Gut microbiota modulates metabolic and immunoregulatory axes and contributes to the pathophysiology of diseases with inflammatory components, such as atherosclerosis, diabetes, and ischemic stroke. Inflammation is emerging as a critical player in the pathophysiology of intracranial aneurysm. Therefore, we hypothesized that the gut microbiota affects aneurysm formation by modulating inflammation. We induced intracranial aneurysms in mice by combining systemic hypertension and a single injection of elastase into the cerebrospinal fluid. Depletion of the gut microbiota was achieved via an oral antibiotic cocktail of vancomycin, metronidazole, ampicillin, and neomycin. Antibiotics were given three weeks before aneurysm induction and either continued until the end of the experiment or stopped one day before aneurysm induction. We also assessed the effects of the gut microbiota depletion on macrophage infiltration and mRNA levels of inflammatory cytokines. Gut microbiota depletion by antibiotics reduced the incidence when antibiotics were started three weeks before aneurysm induction and continued until the end of the experiment (83% vs. 6%, P < 0.001). Even when antibiotics were stopped one day before aneurysm induction, the gut microbiota depletion significantly reduced the incidence of aneurysms (86% vs. 28%, P < 0.05). Both macrophage infiltration and mRNA levels of inflammatory cytokines were reduced with gut microbiota depletion. These findings suggest that the gut microbiota contributes to the pathophysiology of aneurysms by modulating inflammation. Human studies are needed to determine the exact contribution of the gut microbiota to the pathophysiology of aneurysm formation and disease course in humans.

Clinical observations suggest that post-menopausal women have a higher incidence of aneurysmal rupture than premenopausal women. We hypothesize that a relative deficiency in estrogen may increase the risks for aneurysmal growth and subarachnoid hemorrhage in post-menopausal women. We assessed the effects of estrogen and selective estrogen receptor subtype agonists on the development of aneurysmal rupture in ovariectomized female mice. We utilized an intracranial aneurysm mouse model that recapitulates the key features of human intracranial aneurysms, including spontaneous rupture. Ten- to twelve-week-old ovariectomized female mice received treatment with estrogen, non-selective estrogen receptor antagonist, estrogen receptor-α agonist, or estrogen receptor-β agonist starting 6 days after aneurysm induction so that the treatments affected the development of aneurysmal rupture without affecting aneurysmal formation. Estrogen significantly reduced the incidence of ruptured aneurysms and rupture rates in ovariectomized mice. Non-selective estrogen receptor antagonist abolished the protective effect of estrogen. Though estrogen receptor-α agonist did not affect the incidence of ruptured aneurysms or rupture rates, estrogen receptor-β agonist prevented aneurysmal rupture without affecting the formation of aneurysms. The protective role of estrogen receptor-β agonist was abolished by the inhibition of nitric oxide synthase. We showed that estrogen prevented aneurysmal rupture in ovariectomized female mice. The protective effect of estrogen appeared to occur through the activation of estrogen receptor-β, a predominant subtype of estrogen receptor in human intracranial aneurysms and cerebral arteries.

We investigated the prevalence, risk factors, and optimal timing of treatment for advanced periodontitis in patients undergoing elective heart valve surgery. Dental examinations were given to 209 patients (aged 65 ± 10 years) scheduled for valve surgery. Patients with no or mild periodontitis were assigned as controls (n = 105). Patients with advanced periodontitis underwent tooth extraction and curettage (n = 104), 68 of whom underwent tooth extraction within two weeks (short wait) and 36 of whom underwent extraction longer than two weeks, before surgery. The three groups (control, short, and long wait) were similar in age, gender, diseased valve, and type of surgery received. The average number of teeth extracted was 2.3 ± 2.3. In both univariate and multivariate analysis, risk factors for advanced periodontitis were history of smoking and heart failure. No complications arose from the extractions. Length of postoperative hospital stay, intrafebrile days, white blood cell count and serum C-reactive protein (assessed at postoperative days 1, 3 and 7) were similar among the three groups. During the mean follow-up period of 60 ± 16 months, no patient developed prosthetic valve endocarditis, and there were no postoperative deaths. In conclusion, we found no evidence that receipt and timing of dental treatment affected surgical success rates and postoperative course.

Background and Purpose Inflammation is emerging as a key component of the pathophysiology of intracranial aneurysms. Peroxisome proliferator-activated receptor-γ (PPARγ) is a nuclear hormone receptor of which activation modulates various aspects of inflammation. Methods Using a mouse model of intracranial aneurysm, we examined the potential roles of PPARγ in the development of rupture of intracranial aneurysm. Results A PPARγ agonist, pioglitazone (PGZ), significantly reduced the incidence of ruptured aneurysms and the rupture rate without affecting the total incidence aneurysm (unruptured aneurysms and ruptured aneurysms). PPARγ antagonist (GW9662) abolished the protective effect of PGZ. The protective effect of PGZ was absent in mice lacking macrophage PPARγ. PGZ treatment reduced mRNA levels of inflammatory cytokines (monocyte chemoattractant factor-1, interleukin-1, and interleukin-6) that are primarily produced by macrophages in the cerebral arteries. PGZ treatment reduced the infiltration of M1 macrophage into the cerebral arteries and the macrophage M1/M2 ratio. Depletion of macrophages significantly reduced the rupture rate. Conclusion Our data showed that the activation of macrophage PPARγ protects against the development of aneurysmal rupture. PPARγ in inflammatory cells may be a potential therapeutic target for the prevention of aneurysmal rupture.

Anomalous subaortic left brachiocephalic vein (ASLBV) is a rare systemic venous anomaly. We review our experience with patients associated with ASLBV who underwent cardiac surgery at three institutions. From 1989 to 2009, the medical records of surgically treated patients with ASLBV were analyzed; the incidence of ASLBV, clinical characteristics, and associated anatomical findings were assessed. Fifteen patients had ASLBV. All ASLBVs coursed left lateral to the aortic arch, passed under the ascending aorta anterior to the central pulmonary artery, and joined the right brachiocephalic vein. Fourteen patients had congenital heart disease (CHD), and the remaining patient did not have cardiac anomalies. Its incidence was 0.57% (14 of 2,449) in patients with CHD and only 0.02% (1 of 4,805) in patients without CHD. In patients with CHD, 73.3% (11 of 15) of the patients had conotruncal cardiac anomalies such as tetralogy of Fallot, ventricular septal defect with pulmonary atresia, truncus arteriosus, and interruption of the aortic arch. Eight patients had aortic arch anomalies, including right aortic arch and cervical aortic arch. The deletion of chromosomal 22q11.2 was confirmed in two patients, and one patient was diagnosed with DiGeorge syndrome. ASLBV was clinically silent even without any surgical intervention. ASLBV is a very rare anomaly and is highly associated with conotruncal cardiac anomalies and aortic arch anomalies, including right aortic arch and cervical aortic arch. Preoperative diagnosis is important when any surgical interventions are intended, especially, in patients with conotruncal cardiac anomalies.

Angiotensin-(1-7) (Ang-(1-7)) can regulate vascular inflammation and remodeling, which are processes that have important roles in the pathophysiology of intracranial aneurysms. In this study, we assessed the effects of Ang-(1-7) in the development of intracranial aneurysm rupture using a mouse model of intracranial aneurysms in which aneurysmal rupture (i.e., aneurysmal subarachnoid hemorrhage) occurs spontaneously and causes neurologic symptoms. Treatment with Ang-(1-7) (0.5 mg/kg/day), Mas receptor antagonist (A779 0.5 mg/kg/day or 2.5 mg/kg/day), or angiotensin II type 2 receptor (AT2R) antagonist (PD 123319, 10 mg/kg/day) was started 6 days after aneurysm induction and continued for 2 weeks. Angiotensin-(1-7) significantly reduced the rupture rate of intracranial aneurysms without affecting the overall incidence of aneurysms. The protective effect of Ang-(1-7) was blocked by the AT2R antagonist, but not by the Mas receptor antagonist. In AT2R knockout mice, the protective effect of Ang-(1-7) was absent. While AT2R mRNA was abundantly expressed in the cerebral arteries and aneurysms, Mas receptor mRNA expression was very scarce in these tissues. Angiotensin-(1-7) reduced the expression of tumor necrosis factor-α and interleukin-1β in cerebral arteries. These findings indicate that Ang-(1-7) can protect against the development of aneurysmal rupture in an AT2R-dependent manner.

BackgroundThe purpose of this study was to quantify myocardial strain on the subendocardial and epicardial layers of the left ventricle (LV) using tagged cardiovascular magnetic resonance (CMR) and to investigate the transmural degree of contractile impairment in the chronic ischemic myocardium.Methods3T tagged CMR was performed at rest in 12 patients with severe coronary artery disease who had been scheduled for coronary artery bypass grafting. Circumferential strain (C-strain) at end-systole on subendocardial and epicardial layers was measured using the short-axis tagged images of the LV and available software (Intag; Osirix). The myocardial segment was divided into stenotic and non-stenotic segments by invasive coronary angiography, and ischemic and non-ischemic segments by stress myocardial perfusion scintigraphy. The difference in C-strain between the two groups was analyzed using the Mann-Whitney U-test. The diagnostic capability of C-strain was analyzed using receiver operating characteristics analysis.ResultsThe absolute subendocardial C-strain was significantly lower for stenotic (-7.5 ± 12.6%) than non-stenotic segment (-18.8 ± 10.2%, p < 0.0001). There was no difference in epicardial C-strain between the two groups. Use of cutoff thresholds for subendocardial C-strain differentiated stenotic segments from non-stenotic segments with a sensitivity of 77%, a specificity of 70%, and areas under the curve (AUC) of 0.76. The absolute subendocardial C-strain was significantly lower for ischemic (-6.7 ± 13.1%) than non-ischemic segments (-21.6 ± 7.0%, p < 0.0001). The absolute epicardial C-strain was also significantly lower for ischemic (-5.1 ± 7.8%) than non-ischemic segments (-9.6 ± 9.1%, p < 0.05). Use of cutoff thresholds for subendocardial C-strain differentiated ischemic segments from non-ischemic segments with sensitivities of 86%, specificities of 84%, and AUC of 0.86.ConclusionsAnalysis of tagged CMR can non-invasively demonstrate predominant impairment of subendocardial strain in the chronic ischemic myocardium at rest.

OBJECTIVES The aim of the study is to compare a technique of pump-controlled retrograde trial off (PCRTO) to insertion of an arterio-venous (AV) bridge to conduct a trial from venoarterial extracorporeal membrane oxygenation (VA ECMO). METHODS We studied all patients who were weaned from VA ECMO using either PCRTO or AV bridging from November 2014 to April 2018. Demographic data, indications for ECMO, duration of ECMO, duration of trial period off ECMO and survival were compared between the 2 groups. RESULTS Seventy-nine patients were placed on VA ECMO from November 2014 to April 2018, of whom, 51 (65%) patients met the study inclusion criteria: 31 (61%) patients who had a trial period from VA ECMO using PCRTO and 20 (39%) patients who were weaned using an AV bridge. The indications for ECMO included cardiac (n = 16 and 11, respectively) and non-cardiac aetiologies (n = 15 and 9, respectively). There was 1 death in each group. The duration of the trial off VA ECMO was significantly shorter in the PCRTO group (median = 88.0 vs 196.6 min, P < 0.001). There were 2 conversions from PCRTO to AV bridging during the trial period off ECMO (2.9-kg neonate following a Norwood procedure and 2.2-kg patient following repair of ectopia cordis). CONCLUSIONS PCRTO is a safe, simple and reproducible approach for enabling a trial period while preserving the circuit during weaning from VA ECMO. In our study, the duration of the trial period off VA ECMO was significantly shorter in the PCRTO group. PCRTO avoids manipulation of the ECMO circuit, provides a ‘stress test’ to evaluate cardiorespiratory reserve during the trial period off ECMO, is applicable for a wide variety of cardiac and non-cardiac indications and facilitates multiple attempts at weaning from ECMO.