Long-term clinical outcomes and prognostic indicators for focal impulse and rotor modulation guided ablation: A single-center observational study.

BACKGROUND: Electrophysiologists have developed a computational mapping approach to localize sources that may perpetuate persistent atrial fibrillation (AF). Focal impulse and rotor modulation (FIRM)-guided ablation of these sources have produced variable results. The current study further assesses single-procedure success rates of FIRM-guided ablation for preventing AF or atrial tachyarrhythmia recurrence and analyzes different baseline characteristics as prognostic indicators for individuals experiencing these undesired outcomes. METHODS: Seventy-one consecutive patients (mean age 64.58 ± 9.05 years and 36.6% female) with drug-refractory persistent AF with and without prior history of pulmonary vein antral isolation (PVAI) underwent FIRM-guided ablation. Patients without prior history of PVAI underwent FIRM-guided ablation in addition to de novo PVAI. Patients with prior history of PVAI had the pulmonary veins reassessed at the time of FIRM-guided ablation for reconnection as well as re-isolation, when necessary. These patients were then prospectively followed for AF and atrial tachyarrhythmia recurrence. RESULTS: FIRM analysis revealed rotors in the right atrium in 66.2% (1.77 ± 1.53 mean rotors per patient) and in the left atrium in 85.9% (2.65 ± 1.52 mean rotors per patient) of patients analyzed in the current study. After a single FIRM-guided ablation procedure, AF and atrial tachyarrhythmia recurrence was demonstrated in 21.1% (15/71) and 33.8% (24/71) of patients, respectively. The entire cohort of patients were followed for a mean duration of 23.20 ± 8.38 months with the mean time to AF recurrence found to be 12.35 ± 10.44 months. Furthermore, valvular heart disease (i.e. moderate mitral or tricuspid regurgitation) was found to be a statistically significant independent predictor for AF recurrence following FIRM-guided ablation (p = .033). CONCLUSIONS: FIRM-guided ablation in combination with PVAI is a suitable and effective approach for symptomatic individuals with drug-refractory persistent AF with and without prior history of PVAI. Randomized controlled studies are warranted.

Best anesthetics for assessing left ventricular systolic function by echocardiography in mice.

Our review of the literature of the major cardiovascular journals for the past three years showed that for all studies using anesthesia for mouse echocardiography, the predominant anesthetic was isoflurane, which was used in 76% of the studies. The goal of this investigation was to determine if isoflurane is indeed the best anesthetic. Accordingly, we compared isoflurane with 2,2,2-tribromoethanol (Avertin), ketamine-xylazine, and ketamine on different days in the same 14 mice, also studied in the conscious state without anesthesia. A randomized crossover study design was employed to compare the effects on left ventricular (LV) systolic function and heart rate of the four different anesthetic agents assessed by transthoracic echocardiography. As expected, each anesthetic depressed LV ejection fraction and heart rate when compared with values in conscious mice. Surprisingly, isoflurane was not the best, but actually second to last in maintaining normal LV function and heart rate. The anesthetic with the least effect on LV function and heart rate was ketamine alone at a dose of 150 mg/kg, followed by Avertin at 290 mg/kg, isoflurane at 3% induction and 1 to 2% maintenance, and lastly ketamine-xylazine at 100 and 10 mg/kg, respectively. In summary, these results indicate that ketamine alone exerts the least depressant effects on LV function and heart rate, with Avertin second, suggesting that these anesthetics should be used when it is not feasible to study the animals in the conscious state as opposed to the most commonly used anesthetic, isoflurane.

Inhibition of adenylyl cyclase type 5 increases longevity and healthful aging through oxidative stress protection.

Mice with disruption of adenylyl cyclase type 5 (AC5 knockout, KO) live a third longer than littermates. The mechanism, in part, involves the MEK/ERK pathway, which in turn is related to protection against oxidative stress. The AC5 KO model also protects against diabetes, obesity, and the cardiomyopathy induced by aging, diabetes, and cardiac stress and also demonstrates improved exercise capacity. All of these salutary features are also mediated, in part, by oxidative stress protection. For example, chronic beta adrenergic receptor stimulation induced cardiomyopathy was rescued by AC5 KO. Conversely, in AC5 transgenic (Tg) mice, where AC5 is overexpressed in the heart, the cardiomyopathy was exacerbated and was rescued by enhancing oxidative stress resistance. Thus, the AC5 KO model, which resists oxidative stress, is uniquely designed for clinical translation, since it not only increases longevity and exercise, but also protects against diabetes, obesity, and cardiomyopathy. Importantly, inhibition of AC5's action to prolong longevity and enhance healthful aging, as well as its mechanism through resistance to oxidative stress, is unique among all of the nine AC isoforms.

Type 5 adenylyl cyclase disruption leads to enhanced exercise performance.

The most important physiological mechanism mediating enhanced exercise performance is increased sympathetic, beta adrenergic receptor (ß-AR), and adenylyl cyclase (AC) activity. This is the first report of decreased AC activity mediating increased exercise performance. We demonstrated that AC5 disruption, that is, knock out (KO) mice, a longevity model, increases exercise performance. Importantly for its relation to longevity, exercise was also improved in old AC5 KO. The mechanism resided in skeletal muscle rather than in the heart, as confirmed by cardiac- and skeletal muscle-specific AC5 KO's, where exercise performance was no longer improved by the cardiac-specific AC5 KO, but was by the skeletal muscle-specific AC5 KO, and there was no difference in cardiac output during exercise in AC5 KO vs. WT. Mitochondrial biogenesis was a major mechanism mediating the enhanced exercise. SIRT1, FoxO3a, MEK, and the anti-oxidant, MnSOD were upregulated in AC5 KO mice. The improved exercise in the AC5 KO was blocked with either a SIRT1 inhibitor, MEK inhibitor, or by mating the AC5 KO with MnSOD hetero KO mice, confirming the role of SIRT1, MEK, and oxidative stress mechanisms. The Caenorhabditis elegans worm AC5 ortholog, acy-3 by RNAi, also improved fitness, mitochondrial function, antioxidant defense, and lifespan, attesting to the evolutionary conservation of this pathway. Thus, decreasing sympathetic signaling through loss of AC5 is not only a mechanism to improve exercise performance, but is also a mechanism to improve healthful aging, as exercise also protects against diabetes, obesity, and cardiovascular disease, which all limit healthful aging.