RESUMO
RATIONALE: Atrial fibrillation (AF) contributes significantly to morbidity and mortality in elderly and hypertensive patients and has been correlated to enhanced atrial fibrosis. Despite a lack of direct evidence that fibrosis causes AF, reversal of fibrosis is considered a plausible therapy. OBJECTIVE: To evaluate the efficacy of the antifibrotic hormone relaxin (RLX) in suppressing AF in spontaneously hypertensive rats (SHR). METHODS AND RESULTS: Normotensive Wistar-Kyoto (WKY) and SHR were treated for 2 weeks with vehicle (WKY+V and SHR+V) or RLX (0.4 mg/kg per day, SHR+RLX) using implantable mini-pumps. Hearts were perfused, mapped optically to analyze action potential durations, intracellular Ca²âº transients, and restitution kinetics, and tested for AF vulnerability. SHR hearts had slower conduction velocity (CV; P<0.01 versus WKY), steeper CV restitution kinetics, greater collagen deposition, higher levels of transcripts for transforming growth factor-ß, metalloproteinase-2, metalloproteinase-9, collagen I/III, and reduced connexin 43 phosphorylation (P<0.05 versus WKY). Programmed stimulation triggered sustained AF in SHR (n=5/5) and SHR+V (n=4/4), but not in WKY (n=0/5) and SHR+RLX (n=1/8; P<0.01). RLX treatment reversed the transcripts for fibrosis, flattened CV restitution kinetics, reduced action potential duration at 90% recovery to baseline, increased CV (P<0.01), and reversed atrial hypertrophy (P<0.05). Independent of antifibrotic actions, RLX (0.1 µmol/L) increased Na⺠current density, INa (≈2-fold in 48 hours) in human cardiomyocytes derived from inducible pluripotent stem cells (n=18/18; P<0.01). CONCLUSIONS: RLX treatment suppressed AF in SHR hearts by increasing CV from a combination of reversal of fibrosis and hypertrophy and by increasing INa. The study provides compelling evidence that RLX may provide a novel therapy to manage AF in humans by reversing fibrosis and hypertrophy and by modulating cardiac ionic currents.
Assuntos
Fibrilação Atrial/tratamento farmacológico , Cardiomiopatias/tratamento farmacológico , Miócitos Cardíacos/fisiologia , Relaxina/fisiologia , Relaxina/uso terapêutico , Animais , Fibrilação Atrial/fisiopatologia , Cardiomiopatias/fisiopatologia , Fibrose/fisiopatologia , Fibrose/prevenção & controle , Sistema de Condução Cardíaco/efeitos dos fármacos , Sistema de Condução Cardíaco/fisiologia , Humanos , Hipertrofia/tratamento farmacológico , Hipertrofia/fisiopatologia , Masculino , Miócitos Cardíacos/patologia , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/uso terapêuticoRESUMO
BACKGROUND: Atrial fibrillation (AF) contributes significantly to morbidity and mortality in elderly patients and has been correlated with enhanced age-dependent atrial fibrosis. Reversal of atrial fibrosis has been proposed as therapeutic strategy to suppress AF. OBJECTIVE: To test the ability of relaxin to reverse age-dependent atrial fibrosis and suppress AF. METHODS: Aged F-344 rats (24 months old) were treated with subcutaneous infusion of vehicle or relaxin (0.4 mg/kg/day) for 2 weeks. Rat hearts were excised, perfused on a Langendorff apparatus, and stained with voltage and Ca(2+) indicator dyes. Optical mapping and programmed electrical stimulation was used to test arrhythmia vulnerability and changes in electrophysiological characteristics. Changes in protein expression and Na(+) current density (INa) were measured by tissue immunofluorescence and whole-cell patch clamp technique. RESULTS: In aged rats, sustained AF was readily induced with a premature pulse (n = 7/8) and relaxin treatment suppressed sustained AF by a premature impulse or burst pacing (n = 1/6) (P < .01). Relaxin significantly increased atrial action potential conduction velocity and decreased atrial fibrosis. Relaxin treatment increased Nav1.5 expression (n = 6; 36% ± 10%) and decreased total collagen and collagen I (n = 5-6; 55%-66% ± 15%) in aged atria (P < .05) and decreased collagen I and III and TGF-ß1 mRNA (P < .05). Voltage-clamp experiments demonstrated that relaxin treatment (100 nM for 2 days) increased atrial INa by 46% ± 4% (n = 12-13/group, P < .02). CONCLUSION: Relaxin suppresses AF through an increase in atrial conduction velocity by decreasing atrial fibrosis and increasing INa. These data provide compelling evidence that relaxin may serve as an effective therapy to manage AF in geriatric patients by reversing fibrosis and modulating cardiac ionic currents.
Assuntos
Fibrilação Atrial/tratamento farmacológico , Átrios do Coração/metabolismo , Sistema de Condução Cardíaco/fisiopatologia , Miócitos Cardíacos/metabolismo , Relaxina/farmacologia , Canais de Sódio/biossíntese , Regulação para Cima , Potenciais de Ação/efeitos dos fármacos , Animais , Fibrilação Atrial/patologia , Fibrilação Atrial/fisiopatologia , Células Cultivadas , Modelos Animais de Doenças , Fibrose/patologia , Fibrose/fisiopatologia , Átrios do Coração/efeitos dos fármacos , Átrios do Coração/patologia , Sistema de Condução Cardíaco/efeitos dos fármacos , Masculino , Miócitos Cardíacos/patologia , Ratos , Ratos Endogâmicos F344 , Ratos Endogâmicos WKY , Canais de Sódio/efeitos dos fármacosRESUMO
Administration of recombinant human relaxin (rhRLX) to conscious rats increases global arterial compliance, and small renal arteries (SRA) isolated from these rats demonstrate increased passive compliance. Here we characterize relaxin-induced vascular remodeling and examine its functional relevance. SRA and external iliac arteries (EIA) were examined in rhRLX-treated (1.0 µg/h for 5 days) and relaxin knockout mice. Arterial geometric remodeling and compositional remodeling were quantified using immunohistochemical and biochemical techniques. Vascular mechanical properties were quantified using an ex vivo preparation wherein pressure-diameter data were obtained at various axial lengths. Compared with vehicle-treated mice, SRA from rhRLX-treated mice showed outward geometric remodeling (increased unstressed wall area and wall-to-lumen area ratio), increased smooth muscle cell (SMC) density, reduction in collagen-to-total protein ratio, and unchanged elastin-to-tissue dry weight ratio. Compared with wild-type mice, relaxin knockout mice exhibited the opposite pattern: decreased unstressed wall area and wall-to-lumen area ratio, decreased SMC density, and increased collagen-to-total protein ratio. Although tissue biaxial strain energy of SRA was not different between rhRLX- and vehicle-treated groups at low-to-physiological circumferential and axial strains, it was lower for the rhRLX-treated group at the highest circumferential strain. In contrast to SRA, relaxin administration was not associated with any vascular remodeling or changes in passive mechanics of EIA. Thus relaxin induces both geometric and compositional remodeling in vessel-specific manner. Relaxin-induced geometric remodeling of SRA is responsible for the increase in passive compliance under low-to-physiological levels of circumferential and axial strains, and compositional remodeling becomes functionally relevant only under high circumferential strain.
Assuntos
Artéria Ilíaca/metabolismo , Relaxina/metabolismo , Artéria Renal/metabolismo , Animais , Fenômenos Biomecânicos , Pressão Sanguínea , Colágeno/metabolismo , Complacência (Medida de Distensibilidade) , Elastina/metabolismo , Feminino , Gelatinases/metabolismo , Humanos , Artéria Ilíaca/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Recombinantes/metabolismo , Relaxina/administração & dosagem , Relaxina/deficiência , Relaxina/genética , Artéria Renal/patologia , Estresse Mecânico , Fatores de TempoRESUMO
BACKGROUND: Postoperative tachyarrhythmias remain a common complication after congenital cardiac operations. Dexmedetomidine (DEX), an α-2 adrenoreceptor agonist, can have a therapeutic role in supraventricular tachyarrhythmias for cardioversion to sinus rhythm or heart rate control. Whether routine perioperative use of DEX decreases the incidence of supraventricular and ventricular tachyarrhythmias was studied. METHODS: In this prospective cohort study, 32 pediatric patients undergoing cardiothoracic operations received DEX and were compared with 20 control patients who did not receive DEX. RESULTS: Dexmedetomidine was started after anesthesia induction and continued intraoperatively and postoperatively for 38±4 hours (mean dose, 0.76±0.04 µg/kg/h). Ten control patients and 2 DEX patients sustained 16 episodes of tachyarrhythmias (p=0.001), including a 25% vs 0% (p=0.01) incidence of ventricular tachycardia and 25% vs 6% (p=0.05) of supraventricular arrhythmias in the control and DEX group, respectively. Transient complete heart block occurred in 2 control patients and in 1 DEX patient. Control patients had a higher heart rate (141±5 vs 127±3 beats/min, p=0.03), more sinus tachycardia episodes (40% vs 6%; p=0.008), required more antihypertensive drugs with nitroprusside (20±7 vs 4±1 µg/kg; p=0.004) and nicardipine (13±5 vs 2±1 µg/kg; p=0.02), and required more fentanyl (39±8 vs 19±3 µg/kg; p=0.005). CONCLUSIONS: Perioperative use of dexmedetomidine is associated with a significantly decreased incidence of ventricular and supraventricular tachyarrhythmias, without significant adverse effects.