with 8,017 incident AF cases showed a robust correlation between NT-proBNP level and an elevated risk of AF (upper versus lower quartile, RR 3.84; 95% CI [3.03–4.87]; per SD increment, RR 1.70; 95% CI [1.54–1.88]), with more pronounced associations in older populations.⁶⁷ Consequently, NT-proBNP may have significant consequences for population-based screening.⁶⁷ The SAFAS study found that CRP >3 mg/l and age were independently correlated with ACM, with ORs of 2.60 (95% CI [1.30–5.21]) and 1.07 (95% CI [1.04–1.10]), respectively.⁶⁸ Nonetheless, upon adjusting for the LA volume index, ACM as defined by the ARCADIA trial was not independently correlated with AF detection post-stroke in the SAFAS study.⁶⁸

Recently, a sub-study of the EAST-AFNET 4 trial that assessed 14 biomarkers reflecting AF-related cardiovascular disease processes showed an independent association of three biomarkers with rhythm status: higher baseline angiopoietin 2 (OR 0.76; 95% CI [0.65–0.89]), bone morphogenetic protein 10 (OR 0.83; 95% CI [0.71–0.97]) and NT-proBNP (OR 0.73; 95% CI [0.60–0.88]).⁶⁹

Taken together, although numerous possible biomarker indicators for ACM exist, there is no agreement on the most effective parameters or appropriate cut-offs of multiple biomarkers to accurately identify clinically significant levels of ACM. Accordingly, neither the EHRAS nor the ESC/HFA consensus statements delineate biomarkers or diagnostic criteria for the identification of ACM.^26,27

Atrial Cardiomyopathy, AF and Heart Failure Substrates

Multiple experimental animal models and clinical data have demonstrated a close interdependent symbiotic and bidirectional relationship between HF and AF, indicating that ‘AF begets HF’ and ‘HF begets AF’. Investigations in fundamental, translational and clinical sciences advance our comprehension of disease manifestation in people and create prospects for therapeutic interventions.⁷⁰ ACM may significantly contribute to the detrimental cycle of AF and HF, influenced by various causes, including HF (Figure 2 ).

In a goat model of atrial pacing, Wijffels et al. demonstrated a marked shortening of atrial ERP, inversed physiological rate adaptation, as well as heightened inducibility and persistence of AF, with complete reversibility of all AF-related alterations within 1 week of sinus rhythm.⁷¹ Subsequent experiments demonstrated that the electrical remodelling induced by AF was not influenced by alterations in autonomic tone (via atropine or propranolol infusion), ischaemia, stretch (volume overload) or atrial natriuretic factor, but instead was a direct response to the elevated rate of electrical activation.⁷² These investigations proved the principle that ‘AF begets AF’ by promoting a rate-related ACM. The connection between ACM and HF was first characterised in detail by Li et al.⁷³ In their canine model of HF induced by rapid ventricular pacing, there was a significant increase in conduction heterogeneity during atrial pacing, in contrast to the control group and a group that underwent only rapid atrial pacing for AF induction. Moreover, histological analysis of the isolated atria from these dogs demonstrated significantly more interstitial fibrosis in HF animals versus the control group and the dogs subjected to only rapid atrial pacing for AF induction.⁷³ In agreement, Molina et al. demonstrated increased remodelling in atrial samples from patients with HFrEF compared with those with normal LV function, including elevated expression of profibrotic markers (collagen-1a, fibronectin, periostin), irrespective of the presence of AF.⁷⁴ Moreover, HFrEF patients had distinct proarrhythmic atrial electrical remodelling, characterised by proarrhythmic atrial Ca²⁺ handling abnormalities due to elevated Ca²⁺ influx from the sarcoplasmic reticulum and heightened RyR2 activity.⁷⁴ Thus, HF generates a markedly susceptible ACM characterised by distinct degrees of profibrotic, electrical and Ca²⁺-handling atrial remodelling, differing from that resulting only from AF. Moreover, the atrial tachyarrhythmia and rapid ventricular response during AF produce distinct atrial remodelling; with their combined effects producing an even more pronounced ACM, as shown by studies in a dog model of atrial tachypacing with or without atrioventricular block to limit ventricular rate.⁷⁵

Due to the underlying ACM, AF is frequently observed in patients with HFpEF. The importance of AF in HFpEF is reflected in the H₂FPEF (heavy, 2 or more hypertensive drugs, atrial fibrillation, pulmonary hypertension, elder age > 60 years, elevated filling pressures) scoring system for HFpEF. AF, with the highest specificity of 96% for HFpEF, was allocated the maximum 3 points, while obesity received 2 points, and each of the other variables was assigned 1 point, producing a total of 9 points.⁷⁶ The HFA of the ESC emphasises the importance of AF in their stepwise diagnostic procedure, given that it is a strong predictor of underlying HFpEF.⁷⁷

Risk Factors

Several risk factors common to both ACM and HF are reviewed in brief below (Table 2 ).

Advanced Age

This is the single most important determinant of the risk of AF. Mehdizadeh et al. demonstrated AF susceptibility with programmed electrical stimulation with slower atrial conduction in aged rats, and histopathological evidence of marked atrial fibrosis compared with control animals.⁷⁸ Furthermore, with previously validated senolytic therapy of dasatinib and quercetin, AF induction was reduced, and markers of cellular senescence and atrial fibrosis were suppressed in rats with MI.⁷⁸ Modulating cell senescence might therefore provide a basis for novel therapeutic approaches to AF. Leveraging a proteomic approach, Salman et al. identified two senescence-associated secretory phenotype (SASP) factors, composed of proteins released by senescent cells in humans associated with older age, lower estimated glomerular filtration rate, and more advanced New York Heart Association class for HF, and significant risk of death independent of NT-proBNP levels.⁷⁹ Altering cell senescence may thus also be potentially targeted for HF therapy. In patients with AF significant correlation has been demonstrated between advanced age with elevated LA pressure and stiffness, diminished LA reservoir strain, augmented LA volumes, and high NT-proBNP levels.⁸⁰

Hypertension and Diabetes

HTN and diabetes are recognised as causative factors of AF.^15–17 HTN induces hypertrophy of the ventricular muscle, atrial dilatation, increased intracardiac pressures, mechanical dysfunction of both atria and ventricles, aberrant expression of ion channels, dysregulation of the RAAS, and autonomic dysfunction.¹⁵ In individuals with cardiac implantable electronic devices who develop AF over time, the reduction in AEGM amplitudes from baseline is less pronounced in those with HTN compared with those without, indicating that hypertensive patients have greater scarring from advancing ACM before AF development.⁶⁴ Diabetes, even in conjunction with HTN, independently induces LA enlargement and aberrant global strain, as shown using speckle-tracking echocardiography.⁸¹ The coexistence of HTN and diabetes is associated with further deterioration of LA reservoir and conduit functioning.⁸²

Hypertrophic Cardiomyopathy

This is a prevalent genetic hereditary cardiac disorder characterised by varied and intricate phenotypic manifestations, and it is frequently linked to AF, with asymptomatic AF potentially occurring in up to 50% of patients.^83,84 The onset of AF can be anticipated by examining LA enlargement and dysfunction, which serve as a predisposing substrate, indicative of the presence of ACM.⁸³ A study using cardiac MRI with LGE imaging in hypertrophic cardiomyopathy (HCM) patients with and without paroxysmal AF found that all participants had LGE evidence of fibrosis in the LA posterior wall. Patients with paroxysmal AF had increased LA volume, reduced LA EF, diminished global peak longitudinal LA strain, and elevated levels of LA-LGE, providing further support for the association of ACM and its role in the onset of AF in HCM.⁸⁵

Sarcoidosis

This is a systemic granulomatous disorder with both clinical and subclinical cardiac involvement, a unique form of ACM. Patients with clinically evident cardiac sarcoidosis face a 30% cumulative risk of developing AF within 5 years of diagnosis.⁸⁶ In AF-naive patients with cardiac sarcoidosis, ¹⁸F-fluorodexoyglucose PET (¹⁸F-FDG PET) scans show atrial uptake, indicative of atrial inflammation, in one-third of patients, alongside raised cardiac troponins and NT-proBNP levels.⁸⁶ An enlarged LA on CMR, coupled with atrial ¹⁸F-FDG uptake on PET, reflecting the presence of an ACM, independently forecasts AF.⁸⁶

Cardiac Amyloidosis

This is defined by the myocardial accumulation of amyloid fibrils derived from monoclonal immunoglobulin light chains (L) (AL) or misfolded transthyretin protein (TTR) (ATTRv [hereditary] and ATTRwt [wild-type, acquired]), and is a major contributor to restrictive cardiomyopathy.^19–22 Cardiac amyloidosis can now be identified without atrial biopsy, and class IVa ACM may have inherent prognostic significance.²⁰ The cumulative incidence of AF among those without AF at diagnosis was 16% at 1 year, 25% at 2 years and 45% at 3 years following the diagnosis of ATTRwt.²¹ Inflammation and related signalling pathways, coupled with significant fibrosis from amyloid-laden atrial fibroblasts, are seen as contributors to ACM.⁸⁷ Atrial dysfunction in cardiac amyloidosis is characterised by diminished atrial EF, interatrial block and anomalies in atrial strain, all of which forecast the occurrence of AF.⁸⁸

Cancers and Chemotherapeutic Drugs

These are increasingly recognised as contributors to ACM, AF and HF by many mechanisms, including activation of the NLR3 inflammasome, increased CRP and interleukins, and the promotion of inflammation and fibrosis.^23–25,89 In the ARCADIA trial, of the 3,745 patients with ACM and cryptogenic stroke, 13.5% were diagnosed with a form of cancer.⁶⁶ In the ARCADIA trial’s diagnostic criteria for ACM, a history of cancer correlated with elevated median NT-proBNP and LA diameter index, although median P wave terminal force in ECG lead V₁ remained comparable.⁹⁰ While doxorubicin is a well-known chemotherapeutic drug associated with cardiotoxicities, more targeted therapies such as kinase inhibitors have also been associated with increased incidence of AF in patients.²⁴

Atrial Cardiomyopathy, AF and Management

Medical therapy with β-blockers, ARNI, MRA and SGLT2I has resulted in marked improvement in HF-related mortality and morbidity over the last two decades.^2,3 Similarly, significant progress made in both the pharmacological and non-pharmacological arenas over the last two decades has led to a shift in approach to management of AF with more emphasis on the rhythm control strategy and early intervention.^6–8

Benefits of early intervention with a rhythm control strategy for AF were highlighted by the findings of EAST-AFNET 4.⁹¹ That randomised trial, which included CA along with anti-arrhythmic drugs for early rhythm control therapy of AF, demonstrated a lower risk of death from cardiovascular causes, stroke, or hospitalisation for HF or acute coronary syndrome than usual care over a follow-up time of more than 5 years.⁹¹ These results were replicated in a pooled analysis of four observational real-world studies that fulfilled the inclusion criteria of EAST-AFNET 4 involving 130,970 patients with AF.⁹² The effectiveness of early rhythm control is mediated by the presence of sinus rhythm at 12 months in the EAST-AFNET 4 trial.⁹³ In patients not in sinus rhythm at 12 months, early rhythm control did not reduce future cardiovascular outcomes (HR 0.94; 95% CI [0.65–1.67]).⁹³ This important observation may be explained on the basis of the degree of underlying ACM influenced by AF and its triggers.

Pertaining to CA of AF, while electrical pulmonary vein (PV) isolation remains the mainstay for all forms of AF, ablation strategies for non-paroxysmal and longer persistent AF often involve additional lesions including linear ablation across cavotricuspid isthmus, LA posterior wall isolation, and adjunctive ablation of extra PV sites including the superior vena cava.⁹⁴ Such additional ablation beyond PV isolation, in essence, reflects more extensive ACM. While CA of AF improves mortality and morbidity from AF in patients with all ranges of HF, outcome data in various subgroups of HF vary considerably. Data from a large registry from Japan showed a threefold higher risk of a composite of all-cause death, HF hospitalisation, and stroke or systemic embolism after AF ablation in patients with HFrEF compared with patients with HFmrEF or HFpEF.⁹⁵ However, well-designed randomised control trials, including CASTLE-AF and CASTLE-HTX, showed a beneficial role of CA of AF in patients with severe and end-stage HFrEF needing advanced therapies and cardiac transplant evaluation.^96,97

On the other end of the HF spectrum, that is, HFpEF, CA of AF also reduces AF-related mortality and morbidity compared with medical management and anti-arrhythmic drugs.⁹⁸ In patients with HFpEF, CA of AF has been reported to result in mechanical remodelling with lower filling pressures, improvement in functional valvular regurgitation, greater peak cardiac output, and improved functional capacity.⁹⁸ Such mechanical improvement indices are also accompanied by improvement in the biomarkers (i.e. lower natriuretic peptides).⁹⁸ As such, improvements in cardiac mechanical function and atrial electrical reverse remodelling observed with CA of AF over a wide range of HF suggest that effective rhythm control can not only prevent progression of AF to more persistent forms but also reverse AF-induced atrial remodelling and ACM. Such interconnectedness between ACM, AF and HF further indicates the involvement of ACM in the complexity of management of AF and HF.

From the preventative aspect of ACM, given that there is no effective preventative therapy presently available that may halt and reverse atrial fibrosis and ACM before manifestation of AF, the current management is focused first on not only early rhythm control for AF but also early detection of AF with several mobile health approaches.^49–52,99 Of the pharmacological agents, vericiguat used in HF may potentially play a preventative role.

The VICTORIA study, a Phase III, randomised, double-blind, placebo-controlled trial involving 5,050 patients with chronic HFrEF, found that the incidence of death from cardiovascular causes or hospitalisation for HF was lower in the vericiguat group compared with the placebo group (HR 0.90; 95% CI [0.82–0.98]) over a median duration of 10.8 months.¹⁰⁰ A sub-study analysis of the VICTORIA study indicated that AF was observed in nearly half of the study population; a baseline history of AF was associated with an elevated risk of cardiovascular mortality. Given the evidence of diminished myocardial fibrosis from a rabbit model basic science study, and the detrimental effects of AF on cardiovascular mortality and HF morbidity shown by the VICTORIA study, a clinical trial suggests that more such basic and translational research is needed to validate the role of vericiguat in the prevention and treatment of AF.¹⁰¹

Future Perspectives

As new details from basic to translational science are emerging, many newer strategies are being explored to halt and even reverse the atrial fibrotic changes associated with ACM. Vericiguat, a drug already in clinical practice to treat HFrEF, has been shown to reduce electrical and structural remodelling in a rabbit model of AF.^53,100,101 Modulating cell senescence might provide a basis for novel therapeutic approaches to AF.^78,79 Innovative strategies to prevent AF in the challenging clinical situation of HFpEF, are being explored by addressing the electrophysiological and fibrotic changes associated with this condition. In a rat model of HFpEF, animals on a high-salt diet for 7 weeks demonstrated increased AF inducibility, prolonged action potential duration, reduced conduction velocity, and fibrotic LA remodelling.¹⁰² Treatment with immortalised cardiosphere-derived extracellular vesicles ameliorated detrimental electrical remodelling, restoring action potential duration to baseline levels, reorganising connexin 43 and decreasing AF inducibility, as well as fibrosis, inflammation and oxidative stress, without affecting blood pressure and diastolic function.¹⁰²

Conclusion

AF and HF are two interdependent conditions that have symbiotic and bidirectional relationships. ACM involves structural, architectural, contractile or electrophysiological alterations in the atria, and results from diverse mechanisms stemming from risk factors and comorbidities. ACM may not only be an initiator of AF, it may also be a significant contributor to the detrimental cycle of AF and HF by perpetuating AF, influenced by various causes, including HF. While significant knowledge gaps remain, our understanding of ACM and the ability to detect its presence non-invasively has improved in recent years. Application of this knowledge may help improve clinical management of AF related to different substrates of HF and, in turn, help to reduce morbidity and mortality associated with both AF and HF.