Heart Fail Rev DOI 10.1007/s10741-014-9424-0
Atrial fibrillation as manifestation and consequence of underlying cardiomyopathies: from common conditions to genetic diseases Adam Mohmand-Borkowski • W. H. Wilson Tang
Ó Springer Science+Business Media New York 2014
Abstract While atrial fibrillation is common comorbidity in patients with cardiomyopathy and heart failure, diagnosis and management often focuses on tackling rate and rhythm control rather than elucidating pathogenic mechanisms related to underlying myocardial substrates. This review summarizes our current understanding of the natural history of cardiomyopathies presenting with atrial fibrillation, and the importance of managing underlying cardiomyopathic condition as diagnostic and treatment strategy for atrial fibrillation. Keywords
Atrial fibrillation Cardiomyopathy Genetic
Introduction The pathogenesis of atrial fibrillation (AF) is multifactorial, with the classic teaching focusing on factors that trigger, perpetuate, and sustain the tachyarrhythmia. It is believed that frequent short-terminating episodes (paroxysmal AF) are mostly dependent on trigger mechanisms, whereas perpetuating factors and pathologic substrate sustain the arrhythmia and play the crucial role in patients who progress to persistent AF. Although there are multiple AF triggers, many do not necessarily cause sustained AF in the absence of perpetuating factors and/or underlying pathologic substrate. However, once triggered, AF may be selfsustained, with no further need of triggering activity to maintain tachyarrhythmia.
A. Mohmand-Borkowski W. H. W. Tang (&) Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic, 9500 Euclid Avenue, Desk J3-4, Cleveland, OH 44195, USA e-mail: [email protected]
Much attention has focused on the elimination of AF triggers (such as radiofrequency ablation of the premature atrial complexes from the pulmonary veins). Current clinical guideline classifications of AF (paroxysmal, persistent, longstanding persistent, or permanent) and their management largely focus on the expected temporal and rhythmic evolution of AF progression rather than their underlying pathophysiological processes. These approaches appear to be successful only in selected patients, while others may be ‘‘refractory’’ and continue to progress despite adequate rate and rhythm control. There is growing recognition that the role of underlying myocardial substrate serves as an important driver of the development, progression, and maintenance of diseases with AF as a manifestation. It is conceivable that AF may serve as an initial presentation of underlying cardiomyopathy, and this may explain why some AF cases are more refractory to treatment and portend poor prognosis. Regardless, the presence of AF in patients with underlying heart failure (HF) portends poor prognosis. In the Framingham Study analysis of 708 patients with heart failure who were in sinus rhythm at baseline, 159 patients (22 %) developed AF at an average of 4.2 years of follow-up. Importantly, development of AF in heart failure patients in this analysis was associated with 2.7-fold increased risk of death in women and a 1.6-fold higher risk in men [1]. Additionally, data from the Olmsted County cohort demonstrated that compared with patients without AF, those with AF prior to HF had a 29 % increased risk of death, whereas those who developed AF after HF exhibited [2fold increased risk of death [2]. This review summarizes our current understanding of the natural histories of several cardiomyopathies with AF and HF as common manifestations, and the importance in tackling the presence of underlying cardiomyopathic condition as diagnostic and treatment strategies.
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Contribution of cardiomyopathy in atrial fibrillation Morphologic substrate to maintain AF triggers It is important to emphasize that the presence of underlying structural heart disease remains to be one of the most common contributors to AF pathogenesis. Cardiomyopathy may serve as a morphologic substrate (or ‘‘second factor’’) developed as part of the natural history that is necessary for AF triggers to become sustained. The most common example is the development of AF in patients without history of structural heart disease, in the setting of inflammation and oxidative stress related to myopericarditis (e.g., following cardiac surgery). Other examples include development of cardiac fibrosis in both ischemic and non-ischemic cardiomyopathies, or age-related degeneration of atrial tissue and widespread conduction slowing. Although separate terms of atrial electrical and structural remodeling in AF are frequently used, growing data evidence suggest that it is a tightly interconnected process at the cellular level. Hypertensive cardiomyopathy is a common structural heart disease regarded as a morphologic substrate of AF that leads to progressive atrial myopathy. In the Framingham Heart Study, the rate of AF was 1.42 times increased in men with a history of hypertension [3]. Although the risk of AF increases by 28 % for every 4 mm increase in left ventricular wall thickness, it does not appear to have a linear correlation with degree of hypertrophy and associated hemodynamic alternations. This observation is supported by the fact that 21 % of patients with hypertension showed enlarged left atrial dimension [4 cm without left ventricular hypertrophy [4]. Many of them also have underlying sleep-disordered breathing, which also compounds the sympathetic activation leading to further AF triggers. Atrial stretch and loading as AF trigger and perpetuating factor Pressure or volume overload associated with the progression of structural heart disease changes electrophysiologic and morphological properties of atria in humans and, in turn, facilitates the occurrence of AF in these patients. Examples include hemodynamic and structural changes in the hypertensive cardiomyopathy, valvular heart diseases, as well as restrictive cardiomyopathies such as cardiac amyloidosis. Acute increase in atrial volume and pressure leads to changes of atrial electrophysiologic properties in conduction and refractoriness. It shortens, the atrial effective refractory period proportionally to a degree of stretch decreases conduction velocity in atrial tissue and increases
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spatial heterogeneity in conduction creating substrate for AF via shortening the reentrant wavelength and favoring functional block. This can also lead to the loss of rate adaptation, increase in effective refractory period dispersion and regional slowing of conduction, increased refractoriness, and sinus node dysfunction [5]. Increase in intra-atrial pressure and atrial stretch can occur as a consequence of worsening hemodynamics in HF patients (e.g., increased left ventricular systolic pressure and/or increased left ventricular end-diastolic volume). Increase in intra-atrial pressure was shown in animal models to increase the propensity of the pulmonary vein junction to induce focal activity or sustain reentry [6]. As such, atrial stretch may be responsible not only for sustaining but also for triggering an arrhythmia [7]. These factors may explain the propensity of patients with acutely decompensated HF to develop AF. In fact, acute hemodynamic changes even in patients with subclinical cardiomyopathy can potentially induce AF paroxysm. Clinical evaluation for triggers of acute atrial stretch (e.g., labile hypertension in patients with no structural heart disease, or acute increase in left ventricular end-diastolic volume in patients with HF) should be an integral part of management of patients with paroxysmal or persistent AF [8]. In the course of chronic atrial pressure and volume overload, atrial dilatation, atrial myocyte hypertrophy, and interstitial fibrosis occurs and creates a substrate for AF [5]. Stretch-activated channels can be activated by smaller mechanical stimuli [9], and slowing of conduction transverse to the cellular orientation is observed in the presence of cellular hypertrophy [10]. Tissue fibrosis increases anisotropy in conduction and the dispersion of refractoriness, which further facilitate AF [11]. Atrial fibrosis may be influenced by multiple factors (e.g., patient hemodynamic status) as exemplified by the observation that freshly isolated atrial fibroblasts from HF patients display distinct extracellular matrix gene expression and morphological differences as control atrial fibroblasts [12]. Selective changes of natriuretic peptide convertases like corin and furin may also have significance in the regulation of pronatriuretic peptide processing and atrial remodeling in early stages of HF [13]. In addition, AF itself can lead to atrial dilatation, thereby increasing the probability of persistence of AF and further structural remodeling.
Atrial fibrillation as a consequence of underlying myopathic processes Often overlooked in everyday clinical practice, the presence of specific preexisting myopathic conditions (possibly genetically determined in some cases) may be responsible for some resistant to treatment cases of AF.
Heart Fail Rev Table 1 Manifestations of atrial fibrillation associated with cardiomyopathies Cardiomyopathy
Estimated AF prevalence (%)
Voltage
Accessory pathways
Conduction block
; LVEF
LVH
Known gene mutations
Fibrotic atrial
60–80
Low
No
Yes
No
No
Variable
Hypertensive
10–15
High
No
No
Subset
Yes
Variable
Hypertrophic
20–25
High
No
No
Subset
Yes
MHC7, MYBPC3, TNNT2
Glycogen storage
10–15
Low
Common
Yes
Subset
Yes
LAMP2, PRKAG2
Fabry
5–10
Low
No
Yes
No
Yes
GLA
Idiopathic dilated
20–25
Variable
Subset
Subset
Yes
Subset
LMNA, SCN5A
Idiopathic restrictive
75
Low
No
Yes
No
No
TNNI3
Non-compaction
20–25
Variable
No
Subset
Subset
Yes
G4.5/a-dystrobrevin/ZASP, TNNT2
Transthyretin amyloid
30
Low
No
Yes
Subset
Yes
TTR
Distinct AF characteristics associated with different cardiomyopathies are useful in differential diagnosis of underlying myopathy and choice of appropriate diagnostic testing (Table 1). Atrial myopathy Although atrial dilation is the most consistent risk factor of AF (risk of AF increases by 39 % for every 5 mm increase of left atrial diameter), the mechanistic link between atrial abnormalities and AF is complex. Observational data on patients with advanced dilated cardiomyopathy suggest that some cardiomyopathy patients do not develop AF despite severe LA enlargement, while others exhibit significant myopathy and fibrosis leading to refractory AF. Failure to explain inconsistency between clinical presentation and extent of structural left atrial abnormalities, as well growing evidence of progressive subclinical atrial disease in some patient with ‘‘lone AF’’ led to recognition of isolated atrial cardiomyopathy as a potential underlying cause of unexplained rapidly progressive AF. Fibrotic atrial cardiomyopathy Fibrotic atrial cardiomyopathy (FACM) is a primary disease with arrhythmic presentation varying from asymptomatic to severe atrial tachyarrhythmia, sinus node dysfunction, and conduction abnormalities being only a manifestation of underlying progressive atrial cardiomyopathy [14]. FACM represents a progressive fibrotic atrial disease in the absence of any other detectable underlying structural heart disease. Multiple areas of unidirectional block occur with multiple entry and exit points, in turn promoting the generation of new wavelengths. Additionally, dispersion of refractoriness is increased, thereby promoting AF in patients with atrial cardiomyopathy.
FACM as a primary diagnosis should be considered in AF patients with no other underlying heart disease and severity of associated tachyarrhythmia frequently disproportional to their atrial size. These patients frequently have a relatively short history of AF and have a low CHADS2 score, which leads to under appreciation of severity of underlying substrate and repeated failed attempts of rhythm control. Electroanatomic mapping of left and right atria in FACM reveals fragmented small electrograms and low voltages. Delayed enhancement magnetic resonance imaging (DE-MRI) appears to be the current noninvasive technique of choice for detecting atrial fibrosis and diagnosing FACM. Extent of MRIdetected left atrial fibrosis was shown to be independent of the type of AF and associated comorbidities, supporting the presence of subclinical cardiomyopathy causing fibrosis rather that AF-induced atrial remodeling [15]. Delayed enhancement MRI was also examined as a tool in detecting, quantifying, and localizing abnormal atrial tissue before catheter ablation. In the study on DE-MRI used for guiding a catheter ablation, the recurrence of AF after catheter ablation was dependent on the degree of delayed enhancement (lowest in the patient group with minimal enhancement and highest in the patient group with extensive enhancement) [16]. Importantly, not only extend but also location of delayed enhancement was predictive for a recurrence of AF after catheter ablation. Patient who had favorable ablation results had delayed enhancement limited to posterior wall and septum of left atrium, while patients who failed catheter ablation had delayed enhancement in all parts of the left atrium. A correlation between areas of enhancement on DE-MRI and low voltage on electroanatomic maps was seen in all patients [16]. As low voltage during invasive electrophysiology study has been shown to represent areas of fibrosis/scaring in
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anatomopathological studies, DE-MRI establishes its role as a valuable noninvasive tool to assess health of atrial tissue. Recently, progressive atrial electroanatomic substrate remodeling has been reported in FACM, despite successful catheter ablation. In this small study on AF patients with no apparent structural heart disease, follow-up with electroanatomic mapping at 10 ± 13 months after successful ablation revealed no reversal of remodeling. Further reduced voltage, worsening or no improvement in conduction, and prolongation of regional refractoriness were reported with only a reversal of left atrial dilatation [17]. Therefore, it appears that elimination of classic triggers of AF with PV isolation cannot stop the underlying progressive structural atrial disease. However, the ‘‘point of no return’’ when likely reversible electrical abnormalities in function of atrial ionic channels become associated with likely irreversible structural changes is not defined. Also, these patients may be challenging from a stroke prevention standpoint, as progressive atrial fibrosis leads to impairment of atrial mechanical function. Need for oral anticoagulation, even in the absence of other risk factors, should be carefully considered in patients with extensive atrial fibrosis. Mendelian inherited cardiomyopathies Recent discoveries of the genetic origin of many cardiomyopathies have changed our understanding of their pathogenesis and natural course as well as diagnostic approach and management. Common cardiomyopathies complicated by AF such as hypertrophic, dilated, restrictive, or metabolic cardiomyopathies are now known to be single-gene disorders. Additionally, genetic predisposition to AF and its association to inherited cardiomyopathies have been recognized by current AF guidelines [8]. As occurrence of these entities appears to be more common than previously thought, it is important to consider underlying genetic cardiomyopathies in patients (especially young and/or with positive family history) presenting with new onset of AF commonly in the setting of unexplained cardiomyopathy. Hypertrophic cardiomyopathy Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiomyopathy with the prevalence of 1:500 in the general population. Sarcomeric gene mutations in HCM are usually inherited as autosomal dominant, although de novo mutations in these same genes can also produce sporadic cases of the disease. Yield of clinically available genetic testing is estimated at 40–70 %. Most common gene mutations among HCM patients who have been
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successfully genotyped include beta-cardiac myosin heavy chain (MYH7) 30–50 %, myosin binding protein C (MYBPC3) 20–40 %, regulatory myosin light chain (MYL2) \3 %, essential myosin light chain (MYL3) \1 %, titin (TTN)\1 %, cardiac troponin T (TNNT) 25–20 %, cardiac troponin I (TNNI3) \5 %, alpha-tropomyosin (TPM1) \5 %, and actin (ACTC) \1 %. Characteristics of the disease (including left ventricular hypertrophy, diastolic dysfunction, abnormal sympathetic innervation, and enhanced myocardial fibrosis) promote developing AF. Dynamic changes in hemodynamics due to left ventricular outflow tract obstruction, elevated left ventricular enddiastolic pressures, and mitral regurgitation due to systolic anterior motion further increase the risk of AF. AF is the most common sustained arrhythmia in HCM and occurs in 20–25 % of patients with the incidence of AF typically increasing with disease duration [18, 19]. AF is poorly tolerated in patients with HCM, and the presence of AF with rapid ventricular response may be life-threatening in these patients leading to hemodynamic compromise and/or degeneration to ventricular fibrillation. Hence, AF rhythm control is highly recommended, because of poor hemodynamic tolerance of tachyarrhythmias [19]. It is important to recognize that the use of many antiarrhythmic drugs associated with increased risk of proarrhythmia is the setting of cardiac hypertrophy. Amiodarone is the drug of choice for maintaining sinus rhythm in HCM; however, considering its side effect profile, the rhythm control approach with catheter ablation may be preferred [8, 20]. Small study on patients with HCM and AF showed that PV antrum isolation is a feasible therapeutic strategy. Although AF recurrence after the first PV antrum ablation in HCM patients was almost 50 %, after second ablation rhythm control was achieved in 70 % of HCM patients (mean follow-up of 341 ± 237 days [21]. These original data were further supported by a recently published study, which showed that radiofrequency ablation was successful in restoring sinus rhythm and improving symptomatic status in most HCM patients with refractory AF, although redo procedures were often necessary. The study investigators found that mildly symptomatic, younger patients with HCM and small atrial size have the best chance of successful procedure outcome [22]. Additionally, outcome of catheter ablation in HCM patients is significantly better in paroxysmal AF than in persistent AF [8]. In HCM patients with AF undergoing myectomy, Maze procedure at the time of the surgery should be considered. Systemic anticoagulation is recommended indefinitely for HCM patients and AF. Rate control agents (beta-blockers or calcium channel blockers) are used as a first line to relieve symptoms in patients in sinus rhythm with left ventricular outflow tract obstruction. The presence of AF should be considered at the time of decision to implant a
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cardioverter defibrillator in HCM patients as it is associated with a higher risk of inappropriate shocks, particularly in the first year following implantation [8]. Metabolic cardiomyopathies In the setting of unexplained left ventricular hypertrophy, mutations have been described in non-sarcomere proteins that mimic the gross phenotype of HCM, which have been observed with progressive atrioventricular block, AF, ventricular preexcitation/Wolff–Parkinson–White (WPW) syndrome. Some of these patients may have underlying metabolic cardiomyopathies such as LAMP-2 mutations (so-called Danon’s disease), PRKAG2 mutations, and cardiac Fabry disease, in which AF may be the first clinical presentation. Left ventricular hypertrophy, diagnosed in imaging studies, is a typical feature of these cardiomyopathies, which commonly leads to misdiagnosis of HCM. Cardiac biopsy distinguishes these cardiomyopathies showing myocytes with vacuoles containing lipids (cardiac Fabry disease due to GLA mutations), glycogen (PRKAG2 mutations), or lysosomal remnants (LAMP2 mutations), and the absence of the prominent myocyte disarray seen in HCM [23]. The progressive and malignant nature of these diseases (often complicated by HF and tachyarrhythmias) frequently necessities prompt considerations for replacement therapies (e.g., listing for heart transplantation in patients without systemic involvement). Cardiac Danon disease is caused by mutation in the X-linked (Xq2) lysosome-associated membrane protein-2 (LAMP2) and often occurs in the first two decades in its adult forms. It may present as marked left ventricular hypertrophy occurring with subclinical systemic disease or a multisystem disorder involving heart muscle, the nervous system, liver, and the skeletal system. LAMP2 mutations are characterized by early disease onset (typically in childhood) and male predominance. Deficiency in lysosomal proteins causes hypertrophy and electrophysiologic abnormalities. The electrocardiogram in patients with Danon disease shows unusually high voltage and ventricular preexcitation. Massive concentric hypertrophy is frequently seen in echocardiogram, although LAMP-2 mutation may also present as dilated cardiomyopathy. LAMP2 cardiomyopathy is associated with the presence of accessory pathway leading to rapid AF as well as recurrent ventricular arrhythmias and often has high rates of sudden cardiac death in family histories [24, 25]. Like HCM due to sarcomeric mutations, AF is poorly tolerated due to the significant underlying cardiomyopathy. Danon disease is not infrequent cause of initially unexplained concentric left ventricular hypertrophy. Recent study investigated the prevalence of Danon disease among an unselected population of 50 patients with concentric left ventricular
hypertrophy who underwent endomyocardial biopsy. Genetic testing for LAMP2 mutations was done in patients, who had biopsy results negative for amyloid. The prevalence of Danon disease was 6 % in unselected concentric left ventricular hypertrophy patients or 8 % after excluding patients with cardiac amyloidosis in endomyocardial biopsies [26]. Protein Kinase Disorder-associated Cardiomyopathy caused by PRKAG2 mutations in chromosome 7q3, which is not associated with the systemic manifestations. Cardiac hypertrophy is present in 30–50 % of affected individuals. Patients frequently present in late adolescence or early adulthood with highly symptomatic tachyarrhythmias and cardiac hypertrophy. Atrial fibrillation is the most commonly associated tachyarrhythmia. Ventricular preexcitation is also common [27]. Progressive conduction system disease necessitates permanent pacemaker implantation in 30 % of patients with glycogen cardiomyopathy. Sudden cardiac death and/or rapid progression to end-stage HF may occur requiring listing for heart transplant [27]. Adequate anticoagulation for stroke prevention and rate control medications, as needed, are used to manage milder forms of disease [19]. Anderson-Fabry Disease is caused by GLA mutation resulting in deficiency of alpha-galactosidase A and glycosphingolipid deposits in cardiac myocytes. It is a rare X-linked lysosomal storage disease usually presenting as a systemic syndrome (cardiac hypertrophy, nephropathy, skin lesions, autonomic dysfunction, and sensorineural deafness) [23, 28]. Some patients have mostly cardiac involvement characterized by concentric left ventricular hypertrophy, arrhythmias, and conduction blocks. The shortened duration of the PR interval correlates with the severity of cardiac disease, and sudden cardiac death in Fabry cardiomyopathy is likely to be related to bradycardia [29]. ‘‘Lone AF’’ with under-detected presence of glycosphingolipid deposits in atrial cardiomyocytes can be a first manifestation of Fabry disease. Enzyme replacement of recombinant alpha-galactosidase A in early diagnosed patients can be curative, even though disease progression with arrhythmia and conduction blocks is not uncommon. Other specific cardiomyopathies Lamin A/C cardiomyopathy is responsible for up to 10 % of familial dilated cardiomyopathy cases and is one of the most commonly inherited forms of dilated cardiomyopathies associated with progressive AF. Patients with lamin A/C mutations frequently present with conduction system disease requiring permanent pacemaker placement. With progression of the disease, over half of the affected individuals may develop isolated AF in their fourth and fifth decade (some with earlier onset), which are largely
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refractory to standard therapies. Incidence of thromboembolic events in patients with lamin A/C deficiency approaches 30 % regardless of AF, and therefore, anticoagulation is recommended in these patients. With this constellation of conduction system disease, dilated cardiomyopathy, and AF, biventricular pacing and rate control with beta-blockers are usually recommended [19]. SCN5A-associated dilated cardiomyopathy has a variable phenotype related to the loss-of-function mutations of different segments of the voltage-sensitive sodium channels. There are many channelopathies that may contribute to underlying cardiac dysfunction, but they are often associated with ventricular tachyarrhythmia and sudden cardiac death. Often associated with long-QT syndromes, mutations in SCN5A were detected in 1.7 % of dilated cardiomyopathy families, and often linked to those with high prevalence of arrhythmia (including AF, ventricular tachycardia, sick sinus syndrome, or conduction blocks). Left ventricular non-compaction (sometimes referred to as spongy myocardium or hypertrabeculation syndrome) represents another poorly understood and challenging clinical condition. It often presents with altered myocardial wall with prominent trabeculae and deep intratrabecular recesses, and may be associated with neuromuscular disorders or other inherited cardiomyopathies. Following ventricular tachycardia, AF is the second most common arrhythmia in patients with left ventricular non-compaction. It is estimated that the incidence of AF ranges from 6–26 % of affected individuals [30]. Considering high thromboembolic risk associated with left ventricular noncompaction, any patient with AF and non-compaction should be anticoagulated regardless of the CHADS2 (or CHA2DS2–VASc score). Chronic anticoagulation is also recommended in patients with left ventricular non-compaction event in the absence of AF when left ventricular ejection fraction falls below 40 % [31]. Idiopathic restrictive cardiomyopathy is a very rare but distinct entity characterized by isolated, non-dilated, nonhypertrophied ventricles with diastolic dysfunction resulting in dilated atria and variable systolic function without identifiable causes. It has to be differentiated from much more prevalent, secondary restrictive cardiomyopathy in the setting of underlying diseases such as sarcoidosis or hemochromatosis. Idiopathic RCM is more common in older women than men (although it can also develop in young individuals) and up to 75 % of patients may experience AF. Atrial fibrillation is very poorly tolerated in these patients secondary to worsening high baseline filling pressures, loosing atrioventricular synchrony, and atrial contraction. Beta-blockers and non-dihydropyridine calcium channel blockers may be used for rate control. Calcium-dependent, biochemical abnormality of rapid filling phase of cardiac relaxation has been reported in idiopathic restrictive
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cardiomyopathy and it led to preferential recommendation of calcium channel blockers for by some experts [32]. Digoxin increases intracellular calcium and should be used with caution. All patients with restrictive cardiomyopathy and AF should be anticoagulated unless contraindicated. Like metabolic cardiomyopathies, this condition is often associated with poor prognosis and prompt evaluation for advanced heart failure therapies is warranted as they are often refractory to common therapeutics. Cardiac amyloidosis is characterized by extracellular deposition of amyloid (formed from the breakdown of normal or abnormal proteins) in the heart, as part of systemic amyloidosis or as a localized phenomenon. Cardiac involvement and prevalence of AF varies depending on the type of amyloidosis. Cardiac amyloidosis is often associated with specific mutations of the transthyretin protein (particular with V122I, I68L, L111M, T60A in chromosome 18q12), and a third of the subjects may have coexisting AF. There are also wild-type (senile) transthyretin amyloidosis, with AF occurring in the late stages of the diseases. Isolated atrial amyloid is often associated with deposition of atrial natriuretic peptide, which is primarily occurring in elderly women and associated with atrial conduction and arrhythmia. Light-chain (AL) cardiac amyloidosis is associated with high mortality and high risk of thromboembolic stroke, although AF appears to be less common that in other types of amyloidosis. AF is poorly tolerated in patients with cardiac amyloidosis due to restrictive physiology and hypotension. Although cardiac amyloid is associated with severely impaired atrial contractile function, clinical improvement is frequently observed after restoration of sinus rhythm (likely due to restoration of AV synchrony and regularization of heart rate). Use of amiodarone for the maintenance of sinus rhythm does not appear to be associated with any additional, amyloidosis-related side effects [33]. Role of catheter ablation of AF in cardiac amyloidosis is not well established; however, long-term successful rate is considered to be low due to progressive nature of atrial myopathy with amyloidosis. Low dose of beta-blockade and digoxin is frequently used for rate control. Digoxin should be used cautiously, due to increased risk of digoxin toxicity possibly related to the binding of digoxin to amyloid fibrils. Use of calcium channel blockers for rate control can be associated with worsening heart failure and should be avoided [33]. Amyloid cardiomyopathy (especially AL amyloidosis) is associated with increased risk of thromboembolism. Amyloid infiltrates the atrial and ventricular myocardium leading to atrial electromechanical dysfunction, which can predispose to thrombus formation even in the sinus rhythm. In the series of 116 autopsies (or explanted hearts) from Mayo Clinic, the frequency of intracardiac thrombus was
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very high (33 %). The history of AF and AL amyloidosis was associated with an extremely high risk for thromboembolism (OR 55) [34]. Same investigators in the subsequent study showed that the presence of AF, poor left ventricular diastolic function, and lower left atrial appendage emptying velocity were independently associated with increased risk for intracardiac thrombosis and use of anticoagulation therapy was associated with a significantly decreased risk [35]. Based on the above findings, anticoagulation is recommended in any patient with cardiac amyloid who develops AF and should be considered in patients in normal sinus rhythm with a diminutive transmitral A wave in Doppler echocardiogram or depressed left atrial appendage velocity on transesophageal echo (especially in patients with AL amyloidosis).
Tachyarrhythmia-induced cardiomyopathy associated atrial fibrillation with rapid ventricular response It is important to differentiate AF as a presentation of underlying cardiomyopathy from ventricular systolic dysfunction induced by AF with rapid ventricular response. Although most of tachyarrhythmias can induce cardiomyopathy [i.e., AF does not appear to be a specific trigger for tachycardia-induced cardiomyopathy (TIC)], AF is the most common cause in adults. It is suggested that AF with rapid ventricular rate can depress left ventricular systolic function by 15–20 % [36]. A significant subset of AF patients present with symptoms of acute decompensated HF and TIC should always be considered in AF patients presenting with new HF onset. The underlying pathophysiology of TIC is not well understood, with several mechanisms likely involved. Genetic predisposition exists, and patients with TIC have higher serum levels of angiotensin-converting enzyme (ACE), resulting paradoxically from the deletion of the gene encoding ACE [37]. In an animal model, tachycardia has been shown to lower high-energy stores, decrease Na–KATPase activity, and diminish ATP, phosphocreatine and creatine in myocardium [38, 39]. It is postulated that these effects of tachycardia could lead to subclinical ischemia with resulting reversible cardiomyopathy [40]. Oxidative stress resulting in decreased B-adrenoceptor responsiveness, changes in Ca-channel activity, and sarcoplasmic reticulum responsiveness to calcium is another mechanism implicated in TIC [41]. Main structural and functional features of TIC include left ventricular chamber dilatation, extracellular matrix remodeling, and reduced global contractility with severity of systolic dysfunction depending on tachycardia rate and duration [42]. The therapeutic approach usually involves appropriate guideline-based treatment for HF and AF. However, considering possible dramatic improvement in left ventricular function with ventricular rate control,
aggressive treatment for tachyarrhythmias should be a priority. Several characteristics can help in diagnosis of TIC in patients presenting with AF and newly diagnosed left ventricular dysfunction. Development of TIC can be relatively rapid compared with that of idiopathic dilated cardiomyopathy. In a large animal model of rapid ventricular pacing, ventricular function started to fall as soon as 24 h, with continued further worsening of left ventricular function for 3–5 weeks. With cessation of rapid pacing, improvements of hemodynamics are seen in 48 h, with recovery of left ventricular systolic function within several weeks. Human studies suggest that the mean period between the onset of tachycardia and the development of TIC is about 4 weeks, and recovery of cardiac function after control of the tachycardia takes place in an average of 4–6 weeks [43]. Tachycardia-induced cardiomyopathy is most often reversible with appropriate rate or rhythm control and usually not associated with extreme left ventricular dilation. In a small study on patients with TIC, no significant difference in outcomes between rate versus rhythm control was reported. Left ventricular end-diastolic dimension less than 61 mm was the only independent predictor that differentiated TIC from idiopathic dilated cardiomyopathy [44]. In patients with asymptomatic paroxysm of AF triggering TIC, strategies to rhythm control have advantage over rate control and were shown to be effective in reversing left ventricular dysfunction. In study on patients with AF and decreased ejection fraction undergoing radiofrequency ablation for AF, procedural success was similar to patients with AF and normal ejection fraction [45]. Heart failure can rapidly return after the recurrence of tachyarrhythmia. Cases of sudden death have been reported [46], suggesting the necessity for careful follow-up regardless if rate or rhythm control strategy of AF was chosen. Recent study on patients with history of successfully ablated incessant focal atrial tachycardia (with or without associated TIC) examined difference in long-term outcomes depending on the presence or absence of cardiomyopathy at the time of initial presentation. At a mean of 5 years following successful arrhythmia ablation, patients who have had tachycardia-induced cardiomyopathy exhibit significant differences in left ventricular structure and function including diffuse fibrosis indicating that long-term recovery is incomplete [47]. Table 2 summarizes clinical characteristics of patients with TIC and AF.
Conclusions Electromechanical remodeling occurs in AF and cardiomyopathy. Although clinically presenting either as a tachyarrhythmia or structural heart disease with HF, both of these syndromes have multiple similarities on a cellular
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Heart Fail Rev Table 2 Tachycardia-induced cardiomyopathy associated with AF Presentation
Rapid onset of LV dysfunction (3–5 weeks) in patients presenting with AF and rapid ventricular response
History
Frequently no prior structural heart disease or multiple risk factors for HF
Cardiac imaging
Usually global LV systolic dysfunction, without severe LV dilation (LVED \6.1 cm)
Management
Rate or rhythm control therapy. Consider rhythm control in patients with paroxysmal AF resulting in tachycardia-induced cardiomyopathy
Response to therapy
LV dysfunction usually normalizes with appropriate rate/rhythm control therapy in 4–6 weeks
Follow-up
Heart failure rapidly returns with recurrence of tachyarrhythmia, consider regular rhythm monitoring even after resolution of cardiomyopathy
Prognosis
Usually good
Table 3 Clinical approach to atrial fibrillation patients and suspected underlying cardiomyopathies Clinical history
Consider underlying genetic cardiomyopathy in patients with family history of cardiomyopathy, severe LVH at young age, or cardiomyopathy with multi-system involvement Consider underlying isolated atrial cardiomyopathy in patients with ‘‘lone AF’’ and rapidly progressing tachyarrhythmia, especially in the absence of severe LA dilation
Diagnostic testing
Genetic testing in patients with suspected inherited cardiomyopathies Cardiac magnetic resonance imaging with delayed enhancement in patients with rapidly progressive AF in the absence of structural heart disease with severe LA dilation and other risk factors, and to evaluate the degree of fibrosis in patients with long-standing persistent AF prior to a decision on catheter ablation of AF Hemodynamic evaluation to assess for underlying pressure/volume overloaded and low-output states Cardiac biopsy in patient with AF and suspected infiltrative or metabolic cardiomyopathies
Management considerations
Optimize hemodynamics in patients with AF and acutely decompensated HF triggering AF [8]. Follow appropriate guidelines based on heat failure therapies Consider upstream anti-remodeling therapy (neurohormonal antagonists) in patients with underlying atrial cardiomyopathy even in the absence of LV dysfunction, although beware of intolerance in the setting of restrictive physiologya Consider catheter ablation of AF in patients with hypertrophic cardiomyopathy and paroxysmal AF [22], and consider lack of benefit with catheter ablation of AF in patients with extensive atrial fibrosis/isolated atrial cardiomyopathy [17] Refer patients with genetic cardiomyopathies presenting with AF for consideration of advanced HF therapies
a
Randomized, controlled trials failed to show benefit of upstream therapy for the prevention of AF recurrence in patients with mild or no underlying heart disease [48, 49]. Use of ARB or ACE-I can be considered in combination of an antiarrhythmic drug to increase the likelihood of maintaining sinus rhythm after cardioversion [8, 50]
level. AF with uncontrolled rate can lead to reversible, tachycardia-induced cardiomyopathy. Cardiomyopathy serves as a substrate for already triggered AF and is a driving force of the disease in isolated atrial cardiomyopathy. The key role of cardiomyopathy in the pathogenesis and progression of AF should lead to a broader than recommended diagnostic workup at the time of initial AF diagnosis, efforts to limit undergoing electrical and structural remodeling above rhythm and rate control strategies, and a patient-specific therapeutic approach considering underlying pathophysiology of the disease (Table 3). Acknowledgments Dr. Tang is supported by National Institutes of Health Grants R01HL103931 and R01HL105993.
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Conflict of interest to disclose.
Dr. Mohmand-Borkowski has no relationships
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Heart Fail Rev 4. Tedesco MA et al (2001) Left atrial size in 164 hypertensive patients: an echocardiographic and ambulatory blood pressure study. Clin Cardiol 24:603–607 5. Hammwohner M, Goette A (2011) Evidence for mechano-electric coupling from clinical trials on AF. In: Kohl P, Sachs F, Franz MR (eds) Cardiac mechano-electric coupling and arrhythmia, 2nd edn. Oxford University Press, Oxford, pp 395–401 6. Kalifa J et al (2003) Intra-atrial pressure increases rate and organization of waves emanating from the superior pulmonary veins during atrial fibrillation. Circulation 108:668–671 7. Franz MR, Bode F (2011) Acute stretch effects on atrial electrophysiology. In: Kohl P, Sachs F, Franz MR (eds) Cardiac mechano-electric coupling and arrhythmia, 2nd edn. Oxford University Press, Oxford, pp 168–172 8. Camm J et al (2010) Guidelines for the management of atrial fibrillation. Eur Heart J 31:2369–2429 9. Kamkin A et al (2000) Stretch-activated currents in ventricular myocytes: amplitude and arrhythmogenic effects increase with hypertrophy. Cardiovasc Res 48(3):409–420 10. Spach MS et al (2001) Changes in anisotropic conduction caused by remodeling cell size and the cellular distribution of gap junctions and Na(?) channels. J Electrocardiol 34(Suppl):69–76 11. Schotten U (2011) Mechano-electric coupling from in chronic AF. In: Kohl P, Sachs F, Franz MR (eds) Cardiac mechanoelectric coupling and arrhythmia, 2nd edn. Oxford University Press, Oxford, pp 204–211 12. Dawson K, Wu C-T, Qi XY, Nattel S (2012) Congestive heart failure effects on atrial fibroblast phenotype: differences between freshly-isolated and cultured cells. PLoS ONE 7(12):e52032. doi:10.1371/journal.pone.0052032 13. Ichiki T et al (2013) Differential expression of the pro-natriuretic peptide convertases corin and furin in experimental heart failure and atrial fibrosis. Am J Physiol Regul Integr Comp Physiol 304(2):R102–R109. doi:10.1152/ajpregu.00233.2012 14. Kottkamp H (2012) Atrial fibrillation substrate: the ‘‘unknown species’’—from lone atrial fibrillation to fibrotic atrial cardiomyopathy. Heart Rhythm 9(4):481–482 15. Mahnkopf C et al (2010) Evaluation of the left atrial substrate in patients with lone atrial fibrillation using delayed-enhanced MRI: implications for disease progression and response to catheter ablation. Heart Rhythm 7:1475–1481 16. Oakes RS et al (2009) Detection and quantification of left atrial structural remodeling with delayed-enhancement magnetic resonance imaging in patients with atrial fibrillation. Circulation 119:1758–1767 17. Teh AW et al (2012) Long-term effects of catheter ablation for lone atrial fibrillation: progressive atrial electroanatomic substrate remodeling despite successful ablation. Heart Rhythm 9(4):473–480 18. Maron BJ, Maron MS (2013) Hypertrophic cardiomyopathy. Lancet 381(9862):242–255 19. Darby AE, Dimarco JP (2012) Management of atrial fibrillation in patients with structural heart disease. Circulation 125(7): 945–957 20. Bunch TJ et al (2008) Substrate and procedural predictors of outcomes after catheter ablation for atrial fibrillation in patients with hypertrophic cardiomyopathy. J Cardiovasc Electrophysiol 19:1009–1014 21. Kilicaslan F et al (2006) Efficacy of catheter ablation of atrial fibrillation in patients with hypertrophic obstructive cardiomyopathy. Heart Rhythm 3(3):275–280 22. Di Donna P et al (2010) Efficacy of catheter ablation for atrial fibrillation in hypertrophic cardiomyopathy: impact of age, atrial remodelling, and disease progression. Europace 12:347–355 23. Seidman JE, Pyeritz RE, Seidman CE (2012) Inherited causes of cardiovascular disease. In: Bonow R, Mann D, Zipes D, Libby P
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Atrial fibrillation as manifestation and consequence of underlying cardiomyopathies: from common conditions to genetic diseases Adam Mohmand-Borkowski • W. H. Wilson Tang
Ó Springer Science+Business Media New York 2014
Abstract While atrial fibrillation is common comorbidity in patients with cardiomyopathy and heart failure, diagnosis and management often focuses on tackling rate and rhythm control rather than elucidating pathogenic mechanisms related to underlying myocardial substrates. This review summarizes our current understanding of the natural history of cardiomyopathies presenting with atrial fibrillation, and the importance of managing underlying cardiomyopathic condition as diagnostic and treatment strategy for atrial fibrillation. Keywords
Atrial fibrillation Cardiomyopathy Genetic
Introduction The pathogenesis of atrial fibrillation (AF) is multifactorial, with the classic teaching focusing on factors that trigger, perpetuate, and sustain the tachyarrhythmia. It is believed that frequent short-terminating episodes (paroxysmal AF) are mostly dependent on trigger mechanisms, whereas perpetuating factors and pathologic substrate sustain the arrhythmia and play the crucial role in patients who progress to persistent AF. Although there are multiple AF triggers, many do not necessarily cause sustained AF in the absence of perpetuating factors and/or underlying pathologic substrate. However, once triggered, AF may be selfsustained, with no further need of triggering activity to maintain tachyarrhythmia.
A. Mohmand-Borkowski W. H. W. Tang (&) Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic, 9500 Euclid Avenue, Desk J3-4, Cleveland, OH 44195, USA e-mail: [email protected]
Much attention has focused on the elimination of AF triggers (such as radiofrequency ablation of the premature atrial complexes from the pulmonary veins). Current clinical guideline classifications of AF (paroxysmal, persistent, longstanding persistent, or permanent) and their management largely focus on the expected temporal and rhythmic evolution of AF progression rather than their underlying pathophysiological processes. These approaches appear to be successful only in selected patients, while others may be ‘‘refractory’’ and continue to progress despite adequate rate and rhythm control. There is growing recognition that the role of underlying myocardial substrate serves as an important driver of the development, progression, and maintenance of diseases with AF as a manifestation. It is conceivable that AF may serve as an initial presentation of underlying cardiomyopathy, and this may explain why some AF cases are more refractory to treatment and portend poor prognosis. Regardless, the presence of AF in patients with underlying heart failure (HF) portends poor prognosis. In the Framingham Study analysis of 708 patients with heart failure who were in sinus rhythm at baseline, 159 patients (22 %) developed AF at an average of 4.2 years of follow-up. Importantly, development of AF in heart failure patients in this analysis was associated with 2.7-fold increased risk of death in women and a 1.6-fold higher risk in men [1]. Additionally, data from the Olmsted County cohort demonstrated that compared with patients without AF, those with AF prior to HF had a 29 % increased risk of death, whereas those who developed AF after HF exhibited [2fold increased risk of death [2]. This review summarizes our current understanding of the natural histories of several cardiomyopathies with AF and HF as common manifestations, and the importance in tackling the presence of underlying cardiomyopathic condition as diagnostic and treatment strategies.
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Contribution of cardiomyopathy in atrial fibrillation Morphologic substrate to maintain AF triggers It is important to emphasize that the presence of underlying structural heart disease remains to be one of the most common contributors to AF pathogenesis. Cardiomyopathy may serve as a morphologic substrate (or ‘‘second factor’’) developed as part of the natural history that is necessary for AF triggers to become sustained. The most common example is the development of AF in patients without history of structural heart disease, in the setting of inflammation and oxidative stress related to myopericarditis (e.g., following cardiac surgery). Other examples include development of cardiac fibrosis in both ischemic and non-ischemic cardiomyopathies, or age-related degeneration of atrial tissue and widespread conduction slowing. Although separate terms of atrial electrical and structural remodeling in AF are frequently used, growing data evidence suggest that it is a tightly interconnected process at the cellular level. Hypertensive cardiomyopathy is a common structural heart disease regarded as a morphologic substrate of AF that leads to progressive atrial myopathy. In the Framingham Heart Study, the rate of AF was 1.42 times increased in men with a history of hypertension [3]. Although the risk of AF increases by 28 % for every 4 mm increase in left ventricular wall thickness, it does not appear to have a linear correlation with degree of hypertrophy and associated hemodynamic alternations. This observation is supported by the fact that 21 % of patients with hypertension showed enlarged left atrial dimension [4 cm without left ventricular hypertrophy [4]. Many of them also have underlying sleep-disordered breathing, which also compounds the sympathetic activation leading to further AF triggers. Atrial stretch and loading as AF trigger and perpetuating factor Pressure or volume overload associated with the progression of structural heart disease changes electrophysiologic and morphological properties of atria in humans and, in turn, facilitates the occurrence of AF in these patients. Examples include hemodynamic and structural changes in the hypertensive cardiomyopathy, valvular heart diseases, as well as restrictive cardiomyopathies such as cardiac amyloidosis. Acute increase in atrial volume and pressure leads to changes of atrial electrophysiologic properties in conduction and refractoriness. It shortens, the atrial effective refractory period proportionally to a degree of stretch decreases conduction velocity in atrial tissue and increases
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spatial heterogeneity in conduction creating substrate for AF via shortening the reentrant wavelength and favoring functional block. This can also lead to the loss of rate adaptation, increase in effective refractory period dispersion and regional slowing of conduction, increased refractoriness, and sinus node dysfunction [5]. Increase in intra-atrial pressure and atrial stretch can occur as a consequence of worsening hemodynamics in HF patients (e.g., increased left ventricular systolic pressure and/or increased left ventricular end-diastolic volume). Increase in intra-atrial pressure was shown in animal models to increase the propensity of the pulmonary vein junction to induce focal activity or sustain reentry [6]. As such, atrial stretch may be responsible not only for sustaining but also for triggering an arrhythmia [7]. These factors may explain the propensity of patients with acutely decompensated HF to develop AF. In fact, acute hemodynamic changes even in patients with subclinical cardiomyopathy can potentially induce AF paroxysm. Clinical evaluation for triggers of acute atrial stretch (e.g., labile hypertension in patients with no structural heart disease, or acute increase in left ventricular end-diastolic volume in patients with HF) should be an integral part of management of patients with paroxysmal or persistent AF [8]. In the course of chronic atrial pressure and volume overload, atrial dilatation, atrial myocyte hypertrophy, and interstitial fibrosis occurs and creates a substrate for AF [5]. Stretch-activated channels can be activated by smaller mechanical stimuli [9], and slowing of conduction transverse to the cellular orientation is observed in the presence of cellular hypertrophy [10]. Tissue fibrosis increases anisotropy in conduction and the dispersion of refractoriness, which further facilitate AF [11]. Atrial fibrosis may be influenced by multiple factors (e.g., patient hemodynamic status) as exemplified by the observation that freshly isolated atrial fibroblasts from HF patients display distinct extracellular matrix gene expression and morphological differences as control atrial fibroblasts [12]. Selective changes of natriuretic peptide convertases like corin and furin may also have significance in the regulation of pronatriuretic peptide processing and atrial remodeling in early stages of HF [13]. In addition, AF itself can lead to atrial dilatation, thereby increasing the probability of persistence of AF and further structural remodeling.
Atrial fibrillation as a consequence of underlying myopathic processes Often overlooked in everyday clinical practice, the presence of specific preexisting myopathic conditions (possibly genetically determined in some cases) may be responsible for some resistant to treatment cases of AF.
Heart Fail Rev Table 1 Manifestations of atrial fibrillation associated with cardiomyopathies Cardiomyopathy
Estimated AF prevalence (%)
Voltage
Accessory pathways
Conduction block
; LVEF
LVH
Known gene mutations
Fibrotic atrial
60–80
Low
No
Yes
No
No
Variable
Hypertensive
10–15
High
No
No
Subset
Yes
Variable
Hypertrophic
20–25
High
No
No
Subset
Yes
MHC7, MYBPC3, TNNT2
Glycogen storage
10–15
Low
Common
Yes
Subset
Yes
LAMP2, PRKAG2
Fabry
5–10
Low
No
Yes
No
Yes
GLA
Idiopathic dilated
20–25
Variable
Subset
Subset
Yes
Subset
LMNA, SCN5A
Idiopathic restrictive
75
Low
No
Yes
No
No
TNNI3
Non-compaction
20–25
Variable
No
Subset
Subset
Yes
G4.5/a-dystrobrevin/ZASP, TNNT2
Transthyretin amyloid
30
Low
No
Yes
Subset
Yes
TTR
Distinct AF characteristics associated with different cardiomyopathies are useful in differential diagnosis of underlying myopathy and choice of appropriate diagnostic testing (Table 1). Atrial myopathy Although atrial dilation is the most consistent risk factor of AF (risk of AF increases by 39 % for every 5 mm increase of left atrial diameter), the mechanistic link between atrial abnormalities and AF is complex. Observational data on patients with advanced dilated cardiomyopathy suggest that some cardiomyopathy patients do not develop AF despite severe LA enlargement, while others exhibit significant myopathy and fibrosis leading to refractory AF. Failure to explain inconsistency between clinical presentation and extent of structural left atrial abnormalities, as well growing evidence of progressive subclinical atrial disease in some patient with ‘‘lone AF’’ led to recognition of isolated atrial cardiomyopathy as a potential underlying cause of unexplained rapidly progressive AF. Fibrotic atrial cardiomyopathy Fibrotic atrial cardiomyopathy (FACM) is a primary disease with arrhythmic presentation varying from asymptomatic to severe atrial tachyarrhythmia, sinus node dysfunction, and conduction abnormalities being only a manifestation of underlying progressive atrial cardiomyopathy [14]. FACM represents a progressive fibrotic atrial disease in the absence of any other detectable underlying structural heart disease. Multiple areas of unidirectional block occur with multiple entry and exit points, in turn promoting the generation of new wavelengths. Additionally, dispersion of refractoriness is increased, thereby promoting AF in patients with atrial cardiomyopathy.
FACM as a primary diagnosis should be considered in AF patients with no other underlying heart disease and severity of associated tachyarrhythmia frequently disproportional to their atrial size. These patients frequently have a relatively short history of AF and have a low CHADS2 score, which leads to under appreciation of severity of underlying substrate and repeated failed attempts of rhythm control. Electroanatomic mapping of left and right atria in FACM reveals fragmented small electrograms and low voltages. Delayed enhancement magnetic resonance imaging (DE-MRI) appears to be the current noninvasive technique of choice for detecting atrial fibrosis and diagnosing FACM. Extent of MRIdetected left atrial fibrosis was shown to be independent of the type of AF and associated comorbidities, supporting the presence of subclinical cardiomyopathy causing fibrosis rather that AF-induced atrial remodeling [15]. Delayed enhancement MRI was also examined as a tool in detecting, quantifying, and localizing abnormal atrial tissue before catheter ablation. In the study on DE-MRI used for guiding a catheter ablation, the recurrence of AF after catheter ablation was dependent on the degree of delayed enhancement (lowest in the patient group with minimal enhancement and highest in the patient group with extensive enhancement) [16]. Importantly, not only extend but also location of delayed enhancement was predictive for a recurrence of AF after catheter ablation. Patient who had favorable ablation results had delayed enhancement limited to posterior wall and septum of left atrium, while patients who failed catheter ablation had delayed enhancement in all parts of the left atrium. A correlation between areas of enhancement on DE-MRI and low voltage on electroanatomic maps was seen in all patients [16]. As low voltage during invasive electrophysiology study has been shown to represent areas of fibrosis/scaring in
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anatomopathological studies, DE-MRI establishes its role as a valuable noninvasive tool to assess health of atrial tissue. Recently, progressive atrial electroanatomic substrate remodeling has been reported in FACM, despite successful catheter ablation. In this small study on AF patients with no apparent structural heart disease, follow-up with electroanatomic mapping at 10 ± 13 months after successful ablation revealed no reversal of remodeling. Further reduced voltage, worsening or no improvement in conduction, and prolongation of regional refractoriness were reported with only a reversal of left atrial dilatation [17]. Therefore, it appears that elimination of classic triggers of AF with PV isolation cannot stop the underlying progressive structural atrial disease. However, the ‘‘point of no return’’ when likely reversible electrical abnormalities in function of atrial ionic channels become associated with likely irreversible structural changes is not defined. Also, these patients may be challenging from a stroke prevention standpoint, as progressive atrial fibrosis leads to impairment of atrial mechanical function. Need for oral anticoagulation, even in the absence of other risk factors, should be carefully considered in patients with extensive atrial fibrosis. Mendelian inherited cardiomyopathies Recent discoveries of the genetic origin of many cardiomyopathies have changed our understanding of their pathogenesis and natural course as well as diagnostic approach and management. Common cardiomyopathies complicated by AF such as hypertrophic, dilated, restrictive, or metabolic cardiomyopathies are now known to be single-gene disorders. Additionally, genetic predisposition to AF and its association to inherited cardiomyopathies have been recognized by current AF guidelines [8]. As occurrence of these entities appears to be more common than previously thought, it is important to consider underlying genetic cardiomyopathies in patients (especially young and/or with positive family history) presenting with new onset of AF commonly in the setting of unexplained cardiomyopathy. Hypertrophic cardiomyopathy Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiomyopathy with the prevalence of 1:500 in the general population. Sarcomeric gene mutations in HCM are usually inherited as autosomal dominant, although de novo mutations in these same genes can also produce sporadic cases of the disease. Yield of clinically available genetic testing is estimated at 40–70 %. Most common gene mutations among HCM patients who have been
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successfully genotyped include beta-cardiac myosin heavy chain (MYH7) 30–50 %, myosin binding protein C (MYBPC3) 20–40 %, regulatory myosin light chain (MYL2) \3 %, essential myosin light chain (MYL3) \1 %, titin (TTN)\1 %, cardiac troponin T (TNNT) 25–20 %, cardiac troponin I (TNNI3) \5 %, alpha-tropomyosin (TPM1) \5 %, and actin (ACTC) \1 %. Characteristics of the disease (including left ventricular hypertrophy, diastolic dysfunction, abnormal sympathetic innervation, and enhanced myocardial fibrosis) promote developing AF. Dynamic changes in hemodynamics due to left ventricular outflow tract obstruction, elevated left ventricular enddiastolic pressures, and mitral regurgitation due to systolic anterior motion further increase the risk of AF. AF is the most common sustained arrhythmia in HCM and occurs in 20–25 % of patients with the incidence of AF typically increasing with disease duration [18, 19]. AF is poorly tolerated in patients with HCM, and the presence of AF with rapid ventricular response may be life-threatening in these patients leading to hemodynamic compromise and/or degeneration to ventricular fibrillation. Hence, AF rhythm control is highly recommended, because of poor hemodynamic tolerance of tachyarrhythmias [19]. It is important to recognize that the use of many antiarrhythmic drugs associated with increased risk of proarrhythmia is the setting of cardiac hypertrophy. Amiodarone is the drug of choice for maintaining sinus rhythm in HCM; however, considering its side effect profile, the rhythm control approach with catheter ablation may be preferred [8, 20]. Small study on patients with HCM and AF showed that PV antrum isolation is a feasible therapeutic strategy. Although AF recurrence after the first PV antrum ablation in HCM patients was almost 50 %, after second ablation rhythm control was achieved in 70 % of HCM patients (mean follow-up of 341 ± 237 days [21]. These original data were further supported by a recently published study, which showed that radiofrequency ablation was successful in restoring sinus rhythm and improving symptomatic status in most HCM patients with refractory AF, although redo procedures were often necessary. The study investigators found that mildly symptomatic, younger patients with HCM and small atrial size have the best chance of successful procedure outcome [22]. Additionally, outcome of catheter ablation in HCM patients is significantly better in paroxysmal AF than in persistent AF [8]. In HCM patients with AF undergoing myectomy, Maze procedure at the time of the surgery should be considered. Systemic anticoagulation is recommended indefinitely for HCM patients and AF. Rate control agents (beta-blockers or calcium channel blockers) are used as a first line to relieve symptoms in patients in sinus rhythm with left ventricular outflow tract obstruction. The presence of AF should be considered at the time of decision to implant a
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cardioverter defibrillator in HCM patients as it is associated with a higher risk of inappropriate shocks, particularly in the first year following implantation [8]. Metabolic cardiomyopathies In the setting of unexplained left ventricular hypertrophy, mutations have been described in non-sarcomere proteins that mimic the gross phenotype of HCM, which have been observed with progressive atrioventricular block, AF, ventricular preexcitation/Wolff–Parkinson–White (WPW) syndrome. Some of these patients may have underlying metabolic cardiomyopathies such as LAMP-2 mutations (so-called Danon’s disease), PRKAG2 mutations, and cardiac Fabry disease, in which AF may be the first clinical presentation. Left ventricular hypertrophy, diagnosed in imaging studies, is a typical feature of these cardiomyopathies, which commonly leads to misdiagnosis of HCM. Cardiac biopsy distinguishes these cardiomyopathies showing myocytes with vacuoles containing lipids (cardiac Fabry disease due to GLA mutations), glycogen (PRKAG2 mutations), or lysosomal remnants (LAMP2 mutations), and the absence of the prominent myocyte disarray seen in HCM [23]. The progressive and malignant nature of these diseases (often complicated by HF and tachyarrhythmias) frequently necessities prompt considerations for replacement therapies (e.g., listing for heart transplantation in patients without systemic involvement). Cardiac Danon disease is caused by mutation in the X-linked (Xq2) lysosome-associated membrane protein-2 (LAMP2) and often occurs in the first two decades in its adult forms. It may present as marked left ventricular hypertrophy occurring with subclinical systemic disease or a multisystem disorder involving heart muscle, the nervous system, liver, and the skeletal system. LAMP2 mutations are characterized by early disease onset (typically in childhood) and male predominance. Deficiency in lysosomal proteins causes hypertrophy and electrophysiologic abnormalities. The electrocardiogram in patients with Danon disease shows unusually high voltage and ventricular preexcitation. Massive concentric hypertrophy is frequently seen in echocardiogram, although LAMP-2 mutation may also present as dilated cardiomyopathy. LAMP2 cardiomyopathy is associated with the presence of accessory pathway leading to rapid AF as well as recurrent ventricular arrhythmias and often has high rates of sudden cardiac death in family histories [24, 25]. Like HCM due to sarcomeric mutations, AF is poorly tolerated due to the significant underlying cardiomyopathy. Danon disease is not infrequent cause of initially unexplained concentric left ventricular hypertrophy. Recent study investigated the prevalence of Danon disease among an unselected population of 50 patients with concentric left ventricular
hypertrophy who underwent endomyocardial biopsy. Genetic testing for LAMP2 mutations was done in patients, who had biopsy results negative for amyloid. The prevalence of Danon disease was 6 % in unselected concentric left ventricular hypertrophy patients or 8 % after excluding patients with cardiac amyloidosis in endomyocardial biopsies [26]. Protein Kinase Disorder-associated Cardiomyopathy caused by PRKAG2 mutations in chromosome 7q3, which is not associated with the systemic manifestations. Cardiac hypertrophy is present in 30–50 % of affected individuals. Patients frequently present in late adolescence or early adulthood with highly symptomatic tachyarrhythmias and cardiac hypertrophy. Atrial fibrillation is the most commonly associated tachyarrhythmia. Ventricular preexcitation is also common [27]. Progressive conduction system disease necessitates permanent pacemaker implantation in 30 % of patients with glycogen cardiomyopathy. Sudden cardiac death and/or rapid progression to end-stage HF may occur requiring listing for heart transplant [27]. Adequate anticoagulation for stroke prevention and rate control medications, as needed, are used to manage milder forms of disease [19]. Anderson-Fabry Disease is caused by GLA mutation resulting in deficiency of alpha-galactosidase A and glycosphingolipid deposits in cardiac myocytes. It is a rare X-linked lysosomal storage disease usually presenting as a systemic syndrome (cardiac hypertrophy, nephropathy, skin lesions, autonomic dysfunction, and sensorineural deafness) [23, 28]. Some patients have mostly cardiac involvement characterized by concentric left ventricular hypertrophy, arrhythmias, and conduction blocks. The shortened duration of the PR interval correlates with the severity of cardiac disease, and sudden cardiac death in Fabry cardiomyopathy is likely to be related to bradycardia [29]. ‘‘Lone AF’’ with under-detected presence of glycosphingolipid deposits in atrial cardiomyocytes can be a first manifestation of Fabry disease. Enzyme replacement of recombinant alpha-galactosidase A in early diagnosed patients can be curative, even though disease progression with arrhythmia and conduction blocks is not uncommon. Other specific cardiomyopathies Lamin A/C cardiomyopathy is responsible for up to 10 % of familial dilated cardiomyopathy cases and is one of the most commonly inherited forms of dilated cardiomyopathies associated with progressive AF. Patients with lamin A/C mutations frequently present with conduction system disease requiring permanent pacemaker placement. With progression of the disease, over half of the affected individuals may develop isolated AF in their fourth and fifth decade (some with earlier onset), which are largely
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refractory to standard therapies. Incidence of thromboembolic events in patients with lamin A/C deficiency approaches 30 % regardless of AF, and therefore, anticoagulation is recommended in these patients. With this constellation of conduction system disease, dilated cardiomyopathy, and AF, biventricular pacing and rate control with beta-blockers are usually recommended [19]. SCN5A-associated dilated cardiomyopathy has a variable phenotype related to the loss-of-function mutations of different segments of the voltage-sensitive sodium channels. There are many channelopathies that may contribute to underlying cardiac dysfunction, but they are often associated with ventricular tachyarrhythmia and sudden cardiac death. Often associated with long-QT syndromes, mutations in SCN5A were detected in 1.7 % of dilated cardiomyopathy families, and often linked to those with high prevalence of arrhythmia (including AF, ventricular tachycardia, sick sinus syndrome, or conduction blocks). Left ventricular non-compaction (sometimes referred to as spongy myocardium or hypertrabeculation syndrome) represents another poorly understood and challenging clinical condition. It often presents with altered myocardial wall with prominent trabeculae and deep intratrabecular recesses, and may be associated with neuromuscular disorders or other inherited cardiomyopathies. Following ventricular tachycardia, AF is the second most common arrhythmia in patients with left ventricular non-compaction. It is estimated that the incidence of AF ranges from 6–26 % of affected individuals [30]. Considering high thromboembolic risk associated with left ventricular noncompaction, any patient with AF and non-compaction should be anticoagulated regardless of the CHADS2 (or CHA2DS2–VASc score). Chronic anticoagulation is also recommended in patients with left ventricular non-compaction event in the absence of AF when left ventricular ejection fraction falls below 40 % [31]. Idiopathic restrictive cardiomyopathy is a very rare but distinct entity characterized by isolated, non-dilated, nonhypertrophied ventricles with diastolic dysfunction resulting in dilated atria and variable systolic function without identifiable causes. It has to be differentiated from much more prevalent, secondary restrictive cardiomyopathy in the setting of underlying diseases such as sarcoidosis or hemochromatosis. Idiopathic RCM is more common in older women than men (although it can also develop in young individuals) and up to 75 % of patients may experience AF. Atrial fibrillation is very poorly tolerated in these patients secondary to worsening high baseline filling pressures, loosing atrioventricular synchrony, and atrial contraction. Beta-blockers and non-dihydropyridine calcium channel blockers may be used for rate control. Calcium-dependent, biochemical abnormality of rapid filling phase of cardiac relaxation has been reported in idiopathic restrictive
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cardiomyopathy and it led to preferential recommendation of calcium channel blockers for by some experts [32]. Digoxin increases intracellular calcium and should be used with caution. All patients with restrictive cardiomyopathy and AF should be anticoagulated unless contraindicated. Like metabolic cardiomyopathies, this condition is often associated with poor prognosis and prompt evaluation for advanced heart failure therapies is warranted as they are often refractory to common therapeutics. Cardiac amyloidosis is characterized by extracellular deposition of amyloid (formed from the breakdown of normal or abnormal proteins) in the heart, as part of systemic amyloidosis or as a localized phenomenon. Cardiac involvement and prevalence of AF varies depending on the type of amyloidosis. Cardiac amyloidosis is often associated with specific mutations of the transthyretin protein (particular with V122I, I68L, L111M, T60A in chromosome 18q12), and a third of the subjects may have coexisting AF. There are also wild-type (senile) transthyretin amyloidosis, with AF occurring in the late stages of the diseases. Isolated atrial amyloid is often associated with deposition of atrial natriuretic peptide, which is primarily occurring in elderly women and associated with atrial conduction and arrhythmia. Light-chain (AL) cardiac amyloidosis is associated with high mortality and high risk of thromboembolic stroke, although AF appears to be less common that in other types of amyloidosis. AF is poorly tolerated in patients with cardiac amyloidosis due to restrictive physiology and hypotension. Although cardiac amyloid is associated with severely impaired atrial contractile function, clinical improvement is frequently observed after restoration of sinus rhythm (likely due to restoration of AV synchrony and regularization of heart rate). Use of amiodarone for the maintenance of sinus rhythm does not appear to be associated with any additional, amyloidosis-related side effects [33]. Role of catheter ablation of AF in cardiac amyloidosis is not well established; however, long-term successful rate is considered to be low due to progressive nature of atrial myopathy with amyloidosis. Low dose of beta-blockade and digoxin is frequently used for rate control. Digoxin should be used cautiously, due to increased risk of digoxin toxicity possibly related to the binding of digoxin to amyloid fibrils. Use of calcium channel blockers for rate control can be associated with worsening heart failure and should be avoided [33]. Amyloid cardiomyopathy (especially AL amyloidosis) is associated with increased risk of thromboembolism. Amyloid infiltrates the atrial and ventricular myocardium leading to atrial electromechanical dysfunction, which can predispose to thrombus formation even in the sinus rhythm. In the series of 116 autopsies (or explanted hearts) from Mayo Clinic, the frequency of intracardiac thrombus was
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very high (33 %). The history of AF and AL amyloidosis was associated with an extremely high risk for thromboembolism (OR 55) [34]. Same investigators in the subsequent study showed that the presence of AF, poor left ventricular diastolic function, and lower left atrial appendage emptying velocity were independently associated with increased risk for intracardiac thrombosis and use of anticoagulation therapy was associated with a significantly decreased risk [35]. Based on the above findings, anticoagulation is recommended in any patient with cardiac amyloid who develops AF and should be considered in patients in normal sinus rhythm with a diminutive transmitral A wave in Doppler echocardiogram or depressed left atrial appendage velocity on transesophageal echo (especially in patients with AL amyloidosis).
Tachyarrhythmia-induced cardiomyopathy associated atrial fibrillation with rapid ventricular response It is important to differentiate AF as a presentation of underlying cardiomyopathy from ventricular systolic dysfunction induced by AF with rapid ventricular response. Although most of tachyarrhythmias can induce cardiomyopathy [i.e., AF does not appear to be a specific trigger for tachycardia-induced cardiomyopathy (TIC)], AF is the most common cause in adults. It is suggested that AF with rapid ventricular rate can depress left ventricular systolic function by 15–20 % [36]. A significant subset of AF patients present with symptoms of acute decompensated HF and TIC should always be considered in AF patients presenting with new HF onset. The underlying pathophysiology of TIC is not well understood, with several mechanisms likely involved. Genetic predisposition exists, and patients with TIC have higher serum levels of angiotensin-converting enzyme (ACE), resulting paradoxically from the deletion of the gene encoding ACE [37]. In an animal model, tachycardia has been shown to lower high-energy stores, decrease Na–KATPase activity, and diminish ATP, phosphocreatine and creatine in myocardium [38, 39]. It is postulated that these effects of tachycardia could lead to subclinical ischemia with resulting reversible cardiomyopathy [40]. Oxidative stress resulting in decreased B-adrenoceptor responsiveness, changes in Ca-channel activity, and sarcoplasmic reticulum responsiveness to calcium is another mechanism implicated in TIC [41]. Main structural and functional features of TIC include left ventricular chamber dilatation, extracellular matrix remodeling, and reduced global contractility with severity of systolic dysfunction depending on tachycardia rate and duration [42]. The therapeutic approach usually involves appropriate guideline-based treatment for HF and AF. However, considering possible dramatic improvement in left ventricular function with ventricular rate control,
aggressive treatment for tachyarrhythmias should be a priority. Several characteristics can help in diagnosis of TIC in patients presenting with AF and newly diagnosed left ventricular dysfunction. Development of TIC can be relatively rapid compared with that of idiopathic dilated cardiomyopathy. In a large animal model of rapid ventricular pacing, ventricular function started to fall as soon as 24 h, with continued further worsening of left ventricular function for 3–5 weeks. With cessation of rapid pacing, improvements of hemodynamics are seen in 48 h, with recovery of left ventricular systolic function within several weeks. Human studies suggest that the mean period between the onset of tachycardia and the development of TIC is about 4 weeks, and recovery of cardiac function after control of the tachycardia takes place in an average of 4–6 weeks [43]. Tachycardia-induced cardiomyopathy is most often reversible with appropriate rate or rhythm control and usually not associated with extreme left ventricular dilation. In a small study on patients with TIC, no significant difference in outcomes between rate versus rhythm control was reported. Left ventricular end-diastolic dimension less than 61 mm was the only independent predictor that differentiated TIC from idiopathic dilated cardiomyopathy [44]. In patients with asymptomatic paroxysm of AF triggering TIC, strategies to rhythm control have advantage over rate control and were shown to be effective in reversing left ventricular dysfunction. In study on patients with AF and decreased ejection fraction undergoing radiofrequency ablation for AF, procedural success was similar to patients with AF and normal ejection fraction [45]. Heart failure can rapidly return after the recurrence of tachyarrhythmia. Cases of sudden death have been reported [46], suggesting the necessity for careful follow-up regardless if rate or rhythm control strategy of AF was chosen. Recent study on patients with history of successfully ablated incessant focal atrial tachycardia (with or without associated TIC) examined difference in long-term outcomes depending on the presence or absence of cardiomyopathy at the time of initial presentation. At a mean of 5 years following successful arrhythmia ablation, patients who have had tachycardia-induced cardiomyopathy exhibit significant differences in left ventricular structure and function including diffuse fibrosis indicating that long-term recovery is incomplete [47]. Table 2 summarizes clinical characteristics of patients with TIC and AF.
Conclusions Electromechanical remodeling occurs in AF and cardiomyopathy. Although clinically presenting either as a tachyarrhythmia or structural heart disease with HF, both of these syndromes have multiple similarities on a cellular
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Heart Fail Rev Table 2 Tachycardia-induced cardiomyopathy associated with AF Presentation
Rapid onset of LV dysfunction (3–5 weeks) in patients presenting with AF and rapid ventricular response
History
Frequently no prior structural heart disease or multiple risk factors for HF
Cardiac imaging
Usually global LV systolic dysfunction, without severe LV dilation (LVED \6.1 cm)
Management
Rate or rhythm control therapy. Consider rhythm control in patients with paroxysmal AF resulting in tachycardia-induced cardiomyopathy
Response to therapy
LV dysfunction usually normalizes with appropriate rate/rhythm control therapy in 4–6 weeks
Follow-up
Heart failure rapidly returns with recurrence of tachyarrhythmia, consider regular rhythm monitoring even after resolution of cardiomyopathy
Prognosis
Usually good
Table 3 Clinical approach to atrial fibrillation patients and suspected underlying cardiomyopathies Clinical history
Consider underlying genetic cardiomyopathy in patients with family history of cardiomyopathy, severe LVH at young age, or cardiomyopathy with multi-system involvement Consider underlying isolated atrial cardiomyopathy in patients with ‘‘lone AF’’ and rapidly progressing tachyarrhythmia, especially in the absence of severe LA dilation
Diagnostic testing
Genetic testing in patients with suspected inherited cardiomyopathies Cardiac magnetic resonance imaging with delayed enhancement in patients with rapidly progressive AF in the absence of structural heart disease with severe LA dilation and other risk factors, and to evaluate the degree of fibrosis in patients with long-standing persistent AF prior to a decision on catheter ablation of AF Hemodynamic evaluation to assess for underlying pressure/volume overloaded and low-output states Cardiac biopsy in patient with AF and suspected infiltrative or metabolic cardiomyopathies
Management considerations
Optimize hemodynamics in patients with AF and acutely decompensated HF triggering AF [8]. Follow appropriate guidelines based on heat failure therapies Consider upstream anti-remodeling therapy (neurohormonal antagonists) in patients with underlying atrial cardiomyopathy even in the absence of LV dysfunction, although beware of intolerance in the setting of restrictive physiologya Consider catheter ablation of AF in patients with hypertrophic cardiomyopathy and paroxysmal AF [22], and consider lack of benefit with catheter ablation of AF in patients with extensive atrial fibrosis/isolated atrial cardiomyopathy [17] Refer patients with genetic cardiomyopathies presenting with AF for consideration of advanced HF therapies
a
Randomized, controlled trials failed to show benefit of upstream therapy for the prevention of AF recurrence in patients with mild or no underlying heart disease [48, 49]. Use of ARB or ACE-I can be considered in combination of an antiarrhythmic drug to increase the likelihood of maintaining sinus rhythm after cardioversion [8, 50]
level. AF with uncontrolled rate can lead to reversible, tachycardia-induced cardiomyopathy. Cardiomyopathy serves as a substrate for already triggered AF and is a driving force of the disease in isolated atrial cardiomyopathy. The key role of cardiomyopathy in the pathogenesis and progression of AF should lead to a broader than recommended diagnostic workup at the time of initial AF diagnosis, efforts to limit undergoing electrical and structural remodeling above rhythm and rate control strategies, and a patient-specific therapeutic approach considering underlying pathophysiology of the disease (Table 3). Acknowledgments Dr. Tang is supported by National Institutes of Health Grants R01HL103931 and R01HL105993.
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Conflict of interest to disclose.
Dr. Mohmand-Borkowski has no relationships
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