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The decompensation heart is less sensitive to atrial fibrillation (AF) induced by vagal stimulation (VS) but more vulnerable to sympathetic stimulation-induced AF (SS) than normal controls. Dantrolene can significantly reduce SS-enhanced FA in heart failure (CHF). These are the basic findings of a study published online in the "Journal of Cardiac Failure."
Decompensated heart is less sensitive to atrial fibrillation (AF) induced by vagal stimulation (VS) but more vulnerable to sympathetic stimulation (SS) induced FA than normal controls. Dantrolene can significantly reduce SS-enhanced FA in heart failure (CHF). These are the fundamental findings of a study published online in the "Journal of Cardiac Failure".
This evidence – according to the authors, conducted by Youhua Zhang of the New York Institute of the Institute of Osteopathic Medicine -indica that the cardiac ryanodine receptor dysfunction ( of which dantrolene is a known stabilizer) may play a fundamental role in SS-enhanced FA in HF and that stabilizing the dantrolene-defective ryanodine receptor may be a new treatment option for this condition
Mechanism Hypotheses of autonomic dysfunction of arrhythmia
"The HF causes autonomic dysfunction (characterized by sympathetic activation and vagal deactivation) and is badociated with an increase in the incidence of FA" Zhang recall and his colleagues. "HF and AF coexist frequently. The prevalence of AF increases with the severity of IC and the risk of AF reaches about 50% in patients with New York Heart Association (NYHA) functional clbad IV.
On the other hand, the development of AF in patients with HF is a major cause of clinical deterioration. Therefore, the relationship between HF and AF has been described as "HF generates AF and AF generates HF", add the authors.
The autonomic nervous system (sympathetic and vagal) plays an important role in the pathophysiology of AF and HF. The two branches of the autonomic system normally exert opposite effects on the heart (for example on heart rate, atrioventricular conduction and cardiac contractility).
"Both VS and SS can increase the inducibility of AF, although VS are more arrhythmogenic in normal hearts," the researchers say. "Since there is significant autonomic remodeling in the HF, we hypothesized that HF can alter the susceptibility of arrhythmogenesis induced autonomic stimulation," they explain. .
In order to explore the potential underlying mechanism of vulnerability to HS-enhanced FA in the IC, Zhang and his colleagues hypothesized that cardiac receptor dysfunction-like 2 ryanodine (RyR2) and Ca2 + loss may play a role. critical in this condition.
The accumulated evidence indicates that RyR2 dysfunction and diastolic Ca2 + loss exist in HF. The diastolic loss of Ca2 +, by activating the sodium-calcium exchange current to the inside, can depolarize the membrane potential and promote the development of triggered activity, leading to arrhythmogenesis in the cell. 39; HF.
By beta-adrenergic receptor activation and subsequent phosphorylation and oxidation of RyR2, SS can exacerbate the diastolic loss of Ca2 + and subsequently arrhythmogenesis. Therefore, the stabilization of RyR2 function with dantrolene should be able to reduce the enhanced FA by SS in HF.
"This study," explain the researchers, "examined whether decompensated hearts, compared to normal controls, respond in a different way to AF-induced arithmogenesis induced by autonomic stimulation in turn. arrhythmogenesis and the effect of dantrolene on SS enhanced FA in HF ".
Confirmation from the results of two preclinical experiments
a murine model of myocardial infarction (MI) -HF was used. In Experiment 1, the inducibility of AF was compared in 9 IM-HF animals compared to 10 control controls initially, during VS and during SS with isoproterenol infusion. In experiment 2, treatment with dantrolene (n = 8) was compared to a placebo control (n = 9) in relation to the inducibility of SS-induced FA in HF.
Compared with fictitious controls, the inducibility of AF at baseline was higher in the MI-HF group. The inducibility of AF was increased in both groups by autonomic stimulation, the authors write.
However, under VS, the augmented entity was lower in the MI-HF group (49 +/- 11% versus 80 +/- 10%, P = 0.029), but was significantly higher under SS (53 +/- 8)% versus 6 +/- 7%, P <0.001) compared to fictitious controls. Dantrolene significantly attenuated SS-enhanced FA in HF (69 ± 6% versus 29 ± 9%, P = 0.006)
The potential clinical implications of the study
"Our results are consistent with Clinical findings that wave-mediated FA is generally observed in healthy hearts, whereas sympathetic FA is generally present in patients with structural heart disease, especially HF, "the authors say. "In light of sympathetic activation in HF, our data demonstrating that decompensated hearts are more vulnerable to sympathetic FA than sympathetic may account for a higher incidence of AF in HF"
As mentioned, Advantages observed with dantrolene in the reduction of SS-enhanced FA in HF, they suggest that the RyR2 dysfunction may play a critical role in this condition. Therefore, the stabilization of RyR2 could be a new treatment option.
"Increasing evidence indicates that SV may become a beneficial treatment option for HF, however, as HF increases, the incidence of AF and SV may be arrhythmogenic. in FA, there is concern that SV may further increase AF in the HF. "
Contrary to this concern, Zhang and colleagues explain, current evidence indicates that decompensated hearts are less sensitive to FA induced strong VS than normal hearts We have previously shown that the moderate intensity of VS (typically used to treat HF) is not arrhythmogenic even in healthy hearts.
In conclusion [19659004] Compared to normal hearts, hearts affected by HF are more vulnerable to SS-induced AF and less susceptible to VS-induced FA, the researchers write.Because of the presence of sympathetic activation in HF, the increased susceptibility of SS to AF in decompensated hearts may be responsible for increasing the incidence of AF in patients with IC.
In addition, they conclude, our data indicate that the treatment with dantrolene can significantly attenuate the arrhythmogenesis of AF increased by SS in the HF, suggesting that stabilization of the RyR2 dysfunction by dantrolene might be a new antiarrhythmic option in the HF.
Giorgio Ottone
Bibliographic reference:
Delfiner MS, Nofi C, Li Y, et al. Failing hearts are more vulnerable to atrial fibrillation induced by sympathetic stimulation, but not by vagal stimulation: improved by dantrolene treatment. J Card Fail, 2018 June 6. doi: 10.1016 / j.cardfail.2018.05.008. [Epub ahead of print] read
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