Efficacy of isoproterenol in the evaluation of dormant conduction and arrhythmogenic foci identification in atrial fibrillation ablation.

BACKGROUND: Catheter ablation for atrial fibrillation (AF) is an established therapy. However, postoperative recurrence is a serious issue caused by the reconduction of the isolated pulmonary veins (PV) and the onset of non-PV foci. The objectives of this study were to elucidate dormant conduction, confirm PV arrhythmia substrate, induce non-PV foci after PV isolation, and assess the acute efficacy of high dose isoproterenol (ISP) when administered in addition to adenosine. METHODS: The study consisted of 100 patients with drug-refractory AF (paroxysmal and persistent) who underwent ablation therapy (either radio-frequency or cryoballoon ablation) as the first-line of therapy at our hospital. All patients first underwent PV isolation (PVI) and were administered adenosine followed by ISP (6 µg × 5 min). The effects were observed, and the therapeutic strategy was evaluated. RESULTS: Persistent dormant conduction due to ISP administration was observed in 13 patients. In over half of the patients, arrhythmia substrates were identified in the PV. Ten patients presented with persistent PV firing. The ablation of non-PV foci was additionally performed in 23 patients. CONCLUSIONS: We found that dormant conduction, as a result of ISP administration, is persistent and ISP is useful when performing an ablation. In addition, ISP administration is useful for the identification of PV arrhythmia substrates and induction of non-PV foci. However, the effectiveness of ISP may be partially due to the complementary effect of adenosine, and, therefore, a combination of the two drugs seems preferable.

Is adenosine useful for the identification of atrial fibrillation triggers?

INTRODUCTION: Both isoproterenol (Iso) and adenosine (Ado) are used to induce atrial fibrillation (AF) in the electrophysiology lab. However, the utility of Ado has not been systematically established. OBJECTIVE: The purpose of this study was to compare Ado to Iso for the induction of paroxysmal AF. METHODS: Forty patients (16 women; mean age, 60 ± 12 years) with paroxysmal AF, presenting for ablation were prospectively included of whom 36 (90%) received Ado (18-36 mg) and/or Iso (3-20 µg/min incremental dose) in a randomized order (26 [72%] received both drugs). RESULTS: AF was induced with Iso in 15 of 32 (47%) and with Ado in 12 of 30 (40%) patients (P = 0.9). Iso-triggered AF started from the left pulmonary veins (PVs) in 11 of 15 (73%), from the right PVs in 3 of 15 (20%), and from the coronary sinus (CS) in 1 of 15 (7%) cases. Ado-induced AF episodes originated from the left PVs in 6 of 12 (50%), from the right atrium (RA) in 4 of 12 (33%), and from the CS in 2 of 12 (17%) cases. Altogether, Iso-induced AF was more likely initiated from the PVs (93%) compared with Ado (50%) ( P = 0.02). Ado-induced non-PV triggers were not predictive of arrhythmia recurrence after PV isolation. CONCLUSION: Ado much more frequently induces non-PV triggers, especially from the RA. The clinical significance of these foci, however, is questionable.

Effects of caffeine intake prior to stress cardiac magnetic resonance perfusion imaging on regadenoson- versus adenosine-induced hyperemia as measured by T1 mapping.

The antagonistic effects of caffeine on adenosine receptors are a possible cause of false-negative stress perfusion imaging. The purpose of this study was to determine the effects of coffee intake <4 h prior to stress perfusion cardiac magnetic resonance imaging (CMR) in regadenoson- versus adenosine-induced hyperemia as measured with T1-mapping. 98 consecutive patients with suspected coronary artery disease referred for either adenosine or regadenoson perfusion CMR were included in this analysis. Twenty-four patients reported coffee consumption <4 h before CMR (15 patients with adenosine, and 9 patients with regadenoson); 74 patients reported no coffee intake (50 patients with adenosine, and 24 patients with regadenoson). T1 mapping was performed using a modified look-locker inversion recovery sequence. T1 reactivity was determined by subtracting T1rest from T1stress. T1rest, T1stress, and T1 reactivity in patients referred for regadenoson perfusion CMR were not significantly different when comparing patients with <4 h coffee intake and patients who reported no coffee intake (976 ± 4 ms, 1019 ± 48 ms, and 4.4 ± 3.2% vs 971 ± 33 ms, 1023 ± 43 ms, and 5.4 ± 2.4%) (p = 0.70, 0.79, and 0.40), and similar to values in patients without coffee intake undergoing adenosine CMR. In patients with <4 h coffee intake, T1stress, and T1 reactivity were significantly lower for adenosine (898 ± 51 ms, and -7.8 ± 5.0%) compared to regadenoson perfusion CMR (p < 0.001). Coffee intake <4 h prior to regadenoson perfusion CMR has no effect on stress-induced hyperemia as measured with T1 mapping.

CF102 for the treatment of hepatocellular carcinoma: a phase I/II, open-label, dose-escalation study.

BACKGROUND: The A(3) adenosine receptor (A(3)AR) is overexpressed in the tumor and in the peripheral blood mononuclear cells of patients with hepatocellular carcinoma (HCC). The orally active drug candidate CF102, an A(3)AR agonist, induces apoptosis of HCC cells via deregulation of the Wnt signaling pathway. In this open label phase I/II trial, the safety and clinical effects of CF102 were assessed in patients with advanced unresectable HCC. METHODS: The primary objectives of this trial were to examine the safety and pharmacokinetic (PK) behavior of CF102 given orally (1, 5, and 25 mg BID) in 28-day cycles. Evaluation of anti-tumor effects and the utilization of A(3)AR as a biological predictive marker of response to CF102 were the secondary objectives. RESULTS: Eighteen patients received CF102-six at each dose level. No serious drug-related adverse events or dose-limiting toxicities were observed. CF102 demonstrated good oral bioavailability and linear PK behavior. Median overall survival in the study population, 67% of whom had received prior sorafenib, was 7.8 months, and for Child Pugh B patients (28%) it was 8.1 months. Stable disease by RECIST was observed in four patients for at least 4 months. CF102 maintained liver function over a 6-month period. A correlation between receptor overexpression levels at baseline and patients' overall survival was found. One of the patients who presented with skin nodules that were biopsy-proven to be HCC metastases prior to the trial showed complete metastasis regression during three months of treatment with CF102. CONCLUSIONS: CF102 is safe and well-tolerated, showing favorable PK characteristics in Child Pugh A and B HCC patients, justifying further clinical development.