Intermittent vs. Continuous Anticoagulation theRapy in patiEnts with Atrial Fibrillation (iCARE-AF): a randomized pilot study.

PURPOSE: We hypothesized that intermittent anticoagulation based on daily rhythm monitoring using the novel oral anticoagulants (NOACs) is feasible and safe among patients with paroxysmal atrial fibrillation (AF). METHODS: Patients with paroxysmal AF and ≥1 risk factors for stroke were randomized to either intermittent or continuous anticoagulation. Those in the intermittent group were instructed to transmit a daily ECG using an iPhone-based rhythm monitoring device. If AF was detected, patients received one of the NOACs for 48 h-1 week. Patients who failed to transmit an ECG for three consecutive days or more than 7 days total were crossed over to continuous anticoagulation. Patients in the continuous group received one of the NOACs. RESULTS: Fifty-eight patients were randomized to either intermittent (n = 29) or continuous anticoagulation (n = 29). Over a median follow-up of 20 months, 20 patients in the intermittent group failed to submit a daily ECG at least once (median three failed submissions). Four patients (14 %) crossed over to continuous anticoagulation due to failure to submit an ECG for three consecutive days. One stroke (continuous group) occurred during the study. Major bleeding occurred in two patients in the continuous and one patient in the intermittent group, after crossing over to continuous anticoagulation. In a prespecified per-protocol analysis, gastrointestinal bleeding was more frequent in the continuous group (16 vs. 0 %; p = 0.047). CONCLUSIONS: Intermittent anticoagulation based on daily rhythm monitoring is feasible and may decrease bleeding in low-risk patients with paroxysmal AF. A larger trial, adequately powered to detect clinical outcomes, is warranted.

Role of Atrio-Ventricular Junction Ablation in Symptomatic Atrial Fibrillation for Optimization of Cardiac Resynchronization Therapy.

Cardiac resynchronization (CRT) therapy is indicated in patients with at least mildly symptomatic heart failure, left ventricular ejection fraction ≤35% and wide QRS, and has been associated with decreased morbidity and mortality. Unfortunately, approximately 30% of the patients appropriately selected for therapy do not respond to CRT. Among the reasons for non-response, atrial fibrillation (AF) plays a prominent role. AF limits the degree of biventricular pacing during CRT, not only when the ventricular rate is fast and highly irregular, but also during periods of of relatively constant rate, by causing fusion and pseudo-fusion complexes. Importantly, achievement of nearly 100% biventricular pacing is necessary to derive benefit from CRT. A simple, albeit irreversible, method to maximize biventricular pacing in patients with AF who are otherwise eligible for CRT is atrioventricular junction (AVJ) ablation. In this review, we discuss the role of AVJ ablation in CRT optimization in patients with AF. The available evidence from observational non-randomized studies suggests that AVJ ablation in patients with AF qualifying for CRT may offer improvement in heart failure symptoms, better survival, and better cardiac function. In light of the inherent limitations of non-randomized studies, further randomized studies are needed to support this treatment option.

Distinct roles for angiotensin-converting enzyme 2 and carboxypeptidase A in the processing of angiotensins within the murine heart.

Angiotensin-converting enzyme 2 (ACE2), a homologue of angiotensin-converting enzyme (ACE), converts angiotensin (Ang) I to Ang(1-9) and Ang II to Ang(1-7), but does not directly process Ang I to Ang II. Cardiac function is compromised in ACE2 null mice; however, the importance of ACE2 in the processing of angiotensin peptides within the murine heart is not known. We determined the metabolism of angiotensins in wild-type (WT), ACE (ACE(-/-)) and ACE2 null mice (ACE2(-/-)). Angiotensin II was converted almost exclusively to Ang(1-7) in the cardiac membranes of WT and ACE(-/-) strains, although generation of Ang(1-7) was greater in the ACE(-/-) mice (27.4 +/- 4.1 versus 17.5 +/- 3.2 nmol(-1) mg h(-1) for WT). The ACE2 inhibitor MLN4760 significantly attenuated Ang II metabolism and the subsequent formation of Ang(1-7) in both strains. In the ACE2(-/-) hearts, Ang II metabolism and the generation of Ang(1-7) were significantly attenuated; however, the ACE2 inhibitor reduced the residual Ang(1-7)-forming activity in this strain. Angiotensin I was primarily converted to Ang(1-9) (WT, 28.9 +/- 3.1 nmol(-1) mg h(-1); ACE(-/-), 49.8 +/- 5.3 nmol(-1) mg h(-1); and ACE2(-/-), 35.9 +/- 5.4 nmol(-1) mg h(-1)) and to smaller quantities of Ang(1-7) and Ang II. Although the ACE2 inhibitor had no effect on Ang(1-9) formation, the carboxypeptidase A inhibitor benzylsuccinate essentially abolished the formation of Ang(1-9) and increased the levels of Ang I in cardiac membranes. In conclusion, our studies in the murine heart suggest that ACE2 is the primary pathway for the metabolism of Ang II and the subsequent formation of Ang(1-7), a peptide that, in contrast to Ang II, exhibits both antifibrotic and antiproliferative actions.