Review Article

Novel Perspectives on Arrhythmia-Induced Cardiomyopathy Pathophysiology, Clinical Manifestations and an Update on Invasive Management Strategies Domenico G. Della Rocca, MD,* Luca Santini, MD, PhD,* Giovanni B. Forleo, MD, PhD,* Aurora Sanniti, MD,* Armando Del Prete, MD,* Carlo Lavalle, MD,† Luigi Di Biase, MD, PhD,‡§¶║ Andrea Natale, MD,‡§ and Francesco Romeo, MD*

Abstract: Arrhythmia-induced cardiomyopathy is a partially or completely reversible form of myocardial dysfunction due to sustained supraventricular and ventricular arrhythmias. Asynchrony, rapid cardiac rates and rhythm irregularities are the main factors involved in the development of the disease. The reversible nature of arrhythmia-induced cardiac dysfunction allows only for a retrospective diagnosis of the disease once cardiac function is restored following heart rate control. A high level of suspicion is needed to make a diagnosis at an early stage and prevent further progression of the disease. Although reversible, arrhythmia-induced cellular and molecular changes may remain, increasing the risk for sudden death even when normal ejection fraction is restored as well as causing rapid deterioration of cardiac function and development of heart failure symptoms if arrhythmia recurs. Appropriate management based on a combination of pharmacologic and nonpharmacologic strategies to achieve rate control and prevent arrhythmia recurrence is pivotal to avoid further cardiac function deterioration and to control symptoms, significantly reducing the risk of heart failure and sudden cardiac death. Key Words: arrhythmia-induced cardiomyopathy, atrial fibrillation, premature ventricular complex, reversible cardiomyopathy, transcatheter ablation (Cardiology in Review 2015;23: 135–141)

A

rrhythmia-induced cardiomyopathy (AIC) is a cause of ventricular dysfunction as a result of chronic high heart rates that may lead to heart failure (HF).1–5 AIC is a partially or totally reversible disease, exposing patients with healthy or unhealthy hearts to supraventricular or ventricular arrhythmias (Fig. 1). The incidence of AIC is still unclear: the main epidemiological studies to date are based on small sample populations primarily involving atrial fibrillation (AF) patients. Although left ventricular (LV) impairment is the most frequent manifestation of the disease, right ventricular (RV) dysfunction has also been reported.5 The intense metabolic, neurohormonal, and hemodynamic alterations promoted by the high heart rates result in cellular and extracellular changes with resulting negative remodeling and loss of function (Figs. 1,2). In this review, we discuss the

From the *Division of Cardiology, Department of Internal Medicine, University of Rome “Tor Vergata”; †Department of Cardiology, San Filippo Neri Hospital, Rome, Italy; ‡Texas Cardiac Arrhythmia Institute at St. David’s Medical Center; §Department of Biomedical Engineering, University of Texas, Austin, TX; ¶Department of Cardiology, University of Foggia, Foggia, Italy; and ║Albert Einstein College of Medicine at Montefiore Hospital, New York, NY. Disclosure: The authors declare no conflict of interest. Correspondence: Domenico G. Della Rocca, MD, Division of Cardiology, Department of Internal Medicine, University Hospital of Tor Vergata, Viale Oxford, 81, 00133, Roma, Italy. E-mail: [email protected]. Copyright © 2014 Lippincott Williams & Wilkins ISSN: 1061-5377/14/2303-135 DOI: 10.1097/CRD.0000000000000040

Cardiology in Review  •  Volume 23, Number 3, May/June 2015

pathophysiology of AIC and its clinical implications for diagnosis and management.

DEFINITION The term AIC actually encloses a wide range of conditions characterized by an abnormal systolic and/or diastolic cardiac function (atrial and/or ventricular impairment), caused by chronically high and/or irregular atrial or ventricular rates (Fig. 1). The first descriptions of the disease date back to the early 20th century.1,2 Initially, the definition referred to conditions of chronic tachycardia leading to impaired LV function, partially or completely reversible once normal heart rate was restored. Subsequently, the definition has been extended to include atrial function impairment as a result of high atrial or ventricular rates.3 Recent studies have also reported asynchronous cardiac contractions [eg, premature ventricular complexes (PVCs) and right apical ventricular pacing] among the possible causes of arrhythmia-induced cardiac dysfunction.4,6 In young patients without cardiac structural abnormalities, the likelihood of PVC-induced cardiomyopathy is high if they have >20,000 PVCs/ day7,8 originating from the outflow tracts or the fascicles and with no more than 2 morphologies. Crucial in the definition of AIC is the reversible nature of the dysfunction when regular rhythm is restored. Fenelon et al9 classified tachycardia-induced cardiomyopathy into: • “pure forms,” when the functional impairment occurs in a healthy heart and tachycardia is the only recognized cause of the disease; • “impure forms,” when tachycardia exacerbates cardiac dysfunction in the context of an already existing heart disease. Two criteria have been proposed for diagnosis: (1) cardiac dilation or HF and (2) the coexistence of a chronic or frequent cardiac arrhythmia occurring 10–15% of the day in patients with or without an existing cardiomyopathy.

EPIDEMIOLOGY, DIAGNOSIS, AND TIME COURSE Clinical data have shown that AICs are the result of different sustained and nonsustained supraventricular (eg, atrial tachycardia, atrial flutter or AF, intranodal tachycardia, automatic junctional tachycardia, reentrant tachycardia) or ventricular arrhythmias as well as frequent supraventricular arrhythmias and PVCs. High atrial or ventricular pacing rates may also be responsible for the disease (Fig. 1). Asynchrony, rapid cardiac rates (atrial and/or ventricular), and rhythm irregularities are the main causes of the dysfunction (Fig. 2). The onset of ventricular dysfunction mainly depends on the presence of an underlying cardiac disease, and the arrhythmia (type, duration, and rate) responsible for the dysfunction.10 The presence of chronic tachycardia (>100 bpm) should be considered an important warning sign for identifying AIC. However, normal daytime and resting heart rates should not be used as an exclusion criterion in the www.cardiologyinreview.com  |  135

Della Rocca et al

FIGURE 1.  Supraventricular and ventricular causes of arrhythmia-induced cardiomyopathy. AV indicates atrioventricular; BB, bundle branch; PJRT, permanent junctional reciprocating tachycardia; RV, right ventricular; VT, ventricular tachycardia. diagnosis of the disease, especially in AF patients who may experience high overnight and exercise heart rates.11 Other factors (eg, age, drug therapy, comorbidities) may play a role in the development, progression, and reversibility of the dysfunction. Of note, the existence of an arrhythmia is not sufficient for the diagnosis of AIC, that can be made only when cardiac rhythm has slowed down and consequent cardiac functional restoration occurs. A genetic susceptibility might promote the development of arrhythmias as well as link arrhythmias to the progression of cardiac dysfunction. Data linking the duration and frequency of arrhythmia with the extent of ventricular dysfunction are still inconsistent. AIC has been described as a rare form of cardiomyopathy and mostly reported in the wide population of patients suffering from AF. The prevalence

FIGURE 2.  Natural history of arrhythmia-induced cardiomyopathies: from arrhythmia occurrence to heart failure. The risk of sudden cardiac death remains higher even when normal heart rate and left ventricular function are restored. 136  |  www.cardiologyinreview.com

Cardiology in Review  •  Volume 23, Number 3, May/June 2015

and incidence of the disease are difficult to evaluate due to the small number of published studies, as well as the heterogeneity and the small size of the populations involved. These factors represent important limitations for the statistical evaluations of the results. Noninvasive imaging techniques (eg, echocardiography, radionuclide ventriculography) have been used to quantify the likelihood of AIC that would help identify those patients who can potentially benefit from rhythm regularization with consequent restoration of cardiac function. Given the retrospective nature of the diagnosis and the above-mentioned limitations of this diagnostic technique, echocardiography still maintains a key role in the diagnostic and followup process of patients with AIC. The main criticism with the use of echocardiography is that the initial LV function estimation may be artificially low due to rapid cardiac rates.12 Several investigators have observed that patients with AIC have significantly smaller LV diameters in comparison to other forms of dilated cardiomyopathy.13 When patients with LV dysfunction are stratified based on LV diameters, an LV end-diastolic dimension of ≤61 mm has been demonstrated to predict AIC with a sensitivity of 100% and a specificity of 71.4%.14 In the same subgroup of patients, ejection fraction (EF) improvement after treatment was ≥15%, whereas only a ≤5% improvement was observed in patients with idiopathic dilated cardiomyopathy. Although reversible, a recurrent arrhythmia may cause rapid loss of LV function and development of HF symptoms with a high risk of sudden death even in patients with AIC (Fig. 2). Evaluation of myocardial contractile reserve by low dose dobutamine stress echocardiography may be helpful in predicting AIC before sinus rhythm restoration in patients with dilated cardiomyopathy and permanent AF.15 Small prospective studies investigated the effect of AF rapid ventricular responses and the result on cardiac function of rhythm control via cardioversion to sinus rhythm16,17 or rate control via pharmacologic control/AV junction ablation.18 Kieny et al16 prospectively studied a cohort of 17 patients with permanent AF and idiopathic dilated cardiomyopathy undergoing pharmacologic or electrical cardioversion. In patients with sinus rhythm restoration, LVEF significantly improved from an average of 32–53% at 4.7-month follow-up, whereas no difference was observed in patients with unsuccessful cardioversion. In those patients with recurrence of AF, a severe deterioration of LV systolic function was observed. In a cohort of patients with AF and impaired LV systolic function (EF ≤ 45%),18 atrioventricular node ablation and permanent ventricular pacing led to a marked improvement of EF in 25% of the patients 3 and 12 months following the ablation procedure. A study17 on atrial and ventricular functional restoration and metabolic exercise testing in patients with nonvalvular permanent AF demonstrated a discrepancy between the early restoration of atrial functional parameters and the later improvement in LVEF and peak oxygen consumption after cardioversion. This latency in time course of atrial and ventricular functional recovery underlines the intrinsic nature of ventricular cardiomyopathy. Similar results have been described after cardioversion of permanent AF associated with valvular diseases. Several studies have investigated the PVC burden associated with a higher risk of developing AIC. The first evidence of PVC-induced cardiomyopathy dates back to 2000 when Chugh et al4 described the case of a young woman, symptomatic for palpitations and dyspnea during exercise, who experienced a resolution of dilated cardiomyopathy after radiofrequency ablation of a focal source of PVCs. When patients with PVCs are divided into 3 groups based on the total number of daily PVCs (10,000/24 h), the prevalence of arrhythmia-induced cardiac dysfunction has been reported to be 4, 12, and 34%, respectively.7 In patients suffering from PVCs, some features may suggest the diagnosis of AIC such as (1) young healthy patients; (2) absence of coronary artery disease and myocardial scar; (3) frequent PVCs © 2014 Lippincott Williams & Wilkins

Cardiology in Review  •  Volume 23, Number 3, May/June 2015

TABLE 1.  Microstructural and Macrostructural Changes Observed in Arrhythmia-Induced Cardiomyopathy Microstructural Changes  Cardiomyocyte structural derangement  Hypertrophy and loss of cardiac cells  Focal disruption of the basement membrane–sarcolemma interface  Extracellular matrix change and myocardial fibrosis  Impaired coronary reserve Gross Changes  Cardiac chamber dilation  Spheroid left ventricular geometry  Cardiac wall thinning  Mitral regurgitation  Increased pulmonary wedge pressure

of 1 or 2 primary morphologies, and (4) arising from RV/LV outflow tract or the fascicles. However, AIC has been also described in patients with monomorphic or less frequent premature complexes.19

PATHOPHYSIOLOGY Basic Mechanisms of AIC Heart rate, as well as duration and type of arrhythmia play a pivotal role in the progression and reversibility of arrhythmiainduced HF. A direct proportion has been observed to exist between heart rate, duration/site of pacing, and degree of cardiac function impairment.20,21 Chronic rapid pacing has been the most widely used approach to experimentally reproduce the pathophysiology of AIC. Whipple et al22 first demonstrated that rapid atrial or ventricular pacing leads to cardiac dysfunction. Zupan et al23 demonstrated that cardiac dysfunction occurs early after initiation of cardiac pacing and is more pronounced in cases of LV pacing. The LV is frequently more affected than the RV. However, all cardiac chambers can be involved and atrial-AIC and isolated RV dysfunction have been also described.5,24 Atrial-AIC is an uncommon form of cardiomyopathy due to chronic high atrial rates. Schotten et al25 demonstrated that in patients with AF-induced atrial dysfunction, beta-adrenergic desensitization or dysfunction of the sarcoplasmic reticulum are uncommon cellular findings, unlike patients with ventricular tachycardia-induced dysfunction. Conversely, downregulation or altered function of the L-type Ca2+-channel and an increased Ca2+ extrusion via the Na+/Ca2+-exchanger appear to be the main cellular abnormalities for atrial dysfunction. Several morphological changes have been described after chronic rapid pacing (Table 1). Dilation is more pronounced than hypertrophy (frequently leading to a spheroid geometry of the LV) and an increase of the end-systolic volume is more pronounced than that of the end-diastolic volume. Cardiac dilation is frequently associated with an increase in cardiac weight and LV wall thinning (or normal wall thickness rather than thickening). Tomita et al25 showed that rapid cardiac pacing (240 beats/min for 3 weeks) in pigs leads to LV dilation with systolic and diastolic dysfunction, decreased cardiac output, and LV wall thinning but not quantitative changes of ventricular mass, with a complete recovery in systolic but not diastolic function at the end of the pacing period. On the molecular and cellular levels, loss of contractility and abnormal myocyte geometry (eg, increased resting length) are common findings25–27 in LV sections of animals with pacing-induced cardiomyopathy. Myocyte structural derangement with focal disruptions of the basement membrane–sarcolemmal interface (eg, myocyte attachment to laminin, fibronectin, and collagen IV) may explain cardiac remodeling and dysfunction due to chronic high rate pacing.26 Kajstura et al28 demonstrated that pacing-induced dilation © 2014 Lippincott Williams & Wilkins

Novel Perspectives on Arrhythmia-Induced Cardiomyopathy

and wall thinning are associated with multiple foci of fibrosis with a 39% loss of LV cells and a 61% increase in volume of the viable ones. Because cellular hypertrophy has been proposed to modulate swelling-activated or stretch-activated mechanosensitive channels, this may promote dysrhythmias, hypertrophy, and altered contractile function.29 Burchell et al30 investigated the relationship among LV function, norepinephrine plasma levels, beta-adrenergic receptor number/affinity, and response to beta-agonist infusion in pigs exposed to supraventricular pacing-induced tachycardia for 3 weeks. Pacing caused systolic dysfunction and increased plasma norepinephrine levels, but beta-adrenergic receptor number/affinity did not change compared with the control group. Conversely, an impaired response to beta-agonist infusion was observed, suggesting decoupling between the beta-receptor and the components of the intracellular signaling pathway. Of note, ventricular dysfunction tends to worsen over time as adrenergic activation triggers a vicious cycle with further increase of ventricular rate: the ultimate result is HF. Pivotal in the pathogenesis of AIC appears to be the modification of calcium metabolism, as demonstrated by a reduction in density of T-tubules and L-type Ca2+-channels in a canine model of AIC.31,32 This may explain the impaired excitation–contraction coupling observed in failing myocytes. An abnormal calcium channel activity has been associated with prolongation of myocytes action potential and consequent functional abnormalities that affect contractility, electrophysiological properties, and myocardial relaxation (causing an increase in arrhythmogenic risk). Of note, although LV dysfunction can rapidly recover if an appropriate therapy is delivered, cellular and molecular changes may remain, increasing the risk for sudden death even when normal LV function is restored, as well as leading to a rapid restoration of the dysfunction if the arrhythmia recurs (Fig. 2). In addition, the inotropic response to cardiac glycosides has been demonstrated to be altered in AIC. Spinale et al33 observed a reduction in glycoside receptor density and Na+–K+–ATPase activity in pigs with pacinginduced dilated cardiomyopathy. These changes are responsible for reduced responsiveness of LV myocytes to ouabain (eg, poor increase in LV fractional shortening and peak dP/dt from baseline values) and, simultaneously, an increased sensitivity to the toxic effects of the glycoside (eg, development of irreversible ventricular fibrillation following a high cumulative dose administration of ouabain). Other changes in cardiomyocyte membrane currents have been described. The action potential prolongation at physiological cycle length has been linked to a decrease of the 2 components [I(Kr) and I(Ks)] of the delayed rectifier potassium current [I(K)], which may lead to a higher arrhythmogenic risk in HF.34 Oxidative stress plays an important role in arrhythmia-induced HF. Rabbits exposed to rapid cardiac pacing show an increase in oxidative stress as demonstrated by a reduction in the myocardial oxidized/reduced glutathione (GSH/GSSG) ratio and an increase in ox-mtDNA.35 They also develop beta-adrenergic subsensitivity and beta-receptor downregulation. The administration of antioxidants (beta-carotene, ascorbic acid, and alpha-tocopherol) may help reduce cardiac dysfunction, oxidative stress, and sympathetic dysfunction.35 Three primary mechanisms (oxidative stress, myocardial energy depletion, and ischemia) have been proposed to explain the described morphological and functional changes and the resulting myocardial function impairment. In combination with the previously mentioned mechanism of oxidative stress, models of persistent tachycardia are characterized by depletion of energy stores (eg, creatine, phosphocreatine, and adenosine triphosphate), enhanced activity of Krebs cycle enzymes, and mitochondrial structural and functional abnormalities (eg, reduced cytochrome oxidase staining).36,37 The third mechanism, closely linked to myocardial energy depletion, is myocardial ischemia. LV dysfunction and myocyte damage is attributed www.cardiologyinreview.com  |  137

Cardiology in Review  •  Volume 23, Number 3, May/June 2015

Della Rocca et al

TABLE 2.  Major clinical trials comparing catheter ablation strategies with antiarrhythmic drug therapy in AF patients with regard to maintenance of sinus rhythm Patients Free of AF Study Wazni et al Stabile et al65 Oral et al66 Pappone et al67 Jais et al68 Forleo et al69 Wilber et al70 Cosedis Nielsen et al71 Packer et al72 Pokushalov et al73 64

n

Follow-Up (mo)

Type of AF

Ablation Strategy (%)

AAD Strategy (%)

P

70 137 146 198 112 70* 167 294† 245 154§

12 12 12 12 12 12 9 24 12 36

Paroxysmal, persistent Paroxysmal, persistent Permanent Paroxysmal Paroxysmal Paroxysmal, persistent Paroxysmal Paroxysmal Paroxysmal Paroxysmal

8 56 74 86 88 80 66 84 70‡ 75

37 9 58 22 24 43 16 71 7 21

Novel perspectives on arrhythmia-induced cardiomyopathy: pathophysiology, clinical manifestations and an update on invasive management strategies.

Arrhythmia-induced cardiomyopathy is a partially or completely reversible form of myocardial dysfunction due to sustained supraventricular and ventric...
386KB Sizes 0 Downloads 5 Views