• 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • Calkins et al demonstrated that volume loading has a greater


    Calkins et al. demonstrated that volume loading has a greater electrophysiological significance under pathologic conditions such as chronic infarction [8]. Some vasodilators can counteract such electrophysiological changes and suppresses VT. Captopril prolonged the ventricular refractory Senexin B in patients with ventricular dysfunction and inducible VT [9]. hANP and hydralazine hampered VT in a cesium-induced rabbit model [10]. Our observation in the present study is in good agreement with this earlier finding in that modification of pressure and/or volume load attenuates the ventricular arrhythmogenicity. Hydralazine has a positive inotropic effect on isolated mammalian myocardium [11]. Additionally, it increases HR and cardiac output, and enhances cardiac conduction in patients with cardiovascular diseases [11]. The cardiac effects are considered to be due to resultant sympathetic drive to the heart, because beta blockers abolished these phenomena [12]. Relatively higher HR during hydralazine infusion may be relevant to, if partly, its antiarrhythmic action in this rabbit model because bradycardia is one of the exacerbating factors of acquired LQT.
    Limitations The faster HR produced by hydralazine has a possible therapeutic role in the VTs in this model. Bradycardia prolongs APD and is known as one of the risk factors for Torsade de Pointes. However, sustained sympathetic tone is not always therapeutic on such VTs because it also deteriorates intracellular Ca2+ handling. In the present study, hydralazine also suppressed EAD-like hump and PVCs, suggesting that the vasodilation was supposed to produce electrophysiological changes in the cardiomyocyte. Therefore, accelerating HR is not the sole reason why hydralazine provided an anti-VT effect. In other words, hydralazine may have additional therapeutic effects beyond the resultant tachycardia.
    Conflict of interest
    Introduction Long QT syndrome (LQTS) is characterized by cardiac repolarization abnormalities Senexin B that lead to TdP, syncope, and sudden cardiac death [1]. The disease is genetically heterogeneous and caused by mutations in >10 genes, including KCNH2 and KCNE1[2–4]. In LQTS probands with heterozygous genetic variants, compound mutations usually exacerbate the disease severity compared to other family members who carry a single mutation [5–7]. Previously, the coexistence of the single nucleotide polymorphism (SNP) KCNH2-K897T with the latent KCNH2 mutation A1116V was shown to modify the clinical symptoms [8]. A KCNE1 C-terminal polymorphism, D85N, has been found in the normal population. The sequence, a nucleotide replacement from G to A at 253, causes an amino acid change from aspartic acid to asparagine at position 85 [9]. The allele frequency of the polymorphism is reported to be 0.7% in apparently healthy Asians [10]. Paulussen et al. demonstrated that the allele frequency of the same variant among Europeans is 5% in drug-induced LQTS patients who experienced TdP, but 0% in the control population [11]. More recently, we demonstrated that the D85N allele frequency is 0.8% among apparently healthy Japanese individuals and that it is significantly higher among clinically diagnosed LQTS probands (3.9%) [9]. In a patch-clamp experiment using a heterologous expression system in a mammalian cell line, KCNE1-D85N was found to reduce the current densities in KCNQ1/KCNE1 channels (IKs) and KCNH2/KCNE1 channels (IKr) by 28% and 31%, respectively [9]. In the present study, we screened for the D85N polymorphism in 355 LQTS probands in which we could identify a mutation in KCNQ1, KCNH2, or SCN5A, and found 14 patients that carried the polymorphism in addition to a single pathologic LQTS-related gene mutation. Among them, in a family with KCNH2-E58K, D85N appeared to modulate the phenotype of family members. In order to clarify the phenotype–genotype correlation, we then conducted functional assays of the variants by using a heterologous expression system in Chinese hamster ovary (CHO) cells.