Synergistic restoring effects of isoproterenol and magnesium on KCNQ1-inhibited bradycardia cell models cultured in microelectrode array.

OBJECTIVES: Bradycardia is caused by loss-of-function mutations in potassium channels that regulate phase 3 repolarization of the cardiac action potential. The purpose of this study is to monitor the effects of potassium channel (KCNQ1) inhibition and to evaluate the effects of isoproterenol (ISO) and MgSO4 in restoring sinus rhythm in atrial cells. METHODS: Microelectrode array was used to analyze conduction velocity, voltage amplitude and cycle length of atrial cells (HL-1). A combination of ISO and MgSO4 was used to restore sinus rhythm in these cells. RESULTS: mRNA expression levels of KCNQ1 (42.2 vs. 100%, p < 0.0001), connexin 43 (29.6 vs. 100%, p = 0.0033), atrial natriuretic peptide (31.0 vs. 100%, p = 0.0030), cardiac actin (38.2 vs. 100%, p < 0.0001) and α-myosin heavy chain (31.2 vs. 100%, p = 0.00254) were significantly lower in the KCNQ1 gene-inhibited group compared to the control group. When treated with MgSO4 (1 mM) and ISO (10 µM), conduction velocity (0.0208 ± 0.0036 vs. 0.0086 ± 0.0014 m/s, p = 0.0004) and voltage amplitude (1,210.78 ± 65.81 vs. 124.1 ± 13.30 µV, p < 0.0001) were higher, and cycle length (431.55 ± 2.05 vs. 1,015.15 ± 4.31 ms, p < 0.0001) was shorter than in the gene-inhibited group. CONCLUSION: Inhibition of sinus rhythm in the bradycardia cell model was recovered by treatment with ISO and MgSO4, demonstrating the potency of combination therapy in the treatment of bradycardia.

High plasma concentrations of transforming growth factor-ß and tissue inhibitor of metalloproteinase-1: potential non-invasive predictors for electroanatomical remodeling of atrium in patients with non-valvular atrial fibrillation.

BACKGROUND: The degree of electroanatomical remodeling of the left atrial (LA) affects the clinical outcome after rhythm control of atrial fibrillation (AF). Our hypothesis was that plasma concentrations of transforming growth factor (TGF)-ß and tissue inhibitor of metalloproteinase (TIMP)-1 reflect LA voltage and structural remodeling in patients with non-valvular AF. METHODS AND RESULTS: In the study, 242 patients (male 79.4%, 55.1 ± 11.0 years old) with AF (155 paroxysmal AF, 87 persistent AF) underwent catheter ablation. Pre-ablation plasma concentrations of TGF-ß and TIMP-1 and the degree of electroanatomical remodeling quantified by LA voltage map (NavX) and 3D-CT were evaluated. The mean LA voltage and volume were compared in patients with high TGF-ß (≥10.0 ng/ml, H-TGF) vs. low TGF-ß (<10.0 ng/ml, L-TGF) and high TIMP-1 (≥1.1 ng/ml, H-TIMP) vs. low TIMP-1 (<1.1 ng/ml, L-TIMP). Patients with H-TGF had lower mean LA voltage (P=0.014) and greater LA volume (P=0.022), particularly, posterior venous LA volume (P=0.005) than those with L-TGF. In patients with H-TIMP, the mean LA voltage (P=0.019) was lower than those with L-TIMP. LA volume was significantly higher (P<0.001) in patients with ejection fraction ≤58% than those with >58%. CONCLUSIONS: In patients with non-valvular AF, high plasma concentrations TGF-ß and TIMP-1 and low ejection fraction were closely related with electroanatomical remodeling of LA.

Characteristics of complex fractionated atrial electrogram in the electroanatomically remodeled left atrium of patients with atrial fibrillation.

BACKGROUND: Complex fractionated atrial electrogram (CFAE) guided ablation is effective in some patients with persistent atrial fibrillation (PeAF), but the pattern of CFAE may be different in the remodeled left atrium (LA). METHODS AND RESULTS: In 100 AF patients (83 males, 55.0+/-10.6 years old) with AF (51 paroxysmal AF (PAF), 49 PeAF) who underwent catheter ablation, CFAE cycle length (CL) and distribution (NavX 3D map) were compared according to the LA volume (3D-CT) and endocardial voltage (during high right atrial pacing 500-ms (Vol(PACE)) and AF (Vol(AF); NavX). The mean CFAE-CL was longer (P=0.003) and the % area CFAE was smaller (P=0.006) in patients with LA >or=125 ml than those with <125 ml. The mean CFAE-CL was longer in patients with Vol(PACE) <1.7 mV than those with >or=1.7 mV (P=0.002) and in Vol(AF) <0.7 mV than >or=0.7 mV (P<0.001). The % area CFAE was smaller in patients with Vol(PACE) <1.7 mV than those with >or=1.7 mV (P=0.006). The incidence of septal CFAE was consistently high, regardless of the degree of LA remodeling. CONCLUSIONS: In the AF patients with an electroanatomically remodeled LA, the % area of CFAE was smaller and mean CFAE-CL was longer than in those with a less remodeled LA. However, the majority of CFAE are consistently positioned on the septum in the remodeled LA.

Defibillator electrogram T wave alternans as a predictor of spontaneous ventricular tachyarrhythmias in defibrillator recipients.

BACKGROUND: Although T wave alternans (TWA) and the T wave peak-to-end (Tpte) interval are associated with vulnerability to ventricular tachyarrhythmia (VT), no previous reports have demonstrated that TWA immediately precedes spontaneous VT in the human ambulatory setting. METHODS AND RESULTS: Stored electrograms from the implantable cardioverter defibrillators (ICD) of 74 patients (59 males, 55.3+/-12.2 years) were analyzed. TWA (DeltaT amplitude), Tpte interval, QT interval, and RR intervals were measured from magnified digital images immediately before spontaneous VT (VT(Clinical); n=73), or immediately after ICD shocks during artificially-induced VT (VT(Induced); n=74) or inappropriate shocks (Shock(Inapp); n=6). (1) TWA was significantly greater in VT(Clinical) than VT(Induced) (P<0.01) or Shock(Inapp) (P<0.001), but Tpte was not (P=NS). (2) In the VT(Clinical) group, TWA was significantly greater in patients with ischemic VT than in those with non-ischemic cardiomyopathy or idiopathic VF (P<0.05). (3) In the same patient, the TWA for VT(Clinical) was significantly greater than that for VT(Induced) (P<0.01). CONCLUSION: TWA measured from ICD electrograms is significantly greater immediately before spontaneous VT than immediately after inappropriate shocks or shocks during induced VT. These findings indicate that repolarization alternans plays an important role in the induction of VT in humans.