Jack P. Chen

TGR5 contributes to glucoregulatory improvements after vertical sleeve gastrectomy in mice

Objective Vertical sleeve gastrectomy (VSG) produces high rates of type 2 diabetes remission; however, the mechanisms responsible remain incompletely defined. VSG increases circulating bile acid concentrations and bile acid signalling through TGR5 improves glucose homeostasis. Therefore, we investigated the role of TGR5 signalling in mediating the glucoregulatory benefits of VSG. Design VSG or sham surgery was performed in high-fat-fed male Tgr5+/+ (wild type) and Tgr5−/− (knockout) littermates. Sham-operated mice were fed ad libitum or food restricted to match their body weight to VSG-operated mice. Body weight, food intake, energy expenditure, insulin signalling and circulating bile acid profiles were measured and oral glucose tolerance testing, islet immunohistochemistry and gut microbial profiling were performed. Results VSG decreased food intake and body weight, increased energy expenditure and circulating bile acid concentrations, improved fasting glycaemia, glucose tolerance and glucose-stimulated insulin secretion, enhanced nutrient-stimulated glucagon-like peptide 1 secretion and produced favourable shifts in gut microbial populations in both genotypes. However, the body weight-independent improvements in fasting glycaemia, glucose tolerance, hepatic insulin signalling, hepatic inflammation and islet morphology after VSG were attenuated in Tgr5−/− relative to Tgr5+/+ mice. Furthermore, VSG produced metabolically favourable alterations in circulating bile acid profiles that were blunted in Tgr5−/− relative to Tgr5+/+ mice. TGR5-dependent regulation of hepatic Cyp8b1 expression may have contributed to TGR5-mediated shifts in the circulating bile acid pool after VSG. Conclusions These results suggest that TGR5 contributes to the glucoregulatory benefits of VSG surgery by promoting metabolically favourable shifts in the circulating bile acid pool.

Permanent Right-to-Left Shunt Is the Key Factor in Managing Patent Foramen Ovale

OBJECTIVES We sought to prospectively evaluate risk of stroke and impact of transcatheter patent foramen ovale (PFO) closure in patients with permanent right-to left shunt compared with those with Valsalva maneuver-induced right-to-left shunt. BACKGROUND Pathophysiology and properly management of PFO still remain far from being fully clarified: in particular, the contribution of permanent right-to-left shunt remains unknown. METHODS Between March 2006 and October 2010, we enrolled 180 (mean age 44 ± 10.9 years, 98 women) of 320 consecutive patients referred to our center for transcatheter PFO closure, who had spontaneous permanent right-to-left shunt on transcranial Doppler and transthoracic/transesophageal echocardiography. All patients fulfilled the standard current indications for transcatheter closure and underwent preoperative transesophageal echocardiography and brain magnetic resonance imaging, with subsequent intracardiac echocardiographic-guided transcatheter PFO closure. We compared the clinical echocardiographic characteristics of these patients (Permanent Group) with the rest of 140 patients with right-to-left shunt only during Valsalva maneuver (Valsalva Group). RESULTS Compared with the Valsalva Group patients, patients of the Permanent Group had increased frequency of multiple ischemic brain lesions on magnetic resonance imaging, previous recurrent stroke, previous peripheral arteries embolism, migraine with aura, and-more frequently-atrial septal aneurysm and prominent Eustachian valve. The presence of permanent shunt confers the highest risk of recurrent stroke (odds ratio: 5.9, 95% confidence interval: 2.0 to 12, p < 0.001). No differences were recorded between the 2 groups with regard to recurrence of ischemic events after the closure procedure. CONCLUSIONS Despite its small-sample nature, our study suggests that patients with permanent right-to-left shunt have potentially a higher risk of paradoxical embolism compared with those without.

Effect of baseline ST segment elevation on test performance of standard and heart rate-adjusted ST segment depression criteria

Whether the ST segment shift used to evaluate the presence and severity of myocardial ischemia should include the additional deviation due to decreasing amounts of baseline ST segment elevation was examined in 100 clinically normal subjects and in 124 patients with coronary disease. Exercise ST segment depression was calculated in two ways: as the difference between exercise and resting ST segment depression, but excluding any resting ST elevation (STdep), and as the total ST segment difference or excursion, including any baseline resting ST elevation (STdiff). These values were also used for separate calculation of the maximal ST/heart rate slope and delta ST/heart rate index in each case. Given partition values with matched specificity of 95% in clinically normal subjects, 150 microV of STdep was significantly more sensitive for coronary disease than 220 microV of STdiff (61% [76 of 124] versus 50% [62 of 124], p less than 0.005). Comparison of receiver operating characteristic curves confirmed the superior test performance of STdep for the identification of coronary disease in this population (area under the curve 0.920 versus 0.869, p = 0.0019). In contrast, detection of three-vessel coronary obstruction by standard ST segment criteria was not affected by definition of ST segment excursion. Substitution of STdiff for STdep did not change the performance of the ST/heart rate slope of the delta ST/heart rate index for either the detection of coronary disease or for the identification of three-vessel coronary obstruction.(ABSTRACT TRUNCATED AT 250 WORDS)

Polymer-free cerivastatin-eluting stent shows superior neointimal inhibition with preserved vasomotor function compared to polymer-based paclitaxel-eluting stent in rabbit iliac arteries

AIMS The present study was designed to evaluate vasomotor function and vascular biological responses following a novel non-polymeric cerivastatin-eluting stent (CES) versus polymer-based paclitaxel-eluting stent (PES) in a rabbit iliac artery model. Optimisation of DES components and non-polymeric stents may contribute to vascular healing and beneficial to vasomotor function. METHODS AND RESULTS In vitro human aortic and coronary smooth muscle cells (hASMC & hCSMC), as well as endothelial cells (hAEC & hCEC) were cultured. IC50 curves were determined for cerivastatin (CER). In vivo PES (n=6) and CES (n=12) stents were implanted in nine rabbits. Vasomotor function was investigated at 28 days by acetylcholine (ACh) followed by histopathological and histomorphometric analyses. CER was cytotoxic to hASMC and hCSMC (IC50s of 10-6 M and 10-5 M, respectively), although such cytotoxic effects were not observed for hAEC and hCEC at maximal study dose. PES-associated vasodilation response to endothelial-dependent ACh was significantly suppressed at both proximal and distal adjacent arterial segments, as compared to CES. Furthermore, microscopically, neointimal inhibition quantified by the neointimal cross-sectional area (IA) was superior with CES (0.60 + or - 0.27 mm(2)) compared to PES (1.35 + or - 0.16 mm(2); P <0.05). Medial area was smaller for PES (0.3 + or - 0.04 mm(2)) than CES (0.5 + or - 0.03 mm(2), p <0.001). Additionally, significant inflammation and fibrin deposition was clearly evidenced in PES compared to CES (p <0.05). CONCLUSIONS CER elicits a differential effect on hSMC compared to hEC in vitro. In contrast to PES, a novel bioabsorbable sol-gel coated CES demonstrated effective neointimal inhibition with less vessel wall toxicity accompanied by preservation of vasomotor function in the rabbit iliac model.

Five‐year Follow‐up of Intracardiac Echocardiography‐assisted Transcatheter Closure of Complex Ostium Secundum Atrial Septal Defect

OBJECTIVE We sought to prospectively evaluate long-term follow-up results of intracardiac echocardiography-aided transcatheter closure of complex atrial septal defects (ASD) in the adults. DESIGN AND SETTINGS Prospective multicenter registry in tertiary care hospitals. PATIENTS AND INTERVENTIONS Over a 5-year period, we prospectively enrolled 56 patients (mean age 49 ± 16.7 years, 24 females) who have been referred to our center for catheter-based closure of complex secundum ASD (> 25 mm diameter, deficiency of ≥ 1 rim, multiple secundum ASD, multiperforated ASD, associated incomplete floor of the fossa ovalis with or without aneurysm, embryonic remnants of incomplete atrial septation). All patients were screened by means of transesophageal echocardiography before the operation. Eligible patients underwent intracardiac echocardiography study and closure attempt. RESULTS Forty patients underwent a transcatheter closure attempt: transesophageal echocardiography-planned device type and size were modified in 32 patients (64%). Rates of procedural success, predischarge occlusion, and major complications rate were 100%, 90%, and 2%, respectively. On mean follow-up of 5.4 ± 1.8 years, the follow-up occlusion rate was 98%. During follow-up, only one case of permanent atrial fibrillation was observed. There were no cases of aortic/atrial erosion, device thrombosis, or new atrioventricular valve dysfunction. CONCLUSIONS Intracardiac echocardiography-guided complex secundum ASD transcatheter closure is safe and effective and appears to have excellent long-term results, thus minimizing potential complications resulting from the complex anatomy.

COMPARISON OF VASCULAR INFLAMMATION AND ENDOTHELIAL FUNCTION IN RESPONSE TO A NEW NOBORI AND CYPHER DRUG ELUTING STENTS IN PIG CORONARY ARTERIES

Background: Nobori is a 3rd generation Drug Eluting Stent (DES), designed to include drug eluting biodegradable polymer coated only abluminal side of the stent. The new features may differently impact inflammation and endothelium functions as compared to the currently marketed DES. At the present time, preclinical data on direct comparison of these DESs are not available. In this study, we examined vascular inflammation and endothelial function of the segments adjacent to the stent and histology of stented areas of Nobori and Cypher DES.

IMPAIRMENT OF VASOMOTOR FUNCTION OF CONDUIT BUT NOT RESISTANCE ARTERIES AFTER LONG-TERM FEMORAL ARTERY OCCLUSION

Background: Early treatments are profoundly beneicial and improve outcomes in peripheral arterial disease (PAD). However, asymptomatic patients do not receive the optimal treatments as early as patients with CAD. So far, the changes in the vasomotor function with the chronic occlusion of the supericial femoral artery (SFA) are still unknown. We evaluated endothelium function for both conduit and collateral resistance arteries (CA) following long-term SFA ligation in Yucatan miniswine.