Cardiovascular events and death after catheter ablation in very old patients with nonvalvular atrial fibrillation.

BACKGROUND: Catheter ablation of atrial fibrillation (AF) is recommended for selected older patients. However, the preventive effects of AF ablation on cardiovascular events and death remain unclear, especially in older patients. This study aimed to investigate the impact of AF ablation on the incidence of cardiovascular events and death in very old nonvalvular AF (NVAF) patients. METHODS: We conducted a prospective cohort study of consecutive patients with NVAF aged ≥80 years and using direct oral anticoagulants (DOACs). We defined cardiovascular events as acute heart failure (AHF), strokes and systemic embolisms (SSEs), acute coronary syndrome (ACS), and sudden cardiac death (SCD) and cardiovascular death as AHF/SSE/ACS-related death and SCD. We compared the 3-year incidence of cardiovascular events and death between the patients who underwent AF ablation (Ablation group) and those who received medical therapy only (Medication group). RESULTS: Among the 782 NVAF patients using DOACs, propensity score matching provided 208 patients in each group. The Ablation group had a significantly lower 3-year incidence of cardiovascular events and death than the Medication group: cardiovascular events, 24 (13.2%) vs. 43 (23.3%), log-rank P = 0.009 and hazard ratio (HR) 0.52 (95% confidence interval (CI) 0.32-0.86) and cardiovascular deaths, 5 (3.0%) vs. 15 (7.8%), log-rank P = 0.019 and HR 0.32 (95% CI 0.16-0.88). CONCLUSIONS: In very old NVAF patients using DOACs, those who underwent AF ablation had a lower incidence of both cardiovascular events and death than those who received medical therapy only.

Relationship Between Endothelial Dysfunction and the Outcomes After Atrial Fibrillation Ablation.

Background Endothelial dysfunction (ED) is associated with cardiovascular events in patients with atrial fibrillation (AF). However, the utility of ED as a prognostic marker after AF ablation supplementary to the CHA2DS2-VASc score is unclear. This study aimed to investigate the relationship between ED and 5-year cardiovascular events in patients undergoing AF ablation. Methods and Results We conducted a prospective cohort study of patients who underwent a first-time AF ablation and for whom the endothelial function was assessed by the peripheral vascular reactive hyperemia index (RHI) before ablation. We defined ED as an RHI of <2.1. Cardiovascular events included strokes, heart failure requiring hospitalization, arteriosclerotic disease requiring treatment, venous thromboses, and ventricular arrhythmias or sudden cardiac death. We compared the 5-year incidence of cardiovascular events after AF ablation between those with and without ED. Among the 1040 patients who were enrolled, 829 (79.7%) had ED, and the RHI value was found to be associated with the CHA2DS2-VASc score (P=0.004). The 5-year incidence of cardiovascular events was higher among patients with ED than those without ED (98 [11.8%] versus 13 [6.2%]; log-rank P=0.014). We found ED to be an independent predictor of cardiovascular events after AF ablation (hazard ratio [HR], 1.91 [95% CI, 1.04-3.50]; P=0.036) along with a CHA2DS2-VASc score of ≥2 (≥3 for women) (HR, 3.68 [95% CI, 1.89-7.15]; P<0.001). Conclusions The prevalence of ED among patients with AF was high. Assessing the endothelial function could enable the risk stratification of cardiovascular events after AF ablation.

High platelet reactivity is a predictor of left ventricular remodelling in patients with acute myocardial infarction.

AIMS: Acute myocardial infarction (AMI) is associated with left ventricular remodelling (LVR), which leads to progressive heart failure. Platelets play a pivotal role in promoting systemic and cardiac inflammatory responses during the complex process of myocardial wound healing or repair following AMI. This study aimed to investigate the impact of platelet reactivity immediately after primary percutaneous coronary intervention (PCI) on LVR in AMI patients with ST-segment (STEMI) and non-ST-segment elevation (NSTEMI). METHODS AND RESULTS: This prospective, single-centre, observational study included 182 patients with AMI who underwent primary PCI (107 patient with STEMI and 75 patients with NSTEMI). Patients were administered a loading dose of aspirin plus prasugrel before the procedure, and platelet reactivity was assessed using the VerifyNow P2Y12 assay immediately after PCI. Echocardiography was performed before discharge and during the chronic phase (8 ± 3 months after discharge). LVR was defined as a relative ≥20% increase in left ventricular end-diastolic volume index (LVEDVI). LVR in chronic phase was found in 34 patients (18.7%) whose platelet reactivity was significantly higher than those without LVR (259.6 ± 61.5 and 213.1 ± 74.8 P2Y12 reaction units [PRU]; P = 0.001). The occurrence of LVR did not differ between patients with STEMI and patients with NSTEMI (21.5% and 14.7%; P = 0.33). The optimal cut-off value of platelet reactivity for discriminating LVR was ≥245 PRU. LVEDVI significantly decreased at chronic phase in patients without high platelet reactivity (<245 PRU) (from 49.2 ± 13.5 to 45.4 ± 15.8 mL/m2 ; P = 0.02), but not in patients with high platelet reactivity (≥d245 PRU) (P = 0.06). Multivariate logistic analysis showed that high platelet reactivity was an independent predictor of LVR after adjusting for LVEDVI before discharge (odds ratio, 4.13; 95% confidence interval, 1.85-9.79). CONCLUSIONS: High platelet reactivity measured immediately after PCI was a predictor of LVR in patients with AMI during the chronic phase. The role of antiplatelet therapy on inflammation in the myocardium is a promising area for further research.

Dramatic improvement in innominate artery compression syndrome with only postural changes in a bedridden elderly patient.

We present the case of a bedridden elderly patient who demonstrated dramatic improvement in innominate artery compression syndrome with postural changes alone. A 94-year-old woman presented with dyspnea. Physical findings revealed stridor in the right-sided decubitus position. Her symptoms did not improve with conventional asthma treatment. Plain computed tomography revealed tracheal compression by the bent innominate artery. Contrast-enhanced computed tomography with postural changes altered the compression sites of the organs, resolving the tracheal stenosis. The number of similar bedridden elderly patients will increase in an aging society. We report this case to aid physicians in managing such patients.

Translation from nonautonomous type IAP retrotransposon is a critical determinant of transposition activity: implication for retrotransposon-mediated genome evolution.

Retrotransposons constitute a major component of the genome and their proliferation significantly impacts genome evolution. Retrotransposons can propagate autonomously or nonautonomously. Nonautonomous type transposition occurs through trans-complementation by autonomous type retrotransposons. While autonomous type retrotransposons have been studied extensively, the translation products from nonautonomous type retrotransposons are not well characterized. In a previous study, we isolated both autonomous and nonautonomous type intracisternal A particle (IAP) elements from the mouse genome and established a tissue culture assay to examine trans-complementation of nonautonomous type IAP element. Using this system in the present study, we determined an active role for the translation product from nonautonomous type IAP element. Point mutations that either eliminated or truncated the IAP protein were introduced and their effects on trans-complementation were examined. Trans-complementation efficiency correlated with the expression of nonautonomous type IAP protein. The effect of nonautonomous type IAP protein was observed only when it was provided in cis, suggesting an interaction of nonautonomous type IAP protein and its transcript immediately after transcription. Interaction of autonomous and nonautonomous type IAP proteins was demonstrated by immunostaining and coimmunoprecipitation assay. Based on these findings, we propose a model in which nonautonomous type IAP protein associates with its transcript, recruits autonomous type IAP protein, and promotes the assembly of transposition competent IAP particle. The active role of the nonautonomous type IAP protein revealed in this study may provide a new insight into retrotransposon proliferation within the genome.

Retrotransposons influence the mouse transcriptome: implication for the divergence of genetic traits.

Massive accumulation of retrotransposons, comprising >40% of human and mouse genomes, is one of the major events in the evolution of the genome. However, most retrotransposons have lost retrotransposition competency, which makes studying their role in genome evolution elusive. Intracisternal A-particle (IAP) elements are long terminal repeat (LTR)-type mouse retrotransposons consisting of full-length and internally deleted types. Some are retrotransposition competent and their upregulated activity has been reported in mutant mice deficient in genome defense systems, suggesting that IAP elements provide a unique platform for studying the interaction between retrotransposons and mammalian genomes. Using the IAP element as a model case, here we show that mobilization of retrotransposons alters the mouse transcriptome. Retrotransposition assay in cultured cells demonstrated that a subset of internally deleted IAP elements, called IDelta1 type, retrotranspose efficiently when supplied with functional IAP proteins. Furthermore, the IDelta1 type IAP element exhibited substantial transcription-inducing activity in the flanking region. Genomewide transcript analysis of embryonic stem (ES) cells identified IAP-induced transcripts, including fusion transcripts between IAP sequence and endogenous genes. Unexpectedly, nearly half of these IAP elements obtained from ES cells derived from 129 mouse strain were absent in the C57BL/6 genome, suggesting that IAP-driven transcription contributes to the unique trait of the individual mouse strain. On the basis of these data, we propose that retrotransposons are one of the drivers that shape the mammalian transcriptome.

Changes in ghrelin levels of plasma and proventriculus and ghrelin mRNA of proventriculus in fasted and refed layer chicks.

This is a test-report of ghrelin levels in plasma and proventriculus, the glandular portion of the avian stomach, by using a specific radioimmunoassay for acylated ghrelin, as well as the expression of the ghrelin gene in the proventriculus after a 12-h fasting period followed by a 6-h feeding period with 6-day-old layer chicks. After fasting, the plasma ghrelin levels increased from 21.3+/-4.5 to 32.9+/-5.0 fmol/ml, but once refed it returned to the control value. After fasting, the ghrelin mRNA and the peptide levels in the proventriculus increased, and ghrelin mRNA levels remained high but once refed the ghrelin content returned to the control level. Furthermore, in order to examine the effect of increased circulating ghrelin on food intake, a bolus intravenous injection of 500 pmol of chicken ghrelin was given to 8-day-old chicks. The ghrelin injection did not cause any significant changes in food intake. These results indicate that the levels of ghrelin and its mRNA with layer chicks are altered according to the feeding state and this in a similar manner as has been observed in mammals. Unlike in mammals, an increase in circulating ghrelin does not cause the promotion of food intake in chicks.

Inhibitory effect of ghrelin on food intake is mediated by the corticotropin-releasing factor system in neonatal chicks.

It is known that, in rats, central and peripheral ghrelin increases food intake mainly through activation of neuropeptide Y (NPY) neurons. In contrast, intracerebroventricular (ICV) injection of ghrelin inhibits food intake in neonatal chicks. We examined the mechanism governing this inhibitory effect in chicks. The ICV injection of ghrelin or corticotropin-releasing factor (CRF), which also inhibits feeding and causes hyperactivity in chicks. Thus, we examined the interaction of ghrelin with CRF and the hypothalamo-pituitary-adrenal (HPA) axis. The ICV injection of ghrelin increased plasma corticosterone levels in a dose-dependent or a time-dependent manner. Co-injection of a CRF receptor antagonist, astressin, attenuated ghrelin-induced plasma corticosterone increase and anorexia. In addition, we also investigated the effect of ghrelin on NPY-induced food intake and on expression of hypothalamic NPY mRNA. Co-injection of ghrelin with NPY inhibited NPY-induced increase in food intake, and the ICV injection of ghrelin did not change NPY mRNA expression. These results indicate that central ghrelin does not interact with NPY as seen in rodents, but instead inhibits food intake by interacting with the endogenous CRF and its receptor.

Anorexigenic effects of pituitary adenylate cyclase-activating polypeptide and vasoactive intestinal peptide in the chick brain are mediated by corticotrophin-releasing factor.

Intracerebroventricular (ICV) injection of pituitary adenylate cyclase-activating polypeptide-38 (PACAP) or vasoactive intestinal peptide (VIP) inhibits feeding in chicks. However, the underlying anorexigenic mechanism(s) has not yet been investigated. The present study investigated whether these peptides influence the activity of corticotrophin-releasing factor (CRF) neural pathways in the brain of chicks. Firstly, we found that ICV injections of PACAP and VIP increased plasma corticosterone concentrations. The corticosterone-releasing effect of PACAP was completely attenuated by co-injection of astressin, a CRF receptor antagonist, but this effect was only partial for VIP. These results demonstrated that CRF neurons mediate the actions of PACAP and, to a lesser extent, VIP, and suggest that the signaling mechanisms differ between the two peptides. This difference may arise from the two peptides interacting with different receptors because the corticosterone-releasing effect of PACAP, but not VIP, was completely attenuated by co-injection of PACAP (6-38), a PACAP receptor antagonist. Finally, we examined the effect of ICV co-injection of astressin on the anorexigenic effects of PACAP and VIP and found that the effects of both peptides were attenuated by astressin. Overall, the present study suggests that the anorexigenic effects of PACAP and VIP are mediated by the activation of CRF neurons.

Effect of central administration of carnosine and its constituents on behaviors in chicks.

Even though their contents in the brain are high, the function of brain carnosine and its constituents has not been clarified. Both carnosine and anserine inhibited food intake in a dose dependent fashion when injected intracerebroventricularly. The constituents of carnosine, beta-alanine (beta-Ala) and l-histidine (His), also inhibited food intake, but their effects were weaker than carnosine itself. Co-administration with beta-Ala and His inhibited food intake similar to carnosine, but also altered other behaviors. Injection of carnosine induced hyperactivity and increased plasma corticosterone level, whereas beta-Ala plus His induced hypoactivity manifested as sleep-like behavior. This later effect seemed to be derived from beta-Ala, not His. These results suggest that central carnosine may act in the brain of chicks to regulate brain function and/or behavior in a manner different from its constituents.

Comparison of brain arginine-vasotocin and corticotrophin-releasing factor for physiological responses in chicks.

Arginine-vasotocin (AVT), a non-mammalian homologue of mammalian arginine-vasopressin, is a stress-related peptide in the brain of birds. The aim of the present study was to determine the effects of intracerebroventricular (ICV) injection of AVT on feeding behavior, body temperature, corticosterone release and several behavioral parameters in chicks. These effects were compared with those of corticotrophin-releasing factor (CRF), another stress-related peptide. The ICV injection of AVT inhibited feeding behavior, increased rectal temperature, and increased plasma corticosterone concentrations, but these effects were weaker than those of CRF. AVT induced hypoactivity as evidenced by decreased vocalization and stepping while CRF induced hyperactivity. The present results demonstrate that some functions of brain AVT are similar to those of CRF, although these effects are weaker than those induced by CRF. However, some AVT-induced behaviors were different from CRF, indicating that the physiological roles of AVT in the regulation of stress behavior are different from those of CRF in chicks.

Effect of central administration of prolactin-releasing peptide on feeding in chicks.

Prolactin-releasing peptide (PrRP) is one of the inhibitory factors in feeding regulation of mammals. However, no information is available for avian species. The present study was done to clarify the effect of intracerebroventricular (ICV) injection of PrRP on feeding in chicks. Firstly, we found that ICV injection of PrRP (94-1500 pmol) significantly increased food intake in chicks. The result was completely different from those obtained in mammals. The orexigenic effect of PrRP was significantly weaker than that of neuropeptide Y (NPY), a potent orexigenic peptide, on an equimolar basis. The orexigenic effect of NPY was further enhanced with coinjection of PrRP. These results suggest the existence of a novel orexigenic mechanism in the chick brain, which might differ from NPY-involved feeding regulatory pathway. In addition, ICV injection of PrRP significantly decreased the rectal temperature, but the effect was weaker than that of NPY, suggesting that PrRP may inhibit energy expenditure in chicks. Taken together, we showed here that PrRP may be involved in the regulation of both feeding behavior and energy metabolism in the chick brain.

Pituitary adenylate cyclase activating polypeptide and vasoactive intestinal peptide inhibit feeding in the chick brain by different mechanisms.

Intracerebroventricular (ICV) injections of pituitary adenylate cyclase-activating polypeptide-38 (PACAP) and vasoactive intestinal peptide (VIP) inhibit feeding in chicks. However, the precise anorexigenic mechanisms have not been investigated, since both peptides activate the VPAC receptor in mammals. We investigated which receptor mediates the anorexigenic effects of these peptides in chicks. ICV co-injection of PACAP (6-38), a PAC1 receptor antagonist, attenuated the anorexigenic effect of PACAP but not VIP. On the other hand, ICV co-injection of [D-p-Cl-Phe6, Leu17]-VIP, a VPAC receptor antagonist, did not affect the effects of both peptides. Although these results imply that the effect of VIP was not specific, a subsequent experiment demonstrated that ICV injection of anti-chicken VIP antiserum stimulated feeding and suggested that endogenous VIP inhibits feeding in the chick brain. Collectively, the data suggest that the anorexigenic mechanism of PACAP is different from that of VIP and that an undiscovered VIP receptor may be present in the chicken brain.

Central pipecolic acid increases food intake under ad libitum feeding conditions in the neonatal chick.

It has been demonstrated that L-pipecolic acid (L-PA) is a major metabolic intermediate of L-lysine in the mammalian and chicken brain. A previous study showed that intracerebroventricular (i.c.v.) injection of L-PA suppressed feeding in neonatal chicks, and the actions were associated with gamma-aminobutyric acid (GABA)-B receptor activation. It has been reported that endogenous L-PA in the brain fluctuated under different feeding conditions. In the present study, we investigated the effect of i.c.v. injection of L-PA on food intake in the neonatal chick under ad libitum feeding conditions. The food intake was increased by 0.5 or 1.0 mg L-PA under ad libitum feeding conditions contrary to previous studies using fasted birds. A hyperphagic effect of L-PA (0.5 mg) was attenuated by both GABA-A receptor antagonist (picrotoxin, 0.5 microg) and GABA-B receptor antagonist (CGP54626, 21.0 ng). These results indicate that a hyperphagic effect of L-PA is mediated by both GABA-A and GABA-B receptors and L-PA differentially affects food intake under different feeding conditions in the neonatal chick.

Intracerebroventricular injection of vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide inhibits feeding in chicks.

Previous research has indicated an involvement of glucagon superfamily peptides in the regulation of feeding in the domestic chick brain. However the possible roles of vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide-38 (PACAP) have not yet been investigated. We therefore examined the effect of intracerebroventricular (ICV) injections of VIP or PACAP on food intake in chicks. ICV injection of both VIP and PACAP significantly inhibited food intake over 4 h at doses ranging from 12 to 188 pmol. Subsequently, we compared the anorexic effect the glucagon superfamily peptides VIP, PACAP, growth hormone-releasing factor (GRF) and glucagon-like peptide-1 (GLP-1) after ICV injection at an equimolar dose (12 pmol). All four peptides significantly inhibited food intake, although the anorexic effects of VIP and PACAP were weaker than those of GRF and GLP-1. These findings support the hypothesis that glucagon superfamily peptides play an important role in the regulation of appetite in the chick brain.

Chicken ghrelin and growth hormone-releasing peptide-2 inhibit food intake of neonatal chicks.

Ghrelin is an endogenous ligand for the growth hormone secretagogue (GHS) receptor. Ghrelin stimulates feeding in rats, however, intracerebroventricular (i.c.v.) injection of rat ghrelin inhibits feeding of neonatal chicks. In the present study, the effect of i.c.v. injection of different ghrelins including chicken and bullfrog ghrelin, and synthetic GH-releasing peptide (GHRP) on feeding of neonatal chicks was investigated. Chicken ghrelin strongly suppressed feeding. To compare the inhibitory effect, chicken and rat ghrelin were examined. The suppressive effect of feeding by chicken and rat ghrelin was almost identical. Bullfrog ghrelin contains a change in the acylated amino acid from Ser to Thr, strongly suppressed feeding. The i.c.v. injection of GHRP-2 (KP-102), a synthetic GHS, also inhibited feeding. These results indicate that the chicken GHS receptor is affected by several forms of GHS, and that food intake of neonatal chicks is inhibited by GHS receptor agonists.