RESUMEN
BACKGROUND: The cyclic AMP (adenosine monophosphate; cAMP)-hydrolyzing protein PDE4B (phosphodiesterase 4B) is a key negative regulator of cardiac ß-adrenergic receptor stimulation. PDE4B deficiency leads to abnormal Ca2+ handling and PDE4B is decreased in pressure overload hypertrophy, suggesting that increasing PDE4B in the heart is beneficial in heart failure. METHODS: We measured PDE4B expression in human cardiac tissues and developed 2 transgenic mouse lines with cardiomyocyte-specific overexpression of PDE4B and an adeno-associated virus serotype 9 encoding PDE4B. Myocardial structure and function were evaluated by echocardiography, ECG, and in Langendorff-perfused hearts. Also, cAMP and PKA (cAMP dependent protein kinase) activity were monitored by Förster resonance energy transfer, L-type Ca2+ current by whole-cell patch-clamp, and cardiomyocyte shortening and Ca2+ transients with an Ionoptix system. Heart failure was induced by 2 weeks infusion of isoproterenol or transverse aortic constriction. Cardiac remodeling was evaluated by serial echocardiography, morphometric analysis, and histology. RESULTS: PDE4B protein was decreased in human failing hearts. The first PDE4B-transgenic mouse line (TG15) had a ≈15-fold increase in cardiac cAMP-PDE activity and a ≈30% decrease in cAMP content and fractional shortening associated with a mild cardiac hypertrophy that resorbed with age. Basal ex vivo myocardial function was unchanged, but ß-adrenergic receptor stimulation of cardiac inotropy, cAMP, PKA, L-type Ca2+ current, Ca2+ transients, and cell contraction were blunted. Endurance capacity and life expectancy were normal. Moreover, these mice were protected from systolic dysfunction, hypertrophy, lung congestion, and fibrosis induced by chronic isoproterenol treatment. In the second PDE4B-transgenic mouse line (TG50), markedly higher PDE4B overexpression, resulting in a ≈50-fold increase in cardiac cAMP-PDE activity caused a ≈50% decrease in fractional shortening, hypertrophy, dilatation, and premature death. In contrast, mice injected with adeno-associated virus serotype 9 encoding PDE4B (1012 viral particles/mouse) had a ≈50% increase in cardiac cAMP-PDE activity, which did not modify basal cardiac function but efficiently prevented systolic dysfunction, apoptosis, and fibrosis, while attenuating hypertrophy induced by chronic isoproterenol infusion. Similarly, adeno-associated virus serotype 9 encoding PDE4B slowed contractile deterioration, attenuated hypertrophy and lung congestion, and prevented apoptosis and fibrotic remodeling in transverse aortic constriction. CONCLUSIONS: Our results indicate that a moderate increase in PDE4B is cardioprotective and suggest that cardiac gene therapy with PDE4B might constitute a new promising approach to treat heart failure.
Asunto(s)
Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/genética , Expresión Génica , Insuficiencia Cardíaca/etiología , Miocardio/metabolismo , Remodelación Ventricular/genética , Agonistas Adrenérgicos beta/farmacología , Animales , AMP Cíclico/metabolismo , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/metabolismo , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Terapia Genética , Vectores Genéticos/genética , Insuficiencia Cardíaca/diagnóstico , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/metabolismo , Pruebas de Función Cardíaca , Humanos , Isoproterenol/farmacología , Ratones , Ratones Transgénicos , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Fenotipo , Receptores Adrenérgicos beta/metabolismo , Transducción Genética , Remodelación Ventricular/efectos de los fármacosRESUMEN
BACKGROUND: Cryoballoon ablation is widely used for pulmonary vein isolation in patients with atrial fibrillation. There are no data regarding the clinical efficacy of cryoballoon ablation in patients with atypical right pulmonary vein anatomy. AIM: We aimed to evaluate the impact of right pulmonary vein anatomy on the safety and efficacy of cryoballoon ablation. METHODS: Patients referred for cryoballoon ablation of paroxysmal atrial fibrillation were enrolled prospectively. Left atrial computed tomography was performed before cryoballoon ablation to determine whether the right pulmonary vein anatomy was "normal" or "atypical". For patients with atypical anatomy, cryoballoon ablation was only performed for right superior and right inferior pulmonary veins, neglecting accessory pulmonary veins. RESULTS: Overall, 303 patients were included: 254 (83.8%) with normal and 49 (16.2%) with atypical right pulmonary vein anatomy. First-freeze isolation for right superior and right inferior pulmonary veins occurred in 44 (89.8%) and 37 (75.5%) patients with atypical pulmonary vein anatomy, and in 218 (85.8%) and 217 (85.4%) patients with typical pulmonary vein anatomy, respectively (P not significant). Phrenic nerve palsies were only observed in patients with normal anatomy (0 vs. 26 [8.6%]; P=0.039). Mid-term survival free from atrial arrhythmia was similar, regardless of right pulmonary vein anatomy. CONCLUSIONS: A significant proportion of patients have atypical right pulmonary vein anatomy. Procedural characteristics, acute pulmonary vein isolation success and mid-term procedural efficacy were similar, regardless of right pulmonary vein anatomy. In addition to left-side pulmonary vein isolation, cryoballoon ablation of right superior and right inferior pulmonary veins only, neglecting accessory pulmonary veins, is sufficient to obtain acute right-side pulmonary vein isolation and mid-term sinus rhythm maintenance in patients with atypical anatomy.