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  Disease summary:

  
  
  
  
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    Atrial fibrillation (AF) is the most common clinical arrhythmia (affecting ~10% of those in the seventh decade of life) and is a major cause of morbidity and mortality. AF is traditionally regarded as a sporadic, nongenetic disorder, but the ability to sustain the arrhythmia has long been known to require some underlying diathesis. There is growing evidence of an important heritable basis for many forms of AF, with the recent identification of several genetic determinants.

    
    
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    In AF the normal electrical impulses that are generated by sinoatrial node are replaced by waves of disorganized electrical activity that result from a combination of very rapidly firing triggers and abnormal conduction within local atrial re-entry circuits. This prevents co-ordinated contraction of the muscle which instead fibrillates in an uncontrolled manner (this leads to the arrhythmia’s name). As a result the impulses reaching the ventricle to generate the hemodynamically important contracile activity are also highly irregular.

    
    
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    The arrhythmia involves the two upper chambers (right and left atria) of the heart, though in some instances the origins of the rapid electrical triggers may be in bands of cardiac muscle that envelop the ends of the pulmonary veins as they insert into the posterior aspect of the left atrium.

    
    
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    Clinical presentation: AF most often arises in the setting of other forms of heart disease, though there is evidence of shared mechanisms across these different contexts. AF may also arise in the absence of evidence of any associated cardiac disorder, so called lone AF. AF is often asymptomatic, but it may result in palpitations, dyspnea, chest tightness or pain, and even congestive heart failure (HF) in those predisposed. Individuals with AF have an increased risk of stroke both embolic and hemorrhagic. There may be typical precipitants for AF episodes including exercise or sleep.

  
  

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  Differential diagnosis:

  
  
  
  
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    There are few other arrhythmias which exhibit the rapid irregular rhythm seen in AF. One arrhythmia that may be confused with AF is atrial flutter which results from a more organized macroreentry circuit, most commonly in the right atrium. As a result of the anatomic nature of the flutter circuit the atrial electrical activity is much more regular in nature, and AF can be distinguished from atrial flutter as the latter exhibits characteristic saw-toothed flutter waves of constant amplitude and frequency on a standard electrocardiogram. Importantly, there is no evidence of organized atrial activity on the electrocardiogram in AF, but both rhythms may result in irregular ventricular rhythm because of the nature of conduction between the atrium and the ventricle.

  
  

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  Monogenic forms:

  
  
  
  
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    There are several genetic loci that have been reported in large kindreds with Mendelian AF (Table 21-1).

  
  

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  Family history:

  
  
  
  
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    Estimates of the sibling recurrence risks range from 1.5- to 70-fold depending on the population that has been studied and the intensity of ascertainment. In a chart review of more than 2000 patients referred to arrhythmia specialists for managment of AF, investigators at the Mayo Clinic found that 5% had a family history of AF. This number was as high as 15% among patients with lone AF. Nearly 40% of individuals with lone AF referred to an electrophysiologist had at least one relative with the arrhythmia, and a substantial number reported having multiple relatives with AF.

  
  

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  Twin studies:

  
  
  
  
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    In a representative study, concordance rates were twice as high for monozygotic pairs than for dizygotic pairs regardless of gender, 22.0% versus 11.6% (p <.0001). Estimates of the heritability of AF are approximately 62% (55%-68%) under an additive model.

  
  

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  Environmental factors:

  
  
  
  
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    Numerous environmental factors have been associated with AF. The most obvious such factors include a wide range of acquired cardiac disorders: hypertension, coronary artery disease, some forms of valvular heart disease, congestive HF, and prior cardiac surgery. In some of these there may be shared heritable contributions to both AF and the underlying condition. AF is also associated with other acquired disorders including a number of pulmonary diseases such as pneumonia, lung cancer and pulmonary embolism, thyroid disorders, and systemic inflammation or infection. Other well-substantiated stimuli for AF are obesity, diabetes, and excessive alcohol consumption.

  
  

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  Genome-wide associations:

  
  
  
  
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    Multiple associations exist including a major locus on 4q25 that exhibits one of the largest effect sizes observed in genetic association studies to date. Interestingly, this locus is also associated with atrial flutter.

  
  

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  Pharmacogenomics:

  
  
  
  
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    There are currently no specific pharmacogenetic management strategies for AF, however, there is an emerging literature on the pharmacogenetics of warfarin use (see Chap. 6).

  
  

The fundamental diagnostic criteria for AF are

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  Absence of an organized atrial rhythm

  
  
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  Irregular conduction of electrical impulses to the ventricle

Diagnostic evaluation should include

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  History and physical examination

  
  
  
  
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    Characterization of the presence and extent of symptoms

    
    
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    Definition of the type of AF (newly diagnosed, paroxysmal, persistent, or permanent); see Table 21-1

    
    
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    Possible precipitating factors including exercise, sleep apnoea, alcohol, or other known environmental contributors

    
    
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    Response to pharmacologic agents (if any)

    
    
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    History of underlying heart disease or precipitating factors for AF (eg, hyperthyroidism, alcohol)

  
  

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  Electrocardiography to define other cardiac conditions. Importantly, ventricular pre-excitation should be excluded as this impacts therapy directly. In addition, in paroxysmal cases Holter monitoring may allow the burden of AF to be assessed independently from any symptoms.

  
  
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  Transthoracic echocardiogram to assess for structural heart disease, to define cardiac chamber sizes, and to exclude pericardial disease or other rare contributors such as cardiac tumors.

  
  
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  Chest radiograph to evaluate lung parenchyma and pulmonary vasculature.

  
  
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  Laboratory evaluation should include baseline assessment of thyroid, renal and hepatic function, as well as markers of any clinically suspected contributing conditions. In addition, it is important to define baseline coagulation parameters.

Clinical Characteristics

AF often presents with isolated self-terminating episodes in its earliest stages, but these transient manifestations are themselves evidence of an underlying diathesis, in particular if they occur in the absence of any other cardiac disease. The natural history of such paroxysmal AF is that the episodes will tend to become more frequent and prolonged, often requiring intervention in the form of direct current cardioversion to revert to sinus rhythm. Where AF is associated with other cardiac or medical problems, the natural history parallels that of the underlying disorder. Ultimately, a substantial proportion of those with AF will develop persistent or permanent AF. While this is typically in old age, in those where the inherited contribution is greatest permanent AF may supervene earlier in life.

Many different triggers are recognized by patients and their physicians including exercise, alcohol, sleep, or fevers. While these triggers may act in a very precise manner, such as onset of AF at a specific heart rate during exercise, they do not appear to discriminate distinctive natural histories. Different triggers will often segregate within the same extended kindreds with AF, where presumably the same primary underlying mechanism is shared. There is also considerable variation in the extent of symptoms in paroxysmal AF, which is associated with different success rates for management and may reflect intrinsic differences in the biology.

Heart Failure Risk