Atrial fibrillation with Heart Failure is a constellation of co-morbid conditions that now constitutes a major cardiovascular epidemic, with HF now the most common complication of AF. Mechanistically, both conditions promote substrate disease in the atrium and ventricle. AF is an independent rixk factor in HF progression and pump failure death. While early studies comparing rhythm control antiarrhythmic drugs and rate control drugs showed no significant benefit in cardiovascular outcomes, AF did promote HF emergence and hospitalizations. Newer rhythm control strategies with present day antiarrhythmic drugs and catheter ablation support benefits in cardiovascular outcomes in AF with HF. Catheter ablation improved HF outcomes in HF with reduced ejection fraction but further and larger studies are needed, especially for AF with HF with preserved ejection fraction.
Key points
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Atrial fibrillation with Heart Failure is now constitutes a major cardiovascular epidemic, with HF now the most common complication of AF.
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AF is an independent rixk factor in HF progression and pump failure death.
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While early studies of antiarrhythmic and rate control drugs showed no significant benefit in cardiovascular outcomes, AF promotes HF emergence and hospitalizations.
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Newer rhythm control strategies with present day antiarrhythmic drugs and catheter ablation support benefits in cardiovascular outcomes in AF with HF.
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Catheter ablation improved HF outcomes in HF with reduced ejection fraction but further and larger studies are needed especially for AF with HF with preserved ejection fraction.
A brief history of the disease state
The coexistence of a common arrhythmia, atrial fibrillation (AF), and the syndrome of heart failure (HF) was certainly known in early medical literature. Clinical descriptions of individual with HF symptoms and signs were known and described in Chinese and Arabian medical texts. , William Harvey in his experimental studies on the circulation first described irregular motion in the atrial appendages, which was present even in terminal animal experiments. He referred to this as “fibrillation of the auricles.” William Withering’s accounts of the use of the leaf extract of the Foxglove ( Digitalis purpura containing digitalis) in the treatment of “dropsy”, the then medical term for symptoms and signs of congestive HF interestingly provided description of coexisting AF and HF. He described in great detail the resolution of severe anasarca or edema with the extract; this was ascribed by him to the “diuretic” properties of the extract. However, he may well have also reported the earliest use of digitalis, a drug with potential anti-arrhythmic properties in AF with concomitant HF. He noted that a 38 year old pregnant patient in the third trimester with dyspnea, edema, and a “weak, irregular pulse” when treated with digitalis leaf, her pulse became “full and more regular” with resolution of HF symptoms. HF recurred 3 months postpartum and responded again to digitalis. The coexistence of AF with other cardiopulmonary diseases, for example, mitral stenosis and pulmonary congestion, was widely documented in the 19th century. Thus, the clinical constellation of AF with concomitant HF was recognized in early medical literature.
The first documented recordings attributable to AF were made by James Mackenzie who documented an irregular jugular venous pulse tracing in subjects with an irregular pulse. He noted the absence of an atrial wave in the venous pulse and surmised that this was due to loss of contraction of the high atrium and simultaneous contraction of the low atrium and ventricle leading to the term “ nodal rhythm. ” Perspicaciously, he also noted the following “ The nodal rhythm is present in the majority of cases of severe HF, and in a great many, the immediate breakdown is attributable to the inception by the heart of this abnormal rhythm ” and in doing so, he clearly recognized the pernicious effects of AF in HF. It was the development of the electrocardiogram led to recording of surface electrical activity during AF manifest as “fibrillatory (f)” waves in AF. The HF syndrome (“dropsy”) became defined as a constellation of clinical signs and symptoms. Osler recognized it as a complication of other cardiac diseases such as valvular heart disease. Objective documentation of HF in an organ had to await the discovery of radiographs by William Rontgen. The understanding of HF as a late stage syndrome related to many cardiac diseases was greatly advanced by Starling’s publication of his “Law of the Heart” in 1918 and lead to Sarnoff’s studies on ventricular function curves. The objective demonstration of elevated cardiovascular pressures by cardiac catheterization provided a pivotal objective clinical parameter to document and measure severity of HF.
Definitions, classifications, and life cycle stages in atrial fibrillation and heart failure
The definitions of both conditions have evolved significantly overtime.
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HF is currently defined as a clinical syndrome with symptoms and/or signs caused by a structural and/or functional cardiac abnormality and corroborated by elevated natriuretic peptide levels and/or objective evidence of pulmonary or systemic congestion.
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Phenotypes of HF have been long based on left ventricular ejection fraction (EF). Initially HF was classified as HF with reduced (r) and preserved (p) EF, with a cutoff at below 45% for heart failure with reduced ejection fraction (HFrEF) and 45% or more for heart failure with preserved ejection fraction (HFpEF).
Newer stratification has modified this to include additional strata.
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The definition of HFrEF is modified to EF 40% or less
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Insertion of the category of HF with midrange EF (HFmrEF, EF 41% to 50%) and modification of HFpEF to EF greater than 50%.
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A new category for HF with mid-range improved EF is added for subjects whose EF improves on medical therapy above 40% or by 10%.
Current day classification of the HF also defines stages in the HF life cycle from A to D, ranging from a at-risk population (stage A), pre-HF (stage B), symptomatic HF (stage C), and advanced HF (stage D). Most of the discussion in this study will focus on stages C and D but increasing interest is emerging on the role of AF treatment strategy on HF stages B and C.
The evolution of the modern classification of AF has emerged from a consensus document of international societies of arrhythmology. It was based on AF episode duration, ability to self terminate or requiring interventions for termination, or failure to successfully terminate and revert to stable sinus rhythm with interventions.
A newer proposal looking at the stages of AF life cycle rather than classification of AF events mirrors the HF terminology and defines 4 stages of the AF life cycle.
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Stage 1 of the life cycle includes those at risk for AF with or without modifiable comorbid conditions that confer risk.
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Stage 2, referred to as pre-AF, includes individuals with structural or electrical abnormalities that predispose a patient to AF.
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Stage 3 includes 3 categories of manifest AF.
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Stage 3A, which was previously defined as paroxysmal AF, includes AF episodes that self terminate within 7 days.
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Stage 3B, which is commonly referred to as persistent AF, includes AF episodes not self terminating within 7 days and require intervention for termination.
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Stage 3C includes long-standing persistent AF, defined as an episode duration of greater than 12 months.
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Stage 3D in the life cycle refers to successfully ablated (surgically or percutaneously) AF subjects
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Stage 4 in the AF life cycle is defined as a condition of permanent AF when no further efforts at rhythm control are undertaken after discussion with the patient and clinician.
It is important for the reader to appreciate that due to the relatively short existence of current AF and HF stages limits their easy transference to the large body of science that exists on the subject of therapeutic strategies for management of coexisting AF and HF. Suffice it to say that most of the current knowledge on treatment strategies is obtained in the symptomatic stages of both conditions.
Epidemiology of Atrial Fibrillation and Heart Failure
AF and HF are now widely recognized as the leading cardiovascular epidemics of the 21st century. Global prevalence of these 2 conditions is high and it is currently estimated that 59.7 million individuals suffer from AF worldwide and 64 million have clinical HF. , While AF prevalence is higher in countries with longer life expectancy, HF is highly prevalent across the globe. It is estimated that by 2030, the United States will have 12 million individuals with AF and 8 million with HF. , Among newly diagnosed HF subjects, 44% had HFrEF in one epidemiologic study. Coexistence of these conditions is common. Recent epidemiologic data place estimates of prevalence of HF in individuals with newly diagnosed AF at 37%, and for AF prevalence in newly diagnosed HF at 57%. Currently, 50% of all newly diagnosed HF subjects have HFpEF. Overall, 64% of individuals suffering from HFpEF are likely to experience AF in their life cycle. Based on this, over 6 million Americans are likely to experience the constellation of these 2 conditions, AF with HFpEF by 2030. Prevalence of AF in different types of HF can differ. Son and colleagues demonstrated a higher AF prevalence in HFpEF than HFmrEF and HFrEF in both men and women, as well as in those below the age of 60 years and each decade thereafter.
AF predisposes to the development of new HF (relative risk increase 3.4 in both women and men in the Renfrew–Paisley study) and secondarily increased cardiovascular and all-cause mortality. There is a significant incidence of new subjects with either condition over-time. In the Framingham study, prevalent HF is associated with a progressive increase in the incidence of newly diagnosed AF approaching 15% at 5 years. The temporal association of these 2 conditions is also available. While a significant proportion (range 38%–45%) of HFrEF and HFpEF subjects do not have AF, those with previous AF are more likely to have new HF (20%–30%), and to lesser degree with concurrent AF (20%) and projected to be least with future AF. Similarly, in study participants with new onset AF, new onset HF increased in incidence from prior AF events to concurrent AF and future AF. Incident HFpEF was the most common form exceeding HFrEF and HFmrEF. Prevalent AF was associated with an approximately 5% absolute incidence of either form of new HF at 5 years. These data imply that the development of the other comorbidity is a long-term process encompassing a decade or longer.
It is now increasingly apparent that HF is now the most common present-day complication of AF. AF increased risk of HF with an HR: 4.8, with the most common subset being HFpEF. Early clinical studies focused on stroke risk in HF. Increased stroke risk has been demonstrated in both HFrEF and HFpEF resulting in recommendations to anticoagulate these patients. The Prevention of Renal and Vascular End-Stage Disease study followed 8265 participants with a total follow-up 80,352 person-years. Overall, the relative risk of new, that is, incident, HF during follow-up exceeded stroke and vascular events (HF = HR 18.14, Stroke = HR 5.53, peripheral vascular events = HR 1.63 respectively). Two hundred sixty-five subjects developed AF. The relative risk of new (incident) HF during follow-up with AF also greatly exceeded stroke and vascular event risk (HF = .6.01, stroke = 2.2, peripheral vascular events = 2.23, respectively).
Pathophysiology of atrial fibrillation with heart failure relevant to treatment strategies
Atrial cardiomyopathy is present in AF subjects without and with comorbid conditions. Recent guidelines have codified the definition of atrial cardiomyopathy as the disease process underpinning clinical AF.
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Atrial cardiomyopathy has been defined as “ any complex of structural, architectural, contractile, or electrophysiological changes affecting the atria with the potential to produce clinically relevant manifestations . ”
It is widely accepted that atrial cardiomyopathy exists per se in AF and with HF and may vary with the etiology of HF and duration of AF. Coexistence of both conditions would be associated with a significant atrial myopathy. It follows that pathophysiologic aspects of the atrial cardiomyopathy in AF associated with HF are likely to be relevant to treatment strategies employed in clinical practice.
Our pathophysiologic knowledge of AF, HF, and in conjunction with each other is derived from multiple different sources including experimental studies in animals, and human tissue as well as clinical observations and formal studies.
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Current mechanistic concepts of AF suggest that a cascade of atrial myocardial changes collectively referred to as atrial remodeling ensue with the onset and persistence of the arrhythmia. HF also is associated with changes in atrial electrical and mechanical function as well as ventricular performance and neurohormonal pathways that predispose to AF. ,
A short summary of common pathophysiologic pathways of AF and HF development reveals overlapping mechanisms. The cascading changes with rapid atrial pacing and induced AF in the experimental studies of Allessie and colleagues in the normal goat atrium opened a window into understanding human AF.
Electrical Atrial Remodeling (“Atrial Fibrillation Begets Atrial Fibrillation”)
They described acute electrical remodeling in the atrium with rapid pacing as the first step leading to sustained AF in this model. They proceeded to outline the continuing evolution of adverse atrial effects of AF. The cardinal finding of electrical remodeling was shortening of atrial action potential duration with reduced effective refractory period and loss of physiologic rate adaptation of refractoriness. Experimental studies suggest this is mediated by changes in ion channels. There is a prominent reduction (estimated at 70%) in L-type calcium current and to some extent I to that reduce phases 1 and 2 of the action potential reducing its duration. Importantly, L-type calcium current is involved in excitation–contraction coupling. There is also evidence that the inward rectifier potassium current (I k1 ) and the acetylcholine-activated potassium current (I K Ach ) are increased at hyperpolarized voltages inhuman atrium derived from patients with normal or minimally impaired left ventricular function.
Contractile Remodeling
The next step in the cascade is impaired mechanical function of the atrium. Contractile dysfunction of the atrium has been well documented after prolonged AF in experimental and clinical settings. A reduction in I CaL is surmised to mediate impaired excitation-contraction coupling and contractile performance of the atrium. Other factors may include impaired ventricular mechanical performance during AF is ascribed to rapid ventricular rates impairing ventricular filling, irregular ventricular rates with inability to lose of passive atrial filling during short R–R intervals that is not adequately compensated by longer intervals and loss of atrial pump function in diastole. These deleterious hemodynamic effects can impact ventricular structure as well.
Structural Remodeling
The third step in the cascade is atrial structural remodeling with prolonged and sustained AF. Loss of sarcomeres and increased cytoplasmic glycogen accumulation occur with progressive myolysis. Definite structural changes include reduced desmin striation and connexin 40 depletion at gap junctions. Ultrastructural changes in nuclear and mitochondrial morphology and intercellular fibrosis evolve. Interstitial or replacement atrial fibrosis is a common accompaniment with clinical AF. The process of atrial fibrosis has been studied in some depth and has significant complexity. It is relevant to both AF and HF as both involve presence or development of progressive fibrosis. Interstitial fibrosis now referred to as reactive fibrosis shows increased collagen between cardiac muscle bands without altering architecture and is often seen in persistent AF and may be potentially reversible to some extent. Replacement fibrosis involves replacing dead cardiomyocytes with fibroblasts and extracellular matrix to preserve tissue integrity but impairing electrical propagation to a much greater degree and much less likely to be reversible. Replacement fibrosis is particularly seen in AF models with HF and may have analogies with clinical AF with HF or other comorbidities. Fibroblasts, long considered a passive onlooker, are now regarded as actively participating in the evolution of atrial cardiomyopathy. Complex signaling systems promote fibrosis including connective tissue growth factor, angiotensin-II, platelet-derived growth factor, and transforming growth factor (TGF)-b. Calcium entry may have a role profibrotic activation of fibroblast activity with ion channel dysregulation in such cells. Fibrosis leads to localized regions of conduction slowing, increasing conduction heterogeneity and these may promote development of or persistence of AF. There can be a role for microRNAs in signaling pathways promoting atrial fibrosis. Atrial miR-21 expression has been shown to be increased in HF and rapid atrial activation.
Combined Effects of Atrial Fibrillation and Rapid Ventricular Rates
In other experimental studies in dogs, rapid atrial pacing shortens atrial refractoriness and action potential duration and slows atrial conduction. Rapid ventricular pacing equally slows atrial conduction but does not shorten atrial refractoriness or action potential duration. AF and rapid ventricular pacing increase atrial fibrosis in an additive manner. The combination of AF and fast ventricular rates leads to an even higher amount of atrial remodeling ( Fig. 1 ).
This study attempted to parse the contributions of AF-induced atrial arrhythmias versus ventricular arrhythmias to atrial remodeling. Each component produced discrete features: AF-induced atrial tachyarrhythmias caused accelerated repolarization and abbreviated refractoriness, strongly increased vulnerability to AF-induction by premature ectopic beats, conduction slowing, and moderate atrial fibrosis; whereas ventricular arrhythmia, that was mimicked by rapid ventricular pacing, slightly increased vulnerability, slowed conduction, and induced moderate fibrosis without affecting repolarization/refractoriness. Combined atrial and ventricular tachyarrhythmias abbreviated refractoriness, strongly increased vulnerability and fibrosis, and greatly increased AF stability and duration. This work suggests that in the absence of ventricular rate control, the rapid ventricular response can cause AF-promoting atrial remodeling without overt HF.
There is strong evidence that HF can result in changes in the atrium that promote development or persistence of AF. Increased intracardiac pressures and “tissue stretch” can result in marked spatial dispersion of electrophysiologic properties and may or may not also impact atrial extracellular matrix. , Atrial chamber enlargement and hypertrophy also have similar effects promoting atrial ectopy and heterogeneity of both depolarization and repolarization in the atrium, predisposing to AF. In animal HF models, the extent of these changes is much more pronounced in the left atrium than the left ventricle. The ventricular tachypacing model of HF produced more fibrosis in the left atrium than the ventricle with more rapid rise in angiotensin II concentrations in the atrium. Structural changes were more apparent in the left atrium than the left ventricle. Profibrotic signaling systems increased more significantly in the left atrium than ventricle. Neurohormonal changes in HF such as rise in angiotensin-II levels promote the fibrotic remodeling response. However, these changes are not uniform and may vary with HF phenotype and stage. In human atrial tissue obtained from subjects with terminal HF, the action potential duration is actually prolonged, I K r ionic current was either undetectable or very reduced, and I K to current was also reduced in diseased cells. ,
Intertwined Relationship of Atrial Fibrillation and Heart Failure
The intertwined relationship between AF and HF is summarized in Fig. 2 . As can be seen, there is a multifactorial intricate relationship among structural changes, physiologic alterations, cardiac tissue remodeling, and circulatory and intracardiac hemodynamics. The detailed discussion can be found in the referenced works (see Fig. 2 ).
Pathophysiology of Heart Failure with Preserved Ejection Fraction
Recently, a great deal of attention has been focused on the pathophysiologic mechanisms of HFpEF. In contrast to the findings described earlier, often derived from HFrEF models or subjects, the key mechanisms show significant differences ( Box 1 ).
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Pro-inflammatory state (TNFα, IL1β, IL6, and C-reactive protein) leads to cardiac and systemic endothelial dysfunction.
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Cardiac microvascular endothelial cell : Regulation of cardiomyocyte relaxation impaired.
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Impaired cardiac microvascular dysfunction reduces coronary perfusion and promotes diastolic dysfunction.
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Endothelial dysfunction leads to imbalance between reduced availability of protective molecules and increased secretion of detrimental factors.
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Cardiomyocyte remodeling : hypertrophy, altered calcium handling, imbalanced myocardial energetics = diastolic dysfunction.
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Resting diastolic tension increased by rise in cytosolic calcium rise and sarcomeric protein (titin) phosphorylation status.
The atrial cardiomyopathy associated with HFpEF has been characterized more recently in animals and to a lesser extent in man. Part of the challenge is that varying phenotypes of HFpEF may impact AF and its underlying atrial cardiomyopathy may be multifactorial. Attempts to reproduce these phenotypes in experimental models are in their infancy. Nevertheless, in an aged rat model with HFpEF with left ventricular diastolic dysfunction (LVDD), prolongation of action potential duration and heterogeneity of atrial refractoriness, atrial fibrosis, and decreased interatrial and atriovestricular (AV) nodal conduction velocity were seen. Inflammatory markers were present more often in atrial tissue from HFpEF rats with elevated levels of atrial cytokines, cytokine-induced neutrophil chemoattractants, and macrophages being noted. Rapid atrial pacing protocols were more likely to induce nonsustained AF less than 30s and one sustained AF event in HFpEF rats than in control animals.
Limited studies in tissues from human subjects have yielded intriguing results relevant to electrophysiologic and mechanical mechanisms of HFpEF. An early report on endomyocardial biopsy samples showed an accumulation of cardiac collagen with a decrease in the major collagenase system (matrix metalloproteinase-1) in the heart. Inflammatory cells, which expressed the profibrotic growth factor TGF-, were seen. In in vitro studies, TGF- resulted in transdifferentiation of fibroblasts to myofibroblasts, which in turn produced more collagen and decreased the amount of matrix metalloproteinase-1, suggesting overall a positive collagen turnover balance in the cardiac matrix in HFpEF. This correlation among increased cardiac collagen, amount of inflammatory cells, and LVDD suggests a direct influence of inflammation on fibrosis triggering diastolic dysfunction.
More suggestive evidence in the peripheral blood of patients with HFpEF showed increased levels of monocytes and pro-inflammatory markers. Monocyte percentages were increased in asymptomatic diastolic dysfunction and subjects with HFpEF and correlated with echocardiographic indices of LVDD. The authors suggest that increased peripheral inflammation, monocytosis, and monocyte differentiation to anti-inflammatory/profibrotic M2 macrophages likely associate with HFpEF and its precedent asymptomatic LVDD phase.
Prognosis of atrial fibrillation with heart failure
The emergence of new HF in subjects with AF increases the risk of cardiac and all-cause death. In the Framingham study, the relative risk of mortality increased with a hazard ratio (HR) of 1.25 (HFpEF HR 1.33, HFrEF HR 1.18). In the atrial fibrillation follow-up investigation of rhythm management (AFFIRM) trial, newly emergent HF resulted in a progressively higher risk of cardiac death, that is, with 1 HF class increase (HR 2.86) and an increase of 2 HF classes (HR 4.27). In similar fashion, new AF in subjects with prevalent HF increased mortality risk (HFpEF—HR 1.83, HrEF HR 2.72). Thus, these data confirm that coexisting AF and HF have a worse prognosis than AF alone. ,
A large body of evidence now exists that substantiate these deleterious effects of AF in HFrEF. In the studies on left ventricular dysfunction (SOLVD) and Candesartan in Heart Failure Assessment of Reduction in Mortality (CHARM) studies, concomitant AF with HFrEF was associated with increased cardiovascular mortality and HF hospitalizations. HF events exceed stroke in this combined AF and HF population. Fig. 3 shows the frequency of HF and stroke events during long-term follow-up in the absence or presence of AF in subjects with HF.
Fig. 4 shows the impact of AF in HFrEF. As illustrated, the presence of AF at baseline increased the relative risk of HF hospitalization by 29% (left panel) and all-cause mortality by 38% (right panel).
Atrial Fibrillation in Heart Failure with Preserved Ejection Fraction
Clinical studies in HFpEF have defined the independent role of AF in HFpEF. In early studies, the adverse impact of AF associated with HFpEF was noted. Fig. 4 shows the impact of AF in HFpEF. As illustrated, the presence of AF at baseline increased the relative risk of HF hospitalization by 72% (top panel) and all-cause mortality by 80% (lower panel) in the CHARM trial. In the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) study, presence of AF increased risk of cardiovascular death/aborted cardiac arrest and HF hospitalization by 38%. These excess in adverse cardiovascular outcomes were ascribed to AF identifying a subset of HFpEF subjects with more likelihood of adverse outcomes.
Saksena and coworkers amplified these findings and established that AF is an independent risk factor for worsening HF and pump failure death. Using propensity score matching to take the role of comorbidities off the table in the TOPCAT Americas study of subjects with HFpEF, they examined the role of AF patterns or varying AF burden on cardiovascular outcomes. Key findings are illustrated in Fig. 5 .
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In these subjects, any AF event was associated with increased cardiovascular (CV) hospitalization risk (HR 1.33, 95% confidence interval [CI] 1.11 to 1.61, P =.003), HF hospitalization risk (HR 1.44, 95% CI 1.12–1.86, P =.004), pump failure death (PFD; HR 1.95, 95% CI 1.05–3.62, P =.035), and HF progression from New York Heart Association classes I/II to III/IV (HR 1.30, 95% CI 1.04–1.62, P =.02). AF on electrocardiogram (ECG) more likely a high AF burden pattern was associated with increased risk of CVD (HR 1.46, 95% CI 1.02–2.09, P =.039), PFD (HR 2.21, 95% CI 1.11–4.40, P =.024), and CVH and heart failure hospitalization (HFH) (HR 1.37, 95% CI 1.09–1.72, P =.006 and HR 1.65, 95% CI 1.22–2.23, P =.001, respectively).
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AF was not associated with risk of sudden death (see Fig. 5 B). Both any AF and AF on ECG cohorts were associated with increased risk of worsening HF pump failure death in the New York Heart Association (NYHA) class III/IV subjects (see Fig. 5 C, D). Barring the unlikely event that future randomized clinical trials can effectively randomize matched subjects with and without AF in these 2 HF phenotypes; these data provide the most robust evidence support the basic science models of AF and HF. They establish that AF promotes HF progression and pump failure death. They provide important insights into the pathogenesis of adverse cardiovascular outcomes in AF with HF and how treatment strategies may target critical steps in the chain of events.
Treatment strategies for atrial fibrillation and heart failure
In considering treatment strategies, current guidelines have now evolved for both conditions based on the clinical classifications outlined earlier. Guideline-directed medical therapy (GDMT) segregates the strategy for individuals at risk for either condition or comorbidities as well as those with subclinical structural and electrophysiologic substrates for HF and AF, respectively. These are detailed elsewhere in this text (Monte and colleagues’ article, “ Atrial Fibrillation Management with Guideline-Directed Medical Therapy and Comorbidity Treatment in Heart Failure Patients ,” in this issue). Strategies for individuals with symptomatic AF and HF (Stage 3) include treatment directed at the arrhythmia with its consequences and GDMT for symptomatic HF. The latter will be considered elsewhere in this text.
Antiarrhythmic approaches include those directed at ventricular rate control during AF (rate control strategy) or restoration of normal sinus or atrial paced rhythm (rhythm control strategy). It bears pointing out that rhythm control results not only in restoration of atrioventricular synchrony but also ventricular rate control, that is, rate and rhythm control. As such the term “rhythm control strategy” by definition incorporates rate control.
Evolving treatment strategies in atrial fibrillation
Medical management of AF is a stepwise process. It is also dictated by clinical presentation, hemodynamic status, and ventricular rate during AF. It is also influenced by availability of therapeutic options, their overall efficacy, and safety and their risk profile in the individual patient. This risk profile is related to age and existing comorbidities. The relationship of HF promoting AF and AF leading to HF emergence or worsening is germane to therapeutic decision-making and algorithm. An example of the former can included structural heart conditions, such as worsening mitral valvular insufficiency that may make AF difficult to manage with either treatment strategy unless the underlying structural disease and its atrial sequelae are addressed. In the latter instance, HF management may prove problematic with symptomatic sustained AF with uncontrolled ventricular response. In individuals with AF and HF, stroke risk is increased and oral anticoagulation therapy is recommended as a first step in the treatment algorithm. GDMT for HF is also considered an essential initial step and its use and optimizations discussed in Chapter 6 Atrial Fibrillation Management with GDMT and comorbity treatment in Heart Failure patients in this text. Management of comorbidities is also essential background therapy in these individuals with AF and HF and is discussed elsewhere.
Principles of a rate control strategy
The association of symptoms in AF with ventricular rate is well established. Rapid rates are commonly associated with palpitations, dyspnea, chest discomfort, and even syncope or near syncope. The rationale for rate control approaches is initially for symptom control and secondarily improved outcomes for the patient. As mentioned in the introduction, digitalis use from the foxglove was associated with slower pulse and even regularization of the pulse. , Currently used agents have a common property of atrioventricular nodal blockade, which allows for rate control during AF. These include beta-blockers and calcium blockers along with digoxin or its analogues. A non-pharmacologic option is the therapeutic of catheter or surgical ablation directed at the AV node or His bundle and insertion of pacemaker or implantable cardioverter defibrillator (ICD) device.
Observational studies on rate control were first conducted with digitalis and its analogues in the 1960s and 1970s to control ventricular rate in AF. It was recognized early on that effective AV nodal blockade with digitalis was not inevitable. , Furthermore, efficacy of AV nodal blockage was attenuated with exercise. To address limited efficacy, digitalis was combined with recently developed beta-blocking compounds for increased effectiveness in observational studies. Combination of digoxin with beta-blocking agents such as atenolol, metoprolol, or sotalol improved heart rate (HR) control. Placebo-controlled studies were initially undertaken with beta-blockers and verapamil in both supraventricular tachycardia and AF. These studies demonstrated their value in ventricular rate control in AF and established their primary role for rate control in AF events. Both intravenous and oral formulations and newer iterations of each class of agents were effective in rate control. , These experiences established the principles of rate control requiring rate control at rest and exercise, and use of monotherapy or combination therapy if needed.
Rate control permitted both reduced symptomatology and improved exercise capacity and improvement in functional measurements including 6 minute walk test and VO 2 max. In the AFFIRM trial, strict rate control was required with targets for resting and exercise heart rates. Different levels of rate control have also been evaluated. In RACE II, a total of 614 patients with permanent AF were randomized to lenient (resting heart rate 110 beats/min) or strict (resting heart rate 80 beats/min, heart rate during moderate exercise 110 beats/min) rate control. There was no difference in quality-of-life scores in the 2 groups. Other studies from the same group showed no differences in functional or quality of life or survival with the 2 methods of rate control in AF with HF.
Similarly, the introduction of AV junctional ablation led to more effective rate control along with the need for cardiac pacemaker implantation. AV nodal ablation and permanent pacemaker implantation were first evaluated for symptoms and functional/objective end points in the Ablate and PACE trial in1998. There was an improvement in most quality-of-life scores after the procedures with improvement in NYHA functional class but no change in treadmill exercise duration and V o 2 max from pre-ablation values. LVEF improved to a modest extent at 3 months but was unchanged at 12 months. Survival at 1 year was 85.3%. Since this study was done, we are now very aware that right ventricular pacing causes left-ventricular dyssynchrony in about half of patients, but the reason for improved or maintained left ventricle (LV) systolic function may be the elimination of the rate-related tachycardiomyopathy. An earlier metanalysis of 6 AF trials did not show evidence of improved mortality or morbidity with atrioventricular junction (AVJ) ablation and pacing versus drug therapy for rate control. However, some end points trended to improve with cardiac resynchronization therapy. Many subsequent studies have championed other pacing modes including cardiac resynchronization pacing and most recently conduction system pacing. In the APAF-cardiac resynchronization therapy (CRT) study, permanent AF subjects with HF hospitalization(s) showed improvement in all-cause mortality with AVJ ablation and cardiac resynchronzation therapy compared to pharmacologic rate control. However, the irreversible nature of this form of ablation and long-term pacing device therapy has been a limiting factor in its acceptance as an early therapy for rate control in paroxysmal or persistent AF. Nevertheless, it remains as option for refractory permanent AF subjects with symptomatic HF, who are candidates for cardiac resynchronization therapy for HF. ,
Principles of rhythm control strategy
The use of rhythm control agents commenced with observational case reports on quinidine. It was used for both prevention of recurrent AF and prior to electrical cardioversion. Quinidine was shown to be efficacious in observational and crossover studies with placebo in preventing recurrent AF. , Early on, an adverse effect recognized as “quinidine syncope” was noted which later was determined to be drug-induced polymorphic ventricular tachycardia that required treatment with intravenous bretylium and other agents. , Comparative studies with other agents for AF prophylaxis, such as the class 1A drug disopyramide and class 3 drug sotalol, showed comparable efficacy in AF subjects without HF. , Limitations of use of several antiarrhythmic drugs in AF with HF have emerged, particularly HFrEF and symptomatic HF. Negative inotropic effects of disopyramide and with sotalol at moderate to high doses were present limiting their use. Class 1c drugs are also avoided in this category. Most recently, increased mortality has been noted with dronedarone in long-standing persistent or permanent AF and symptomatic HFrEF or advanced HFrEF. , It is also precluded after a recent acute HF event but its use in AF with HFpEF has been deemed safe. , , Amiodarone and dofetilide have both been safely used in HFrEF with and without symptoms and other forms of HF. , Conversion of AF to sinus rhythm in AF subjects with HF is often seen with both drugs and both are also used for prophylaxis to prevent recurrent AF. , Current practice guidelines provide a detailed algorithm for selection of individual antiarrhythmic drugs in the subset of AF patients with HF.
Rate versus rhythm control: evolution in management
By the last decade of the twentieth century, both treatment strategies employing antiarrhythmic drugs for AF were available, deemed beneficial to patients, and considered mature. A comparative trial for these 2 approaches was needed. The AFFIRM trial was designed with this consideration in mind, primarily focusing on available drug therapy. At the time of planning, early options in nonpharmacologic therapy were emerging that were permitted in either strategy including AV junctional ablation, catheter ablation of atrial flutter occurring concomitantly with AF, and atrial pacing methods. The trial included subjects with AF who were deemed to have significant risk of stroke and mortality. Both strategies showed similar impact on all-cause mortality in these patients with AF. The results suggested that either strategy was acceptable as first-line therapy. Since publication, the trial data have been scrutinized extensively in the past 2 decades. Importantly, the success in maintaining sinus rhythm in the rhythm control strategy was modest (62.5% at 5 years), while sinus rhythm was present in the rate control strategy subjects in 25%. The subgroup with AF and HF comprised 939 subjects (23.1%) whose outcomes were similar to the overall population. However, a post-hoc analysis of propensity score-matched AF subjects with a history of HF revealed important differences for HF end points. One-half of this subgroup was included in the propernsity score matched (PSM) analysis. These subjects with AF had a history of HF but were in NYHA class 1 or better at enrollment in the study. The outcome with rate and rhythm control strategies was compared.
Table 1 shows the baseline characteristics of this population. They were well matched and HF drug therapy was comparable (see Table 1 ).
