Chapter Outline
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Atrial Myopathy and the Changing Atrial Substrate, 91
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Atrial Remodeling, 92
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The Importance of Atrial Remodeling, 93
Atrial fibrillation (AF) is a potentially lethal arrhythmia, and unfortunately, its prevalence in the general population is increasing annually (see Chapter 2 ). From an interventional therapy standpoint, the two critical components of AF are the “triggers” that induce it and the “substrate” that sustains it. The types of AF triggers and their characteristics are discussed in detail in other chapters of this book, so this chapter focuses on the electrical and anatomic components of the substrate that sustains AF and how that substrate can change over time through a process called “atrial remodeling.” Atrial remodeling can include changes in both the electrical characteristics of the atria (electrical remodeling) and changes in atrial anatomy such as enlargement, hypertrophy, and scarring (anatomic remodeling).
Atrial Myopathy and the Changing Atrial Substrate
Unlike sustained ventricular arrhythmias that are life-threatening if not addressed immediately, AF usually does not pose an imminent threat to a patient’s life. The normal atrial substrate in patients without AF can evolve over time into a form of atrial cardiomyopathy, or atrial myopathy, that is capable of sustaining AF. Patients with structural heart disease, such as severe mitral insufficiency, often develop atrial myopathy before they experience AF, which can impact the decision on how to treat the AF. In addition, multiple episodes of AF and prolonged periods of AF can themselves aggravate atrial myopathy, leading to a spiraling of the entire pathophysiologic process.
Atrial stretch, inflammation, oxidative stress, and neurohumoral influences can initiate the development of atrial myopathy even in patients without structural heart disease. Atrial myopathies can result in electrical, functional, structural, and autonomic remodeling of the atrial substrate. In addition, the natural aging process and acquired structural heart disease can also lead to significant degenerative and fibrotic alterations of the atrial tissue, predisposing patients to develop AF. Natural aging and structural heart disease can also be associated. This may lead to significant degenerative, fibrotic, and other cellular and subcellular changes of the atrial tissue, predisposing patients to develop AF. In patients with advanced atrial tissue changes, the type of AF may “skip” the usual natural history of the arrhythmia from paroxysmal through persistent to long-standing persistent AF (LSpAF) with a significant burden of AF from its first event. Therefore, relating the type of AF to a certain pattern of ablation lesions may be too simplistic and can result in the potential for much higher failure.
Atrial fibrosis is an important component of atrial remodeling and is not only the result of the natural progression of AF; it is also a consequence of multiple catheter-based ablation procedures that leave scars throughout the atrial tissue. Thus, it is necessary to distinguish between the different precursors of atrial fibrosis. Changes in the atrial substrate related to the natural history of AF should be assessed in relation to potential interventions that may attenuate or modify the progression of the disease. One of the most significant pathophysiological processes in the development and progression of AF substrate change is the infiltration of fibrous tissue into the intermuscular atrial muscle space, a condition that is referred to as “endomysial” fibrosis.
Endomysial fibrosis is associated with atrial muscle dissociation and may exert its most important impact on the development of AF by promoting endocardial–epicardial dissociation that can modify atrial electrical activity , by facilitating three-dimensional reconfiguration of the atrial substrate. This enables the electrical waves to travel from one muscle layer to the other and increases the possible pathways for fibrillating waves, electrical fractionation, and dissociation. . The endomysial fibrosis phenomenon is especially significant in atrial areas with an abundance of atrial muscle fiber with clear orientation such as the posterior wall of the left atrium (LA). In the 1960s, the “multiple wavelet theory” was proposed by Gordon Moe, describing how multiple wavefronts intersect with each other, leading to the breakdown of fibrillation wavefronts and the formation of new wavefronts. Later, de Groot and associates showed that in many instances of AF, the atrial mass becomes large enough and the wavelengths short enough to allow “electrical triggers” to propagate and facilitate the formation of new reentrant wavelets. However, Cox and his group showed the presence of multiple macro-reentrant circuits in the atria during AF that they believed to be the mechanism by which AF is sustained, and their findings served as the basis for the surgical Maze procedure and some catheter ablation procedures.
It is important to use caution when analyzing patients with AF after failed catheter ablations, especially when attempting to explain the mechanism of failure based on information that was gathered in patients with no prior catheter or surgical ablation procedures. The scar tissue created by catheter or surgical procedures themselves can modify the atrial substrate in a way that, if incomplete, can lead to AF. Subsequent electrophysiological mapping will then demonstrate only the mechanism of the recurrent AF secondary to failed ablation because it is no longer mapping the natural history and the pathophysiologic evolution of the original clinical AF. These types of findings may have ramifications related to treatment option decisions.
Atrial Remodeling
The LA serves as a reservoir, conduit, and volume booster and is not primarily a contractile chamber (see Chapter 43 ). Normal function of the atria is fundamental to maintaining optimal blood flow and allowing for adaptation to certain changes in ventricular function such as diastolic dysfunction. Normal function of the LA is also paramount in reducing the risk of clot formation and systemic thromboembolism. AF is associated with a significant disruption of normal atrial function, but it also results in the induction of atrial remodeling. Atrial remodeling is a progressive process, and its severity is not always directly associated with the type of AF, the duration of AF, or the size of the atria. The dynamic and progressive nature of atrial remodeling leads to more frequent and widespread electrophysiologic abnormalities that further promote the perpetuation of AF, leading to the phrase “AF begets AF.” The three types of atrial remodeling are electrical remodeling, functional remodeling, and structural remodeling.
Electrical Remodeling
The first signs of electrical remodeling can be identified within hours to several days after the onset of AF. The primary indicator of electrical remodeling during the early stages of AF is a shorter action potential duration that occurs as the result of acutely modified ion channels. Acute electrical remodeling early on in the course of AF with rapid ventricular response plays a seminal role in compensating and achieving Ca 2+ homeostasis. The rapid atrial rate ultimately leads to intracellular calcium overload. High intracellular calcium levels are cytotoxic. Therefore, autoprotective cellular mechanisms are activated to target and control the excess Ca 2+ . These adaptive mechanisms lead to hyperpolarization and shortened action potentials.
Gap junction modification and alteration also occur early in the course of AF and play a major role in the development of macro-reentrant circuits. This process involves alteration in the function of connexins composing the gap junction channels that facilitate the electrical coupling of atrial cells. In general, the process results in dysfunctional gap junctions, varying in severity, throughout the atrial tissue and reduced conduction velocity. The combination of a shorter refractory period and reduced atrial conduction velocities leads to significantly shorter atrial wavelengths, making them much more likely to become self-perpetuating. These changes become even more arrhythmogenic when there is a large enough atrial mass (or area) to allow multiple macro-reentrant circuits to exist simultaneously in the atria, the very definition of AF (see Chapters 4 and 5 ). What starts as an autoregulation process to control the excessive Ca 2+ influx results in a self-perpetuating process that drives AF.
Functional Remodeling
Functional remodeling is most often associated with an elevated risk for thromboembolic events and stroke caused by the loss of synchronized atrial contraction in patients with AF. However, the importance of reduced atrial function goes beyond the increased risk of embolic events. To understand the role of functional remodeling in patients with AF, attention should be directed toward the impaired atrial emptying function that occurs during an episode of AF and that may or may not be restored when patients either spontaneously revert or are converted back into sinus rhythm. The severity and the duration of atrial capacitance abnormalities and contractile dysfunction varies and is somewhat dependent on the duration of AF. Therefore, the risk of thrombus formation secondary to atrial dysfunction during AF has to be monitored carefully in patients with AF. , The functional remodeling process can be defined as a total loss or diminished capacity of the atrial muscle’s ability to stretch and contract normally. It is obvious that there is no effective atrial contraction during AF, but functional remodeling is often associated with reduced contractility function even when sinus rhythm is restored. Functional remodeling cannot be dissociated from electrical remodeling because it too is involved in the cellular processes that occur after Ca 2+ influx into the cells as a result of AF and atrial tachycardia. The compensatory process to autoregulate the calcium levels occurs from, among other things, the activation of specific proteases that lead to the destruction of the Ca 2+ channels and sarcomeres. A brief period of AF allows recovery of the atrial myocardium, but a longer period of AF leads to irreversible damage and significant sarcomere destruction and loss.
It is challenging to define the precise contribution of each component of atrial tachycardia-induced ventricular dysfunction because it may vary with the duration of the atrial arrhythmia, coexisting heart disease, drug therapy, and other potential factors. Therefore, the treatment of the underlying cause of the atrial tachycardia that is causing the ventricular cardiomyopathy may be more effective than treatments that address downstream consequences in the ventricle. It is important to recognize that in many patients, other coexisting cardiac conditions may have preceded the tachycardia-induced cardiomyopathy such as chronic volume overload associated with mitral valve disease or systolic and/or diastolic ventricular dysfunction. Volume overload leads to atrial dilatation and atrial stretch, causing increased atrial wall stiffness and reduced atrial compliance.
Structural Remodeling
Like electrical and functional remodeling, structural remodeling is tightly linked to the progression of AF and is considered to be the consequence of multiple episodes of AF with varied durations. However, the notion that AF is more complex and persistent because of time-dependent structural remodeling alone should be viewed with caution, especially in surgical patients undergoing concomitant cardiac surgical procedures. The associated structural heart anomalies, such as mitral valve insufficiency, can cause structural remodeling of the atria before the first AF episode has occurred, so that the remodeling may not be directly related to the number of AF episodes and their duration. Atrial structural remodeling is usually a combination of atrial dilatation and changes in atrial tissue architecture caused by the destruction of cardiomyocytes from enzymatic or apoptotic activity, modification in extracellular matrix function, and increased production of fibroblasts, leading to fibrosis and, in extreme situations, calcification. In advanced states of atrial structural remodeling, dissociation of atrial muscle is observed because of a phenomenon that was mentioned earlier this chapter, endomysial fibrosis. ,
Increased epicardial fat or adipose tissue is another significant aspect of structural remodeling. As surgeons, we often see a large amount of epicardial fat when operating on patients with AF, but the fat becomes more significant when it infiltrates the atrial myocardium. This can lead to electrical instability, which may impede the ability to ablate the atrium adequately as part of the treatment of AF. Adipose tissue accumulation can also be detrimental to tissue energy consumption, inflammation, and fibrosis. As mentioned, epicardial adipose tissue accumulation is more prominent in patients with persistent and LSpAF than in most patients with paroxysmal AF (PAF). This observation is consistent with the observation that patients with persistent AF usually exhibit more advanced structural remodeling than patients with PAF. ,
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