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Atrial Failure as a Clinical Entity
JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
VOL. 75, NO. 2, 2020
ª 2020 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION PUBLISHED BY ELSEVIER
JACC REVIEW TOPIC OF THE WEEK
Atrial Failure as a Clinical Entity JACC Review Topic of the Week Felipe Bisbal, MD, PHD,a,b,c Adrian Baranchuk, MD,d Eugene Braunwald, MD,e Antoni Bayés de Luna, MD, PHD,c,f Antoni Bayés-Genís, MD, PHDa,b,c
ABSTRACT Atrial dysfunction has been widely considered a marker or consequence of other cardiac conditions rather than the cause itself. Here, we propose the term atrial failure as a clinically relevant entity, defined as any atrial dysfunction causing impaired heart performance, symptoms, and worsening quality of life or life expectancy. Aspects of the etiology, mechanisms, and consequences of atrial failure are discussed. Recent advances in cardiac electrophysiology and imaging have improved our understanding of the highly complex atrial anatomy and function, underlying the paramount importance of the atria in optimal heart performance. It is time to reappraise the concept of the failing atrium as a primary cause or aggravating factor of the symptoms in many of our patients. The concept of atrial failure may foster basic and translational research to gain a better understanding of how to identify and manage atrial dysfunction. (J Am Coll Cardiol 2020;75:222–32) © 2020 by the American College of Cardiology Foundation.
“. . . and, if at this time, with its auricle alone
atrial fibrillation (AF) and the increasing sophisticat-
beating, you cut off the apex of the heart with a
ion of cardiac imaging modalities. A deeper under-
pair of scissors, you will see the blood flow out
standing
from the wound with each beat of the auricle.
revealed its crucial role in the hemodynamics of
You will thus realize that the blood gets into the
the heart, but this knowledge is not always trans-
ventricles not through any pull exerted by the distended heart, but through the driving force exerted by the beat of the auricles.”
D
—William Harvey, 1628
of
atrial
structure
and
function
has
lated into clinical practice. A myriad of conditions may impair LA performance by affecting its mechanical and homeostatic functions or its electrical coupling to the ventricle. Impaired left ventricular (LV) hemodynamics, increased thrombo-
espite the observations described by Har-
genicity, and pulmonary hypertension may occur,
vey early in the 17th century and the
leading to highly variable clinical manifestations
foundational physiological properties of
including heart failure (HF), myocardial ischemia,
the left atrium (LA) reported >50 years ago (1,2),
and thromboembolic events (Central Illustration).
the LA has been quite neglected by researchers,
Atrial dysfunction has been widely considered to
and its role in cardiac function minimized. More
be a marker or consequence of other cardiac condi-
recently, the LA has garnered great attention with
tions, rather than a potential cause. In this review, we
the development of interventional therapies for
propose the term atrial failure as an independent,
Listen to this manuscript’s audio summary by
From the aHeart Institute (iCor), University Hospital Germans Trias i Pujol, Badalona, Barcelona, Spain; bCIBERCV, Instituto de
Editor-in-Chief
Salud Carlos III, Madrid, Spain; cDepartment of Medicine, Universitat Autònoma Barcelona, Barcelona, Spain; dDepartment of
Dr. Valentin Fuster on
Medicine, Division of Cardiology, Heart Rhythm Service, Queen’s University, Kingston General Hospital, Kingston, Ontario,
JACC.org.
Canada; eCardiovascular Division, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts; and the fInstitut Català Ciències Cardiovasculars, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. This work was supported by Instituto de Salud Carlos III, Ministerio de Economía y Competitividad, Spain (PI18/01227), CIBER Cardiovascular (CB16/11/00403); and La MARATO - TV3 (ID 201527). The authors have reported that they have no relationships relevant to the contents of this paper to disclose. Manuscript received August 12, 2019; revised manuscript received October 9, 2019, accepted November 5, 2019.
ISSN 0735-1097/$36.00
https://doi.org/10.1016/j.jacc.2019.11.013
Bisbal et al.
JACC VOL. 75, NO. 2, 2020 JANUARY 21, 2020:222–32
HIGHLIGHTS Atrial dysfunction is often neglected. We propose atrial failure as a clinically relevant entity. The concept of atrial failure may foster research leading to a better understanding of atrial dysfunction.
flow patterns, favoring early diastolic LV
ABBREVIATIONS
filling while avoiding blood stasis (5).
AND ACRONYMS
The left atrial appendage (LAA), a trabeculated, independently attached structure with high anatomical variability, has an important endocrine function. Its separation from the LA body makes appendage blood turnover
highly
dependent
on
systolic
contraction. Loss of LAA contraction (i.e., AF) and specific morphological features have with
blood
stasis
and
AV = atrioventricular HF = heart failure HFpEF = heart failure with preserved ejection fraction
LA = left atrium LAA = left atrial appendage LV = left ventricle
been
diversity of etiologies, mechanisms, and manifesta-
thrombus formation (6). Both atria are con-
MI = myocardial infarction
tions. Aspects of the etiology, mechanisms, and con-
nected by organized bundles of myocytes
PV = pulmonary vein
sequences of atrial failure are discussed.
located at the epicardial anterior interatrial groove (Bachmann’s bundle), septum, and coronary sinus,
DEFINITION OF ATRIAL FAILURE
allowing bi-atrial synchronous activation.
We propose a definition of atrial failure as “any atrial (anatomical,
associated
AF = atrial fibrillation
clinically relevant entity beyond AF and HF, with a
dysfunction
mechanical,
electrical,
and/or rheological, including blood homeostasis) causing impaired heart performance and symptoms, and worsening quality of life or life expectancy, in the absence of significant valvular or ventricular abnormalities.” Other relevant definitions are provided in Table 1. Several aspects of atrial failure have been previously addressed (3); however, as happened with HF syndrome, atrial failure syndrome is likely to be subject to a more refined redefinition in the future as more knowledge on this entity is obtained. Congestive HF may not occur exclusively because of a failing LV. Even with preserved LV function, other conditions (such as a diseased/dysfunctional LA) may impair global heart performance. In the absence of LV disease, atrial fibrotic changes and dysfunction may trigger HF syndrome, stroke, or arrhythmias (Figure 1).
The LA has a crucial role in LV filling and global heart performance and a dynamic interaction with ventricular diastole and systole. Timely atrioventricular (AV) coupling is essential to the synchronization of atrial cycle phases to LV diastole. Inflow to the LA from the PVs occurs during LV systole and isovolumetric relaxation (reservoir function), and accounts for approximately 40% to 50% of the
LV
stroke
volume.
Passive
blood
transfer
during LV diastole (conduit function) constitutes approximately 20% to 30% of stroke volume and precedes the active atrial contraction (booster-pump function), which transfers the remaining volume (w20%–30%) to the LV; retrograde flow to the PVs also occurs (2). The performance of both the reservoir and conduit phases is determined by atrial compliance, ventricular relaxation, and transmitral pressure gradient (7). Conditions impairing any atrial function, especially mechanical
ANATOMY AND FUNCTION OF THE LA
alterations
leading
to
an
abnormal
pressure-volume relationship (8), may affect global cardiac performance, leading to symptoms and
It is thought that partitioning of the heart into inflow
worsening outcomes. In contrast to atrial cardiomy-
and
cepha-
opathy (disease-specific anatomic/histological fea-
lochordates approximately 600 million years ago and
tures associated with myocardial disease), atrial
that an ancestral atrial chamber first developed
failure refers to the functional consequences of any
approximately 100 million years later, in ancient
atrial condition, including but not restricted to pri-
hagfish and lamprey (4). The atrium then became the
mary atrial disease.
outflow
segments
223
Atrial Failure
was
present
in
main inflow component of the heart in vertebrate organisms.
ETIOLOGY OF ATRIAL FAILURE
The LA is a highly complex structure, with close interaction between its anatomical, ultrastructural,
A list of the proposed causes and triggers of atrial
and functional aspects. The LA has 2 parts: the
failure is provided in Table 2.
postero-superior inflow (venous) and antero-inferior
ATRIAL RHYTHM DISORDERS. Synchronous atrial
outflow (vestibular) components. The 3-dimensional
activation allows effective active contraction with
asymmetrical configuration of the systemic pulmo-
timely coupling. Rapid atrial arrhythmias (e.g., AF)
nary vein (PV) attachment allows specific vortical
produce
ineffective
active
contraction.
Rapid,
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Atrial Failure
C E NT R AL IL L U STR AT IO N Atrial Failure
Bisbal, F. et al. J Am Coll Cardiol. 2020;75(2):222–32.
Schematic on the causes, mechanisms, and clinical manifestations of atrial failure. The 4D atrial flow image has been reproduced with permission from Garcia et al. (66). AF ¼ atrial fibrillation; AV ¼ atrioventricular; LV ¼ left ventricular.
irregular conduction to the ventricles impairs both
(left bundle branch block or advanced interatrial
systolic and diastolic LV function, associated with
block, respectively). In advanced interatrial block,
tachycardia-induced
short,
derangement in the interatrial contraction sequence
Suboptimal electrical AV coupling, as observed
of atrial failure, HF, and activated thrombogenic
cardiomyopathy
and
irregular LV filling, respectively.
(i.e., interatrial dyssynchrony) is an additional trigger
with a long PR interval and asynchronous right ventricular
pacing,
may
lead
to
inefficient
cascade (9) (Figure 2).
atrial
contraction and reduced ventricular end diastolic
ATRIAL CARDIOMYOPATHY. Fibrosis is a common
filling. This may also be evident when AV coupling is
finding of most primary and secondary atrial pathol-
compromised due to delayed LV or LA activation
ogies, leading to increased stiffness and reduced
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Atrial Failure
T A B L E 1 Definitions
Term
Definition
Example
High fibrosis burden and sphericity causing stroke in a patient with lone atrial fibrillation (CHA2DS2VASc ¼ 0) Advanced atrial dyssynchrony causing abnormal left ventricular filling and symptoms (Figure 3)
Atrial failure
Any atrial dysfunction causing impaired heart performance and symptoms and worsening quality of life or life expectancy, in the absence of significant valvular or ventricular abnormalities
Atrial cardiomyopathy
Diseases of the myocardium associated with mechanical and/or electrical Isolated fibrotic atrial cardiomyopathy leading to dysfunction that usually (but not invariably) exhibit inappropriate atrial impaired atrial function and heart failure fibrosis, hypertrophy, or dilatation and are due to a variety of causes symptoms (Figure 2) (adapted from Maron et al. [64])
Atrial remodeling
Response of atrial myocytes to electrical, mechanical, or metabolic stressors (mainly rapid atrial tachyarrhythmias or pressure and volume overload) leading to persistent change in LA size, function or electrophysiological properties (adapted from Thomas and Abhayaratna [65])
Dilated/spherical left atrium due to valvular disease, atrial fibrillation, or hypertension
CHA2DS2-VASc ¼ congestive heart failure, hypertension, age $75 years, diabetes mellitus, prior stroke, transient ischemic attack, or thromboembolism, vascular disease, age 65–74 years, sex category (female).
contractility (10). Recently, a consensus document
variable among individuals with AF and may be
proposed a classification of atrial cardiomyopathies (11).
associated with genetic factors/predisposition (21).
Idiopathic atrial cardiomyopathy is associated with
Notably, in some instances, AF may be a marker of
increased fibrosis, atrial arrhythmias, and impaired atrial
high atrial fibrosis burden rather than its cause (22).
function (11). Induced stiff LA syndrome after ablation,
Many cardiac conditions can lead to LA remodeling
estimated as occurring in approximately 2% to 8% of
that ultimately harbors AF. Ventricular- and valvular-
cases, has been related to decreased LA contractility and
mediated atrial remodeling includes a myriad of
compliance, with a direct correlation between scar
interstitial fibrosis, inflammation, myocyte hypertro-
burden and functional impairment (12,13). Atrial ischemia
phy, and necrosis, as well as glycogen accumulation.
may be a common, although underdiagnosed, cause of
Parallel to structural changes, impaired LA function is
atrial myopathy with impaired reservoir and booster-
the rule in most cases and carries with it an adverse
pump functions (14); it has been linked to increased
prognosis (23,24).
arrhythmic events (15), mitral regurgitation (14), and worse clinical outcomes (16). Atrial involvement in myocarditis may also be underestimated. Up to 30% of patients with myocarditis develop AF, and it may be a cause of atrial dysfunction (17).
MECHANISMS AND MANIFESTATIONS OF ATRIAL FAILURE Altered flow dynamics, suboptimal LV filling, and AF resulting from atrial failure may cause pulmonary
ATRIAL REMODELING. Atrial remodeling refers to
hypertension, HF, and increased thrombogenicity.
adverse electrophysiological, cellular, and structural
The presence of atrial failure may predispose a pa-
changes in atrial myocardial tissue in response to
tient to new-onset AF, which perpetuates and may
pressure and volume overload or arrhythmic insults.
even worsen a failing LA and its consequences in a
The main causes of LA remodeling include AF and
vicious circle (25). Therefore, we hypothesize that
ventricular/valve disease. Nevertheless, noncardiac
atrial failure, as happens with overt HF (26), activates
conditions, such as sleep apnea syndrome, hyper-
neurohormonal pathways (mainly of the renin-
tension, diabetes, and obesity, are important con-
angiotensin-aldosterone system and the sympathetic
tributors
nervous system), which may further impair atrial
to
LA
remodeling
through
different
pathways (18). Many conditions may coexist and
function (Central Illustration).
accelerate the adverse remodeling, driven in most
ATRIAL FAILURE AND RISK OF THROMBOEMBOLIC
cases by the presence of AF.
EVENTS. Embolic cardiovascular events have been
In addition to ion-channel changes and impaired
classically linked to an LAA source in the context of
electrophysiological properties, interstitial fibrosis is
AF, thus setting the rationale for surgical and
the hallmark of AF-induced LA remodeling and is
percutaneous LAA exclusion strategies. Recent evi-
associated with chamber dilation, spherical defor-
dence has challenged this assumption, providing
mation (19), and reduced atrial function (20), further
new insights into the existing link between atrial
promoting AF in a vicious circle (“AF begets AF”). The
disease and the risk of stroke independent of AF.
degree of structural tissue remodeling is highly
The lack of a robust association between the timing
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Atrial Failure
F I G U R E 1 Atrial Standstill
A I
B
C
132ms
II III aVR aVL aVF V1 V2 V3
Scar
V4 V5 V6 Healthy
Atrial and AV Dyssynchrony
↓ LV filling
Atrial Tissue Fibrosis
Atrial Standstill
Blood stasis
↓ Booster-pump
↓ Compliance
Endothelial dysfunction
Global HF & ↑ Risk Stroke Patient with a history of hypertension presenting with fatigue and dyspnea. Diagnostic workup revealed pathological P-wave duration (A), decreased left atrial (LA) function, absence of A waves in transmitral pulsed-Doppler echocardiography (B), and extensive fibrosis (Utah IV) detected by late gadolinium enhancement magnetic resonance imaging (C). The absence of significant ventricular abnormalities on magnetic resonance imaging and normal LA size suggest a primary atrial cardiomyopathy. AV ¼ atrioventricular; HF ¼ heart failure; LV ¼ left ventricular.
of AF episodes and stroke suggests that AF could be
and stroke (30,31). In addition, the amount of fibrosis
a marker of atrial myopathy rather than a cause of
in patients with stroke of unknown etiology is
thrombus formation (27). Current evidence for atrial
reportedly greater than in patients with an identified
myopathy promotes atrial substrate as an important
cause and comparable to those with AF (32). The link
cause of increased thrombogenicity, questioning the
between structural tissue abnormalities and a pro-
arrhythmia-mediated concept of thrombus forma-
thrombotic state is yet to be defined. Endothelial
tion alone as the leading cause of thromboembolic
damage and regional or global wall motion abnor-
stroke (28). Recent data from the MESA population
malities associated with increased fibrosis could
shows a strong association between LA reservoir
explain the increased risk of stroke (20,33).
function and incident embolic events, even after
The 3-dimensional asymmetrical configuration of
adjusting for established risk factors and presence
cardiac structures has beneficial effects in flow dy-
of documented AF (29).
namics. At the LA level, eccentric alignment with
In a highly selected AF population referred for
separate paths of left and right PV inflow and vortex
catheter ablation, LA structural remodeling has been
formation avoids blood stasis and redirects blood flow
associated with an increased risk of LAA thrombus
toward the mitral valve (conduit function) (5,34).
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Atrial Failure
VO 2 (40,41). Up to 45% of patients presenting with
T A B L E 2 Causes and Triggers of Atrial Failure
new-onset HF symptoms have LA dysfunction as the
A. Electrical Dyssynchrony AV dyssynchrony o Left bundle branch block o First-degree AV block o Suboptimal pacemaker programming Atrial dyssynchrony o Advanced interatrial block o Slow intra-atrial conduction velocities
underlying mechanism (42), suggesting that LA failure is an early driver in HFpEF syndrome and a crucial pathogenic factor. In addition to mechanical LA impairment driven by increased stiffness and pressure pulsatility (8), electrical atrial dysfunction and impaired LA-LV coupling could play a relevant
B. Booster-Pump and Reservoir Dysfunction Fast/disorganized atrial activation o Atrial fibrillation o Focal/reentrant atrial tachycardia Extensive atrial fibrosis o Advanced atrial remodeling o Extensive post-ablation scarring o Atrial infarction o Atrial cardiomyopathy
role in patients with HFpEF (43,45). Standalone atrial failure may cause HF symptoms, stroke, or pulmonary hypertension (29,40–42); however, atrial failure may more frequently worsen previously
asymptomatic
LV
dysfunction
and
decompensate or aggravate HF syndrome (Central
C. Impaired Conduit Function Severe atrial dilation Spherical atrial deformation Altered transmitral pressure gradient
Illustration). At early stages of LV dysfunction, adaptive atrial chamber dilation accommodates higher preload without a significant increase in pulmonary wedge pressure; an increase in active pump function
AV [ atrioventricular.
contributes
to
maintaining
adequate
LV
filling
(Frank-Starling curve) (2,46). Progressive insults with Reduced peak velocity increases stasis in both the LA and LAA, alters vortical flow (as observed by 4-dimensional study in the LV), and facilitates thrombus formation (35,36). The diseased atrium may undergo geometric changes (spherical deformation) and chamber dilation, reducing the normal curvatures and asymmetry of the LA. These processes interfere with physiological flow dynamics (altered vortex formation), increasing blood stasis and stroke risk (37,38). Factors associated with atrial disease facilitate thrombus formation and increase the risk of stroke but are not exclusively linked to AF (Figure 3). In addition, stroke may further facilitate LA remodeling through
sympathetic
ganglionated
plexi,
activation leading
to
of LA
the
cardiac
endothelial
dysfunction and fibrosis (39).
increasing chamber dilation alter the conduit function as the first sign of atrial failure (41); nevertheless, a greater volume does not correspond to increased fiber shortening and contractility. Progressive impairment in global LA function fails to accommodate the excessive volume/pressure, leading to high LA and pulmonary wedge pressures and overt atrial failure syndrome. In the context of advanced tissue remodeling, development of AF is common, which further impairs electrical and mechanical LA function and has a deleterious effect on global cardiac performance, perpetuating a dangerous and vicious circle (47).
EXTRA-ATRIAL CONSEQUENCES OF ATRIAL FAILURE The deleterious effects of LV dysfunction on LA
ATRIAL AND VENTRICULAR INTERACTION IN HF.
structure and function are well defined; however,
Heart
fraction
the opposite interplay is less well characterized.
(HFpEF) is part of the HF spectrum. Abnormal LV
Some data suggest that AF promotes adverse ven-
diastolic function may be the substrate for HF in
tricular remodeling; preclinical histological and hu-
many patients, but in some instances HFpEF may be
man MRI studies have shown that the presence of
the consequence of a failing LA (40–42). Recent evi-
AF is associated with increased LV interstitial
dence suggests that LA function and remodeling are
fibrosis (47,48).
failure
with
preserved
ejection
independently associated with, or may precede, the
Ventricular dilation and altered systolic and dia-
onset of HF in an asymptomatic healthy population,
stolic function are common findings in studies of
as observed in a preclinical magnetic resonance im-
sustained rapid ventricular response to atrial ar-
aging (MRI) study (43,44). A reduced atrial reserve
rhythmias. At the histopathological level, the LV
during exercise may represent the first sign of a
myocardium exhibits inflammation, cardiomyocyte
failing LA in such a population. Compared with con-
morphological changes, and loss of the normal
trols, the only distinctive feature of patients with
myocardial extracellular matrix structure, composi-
HFpEF is reduced atrial reservoir and conduit capac-
tion, and function; this likely explains the increased
ity,
risk of HF and sudden cardiac death in these patients
which
independently
correlates
with
peak
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F I G U R E 2 Interatrial Block
Patient with ischemic cardiomyopathy and paroxysmal atrial fibrillation (AF) presenting with exercise intolerance. Electrocardiogram shows paced, prolonged P-wave duration of 190 ms with advanced interatrial block pattern (A). Transmitral pulsed-Doppler echocardiography shows normal filling pattern at rest (60 beats/min [bpm]); however, a progressive fusion of E and A waves is observed as heart rate increases (B). Note complete fusion of E and A waves at 100 beats/min, contributing to worsening of symptoms and global heart performance. Left atrial (LA) mapping revealed initial septal activation only, with no contribution of the interatrial Bachmann bundle and coronary sinus connections, with a long total LA activation time (C). Poor interatrial coupling and slow LA activation explain the markedly prolonged P-wave duration.
(49,50).
neurohormonal
remodeling and dysfunction and to determine the
pathways, including renin-angiotensin-aldosterone
Reactive
activation
of
point of no return from which recovery is unlikely
system and vasoactive peptides, may further pro-
despite suppression of arrhythmia.
mote adverse remodeling. Tachycardia-induced car-
Atrial rhythm and contraction contribute to effi-
diomyopathy may not be as “benign” and reversible
cient coronary blood flow. Irregular, shortened dias-
as initially thought; despite suppression of the causal
tole with an altered flow reserve induced by AF is a
atrial arrhythmia (not exclusively AF), LV dimensions
common cause of ventricular ischemia and type 2
and function, as well as T1 mapping values (a surro-
myocardial infarction (MI) (53). Patients with AF are
gate of diffuse interstitial fibrosis), do not normalize
at a 3-fold increased risk of MI, independent of other
in all patients (51,52). Further studies are needed to
risk factors. The coexistence of risk factors common
explore the broad spectrum of atrial-induced LV
to both entities, along with increased inflammation
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Atrial Failure
F I G U R E 3 Pathophysiology of Stroke in Atrial Failure
Valvular Ventricular cardiomyopathy Hypertension Sleep apnea syndrome Obesity Metabolic diseases
Atrial Cardiomyopathy
↑ Spherical deformation ↑ Dilation
Left Atrium Remodeling
↓ Reservoir/ Booster-pump
↑ Fibrosis
↑ Stasis
Endothelial dysfunction Wall motion abnormalities
Rhythm disorders
Endothelial dysfunction ↑ Stasis ↑ von Willebrand factor
Altered Vortex formation ↑ Stasis
Stroke
Functional, tissue, and electrical changes caused by primary or secondary atrial myopathy drive flow and endothelial and wall motion abnormalities, facilitating thrombus formation. The 4D atrial flow image is reproduced with permission from Föll et al. (67).
and platelet activation, are likely the drivers of this excess
risk.
Importantly,
anticoagulant
therapy
Atrial functional mitral and tricuspid regurgitation represent an atrial-induced valvular disease that may
seems to protect against incident MI in the AF pop-
produce or exacerbate HF and promote AF (56,57).
ulation (54). Ventricular MI due to atrial embolic
Rotation/displacement
source is a well-recognized cause of ischemia in AF
valvular plane and anterior tethering due to LA or RA
of
the
posterior
mitral
patients (55). As observed in patients with stroke,
dilation have been proposed as the main underlying
atrial dysfunction per se increases the risk of throm-
mechanisms (58). Recent data warning of the excess
boembolic events (29) and may eventually account
of mortality and incident HF associated with atrial
for embolic MI as well. Further studies are needed to
functional mitral regurgitation (59) suggest a poten-
provide a comprehensive evaluation of atrial me-
tial mechanism for the observed survival benefits of
chanical function in patients with MI of embolic
AF ablation in patients with HF. Could reduction in
origin.
AF burden improve atrial functional mitral and
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230
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Atrial Failure
T A B L E 3 Diagnostic Strategies and Potential Interventions
Areas of Impact
Clinical Implications of Atrial Failure
Proposed Diagnostic Strategies
Potential Future Interventions
Risk of stroke
Identify non-AF individuals at risk of stroke Identify AF individuals at low risk of stroke
Atrial size/shape: MRI/CTA Fibrosis detection: MRI (LGE) Mechanical function: Echo, MRI (strain) Biomarkers
OAC might be indicated in individuals without AF or discouraged in patients with AF Upstream therapy to reduce fibrosis/thrombotic milieu
Heart failure
Identify mechanism of HF symptoms in the absence of LV abnormalities
Fibrosis detection: MRI (LGE) Mechanical function: Echo, MRI (strain) Quantification MR (Echo, MRI) Biomarkers
Tailored HF treatment Upstream therapy to reduce fibrosis Interventions to reduce MR Left atrial pacing
Mechanical LA dysfunction Atrial functional MR Atrial dyssynchrony AF management
Identify the arrhythmia mechanism Assess stage of atrial disease Assess likelihood of successful rhythm control
Atrial size/shape: MRI/CTA Fibrosis detection: MRI (LGE) Biomarkers
Tailored ablation approach (substrate-based vs. pulmonary vein isolation) Selection of candidates for rhythm or rate control
Dyssynchrony
Assess degree of interatrial and atrioventricular dyssynchrony
Right and left E/A (Echo)
Left atrial or bi-atrial pacing
Extra-atrial involvement
Assess LV abnormalities due to atrial failure Assess atrial functional MR Assess AF-driven functional TR
LV size and function: Echo, MRI Fibrosis detection: MRI (T1, LGE) Characterization of valvular insufficiency (Echo, MRI)
Sudden death risk stratification OAC indicated in advanced atrial failure to prevent embolic myocardial infarction AF suppression by ablation to improve MR/TR Interventions to reduce MR/TR (MitraClip, annuloplasty)
AF ¼ atrial fibrillation; CTA ¼ computed tomography angiography; HF ¼ heart failure; LA ¼ left atrium; LGE ¼ late gadolinium enhancement; LV ¼ left ventricle; MR ¼ mitral regurgitation; MRI ¼ magnetic resonance imaging; OAC ¼ oral anticoagulation; TR ¼ tricuspid regurgitation.
tricuspid regurgitation and prolong lifespan in this
CONCLUSIONS
population? Further studies are needed to explain this mechanism.
Atrial failure has emerged as a new entity defined as any atrial dysfunction causing impaired heart
DIAGNOSTIC STRATEGIES AND
performance, appearance of symptoms, and wors-
POTENTIAL INTERVENTIONS
ening quality of life or life expectancy, in the
Table 3 summarizes the main clinical aspects and implications of atrial failure, as well as the related diagnostic strategies and potential interventions. Atrial failure must be considered in the presence of compatible symptoms and any structural, functional, or electrical abnormalities of the LA not attributable to any other cardiac or extracardiac condition. Imaging results are key to determine LA function, detect atrial fibrosis, and assess blood flow patterns. Biomarkers are an emerging diagnostic and prognostic tool, with good performance to predict ischemic and bleeding risk (e.g., high-sensitivity troponin T, N-terminal pro–B-type natriuretic peptide, growth/ differentiation factor 15) (60), as well as fibrosis
absence of significant valvular or ventricular abnormalities. Recent advances in cardiac electrophysiology
and
imaging
have
improved
our
understanding of the highly complex atrial anatomy
and
function,
revealing
the
paramount
importance of the atria in optimal heart performance. It is time to reappraise the role of atrial dysfunction in the symptoms of many of our patients: marker, aggravating factor, consequence, or primary cause? Here, we propose the concept of atrial failure, which may foster basic and translational research to gain a better understanding of how to identify and manage atrial dysfunction in the 21st century.
burden or AF ablation success (microRNA miR-21)
ACKNOWLEDGMENTS The authors are grateful to
(61). Atrial voltage abnormalities may help to predict
Carolina Gálvez-Montón PhD, DVM, for the graphic
myocardial fibrosis,
impaired
LA
function, and
increased risk of stroke (62,63). Although any atrial
art contribution and Albert Teis for the support with cardiac imaging.
dysfunction in the context of compatible symptoms might be considered as atrial failure, establishing the
ADDRESS FOR CORRESPONDENCE: Dr. Felipe Bisbal,
development of a broad consensus. Acceptance of
Heart Institute - Hospital Universitari Germans Trias i
this concept will likely foster research in this field,
Pujol, Carretera Canyet s/n, 08916 Badalona, Barce-
and the term necessarily will be redefined with
lona, Spain. E-mail: [email protected]. Twitter:
greater precision as we gain more knowledge.
@bisbal_EP, @adribaran.
appropriate
diagnostic
criteria
will
require
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KEY WORDS atrial failure, atrial fibrillation, atrial function, heart failure, interatrial block, stroke
VOL. 75, NO. 2, 2020
ª 2020 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION PUBLISHED BY ELSEVIER
JACC REVIEW TOPIC OF THE WEEK
Atrial Failure as a Clinical Entity JACC Review Topic of the Week Felipe Bisbal, MD, PHD,a,b,c Adrian Baranchuk, MD,d Eugene Braunwald, MD,e Antoni Bayés de Luna, MD, PHD,c,f Antoni Bayés-Genís, MD, PHDa,b,c
ABSTRACT Atrial dysfunction has been widely considered a marker or consequence of other cardiac conditions rather than the cause itself. Here, we propose the term atrial failure as a clinically relevant entity, defined as any atrial dysfunction causing impaired heart performance, symptoms, and worsening quality of life or life expectancy. Aspects of the etiology, mechanisms, and consequences of atrial failure are discussed. Recent advances in cardiac electrophysiology and imaging have improved our understanding of the highly complex atrial anatomy and function, underlying the paramount importance of the atria in optimal heart performance. It is time to reappraise the concept of the failing atrium as a primary cause or aggravating factor of the symptoms in many of our patients. The concept of atrial failure may foster basic and translational research to gain a better understanding of how to identify and manage atrial dysfunction. (J Am Coll Cardiol 2020;75:222–32) © 2020 by the American College of Cardiology Foundation.
“. . . and, if at this time, with its auricle alone
atrial fibrillation (AF) and the increasing sophisticat-
beating, you cut off the apex of the heart with a
ion of cardiac imaging modalities. A deeper under-
pair of scissors, you will see the blood flow out
standing
from the wound with each beat of the auricle.
revealed its crucial role in the hemodynamics of
You will thus realize that the blood gets into the
the heart, but this knowledge is not always trans-
ventricles not through any pull exerted by the distended heart, but through the driving force exerted by the beat of the auricles.”
D
—William Harvey, 1628
of
atrial
structure
and
function
has
lated into clinical practice. A myriad of conditions may impair LA performance by affecting its mechanical and homeostatic functions or its electrical coupling to the ventricle. Impaired left ventricular (LV) hemodynamics, increased thrombo-
espite the observations described by Har-
genicity, and pulmonary hypertension may occur,
vey early in the 17th century and the
leading to highly variable clinical manifestations
foundational physiological properties of
including heart failure (HF), myocardial ischemia,
the left atrium (LA) reported >50 years ago (1,2),
and thromboembolic events (Central Illustration).
the LA has been quite neglected by researchers,
Atrial dysfunction has been widely considered to
and its role in cardiac function minimized. More
be a marker or consequence of other cardiac condi-
recently, the LA has garnered great attention with
tions, rather than a potential cause. In this review, we
the development of interventional therapies for
propose the term atrial failure as an independent,
Listen to this manuscript’s audio summary by
From the aHeart Institute (iCor), University Hospital Germans Trias i Pujol, Badalona, Barcelona, Spain; bCIBERCV, Instituto de
Editor-in-Chief
Salud Carlos III, Madrid, Spain; cDepartment of Medicine, Universitat Autònoma Barcelona, Barcelona, Spain; dDepartment of
Dr. Valentin Fuster on
Medicine, Division of Cardiology, Heart Rhythm Service, Queen’s University, Kingston General Hospital, Kingston, Ontario,
JACC.org.
Canada; eCardiovascular Division, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts; and the fInstitut Català Ciències Cardiovasculars, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. This work was supported by Instituto de Salud Carlos III, Ministerio de Economía y Competitividad, Spain (PI18/01227), CIBER Cardiovascular (CB16/11/00403); and La MARATO - TV3 (ID 201527). The authors have reported that they have no relationships relevant to the contents of this paper to disclose. Manuscript received August 12, 2019; revised manuscript received October 9, 2019, accepted November 5, 2019.
ISSN 0735-1097/$36.00
https://doi.org/10.1016/j.jacc.2019.11.013
Bisbal et al.
JACC VOL. 75, NO. 2, 2020 JANUARY 21, 2020:222–32
HIGHLIGHTS Atrial dysfunction is often neglected. We propose atrial failure as a clinically relevant entity. The concept of atrial failure may foster research leading to a better understanding of atrial dysfunction.
flow patterns, favoring early diastolic LV
ABBREVIATIONS
filling while avoiding blood stasis (5).
AND ACRONYMS
The left atrial appendage (LAA), a trabeculated, independently attached structure with high anatomical variability, has an important endocrine function. Its separation from the LA body makes appendage blood turnover
highly
dependent
on
systolic
contraction. Loss of LAA contraction (i.e., AF) and specific morphological features have with
blood
stasis
and
AV = atrioventricular HF = heart failure HFpEF = heart failure with preserved ejection fraction
LA = left atrium LAA = left atrial appendage LV = left ventricle
been
diversity of etiologies, mechanisms, and manifesta-
thrombus formation (6). Both atria are con-
MI = myocardial infarction
tions. Aspects of the etiology, mechanisms, and con-
nected by organized bundles of myocytes
PV = pulmonary vein
sequences of atrial failure are discussed.
located at the epicardial anterior interatrial groove (Bachmann’s bundle), septum, and coronary sinus,
DEFINITION OF ATRIAL FAILURE
allowing bi-atrial synchronous activation.
We propose a definition of atrial failure as “any atrial (anatomical,
associated
AF = atrial fibrillation
clinically relevant entity beyond AF and HF, with a
dysfunction
mechanical,
electrical,
and/or rheological, including blood homeostasis) causing impaired heart performance and symptoms, and worsening quality of life or life expectancy, in the absence of significant valvular or ventricular abnormalities.” Other relevant definitions are provided in Table 1. Several aspects of atrial failure have been previously addressed (3); however, as happened with HF syndrome, atrial failure syndrome is likely to be subject to a more refined redefinition in the future as more knowledge on this entity is obtained. Congestive HF may not occur exclusively because of a failing LV. Even with preserved LV function, other conditions (such as a diseased/dysfunctional LA) may impair global heart performance. In the absence of LV disease, atrial fibrotic changes and dysfunction may trigger HF syndrome, stroke, or arrhythmias (Figure 1).
The LA has a crucial role in LV filling and global heart performance and a dynamic interaction with ventricular diastole and systole. Timely atrioventricular (AV) coupling is essential to the synchronization of atrial cycle phases to LV diastole. Inflow to the LA from the PVs occurs during LV systole and isovolumetric relaxation (reservoir function), and accounts for approximately 40% to 50% of the
LV
stroke
volume.
Passive
blood
transfer
during LV diastole (conduit function) constitutes approximately 20% to 30% of stroke volume and precedes the active atrial contraction (booster-pump function), which transfers the remaining volume (w20%–30%) to the LV; retrograde flow to the PVs also occurs (2). The performance of both the reservoir and conduit phases is determined by atrial compliance, ventricular relaxation, and transmitral pressure gradient (7). Conditions impairing any atrial function, especially mechanical
ANATOMY AND FUNCTION OF THE LA
alterations
leading
to
an
abnormal
pressure-volume relationship (8), may affect global cardiac performance, leading to symptoms and
It is thought that partitioning of the heart into inflow
worsening outcomes. In contrast to atrial cardiomy-
and
cepha-
opathy (disease-specific anatomic/histological fea-
lochordates approximately 600 million years ago and
tures associated with myocardial disease), atrial
that an ancestral atrial chamber first developed
failure refers to the functional consequences of any
approximately 100 million years later, in ancient
atrial condition, including but not restricted to pri-
hagfish and lamprey (4). The atrium then became the
mary atrial disease.
outflow
segments
223
Atrial Failure
was
present
in
main inflow component of the heart in vertebrate organisms.
ETIOLOGY OF ATRIAL FAILURE
The LA is a highly complex structure, with close interaction between its anatomical, ultrastructural,
A list of the proposed causes and triggers of atrial
and functional aspects. The LA has 2 parts: the
failure is provided in Table 2.
postero-superior inflow (venous) and antero-inferior
ATRIAL RHYTHM DISORDERS. Synchronous atrial
outflow (vestibular) components. The 3-dimensional
activation allows effective active contraction with
asymmetrical configuration of the systemic pulmo-
timely coupling. Rapid atrial arrhythmias (e.g., AF)
nary vein (PV) attachment allows specific vortical
produce
ineffective
active
contraction.
Rapid,
224
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Atrial Failure
C E NT R AL IL L U STR AT IO N Atrial Failure
Bisbal, F. et al. J Am Coll Cardiol. 2020;75(2):222–32.
Schematic on the causes, mechanisms, and clinical manifestations of atrial failure. The 4D atrial flow image has been reproduced with permission from Garcia et al. (66). AF ¼ atrial fibrillation; AV ¼ atrioventricular; LV ¼ left ventricular.
irregular conduction to the ventricles impairs both
(left bundle branch block or advanced interatrial
systolic and diastolic LV function, associated with
block, respectively). In advanced interatrial block,
tachycardia-induced
short,
derangement in the interatrial contraction sequence
Suboptimal electrical AV coupling, as observed
of atrial failure, HF, and activated thrombogenic
cardiomyopathy
and
irregular LV filling, respectively.
(i.e., interatrial dyssynchrony) is an additional trigger
with a long PR interval and asynchronous right ventricular
pacing,
may
lead
to
inefficient
cascade (9) (Figure 2).
atrial
contraction and reduced ventricular end diastolic
ATRIAL CARDIOMYOPATHY. Fibrosis is a common
filling. This may also be evident when AV coupling is
finding of most primary and secondary atrial pathol-
compromised due to delayed LV or LA activation
ogies, leading to increased stiffness and reduced
Bisbal et al.
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Atrial Failure
T A B L E 1 Definitions
Term
Definition
Example
High fibrosis burden and sphericity causing stroke in a patient with lone atrial fibrillation (CHA2DS2VASc ¼ 0) Advanced atrial dyssynchrony causing abnormal left ventricular filling and symptoms (Figure 3)
Atrial failure
Any atrial dysfunction causing impaired heart performance and symptoms and worsening quality of life or life expectancy, in the absence of significant valvular or ventricular abnormalities
Atrial cardiomyopathy
Diseases of the myocardium associated with mechanical and/or electrical Isolated fibrotic atrial cardiomyopathy leading to dysfunction that usually (but not invariably) exhibit inappropriate atrial impaired atrial function and heart failure fibrosis, hypertrophy, or dilatation and are due to a variety of causes symptoms (Figure 2) (adapted from Maron et al. [64])
Atrial remodeling
Response of atrial myocytes to electrical, mechanical, or metabolic stressors (mainly rapid atrial tachyarrhythmias or pressure and volume overload) leading to persistent change in LA size, function or electrophysiological properties (adapted from Thomas and Abhayaratna [65])
Dilated/spherical left atrium due to valvular disease, atrial fibrillation, or hypertension
CHA2DS2-VASc ¼ congestive heart failure, hypertension, age $75 years, diabetes mellitus, prior stroke, transient ischemic attack, or thromboembolism, vascular disease, age 65–74 years, sex category (female).
contractility (10). Recently, a consensus document
variable among individuals with AF and may be
proposed a classification of atrial cardiomyopathies (11).
associated with genetic factors/predisposition (21).
Idiopathic atrial cardiomyopathy is associated with
Notably, in some instances, AF may be a marker of
increased fibrosis, atrial arrhythmias, and impaired atrial
high atrial fibrosis burden rather than its cause (22).
function (11). Induced stiff LA syndrome after ablation,
Many cardiac conditions can lead to LA remodeling
estimated as occurring in approximately 2% to 8% of
that ultimately harbors AF. Ventricular- and valvular-
cases, has been related to decreased LA contractility and
mediated atrial remodeling includes a myriad of
compliance, with a direct correlation between scar
interstitial fibrosis, inflammation, myocyte hypertro-
burden and functional impairment (12,13). Atrial ischemia
phy, and necrosis, as well as glycogen accumulation.
may be a common, although underdiagnosed, cause of
Parallel to structural changes, impaired LA function is
atrial myopathy with impaired reservoir and booster-
the rule in most cases and carries with it an adverse
pump functions (14); it has been linked to increased
prognosis (23,24).
arrhythmic events (15), mitral regurgitation (14), and worse clinical outcomes (16). Atrial involvement in myocarditis may also be underestimated. Up to 30% of patients with myocarditis develop AF, and it may be a cause of atrial dysfunction (17).
MECHANISMS AND MANIFESTATIONS OF ATRIAL FAILURE Altered flow dynamics, suboptimal LV filling, and AF resulting from atrial failure may cause pulmonary
ATRIAL REMODELING. Atrial remodeling refers to
hypertension, HF, and increased thrombogenicity.
adverse electrophysiological, cellular, and structural
The presence of atrial failure may predispose a pa-
changes in atrial myocardial tissue in response to
tient to new-onset AF, which perpetuates and may
pressure and volume overload or arrhythmic insults.
even worsen a failing LA and its consequences in a
The main causes of LA remodeling include AF and
vicious circle (25). Therefore, we hypothesize that
ventricular/valve disease. Nevertheless, noncardiac
atrial failure, as happens with overt HF (26), activates
conditions, such as sleep apnea syndrome, hyper-
neurohormonal pathways (mainly of the renin-
tension, diabetes, and obesity, are important con-
angiotensin-aldosterone system and the sympathetic
tributors
nervous system), which may further impair atrial
to
LA
remodeling
through
different
pathways (18). Many conditions may coexist and
function (Central Illustration).
accelerate the adverse remodeling, driven in most
ATRIAL FAILURE AND RISK OF THROMBOEMBOLIC
cases by the presence of AF.
EVENTS. Embolic cardiovascular events have been
In addition to ion-channel changes and impaired
classically linked to an LAA source in the context of
electrophysiological properties, interstitial fibrosis is
AF, thus setting the rationale for surgical and
the hallmark of AF-induced LA remodeling and is
percutaneous LAA exclusion strategies. Recent evi-
associated with chamber dilation, spherical defor-
dence has challenged this assumption, providing
mation (19), and reduced atrial function (20), further
new insights into the existing link between atrial
promoting AF in a vicious circle (“AF begets AF”). The
disease and the risk of stroke independent of AF.
degree of structural tissue remodeling is highly
The lack of a robust association between the timing
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Atrial Failure
F I G U R E 1 Atrial Standstill
A I
B
C
132ms
II III aVR aVL aVF V1 V2 V3
Scar
V4 V5 V6 Healthy
Atrial and AV Dyssynchrony
↓ LV filling
Atrial Tissue Fibrosis
Atrial Standstill
Blood stasis
↓ Booster-pump
↓ Compliance
Endothelial dysfunction
Global HF & ↑ Risk Stroke Patient with a history of hypertension presenting with fatigue and dyspnea. Diagnostic workup revealed pathological P-wave duration (A), decreased left atrial (LA) function, absence of A waves in transmitral pulsed-Doppler echocardiography (B), and extensive fibrosis (Utah IV) detected by late gadolinium enhancement magnetic resonance imaging (C). The absence of significant ventricular abnormalities on magnetic resonance imaging and normal LA size suggest a primary atrial cardiomyopathy. AV ¼ atrioventricular; HF ¼ heart failure; LV ¼ left ventricular.
of AF episodes and stroke suggests that AF could be
and stroke (30,31). In addition, the amount of fibrosis
a marker of atrial myopathy rather than a cause of
in patients with stroke of unknown etiology is
thrombus formation (27). Current evidence for atrial
reportedly greater than in patients with an identified
myopathy promotes atrial substrate as an important
cause and comparable to those with AF (32). The link
cause of increased thrombogenicity, questioning the
between structural tissue abnormalities and a pro-
arrhythmia-mediated concept of thrombus forma-
thrombotic state is yet to be defined. Endothelial
tion alone as the leading cause of thromboembolic
damage and regional or global wall motion abnor-
stroke (28). Recent data from the MESA population
malities associated with increased fibrosis could
shows a strong association between LA reservoir
explain the increased risk of stroke (20,33).
function and incident embolic events, even after
The 3-dimensional asymmetrical configuration of
adjusting for established risk factors and presence
cardiac structures has beneficial effects in flow dy-
of documented AF (29).
namics. At the LA level, eccentric alignment with
In a highly selected AF population referred for
separate paths of left and right PV inflow and vortex
catheter ablation, LA structural remodeling has been
formation avoids blood stasis and redirects blood flow
associated with an increased risk of LAA thrombus
toward the mitral valve (conduit function) (5,34).
Bisbal et al.
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Atrial Failure
VO 2 (40,41). Up to 45% of patients presenting with
T A B L E 2 Causes and Triggers of Atrial Failure
new-onset HF symptoms have LA dysfunction as the
A. Electrical Dyssynchrony AV dyssynchrony o Left bundle branch block o First-degree AV block o Suboptimal pacemaker programming Atrial dyssynchrony o Advanced interatrial block o Slow intra-atrial conduction velocities
underlying mechanism (42), suggesting that LA failure is an early driver in HFpEF syndrome and a crucial pathogenic factor. In addition to mechanical LA impairment driven by increased stiffness and pressure pulsatility (8), electrical atrial dysfunction and impaired LA-LV coupling could play a relevant
B. Booster-Pump and Reservoir Dysfunction Fast/disorganized atrial activation o Atrial fibrillation o Focal/reentrant atrial tachycardia Extensive atrial fibrosis o Advanced atrial remodeling o Extensive post-ablation scarring o Atrial infarction o Atrial cardiomyopathy
role in patients with HFpEF (43,45). Standalone atrial failure may cause HF symptoms, stroke, or pulmonary hypertension (29,40–42); however, atrial failure may more frequently worsen previously
asymptomatic
LV
dysfunction
and
decompensate or aggravate HF syndrome (Central
C. Impaired Conduit Function Severe atrial dilation Spherical atrial deformation Altered transmitral pressure gradient
Illustration). At early stages of LV dysfunction, adaptive atrial chamber dilation accommodates higher preload without a significant increase in pulmonary wedge pressure; an increase in active pump function
AV [ atrioventricular.
contributes
to
maintaining
adequate
LV
filling
(Frank-Starling curve) (2,46). Progressive insults with Reduced peak velocity increases stasis in both the LA and LAA, alters vortical flow (as observed by 4-dimensional study in the LV), and facilitates thrombus formation (35,36). The diseased atrium may undergo geometric changes (spherical deformation) and chamber dilation, reducing the normal curvatures and asymmetry of the LA. These processes interfere with physiological flow dynamics (altered vortex formation), increasing blood stasis and stroke risk (37,38). Factors associated with atrial disease facilitate thrombus formation and increase the risk of stroke but are not exclusively linked to AF (Figure 3). In addition, stroke may further facilitate LA remodeling through
sympathetic
ganglionated
plexi,
activation leading
to
of LA
the
cardiac
endothelial
dysfunction and fibrosis (39).
increasing chamber dilation alter the conduit function as the first sign of atrial failure (41); nevertheless, a greater volume does not correspond to increased fiber shortening and contractility. Progressive impairment in global LA function fails to accommodate the excessive volume/pressure, leading to high LA and pulmonary wedge pressures and overt atrial failure syndrome. In the context of advanced tissue remodeling, development of AF is common, which further impairs electrical and mechanical LA function and has a deleterious effect on global cardiac performance, perpetuating a dangerous and vicious circle (47).
EXTRA-ATRIAL CONSEQUENCES OF ATRIAL FAILURE The deleterious effects of LV dysfunction on LA
ATRIAL AND VENTRICULAR INTERACTION IN HF.
structure and function are well defined; however,
Heart
fraction
the opposite interplay is less well characterized.
(HFpEF) is part of the HF spectrum. Abnormal LV
Some data suggest that AF promotes adverse ven-
diastolic function may be the substrate for HF in
tricular remodeling; preclinical histological and hu-
many patients, but in some instances HFpEF may be
man MRI studies have shown that the presence of
the consequence of a failing LA (40–42). Recent evi-
AF is associated with increased LV interstitial
dence suggests that LA function and remodeling are
fibrosis (47,48).
failure
with
preserved
ejection
independently associated with, or may precede, the
Ventricular dilation and altered systolic and dia-
onset of HF in an asymptomatic healthy population,
stolic function are common findings in studies of
as observed in a preclinical magnetic resonance im-
sustained rapid ventricular response to atrial ar-
aging (MRI) study (43,44). A reduced atrial reserve
rhythmias. At the histopathological level, the LV
during exercise may represent the first sign of a
myocardium exhibits inflammation, cardiomyocyte
failing LA in such a population. Compared with con-
morphological changes, and loss of the normal
trols, the only distinctive feature of patients with
myocardial extracellular matrix structure, composi-
HFpEF is reduced atrial reservoir and conduit capac-
tion, and function; this likely explains the increased
ity,
risk of HF and sudden cardiac death in these patients
which
independently
correlates
with
peak
227
228
Bisbal et al.
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Atrial Failure
F I G U R E 2 Interatrial Block
Patient with ischemic cardiomyopathy and paroxysmal atrial fibrillation (AF) presenting with exercise intolerance. Electrocardiogram shows paced, prolonged P-wave duration of 190 ms with advanced interatrial block pattern (A). Transmitral pulsed-Doppler echocardiography shows normal filling pattern at rest (60 beats/min [bpm]); however, a progressive fusion of E and A waves is observed as heart rate increases (B). Note complete fusion of E and A waves at 100 beats/min, contributing to worsening of symptoms and global heart performance. Left atrial (LA) mapping revealed initial septal activation only, with no contribution of the interatrial Bachmann bundle and coronary sinus connections, with a long total LA activation time (C). Poor interatrial coupling and slow LA activation explain the markedly prolonged P-wave duration.
(49,50).
neurohormonal
remodeling and dysfunction and to determine the
pathways, including renin-angiotensin-aldosterone
Reactive
activation
of
point of no return from which recovery is unlikely
system and vasoactive peptides, may further pro-
despite suppression of arrhythmia.
mote adverse remodeling. Tachycardia-induced car-
Atrial rhythm and contraction contribute to effi-
diomyopathy may not be as “benign” and reversible
cient coronary blood flow. Irregular, shortened dias-
as initially thought; despite suppression of the causal
tole with an altered flow reserve induced by AF is a
atrial arrhythmia (not exclusively AF), LV dimensions
common cause of ventricular ischemia and type 2
and function, as well as T1 mapping values (a surro-
myocardial infarction (MI) (53). Patients with AF are
gate of diffuse interstitial fibrosis), do not normalize
at a 3-fold increased risk of MI, independent of other
in all patients (51,52). Further studies are needed to
risk factors. The coexistence of risk factors common
explore the broad spectrum of atrial-induced LV
to both entities, along with increased inflammation
Bisbal et al.
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Atrial Failure
F I G U R E 3 Pathophysiology of Stroke in Atrial Failure
Valvular Ventricular cardiomyopathy Hypertension Sleep apnea syndrome Obesity Metabolic diseases
Atrial Cardiomyopathy
↑ Spherical deformation ↑ Dilation
Left Atrium Remodeling
↓ Reservoir/ Booster-pump
↑ Fibrosis
↑ Stasis
Endothelial dysfunction Wall motion abnormalities
Rhythm disorders
Endothelial dysfunction ↑ Stasis ↑ von Willebrand factor
Altered Vortex formation ↑ Stasis
Stroke
Functional, tissue, and electrical changes caused by primary or secondary atrial myopathy drive flow and endothelial and wall motion abnormalities, facilitating thrombus formation. The 4D atrial flow image is reproduced with permission from Föll et al. (67).
and platelet activation, are likely the drivers of this excess
risk.
Importantly,
anticoagulant
therapy
Atrial functional mitral and tricuspid regurgitation represent an atrial-induced valvular disease that may
seems to protect against incident MI in the AF pop-
produce or exacerbate HF and promote AF (56,57).
ulation (54). Ventricular MI due to atrial embolic
Rotation/displacement
source is a well-recognized cause of ischemia in AF
valvular plane and anterior tethering due to LA or RA
of
the
posterior
mitral
patients (55). As observed in patients with stroke,
dilation have been proposed as the main underlying
atrial dysfunction per se increases the risk of throm-
mechanisms (58). Recent data warning of the excess
boembolic events (29) and may eventually account
of mortality and incident HF associated with atrial
for embolic MI as well. Further studies are needed to
functional mitral regurgitation (59) suggest a poten-
provide a comprehensive evaluation of atrial me-
tial mechanism for the observed survival benefits of
chanical function in patients with MI of embolic
AF ablation in patients with HF. Could reduction in
origin.
AF burden improve atrial functional mitral and
229
230
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Atrial Failure
T A B L E 3 Diagnostic Strategies and Potential Interventions
Areas of Impact
Clinical Implications of Atrial Failure
Proposed Diagnostic Strategies
Potential Future Interventions
Risk of stroke
Identify non-AF individuals at risk of stroke Identify AF individuals at low risk of stroke
Atrial size/shape: MRI/CTA Fibrosis detection: MRI (LGE) Mechanical function: Echo, MRI (strain) Biomarkers
OAC might be indicated in individuals without AF or discouraged in patients with AF Upstream therapy to reduce fibrosis/thrombotic milieu
Heart failure
Identify mechanism of HF symptoms in the absence of LV abnormalities
Fibrosis detection: MRI (LGE) Mechanical function: Echo, MRI (strain) Quantification MR (Echo, MRI) Biomarkers
Tailored HF treatment Upstream therapy to reduce fibrosis Interventions to reduce MR Left atrial pacing
Mechanical LA dysfunction Atrial functional MR Atrial dyssynchrony AF management
Identify the arrhythmia mechanism Assess stage of atrial disease Assess likelihood of successful rhythm control
Atrial size/shape: MRI/CTA Fibrosis detection: MRI (LGE) Biomarkers
Tailored ablation approach (substrate-based vs. pulmonary vein isolation) Selection of candidates for rhythm or rate control
Dyssynchrony
Assess degree of interatrial and atrioventricular dyssynchrony
Right and left E/A (Echo)
Left atrial or bi-atrial pacing
Extra-atrial involvement
Assess LV abnormalities due to atrial failure Assess atrial functional MR Assess AF-driven functional TR
LV size and function: Echo, MRI Fibrosis detection: MRI (T1, LGE) Characterization of valvular insufficiency (Echo, MRI)
Sudden death risk stratification OAC indicated in advanced atrial failure to prevent embolic myocardial infarction AF suppression by ablation to improve MR/TR Interventions to reduce MR/TR (MitraClip, annuloplasty)
AF ¼ atrial fibrillation; CTA ¼ computed tomography angiography; HF ¼ heart failure; LA ¼ left atrium; LGE ¼ late gadolinium enhancement; LV ¼ left ventricle; MR ¼ mitral regurgitation; MRI ¼ magnetic resonance imaging; OAC ¼ oral anticoagulation; TR ¼ tricuspid regurgitation.
tricuspid regurgitation and prolong lifespan in this
CONCLUSIONS
population? Further studies are needed to explain this mechanism.
Atrial failure has emerged as a new entity defined as any atrial dysfunction causing impaired heart
DIAGNOSTIC STRATEGIES AND
performance, appearance of symptoms, and wors-
POTENTIAL INTERVENTIONS
ening quality of life or life expectancy, in the
Table 3 summarizes the main clinical aspects and implications of atrial failure, as well as the related diagnostic strategies and potential interventions. Atrial failure must be considered in the presence of compatible symptoms and any structural, functional, or electrical abnormalities of the LA not attributable to any other cardiac or extracardiac condition. Imaging results are key to determine LA function, detect atrial fibrosis, and assess blood flow patterns. Biomarkers are an emerging diagnostic and prognostic tool, with good performance to predict ischemic and bleeding risk (e.g., high-sensitivity troponin T, N-terminal pro–B-type natriuretic peptide, growth/ differentiation factor 15) (60), as well as fibrosis
absence of significant valvular or ventricular abnormalities. Recent advances in cardiac electrophysiology
and
imaging
have
improved
our
understanding of the highly complex atrial anatomy
and
function,
revealing
the
paramount
importance of the atria in optimal heart performance. It is time to reappraise the role of atrial dysfunction in the symptoms of many of our patients: marker, aggravating factor, consequence, or primary cause? Here, we propose the concept of atrial failure, which may foster basic and translational research to gain a better understanding of how to identify and manage atrial dysfunction in the 21st century.
burden or AF ablation success (microRNA miR-21)
ACKNOWLEDGMENTS The authors are grateful to
(61). Atrial voltage abnormalities may help to predict
Carolina Gálvez-Montón PhD, DVM, for the graphic
myocardial fibrosis,
impaired
LA
function, and
increased risk of stroke (62,63). Although any atrial
art contribution and Albert Teis for the support with cardiac imaging.
dysfunction in the context of compatible symptoms might be considered as atrial failure, establishing the
ADDRESS FOR CORRESPONDENCE: Dr. Felipe Bisbal,
development of a broad consensus. Acceptance of
Heart Institute - Hospital Universitari Germans Trias i
this concept will likely foster research in this field,
Pujol, Carretera Canyet s/n, 08916 Badalona, Barce-
and the term necessarily will be redefined with
lona, Spain. E-mail: [email protected]. Twitter:
greater precision as we gain more knowledge.
@bisbal_EP, @adribaran.
appropriate
diagnostic
criteria
will
require
Bisbal et al.
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Atrial Failure
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KEY WORDS atrial failure, atrial fibrillation, atrial function, heart failure, interatrial block, stroke