RESUMEN
The cardiac pacemaker current I(f) is a major determinant of diastolic depolarization in sinus nodal cells and has a key role in heartbeat generation. Therefore, we hypothesized that some forms of "idiopathic" sinus node dysfunction (SND) are related to inherited dysfunctions of cardiac pacemaker ion channels. In a candidate gene approach, a heterozygous 1-bp deletion (1631delC) in exon 5 of the human HCN4 gene was detected in a patient with idiopathic SND. The mutant HCN4 protein (HCN4-573X) had a truncated C-terminus and lacked the cyclic nucleotide-binding domain. COS-7 cells transiently transfected with HCN4-573X cDNA indicated normal intracellular trafficking and membrane integration of HCN4-573X subunits. Patch-clamp experiments showed that HCN4-573X channels mediated I(f)-like currents that were insensitive to increased cellular cAMP levels. Coexpression experiments showed a dominant-negative effect of HCN4-573X subunits on wild-type subunits. These data indicate that the cardiac I(f) channels are functionally expressed but with altered biophysical properties. Taken together, the clinical, genetic, and in vitro data provide a likely explanation for the patient's sinus bradycardia and the chronotropic incompetence.
Asunto(s)
Arritmia Sinusal/diagnóstico , Fibrilación Atrial/diagnóstico , Bradicardia/diagnóstico , Canales Iónicos/genética , Proteínas Musculares/genética , Anciano , Animales , Arritmia Sinusal/complicaciones , Arritmia Sinusal/genética , Fibrilación Atrial/complicaciones , Fibrilación Atrial/genética , Bradicardia/complicaciones , Bradicardia/genética , Células COS , AMP Cíclico/metabolismo , Canales Catiónicos Regulados por Nucleótidos Cíclicos , Análisis Mutacional de ADN , Electrocardiografía , Técnicas Electrofisiológicas Cardíacas , Electrofisiología , Exones , Femenino , Frecuencia Cardíaca/genética , Humanos , Canales Regulados por Nucleótidos Cíclicos Activados por Hiperpolarización , Intrones , Canales Iónicos/biosíntesis , Proteínas Musculares/biosíntesis , Mutación , Técnicas de Placa-Clamp , Canales de Potasio , Subunidades de Proteína/biosíntesis , Subunidades de Proteína/genética , Transporte de Proteínas , Síncope/etiología , TransfecciónRESUMEN
The impact of static muscle tension on total respiratory resistance (TRR) was examined. Participants (24 healthy, 24 asthmatic) performed biofeedback-assisted sequences of tensing (15 s) and relaxing (20 s) forehead and forearm muscles. Muscle tension levels were 40% or 80% of the maximum individual force. Oscillatory TRR, electromyograms, ventilation, heart period, and respiratory sinus arrhythmia were recorded. Baseline TRR did not change over the session as a whole. Decreases in TRR during forehead tension in both groups were accompanied by increases in end-expiratory volume, which could have mediated TRR changes. During forearm tension, decreases in TRR with minimal ventilation changes were only observed in healthy participants, whereas asthmatic patients revealed marked increases in respiratory volume and flow. These results indicate that static muscle activity and TRR are negatively related. Ventilatory changes can exaggerate or diminish evidence for this relationship.