RESUMEN
BACKGROUND: Arrhythmia-induced cardiomyopathy (AIC) is a known entity, but prospective evidence for its characterization is limited. OBJECTIVES: This study aimed to: 1) determine the relative frequency of the pure form of AIC in the clinically relevant cohort of patients with newly diagnosed, otherwise unexplained left ventricular systolic dysfunction (LVSD) and tachyarrhythmia; 2) assess the time to recovery from LVSD; and 3) identify parameters for an early diagnosis of AIC. METHODS: Patients were prospectively included, underwent effective rhythm restoration, and were followed-up at 2, 4, and 6 months to evaluate clinical characteristics, biomarkers, and cardiac imaging including cardiac magnetic resonance imaging. Patients with recurred arrhythmia were excluded from analysis. RESULTS: 41 of 50 patients were diagnosed with AIC 6 months after rhythm restoration. Left ventricular (LV) ejection fraction increased 2 months after rhythm restoration from 35.4% ± 8.2% to 52.7% ± 8.0% in AIC patients vs 37.0% ± 9.5% to 43.3% ± 7.0% in non-AIC patients. From month 2 to 6, LV ejection fraction continued to increase in AIC patients (57.2% ± 6.1%; P < 0.001) but remained stable in non-AIC patients (44.0% ± 7.8%; P = 0.628). Multivariable logistic regression analysis revealed that lower LV end-diastolic diameter at baseline could be used for early diagnosis of AIC, whereas biomarkers and other morphological or functional parameters, including late LV gadolinium enhancement, did not show suitability for early diagnosis. CONCLUSIONS: We observed a high prevalence of AIC in patients with otherwise unexplained LVSD and concomitant tachyarrhythmia, suggesting that this condition may be underdiagnosed in clinical practice. Most patients recovered fast, within months, from LVSD. A low initial LV end-diastolic diameter may constitute an early marker for diagnosis of AIC.
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Cardiomiopatías , Insuficiencia Cardíaca , Taquicardia , Humanos , Masculino , Femenino , Persona de Mediana Edad , Cardiomiopatías/fisiopatología , Cardiomiopatías/complicaciones , Cardiomiopatías/diagnóstico por imagen , Estudios Prospectivos , Taquicardia/fisiopatología , Anciano , Insuficiencia Cardíaca/fisiopatología , Insuficiencia Cardíaca/complicaciones , Disfunción Ventricular Izquierda/fisiopatología , Disfunción Ventricular Izquierda/diagnóstico por imagen , Adulto , Volumen Sistólico/fisiologíaRESUMEN
BACKGROUND: Arrhythmia-induced cardiomyopathy (AIC) is characterized by the reversibility of left ventricular (LV) systolic dysfunction (LVSD) after rhythm restoration. This study is a cardiac magnetic resonance tomography substudy of our AIC trial with the purpose to investigate whether left ventricular fibrosis affects the time to recovery (TTR) in patients with AIC. METHOD: Patients with newly diagnosed and otherwise unexplainable LVSD and tachyarrhythmia were prospectively recruited. LV ejection fraction (LVEF) was measured by echocardiography at baseline and 2, 4, and 6 months after rhythm control, and stress markers were assessed. After initial rhythm control, LV fibrosis was assessed through late gadolinium enhancement (LGE). Patients were diagnosed with AIC if their LVEF improved by ≥15% (or ≥10% when LVEF reached ≥50%). Non-responders served as controls (non-AIC). RESULTS: The LGE analysis included 39 patients, 31 of whom recovered (AIC). LV end-systolic diameters decreased and LVEF increased during follow-up. LV LGE content correlated positively with TTR (r = 0.63, p = 0.003), with less LGE favoring faster recovery, and negatively with ΔLVEF (i.e., LVEF at month 2 compared to baseline) as a marker of fast recovery (r = -0.55, p = 0.012), suggesting that LV fibrosis affects the speed of recovery. CONCLUSION: LV fibrosis correlated positively with the time to recovery in patients with AIC. This correlation may help in the estimation of the recovery period and in the optimization of diagnostic and therapeutic strategies for patients with AIC.
RESUMEN
Arrhythmia-induced cardiomyopathy (AIC) is classified as a form of dilated cardiomyopathy in which left ventricular systolic dysfunction (LVSD) is triggered by tachycardic or arrhythmic heart rates. On the one hand AIC can develop in patients without cardiac disease and on the other hand it can appear in patients with pre-existing LVSD, leading to a further reduction in left ventricular (LV) ejection fraction. A special aspect of AIC is the potential termination or partial reversibility of LVSD; thus, AIC is curatively treatable by the elimination of the underlying arrhythmia. Since arrhythmias are often seen merely as a consequence than as an underlying cause of LVSD, and due to the fact that the diagnosis of AIC can be made only after recovery of LV function, the prevalence of AIC is probably underestimated in clinical practice. Pathophysiologically, animal models have shown that continuous tachycardic pacing induces consecutive changes such as the occurrence of LVSD, increased filling pressures, LV dilatation, and decreased cardiac output. After termination of tachycardia, reversibility of the described pathologies can usually be observed. Studies in human ventricular myocardium have recently demonstrated that various cellular structural and functional mechanisms are activated even by normofrequent atrial fibrillation, which may help to explain the clinical AIC phenotype.
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Fibrilación Atrial , Cardiomiopatía Dilatada , Cardiopatías , Disfunción Ventricular Izquierda , Animales , Humanos , Función Ventricular Izquierda , Disfunción Ventricular Izquierda/diagnóstico , Disfunción Ventricular Izquierda/etiología , Disfunción Ventricular Izquierda/terapia , Cardiomiopatía Dilatada/diagnósticoRESUMEN
BACKGROUND: Atrial fibrillation (AF) can either be a consequence or an underlying mechanism of left ventricular systolic dysfunction. Patients included in the CASTLE-AF (Catheter Ablation vs. Standard Conventional Treatment in Patients With LV Dysfunction and AF) trial who suffered from AF and left ventricular systolic dysfunction benefited from an AF burden <50% after catheter ablation compared with those patients with an AF burden >50%. OBJECTIVES: This analysis tried to explain the clinical findings of the CASTLE-AF trial regarding AF burden in a "back-to-bench" approach. METHODS: To study the ventricular effects of different AF burdens, experiments were performed using human ventricular induced pluripotent stem cell-derived cardiomyocytes undergoing in vitro AF simulation. Epifluorescence microscopy, action potential measurements, and measurements of sarcomere regularity were conducted. RESULTS: Induced pluripotent stem cell-derived cardiomyocytes stimulated with AF burden of 60% or higher displayed typical hallmarks of heart failure. Ca2+ transient amplitude was significantly reduced indicating negative inotropic effects. Action potential duration was significantly prolonged, which represents a potential trigger for arrhythmias. A significant decrease of sarcomere regularity could explain impaired cardiac contractility in patients with high AF burden. These effects were more pronounced after 7 days of AF simulation compared with 48 hours. CONCLUSIONS: Significant functional and structural alterations occurred at the cellular level at a threshold of â¼50% AF burden as it was observed to be harmful in the CASTLE-AF trial. Therefore, these translational results may help to understand the findings of the CASTLE-AF trial.
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Fibrilación Atrial , Ablación por Catéter , Insuficiencia Cardíaca , Disfunción Ventricular Izquierda , Humanos , Fibrilación Atrial/cirugía , Ablación por Catéter/métodos , Insuficiencia Cardíaca/etiología , Remodelación Ventricular/fisiología , Ensayos Clínicos como AsuntoRESUMEN
RATIONALE: Atrial fibrillation (AF) and heart failure often coexist, but their interaction is poorly understood. Clinical data indicate that the arrhythmic component of AF may contribute to left ventricular (LV) dysfunction. OBJECTIVE: This study investigates the effects and molecular mechanisms of AF on the human LV. METHODS AND RESULTS: Ventricular myocardium from patients with aortic stenosis and preserved LV function with sinus rhythm or rate-controlled AF was studied. LV myocardium from patients with sinus rhythm and patients with AF showed no differences in fibrosis. In functional studies, systolic Ca2+ transient amplitude of LV cardiomyocytes was reduced in patients with AF, while diastolic Ca2+ levels and Ca2+ transient kinetics were not statistically different. These results were confirmed in LV cardiomyocytes from nonfailing donors with sinus rhythm or AF. Moreover, normofrequent AF was simulated in vitro using arrhythmic or rhythmic pacing (both at 60 bpm). After 24 hours of AF-simulation, human LV cardiomyocytes from nonfailing donors showed an impaired Ca2+ transient amplitude. For a standardized investigation of AF-simulation, human iPSC-cardiomyocytes were tested. Seven days of AF-simulation caused reduced systolic Ca2+ transient amplitude and sarcoplasmic reticulum Ca2+ load likely because of an increased diastolic sarcoplasmic reticulum Ca2+ leak. Moreover, cytosolic Na+ concentration was elevated and action potential duration was prolonged after AF-simulation. We detected an increased late Na+ current as a potential trigger for the detrimentally altered Ca2+/Na+-interplay. Mechanistically, reactive oxygen species were higher in the LV of patients with AF. CaMKII (Ca2+/calmodulin-dependent protein kinase IIδc) was found to be more oxidized at Met281/282 in the LV of patients with AF leading to an increased CaMKII activity and consequent increased RyR2 phosphorylation. CaMKII inhibition and ROS scavenging ameliorated impaired systolic Ca2+ handling after AF-simulation. CONCLUSIONS: AF causes distinct functional and molecular remodeling of the human LV. This translational study provides the first mechanistic characterization and the potential negative impact of AF in the absence of tachycardia on the human ventricle.
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Fibrilación Atrial , Calcio/metabolismo , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Humanos , Miocitos Cardíacos/metabolismo , Canal Liberador de Calcio Receptor de Rianodina/metabolismo , Retículo Sarcoplasmático/metabolismoRESUMEN
AIMS: Tachyarrhythmia due to atrial fibrillation (AF) is often associated with reduced left ventricular (LV) function and has been proposed to cause arrhythmia-induced cardiomyopathy (AIC). However, the precise diagnostics of AIC and reversibility after rhythm restoration are poorly understood. Our aim was to investigate systolic LV function in tachycardic AF and to evaluate the direct effect of rhythm restoration. METHODS: We prospectively studied 24 patients (71% male, age 65 ± 9 years) with tachycardic AF and newly diagnosed reduced left ventricular ejection fraction (LVEF). Just before and immediately after electrical cardioversion (ECV), transthoracic echocardiography was performed. Geometric as well as functional data were assessed. RESULTS: Patients presented with a heart rate (HR) of 117.4 ± 21.6/min and a 2D-/3D-LVEF of 32 ± 9/31 ± 8%. ECV to sinus rhythm normalized HR to 77 ± 11/min with an increase of 2D-/3D-LVEF to 37 ± 9/37 ± 10% (p < 0.01 vs. baseline, each). Left ventricular geometry changed with an increase of end-diastolic volume (LVEDV) while end-systolic volume (LVESV) remained unchanged. Parameters concerning myocardial deformation (global longitudinal strain (GLS), strain rate (SR)) decreased whereas the RR interval-corrected GLS (GLSc) remained unchanged. In a simple linear regression model, GLS correlated with 2D- and 3D-LVEF not only before (pre) ECV, but also after (post) ECV. We demonstrate that the increase of LVEF and GLS (ratios pre/post) correlates with the change of HR (ΔHR; R2 = 0.20, 0.33 and 0.32, p < 0.05 each), whereas ratios of GLSc and SR do not significantly correlate with HR (R2 = 0.03 and 0.01, p = n.s. each). CONCLUSION: In patients with tachyarrhythmia and reduced ejection fraction, ECV leads to immediate improvement in EF and GLS while HR-corrected LV contractility remains unchanged. This suggests that the immediate effects of rhythm restoration are mostly related to changes in left ventricular volume, but not to an acute improvement of heart-rate independent contractility.