Heart failure modulates electropharmacological characteristics of sinoatrial nodes

Abstract

Abstract. The impact of heart failure (HF) on sinoatrial node (SAN) channel regulation and electropharmacological responses has remained elusive. The present study aimed to investigate the effects of HF on the electrical activity of SANs with and without pharmacological interventions. Action potentials (APs) were recorded in isolated SANs from normal rabbits (control) and those with HF (rapid ventricular pacing for 4 weeks) prior to and after administration of a funny current blocker (ivabradine; 0.1, 0.3, 3 or 10 µM), a calmodulin kinase II inhibitor (KN-93; 0.3 or 3 µM), a sarcoplasmic reticulum Ca 2+ release inhibitor (ryanodine; 0.3 or 3 µM), a sodium current inhibitor (tetrodotoxin; 1, 3 or 10 µM) and a late sodium current inhibitor (ranolazine; 10 µM). Western blot analysis was used to investigate the protein expression in SANs from normal rabbits and those with HF. Control SANs had a higher beating rate than SANs from rabbits with HF (2.3±0.1 vs. 1.5±0.1 Hz; P<0.001). Similarly, ivabradine (10 µM), KN-93 (3 µM), ranolazine (10 µM) and ryanodine (3 µM) decreased the beating rates of SANs in the control (n=6) and HF (n=6) groups. Ivabradine treatment resulted in a higher incidence of AP block in HF vs. control SANs (66.7 vs. 0%; P<0.05). Tetrodotoxin (1, 3 or 10 µM) decreased the beating rate to a higher extent in SANs from rabbits with HF than in those from control rabbits and induced a higher incidence of AP block (66.7 vs. 0%; P<0.05). Furthermore, SANs from rabbits with HF had higher protein levels of phospholamban (PLB) and lower levels of hyperpolarization-activated cyclic nucleotide-gated potassium channel 4, ryanodine receptor and phosphorylated PLB than control SANs. In conclusion, HF modulates electropharmacological responses in the SAN by channel regulation, which may result in SAN dysfunction.

Impaired neuronal sodium channels cause intranodal conduction failure and reentrant arrhythmias in human sinoatrial node

“…Interestingly, although previous studies in animal models have identified a remarkable range of varying, species-specific roles for Nav isoforms in the SAN [14][15][16]30 , our findings demonstrate that Nav channels may contribute very differently to human SAN pacemaking and conduction 15,16,32 . Studies have found that micromolar TTX can depress heart rate in adult mouse 33 and rabbit SAN preparations 34 , providing evidence that cNav can contribute to SAN automaticity in some adult mammalian hearts. However, in contrast to the mouse SAN study 30 , where nanomolar TTX impaired SAN automaticity but did not inhibit conduction, we found that nanomolar TTX impaired intranodal conduction (~250%) with negligible effects on SAN automaticity (~6%) and atrial conduction (~6%) at physiological conditions.…”

RyR2 and Calcium Release in Heart Failure

“…In a canine model of HF induced by rapid pacing and using optical mapping, SAN bradycardia is associated with suppression of LCR together with the unresponsiveness of Ca 2+ clock to isoproterenol and caffeine stimulation (Shinohara et al, 2010). In a similar rabbit HF model, alterations of SAN electro-pharmacological responses have been related to lower expression of RyR2, as well as inhibition of SERCA reuptake due to altered phosphorylation of PLN (Chang et al, 2017). By contrast, RyR2 expression, along with other Ca 2+ handling proteins, is increased in the SAN but not in atrial tissue in a HF rat model (Yanni et al, 2011).…”

Slowing down as we age: aging of the cardiac pacemaker’s neural control

“…The increase in left ventricular end diastolic pressure observed in heart failure patients causes an increase in the intra-atrial pressure and atrial stretch, which results in atrial electrical remodeling and atrial dilatation [ 107 ]. It has been proposed that cellular and tissue alterations caused by heart failure can also cause electrical and structural remodeling of the pacemaker [ 108 ]; the identified mechanisms so far include a decrease in the HCN4 and sodium currents [ 109 , 110 ]. However, it is not clear how malfunction of the ventricular chambers can result in ionic changes of pacemaker cells.…”