Atrial Remodelling in Heart Failure: Recent Developments and Relevance for Heart Failure with Preserved Ejection Fraction

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Abstract

As specialized compartments of the heart, the atria feature unique mechanical and structural properties that differ considerably from those of the ventricular myocardium. Beyond their contribution to cardiac output as a reservoir, conduit, and booster pump at different phases of the cardiac cycle, the atria determine heart rhythm, regularity, and rate (chronotropy). They also function as mechanical sensors and exert relevant endocrine activity (e.g. natriuretic peptides). Atrial remodelling is often observed in association with ventricular remodelling in heart failure (HF) but by itself adds to the complexity of the disease. In a recent consensus statement, atrial remodelling has been defined as ‘any complex of structural, architectural, contractile or electrophysiological changes affecting the atria with the potential to produce clinically-relevant manifestations’ and giving rise to an atrial cardiomyopathy.1 The authors have further proposed a novel classification to differentiate histological changes European Heart Rhythm Association (EHRA I–IV). In clinical settings, characterization and understanding of atrial remodelling in the context of HF and co-morbidities currently remain dependent on cardiac imaging-derived read-outs, as outlined later. Left atrial (LA) enlargement (LAE) is frequently used synonymously with atrial remodelling. However, also in HF, hypertrophy and fibrosis of the atrial wall, atrial fibrillation (AF; suggesting electrical remodelling), and atrial contractile dysfunction all may occur in the absence of LAE,2-5 indicating the necessity for a more comprehensive assessment of the atrial phenotype. Individual electrocardiogram (ECG) criteria (P-wave morphology) are not a reliable measure for LAE and right atrial (LA) enlargement (RAE) but may serve as a screening tool.6 LA size or volume by echocardiography, corrected for body size [i.e. LA volume index (LAVI)] are commonly used to describe LAE, with 2D echocardiography underestimating volumes as measured by 3D echocardiography, cardiac computed tomography, or cardiac magnetic resonance.7 Volumes relate to the reservoir function of the LA. Neither LA size nor LAVI is gender dependent, yet they increase with age.8 Measurement of atrial volumes additionally allows to calculate atrial contractility (i.e. LA emptying fraction and LA expansion index), but without differentiating between passive (conduit and reservoir) and active (booster pump) function. Atrial strain and atrial strain rate based on speckle tracking echocardiography have been recently implemented for the differentiation of LA reservoir and conduit function. Methodically more challenging, LA strain rate allows to measure active LA contraction (i.e. booster pump).9 In experimental settings, in analogy to the ventricle, pressure-volume catheters have been used to quantify LA stiffness and atrioventricular coupling.10 Cardiac magnetic resonance late gadolinium enhancement regions are used to characterize atrial fibrous remodelling.11 Magnetic resonance imaging (MRI) T1 mapping allows to assess the degree of fibrosis in ventricular remodelling; however, it has failed to convincingly do so in the LA.12 Finally, in selected patients, electro-anatomical mapping allows the quantification and localization of low-voltage areas to assess an additional local functional parameter of atrial remodelling. However, to date, the exact relation between the extent and severity of low-voltage regions and the degree of LA fibrosis/remodelling needs further clarification. Biomarkers have been used as a surrogate for atrial remodelling, reflecting mechanical stress, fibrosis, or inflammation; but individual markers to date lack atrial specificity.13-15 Left atrial enlargement as a sign of atrial remodelling is observed in about half of the patients with stable chronic HF with large variations between studies, likely reflecting heterogeneous disease aetiologies and stages (Table 1). In HF with reduced ejection fraction (HFrEF), LA emptying fraction has been shown to be significantly decreased.23 LA emptying fraction and LA strain are also reduced in HF with preserved ejection fraction (HFpEF) in clinical studies9, 24, 25 and randomized controlled trials [e.g. Effect of Phosphodiesterase-5 Inhibition on Exercise Capacity and Clinical Status in Heart Failure with Preserved Ejection Fraction (RELAX trial) substudy26 and Candesartan in Heart failure - Assessment of moRtality and Morbidity (CHARM trial)-preserved]. Regional differences in LA strain may also be an early sign of electrical remodelling leading to AF.27 In HFrEF, LA fibrosis has been reported to range from 13% to 27% of the LA area as compared with 1.4% in control.28 In HFpEF, LA fibrosis as assessed using histology and MRI imaging was shown to be 30.1 ± 4.6% of the LA area (n = 18 HFpEF patients).29 However, aetiology-dependent differences in prevalence of atrial fibrosis in HF have not been systematically studied. Signs of LA electrical remodelling in HF (HFrEF) include conduction abnormalities (as reflected by P-wave morphology in ECG), prolonged refractoriness (in contrast to AF-induced remodelling), and sinus node dysfunction.30 Incidental AF serves as a marker of electrophysiological remodelling. The prevalence of AF in HF has been reported from 5% in New York Heart Association (NYHA) I to 25–50% in NYHA III/IV,31, 32 with higher prevalence in HFpEF vs. HFrEF (see subsequent discussion). Left atrial volume index is strongly associated with cardiovascular disease33 and a predictor of new HF irrespective of systolic left ventricular (LV) function.18, 34, 35 LAE is also an independent predictor for the development of early [American Heart Association (AHA) stage B] non-ischaemic HF.36 With regard to secondary events, LAVI correlates with a higher incidence of congestive HF recurrence37 and sudden cardiac death.38 LA size is used as an independent marker of risk in several HF risk scores, such as the Coronary Artery Revascularization in Diabetes (CARDIA) risk score [based on the Framingham 10 year global cardiovascular (CV) Framingham risk score (FRS)39], the Redin-SCORE,40 and the MUerte Subita en Insuficiencia Cardiaca (MUSIC) Risk score. Indexed LA diameter is increasingly being used as predictor of long-term outcomes in patients evaluated for aortic valve replacement, and its assessment may guide patient management.41 LA function (at rest) is a predictor of exercise capacitance in HFrEF,42 and LA contractile dysfunction has been shown to be associated with a higher risk of HF hospitalization independent of potential clinical confounders.43 Atrial remodelling is of particular interest in patients with HFpEF,44 where it has been associated with increased mortality45 and has been recognized as a hallmark feature of the disease.44 Melenovsky et al. have shown that preserved LA function was significantly associated with lower mortality in HFpEF.46 Moreover, in HFpEF, impaired LA conduit function is associated with exercise intolerance, independent of LV stiffness and relaxation.47 On the other hand, in the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial, contractile LA dysfunction (reduced peak LA strain) in HFpEF was not associated with a higher risk of HF hospitalizations when also accounting for LV systolic and diastolic function.43 This is explained by the robust interrelation between peak LA strain, LV global longitudinal strain, and E/e′.25 The role of atrial contraction in different aetiologies and stages of HF is quantitatively not very well explored. Modelling suggests that a timely atrial contraction significantly improves LV stroke work.48 In a recent report from a cohort of HF patients (51% HFpEF), atrial remodelling in HFrEF was characterized by increased LA volumes and lower contraction amplitude (pulsatility) as compared with HFpEF, whereas HFpEF was associated with higher LA pressures and increased LA wall stiffness.46 Vice versa, in patients with HFrEF receiving cardiac synchronization therapy (CRT), a reduction in LA strain induced by atrial pacing resulted in a significant reduction in global LV strain.49 Atrial contribution to ventricular filling can decline with the progression of HF, as increased atrial mechanical load leads to atrial dysfunction.50 HFpEF is characterized by impaired LV diastolic filling, and LA ejection volume contributes to LV filling. Clearly, more work is needed to dissect the relative contribution of atrial dysfunction to impaired LV filling in different HFpEF phenotypes. Atrial fibrillation is common HF, with reported prevalences of 21–65% in HFpEF, which is higher than what has been reported in HFrEF (<10–50%).51 AF is often linked to the presence of fibrotic remodelling, as fibrosis creates conduction obstacles that perpetuate the genesis of re-entry circuits.52 Fibrosis is especially prevalent in atrial remodelling in patients with HFpEF.29 In the RELAX trial, HFpEF patients with AF (37%) had more advanced disease and a significantly reduced exercise capacitance, which might be also related to the development of tachy-cardiomyopathy.53 Likewise, others reported that AF is independently associated with greater exertional intolerance, natriuretic peptide elevation, and left anterior descending artery remodelling in HFpEF.53, 54 Vice versa, in Framingham Heart Study participants, pre-existing AF tended to be more strongly associated with new-onset HFpEF (hazard ratio 2.34) than did HFrEF (hazard ratio 1.32), highlighting the relevance of atrial function in HFpEF.55 Physiologically, endocrine function of the heart is mainly located to the atria.56 Natriuretic peptides [e.g. atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP)] and vasopressin are secreted by atrial myocytes (and possibly fibroblasts) in response to acute stretch and neurohumoral activation (angiotensin, endothelin, and catecholamines)57, 58 and have a pivotal role in volume regulation.56 In HF, ANP and BNP production increases in the atria, and BNP is also produced in the ventricle.59 As reviewed elsewhere, atrial myocyte ANP secretion is impaired in HFrEF.60 Fibrotic atrial remodelling may contribute to the reduced amount of natriuretic peptides secreted from the atria.61 Interestingly, the increase of natriuretic peptides is less pronounced in HFpEF than in HFrEF.62 Increased BNP clearance by adipose tissue (in HFpEF) and decreased BNP production due to ‘cardiac cachexia’ have been proposed as mechanisms,62 but an impaired production or secretion in the atrial (or ventricular) myocardium in HFpEF remains to be explored.63 Beta-blockade with metoprolol increases plasma BNP levels in HFrEF.64 BNP given subcutaneously can improve the haemodynamic response to acute volume load in patients with HFpEF,65 corroborating a relative deficit of natriuretic peptides. Likewise, increasing natriuretic peptide availability by neprilysin inhibition with simultaneous angiotensin II receptor blockade and neprilysin inhibition has been shown to be beneficial (see below ‘Atrial Reverse Remodeling with Therapy’). The role of atrial remodelling in the disproportionate levels of natriuretic peptides and their precursors in response to chronic and acute stress in particular in HFpEF warrants further research. Chronotropic incompetence is a common and likely undervalued cause of reduced exercise capacitance in HFrEF and HFpEF.66 Borlaugh et al. demonstrated that in particular in HFpEF patients, an attenuated increase in heart rate rather than inappropriate stroke volume was the cause of a reduced cardiac output reserve during exercise.67 While in patients with HFrEF, down-regulation of myocardial beta-adrenergic receptors and sinus node remodelling and dysfunction have been demonstrated as potential causes of chronotropic incompetence,68 its pathophysiology in HFpEF has not yet been studied in detail. As published recently in this journal, 3D echocardiography-based assessment of stroke volume and heart rate during exercise may allow differentiating patients with reduced chronotropic reserve from others in a heterogeneous HFpEF population.69 Left atrial enlargement has been shown to predict the risk for stroke even when adjusted for the prevalence of AF.70 The Asymptomatic Atrial Fibrillation and Stroke Evaluation in Pacemaker Patients and the Atrial Fibrillation Reduction Atrial Pacing Trial (ASSERT) and Anticoagulation Guided by Remote Rhythm Monitoring in Patients With Implanted Cardioverter-Defibrillator and Resynchronization Devices (IMPACT) trials also suggested that stroke risk is increased in remodelled atria even if patients are in sinus rhythm. Vice versa, hypercoagulability itself may promote atrial remodelling by activation of pro-fibrotic signalling molecules like TGF-beta increasing thrombin. Inhibition of thrombin has been associated with attenuated atrial remodelling.71 Similar to the LA, RA size is strongly correlated to right ventricular end-diastolic pressure and is thereby linked to pulmonary artery hypertension and right HF.72 RA dysfunction and the severity of right HF can be assessed using RA longitudinal strain by speckle tracking echocardiography.73 As a biomarker, an RA larger than LA is associated with increased mortality in elderly HF patients,22 and systolic blood pressure to RA pressure ratio is a marker that identifies a spectrum of complications after hospitalization of patients with decompensated systolic HF.74 In HF, increased pressure or volume load in the ventricle is a strong trigger for atrial enlargement and remodelling. In chronic conditions, LA volume and strain correlate with LV end-diastolic pressures irrespective of EF.75, 76 Mechanical stress induces stretching and stiffening of the atria.77 Atrial fibrosis is perpetuated by atrial distention78-80 and related to activation of pro-fibrotic signalling cascades and apoptosis/necrosis of cells as well as activation of a foetal gene programme.81 This in turn negatively impacts atrial reservoir function (through stiffening) and active atrial kick (through over-stretching and Frank–Starling mechanism). Increased ventricular pressures may contribute to remodelling of the LA (as in arterial hypertension) or the RA (as in pulmonary hypertension secondary to chronic pulmonary disease). Mechanical load is a strong confounder in investigating other load-independent mechanisms for atrial remodelling in HF and arguably may diminish the role of other co-morbidities in shaping atrial remodelling in later HF stages. On the other hand, even in advanced HFrEF, the impact of reducing mechanical load (e.g. by CRT) on myocardial remodelling is lower in the presence of other co-morbidities, suggesting (but not proving) load-independent effects of relevant co-morbidities on atrial remodelling in HF.82 In early-stage hypertensive HFpEF, LA cardiomyocyte hypertrophy, titin hyperphosphorylation, and microvascular dysfunction occur in association with increased systolic and diastolic LA chamber stiffness, impaired atrioventricular coupling and decreased LV stroke volume.10 Neuroendocrine activation triggered by low cardiac output is a hallmark of HFrEF but likely also plays a role in HFpEF.83, 84 Systemic and myocardial levels of catecholamines, aldosterone, and angiotensin are increased in HF and perpetuate atrial remodelling owing to their prohypertropic and pro-fibrotic effects.85,86 In HFpEF, chronic kidney disease (CKD) is highly prevalent with the majority of patients suffering mild to moderate renal impairment.87 Others have reported similar prevalence of CKD in HFpEF and HFrEF.88 CKD-associated renal arterial hypertension has been identified as a trigger of maladaptive LA remodelling in a model of early-stage HFpEF.10 The prevalence of diabetes is similar in HFpEF and HFrEF88 and independently associated with LAE.89 A higher prevalence of obesity has been reported in HFpEF (51%) vs. HFrEF (37%88). LA enlargement correlates with epicardial fat thickness90 and visceral fat mass.91 In patients undergoing AF ablation (n = 236), low-voltage areas suggestive of atrial fibrosis were much more common (46% of patients) in patients with metabolic syndrome than in those without (8%92). The pathomechanisms of atrial remodelling in metabolic syndrome are unclear and, as in ventricular metabolic remodelling, may be multifactorial including inflammation, oxidative stress, pro-fibrotic pathways, and others.93 Atrial fibrillation in HF is a result of atrial remodelling (Figure 1). Mechanical stretch facilitates arrhythmia initiation94 and structural changes (e.g. fibrosis), thus providing the substrate for sustained arrhythmias.95 At the same time, AF itself is a strong promoter of tachyarrhythmia-induced atrial cardiomyopathy. Electrical atrial remodelling during AF, however, differs from HF-related atrial remodelling.7 The current understanding of the pathomechanisms underlying AF-induced remodelling has been extensively reviewed.1, 52 The aforementioned common risk factors and other cardiovascular risk factors, including age and vascular disease, may synergistically promote atrial remodelling. Indeed, the CHA2DS2-VASc risk score established to evaluate stroke risk in AF also reflects the risk of incidental AF96 and correlates with LA enlargement.97 Reverse atrial remodelling in patients with HF or at risk of HF has been shown to improve clinical endpoints like the incidence of AF98 and is independently associated with decreased mortality.99 Weight reduction with intensified risk factor management induces reverse atrial remodelling and reduces AF prevalence.100 Exercise training was also associated with a reduction in LA volume in HFpEF.101 Several classes of classical HFrEF drugs [e.g. angiotensin-converting enzyme (ACE) inhibitors, angiotensin-receptor blockers, and spironolactone] have been associated with a reduction in LAE in patients with structural heart disease102 in part related to their blood-pressure-lowering effect.103 Treatment with ACE inhibitors and angiotensin receptor blockers also positively affects contractile function of the LA in HF.104, 105 In the absence of HF, quinapril effectively reduced LA volume independent of its effects on systolic blood pressure, suggesting direct effects on the atrial myocardium. Similarly, increasing the levels of natriuretic peptides, e.g. with neprilysin inhibition, has had beneficial effects on LA size in HFrEF106 and in HFpEF [Prospective comparison of ARNI with ARB on Management Of heart failUre with preserved ejectioN fracTion (PARAMOUNT trial107)] independent of the drug's blood-pressure-lowering effects.108 Lowering heart rate could improve atrial contribution to LV filling in Interestingly, recent from the to Treatment in Patients with Heart Failure trial) that heart rate has beneficial effects in HFpEF independent of atrial contribution (i.e. sinus vs. Cardiac synchronization therapy was associated with a significantly increased LA strain, suggestive of reverse function atrial Of electrical atrial activation and contraction (as to significantly improves cardiac output with AF as a result of atrial remodelling in HF has been proposed with the of electrical remodelling induced by AF and contribution of the LA to ventricular filling in sinus Indeed, and AF ablation was associated with reverse atrial remodelling in and also of atrial function may contribute to the of the vs. Patients With and LV where AF ablation significantly decreased the of mortality and hospitalization for In in the of Atrial Fibrillation in Heart Failure (n = at the an early therapy of and ACE inhibitors or angiotensin receptor was to therapy in sinus in HF patients with AF is currently mainly in the presence of In in the absence of AF, with is not based on randomized risk factors such as the CHA2DS2-VASc or may HF patients at increased risk for but further are needed to the for patient and evaluate the novel Atrial function and remodelling are strongly by LV and atrial size may even serve as of LV As outlined however, suggests that atrial remodelling independently adds to the complexity of the The role of different co-morbidities for atrial remodelling at later stages of HF in the context of increased mechanical load needs to be The recently proposed classification for atrial is a in an aetiology-dependent and understanding of atrial remodelling as a for novel clinical mainly MRI in on fibrosis, inflammation, and for a characterization of the atrial In a of established during HF and associated with atrial remodelling might contribute to the development of risk e.g. and have been shown to be markers of atrial remodelling and to correlate with the extent of LA recently has been suggested as a for increased fibrosis, cardiomyocyte and in are also associated with an increased risk of in Framingham in HF risk was increased by for atrial remodelling associated with HF have been in thrombin inhibition has been shown to HF-related and atrial remodelling in the trials for Treatment of Atrial fibrillation in patients with heart failure and an and a of evaluate the role of AF ablation on clinical endpoints in different HF and it is to that reverse atrial remodelling be a for a sustained of AF However, the of reverse atrial remodelling is advanced imaging like quantification of atrial and novel are needed to this The to further characterize the of atrial remodelling using advanced imaging but also clinical like have been and were to report the degree of electrophysiological changes in the atria owing to structural remodelling. In atrial contribution to ventricular filling, atrial sinus and atrial endocrine and function are that to be further in

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