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PURPOSE: American Indians/Alaska Native (AI/AN) persons are disproportionately affected by hepatitis C virus (HCV). The Northwest Portland Area Indian Health Board Indian Country Extension for Community Healthcare Outcomes (ECHO) telehealth clinic supports primary care providers (PCPs) in treating HCV. We evaluated the extent to which Indian Country ECHO increases access to HCV treatment and holistically serves AI/AN patients. METHODS: We conducted a retrospective descriptive analysis of Indian Country ECHO treatment recommendations from 2017 to 2021. Recommendations were classified into the following categories: HCV treatment with direct-acting antiviral medication, prevention, substance use disorder treatment, lab or imaging orders, pharmacological considerations, behavior changes, other, and referral. Subanalysis of treatment recommendations was completed for patients with cirrhosis. FINDINGS: Of the 776 patients from 77 Indian Health System facilities who presented at Indian Country ECHO, 718 (93%) received treatment recommendations. Most patients (93%) received recommendations for HCV treatment by their PCP; only 3% received a recommendation for referral to a hepatologist or liver transplant center for additional care. Most patients received at least 1 recommendation beyond the scope of HCV treatment provision. Cirrhosis criteria were met by 8% of patients, of which 80% received recommendations for HCV treatment by their PCP and 25% received recommendations for referral to a specialist for additional care. CONCLUSIONS: Most patients presented at the Indian Country ECHO received recommendations for HCV treatment by their PCP, along with recommendations beyond the scope of HCV. Indian Country ECHO telehealth clinic provides comprehensive recommendations to effectively integrate evidence-based HCV treatment with holistic care at the primary care level.
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Hepatitis C Crónica , Hepatitis C , Telemedicina , Humanos , Hepacivirus , Antivirales/uso terapéutico , Estudios Retrospectivos , Hepatitis C Crónica/tratamiento farmacológico , Hepatitis C/tratamiento farmacológico , Servicios de Salud ComunitariaRESUMEN
The spontaneous action potential (AP) firing rate of sinoatrial nodal cells (SANC) is regulated by a system of intracellular Ca2+ and membrane ion current clocks driven by Ca2+-calmodulin-activated adenylyl cyclase-protein kinase-A signaling. The mean AP-cycle length (APCL) and APCL variability inform on the effectiveness of clock coupling. Endogenous ATP metabolite adenosine binds to adenosine receptors (A1, A3) that couple to Gi protein-coupled receptors, reducing spontaneous AP firing rate via Gßγ signaling that activates IKAch,Ado. Adenosine also inhibits adenylyl cyclase activity via Gαi signaling, impacting cAMP-mediated protein kinase-A-dependent protein phosphorylation. We hypothesize that in addition to IKAch,Ado activation, adenosine impacts also Ca2+ via Gαi signaling and that both effects reduce AP firing rate by reducing the effectiveness of the Ca2+ and membrane clock coupling. To this end, we measured Ca2+ and membrane potential characteristics in enzymatically isolated single rabbit SANC. 10 µM adenosine substantially increased both the mean APCL (on average by 43%, n = 10) and AP beat-to-beat variability from 5.1 ± 1.7% to 7.2 ± 2.0% (n = 10) measured via membrane potential and 5.0 ± 2.2% to 10.6 ± 5.9% (n = 40) measured via Ca2+ (assessed as the coefficient of variability = SD/mean). These effects were mediated by hyperpolarization of the maximum diastolic membrane potential (membrane clock effect) and suppression of diastolic local Ca2+releases (LCRs) (Ca2+-clock effect): as LCR size distributions shifted to smaller values, the time of LCR occurrence during diastolic depolarization (LCR period) became prolonged, and the ensemble LCR signal became reduced. The tight linear relationship of coupling between LCR period to the APCL in the presence of adenosine "drifted" upward and leftward, i.e. for a given LCR period, APCL was prolonged, becoming non-linear indicating clock uncoupling. An extreme case of uncoupling occurred at higher adenosine concentrations (>100 µM): small stochastic LCRs failed to self-organize and synchronize to the membrane clock, thus creating a failed attempt to generate an AP resulting in arrhythmia and cessation of AP firing. Thus, the effects of adenosine to activate Gßγ and IKACh,Ado and to activate Gαi, suppressing adenylyl cyclase activity, both contribute to the adenosine-induced increase in the mean APCL and APCL variability by reducing the fidelity of clock coupling and AP firing rate.
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OBJECTIVES: The purpose of this study was to discover regulatory universal mechanisms of normal automaticity in sinoatrial nodal (SAN) pacemaker cells that are self-similar across species. BACKGROUND: Translation of knowledge of SAN automaticity gleaned from animal studies to human dysrhythmias (e.g., "sick sinus" syndrome [SSS]) requiring electronic pacemaker insertion has been suboptimal, largely because heart rate varies widely across species. METHODS: Subcellular Ca2+ releases, whole cell action potential (AP)-induced Ca2+ transients, and APs were recorded in isolated mouse, guinea pig, rabbit, and human SAN cells. Ca2+-Vm kinetic parameters during phases of AP cycles from their ignition to recovery were quantified. RESULTS: Although both AP cycle lengths (APCLs) and Ca2+-Vm kinetic parameters during AP cycles differed across species by 10-fold, trans-species scaling of these during AP cycles and scaling of these to APCL in cells in vitro, electrocardiogram RR intervals in vivo, and body mass (BM) were self-similar (obeyed power laws) across species. Thus, APCL in vitro, heart rate in vivo, and BM of any species can be predicted by Ca2+-Vm kinetics during AP cycles in SAN cells measured in any single species in vitro. CONCLUSIONS: In designing optimal heart rate to match widely different BM and energy requirements from mice to humans, nature did not "reinvent pacemaker cell wheels," but differentially scaled kinetics of gears that regulate the rates at which the "wheels spin." This discovery will facilitate the development of novel pharmacological and biological pacemakers featuring a normal, wide-range rate regulation in animal models and the translation of these to humans to target recalcitrant human SSS.
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Calcio , Nodo Sinoatrial , Potenciales de Acción , Animales , Cobayas , Frecuencia Cardíaca , Potenciales de la Membrana , Ratones , ConejosRESUMEN
Action potential (AP) firing rate and rhythm of sinoatrial nodal cells (SANC) are controlled by synergy between intracellular rhythmic local Ca2+ releases (LCRs) ("Ca2+ clock") and sarcolemmal electrogenic mechanisms ("membrane clock"). However, some SANC do not fire APs (dormant SANC). Prior studies have shown that ß-adrenoceptor stimulation can restore AP firing in these cells. Here we tested whether this relates to improvement of synchronization of clock coupling. We characterized membrane potential, ion currents, Ca2+ dynamics, and phospholamban (PLB) phosphorylation, regulating Ca2+ pump in enzymatically isolated single guinea pig SANC prior to, during, and following ß-adrenoceptor stimulation (isoproterenol) or application of cell-permeant cAMP (CPT-cAMP). Phosphorylation of PLB (Serine 16) was quantified in the same cells following Ca2+ measurement. In dormant SANC LCRs were small and disorganized at baseline, membrane potential was depolarized (-38 ± 1 mV, n = 46), and ICaL, If, and IK densities were smaller vs SANC firing APs. ß-adrenoceptor stimulation or application of CPT-cAMP led to de novo spontaneous AP generation in 44 and 46% of dormant SANC, respectively. The initial response was an increase in size, rhythmicity and synchronization of LCRs, paralleled with membrane hyperpolarization and small amplitude APs (rate â¼1 Hz). During the transition to steady-state AP firing, LCR size further increased, while LCR period shortened. LCRs became more synchronized resulting in the growth of an ensemble LCR signal peaked in late diastole, culminating in AP ignition; the rate of diastolic depolarization, AP amplitude, and AP firing rate increased. ICaL, IK, and If amplitudes in dormant SANC increased in response to ß-adrenoceptor stimulation. During washout, all changes reversed in order. Total PLB was higher, but the ratio of phosphorylated PLB (Serine 16) to total PLB was lower in dormant SANC. ß-adrenoceptor stimulation increased this ratio in AP-firing cells. Thus, transition of dormant SANC to AP firing is linked to the increased functional coupling of membrane and Ca2+ clock proteins. The transition occurs via (i) an increase in cAMP-mediated phosphorylation of PLB accelerating Ca2+ pumping, (ii) increased spatiotemporal LCR synchronization, yielding a larger diastolic LCR ensemble signal resulting in an earlier increase in diastolic INCX; and (iii) increased current densities of If, ICaL, and IK.